Biochemistry and nutrition

Osmosis Question Bank • Foundational Sciences

Topics in this section:

• General principles of carbohydrate metabolism
• General principles of amino acid metabolism
• General principles of fat and cholesterol metabolism
• General principles of nutrition
• Metabolic disorders
• Nutritional disorders

General principles of carbohydrate metabolism

8 Qs

1. A study is conducted on the storage of glycogen in the body. According to the study, one molecule of glycogen can contain up to 55,000 glucose molecules, and thus helps immensely in storing glucose. Which of the following features helps in allowing glycogen synthesis to accommodate for a large amount of glucose molecules?  

A. Glucose molecules are added in linear and branching patterns.

✅ Correct: See Main Explanation.  

B. Glucose molecules are added in linear patterns only.  

❌ Incorrect: In the synthesis of glycogen, glucose molecules are added in a linear and branching pattern, which helps compacting a large amount of glucose and also helps in rapid addition and removal of glucose.  

C. Storing glycogen in the mitochondria.

❌ Incorrect: Glycogen is stored in the cytosol where it will be readily available when needed.  

D. Glycogen is a hydrophobic molecule.  

❌ Incorrect: Glycogen is a hydrophilic, not hydrophobic, molecule.  

E. Glycogen is stored in every organ in the body.

❌ Incorrect: The main two organs for glycogen synthesis and storage are the liver and the skeletal muscle. Although glycogen can be found in other tissues (e.g., brain, kidneys), its function is not well understood.  

Explanation

Glycogen is a polymer of glucose molecules that functions as a main storage form of glucose in the liver and skeletal muscles. The synthesis of glycogen from glucose is a multistep process which involves the addition of glucose molecules to the glycogen until a full structure is made.  

The structure of glycogen is made of a main chain of glucose, where glucose molecules are added in a linear fashion in addition to branching glucose molecules from the main chain. This allows glycogen to be compact and gives it a spherical shape while also allowing for a rapid addition and removal of glucose molecules from the glycogen.  

2. A researcher is studying the physiological changes that take place during exercise. She observes there is increased glycogen metabolism by skeletal muscles during aerobic exercise. Which of the following hormones is most likely responsible for this change?

A. Somatostatin

❌ Incorrect: Somatostatin is a hormone secreted by pancreatic D cells. It suppresses gastric acid as well as pancreatic and intestinal fluid secretion. Furthermore, somatostatin can decrease insulin and glucagon release. However, somatostatin is not responsible for promoting glycogenolysis during exercise.  

B. Epinephrine

✅ Correct: See Main Explanation.  

C. Insulin  

❌ Incorrect: Insulin promotes glycogenesis, which is the production of glycogen, as opposed to the breakdown of glycogen. As a result, insulin would not account for the physiological changes observed by the researcher.  

D. Testosterone

❌ Incorrect: Testosterone can lead to growth spurts, increased muscle mass, and development of male genitalia. However, it is not responsible for promoting glycogenolysis during exercise.  

E. Cortisol

❌ Incorrect: Cortisol can cause increased insulin resistance and promote the breakdown of glycogen into glucose. However, during exercise, glycogenolysis is primarily mediated by epinephrine and glucagon.  

Explanation

Glucagon and epinephrine are two important hormones released by the body during exercise.    

During exercise, glucose within the bloodstream is taken up by muscle cells and metabolized to generate ATP. In response to the decrease in blood sugar, the pancreas releases glucagon. Glucagon promotes the liver to break down its stored glycogen into glucose via a process called glycogenolysis. The newly produced glucose can be released into the bloodstream and subsequently taken up by muscle cells.    

Likewise, epinephrine is produced by the adrenal glands and promotes muscle cells to break down their glycogen stores into glucose via glycogenolysis.    

Furthermore, glucagon and epinephrine promote lipolysis, which is the breakdown of lipids and fats into free fatty acids. The fatty acids are released into the circulation and transported to working muscle cells. Within the mitochondria of these cells, the fatty-acids undergo beta-oxidation and are converted into acetyl-CoA, which can be used to generate energy via the Krebs cycle.

3. A study is conducted to determine the physiology of the digestion and absorption of carbohydrates. The digestion of carbohydrates begins in the mouth and finishes in the small intestine where it is absorbed. Which of the following is true about the absorption of carbohydrates?  

A. Galactose is absorbed using sodium-dependent channels  

✅ Correct: See Main Explanation.  

B. Glucose is absorbed by simple diffusion  

❌ Incorrect: Glucose absorption is done using special channels called SGLT1, which uses sodium. It cannot be absorbed by simple diffusion.  

C. Sucrose is absorbed using facilitated diffusion  

❌ Incorrect: Only monosaccharides can be absorbed by the small intestine. Disaccharides (e.g., sucrose) must be broken down in order to be absorbed.  

D. Fructose is absorbed using sodium-dependent channels  

❌ Incorrect: Fructose is absorbed into the enterocytes by facilitated diffusion. Unlike glucose and galactose, the absorption of fructose is independent of sodium.  

E. Fructose can be absorbed against its concentration gradient  

❌ Incorrect: Fructose is absorbed by facilitated diffusion and can only be absorbed down its concentration gradient.  

Explanation

Carbohydrates are one of the major macronutrients in the human diet and are very important for the human body. The digestion of carbohydrates begins in the mouth, with the enzyme amylase found in saliva, and ends in the small intestines, where the absorption of carbohydrates takes place. Carbohydrates can only be absorbed as monosaccharides in the small intestine; the three monosaccharides are glucose, galactose, and fructose.   

The absorption of glucose and galactose follows a similar path. Glucose and galactose are actively transported into the enterocytes using Na+-glucose cotransporter (SGLT1). SGLT1 uses the electrochemical gradient of sodium to transport glucose and galactose into the cell. Once in the enterocytes, glucose, and galactose enter the blood through the GLUT2 transporters located in the basolateral membrane.  

On the other hand, fructose absorption is independent of sodium. Fructose is taken into the enterocytes by facilitated diffusion using the GLUT5 channels. Then the fructose enters the blood using the same GLUT2 channels used to transport glucose and galactose at the basolateral membrane.  

4. A researcher studies the effects of two hormones on the glycogen metabolism. According to the study, the two hormones mediate the breakdown of glycogen. In addition, he notices the effects of hormone X are on the liver, while the effects of hormone Y are on the skeletal muscle. Which of the following are most likely hormones X and Y?  

A.

Hormone X	Hormone Y
Glucagon	Epinephrine

✅ Correct: See Main Explanation.   

B.

Hormone X	Hormone Y
Epinephrine	Glucagon

❌ Incorrect: Epinephrine mediates the breakdown of glycogen in skeletal muscles, while glycogen mediates the breakdown of glycogen in the liver.

C.

Hormone X	Hormone Y
Insulin	Glucagon

❌ Incorrect: Insulin mediates the synthesis, not the breakdown, of glycogen.   

D.

Hormone X	Hormone Y
Glucagon	Vasopressin

❌ Incorrect: Vasopressin is not a mediator of glycogen breakdown in skeletal muscles.   

E.

Hormone X	Hormone Y
Insulin	Epinephrine

❌ Incorrect: Insulin mediates the synthesis, not the breakdown, of glycogen.   

Explanation

Glycogen is the main storage form of glucose and is mainly located in two organs, the liver and the skeletal muscles. When glucose is needed (e.g., fasting, exercise), glycogen is broken down to glucose to be utilized in providing energy. The main mediators of glycogenolysis are epinephrine and glucagon.  

In skeletal muscle, glycogen is broken down, but is not released into the bloodstream, and is used by the muscle to provide energy. This is seen usually in states of exercise. Epinephrine is the main mediator of glycogen breakdown in skeletal muscle.  

On the other hand, glycogen in the liver is broken down into glucose and released into the bloodstream to maintain normal levels of glucose in states of decreased blood glucose levels (e.g., fasting). Glucagon is the main mediator of glycogen breakdown in the liver.  

The ability to release the glucose from glycogen into the bloodstream in the liver is mainly due to the presence of the enzyme called glucose-6 phosphatase, which converts glucose-6 phosphate to glucose, which can then be exported outside the cells. The enzyme glucose-6 phosphatase is not present in skeletal muscle, and hence skeletal muscle cannot export glucose into the bloodstream, and the glucose from glycogen breakdown in skeletal muscle is used by the muscle cell itself to provide energy for contractions.  

5. A study is conducted to determine the effects of insulin on certain enzymes involved in glycogen metabolism in the liver cells. According to the study, insulin activates tyrosine kinase receptors on the cell membrane of the liver cells, which leads to a cascade of events and eventually activates enzyme X involved in glycogenesis by dephosphorylating enzyme X. Which of the following is the most likely identity of enzyme X?  

A. Glycogen synthase   

✅ Correct: See Main Explanation.  

B. Glycogen phosphorylase  

❌ Incorrect: Glycogen phosphorylase is an enzyme that catalyzes the metabolism of glycogen into glucose molecules. This enzyme is deactivated by insulin by dephosphorylating this enzyme.  

C. Branching enzyme  

❌ Incorrect: Branching enzyme is not activated by dephosphorylation.  

D. Hexokinase

❌ Incorrect: Hexokinase is not activated by insulin.  

E. Debranching enzyme  

❌ Incorrect: Debranching enzyme is not activated by insulin.  

Explanation

Glycogenesis is the process of forming glycogen molecules from glucose in order to store it. At first glycogen molecules are added in a linear fashion by an enzyme called glycogen synthase: This enzyme is active in the dephosphorylated state. This is followed by creating branched chains of glucose to the glycogen molecule, which is done by the branching enzyme.   

On the other hand, glycogenolysis starts with cutting of the linear glucose molecules, a process that is performed by glycogen phosphorylase, which is active in the phosphorylated form. This is followed by removing the branched chain of glucose by the debranching enzyme. Finally, this leads to the formation of glucose 6-phosphate molecules. In the liver, there is an enzyme called glucose 6-phosphatase, which converts glucose 6-phosphate to glucose, allowing it to be exported outside the cells. This enzyme is not present in the skeletal muscle cells, and therefore, the glucose 6-phosphate produced by glycogenolysis in skeletal muscle cannot be exported and is used by the skeletal muscle cells themselves.  

The effects of insulin and glucagon on glycogen metabolism in the liver can be explained by their effects on these hormones. First, insulin activates a tyrosine kinase receptor, which leads to the activation of an enzyme called protein phosphatase. Protein phosphatase dephosphorylates glycogen synthase (and hence activates it) and glycogen phosphorylase ( and hence deactivates it). On the other hand, glucagon receptor activation leads to the production of cyclic AMP (cAMP) and activates protein kinase A. Protein kinase A then phosphorylates glycogen synthase (deactivating it) and glycogen phosphorylase (activating it).  

6. An athlete takes part in a 100-meter sprint and completes the race within 12 seconds. Via which of the following processes did the athlete’s muscles primarily generate energy during the race?  

A. Breakdown of glycogen stores  

❌ Incorrect: During the first 30 seconds of high-intensity exercise, existing ATP stores, substrate level phosphorylation, and anaerobic metabolism are the primary sources of energy for muscle tissue. Only minutes to hours after initiating exercise do glycogen stores get broken down for energy.  

B. Beta-oxidation of fatty acids

❌ Incorrect: During the first 30 seconds of high-intensity exercise, existing ATP stores, substrate level phosphorylation, and anaerobic metabolism are the primary sources of energy for muscle tissue. Only minutes to hours after initiating exercise do fatty acids get broken down for energy.  

C. Conversion of ketone bodies to acetyl-CoA  

❌ Incorrect: Ketone bodies are produced after prolonged periods of starvation. In contrast, they are not typically produced during short periods of high-intensity exercise.  

D. Substrate phosphorylation using creatine phosphate  

✅ Correct: See Main Explanation.  

E. Oxidative phosphorylation of glucose molecules  

❌ Incorrect: Upon initiation of exercise, the body first relies on existing ATP stores, substrate level phosphorylation, and anaerobic metabolism for energy. Only after around a minute of exercise does aerobic respiration (i.e. oxidative phosphorylation) become the predominant energy source.  

Explanation

During exercise, muscle fibers consume significant quantities of energy. The energy source utilized varies over time. When the body is undergoing intense short-term exercise (e.g. sprinting), the main sources of energy include existing ATP, creatine phosphate, and anaerobic respiration.    

During the initial seconds of exercise, the body uses existing ATP molecules within muscle cells. This ATP reserve is limited and is able to sustain muscle contractions for a single bout of exercise (e.g. hitting a tennis ball).    

The body subsequently needs to generate more ATP. This is initially achieved via substrate phosphorylation, wherein a phosphate group is directly added to an ADP molecule. In muscles, the phosphate comes from creatine phosphate. Unfortunately, creatine phosphate runs out within around 30 seconds after the onset of exercise.    

Next, the body generates ATP via anaerobic glycolysis, which is the breakdown of glucose into pyruvate and lactic acid. This process does not require oxygen, but only yields about 2 ATP per glucose molecule.  

Finally, after around a minute of exercise, the body is able to provide enough oxygen to the muscle tissue and aerobic respiration, which generates 32 ATP per glucose molecule, becomes the primary source of energy. During prolonged periods of exercise (e.g. marathon running), fatty acids and glycogen can also be broken down to generate energy.  

7. A group of researchers are studying glycogenesis in the liver cells. Which of the following hormones stimulates glycogen synthesis?  

A. Insulin

✅ Correct: See Main Explanation.  

B. Glucagon

❌ Incorrect: Glucagon is a pancreatic enzyme that is released when the blood glucose levels drop. It mediates the breakdown of glycogen and inhibits its synthesis.  

C. Epinephrine

❌ Incorrect: Epinephrine, like glucagon, also mediates the breakdown of glycogen.  

D. Vasopressin

❌ Incorrect: Vasopressin has no effect on glycogenesis.

E. Angiotensin-1   

❌ Incorrect: Angiotensin-1 has no effects on glycogenesis.  

Explanation

Glucose is the principal energy source in the body. Glycogen is the primary storage form of glucose. Glycogen synthesis is used to store glucose inside the cells, which helps maintain normal blood glucose levels and also can be broken down to glucose in states of decreased levels of blood glucose (e.g., fasting).  

The process of synthesis of glycogen from glucose is called glycogenesis. Glycogenesis takes place primarily in two organs, the liver and the skeletal muscles. The main mediator of glycogen synthesis is insulin. Insulin is secreted after meals (especially carbohydrate-rich meals) and functions to maintain normal glucose levels in the blood. Insulin stimulates the glucose uptake in the tissues and also stimulates the enzymes necessary for glycogen synthesis (i.e., glycogen synthase).  

On the other hand, epinephrine and glucagon inhibits the synthesis of glycogen by inhibiting the glycogen synthase and mediates its breakdown. These hormones are released when blood glucose levels drop and function to raise the blood glucose levels back to normal.  

8. An investigator is evaluating the metabolism of glucose after a meal and during strenuous exercise. According to his study, the glucose showed uptake into two main organs after a meal and stored in the form of a glycogen. In addition, he noticed that in the first organ (organ Z), glycogen storage is metabolized and broken down to glucose, which is then transported to the blood, while in the second organ (organ X), the glucose from glycogen metabolism is not exported outside the cells into the bloodstream but is used by the cells of that same organ. Which of the following are most likely organs studied in this experiment?  

A.

Organ Z	Organ X
Liver	Skeletal muscles

✅ Correct: See Main Explanation.   

B.

Organ Z	Organ X
Liver	Kidney

❌ Incorrect: Although glycogen can be found in the kidneys, its function is still not well understood.

C.

Organ Z	Organ X
Skeletal muscle	Liver

❌ Incorrect: Glucose from glycogen breakdown in the liver is exported outside into the bloodstream; however, glucose produced from glycogen breakdown in the skeletal muscle is not exported and is used by the skeletal muscle cells themselves.   

D.

Organ Z	Organ X
Liver	Brain

❌ Incorrect: Although glycogen can also be found in the brain, its function is not well understood.   

E.

Organ Z	Organ X
Brain	Heart

❌ Incorrect: Glycogen can be found in the heart and the brain, but the function of glycogen in these organs is not well understood and is not thought to be contributing to the storage and regulation of glucose.   

Explanation

Glycogen is a polymer of glucose molecules that functions mainly in the storage and regulations of blood glucose levels. In states of high blood glucose (e.g., after a meal), the synthesis of glycogen from glucose increases, and vice versa when the blood sugar levels drop.  

The main two sites for glycogen storage and metabolism are the liver and the skeletal muscle. However, the function of glycogen in these two organs differ. In the liver, glycogen is stored and, when blood glucose levels drop, it is broken down into glucose molecules and is then exported outside the liver into the blood to maintain normal blood glucose levels.  

However, in the skeletal muscle, the glycogen metabolism and the resulting glucose molecules are not exported into the bloodstream but are used by the skeletal muscles themselves to generate energy needed for contractions.  

The ability to release the glucose from glycogen into the bloodstream in the liver is mainly due to the presence of the enzyme called glucose-6 phosphatase, which converts glucose-6 phosphate to glucose, which can then be exported outside the cells. The enzyme glucose-6 phosphatase is not present in skeletal muscle, and hence, skeletal muscle cannot export glucose into the bloodstream, and the glucose from glycogen breakdown in skeletal muscle is used by the muscle cell itself to provide energy for contractions.  

Finally, glycogen can be found in other tissues including the heart, the kidneys, and the brain. However, its function in those organs are not well understood and is believed to not be a major contributor to the regulation of blood glucose levels.   

General principles of amino acid metabolism

4 Qs

1. A group of researchers are investigating the digestion and absorption of proteins in the gastrointestinal tract of the human body. Which of the following is true regarding protein digestion and absorption?  

A. The majority of the protein digestion takes place in the stomach  

❌ Incorrect: Although protein digestion begins in the stomach, it accounts only for small amounts of protein digestion. The majority of protein digestion takes place in the small intestine by pancreatic enzymes.  

B. Protein digestion only occurs in the small intestine  

❌ Incorrect: Although the majority of protein digestion occurs in the small intestine, some proteins are also digested in the stomach.  

C. Only free amino acids are absorbed into the enterocytes  

❌ Incorrect: Enterocytes absorb free amino acids as well as oligopeptides.  

D. Hydrochloric acid and trypsin in the stomach begin the digestion of proteins  

❌ Incorrect: Hydrochloric acid and pepsin in the stomach begin the digestion of proteins. Trypsin is a pancreatic enzyme that breaks down proteins in the small intestine.  

E. Hydrochloric acid and pepsin in the stomach begins the digestion of proteins  

✅ Correct: See Main Explanation.  

Explanation

Protein digestion and absorption is a complex process that takes place in the gastrointestinal tract to obtain the necessary amino acids needed by the body. The process of protein digestion starts in the stomach. In the stomach, hydrochloric acid weakens the peptide bonds. An enzyme called pepsinogen is produced by the chief cells in the stomach and is converted into the active form pepsin by the acidity of the stomach, which is then able to cleave peptide bonds yielding smaller peptides and amino acids.  

After that, proteins reach the small intestine, where the majority of protein digestion and absorption occurs. In the small intestine, pancreatic proteolytic enzymes are secreted as zymogens, which are inactive to protect the pancreas. Once these zymogens reach the small intestine, brush border enterokinase cleaves trypsinogen into trypsin. Then trypsin cleaves other zymogens to their active form including chymotrypsin, carboxypeptidase, and elastase. Also, trypsin cleaves additional trypsinogen into trypsin. All these proteolytic enzymes cleave proteins into free amino acids, dipeptides, and tripeptides; in these forms, they are able to be absorbed by enterocytes. Once in the enterocytes, di- and tripeptides are cleaved by proteolytic enzymes inside the enterocytes into free amino acids, which are then transported to the blood.  

2. A group of students are studying the metabolic sites of major cellular processes. Which of the following best describes the location of the urea cycle in the cell?  

A. Mitochondria only  

❌ Incorrect: Reactions that occur solely in the mitochondria include fatty acid oxidation (β-oxidation), acetyl- CoA production, TCA cycle, oxidative phosphorylation, and ketogenesis.  

B. Cytoplasm only  

❌ Incorrect: Metabolic processes that occur solely in the cytoplasm include glycolysis; HMP shunt; and synthesis of cholesterol (SER), proteins (ribosomes, RER), fatty acids, and nucleotides.  

C. Mitochondria and cytoplasm  

✅ Correct: See Main Explanation.  

D. Nucleolus only  

❌ Incorrect: The urea cycle does not occur in the nucleolus.  

E. Cytoplasm and nucleus  

❌ Incorrect: The urea cycle does not occur in the nucleolus.  

Explanation

The urea cycle is the series of enzyme reactions in liver cell mitochondria and cytoplasm responsible for the removal of excess nitrogen and the potentially toxic by-product ammonia via the production of urea. More importantly, the urea cycle helps keep in balance nitrogen atoms in the human body.  

3. Biochemistry researchers are studying the metabolic pathway involved in the removal of toxic ammonia molecules. Which of the following reactions of these metabolic pathways occurs in the mitochondria?  

A. NH₃ + carbon dioxide → carbamoyl phosphate  

✅ Correct: See Main Explanation

B. Alpha-ketoglutarate + NH₃ → glutamate  

❌ Incorrect: This reaction is not a part of the urea cycle.  

C. Citrulline + aspartate → argininosuccinate  

❌ Incorrect: This reaction occurs in the cytoplasm.  

D. Argininosuccinate → arginine + fumarate  

❌ Incorrect: This reaction occurs in the cytoplasm.  

E. Arginine → urea + ornithine  

❌ Incorrect: This reaction occurs in the cytoplasm.  

Explanation

The urea cycle occurs in the mitochondria and cytoplasm of the liver cells. In the mitochondria, ammonia is converted to carbamoyl phosphate, which in turn, reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate then arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, which returns to the mitochondria and can re-enter the cycle to generate additional urea. The net reaction is the combination of two molecules of ammonia with one of carbon dioxide, yielding urea and water.  

4. Biochemistry researchers are studying the metabolic pathway involved in the removal of toxic ammonia molecules. Which of the following regulates the step shown below?  

NH₃ + carbon dioxide → carbamoyl phosphate  

A. Malonyl-CoA  

❌ Incorrect: Malonyl-CoA negatively regulates the rate-limiting enzyme in fatty acid oxidation.  

B. Inosine monophosphate  

❌ Incorrect: Inosine monophosphate negatively regulates the rate-limiting enzyme in de novo purine synthesis.  

C. Phosphoribosyl pyrophosphate  

❌ Incorrect: Phosphoribosyl pyrophosphate (PRPP) positively regulates the rate-limiting enzyme in de novo pyrimidine synthesis.  

D. N-acetylglutamate  

✅ Correct: See Main Explanation.  

E. Palmitoyl-CoA  

❌ Incorrect: Palmitoyl-CoA negatively regulates the rate-limiting enzyme in fatty acid synthesis.  

Explanation

The rate-limiting step of the urea cycle is as follows:  

NH₃ + carbon dioxide → carbamoyl phosphate  

It is catalyzed by the enzyme carbamoyl phosphate synthetase I (CPS-I), located within the mitochondria. This enzyme catalyzes the reaction that converts ammonia from glutamate into carbamoyl phosphate. CPS is regulated allosterically by increased concentrations of N-acetylglutamate, produced from the combination of acetyl-CoA and glutamate as well as increased concentration of arginine.  

General principles of fat and cholesterol metabolism

19 Qs

1. A patient with uncontrolled diabetes mellitus is admitted to the intensive care unit for the management of diabetic ketoacidosis (DKA). Which of the following ketone bodies accumulate in patients with DKA?  

A. Acetone only  

❌ Incorrect: This answer choice is incorrect. All three ketone bodies accumulate in patients with DKA.  

B. Β-hydroxybutyrate only  

❌ Incorrect: This answer choice is incorrect. All three ketone bodies accumulate in patients with DKA.

C. Acetoacetate only   

❌ Incorrect: This answer choice is incorrect. All three ketone bodies accumulate in patients with DKA.  

D. Acetone and acetoacetate  

❌ Incorrect: This answer choice is incorrect. All three ketone bodies accumulate in patients with DKA.  

E. Acetoacetate, acetone, and β-hydroxybutyrate  

✅ Correct: See Main Explanation.  

Explanation

Three ketone bodies are produced and accumulate in diabetic ketoacidosis. Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and β-hydroxybutyrate. Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies.  

2. A group of students are studying the metabolic sites of major cellular processes. Which of the following steps in fatty acid synthesis is crucial to transport acetyl-CoA from the mitochondria to the cytoplasm?  

A. Carnitine shuttle   

❌ Incorrect: The carnitine shuttle represents a mechanism by which long-chain fatty acids are transported into the mitochondrial matrix for the purpose of β-oxidation and energy production. It has no role in the transport of acetyl-CoA from the mitochondria to the cytoplasm in fatty acid synthesis.  

B. Citrate shuttle  

✅ Correct: See Main Explanation.  

C. Transamination reactions  

❌ Incorrect: Transamination reactions interconvert pairs of α-amino acids and α-keto acids and are catalyzed by aminotransferases. It has no role in the transport of acetyl-CoA from the mitochondria to the cytoplasm.  

D. Cori cycle  

❌ Incorrect: Cori cycle refers to the process of transporting lactate from cells that are undergoing anaerobic metabolism to the liver where it is used to provide glucose back to the cells. It has no role in the transport of acetyl-CoA from the mitochondria to the cytoplasm.

E. Cahill cycle  

❌ Incorrect: Cahill cycle is one of the two mechanisms in humans which help in the transport of ammonia to the liver from tissues so that ammonia can be converted into urea. It has no role in the transport of acetyl-CoA from the mitochondria to the cytoplasm.

Explanation

For fatty acid biosynthesis, acetyl-CoA has to be transported from the mitochondria to the cytoplasm. This is done via a shuttle system called the citrate shuttle. The citrate shuttle transports acetyl-CoA out of the mitochondria by combining it with oxaloacetate to form citrate. Once citrate is in the cytoplasm, it is converted back into acetyl-CoA and oxaloacetate, allowing acetyl-CoA to be used in fatty acid synthesis.

3. A mountain climber in the Himalayas has been out of food and water for the last four days. Which of the following is the main source of energy for maintaining metabolic processes in the brain in this patient?  

A. Glycolysis

❌ Incorrect: Glycolysis and aerobic respiration are the main sources of energy in fed state.  

B. Gluconeogenesis

❌ Incorrect: Hepatic gluconeogenesis from peripheral tissue lactate and alanine and from adipose tissue glycerol and propionyl- CoA provides energy between 1-3 days of starvation.  

C. Free fatty acids  

❌ Incorrect: Adipocytes release free fatty acids (FFA) between 1-3 days of starvation–skeletal myocytes and hepatocytes can shift fuel use from glucose to FFA between 1-3 days of starvation.

D. Ketone bodies   

✅ Correct: See Main Explanation.  

E. Glycogenesis

❌ Incorrect: Hepatic glycogenolysis is the major source of energy during fasting state between meals. Glycogen reserves depleted after day one of starvation.  

Explanation

In the state of starvation, after three days, ketone bodies become the main source of energy for the brain. Ketone bodies are a group of carbon-containing molecules produced by liver mitochondria using a 2-carbon molecule called acetyl-CoA. The liver makes ketone bodies in physiologic states like prolonged fasting or exercise as well as in pathological states like type 1 diabetes mellitus or alcoholism. Ketone bodies can be released into the circulation and get picked up by the majority of cells. Inside the cells, they are reconverted back into acetyl-CoA, at which point they can then enter the mitochondria and produce ATP.  

4. A study is done on the processes of fat digestion and absorption in order to develop novel pharmacologics that can help prevent diseases associated with increased levels of fat and lipids in the blood. Which of the following is true regarding the digestion and absorption of fats and lipids?  

A. Absorbed fat and lipids get transported from enterocytes through lymphatic ducts  

✅ Correct: See Main Explanation.  

B. Lipase is the enzyme that breaks down fat globules and is only produced by the pancreas  

❌ Incorrect: Lipase is found in lingual secretions, stomach secretions, and pancreatic secretions.  

C. Free fatty acids and monoglycerides from digested fat get absorbed into the enterocytes and then directly into the blood   

❌ Incorrect: Free fatty acids and monoglycerides, once absorbed into the enterocytes, assemble again into triglycerides which are carried by chylomicrons into the lymphatic system.  

D. The process of fat digestion and absorption ends in the duodenum  

❌ Incorrect: The process of fat digestion and absorption continues through the small bowel into the jejunum.  

E. Digested fats get absorbed into enterocytes as triglycerides  

❌ Incorrect: Fat and lipid digestion yields monoglycerides and free fatty acids, which are absorbed into the enterocytes. Within the enterocytes, monoglycerides and fatty acids assemble again into triglycerides.  

Explanation

Fats and lipids are essential components of the human diet, and the process of digestion and absorption of fats and lipids is a complex process that starts in the mouth.  

The enzyme lipase is the major enzyme responsible for breaking down fats. It is secreted firstly in the saliva and starts the process of breaking down fat while in the mouth, which continues in the stomach too. However, the majority of the process of fat digestion and absorption takes place in the small intestines.   

When fat globules reach the duodenum, pancreatic secretions containing lipase start breaking down fat globules. This process is facilitated by bile salts, which increases the surface area of fat globules for lipase to work. Lipase breaks down fat globules into free fatty acids and monoglycerides, which are then absorbed by the enterocytes.

Once in the enterocytes, free fatty acids and monoglycerides join again into triglycerides, which are assembled into chylomicrons. Finally, chylomicrons exit the enterocytes into the lymphatic capillaries, until it reaches the thoracic duct, and finally enter the bloodstream.  

5. Biochemistry researchers are studying the pathway of fatty acid synthesis with students in the laboratory. Which of the following is the rate-limiting step of fatty acid synthesis?  

A. Fatty acyl-CoA → long-chain acylcarnitine  

❌ Incorrect: This answer choice is the rate-limiting step of beta-oxidation of fatty acid.  

B. Acetyl-CoA  → Malonyl-CoA

✅ Correct: See Main Explanation.  

C. Phosphoenolpyruvate → pyruvate  

❌ Incorrect: This answer choice is the last step of the glycolytic pathway catalyzed by pyruvate kinase.  

D. Oxaloacetate → phosphoenolpyruvate  

❌ Incorrect: This is an irreversible step in gluconeogenesis and is catalyzed by phosphoenolpyruvate carboxykinase.

E. Pyruvate  →  oxaloacetate  

❌ Incorrect: This step is catalyzed by pyruvate carboxylase in gluconeogenesis.  

Explanation

 Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH. The rate-limiting step is the conversion of malonyl-CoA to acetyl-CoA which is catalyzed by acetyl-CoA carboxylase. This enzyme is regulated by the following factors:  
- Activators: Insulin and citrate  
- Inhibitors: Glucagon and palmitoyl-CoA  

6. A group of students are studying the metabolic sites of major cellular processes. Which of the following best describes the cellular location of the fatty acid oxidation in the cell?  

A. Mitochondria only  

✅ Correct: See Main Explanation.  

B. Cytoplasm only   

❌ Incorrect: Metabolic processes that occur in cytoplasm include glycolysis, HMP shunt, and synthesis of cholesterol (SER), proteins (ribosomes, RER), fatty acids, and nucleotides.  

C. Mitochondria, cytoplasm and endoplasmic reticulum  

❌ Incorrect: Gluconeogenesis takes place in the cytoplasm, mitochondria, and endoplasmic reticulum.  

D. Nucleolus only  

❌ Incorrect: Fatty acid oxidation occurs in the mitochondria.

E. Cytoplasm and nucleus  

❌ Incorrect: Fatty acid oxidation occurs in the mitochondria.  

Explanation

Fatty acid β-oxidation is a multistep process by which fatty acids are broken down by various tissues to produce energy. It primarily takes place in the mitochondria of the heart, skeletal muscle, and liver cells.  

7. A group of students are studying the metabolic sites of major cellular processes. Which of the following best describes the mechanism by which long-chain fatty acids are transported into the mitochondrial matrix for the purpose of β-oxidation and energy production?

A. Carnitine shuttle  

✅ Correct: See Main Explanation.

B. Citrate shuttle  

❌ Incorrect:  The citrate shuttle transports acetyl-CoA from the mitochondria to the cytoplasm, allowing acetyl-CoA to be used in fatty acid synthesis.  It has no role in fatty acid oxidation.  

C. Transamination reactions  

❌ Incorrect: Transamination reactions interconvert pairs of α-amino acids and α-keto acids and are catalyzed by aminotransferases. It has no role in fatty acid oxidation.  

D. Cori cycle  

❌ Incorrect: Cori cycle refers to the process of transporting lactate from cells that are undergoing anaerobic metabolism to the liver where it is used to provide glucose back to the cells. It has no role in fatty acid oxidation.  

E. Cahill cycle  

❌ Incorrect: Cahill cycle is one of the two mechanisms in humans which help in the transport of ammonia to the liver from tissues so that ammonia can be converted into urea. It has no role in fatty acid oxidation.  

Explanation

Fatty acid β-oxidation is a multistep process by which fatty acids are broken down by various tissues to produce energy. Once the fatty acid is inside the cell, a cytosolic enzyme called fatty acyl-CoA synthetase adds a coenzyme A molecule to the end of the fatty acid, turning it into a metabolically active fatty acyl-CoA. The mitochondria is composed of two membranes–an outer membrane and an inner membrane–with a small space in between and the mitochondrial matrix at the core. The enzymes required for beta-oxidation are located in the mitochondrial matrix; however, the fatty acid cannot cross the inner mitochondrial membrane when CoA is attached to it. Therefore, an enzyme within the outer mitochondrial membrane called carnitine acyltransferase 1 (CAT1), replaces the CoA with carnitine, making fatty acyl-carnitine and a free CoA, both of which can easily cross the inner mitochondrial membrane. Then, along the inner mitochondrial membrane, another enzyme called carnitine acyltransferase 2 (CAT2), substitutes carnitine and CoA back; therefore, regenerating fatty acyl-CoA and free carnitine–which is now within the mitochondrial matrix. This whole process is called the carnitine shuttle.  

8. A patient with uncontrolled diabetes mellitus is admitted to the intensive care unit for the management of diabetic ketoacidosis. One of the medical students notices that the patient's breath smells sweet, similar to the odor of fruits. Which of the following ketone bodies is responsible for this odor?  

A. Acetone only  

✅ Correct: See Main Explanation.  

B. β-hydroxybutyrate only  

❌ Incorrect: This answer choice is incorrect. Although acetone is exhaled by the lungs, β-hydroxybutyrate is not.  

C. Acetoacetate only  

❌ Incorrect: This answer choice is incorrect. Acetoacetate is not exhaled by lungs.  

D. Acetone and acetoacetate  

❌ Incorrect: This answer choice is incorrect. Although acetone is exhaled by the lungs, acetoacetate is not.  

E. Acetoacetate, acetone, and β-hydroxybutyrate  

❌ Incorrect: This answer choice is incorrect. Although acetone is exhaled by the lungs, acetoacetate and β-hydroxybutyrate are not.  

Explanation

During ketone body metabolism, the extrahepatic tissues utilize acetoacetate and β-hydroxybutyrate (3-hydroxybutyrate) as respiratory substrates. Acetone is a waste product which, as it is volatile, can be excreted via the lungs. That is why in pathological states like diabetic ketoacidosis, the patient’s breath can smell like fruit—this is actually the scent of acetone.  

9. Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. Which of the following organs/cells utilize ketone bodies for energy?  

A. Red blood cells   

❌ Incorrect: Red blood cells cannot utilize ketones; they strictly use glucose.  

B. Hepatocytes

❌ Incorrect: Although hepatocytes are the source of ketone bodies, the liver cannot use them for energy because it lacks the enzyme thiophorase (β-ketoacyl-CoA transferase).  

C. Neurons

✅ Correct: See Main Explanation.  

D. Renal tubular cells  

❌ Incorrect: Ketone bodies are filtered and reabsorbed in the kidney. It is not utilized by the kidney for energy.  

E. Adrenal epithelial cells  

❌ Incorrect: Adrenal epithelial cells do not utilize ketone bodies.  

Explanation

Ketone bodies can be utilized as fuel in the heart, brain, and muscle but not the liver. Once formed, the ketone bodies are transported from the liver to other tissues where acetoacetate and β-hydroxybutyrate can be reconverted to acetyl-CoA to produce reducing equivalents (NADH and FADH2) via the citric acid cycle. Though it is the source of ketone bodies, the liver cannot use them for energy because it lacks the enzyme thiophorase (β-ketoacyl-CoA transferase).   

10. Biochemistry researchers are studying the pathway of fatty acid oxidation with students in the laboratory. Which of the following is the rate-limiting step of fatty acid oxidation?  

A. Fatty acyl-CoA → long-chain acylcarnitine  

✅ Correct: See Main Explanation.  

B. Malonyl CoA  → acetyl-CoA  

❌ Incorrect: This answer choice is the rate-limiting step of fatty acid synthesis.  

C. Phosphoenolpyruvate → pyruvate  

❌ Incorrect: This answer choice is the last step of the glycolytic pathway catalyzed by pyruvate kinase.  

D. Oxaloacetate → phosphoenolpyruvate  

❌ Incorrect:  This is irreversible in gluconeogenesis and is catalyzed by phosphoenolpyruvate carboxykinase.

E. Pyruvate  →  oxaloacetate  

❌ Incorrect: This step is catalyzed by pyruvate carboxylase in gluconeogenesis.  

Explanation

Fatty acid β-oxidation is a multistep process by which fatty acids are broken down by various tissues to produce energy. Fatty acids primarily enter a cell via fatty acid protein transporters on the cell surface.  Once inside the cell, a -CoA group is added to the fatty acid by fatty acyl-CoA synthase, forming long-chain acyl-CoA. Carnitine palmitoyltransferase 1 converts the long-chain acyl-CoA to long-chain acylcarnitine and allows the fatty acid moiety to be transported across the inner mitochondrial membrane via carnitine translocase (CAT), which exchanges long-chain acylcarnitines for carnitine. This is also the rate-limiting step in fatty acid β-oxidation. This step is inhibited by malonyl-CoA.  

11. A group of students are studying the metabolic sites of major cellular processes. Which of the following best describes the cellular location of ketone bodies synthesis in the cell?  

A. Mitochondria only  

✅ Correct: See Main Explanation.  

B. Cytoplasm only  

❌ Incorrect: Glycolysis; HMP shunt; and synthesis of cholesterol (SER), proteins (ribosomes, RER), fatty acids, and nucleotides occur in the cytoplasm.  

C. Mitochondria, cytoplasm, and endoplasmic reticulum  

❌ Incorrect: Gluconeogenesis takes place in the cytoplasm, mitochondria, and endoplasmic reticulum.  

D. Nucleolus only  

❌ Incorrect: Ketogenesis occurs in the mitochondria of hepatocytes.  

E. Cytoplasm and nucleus  

❌ Incorrect:  Ketogenesis occurs in the mitochondria of hepatocytes.

Explanation

Ketone bodies (e.g., acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of HMG-CoA by two key enzymes: HMG-CoA synthase and HMG-CoA lyase.  

12. A group of students are studying the metabolic sites of major cellular processes. Which of the following best describes the cellular location of fatty acid synthesis in the cell?  

A. Mitochondria only  

❌ Incorrect: Reactions that occur solely in the mitochondria include fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, and ketogenesis.  

B. Cytoplasm only  

✅ Correct: See Main Explanation.  

C. Mitochondria, cytoplasm, and endoplasmic reticulum  

❌ Incorrect: Gluconeogenesis takes place in the cytoplasm, mitochondria, and endoplasmic reticulum.  

D. Nucleolus only  

❌ Incorrect: Fatty acid synthesis occurs in the cytoplasm.  

E. Cytoplasm and nucleus  

❌ Incorrect: Fatty acid synthesis occurs in the cytoplasm.  

Explanation

Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH. This process takes place in the cytoplasm of the cell. It predominantly occurs in the liver, lactating mammary glands, and adipose tissue.  

13. A 46-year-old man presents to the office for the evaluation of abnormal lipid profile. He does not have any active complaints at this visit. Past medical history is significant for hypertension and dyslipidemia. Current medication includes lisinopril. Approximately 6 months ago, he was started on a low-fat diet to help him lose weight and improve dyslipidemia. Family history is significant for type II diabetes mellitus and myocardial infarction in his father. Temperature is 37.0°C (98.6°F), pulse is 70/min, respirations are 16/min, and blood pressure is 130/85 mmHg. Physical examination is unremarkable. A repeat lipid panel obtained last week reveals low-density lipoprotein (LDL) levels of 250 mg/dL. Chart review reveals the patient was unable to tolerate statin therapy in the past due to myopathy. The physician recommends the initiation of ezetimibe. Which of the following best describes the most likely mechanism of action of ezetimibe?  

A. Inhibition of lipolysis in adipose tissue

❌ Incorrect: Niacin, a lipid lowering drug, acts to prevent lipolysis by inhibiting hormone-sensitive lipase in adipose tissue. Its overall effect is a major increase in HDL and a decrease in LDL. Ezetimibe has no direct effect on lipolysis in adipose tissue.  

B. Inhibition of hydroxymethylglutaryl (HMG) CoA reductase

❌ Incorrect: Statins are lipid-lowering drugs that competitively inhibit HMG CoA reductase, an enzyme which normally converts HMG CoA to mevalonate. This leads to a decrease in hepatic cholesterol synthesis and increase in LDL recycling. Although ezetimibe helps reduce LDL levels, it does not directly affect HMG CoA reductase.  

C. Inhibition of intestinal bile acid reabsorption

❌ Incorrect: Bile acid resins (e.g., cholestyramine, colestipol) are lipid lowering drugs that act by binding the bile acids (not cholesterol) in the intestine to prevent its reabsorption at the intestinal brush border.  

D. Inhibition of intestinal cholesterol absorption

✅ Correct: See Main Explanation.  

E. Inhibition of low-density-lipoprotein receptor (LDL-R) degradation

❌ Incorrect: PCSK9 inhibitors act by inhibiting the degradation of LDL-R, facilitating the removal of LDL from the bloodstream. Alirocumab is a common example of this drug.  

Explanation

This patient with elevated LDL cholesterol levels, not improved by dietary changes, is started on ezetimibe, a lipid lowering drug. It prevents cholesterol absorption at the intestinal brush border by inhibiting Niemann-Pick C1 like 1 (NPC1L1) protein, which is a critical mediator of cholesterol absorption. This results in a significant reduction in LDL-cholesterol levels. However, little to no effect is observed on very-low-density lipoproteins (VLDL) or high-density lipoproteins (HDL) levels. It is usually indicated in patients with hyperlipidemia in combination with statins or as a monotherapy to prevent the side effects of high dose statins (e.g., myopathy, deranged liver aminotransferase). Moreover, it can also be combined with fenofibrate to treat mixed hyperlipidemia. Side effects of ezetimibe include gastrointestinal (GI) upset, headache and, rarely, liver damage or myalgias.  

14. A 45-year-old man comes to the office for the evaluation of his abnormal lipid panel and is currently asymptomatic. Past medical history is significant for type II diabetes mellitus, and an episode of pancreatitis 6 months ago. Current medications include metformin and atorvastatin. Family history is significant for myocardial infarction in father and chronic renal failure in mother. He smokes a pack of cigarettes daily, drinks 2 glasses of beer on weekends and does not use illicit drugs. Vitals are within normal limits. His BMI is 33.5 kg/m². Physical examination is noncontributory. Fasting laboratory workup at today’s visit is shown below. The patient is recommended to maintain a low-fat diet to reduce weight, and fenofibrate is added to his medication regime. Which of the following best describes the effect of fenofibrate therapy on serum LDL, HDL and TGs?  

Laboratory value	Results
Glucose	120 mg/dL
Low-density lipoprotein (LDL)	160 mg/dL
High-density lipoprotein (HDL)	30 mg/dL
Triglycerides	700 mg/dL
Hemoglobin A1c	6.6 %

A.

❌ Incorrect: Statins inhibit the action of hydroxymethylglutaryl (HMG) CoA reductase, which normally converts HMG CoA to mevalonate. This leads to a decrease in hepatic cholesterol synthesis and increase in low density lipoproteins (LDL) recycling by the up-regulation of LDL receptors on hepatic cells. It has a moderate effect on TG levels.   

B.

❌ Incorrect: Bile acid resins (e.g. cholestyramine) tend to decrease LDL cholesterol by preventing bile acid reabsorption in the intestine (enterohepatic circulation). It slightly increases the levels of TGs rather than decreasing it.   

C.

❌ Incorrect: These changes are observed with fish oil and marine omega-3 fatty acids. It decreases the transport of free fatty acids to the liver and inhibits the activity of TG-synthesizing enzymes. It decreases TGs only at high doses.   

D.

✅ Correct: See Main Explanation.   

E.

❌ Incorrect: A significant increase in HDL is observed with the use of niacin. A major decrease in TG is not seen.   

Explanation

This patient with moderate-to-severe hypertriglyceridemia (TG >500 mg/dL) and a past medical history of an episode of pancreatitis is likely to benefit from fibrate therapy.

Fibrates activate peroxisome proliferator-activated receptor alpha (PPARα) which is a major regulator of lipid metabolism. PPARα decreases the liver's very-low-density lipoprotein (VLDL) levels and increases the activity of lipoprotein lipase (LPL) in the adipose tissues. LPL in turn hydrolyzes the triglycerides in chylomicron and VLDL to free fatty acids (FFA), thus lowering triglyceride levels. The FFA can be used for energy or converted back to TGs. Finally fibrates also increase the synthesis of HDL by facilitating the transfer of TGs from chylomicrons and VLDL to HDL. Unlike statins, fibrates have little effect on LDL, whereas, statins are not as effective in lowering TGs. Therefore, both can be combined to treat mixed dyslipidemia.  

15. A 46-year-old woman presents to the office for evaluation of an abnormal lipid profile, which was discovered during routine testing. She has no acute symptoms but has had difficulty following a low carbohydrate diet that her previous physician recommended. Past medical history is significant for hypertension and type II diabetes mellitus. Current medications include metformin, lisinopril, and atorvastatin. Family history is significant for type II diabetes mellitus and myocardial infarction in the patient’s father. Temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 20/min, and blood pressure is 135/85 mmHg. Body mass index is 34 kg/m². Physical examination is unremarkable. Laboratory results are shown below. The patient is encouraged to exercise regularly and make dietary modifications. In addition, she is started on a medication to help control her triglyceride level. Which of the following enzymes is most likely affected by this drug?  

Laboratory Value	Results
Glucose	120 mg/dL
Low-density lipoprotein (LDL)	140 mg/dL
High-density lipoprotein (HDL)	30 mg/dL
Triglycerides (TGs)	900 mg/dL
Hemoglobin A1c	6.6%

A. Hydroxymethylglutaryl (HMG) CoA reductase

❌ Incorrect: Statins act to inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This patient is already on a statin, which plays a major role in LDL reduction. In contrast, a fibrate would be more effective in managing the patient’s elevated triglyceride level.  

B. Lipoprotein lipase

✅ Correct: See Main Explanation.  

C. Monoamine oxidase

❌ Incorrect: Monoamine oxidase inhibitors (e.g. phenelzine) act to remove neurotransmitters norepinephrine, serotonin, and dopamine from the brain. They can be used in the treatment of major depressive disorder. Monoamine oxidase inhibitors have no proven efficacy against hypertriglyceridemia.  

D. Hormone-sensitive lipase

❌ Incorrect: Niacin, a lipid-lowering drug, acts to prevent lipolysis by inhibiting hormone-sensitive lipase in adipose tissue. Its overall effect is a major increase in HDL and a decrease in LDL. It is not routinely used for the treatment of hypertriglyceridemia.  

E. Phosphodiesterase-3

❌ Incorrect: Phosphodiesterase-3 inhibitors (e.g. milrinone) prevent the inactivation of intracellular second messengers (e.g., cyclic adenosine monophosphate, cyclic guanosine monophosphate). These medications are useful in the management of heart failure and intermittent claudication. However, they would not help in treating this patient’s hypertriglyceridemia.  

Explanation

This patient has a significantly elevated triglyceride (TG) level (> 500 mg/dL) and should be started on fibrate therapy along with lifestyle modifications.

Fibrates (e.g., fenofibrate, gemfibrozil, bezafibrate) activate peroxisome proliferator-activated receptor alpha (PPARα), which is a major regulator of lipid metabolism. PPARα decreases very-low-density lipoprotein (VLDL) synthesis and increases lipoprotein lipase (LPL) activity in adipose tissues. LPL, in turn, hydrolyzes the TGs in chylomicrons and VLDLs to free fatty acids (FFA), thus lowering triglyceride levels. Moreover, fibrates increase the synthesis of HDLs, facilitating the transfer of TGs from chylomicrons and VLDL to HDL.

Fibrates are typically indicated when TG levels exceed 500 mg/dL and can potentially reduce the patient’s risk of developing pancreatitis. Although there is an increased risk of myopathy with the combined use of statin and fibrates, a combination of atorvastatin-fenofibrate is least likely to cause this adverse effect.  

16. A 45-year-old woman presents to the office for her routine follow-up. She has no active complaints at this visit. Past medical history is significant for hypertension. Current medication includes lisinopril. Family history is significant for type II diabetes mellitus in her mother and myocardial infarction in her father. She drinks 2-3 beers on the weekends and does not smoke or use illicit drugs. Temperature is 37.0°C (98.6°F), pulse is 70/min, respirations are 16/min, and blood pressure is 130/85 mmHg. Physical examination is unremarkable. Her recent fasting lipid profile revealed an elevated low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL). The physician prescribes a lipid-lowering drug that prevents lipolysis by inhibiting hormone-sensitive lipase in adipose tissue. Which of the following is a potential adverse effect of this drug?  

A. Myopathy

❌ Incorrect: Myopathy is a potential adverse effect of statin therapy which decreases liver cholesterol production by inhibiting hydroxymethylglutaryl (HMG) CoA reductase. This patient is most likely prescribed niacin, which can cause myopathy but only when used in combination with a statin.  

B. Hyperuricemia

✅ Correct: See Main Explanation.  

C. Gallstones

❌ Incorrect: Gallstone formation is a potential side effect of fibrate therapy which inhibits cholesterol 7ɑ hydroxylase, an enzyme that synthesizes bile acids. This results in supersaturation of cholesterol in gallbladder and the formation of gallstones. It does not inhibit hormone-sensitive lipase in adipose tissue.  

D. Deficiency of fat soluble vitamins

❌ Incorrect: Use of bile acid resins can lead to a deficiency of fat-soluble vitamins as it binds to bile acids (which help in the absorption of fat-soluble vitamins) in the intestine and prevent their reabsorption.  

E. Delirium

❌ Incorrect: Delirium is an uncommon adverse effect of PCSK-9 inhibitors, which is a relatively new class of lipid-lowering drugs that act by inhibiting the degradation of LDL receptors, facilitating the removal of LDL from the bloodstream. No effect on lipolysis is observed.  

Explanation

This patient with dyslipidemia is prescribed niacin, a lipid lowering drug, which causes an increase in blood uric acid levels and can induce gout (by inhibiting uric acid excretion and/or metabolism).

Normally, free fatty acids (FFA) are released by the action of hormone-sensitive lipase (HSL) on adipose tissue. This FFA is taken up by the liver to form triglycerides (TG), which are one of the components of LDL and VLDL. Niacin prevents lipolysis by inhibiting HSL in adipose tissue which leads to a moderate decrease in VLDL and LDL levels. It can also cause a moderate increase in HDL by decreasing its uptake by the liver.

Niacin can sometimes be indicated in the following circumstances:
 

•  To reduce LDL levels, uncontrolled by a combination of statins and ezetimibe 
•  To elevate HDL levels 
•  As an adjunct therapy for severe hypertriglyceridemia 
•  To reduce the risk of recurrent myocardial infarction 
•  In combination with bile acid resins to slow the progression of atherosclerotic cardiovascular  disease (does not improve cardiovascular mortality or morbidity) 

Its use, however, is limited by its side effect profile, which include prostaglandin-induced facial flushing and pruritus, reversible increase in liver aminotransferases, postural hypotension, gastrointestinal upset, elevations in serum uric acid levels and increase in glucose levels. When used in combination with statins, it increases the risk of developing myopathy.  

17. A 47-year-old man comes to the office because of muscle pain in his upper and lower extremities. He has been having a hard time raising his arms above his head for the past few days. The patient also reports that he easily gets fatigued and it is difficult for him to climb the stairs to his apartment. Past medical history is significant for hyperlipidemia. He was recently started on a low-fat diet and rosuvastatin to help reduce his blood cholesterol levels. Vitals are within normal limits. Physical examination shows weakness and soreness of proximal muscles of upper and lower extremities. Laboratory evaluation reveals elevated levels of serum creatine phosphokinase. Rosuvastatin is immediately discontinued and the patient is started on a new lipid lowering drug which interferes with the action of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9). Which of the following best describes the function of PCSK9?  

A. Conversion of hydroxymethylglutaryl (HMG) CoA to mevalonate

❌ Incorrect: Hydroxymethylglutaryl (HMG) CoA reductase converts HMG CoA to mevalonate, which is a precursor of cholesterol. This enzyme is inhibited by statins and it results in decreased formation of cholesterol, thereby increasing the LDL receptors on hepatocytes and increasing the uptake of serum LDL.  

B. Degradation of low-density lipoprotein receptors (LDL-R) on liver cells

✅ Correct: See Main Explanation.  

C. Hydrolysis of extracellular triglycerides in lipoprotein

❌ Incorrect: Lipoprotein lipase (LPL) hydrolyzes extracellular triglycerides in lipoproteins to free fatty acids and monoglycerides. LPL activity is up-regulated via the activation of peroxisome proliferator-activated receptor alpha (PPARα) by fibrates.  

D. Hydrolysis of intracellular of triglycerides in adipose tissue

❌ Incorrect: Hormone-sensitive lipase hydrolyzes intracellular triglycerides in adipose tissue to free fatty acids. It is stimulated by catecholamines, ACTH, and glucagon and inhibited by niacin (vitamin B3) which is sometimes indicated in the management of dyslipidemia.  

E. Degradation of monoaminergic neurotransmitters

❌ Incorrect: Monoamine oxidase is responsible for the degradation of monoaminergic neurotransmitters (catecholamine, dopamine and serotonin) in the synaptic cleft. Monoamine oxidase inhibitors prevent the degradation of monoamines and are used in the treatment of major depressive disorder. It does not affect the serum lipid levels.  

Explanation

This patient is most likely suffering from statin-induced myopathy and is switched to a new and safer drug that inhibits the activity of PCSK9 (e.g., alirocumab, evolocumab).

PCSK9 is a serine protease, predominantly produced in the liver. It binds to the low-density lipoprotein receptors (LDL-R) on the surface of hepatocytes and leads to its degradation, thereby resulting in elevated blood cholesterol levels. PCSK9 inhibitors are antibodies that bind PCSK9 and prevent LDL-R degradation. This leads to an overall increase in LDL-R on hepatocytes which results in a major decrease in serum LDL (by increasing its uptake in hepatocytes) and is indicated in patients with elevated LDL cholesterol. PCSK9 inhibitors are also shown to decrease the incidence of cardiovascular events in susceptible individuals. It is available as a subcutaneous injection and must be administered every 2-4 weeks. It is a comparatively safe lipid-lowering drug with occasional injection site reactions (pruritus, rash) and rare neurocognitive toxicity (delirium, dementia). Muscle toxicity, however, is not observed.  

18. A 46-year-old woman comes to the office for routine follow-up and has no active complaints at this visit. She was recently diagnosed with hypertriglyceridemia and was started on a low-fat diet along with fenofibrate. Past medical history is significant for hypertension. Current medications include fenofibrate and lisinopril. Family history is significant for myocardial infarction in her father. She does not use tobacco, alcohol or illicit drugs. Temperature is 37.0°C (98.6°F), pulse is 70/min, respirations are 16/min, and blood pressure is 130/85 mmHg. Physical examination is unremarkable. Repeat lipid panel revealed a triglyceride level of 900 mg/dL which was 1100 mg/dL a few weeks ago. A new supplement is added to her diet which decreases triglyceride levels by reducing the production of hepatic very low-density lipoprotein (VLDL) cholesterol. Which of the following nutrients is present in these supplements?  

A. Niacin

❌ Incorrect: Niacin (vitamin B3) is used as a lipid lowering agent that acts by inhibiting hormone sensitive lipase in the adipose tissue, thereby preventing the mobilization of triglycerides. Although it reduces hepatic VLDL synthesis, its major role is to increase high-density lipoprotein (HDL) and is not used primarily in hypertriglyceridemia.  

B. Omega 3 fatty acids

✅ Correct: See Main Explanation.  

C. Retinoic acid

❌ Incorrect: Retinoic acid also known as vitamin A, is an antioxidant and is used primarily in the treatment of acute promyelocytic leukemia and severe acne as all-trans retinoic acid and isotretinoin, respectively. It has no known effect on triglyceride levels.  

D. Folate

❌ Incorrect: Folate (vitamin B9) plays an important role in the synthesis of nitrogenous bases in DNA and RNA. Its supplementation is helpful in pregnant women and patients with megaloblastic anemia. No effect on lipid metabolism is observed.  

E. Ascorbic acid

❌ Incorrect: Ascorbic acid (vitamin C) is an antioxidant that facilitates iron absorption in the intestine by reducing it to Fe⁺². No effect on lipid metabolism is seen.  

Explanation

This patient with hypertriglyceridemia is prescribed an omega-3 fatty acid supplementation which reduces serum triglyceride (TG) levels. Eicosapentaenoic acid and docosahexaenoic acid are two common omega-3 fatty acids which decrease both fasting and postprandial TGs by reducing the hepatic VLDL production. The exact mechanism is not known but a number of theories had been proposed, which include:
 

•  Blockade of the enzyme responsible for TG synthesis in the liver (diacylglycerol acyltransferase or    phosphatidic acid phosphohydrolase) 
•  Increased plasma lipoprotein lipase activity 
•  Decreased lipogenesis in the liver 
•  Increase β oxidation of fatty acids 

It is typically indicated in patients with hypertriglyceridemia (TG > 150 mg/dL). It also helps with improving blood pressure and cardiac function. Common adverse effects include gastrointestinal (GI) upset, fish-like taste and a possible increase in low-density lipoprotein (LDL).  

19. A 45-year-old man comes to the office for routine follow-up. He was diagnosed with dyslipidemia 6 months ago on a fasting lipid panel. He has no active complaints at this visit. Past medical history is significant for hypertension and hypercholesterolemia. Current medications include lisinopril and atorvastatin. Family history is noncontributory. He smokes 1 pack of cigarettes daily, drinks 2-3 beers on weekends and does not use recreational drugs. Temperature is 37.0°C (98.6°F), pulse is 70/min, respirations are 16/min, and blood pressure is 130/85 mmHg. His BMI is 32.5 kg/m². Physical examination is unremarkable. A repeat fasting lipid panel was obtained during today’s visit. Comparison of the results is shown below. The physician counseled him about dietary modifications and decided to add another lipid-lowering drug to this patient’s medication regimen which inhibits bile acid reabsorption in the intestine. Which of the following is the most likely medication this patient was started on?  

Laboratory value	6 months ago	Today
Total cholesterol	370 mg/dL	301 mg/dL
Low-density lipoprotein (LDL)	250 mg/dL	175 mg/dL
High-density lipoprotein (HDL)	30 mg/dL	33 mg/dL
Triglycerides (TGs)	90 mg/dL	89 mg/dL

A. Niacin

❌ Incorrect:  Niacin, a lipid lowering drug, acts to prevent lipolysis by inhibiting hormone-sensitive lipase in adipose tissue. Its overall effect is a major increase in HDL and a decrease in LDL. It, however, does not affect intestinal absorption of bile acids.  

B. Cholestyramine

✅ Correct: See Main Explanation.  

C. Fenofibrate

❌ Incorrect: This drug is a fibrate that activates PPAR-α, causing the up-regulation of lipoprotein lipase levels to increase the clearance of serum triglycerides. This class of drugs also decreases very-low-density lipoproteins (VLDL) and induces HDL synthesis. It has no effect on bile acid reabsorption.  

D. Ezetimibe

❌ Incorrect: Ezetimibe inhibits cholesterol (not bile acid) absorption at the intestinal brush border, reducing liver cholesterol stores and decreasing biliary bile content.  

E. Alirocumab

❌ Incorrect: Alirocumab is a PCSK9 inhibitor that acts by inhibiting the degradation of LDL-R, facilitating the removal of LDL from the bloodstream. No effect on intestinal bile acid absorption is observed with the use of this drug.  

Explanation

This patient has hypercholesterolemia which is not significantly improving with mono-therapy with statins (atorvastatin). The new drug added to his regime is a bile acid resin, common examples of which include cholestyramine, colestipol and colesevelam.

Bile acid resins are large, positively-charged molecules that bind to the negatively-charged bile acid in the intestine, inhibiting reabsorption at the intestinal brush border. The liver compensates for the decreased bile acids by increasing the production of bile salts via its up-regulation of LDL receptor and an increase in the synthesis of hydroxymethylglutaryl (HMG) CoA reductase (which converts HMG CoA to mevalonate, a cholesterol precursor). Bile acid resins are not as effective as statins, which increase the LDL receptors and inhibit HMG-CoA, and that is why they are usually used in combination with statins. The LDL receptors also very slightly increase the uptake of VLDL. A minor increase in HDL levels is also observed. Its combination with a non-statin lipid-lowering agent (e.g., niacin, fibrates) may be useful in patients who are statin-intolerant and require intensive lipid-lowering therapy. Common adverse effects associated with bile acid resins include gastrointestinal upset (nausea, bloating and cramping) and impaired absorption of fat-soluble vitamins (A, D, E and K) and drugs (e.g., digoxin, warfarin).  

General principles of nutrition

2 Qs

1. Which of the following gastrointestinal secretory products are required for the absorption of vitamin B12 in the terminal ileum?  

A. Intrinsic factor  

✅ Correct: See Main Explanation.  

B. Pepsin

❌ Incorrect: Pepsin is secreted by the chief cells in the stomach and helps in protein digestion.  

C. Bicarbonate

❌ Incorrect: Bicarbonate is released by the mucosal cells (stomach, duodenum, salivary glands, pancreas) and Brunner glands (duodenum). It neutralizes acid and is not necessary in the absorption of vitamin B12 in the terminal ileum.  

D. Gastric acid  

❌ Incorrect: Gastric acid is secreted by the parietal cells in the stomach which helps decrease the gastric pH and aids in the digestion of proteins by activating digestive enzymes, which together break down the long chains of amino acids of proteins.  

E. Haptocorrin

❌ Incorrect: Free vitamin B12 in the stomach binds to haptocorrin (R proteins) secreted by salivary glands, which protects B12 from acid degradation. However, it does not help with absorption in the terminal ileum.  

Explanation

Gastric juice contains a protein synthesized by parietal cells called intrinsic factor. This binds to vitamin B12, also known as cobalamin, and is required for the eventual absorption of this vitamin more distally in the intestine in the terminal ileum. Intrinsic factor is specialized for its role by being relatively resistant to degradation by acid and proteolytic enzymes.   

Following ingestion of vitamin B12, the stomach acid releases B12 from its food carrier proteins. The free vitamin B12 binds to haptocorrin (R proteins) secreted by salivary glands, which protects B12 from acid degradation. Eventually, the pancreatic proteases degrade R proteins in the duodenum, where B12 binds to the intrinsic factor (secreted by gastric parietal cells) to protect it from pancreatic enzymes. The intrinsic factor-B12 complex is resistant to degradation from pancreatic enzymes. Finally, this complex binds to a specific receptor located in the apical membrane of epithelial cells lining the terminal ileum, where vitamin B12 is absorbed.  

2. A group of investigators are studying the absorption sites of various vitamins and minerals in the digestive tract. Which of the following is the site of absorption of vitamin B12?  

A. Stomach

❌ Incorrect: The stomach participates in virtually the digestive activities with the exception of ingestion and defecation. Although almost all absorption takes place in the small intestine, the stomach does absorb some nonpolar substances, such as alcohol and aspirin.  

B. Duodenum

❌ Incorrect: Iron is absorbed as ferrous in the duodenum.  

C. Jejunum

❌ Incorrect: The primary function of the jejunum is to absorb sugars, amino acids, and fatty acids.

D. Terminal ileum  

✅ Correct: See Main Explanation.  

E. Colon

❌ Incorrect: The large intestine (colon) is responsible for the reabsorption of water, sodium, potassium, and vitamin K. However, retrospective studies have shown that the large intestine also is responsible for the absorption of small amounts of calcium and magnesium.  

Explanation

Vitamin B12 (cobalamin) is absorbed in the terminal ileum along with bile salts, which requires an intrinsic factor. Iron is absorbed as ferrous Fe²⁺ in the duodenum and folate is also absorbed in the small bowel, primarily in the duodenum and jejunum. It is important to note that parietal cells located in the stomach secrete the intrinsic factor, which is a protein that binds to vitamin B12. B12 must be attached to the intrinsic factor for it to be efficiently absorbed, as receptors on the enterocytes in the terminal ileum of the small bowel only recognize the B12-IF complex. Furthermore, the intrinsic factor protects vitamin B12 from catabolism by intestinal bacteria.  

Metabolic disorders

24 Qs

1. A 50-year-old man comes to the clinic for evaluation of chronic back pain. He works as a librarian and notes that the pain is localized to his lower back and worsens after a long day of standing. The pain has not improved despite treatment with ibuprofen. Past medical history is significant for osteoarthritis of his right hip, for which he underwent a total hip replacement 2 years ago. Family history is noncontributory. Temperature is 37.0°C (98.6°F), pulse is 86/min, respirations are 16/min, and blood pressure is 125/85 mmHg. Ophthalmic examination reveals a bluish pigment deposition in the sclera. Dermatological examination reveals hyperpigmentation in the axillary and inguinal regions. Range of motion at the spine is limited. An x-ray of the erect spine is shown below:

Osmosis High-Yield Notes

Laboratory evaluation reveals elevated levels of homogentisic acid. The production of which of the following end products is likely to be inhibited, considering the most likely diagnosis?  

A. Fumarate

✅ Correct: See Main Explanation.

B. Succinyl CoA

❌ Incorrect: Maple syrup urine disease inhibits the breakdown of branched-chain amino acids to succinyl CoA. Maple syrup urine disease is characterized by severe neurological deficits and a sweet odor to the urine, attributed to a metabolite of leucine. The musculoskeletal and dermatological findings seen in this patient would be unlikely.

C. Melanin

❌ Incorrect: Tyrosine metabolism involves the formation of melanin from DOPA using the enzyme tyrosinase. A deficiency of homogentisate would lead to elevated levels of homogentisic acid and tyrosine levels, and in turn, melanin production would be unaffected.

D. Cysteine

❌ Incorrect: Homocysteine is converted to cysteine using the enzymes cystathionine synthase and the cofactor pyridoxal phosphate. Homocystinuria manifests as a result of deficiency of this enzyme and presents with marfanoid features, lens dislocation, intellectual disability and thrombotic complications. The absence of these findings makes this diagnosis unlikely.

E. Tyrosine

❌ Incorrect: Tyrosine metabolism involves the formation of melanin from DOPA using the enzyme tyrosinase. A deficiency of homogentisate would lead to elevated levels of homogentisic acid; tyrosine levels (and in turn, melanin) would be unaffected.

Explanation

This patient has presented with symptoms of arthritis, history of hip replacement before the age of 55, and hyperpigmentation. Laboratory investigations indicating elevated levels of homogentisic acid and an x-ray revealing intervertebral calcifications are consistent with a diagnosis of alkaptonuria.

Alkaptonuria is an autosomal recessive condition that results from a mutation in the homogentisate oxidase gene, leading to a deficiency of homogentisate oxidase. This enzyme is involved in tyrosine metabolism and converts homogentisate to maleyl acetoacetic acid and eventually to fumarate. Fumarate can then enter the citric acid cycle to produce ATP.

Homogentisic acid polymerises and deposits preferentially in connective tissue throughout the body (including cartilage). This condition is known as ochronosis. Patients are generally asymptomatic at birth and can remain undiagnosed well into the third decade of their lives. The urine of patients with alkaptonuria may darken upon prolonged exposure to air due to oxidation of homogentisic acid.

Most cases of alkaptonuria are detected later in life during an evaluation of arthritis. Ochronotic arthritis can involve hips, knees, and the lumbosacral spine and results in limitation of range of motion. Radiographs of the spine will classically reveal calcification in multiple intervertebral discs. Hyperpigmentation in the sclera, cartilage of the ears, and in the inguinal region may be seen as well and is indicative of homogentisic acid deposition. Complications that result from alkaptonuria include debilitating arthritis, cardiac valve involvement and kidney stones.

 

2. A 2-week-old female neonate is under evaluation in the neonatal ICU for an episode of a seizure. Since starting breastfeeding, she has been irritable, has been feeding poorly, and has had several episodes of vomiting. She was born at 41 weeks of gestation to a 25-year-old woman following an uncomplicated spontaneous vaginal delivery. She has been exclusively breastfed from birth. Temperature is 36.4°C (97.5°F), respiratory rate is 67/min, and pulse is 155/min. Physical examination reveals a somnolent and lethargic infant. Abdominal examination is unremarkable. Neurological examination reveals diffuse hypotonia and somnolence with response to painful stimulation. Laboratory evaluation reveals wide anion gap metabolic acidosis and elevated levels of propionyl CoA in urine. Which of the following vitamins are required for the function of the enzyme that is most likely deficient in this patient? 

A. Biotin

✅ Correct: See Main Explanation.

B. Thiamine

❌ Incorrect:  Thiamine acts as a cofactor for the enzyme branched-chain alpha keto acid dehydrogenase that is involved in the catabolism of branched-chain amino acids to alpha keto acids. A deficiency of branched-chain alpha keto acid dehydrogenase would result in maple syrup urine disease. Although it does cause significant neurological decline and seizures, it would not cause propionic aciduria.

C. Riboflavin

❌ Incorrect: Riboflavin is a cofactor for the enzyme succinate dehydrogenase in the Krebs cycle. A deficiency would not result in neurologic symptoms or propionic aciduria.

D. Ascorbic acid

❌ Incorrect: Ascorbic acid is involved in the hydroxylation of proline and lysine residues in collagen. Symptoms of ascorbic acid deficiency would include bleeding gums, petechiae and subperiosteal hemorrhages.

E. Niacin

❌ Incorrect: Niacin is a constituent of NAD and NADP. Niacin deficiency results in pellagra, characterized by the 3 D’s: dementia, dermatitis and diarrhea. Niacin does not act as a cofactor for enzymes involved in the degradation of odd-chain fatty acids, and its deficiency does not result in propionic aciduria.

Explanation

This patient is presenting with symptoms of poor feeding, irritability, seizures, muscular hypotonia and somnolence, along with increased excretion of propionic acid in urine. This presentation is suggestive of a diagnosis of organic acidemia, specifically due to a deficiency of propionyl CoA carboxylase.

The breakdown of odd-chain fatty acids and branched-chain amino acids (including valine, isoleucine and leucine) results in the formation of propionyl CoA. Propionyl CoA carboxylase converts propionyl CoA to methylmalonyl CoA using the cofactor biotin. Isomerization of methylmalonyl CoA to succinyl CoA is catalyzed by the cobalamin-dependent enzyme methylmalonyl mutase. The end product of this catabolic process results in the formation of succinyl CoA, which enters the Krebs cycle. Propionic acidemia is caused by the absence of the enzyme propionyl CoA carboxylase. As a result, propionic acid accumulates in the central nervous tissue, and excess propionic acid is excreted in urine.

Methylmalonic acidemia is caused by the complete or partial deficiency of the enzyme methylmalonyl CoA mutase and results in the accumulation and excretion of methylmalonic acid. Both these enzyme deficiencies can cause organic acidemia, leading to direct inhibition of gluconeogenesis. Hypoglycemia is a clinical consequence of acidemia and prompts increased fatty acid oxidation, causing ketosis. These biochemical changes cause a metabolic anion gap acidosis. Organic acids also inhibit the urea cycle resulting in elevated serum levels of ammonia.

 

3. A 27-year-old woman comes to her primary care physician for evaluation of bloating and flatulence. The patient’s symptoms have been ongoing for several months and tend to occur after she consumes ice cream or milk. The patient has not lost weight or noticed blood in her stool since symptom onset. Family history is notable for Crohn disease in the patient’s mother. Temperature is 37.0°C (98.6°F), blood pressure is 112/72 mmHg, pulse is 71/min, and respiratory rate is 14/min. Physical examination is unremarkable. Fecal occult blood test is negative. The patient is scheduled for a hydrogen breath test, which returns positive. Which of the following best describes the underlying cause of this patient’s symptoms?  

A. Age-related downregulation of lactase synthesis

✅ Correct: See Main Explanation.

B. Inflammation of the terminal ileum

❌ Incorrect: Crohn disease is an autoimmune condition that typically affects the terminal ileum. The condition can manifest with abdominal pain, bloody diarrhea, and weight loss. In contrast, this patient has not lost weight and has a negative fecal occult blood test. Furthermore, the positive hydrogen breath test makes another diagnosis more likely.

C. Consumption of rod-shaped Gram-negative bacteria found in contaminated food

❌ Incorrect: There are several common bacteria which can cause diarrheal illnesses after consumption of contaminated food, such as Salmonella. However, this afebrile patient has chronic symptoms triggered by consuming lactose-containing foods and has a positive hydrogen breath test, which is more concerning for lactose intolerance.

D. Immune-mediated intestinal damage secondary to gluten hypersensitivity

❌ Incorrect: Celiac disease is characterized by autoimmune damage to the intestines following consumption of foods containing gluten (e.g., bread, cereals). The condition can manifest with diarrhea, weight loss, bloating, and rashes. However, it would not result in a positive hydrogen breath test. 

E. Infection by comma-shaped Gram negative bacteria

❌ Incorrect: Infection by Helicobacter pylori can lead to peptic ulcer disease, which may manifest with abdominal pain and bloating after meals. However, this patient has symptoms triggered by consuming lactose-containing foods and a positive hydrogen breath test, which is more consistent with the presentation of lactose intolerance.

Explanation

This patient presents with bloating and flatulence after consuming dairy products and has a positive hydrogen breath test; these findings are suggestive of lactose intolerance.  

Lactose intolerance is divided into congenital, primary, and secondary forms.

•  Congenital lactose intolerance is an autosomal recessive condition caused by mutations in the gene encoding for lactase. This form manifests with symptoms at birth.  
•  Primary lactose intolerance occurs when expression of the gene coding for lactase is down-regulated after childhood. This condition more often affects individuals of Asian, African, or Native American descent.  
• Secondary lactose intolerance develops due to an underlying intestinal disorder (e.g., gastroenteritis, autoimmune diseases) that damage the small intestine mucosa.

Symptoms of lactose intolerance occur after ingestion of dairy products and include bloating, abdominal cramping, flatulence, and non-bloody diarrhea.   

To diagnose lactose intolerance, a hydrogen breath test can be performed after the patient drinks a lactose solution. In patients with lactose intolerance, hydrogen is produced as a result of bacterial fermentation of the undigested lactose. The hydrogen is reabsorbed into the blood and subsequently exhaled via the lungs, resulting in a positive hydrogen breath test. In addition, a stool test can detect the lactic acid that is produced from the fermentation of non-absorbed lactose by intestinal bacteria.  

Treatment consists of eliminating lactose from the diet. Oral lactase supplements can also be taken when consuming dairy products, which aids in small intestinal digestion of lactose.  

4. A 6-month-old male infant is brought to the pediatrician for evaluation of poor weight gain. The patient was born at 38-weeks gestational age via an uncomplicated vaginal delivery. According to his parents, the patient has had poor feeding, a weak cry, and appears more frail than other children of a similar age. The patient is at the 15th percentile for length and 5th percentile for weight. Temperature is 37.0°C (98.6°F), blood pressure is 95/50 mmHg, and pulse is 102/min. Widespread muscle hypotonia is noted on physical examination. Laboratory testing reveals elevated serum lactate and alanine levels. Further genetic work-up reveals a mutation in the PDHA1 gene. Which of the following best describes the normal function of the enzyme likely deficient in this patient’s condition?  

A. Conversion of glucose to glucose-6-phosphate

❌ Incorrect: Hexokinase and glucokinase are involved in converting glucose to glucose-6-phosphate. A deficiency in either of these enzymes would result in elevated serum glucose levels, as opposed to lactate and alanine levels.  

B. Reduction of NADP+ plus to NADPH

❌ Incorrect: Glucose-6-phosphate dehydrogenase (G6PD) is responsible for converting NADP+ to NADPH. G6PD deficiency predisposes patients to hemolytic anemia when exposed to oxidative stress. The condition would not manifest with muscle hypotonia, poor weight gain, or a weak cry.

C. Phosphorylation of fructose to fructose-1-phosphate

❌ Incorrect: Fructokinase converts fructose to fructose-1-phosphate. A defect in this enzyme would result in essential fructosuria. The condition is largely asymptomatic, and laboratory testing would instead demonstrate elevated serum and urine fructose levels. 

D. Conversion of pyruvate to acetyl-CoA

✅ Correct: See Main Explanation.

E. Breakdown of fructose-1-phosphate to glyceraldehyde 

❌ Incorrect: Aldolase B is responsible for breaking down fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. Deficiency of this enzyme would cause hereditary fructose intolerance, which manifests with cirrhosis, jaundice, and vomiting. Symptoms generally begin only after sources of fructose (e.g., fruits, juices) are introduced into a child’s diet at around 6 months of age.   

Explanation

This patient is presenting with hypotonia, a weak cry, and poor weight gain. Laboratory testing demonstrates elevated alanine and lactate levels along with a PDHA1 gene mutation. In combination, these findings are concerning for pyruvate dehydrogenase complex (PDC) deficiency.   

PDC deficiency is an X-linked recessive condition caused by mutations in the PDHA1 gene. PDC utilizes the cofactors thiamine, lipoic acid, CoA, FAD, and NAD+ to convert pyruvate into acetyl-CoA, which enters the Krebs cycle to produce ATP. In PDC deficiency, acetyl-CoA production is impaired, and there is reduced ATP synthesis. Hence, the condition primarily affects cells with high energy requirements, such as neurons and myocytes. At the same time, pyruvate accumulates and is converted into lactate and alanine.

Symptoms of PDC deficiency typically begin during infancy and include lethargy, hypotonia, and poor feeding. In addition, PDC deficiency may lead to developmental delay, intellectual disability, and seizures.      

Laboratory testing will demonstrate elevated lactate and alanine levels. Treatment consists of adopting a ketogenic diet, which is a diet low in carbohydrates and high in fat and ketogenic amino acids. This diet results in the generation of ketone bodies, which can be used as an alternative energy source by body tissues.  

5. A 24-hour-old male neonate undergoes neonatal screening. He was born at 40 weeks gestation to a 32-year-old woman with Graves disease following an uncomplicated spontaneous vaginal delivery. Temperature is 36.4°C (97.5°F). Head circumference is significant for microcephaly.  Motor examination is normal. Abdominal examination is unremarkable. Laboratory evaluation reveals a deficiency of phenylalanine hydroxylase. Which of the following metabolites are likely to be decreased in this patient? 

A. Dopamine

✅ Correct: See Main Explanation.

B. Phenylalanine

❌ Incorrect: In phenylketonuria, a deficiency of phenylalanine hydroxylase inhibits the conversion of phenylalanine to tyrosine and instead leads to accumulation of phenylalanine.

C. Melatonin

❌ Incorrect: Phenylalanine hydroxylase deficiency leads to a deficiency of melanin and neurotransmitters including dopamine, norepinephrine, and epinephrine. Melatonin is instead formed from serotonin as an end-product of tryptophan metabolism.

D. Serotonin

❌ Incorrect: Phenylalanine hydroxylase deficiency leads to a deficiency of melanin and neurotransmitters including dopamine, norepinephrine, and epinephrine. Serotonin is formed through hydroxylation and decarboxylation of the amino acid tryptophan. Tetrahydrobiopterin (BH4) deficiency, a more severe form of PKU, can cause decreased serotonin, since the cofactor BH4 is necessary for the metabolism of tryptophan.

E. Creatine 

❌ Incorrect: Arginine metabolism results in the formation of creatinine. Urea cycle disorders result from enzyme deficiencies that inhibit the formation of arginine and downstream disposal of nitrogenous wastes. As a result, arginine is deficient in these patients. However, urea cycle disorders do not result from a deficiency of phenylalanine hydroxylase.

Explanation

Newborn screening in the United States includes detection of inborn errors of metabolism including phenylketonuria (PKU).  Screening tests are initiated 2-3 days after birth. Screening for PKU is imperative in all neonates, as delayed diagnosis can result in irreversible neurological deterioration in untreated patients.

Phenylketonuria is an autosomal recessive condition that exists in 2 forms: classic PKU and malignant PKU. Diagnosis involves detection of elevated phenylalanine levels and molecular testing in patients with classic PKU. In malignant PKU, low levels of tetrahydrobiopterin (BH4)  are detected in blood or urine samples.

Classic PKU is caused by a deficiency of phenylalanine hydroxylase and is treated with implementing dietary restriction of phenylalanine. Mothers of infants with PKU are encouraged to continue breastfeeding with the addition of alternative feeding regimens with phenylalanine-free formula feeds. Quantity of breastmilk and frequency of feeds should be under the supervision of a trained metabolic dietician. Restricting the mother’s phenylalanine intake does not affect the content of phenylalanine in breast milk. Patients with malignant PKU are advised to take additional supplementation with tetrahydrobiopterin and neurotransmitter supplementation in the form of L-DOPA and carbidopa. Options for pharmacological therapy include an agent known as sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase. Early implementation, continuation of therapy, and dietary restrictions throughout life have been found to improve neurological outcomes. 

6. A 5-month-old male infant is brought to the pediatrician by his parents to establish care. The patient was delivered at home in Nigeria, and his family recently moved to the United States. Today is his first time visiting a physician. His parent states, “I am worried about his vision. He does not look at us when we call his name.” The patient’s parent states that the patient is only breastfed. The patient has had no episodes of diarrhea or increased flatulence. Family history is noncontributory. Temperature is 37.5°C (99.5°F), blood pressure is 99/56 mmHg, and pulse is 108/min. Fundoscopic examination reveals clouding of the lens bilaterally. No hepatomegaly or jaundice is present. Urine dipstick test is negative for glucose. Additional urine testing is positive for reducing substances. Which of the following best describes the normal function of the enzyme likely deficient in this patient’s condition?  

A. Conversion of galactose to galactose-1-phosphate

✅ Correct: See Main Explanation.

B. Phosphorylation of fructose to fructose-1-phosphate

❌ Incorrect: Fructokinase converts fructose to fructose-1-phosphate. Deficiency of this enzyme would result in essential fructosuria. The condition is largely asymptomatic and would not lead to the formation of infantile cataracts.

C. Conversion of galactose-1-phosphate to glucose-1-phosphate

❌ Incorrect: Galactose-1-phosphate uridyltransferase converts galactose-1-phosphate into glucose-1-phosphate. A defect in this enzyme would result in classic galactosemia, which can manifest with infantile cataracts. However, patients would also have jaundice and hepatomegaly, which are absent in this patient.  

D. Breakdown of fructose-1-phosphate to glyceraldehyde 

❌ Incorrect: Aldolase B is responsible for breaking down fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate. Deficiency of this enzyme would cause hereditary fructose intolerance, which manifests with cirrhosis, jaundice, and vomiting. It would not typically present with infantile cataracts. Additionally, symptoms generally begin only after sources of fructose (e.g., fruits, juices) are introduced into a child’s diet at around 6 months of age. 

E. Breakdown of lactose into glucose and galactose

❌ Incorrect: Lactase is involved in degrading the disaccharide lactose into the monomers glucose and galactose. Lactase deficiency classically presents with bloating, flatulence, and diarrhea after consuming dairy products (e.g., milk, cheese).  

Explanation

This patient is presenting with infantile cataracts and urine testing positive for reducing substances. These findings suggest a deficiency of the enzyme galactokinase, which helps convert galactose to galactose-1-phosphate.   

Galactokinase deficiency is inherited in an autosomal recessive pattern. A deficiency in this enzyme causes galactose to instead be converted into galactitol by aldose reductase. Galactitol mainly accumulates in the lens of the eye and attracts water, which ultimately causes the lens fibers to swell and rupture. This process leads to the formation of infantile cataracts. Cataracts can present as a failure to track objects or develop a social smile, which is when one smiles after seeing another person’s smile.  

Another similar but more severe condition is classic galactosemia, which is due to a deficiency of galactose-1-phosphate uridyltransferase. Classic galactosemia is also inherited in an autosomal recessive pattern. Classic galactosemia typically presents in the first few days of life after initiation of galactose-containing human breast milk or cow's milk-based feedings. It leads to accumulation of not only galactitol, which causes cataracts, but also galactose-1-phosphate, which accumulates in the brain and liver. As a result, patients have additional signs of hypoglycemia (e.g., lethargy, hypotonia), hepatomegaly, jaundice, and intellectual disability. Patients with classic galactosemia are at increased risk of sepsis, particularly by Escheria coli infection. Furthermore, patients may have systemic symptoms such as lethargy and failure to thrive.  

7. A 5-week-old female infant is brought to the clinic for evaluation of failure to thrive. Her symptoms include irritability and poor feeding. She was born at 39 weeks of gestation to a 29-year-old woman with gestational hypertension following an uncomplicated spontaneous vaginal delivery. She has been exclusively breastfed from birth until 2 days ago, when she began having difficulties feeding. Temperature is 37.0°C (98.6°F), respiratory rate is 67/min, and pulse is 155/min. Physical examination reveals dry tongue and decreased skin turgor. Abdominal examination is unremarkable. Neurological examination reveals diffuse hypotonia. She responds to painful stimulation. Further evaluation reveals propionic aciduria. Which of the following laboratory findings would most likely be present in this patient, considering the most likely diagnosis? 

A. Hypoglycemia 

✅ Correct: See Main Explanation.

B. Hyperglycemia

❌ Incorrect: Hypoglycemia is caused by organic acidemia as a result of accelerated metabolism and direct inhibition of gluconeogenesis by organic acid accumulations. Diabetic ketoacidosis is on the differential diagnosis for a metabolic acidosis; however, detection of propionic aciduria indicates a diagnosis of organic acidemia.

C. Elevated methylmalonic acid in urine 

❌ Incorrect: Detection of propionic aciduria would indicate a deficiency of propionyl CoA carboxylase. Downstream processes, including the formation of methylmalonyl CoA, would be inhibited and thus would not result in an elevated level of methylmalonic acid (MMA) in urine. Methylmalonic acidemia results from a deficiency of methylmalonyl CoA and would result in elevated levels of methylmalonyl CoA in urine.

D. Normal anion gap metabolic acidosis 

❌ Incorrect: Diarrhea and renal tubular acidosis are the most common causes of normal anion gap metabolic acidosis. Although this infant has exhibited signs of dehydration, the absence of a history of loose stools and the presence of propionic aciduria suggests an alternative diagnosis.

E. Normal serum ammonia levels

❌ Incorrect: Hyperammonemia is typically seen in cases of organic aciduria, since propionic acid and methylmalonic acid inhibit the function of N-acetylglutamate synthesis, which is necessary for ammonia metabolism.

Explanation

This infant is presenting with symptoms of failure to thrive, poor feeding, and neurologic deterioration with propionic acidemia. This presentation is consistent with a diagnosis of organic acidemia caused by a propionyl CoA carboxylase deficiency.

The breakdown of odd-chain fatty acids and branched-chain amino acids (including valine, isoleucine and leucine) results in the formation of propionyl CoA. Propionyl CoA carboxylase converts propionyl CoA to methylmalonyl CoA using the cofactor biotin. Isomerisation of methylmalonyl CoA to succinyl CoA is catalyzed by the cobalamin-dependent enzyme methylmalonyl mutase. The end product of this catabolic process results in the formation of succinyl CoA, which enters the Krebs cycle. Propionic acidemia is caused by the absence of the enzyme propionyl CoA carboxylase. As a result, propionic acid accumulates in the central nervous tissue, and excess propionic acid is excreted in urine.

Symptoms are caused by accumulation of organic acids proximal to the metabolic block. Clinical symptoms of propionyl CoA include neurological deterioration, failure to thrive, poor feeding, vomiting, seizures, diffuse muscle hypotonia, tachypnea (compensatory respiratory alkalosis) and somnolence. Most patients present within the first several weeks of life, although delayed presentations have been observed.

Elevated levels of propionic acid in urine confirms the diagnosis. Other laboratory investigations that are indicative of a diagnosis of organic acidemia include hypoglycemia (inhibition of gluconeogenesis by organic acidemia), wide anion gap metabolic acidosis (ketosis due to augmented fatty acid oxidation) and hyperammonemia (inhibition of urea cycle enzymes). A diagnosis of organic acidemia involves treatment that aims at correction of metabolic decompensation, protein restriction, fluid replacement and dietary restrictions. Long-term management of organic acidemia involves initiation of a low-protein diet with supplementation of amino acids excluding isoleucine, valine and leucine.  

8. An 8-month-old male infant is brought to the physician for evaluation of failure to thrive. Two months ago, the patient began losing weight and has had progressive muscle weakness. The patient has also had several seizures. The patient’s diet currently consists of breast milk as well as pureed apples and juice, which were added to the patient’s diet at around 6-months of age. Temperature is 37.6°C (99.7°F), blood pressure is 101/50 mmHg, and pulse is 103/min. The patient is currently at the 15th percentile for weight whereas at the patient’s 6-month check-up, the patient was at the 45th percentile. Physical examination is notable for jaundice and hepatomegaly. Laboratory testing is shown below. Urine testing is positive for non-glucose reducing substances. Which of the following sets of additional laboratory findings is most likely present in this patient?  

Laboratory Value	Result
Aspartate aminotransferase (AST)	87 U/L
Alanine aminotransferase (ALT)	93U/L
Bilirubin, Total	2.0 mg/dL
Blood urea nitrogen (BUN)	32 mg/dL
Creatinine	1.7 mg/dL

A.

Serum Glucose	Intracellular Fructose-1-Phosphate	Intracellular Phosphate
Unchanged	Decreased	Unchanged

❌ Incorrect: This set of findings would be expected in essential fructosuria, which is due to a defect in fructokinase. The condition prevents fructose from being converted into fructose-1-phosphate. However, essential fructosuria is asymptomatic and would not explain this patient’s symptoms.

B.

Serum Glucose	Intracellular Fructose-1-Phosphate	Intracellular Phosphate
Increased	Increased	Increased

❌ Incorrect: This patient has jaundice, hepatomegaly, and laboratory testing demonstrating kidney injury. These symptoms started around the same time he began consuming foods that contain fructose (e.g., fruits, juice). As a result, the patient likely has hereditary fructose intolerance, which manifests with hypoglycemia and reduced intracellular phosphate.

C.

Serum Glucose	Intracellular Fructose-1-Phosphate	Intracellular Phosphate
Increased	Decreased	Decreased

❌ Incorrect: This patient likely has hereditary fructose intolerance. The condition is due to a deficiency of aldolase B, which converts fructose-1-phosphate to dihydroxyacetone phosphate and glyceraldehyde. The condition presents with increased, not decreased, intracellular fructose-1-phosphate levels.

D.

Serum Glucose	Intracellular Fructose-1-Phosphate	Intracellular Phosphate
Decreased	Increased	Decreased

✅ Correct: See Main Explanation.

E.

Serum Glucose	Intracellular Fructose-1-Phosphate	Intracellular Phosphate
Decreased	Increased	Increased

❌ Incorrect: This patient has symptoms consistent with hereditary fructose intolerance. In this condition, fructose-1-phosphate accumulates within cells and acts as a phosphate sink. As a result, intracellular free phosphate levels decrease, and ATP synthesis is impaired. 

Explanation

This patient has weight loss, jaundice, hepatomegaly, and a history of seizures. The symptoms started around the same time the patient’s diet was supplemented with foods other than breast milk. Together, these findings are concerning for hereditary fructose intolerance.   

Hereditary fructose intolerance is an autosomal recessive condition characterized by a deficiency of aldolase B. The condition results in the build-up of toxic fructose-1-phosphate. Hence, infants can develop serious problems once they consume fructose-containing foods (e.g., fruit, honey, juice), typically after 6 months of age. Initial symptoms include lethargy, nausea, and vomiting. In addition, hereditary fructose intolerance may cause renal damage, hepatomegaly, and jaundice. Patients can also have severe hypoglycemia, which occurs because fructose-1-phosphate overaccumulation impairs gluconeogenesis and glycogenolysis. Furthermore, fructose-1-phosphate acts as a phosphate sink that decreases intracellular phosphate levels and hinders ATP synthesis. The depletion of intracellular phosphate inhibits phosphorylase A, leading to the cessation of glycogenolysis.  

A similar but milder condition is essential fructosuria, which is due to a mutation in fructokinase and is also inherited in an autosomal recessive pattern. The condition results in impaired conversion of fructose to fructose-1-phosphate. Fructose itself is not toxic and simply gets excreted via urine. As a result, essential fructosuria is asymptomatic.   

9. A 1-month-old infant is brought to the emergency department because of failure to thrive and recurrent vomiting. The patient was born full-term at home via an uncomplicated vaginal delivery. Shortly after birth, the patient began experiencing nausea and vomiting after feedings. The patient was at the 50th percentile for weight at birth. At today’s visit, the patient is at the 25th percentile. Temperature is 36.9°C (98.4°F), pulse is 108/min, blood pressure is 77/40 mmHg, and respiratory rate is 56/min. Physical examination reveals jaundice and hepatomegaly. Fundoscopic examination reveals bilateral clouding of the lens. Urine dipstick is negative for glucose. Additional testing reveals the presence of reducing substances in the urine. Which of the following is the most likely diagnosis?  

A. Von Gierke disease

❌ Incorrect: Elevated serum uric acid levels can be seen in Von Gierke disease due to deficiency of glucose-6-phosphatase enzyme, the first enzyme in glycogen breakdown. The condition is characterized by severe fasting hypoglycemia, impaired gluconeogenesis and glycogenolysis, as well as hepatomegaly. However, the presence of cataracts in this case favors another diagnosis.

B. Pyruvate dehydrogenase complex deficiency

❌ Incorrect: Patients with pyruvate dehydrogenase complex deficiency present with hypotonia, poor feeding, seizures, and developmental delays. However, the condition would not cause reducing substances to be present in the urine or infantile cataracts.

C. Small bowel obstruction

❌ Incorrect: Patients with a bowel obstruction can also present with nausea and vomiting, but the condition would not account for the patient’s bilateral cataracts.

D. Classic galactosemia

✅ Correct: See Main Explanation.

E. Pyloric stenosis

❌ Incorrect: Patients with pyloric stenosis can present with nausea and vomiting after feeding. However, patients with pyloric stenosis do not typically have hepatomegaly or cataracts. This patient’s presentation is instead more suggestive of classic galactosemia. 

Explanation

This patient is presenting with vomiting, hepatomegaly, jaundice, and infantile cataracts. Urine testing reveals the presence of non-glucose reducing substances. In combination, these findings are concerning for classic galactosemia.   

Diagnosis of classic galactosemia and galactokinase deficiency, both of which are disorders affecting galactose metabolism, is based on blood tests showing elevated blood galactose levels. Some of the excess galactose is excreted in the urine, resulting in galactosuria. Of note, a urine dipstick detects only glucose and, hence, will be negative even in patients with galactosuria. However, there are nonspecific urine tests that can detect reducing sugars such as galactose, fructose, or lactose. In other words, if a patient has a reducing substance other than glucose in the urine, then urine dipstick will be negative, but the reducing test will be positive.  

Diagnosis can be confirmed with blood tests demonstrating reduced enzymatic activity of galactose-1-phosphate uridyltransferase (in cases of classic galactosemia) or galactokinase (in cases of galactokinase deficiency). Screening after birth is mandatory in most parts of the United States, which allows early diagnosis and treatment; however, affected infants may become symptomatic before the screening results become available (approximately 10 to 14 days after sample collection), and thus, clinicians must consider the diagnosis in infants with characteristic signs and symptoms. Additionally, if delivery occurs at home, patients may go untested. Both conditions are treated with a galactose-free diet.  

10. An 8-month-old male infant is brought to the emergency department for evaluation of failure to thrive. One month ago, the patient began vomiting after feedings and experienced weight loss. The patient has also had several visits to the pediatric emergency department following seizure episodes despite having no fever or signs of infection. The patient has appeared more tired than usual and is no longer interested in watching cartoons or playing with his parents. The patient’s diet consisted of breast milk until the patient reached 7 months of age. Afterwards, small servings of pureed fruits, ground meat, and juice were added to the patient’s diet. The patient is currently at the 25th percentile for weight, whereas at his 4 month check-up, he was at the 45th percentile. Temperature is 37.0°C (98.6°F), blood pressure is 91/49 mmHg, pulse is 110/min, and respiratory rate is 44/min. Physical examination is notable for hepatomegaly and jaundice of the skin. Urine dipstick is negative for glucose. Which of the following findings is most likely to be found on further evaluation?  

A. Elevated serum uric acid levels

❌ Incorrect: Patients with Lesch-Nyhan syndrome can present with elevated uric acid levels secondary to impaired purine salvage. Clinically, the condition manifests with aggressive behavior, intellectual disability, and gout. In contrast, the patient in this vignette has failure to thrive, hepatomegaly, and jaundice after the patient started consuming complementary foods, which is more concerning for a fructose metabolism disorder.

B. Dilated loops of bowel on CT 

❌ Incorrect: Patients with bowel obstruction will have dilated loops of bowel that can be visualized on a CT scan. Although a bowel obstruction can present with vomiting, it would not account for this patient’s seizures or hepatomegaly.

C. Decreased pyruvate dehydrogenase complex enzyme levels in leukocytes

❌ Incorrect: Pyruvate dehydrogenase complex (PDC) deficiency is a X-linked recessive disorder characterized by hypotonia, poor feeding, developmental and intellectual delay, and seizures. Laboratory testing will demonstrate elevated lactate and alanine levels. However, PDC deficiency would not account for why the patient was asymptomatic for the first 7 months of life.

D. Thickened pyloric muscle on ultrasonography

❌ Incorrect: Patients with pyloric stenosis can present with nausea and vomiting after feeding. Diagnosis involves performing an ultrasound of the abdomen and determining the thickness of the pyloric muscle causing gastric outlet obstruction. However, patients with pyloric stenosis do not typically have hepatomegaly or cataracts. This patient’s presentation is instead more suggestive of hereditary fructose intolerance. 

E. Presence of urinary reducing substances 

✅ Correct: See Main Explanation.

Explanation

This patient experienced weight loss, fatigue, and seizure around the same time fructose-containing foods (e.g., fruits, juice) were introduced into the patient’s diet. Physical examination revealed hepatomegaly and jaundice. In combination, these findings are concerning for hereditary fructose intolerance.  

The first step in the work-up of hereditary fructose intolerance is to check the urine for reducing substances. The diagnosis can then be confirmed by performing 1) genetic testing or 2) liver biopsy and measuring aldolase B levels within the sample. Genetic testing is preferred since it has a higher sensitivity and is less invasive than liver biopsy. Treatment involves lifelong exclusion of fructose and sucrose from the diet.  

A similar but far milder condition is essential fructosuria, which is due to a deficiency of fructokinase. Work-up similarly involves first testing the urine for reducing substances, followed by measuring fructokinase activity in blood samples. Since the condition is asymptomatic, no treatment or dietary restrictions are required.    

11. A 6-day-old infant is brought to a local emergency department after being found unresponsive by the patient’s parents. The neonate is promptly admitted to the NICU and is given D10 normal saline and a bicarbonate infusion. Overnight, the patient develops generalized seizure activity. An MRI performed the following day reveals hypoxic-ischemic encephalopathy. Initial laboratory findings and newborn screening results are demonstrated below. Which of the following is the most likely diagnosis?  

A. Phenylketonuria

❌ Incorrect: Phenylketonuria (PKU) may also present with seizures; however, this condition does not demonstrate high octanoylcarnitine levels on newborn screening. Instead, PKU is often diagnosed by detecting a high ratio of phenylalanine to tyrosine.  

B. Hartnup disease

❌ Incorrect: Hartnup disease presents with a distinctive rash and neurologic symptoms. This condition does not demonstrate high octanoylcarnitine levels on newborn screening.  

C. Adenosine deaminase deficiency

❌ Incorrect: Adenosine deaminase deficiency presents with recurrent infections due to immunosuppression. This condition does not demonstrate high octanoylcarnitine levels on newborn screening.  

D. Medium-chain acetyl-CoA dehydrogenase deficiency

✅ Correct: See Main Explanation.  

E. Primary carnitine deficiency

❌ Incorrect: Primary carnitine deficiency presents with non-ketotic hypoglycemia, transaminitis, and dilated cardiomyopathy. This condition does not demonstrate high octanoylcarnitine levels on newborn screening.  

Explanation

This case describes a neonate presenting with metabolic acidosis and hypoglycemia–of which the differential diagnosis is broad. Notably, the patient’s newborn screening test shows an elevated C8, or octanoylcarnitine level, suggesting an inborn error of metabolism. Specifically, the accumulation of octanoylcarnitine demonstrates this patient’s inability to catabolize fatty acids between 6 and 12 carbon in length during beta-oxidation, consistent with the disease medium-chain acetyl-CoA dehydrogenase (MCAD) deficiency.

MCAD deficiency is caused by a mutation of the ACADM gene and is the most common inborn error of metabolism. Treatment of MCAD deficiency is twofold: frequent feeding to avoid fasting states and subsequent fatty acid catabolism, in addition to prompt administration of dextrose if symptoms of a metabolic crisis ensue.
 

 

12. A 3-day-old female neonate is under evaluation in the neonatal ICU following 2 episodes of generalized seizures. Since starting breastfeeding, the patient has been irritable and feeding poorly, and she has had multiple episodes of vomiting. She was born at 38 weeks gestation to a 22-year-old woman following an uncomplicated spontaneous vaginal delivery. She has been exclusively breastfed from birth. Temperature is 36.4°C (97.5°F), pulse is 145/min, and respiratory rate is 67/min. Physical examination reveals a somnolent and lethargic neonate. Abdominal examination is unremarkable. Neurological examination reveals diffuse hypotonia and somnolence with response to painful stimulation. Sepsis workup is negative. Laboratory evaluation reveals orotic aciduria. Accumulation of which of the following is responsible for this patient’s symptoms? 

A. Ammonia 

✅ Correct: See Main Explanation.

B. Leucine

❌ Incorrect: Accumulation of branched chain amino acids such as leucine, isoleucine and valine is detected in maple syrup urine disease, an inborn error of metabolism. Although it can cause feeding difficulties and significant neurological decline, it does not result in orotic aciduria.

C. Phenylalanine 

❌ Incorrect: Phenylalanine hydroxylase deficiency in phenylketonuria (PKU) causes accumulations of phenylalanine in the central nervous system. It presents as neurological deterioration along with hypopigmentation. It does not, however, result in orotic aciduria.

D. Valine

❌ Incorrect: Maple syrup urine disease would cause elevated levels of valine in urine due to impaired branched amino acid metabolism. Although it can cause feeding difficulties and significant neurological decline, it does not result in orotic aciduria.

E. Homogentisic acid 

❌ Incorrect: Alkaptonuria is caused by a deficiency of homogentisate oxidase and results in accumulation of homogentisic acid. The clinical presentation of this disease is characterized by the progressively debilitating arthritis. Neurological decline is not a typical presentation.

Explanation

Symptoms of encephalopathy, including vomiting, poor feeding, tachypnea, irritability and somnolence, in this neonate in the presence of orotic aciduria strongly suggests a diagnosis of ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder. A deficiency of OTC results in an accumulation of carbamoyl phosphate, which stimulates pyrimidine synthesis and in turn orotic aciduria. Hyperammonemia is responsible for the symptoms of encephalopathy.

Ammonia is the product of protein catabolism derived from dietary sources or skeletal tissue. It is a toxic metabolic product and requires conversion to its soluble, nontoxic form urea for its excretion, a process that occurs in the liver. Physiologically, ammonia formed from the catabolism of amino acids is transported to the liver for detoxification through specific mechanisms, and these mechanisms vary depending on the cell that generates ammonia.

Hyperammonemia can stem from acquired or inherited defects. A common acquired cause of hyperammonemia is chronic liver disease, due to deficient ammonia clearance by the diseased liver. Inherited causes include urea cycle defects, which result from enzyme deficiencies that directly impair ammonia clearance, and organic acidemias, in which accumulation of organic acids secondarily inhibits the urea cycle and leads to hyperammonemia. Neonates with congenital urea cycle disorders become symptomatic after feeding has started because human milk (or infant formula) provides an initial protein load. The typical clinical presentation of hyperammonemia includes somnolence, vomiting, seizures and asterixis in adults (flapping tremors).

Physiologically, ammonia is taken up by cerebral tissue and combines with glutamate to form glutamine in astrocytes. Glutamate is then released to the synapse for excitatory neurotransmission. Hyperammonemia increases glutamine production and, in turn, astrocyte swelling and impaired glutamine release to the neurons. The pathogenesis of the clinical features seen in hyperammonemia is caused by subsequent inhibition of excitatory neurotransmission.

13. A 22-year-old primigravida at 26 weeks gestation comes to the office for routine prenatal care. The patient reports good fetal movement and has no complaints. She has been inconsistent with prenatal care following her initial visit at 12 weeks. An ultrasound for gestational dating at the time was consistent with her last menstrual period. The mother’s blood group is B-negative while the father’s is O-negative. The patient’s past medical history is significant for phenylketonuria. Prior to conceiving, she followed a phenylalanine-restricted diet. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 20/min, and blood pressure is 105/75 mmHg. An ultrasound reveals a fetus at 26 weeks with an estimated weight <10 percentile for gestational age. Laboratory evaluation reveals elevated phenylalanine levels. Which of the following pathologies is the fetus likely to suffer from based on the maternal history? 

A. Congenital heart defects 

✅ Correct: See Main Explanation.

B. Macrocephaly

❌ Incorrect: Congenital infection with toxoplasmosis classically manifests with hydrocephalus, chorioretinitis and intracranial calcifications. Toxoplasma infection is suspected when the mother has been afflicted with an influenza-like clinical illness during pregnancy. An elevated serum level of phenylalanine is likely to cause microcephaly, not macrocephaly.

C. Absent red reflex bilaterally

❌ Incorrect: Congenital infection with rubella is likely to cause bilateral sensorineural hearing loss, congenital heart defects and leukocoria (white pupillary reflex) due to cataracts. An elevated serum level of phenylalanine is unlikely to cause ophthalmic manifestations in the neonate.

D. Hepatosplenomegaly

❌ Incorrect: Congenital infections with rubella and cytomegalovirus can cause generalized symptoms which include hepatosplenomegaly and a “blueberry-muffin” rash, indicative of extramedullary hematopoiesis. Hepatosplenomegaly is not expected in phenylalanine embryopathy.

E. Hydrops fetalis

❌ Incorrect: Congenital parvovirus infection can result in severe fetal anemia and hydrops fetalis. Rh incompatibility is also a cause of hydrops fetalis. Although this patient is Rh-negative, her partner is Rh-negative as well, eliminating the risk of Rh incompatibility.

Explanation

This patient has a history of phenylketonuria (PKU) and evidence of intrauterine growth restriction. This presentation is suggestive of a diagnosis of phenylalanine embryopathy.

Phenylalanine embryopathy results from elevated serum phenylalanine concentrations in pregnant women with PKU. Pregnancy complications such as spontaneous abortion, intrauterine fetal death, preterm delivery, fetal manifestations (intrauterine growth restriction) and neonatal sequelae are expected with elevated phenylalanine levels in the mother. Neonatal complications include microcephaly, intellectual deterioration and congenital heart defects including coarctation of the aorta and hypoplastic left heart syndrome. The risk of developing embryological abnormalities correlates to the maternal blood phenylalanine levels.

Early detection and achieving lowered phenylalanine levels ideally before conception or by 10 weeks of gestation improves outcomes in the fetus. Metabolic control should be achieved as soon as possible in mothers who conceived with elevated phenylalanine levels. Monitoring of serum phenylalanine levels is advised twice weekly. 

14. A 7-year-old girl is brought to the physician for a routine check-up. She is feeling well and has been meeting all developmental milestones. According to the parents, the patient eats a varied diet consisting of whole grains, fruits, vegetables, dairy, and lean meats. Family history is notable for a first cousin who was recently diagnosed with a carbohydrate metabolism disorder. The patient’s parents are concerned that their child may have an undiagnosed underlying condition. Temperature is 37.6°C (99.7°F), blood pressure is 101/50 mmHg, and pulse is 103/min. Physical examination is unremarkable. The patient has 20/20 vision in both eyes. A urine dipstick test is negative for glucose. Further testing reveals the presence of reducing substances within the urine. The patient most likely lacks which of the following enzymes?  

A. Fructokinase

✅ Correct: See Main Explanation.

B. Galactose-1-phosphate uridyltransferase

❌ Incorrect: A deficiency in galactose-1-phosphate uridyltransferase would result in classic galactosemia. Classic galactosemia manifests with hepatomegaly, jaundice, intellectual disability, and sepsis within the first few weeks of life. In contrast, the patient in this vignette is asymptomatic.

C. Aldolase B

❌ Incorrect: A deficiency in aldolase B would result in hereditary fructose intolerance. The condition would lead to the presence of non-glucose reducing substances in the urine; however, the condition would also cause lethargy, renal injury, hepatomegaly, jaundice, and hypoglycemia—none of which is seen in this asymptomatic patient.

D. Galactokinase

❌ Incorrect: Galactokinase deficiency can present with infantile cataracts and idiopathic intracranial hypertension (also termed pseudotumor cerebri). In contrast, this patient is asymptomatic and has normal visual acuity in both eyes.

E. Pyruvate dehydrogenase complex

❌ Incorrect: Pyruvate dehydrogenase complex (PDC) deficiency is an X-linked recessive disorder characterized by hypotonia, poor feeding, development and intellectual delay, and seizures. Laboratory testing will demonstrate elevated lactate and alanine levels. This patient is asymptomatic; furthermore, PDC deficiency would not cause reducing substances to be found within the urine.

Explanation

This patient is asymptomatic but has urine testing positive for non-glucose reducing substances. Essential fructosuria, which is due to a deficiency in fructokinase, best explains this patient’s presentation.  

Essential fructosuria is inherited in an autosomal recessive pattern and results in impaired conversion of fructose to fructose-1-phosphate. Fructose itself is not toxic, and most of the excess fructose is simply excreted via urine, though some of the excess fructose can be converted by hexokinase into fructose-6-phosphate, which can then be used for gluconeogenesis or glycolysis.  

Patients with this condition are asymptomatic, and they do not require any modifications to their diets. However, since fructose is being excreted via urine, urine testing would demonstrate the presence of reducing substances.  

15. A 13-year-old girl comes to the emergency room with abdominal pain. The pain was sudden in onset and localized to the right lower abdomen.  She has had blood in her urine and 2 episodes of vomiting since this morning. She is not sexually active and does not smoke, use illicit drugs or consume alcohol. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 20/min, and blood pressure is 125/85 mmHg. Physical examination reveals nodulocystic acne. Abdominal examination is notable for tenderness in the right flank. Routine urinalysis is positive for blood and 5-10 erythrocytes/hpf. A noncontrast CT detects a staghorn calculus in the right proximal ureter with mild dilation of the pelvic calyxes. Urine cyanide nitroprusside test is found to be positive. Which of the following crystals are likely to be found on urinalysis?

A. Hexagonal crystals 

✅ Correct: See Main Explanation.

B. Envelope-shaped crystals

❌ Incorrect: Calcium oxalate crystals are envelope-shaped crystals and are the most common type of kidney stone. They are commonly associated with hypocitraturia, vitamin C misuse, intake of antifreeze, or Crohn disease. This patient’s positive urine cyanide nitroprusside test, however, makes this diagnosis unlikely.

C. Rhomboid-shaped crystals

❌ Incorrect:  Rhomboid-shaped crystals are associated with hyperuricemia, which may be in the setting of gout or increased cell turnover (e.g. leukemia). Hyperuricemia does not result in a positive urine cyanide nitroprusside test.

D. Coffin lid-shaped crystals

❌ Incorrect:  Struvite stones containing ammonium magnesium phosphate are commonly associated with P. mirabilis urinary tract infections, and crystals appear coffin-shaped in a urinalysis. The patient in the clinical vignette did not have a fever, dysuria or pyuria, making this an unlikely diagnosis. Although struvite stones cause staghorn calculi, they do not result in a positive urine cyanide nitroprusside test.   

E. Wedge-shaped crystals  

❌ Incorrect:  Calcium phosphate stones appear wedge-shaped on urinalysis. Risk factors include hypocitraturia, vitamin C misuse, dehydration and malabsorption. Calcium phosphate crystals do not result in a positive nitroprusside test.

Explanation

This patient has presented with symptoms of a ureteric colic. A positive urine cyanide nitroprusside along with symptoms of a ureteric colic is suggestive of a diagnosis of cystinuria.

Cystinuria is an autosomal recessive condition that results in impaired renal transport in the proximal convoluted tubule (PCT) of amino acids including ornithine, cystine (a homodimer of cysteine), lysine and arginine.  Cystine is physiologically reabsorbed in the PCT. However, in cystinuria, cystine reabsorbing PCT transporters lose their function, and this loss leads to the excretion of cystine. Cystine, being poorly soluble in urine, precipitates as stones. Urinalysis will detect hexagonal-shaped crystals (as seen in the image below), while staghorn calculi can be detected through a noncontrast CT. Cystinuria should be suspected in adolescents or children who present with nephrolithiasis. A positive sodium nitroprusside test confirms the diagnosis and indicates an elevated urinary cystine concentration. The cyanide converts cystine to cysteine, which then binds to the nitroprusside, creating an intense purple color after a few minutes.

By Lance Wheeler - Own work, CC BY-SA 4.0,

Reproduced from wikimedia commons

Conservative treatment in cystinuria involves increasing fluid intake, urinary alkalinization and reducing sodium and protein intake. These measures are targeted towards reducing cystine excretion and improving cystine solubility.  D-penicillamine is a chelating agent used in cystinuria in patients who fail to improve with conservative treatment. Removal of formed stones may require techniques such as extracorporeal shock wave lithotripsy (renal), intracorporeal lithotripsy (ureteric) and cystolitholapaxy (bladder).  

16. A 5-day-old neonate is brought to the emergency department for recurrent episodes of vomiting over the past 24 hours. The patient’s parents say the patient was fine after birth, but the patient suddenly began vomiting and has not eaten since yesterday. The patient is at the 20th percentile for length and below the 10th percentile for weight. Temperature is 36.4°C (97.5°F), pulse is 128/min, and blood pressure is 60/40 mmHg. Physical examination shows jaundice and hepatomegaly. Neurological examination shows normal muscle tone. Urinalysis is negative for glucose but positive for a reducing substance. Blood glucose levels are 90 mg/dL (normal range: >60 mg/dL). Results from the newborn screening panel performed on the day of the child’s birth are still pending. Which of the following substances is most likely to be elevated in this infant?  

A. Uric acid

❌ Incorrect: Elevated serum uric acid levels can be seen in Von Gierke disease due to deficiency of glucose-6-phosphatase enzyme, the first enzyme in glycogen breakdown. It is characterized by severe fasting hypoglycemia, impaired gluconeogenesis and glycogenolysis, as well as hepatomegaly. This infant has normal blood glucose levels despite not eating since yesterday, which favors another diagnosis. Also, jaundice and the presence of reducing substances in the urine are not seen in Von Gierke disease. 

B. Galactose-1-phosphate

✅ Correct: See Main Explanation.

C. Fructose-1-phosphate 

❌ Incorrect: Accumulation of fructose-1-phosphate can be seen in hereditary fructose intolerance, an autosomal recessive condition due to aldolase B enzyme deficiency. As a result, fructose-1-phosphate accumulates, depleting the availability of phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. Manifestations include jaundice, cirrhosis, and vomiting similar to classic galactosemia. However, unlike classic galactosemia, the condition usually manifests later in life because fructose found in fruits is introduced in infants’ diets at approximately 6 months of age. Additionally, hypoglycemia is expected. 

D. Phenylalanine

❌ Incorrect: Accumulation of phenylalanine is seen in phenylketonuria due to phenylalanine hydroxylase or tetrahydrobiopterin (BH4) cofactor deficiencies. Findings include intellectual disability, growth retardation, seizures, fair complexion, eczema, and musty body odor. The presence of hepatomegaly, jaundice, and urine positive for reducing substance favors a diagnosis related to carbohydrate metabolism rather than protein metabolism. 

E. α-ketoacids

❌ Incorrect: Accumulation of α-ketoacids can be seen in maple syrup urine disease, an autosomal recessive condition due to branched-chain α-ketoacid dehydrogenase deficiency. It results in the inability to process the branched chain amino acids isoleucine, leucine, and valine. Presentation includes vomiting, poor feeding, urine with maple syrup/burnt sugar odor, intellectual disability, and death. The presence of hepatomegaly, jaundice, and urine positive for reducing substance favors a diagnosis related to carbohydrate metabolism rather than protein metabolism. 

Explanation

This neonate is presenting with poor feeding and vomiting; physical examination shows jaundice and hepatomegaly, and urinalysis shows a reducing substance in the urine. These findings indicate that this patient most likely has classic galactosemia, which is an autosomal recessive condition due to galactose-1-phosphate uridyltransferase (GALT) deficiency.  

Galactose, an isomer of glucose, is a monosaccharide sugar commonly found in many dairy products as part of the disaccharide lactose (galactose + glucose). In the intestine, the disaccharide is broken down into galactose + glucose. After entering the cells, galactose is phosphorylated to galactose-1-phosphate by galactokinase. Galactose-1-phosphate is then converted to glucose-1-phosphate by the enzyme GALT. Glucose 1-phosphate can be converted to glucose 6-phosphate in order to enter the glycolysis or gluconeogenesis pathways. Alternatively, glucose 1-phosphate can be converted to UDP-glucose to undergo glycogenesis.  

Classic galactosemia leads to the toxic accumulation of galactose 1-phosphate in the cells, leading to damage, for example, in the liver. It also results in the depletion of phosphate in the liver, which reduces its ability to perform gluconeogenesis and glycogenolysis. An additional problem derives from the excess galactose in the serum, which is converted to galactitol by the enzyme aldose reductase. The highly osmotic galactitol accumulates in the lens of the eyes, causing infantile cataracts (similar to sorbitol damage in diabetes). Over time, patients may have failure to thrive and intellectual disability. Notably, classic galactosemia can also predispose neonates to E. coli sepsis.  

Urinalysis detecting the presence of reducing substances in the urine is used as a screening test for inborn errors of carbohydrate metabolism in pediatric patients. It is not specific and only indicates the presence of carbohydrates other than glucose. Diagnosis and screening is made by checking GALT enzyme activity within the red blood cells after birth. Screening is mandatory in most parts of the United States, which allows early diagnosis and treatment; however, affected infants may become symptomatic before the screening results become available (approximately 10 to 14 days after sample collection), and thus, clinicians must consider the diagnosis in infants with characteristic signs and symptoms. Treatment includes avoidance of galactose and milk products.    

17. A 6-month-old infant girl is brought to the pediatrician for evaluation of impaired vision. The patient was born at home via an uncomplicated vaginal delivery but did not receive any postpartum medical evaluation, with the parent stating they wanted a “natural” birth. According to her parents, the patient “tends to stare at the wall, even if cartoons are playing on the television.” The patient also does not smile when the parents are playing with the patient. The patient is at the 10th percentile for length and 5th percentile for weight. Vitals are within normal limits. Physical examination reveals the findings shown below. No hepatomegaly or jaundice is observed. Urine dipstick testing is normal. Further testing reveals the presence of reducing substances within the urine. Which of the following best describes the pathophysiology behind this patient’s visual symptoms?  

Image reproduced from Wikimedia Commons

A. Infection by protozoan found in cat feces

❌ Incorrect: Congenital infection by Toxoplasma gondii can cause macular scarring and impaired vision. However, this patient has opacification of the bilateral lens, which is more concerning for cataracts as opposed to a macular disorder.

B. Inherited mutation in Rb tumor suppressor gene

❌ Incorrect: Mutations in the Rb gene can predispose patients to developing retinoblastoma, which can manifest with visual impairment and a white pupillary reflex. However, this patient also has the presence of non-glucose reducing substances in the urine, which is more concerning for a carbohydrate metabolism disorder (e.g., galactokinase deficiency, classic galactosemia).

C. Fructose accumulation within the anterior chamber

❌ Incorrect: Patients with essential fructosuria or hereditary fructose intolerance may present with elevated serum fructose levels. Essential fructosuria is largely asymptomatic whereas hereditary fructose intolerance can cause failure to thrive, jaundice, and cirrhosis. However, neither condition is associated with the development of infantile cataracts. 

D. Congenital infection by positive-sense RNA virus

❌ Incorrect: Congenital rubella infection can lead to cataract formation along with deafness, heart defects, and a “blueberry muffin” rash. However, this patient also has the presence of reducing substances in the urine, which is more concerning for a carbohydrate metabolism disorder (e.g., galactokinase deficiency, classic galactosemia).  

E. Accumulation of galacticiol within the lens

✅ Correct: See Main Explanation.

Explanation

This infant has bilateral cataracts in the setting of urine testing that is positive for non-glucose reducing substances. She most likely has a disorder of galactose metabolism (e.g., galactokinase deficiency, classic galactosemia). These conditions lead to the accumulation of galactitol within the lens, with subsequent water build-up, lens fiber rupture, and eventual cataract formation.  

Galactokinase deficiency and classic galactosemia are due to a deficiency of the enzymes galactokinase and galactose-1-phosphate uridyltransferase, respectively. Both conditions are characterized by impaired metabolism of galactose, which is instead converted into galactitol by aldose reductase. Galactitol mainly accumulates in the lens of the eye and attracts water, which ultimately causes swelling and rupture of lens fibers. This process leads to the formation of infantile cataracts.   

The main symptom of cataracts is a painless visual impairment. Affected infants may present with a failure to track objects or to develop a social smile (which is when one smiles after seeing another individual’s smile) since they cannot see well. Physical examination will demonstrate leukocoria, which is an abnormal white reflection from the retina that can be observed on fundoscopic examination.  

18. A 1-year-old girl is brought to the clinic for evaluation of developmental delay. The parent states that she occasionally notices a “musty smell” to the patient’s urine when changing her diaper. The pregnancy and birth were unremarkable; however, the patient has not yet been able to sit up or walk on her own. She has not yet begun to say words, although she occasionally babbles. The family immigrated from Croatia 2 months ago, where the mother delivered the baby at home. The patient’s weight is less than the 5th percentile for her age. Head circumference is at the 10th percentile for her age. Temperature is 36.4°C (97.5°F), pulse is 145/min, and respiratory rate is 34/min. Physical examination reveals eczema and hypopigmentation over the chest and arms. Motor examination is normal. Abdominal examination is unremarkable. The physician suspects a genetic disorder. This patient’s condition is caused by deficiency of which of the following enzymes? 

A. Phenylalanine hydroxylase

✅ Correct: See Main Explanation.

B. Pyruvate dehydrogenase

❌ Incorrect: Pyruvate dehydrogenase requires the cofactor thiamine pyrophosphate, derived from vitamin B1. In its absence, clinical manifestations include dry beriberi (peripheral neuropathy), wet beriberi (high-output congestive heart failure) or Wernicke syndrome (ataxia, dementia and ophthalmoplegia). This patient’s constellation of symptoms (e.g., developmental delay, musty odor, fair skin) is suggestive of a different diagnosis.

C. Branched-chain α-keto acid dehydrogenase

❌ Incorrect: Maple syrup urine disease is caused by deficiency of branched-chain α-keto acid dehydrogenase that is involved in the breakdown of branched chain amino acids like isoleucine, leucine, and valine, resulting in a maple syrup odor to the patient’s urine. Although it can also result in severe neurological damage, the condition does not cause hypopigmentation, eczema, or a musty urine odor.

D. Tyrosinase

❌ Incorrect: Albinism is caused by a deficiency of tyrosinase, which prevents the conversion of DOPA (dihydroxyphenylalanine) to melanin. The condition does not cause intellectual deterioration and developmental delay.

E. Homogentisate oxidase 

❌ Incorrect: Alkaptonuria is caused by the congenital deficiency of homogentisate oxidase that converts homogentisic acid to maleylacetoacetate. Homogentisic acid accumulation in joints, tissues and cartilage leads to hyperpigmentation, not hypopigmentation; furthermore, the condition does not cause neurological deterioration.

Explanation

This patient’s presentation with severe neurologic and developmental delay, along with signs of hypopigmentation, is suggestive of a diagnosis of phenylketonuria (PKU). Untreated PKU results in accumulation of phenylketones (and their metabolites), which can adversely affect myelination and neurotransmitter synthesis.

In the United States, neonatal screening tests identify patients with PKU. Screening tests are initiated 2-3 days after birth; testing for PKU is delayed as phenylalanine levels are normal at birth, owing to the presence of maternal phenylalanine hydroxylase. Most newborn infants are asymptomatic prior to initiation of feeds containing phenylalanine (breast milk or formula feeds). Screening of PKU is imperative, as delayed diagnosis can result in irreversible neurological deterioration if lifestyle modifications (a diet that eliminates phenylalanine) or supplementation of BH4 are not initiated early. Although patients identified on neonatal screening may manifest neurologic symptoms despite dietary intervention, these symptoms are less severe than in untreated patients.

 

19. A 1-year-old infant is admitted to the pediatric intensive care unit due to weakness and failure to thrive. The patient's parents are refugees, and before the evaluation, the patient had to sustain long periods without feeding. The patient’s urine is consistently dark brown despite adequate intravenous hydration, as demonstrated in the image below. Physical examination reveals hypotonic limbs. An echocardiogram demonstrates dilated cardiomyopathy with an ejection fraction of 34%. Laboratory findings demonstrate a blood glucose level of 55 mmol/L, ALT of 77 units/L, and AST of 101 units/L. A urinalysis demonstrates evidence of blood without red blood cells or ketonuria. A liver biopsy was obtained. Which of the following findings are most likely to be found on biopsy analysis?

 
^{Image obtained from: Wikipedia}  

A. Accumulation of cytosolic triglycerides

✅ Correct: See Main Explanation.  

B. Distention of hepatic veins and presence of Schistosoma mansoni  

❌ Incorrect: An infection from the Schistosoma family can cause liver disease; however, this infection would not explain the presence of dilated cardiomyopathy and rhabdomyolysis in this patient.  

C. Parasitic eggs with lateral spines

❌ Incorrect: Parasitic eggs with lateral spines are characteristic of S. mansoni and S. japonicum on pathologic examination. These infections would not explain the presence of dilated cardiomyopathy and rhabdomyolysis in this patient.  

D. Fibrotic liver parenchyma with collagen cross-bridging

❌ Incorrect: This pathologic description is characteristic of advanced cirrhosis. This patient’s age and presentation do not coincide with a presentation of cirrhotic liver disease, which primarily affects patients with underlying NASH, hepatitis, or alcoholic liver disease.  

E. Abundance of Kupffer cells

❌ Incorrect: Kupffer cells are liver-specific resident macrophages that primarily reside in liver sinusoids. An overabundance of Kupffer cells may be associated with an infectious or inflammatory process but is a nonspecific finding.  

Explanation

This young patient suffers from fatigue, weakness, and failure to thrive following a prolonged fast. Laboratory evaluation details hypoglycemia, elevated AST and ALT, and rhabdomyolysis (as evidenced by the presence of blood in the urine without red blood cells). Suspiciously, this patient does not have evidence of urine ketone bodies (despite fasting). Furthermore, an echocardiogram reveals dilated cardiomyopathy. Together, these findings are concerning for an innate, inborn error of metabolism, likely systemic carnitine deficiency.

Systemic carnitine deficiency is a rare autosomal recessive disease caused by a genetic defect of the carnitine transporter, which transports fatty acids across the mitochondrial wall. Without a functional carnitine transporter, mitochondrial beta-oxidation cannot occur, and acetyl CoA and other fatty acids and triglycerides accumulate in the cytosol. Fatty acid and triglyceride accumulation in the cytosol is the key pathological finding of this disease, which can be seen in liver and cardiac biopsies.
 

 

20. A 4-day-old female neonate is under evaluation in the neonatal ICU following a seizure-like episode. Since starting breastfeeding, she has been irritable and feeding poorly, and she has had several episodes of vomiting. She was born at 29 weeks gestation to a 29-year-old woman following a caesarean delivery for prolonged labor. The patient has been exclusively breastfed since birth. Temperature is 36.4°C (97.5°F), pulse is 145/min, and respiratory rate is 67/min. On physical examination, the patient appears somnolent and lethargic. Skin turgor is delayed and eyes appear sunken. Abdominal examination is unremarkable. Neurological examination reveals diffuse hypotonia and somnolence without response to painful stimulation. Sepsis workup is negative. Laboratory evaluation reveals orotic aciduria and hyperammonemia. Serum arginine levels are within normal limits. Deficiency of which of the following enzymes is responsible for this patient’s symptoms? 

A. Ornithine transcarbamylase

✅ Correct: See Main Explanation.

B. Carbamoyl phosphate synthetase I

❌ Incorrect: Deficiencies in carbamoyl synthase I can cause hyperammonemia; however, orotic aciduria is not found.

C. Carbamoyl phosphate synthetase II

❌ Incorrect: Carbamoyl synthetase II is a cytosolic enzyme involved in pyrimidine synthesis. It catalyzes the conversion of glutamine and carbon dioxide to form carbamoyl phosphate. Deficiency of this enzyme does not cause hyperammonemia.

D. Arginase

❌ Incorrect: Patients with arginase deficiency typically present in late infancy to preschool years (ages 1-3 years) with choreathethoid movements and spastic diplegia. Additionally, patients typically have an increased serum concentration of arginine due to an inability to break it down.

E. Uridine monophosphate synthase

❌ Incorrect: Uridine monophosphate synthase is an enzyme involved in pyrimidine synthesis. Mutations of this enzyme can cause hereditary orotic aciduria, which manifests with elevated serum levels of orotic acid and megaloblastic anemia; however, unlike OTC deficiency, hyperammonemia is not encountered.

Explanation

Ammonia is a toxic metabolic product formed by the catabolism of amino acids and requires conversion to its soluble, nontoxic form urea for its excretion, a process that occurs in the liver. This process is called the urea cycle and involves the condensation of bicarbonate and ammonia to form carbamoyl phosphate with the enzyme carbamoyl phosphate synthetase I.  Ornithine carbamoylase (OTC) catalyses the addition of carbamoyl phosphate to citrulline to form ornithine.

OTC deficiency, an autosomal recessive disorder, is the most common urea cycle disorder and results in clinical manifestations of hyperammonemia including poor feeding, irritability, vomiting, somnolence, convulsions and cerebral edema. Most patients present typically as neonates in the first 24-48 hours of birth following their first feeds, as breast milk contains a high protein load. Laboratory investigations will reveal hyperammonemia and orotic aciduria, as a deficiency of OTC results in an accumulation of carbamoyl phosphate that stimulates pyrimidine synthesis and in turn orotic aciduria. Additional genetic sequencing may be required to confirm the enzyme defect.

 Treatment in mild hyperammonemia involves initiation of a diet that restricts protein intake to lower serum ammonia levels and volume repletion. Drugs like phenylacetate and sodium benzoate are effective in removal of ammonia by binding to glycine or glutamine and promoting renal excretion of these products. In severe cases or rapid increases of serum ammonia, hemodialysis is warranted.

21. An 11-year-old girl is brought to the emergency room after sudden weakness in her right arm and leg and slurred speech. She has complained of intermittent chest pain during gym class and visual disturbances for the past 2 months. Her parent states that the patient’s performance in school has been poor recently. The family immigrated from Singapore 2 years ago. Her birth and development were unremarkable. Weight at the 50th percentile for her age, while height is at the 85th percentile. Temperature is 37.0°C (98.6°F), pulse is 94/min, respirations are 18/min, and blood pressure is 105/65 mmHg. Physical examination reveals kyphosis and pectus excavatum. Ophthalmic examination reveals bilateral lens luxations. Neurological examination reveals 2/5 power in her right upper and lower limb and positive Babinski sign on the right side. An inborn error of metabolism is suspected as the cause of this patient’s symptoms. Which of the following enzymes is most likely deficient in this patient? 

A. Cystathionine beta-synthase

✅ Correct: See Main Explanation.

B. Branched-chain alpha-keto acid dehydrogenase 

❌ Incorrect: Maple syrup urine disease is caused by a deficiency in branched-chain alpha keto acid dehydrogenase and results in severe neurologic deterioration, including developmental delay and dystonia. However, it does not cause lens dislocation or thrombotic events such as the ischemic stroke seen in this patient.

C. Pyruvate carboxylase

❌ Incorrect: Biotin acts as a cofactor for the enzyme pyruvate carboxylase. Deficiency of biotin results in enteritis, stomatitis, and dermatitis. Neurological symptoms are not common.

D. Ornithine transcarbamylase 

❌ Incorrect: Urea cycle disorders can result in hyperammonemia and cause neurological deficits in newborns, with symptoms including difficulty feeding, irritability, and somnolence. Thrombotic complications presenting during adolescence are unlikely to be encountered.

E. Phenylalanine hydroxylase

❌ Incorrect: Phenylketonuria results from the deficiency of phenylalanine hydroxylase, which causes severe neurologic deterioration and hypopigmentation. Thrombotic complications, such as the ischemic stroke seen in this young patient, would not be encountered.

Explanation

This patient has signs and symptoms indicative of an ischemic stroke. In the setting of skeletal abnormalities (e.g. kyphosis, pectus excavatum), cognitive decline, and a history of angina, this presentation is suggestive of homocystinuria.

Homocystinuria is an autosomal recessive disorder that can result from cystathionine beta-synthase deficiency, methionine synthase deficiency, or decreased affinity of pyridoxal phosphate to cystathionine beta-synthase, leading to significant elevations in plasma and urine homocysteine levels. Clinical manifestations in homocystinuria involve ophthalmic complications (e.g., lens dislocation, myopia), vascular disease (e.g. atherosclerosis), and cognitive decline.

Skeletal abnormalities like kyphosis, pectus excavatum and osteoporosis are postulated to occur due to an interference in collagen cross-linking. Patients with homocystinuria tend to have similar physical findings to those with Marfan syndrome. These marfanoid features include abnormal upper segment to lower segment (US/LS) ratio, arachnodactyly, pectus deformities and increased arm span.

Distinguishing features between Marfan syndrome and homocystinuria include the presence of intellectual disability and thrombotic complications that are seen with homocystinuria. Although both diseases cause severe myopia due to ectopia lentis, dislocations are typically inwards and downwards in homocystinuria, while they are upward in Marfan syndrome.

22. A 27-year-old woman, gravida 1 para 0, presents to the clinic for a routine evaluation. The patient is at 32-weeks gestational age and is feeling well. Family history is notable for a sibling who passed away from a carbohydrate metabolism disorder in early childhood. The patient cannot recall the details but states, “My sister would get very sick every time she drank juice or ate fruits.” The patient is concerned her unborn child may also have this condition. If the child is affected by the same condition, at what time would symptoms likely first manifest?  

A. Shortly after birth

❌ Incorrect: Patients with disorders affecting galactose metabolism will manifest with symptoms shortly after birth, once breastfeeding is initiated. This is because milk contains lactose, a disaccharide that is broken down into galactose and glucose. However, this patient’s sister developed symptoms after consuming juice and fruits, which is more concerning for a fructose metabolism disorder.

B. 2 months of age

❌ Incorrect: The patient’s sister had symptoms suggestive of a fructose metabolism disorder. Infants should be breastfed for the first 6-months of life. Afterwards, complementary foods can be added to their diet. Since breast milk does not contain fructose, patients with a fructose metabolism disorder would be asymptomatic at 2-months-old.

C. 6 months of age

✅ Correct: See Main Explanation.

D. 12 months of age

❌ Incorrect: The World Health Organization (WHO) recommends that infants begin complementary feeding beginning around 6-months of age. Since certain complementary foods (e.g., fruits, juices) contain fructose, patients with fructose metabolism disorders would begin manifesting with symptoms at that time. 

E. 18 months of age

❌ Incorrect: The World Health Organization (WHO) recommends that infants begin complementary feeding beginning around 6-months of age. Since certain complementary foods (e.g., fruits, juices) contain fructose, patients with fructose metabolism disorders would begin manifesting with symptoms at that time. 

Explanation

The patient’s sister had a history of developing symptoms after consuming fructose-rich foods, such as juices and fruits. This history is suggestive of a fructose metabolism disorder. If this patient’s unborn child is also affected, then symptoms will manifest once the child initiates complementary feeding at around 6-months of age.   

According to the World Health Organization (WHO), when infants reach 6-months of age, breast milk alone provides insufficient nutrition. As a result, infants should begin consuming complementary foods (e.g., pureed meats, pureed fruits) to supplement the breast milk. Since breast milk does not contain fructose and complementary foods do, patients with fructose metabolism disorders will develop symptoms around this age.  

In contrast, patients with galactose metabolism disorders will develop symptoms shortly after birth once the infant begins breastfeeding since breast milk contains lactose, which is broken down into glucose and galactose.  

Both galactose and fructose metabolism disorders can cause severe symptoms, including failure to thrive, vomiting, hepatomegaly, and jaundice. Clinically, the conditions are distinguishable based on the timing of their presentation, in addition to the fact that galactose metabolism disorders are associated with infantile cataracts, whereas fructose metabolism disorders are not.  

23. A 6-month-old girl is brought to the emergency department with seizures. The episode lasted less than a minute and terminated without any interventions. Her parents have not noticed a change in stools, excessive crying, or a fever.  Her birth was unremarkable; however, the parents state she has not been able to sit up or roll over on her own yet. The family immigrated from Nigeria 2 months ago. Her weight is less than the 5th percentile for her age. Temperature is 36.4°C (97.5°F), pulse is 145/min, and respiratory rate is 34/min. Head circumference is significant for microcephaly. Physical examination reveals eczema over the chest. Motor examination is normal. Abdominal examination is unremarkable. A genetic disorder is suspected. Laboratory evaluation reveals a deficiency of tetrahydrobiopterin. Which of the following amino acids is most likely essential in this patient given her condition? 

A. Tyrosine

✅ Correct: See Main Explanation.

B. Isoleucine

❌ Incorrect: In maple syrup urine disease, leucine, isoleucine and valine are branched amino acids that accumulate in neural tissue due to a deficiency of branched-chain dehydrogenase enzyme, resulting in intellectual disability, seizures, and a sweet odor to urine. It is not caused by a deficiency in tetrahydrobiopterin.

C. Arginine

❌ Incorrect: Urea cycle disorders result from enzyme deficiencies that inhibit the formation of arginine and downstream disposal of nitrogenous wastes. As a result, arginine becomes an essential amino acid in patients with these disorders. Urea cycle disorders are not caused by a deficiency in tetrahydrobiopterin.

D. Cysteine

❌ Incorrect: In homocystinuria, homocysteine cannot be converted to cystathionine and then to cystine due to a deficiency of cystathionine synthase. As a result, cysteine becomes an essential amino acid in these patients. Homocystinuria can present similarly with intellectual disability and developmental delay, in addition to other findings such as hypercoagulability, ophthalmic conditions (lens dislocation), thrombotic complications (MI, angina) and Marfanoid features. It is not caused by a deficiency in tetrahydrobiopterin.

E. Valine

❌ Incorrect: In maple syrup urine disease, leucine, isoleucine and valine are branched amino acids that accumulate in neural tissue due to a deficiency of branched-chain dehydrogenase enzyme, resulting in intellectual disability, seizures, and a sweet odor to urine. It is not caused by a deficiency in tetrahydrobiopterin.

Explanation

This patient is presenting with seizures, microcephaly, and growth and developmental delay. In the setting of a deficiency of tetrahydrobiopterin, this presentation is consistent with a diagnosis of malignant phenylketonuria.

Phenylketonuria is an autosomal recessive condition that exists in 2 forms: classic PKU and malignant PKU. Classic PKU is the most common form and is caused by a deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine to tyrosine. This deficiency results in accumulation of phenylketones (e.g., phenylacetate, phenylpyruvate). Phenylalanine and its metabolites can adversely affect myelination and neurotransmitter synthesis. Clinical manifestations of phenylketonuria are characterized by intellectual disability, seizures, skin disease (pale skin and eczema due to lack of tyrosine), microcephaly and behavioral abnormalities. Investigations include detection of elevated phenylalanine levels in serum and molecular analysis to confirm PKU mutations. Dietary restriction of phenylalanine is effective in preventing clinical manifestations of phenylketonuria if initiated early, but it cannot reverse preexisting neurologic damage.

Malignant PKU is caused by a deficiency of the cofactor tetrahydrobiopterin (BH4). In its absence, phenylalanine hydroxylase function is impaired. Affected patients have progressive neurologic deterioration due to deficiency of neurotransmitters dopamine, norepinephrine and epinephrine. Serum and urine studies will detect decreased BH4 levels. Treatment involves implementing a low phenylalanine diet and supplementation of BH4 and neurotransmitters including L-dopa and carbidopa. 

24. A 9-month-old girl is brought to the physician for evaluation of failure to thrive. Three months ago, the patient began losing weight and appeared more lethargic than usual. She has also experienced several seizures despite having had no fevers or infections. The patient’s diet consists primarily of breast milk along with small servings of pureed fruits and juice, which were added to the patient’s diet when she was 6-months old. Temperature is 37.0°C (98.6°F), blood pressure is 98/49 mmHg, pulse is 110/min, and respiratory rate is 46/min. The patient is currently at the 20th percentile for weight, whereas three months ago, the patient was at the 50th percentile. Urine dipstick is negative for glucose. Additional testing reveals the presence of reducing substances in the urine. Which of the following findings would most likely be present on physical examination?  

A. Clouding of the bilateral lens

❌ Incorrect: Patients with galactokinase deficiency or classic galactosemia can develop infantile cataracts. However, this patient’s symptoms began around the same time the patient started consuming fruits and juice, which contain fructose. As a result, the patient's symptoms are more concerning for hereditary fructose intolerance. Hereditary fructose intolerance is not associated with infantile cataracts.   

B. Cherry red macula

❌ Incorrect: Patients with Tay-Sachs disease or Niemann-Pick disease can present with a cherry red macula. However, neither of these conditions would result in the presence of non-glucose reducing sugars (e.g., fructose, galactose) in the urine. 

C. Liver palpated 3 cm below costal margin

✅ Correct: See Main Explanation.

D. Palpable flank masses

❌ Incorrect: Patients with autosomal recessive polycystic kidney disease (ARPKD) can present with enlarged kidneys. On physical examination, the kidneys can present as palpable flank masses. ARPKD can manifest with craniofacial abnormalities and pulmonary hypoplasia at birth secondary to oligohydramnios. However, this patient was asymptomatic until she reached 6-months of age, which makes ARPKD unlikely to be the cause of the symptoms.   

E. Pain with flexion of the neck

❌ Incorrect: Patients with meningitis will have nuchal rigidity and pain with flexion of the neck. However, this patient is currently afebrile. Furthermore, the presence of non-glucose reducing sugars in the urine and onset of symptoms around the same time the patient began consuming fruits and juices is more concerning for a disorder affecting carbohydrate metabolism.

Explanation

This patient experienced weight loss, lethargy, and seizure around the same time fructose-containing foods (e.g., fruits, juice) were introduced into the diet. Furthermore, urine testing reveals the presence of non-glucose reducing substances. In combination, these findings are concerning for hereditary fructose intolerance.  

Hereditary fructose intolerance is an autosomal recessive condition characterized by a deficiency of aldolase B. The condition results in the build-up of toxic fructose-1-phosphate. Hence, infants can develop serious symptoms once they consume fructose-containing foods.  

Initial symptoms of hereditary fructose intolerance include lethargy, nausea, and vomiting. In addition, hereditary fructose intolerance can cause renal damage, hepatomegaly, and jaundice. Patients may also have severe hypoglycemia, which occurs because fructose-1-phosphate overaccumulation impairs gluconeogenesis and glycogenolysis. Furthermore, fructose-1-phosphate acts as a phosphate sink, decreasing intracellular phosphate levels and hindering ATP synthesis.  

Of note, a similar but far milder condition is essential fructosuria, which is due to a deficiency of fructokinase. The condition causes impaired conversion of fructose to fructose-1-phosphate. However, since fructose itself is not toxic, it is simply excreted via urine, and patients remain asymptomatic.    

Nutritional disorders

34 Qs

1. A 25-year-old woman goes to the clinic for the evaluation of worsening acne. The lesions are painful, and the patient is concerned as the symptoms have worsened. Her acne has been present for the past 2 years. Past medical history is otherwise unremarkable. She is sexually active with a male partner and uses condoms occasionally. The patient currently uses topical erythromycin and topical tretinoin, and she washes her face twice daily with benzoyl peroxide. Vitals are within normal limits. Physical examination shows multiple large  >5 mm cystic nodules scattered over the face and upper trunk. The remainder of the examination is unremarkable. The physician switches the patient to oral isotretinoin and schedules her for the next follow-up. If the patient conceives while on this new medication, which of the following would her fetus be most at risk of developing?  

A. Epiphyseal stippling

❌ Incorrect: Exposure to warfarin during the first trimester is associated with punctate calcifications (stippling) at bony endplates, depression of the nasal bridge, nasal hypoplasia, and bleeding in the fetus. This patient, however, is not on warfarin.

B. Renal dysgenesis

❌ Incorrect: Renal dysgenesis and oligohydramnios can result from exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers during pregnancy. These antihypertensive medications are contraindicated in pregnancy.  

C. Hypothyroidism 

❌ Incorrect: Fetal hypothyroidism has been associated with maternal use of lithium, propylthiouracil, or methimazole during pregnancy. This patient is not on any of these drugs.  

D. Neural tube defects

❌ Incorrect: The incidence of neural tube defects in infants is associated with the use of medications that impair folate metabolism such as anticonvulsants (e.g. valproate) and methotrexate.  

E. Microcephaly

✅ Correct: See Main Explanation.  

Explanation

This patient’s presentation with multiple scattered nodules >5 mm is consistent with nodular acne (cystic acne). She had not responded to initial therapies, so she was started on oral isotretinoin therapy, which is naturally occurring all-trans retinoic acid, a derivative of vitamin A. It counteracts the pathogenic factors that contribute to the development of acne vulgaris and inhibits follicular keratinization, thereby loosening the keratin plugs of comedones leading to their expulsion.  

In addition to its mucocutaneous side effects (e.g., cheilitis, dry skin and mucous membranes), isotretinoin is also a teratogenic drug and is absolutely contraindicated in pregnancy. Exposure to this medication during the first trimester can cause both spontaneous abortions and severe life-threatening congenital malformations, including craniofacial (microcephaly, small ears), cardiac, thymic (hypoplasia), and central nervous system (hydrocephalus) malformations. Therefore, a negative pregnancy test and two forms of contraception are required before isotretinoin is prescribed, and contraception must be started at least 1 month before isotretinoin therapy. Additionally, a monthly pregnancy test is required while on the treatment.  

2. A 6-day-old boy is brought to the emergency department by his parents because of easy bruising. The infant was born at 38 weeks to a 23-year-old primigravida woman via normal vaginal delivery at home. This is his first medical evaluation. The patient’s mother took prenatal vitamins and maintained a healthy diet during pregnancy. Family history is unremarkable. Vitals are within normal limits. Physical examination reveals an alert infant. Examination shows multiple ecchymoses visible on upper and lower extremities. The remainder of the examination is unremarkable. Laboratory results are shown.
 

Laboratory features
Laboratory value	Result
Platelet count	230,000/mm3
Bleeding time	5 minutes
Prothrombin time	27 seconds
Activated partial thromboplastin time	42 seconds

Which of the following is the most likely cause of this infant’s presentation?

A. Defective collagen synthesis

❌ Incorrect: Defective collagen synthesis can result from failure of hydroxylation of proline and lysine due to vitamin C (ascorbic acid) deficiency. Severely malnourished patients, such as patients with chronic alcohol use, can present with mucosal bleeding and bruising; however, breast milk provides adequate ascorbic acid.

B. Failure of formation of NAD and NADP

❌ Incorrect: Niacin (vitamin B3) is responsible for the formation of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Its deficiency can cause pellagra (diarrhea, dermatitis and dementia).

C. Impaired formation of rhodopsin

❌ Incorrect: Vitamin A is essential for rhodopsin formation, and its deficiency can lead to night blindness and xerophthalmia. Bruising, as seen in this patient, would be atypical.

D. Impaired gamma carboxylation

✅ Correct: See Main Explanation.

E. Ineffective erythropoiesis

❌ Incorrect: Folate is important for erythropoiesis, and its deficiency can present with megaloblastic anemia, not bruising.

Explanation

This infant, who was born at home and did not receive medical care following birth, is now presenting with easy bruising, which is most likely secondary to vitamin K deficiency. Vitamin K is a fat-soluble vitamin, which is an essential cofactor for gamma-glutamyl carboxylase, an enzyme responsible for the carboxylation of coagulation factors II, VII, IX and X.

Vitamin K deficiency is common in infants because their immature liver cannot utilize vitamin K effectively. Moreover, infants have low vitamin K stores due to poor placental transfer during pregnancy, a sterile gut (i.e. they lack gut flora that synthesize vitamin K), and low content of vitamin K in breast milk. Additional risk factors of vitamin K deficiency include exclusive breast feeding or refusal of vitamin K prophylaxis at birth.

Vitamin K deficiency bleeding can present within 24 hours of birth with intracranial hemorrhage (ICH) or within the first 7 days of life with bleeding from mucosal surfaces, the gastrointestinal tract, umbilicus, or circumcision site or with cutaneous bruising (as in this patient). Its deficiency can be prevented in infants by supplementation with vitamin K at birth, which is routinely done for hospital births. Laboratory evaluation usually reveals a prolonged prothrombin time (PT), a mildly prolonged or normal partial thromboplastin time (PTT), and a normal bleeding time (BT), which indicates normal platelet function.  

3. A 25-year-old woman comes to the clinic with generalized fatigue over the last 2 months. She has noticed an inability to concentrate and has recently noticed she becomes short of breath after climbing 3 sets of stairs to her apartment. She denies being depressed or having suicidal thoughts. Five months ago, she was initiated on phenytoin after 2 episodes of generalized tonic-clonic seizures. She recently initiated a high-protein diet consisting mainly of meat and animal products with minimal vegetables. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 20/min, and blood pressure is 125/85 mmHg. BMI is 23 kg/m2. Physical examination is within normal limits. Thyroid function tests are normal. Laboratory testing reveals a hemoglobin of 9.3 g/dL. A peripheral blood smear is performed and shows the following:

 
Reproduced from: Flickr

Which of the following enzymes is inhibited due to the vitamin deficiency most likely responsible for this patient’s symptoms?

A. Methionine synthase

✅ Correct: See Main Explanation.

B. Methylmalonyl-CoA mutase

❌ Incorrect: Vitamin B12 acts as a cofactor for the enzyme methylmalonyl CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. Vitamin B12 deficiency can cause macrocytic, megaloblastic anemia and neurological symptoms including subacute combined degeneration of the spinal cord and peripheral neuropathy. However, this patient has a diet that consists of abundant vitamin B12 (e.g. animal products), and in the absence of neurological findings and a history of phenytoin use, folic acid deficiency is more likely.

C. Cystathionine synthase

❌ Incorrect: Cystathionine synthase converts homocysteine to cystathionine, ending in cysteine synthesis. Pyridoxine acts as a cofactor for this reaction. Pyridoxine deficiency presents with stomatitis and peripheral neuropathy. Megaloblastic anemia is not common.

D. Pyruvate carboxylase 

❌ Incorrect: Biotin is a cofactor for several carboxylation reactions including pyruvate carboxylase that converts pyruvate to oxaloacetate (gluconeogenesis). Biotin deficiency causes dermatitis, alopecia and enteritis. It is not associated with phenytoin use and does not cause megaloblastic anemia.

E. Pyruvate hydrogenase

❌ Incorrect: Pyruvate hydrogenase converts pyruvate to acetyl-CoA. This reaction is supported by the cofactor thiamine pyrophosphate (derived from vitamin B1). Thiamine deficiency manifests as dry beriberi (peripheral neuropathy), wet beriberi (high-output congestive cardiac failure), or Wernicke- Korsakoff syndrome. It is not associated with phenytoin use.

Explanation

This patient with a peripheral smear revealing a hypersegmented neutrophil (suggesting macrocytic, megaloblastic anemia) in the setting of phenytoin use has a presentation suggestive of folate deficiency.

Folic acid deficiency can be a result of inadequate dietary intake (major dietary sources include green leafy vegetables), use of medications that inhibit folate synthesis (methotrexate, sulfonamides and phenytoin), and reduced absorption (malabsorptive syndromes like Crohn disease). Excessive alcohol consumption also inhibits folate absorption. This patient who was recently started on phenytoin is likely experiencing folate deficiency because of its impairment of folic acid absorption in the jejunum. Folate is converted to tetrahydrofolate, which acts as a coenzyme for methylation reactions (methionine synthase) and the synthesis of nitrogenous bases (e.g. thymidine) in DNA and RNA.

Clinical manifestations of folate deficiency include oral involvement (stomatitis and glossitis) and hematological manifestations (macrocytic, megaloblastic anemia). Homocystinuria that develops in the absence of folate can result in a hypercoagulable state predisposing patients to thrombotic events (e.g., MI, stroke).

4. A 48-year-old woman comes to the clinic with generalized fatigue over the last 2 months. She has also noticed painful mouth ulcers over this same time period. Her other medical conditions include recurrent cystitis, for which she takes daily trimethoprim-sulfamethoxazole, and celiac disease, which is managed with a gluten-free diet. She follows a strict gluten-free, vegan diet. Family history is noncontributory. Vitals are within normal limits. Physical examination reveals conjunctival pallor. Complete blood count reveals a hemoglobin of 9 g/dL. Peripheral smear reveals hypersegmented neutrophils and macrocytosis. She is started on folate supplementation. Two months later, she returns with numbness in her extremities and unstable gait. Laboratory investigations reveal a normal peripheral smear and elevated methylmalonic acid levels. Which of the following is likely to undergo degenerative changes, considering this patient’s most likely diagnosis? 

A. Caudate nucleus and putamen

❌ Incorrect: Atrophy of the caudate nucleus and putamen is suggestive of Huntington disease, which is a insidious, neurodegenerative condition that results in progressive neuronal death. Patients typically have a family history of the condition (not seen in this patient), as well as movement abnormalities (e.g. chorea), along with psychiatric and cognitive features (e.g., irritability, depression, delusions). This patient’s neurological symptoms after folate supplementation suggest a different etiology.

B. Anterior commissure of the spinothalamic tracts 

❌ Incorrect: Syringomyelia is a cyst within the spinal cord that expands over time and results in damage to the anterior white commissure of the spinothalamic tract. This damage results in bilateral symmetrical loss of pain and temperature sensation in a cape-like distribution. Elevated methylmalonic acid levels would not be expected.

C. Motor neurons of the anterior horn cells 

❌ Incorrect: Amyotrophic lateral sclerosis (ALS) and poliomyelitis results in lower motor neuron deficits due to involvement of the anterior horn cells of the spinal cords. Characteristic physical findings in ALS include asymmetric limb weakness, fasciculations, atrophy and upper motor neuron deficits with cranial nerve involvement (e.g., dysarthria, dysphagia). The dorsal columns are generally spared. The absence of these findings makes this diagnosis unlikely.

D. Dorsal root ganglion

❌ Incorrect: Involvement of the dorsal root ganglion, the lateral corticospinal tract, the dorsal column pathway, and the spinocerebellar tracts can be seen in Fredreich ataxia, an autosomal recessive trinucleotide repeat disorder. This disorder is associated with diabetes and HOCM and physical findings such as hammer toes and kyphoscoliosis. Fredreich ataxia generally presents in early childhood and would be unlikely in this middle-aged patient.

E. Spinocerebellar tracts

✅ Correct: See Main Explanation.

Explanation

This patient was initially misdiagnosed with a folate deficiency when she presented with a macrocytic, megaloblastic anemia. After initiation of folate, she developed neurological symptoms that included ataxia and worsening peripheral neuropathy. This series of clinical events is suggestive of vitamin B12 deficiency aggravated by folate supplementation.

 

Vitamin B12 acts as a cofactor for methionine synthase (homocysteine to methionine) and methylmalonyl-CoA mutase (converts methylmalonyl-CoA to succinyl-CoA). Vitamin B12 plays a crucial role in DNA synthesis, neuronal function and hematopoiesis. In the absence of vitamin B12 stores, methylmalonyl-CoA accumulates and disrupts myelin synthesis, resulting in the neurological manifestations of vitamin B12 deficiency, also known as subacute combined degeneration of the spinal cord, which includes:

•  Ataxia, due to involvement of the spinocerebellar tract 
•  Spastic paresis with positive Babinski sign, due to involvement of the corticospinal tract  
•  Loss of vibration and proprioception with a positive Romberg sign, due to involvement of the dorsal column pathway

Vitamin B12 and folate are required for DNA synthesis, and therefore, both vitamin B12 deficiency and folate deficiency can cause megaloblastic anemia. Inappropriate folate supplementation in vitamin B12 deficiency can increase the requirement for vitamin B12 and result in further MMA accumulation. Early administration of folate without B12 supplementation can mask the hematologic symptoms of vitamin B12 deficiency but cannot treat the neurologic manifestations and can potentially aggravate these symptoms. Therefore, vitamin B12 should be tested and measured in patients prior to placing patients on folate supplementation. 

5. A 65-year-old man is brought in by his partner to the clinic when she noticed that he has been having episodes where he is disoriented and markedly irritated over the last 6 months. He has had 2-3 episodes of loose stools, sore throat, and skin rashes over his chest and arms over this same time period. He has not had a fever, headache or loss of consciousness. Nine months ago, he was diagnosed with a gastric tumor and was found to have elevated serum chromogranin levels. He declined medical intervention at the time. He does not smoke. He drinks 6-7 beers daily. Temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 20/min, and blood pressure is 125/85 mmHg. BMI is 19 kg/m2. He is oriented to place and person but is slow to answer questions. Physical examination reveals scaly erythematous patches and hyperpigmentation of his arms, chest, and skin below his knees. Pupils are equal and reactive. Extraocular movements are normal. There is no nuchal rigidity on examination. Motor strength is 5/5 in all four extremities. This patient’s symptoms will most likely respond to which of the following supplements? 

A. Thiamine

❌ Incorrect: Thiamine deficiency can cause Wernicke-Korsakoff syndrome, which is characterized by ophthalmoplegia (horizontal nystagmus, lateral rectus palsy), ataxia, confusion and memory loss. Skin manifestations including photosensitive hyperpigmentation and scaly, erythematous skin lesions are uncommon.

B. Riboflavin

❌ Incorrect: Riboflavin deficiency is characterized by oral manifestations which include cheilosis, stomatitis, and glossitis. Dementia, diarrhea, and dermatitis, as seen in this patient, are suggestive of another condition.

C. Cyanocobalamin

❌ Incorrect: Vitamin B12 deficiency causes megaloblastic anemia, subacute combined degeneration of the spinal cord, and peripheral neuropathy. The absence of these findings makes this diagnosis unlikely.

D. Ascorbic acid

❌ Incorrect: Scurvy, seen in patients with vitamin C deficiency, is characterized by bleeding gums, petechiae, and subperiosteal hemorrhages. Altered mental status and dermatitis are indicative of an alternative diagnosis.

E. Niacin

✅ Correct: See Main Explanation.

Explanation

This patient’s clinical features of dementia and dermatitis in the setting of a carcinoid tumor (gastric tumor with elevated serum chromogranin) suggests a niacin deficiency resulting in pellagra.

 

Niacin is a water-soluble vitamin that is formed from the precursor amino acid tryptophan. Tryptophan also serves as the precursor for the neurotransmitter serotonin. In patients with carcinoid syndrome, excess serotonin production leads to depletion of tryptophan, and in turn, niacin. Niacin deficiency is also likely in patients with a history of chronic alcohol use, bariatric surgery, and history of prolonged isoniazid use in the treatment of tuberculosis. Patients may present with the classic triad of symptoms, which includes dermatitis (especially in sun-exposed areas of the body), diarrhea, and dementia, known as the “3 D’s”.    

6. A 10-year-old boy is brought in by his parent to the clinic for evaluation of numbness in his feet and hands. He states that his hands and feet often have a tingling and burning sensation. He has had no abdominal pain, vomiting, constipation, or diarrhea. His past medical history includes latent pulmonary tuberculosis, for which he was started on isoniazid 3 months ago in India. His family recently immigrated from India in the past month, and the patient has continued taking his medication. His mother states he is doing well in school and is currently placed in advanced academic classes. Temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 20/min, and blood pressure is 115/65 mmHg. Neurological examination reveals symmetrical “glove and stocking” distribution peripheral neuropathy of the hands and feet, with diminished perception of touch and temperature. Motor strength is 5/5 in all four extremities, and deep tendon reflexes are 2+ in the upper and lower extremities. Which of the following could have prevented this patient’s current symptoms? 

A. Vitamin supplementation

✅ Correct: See Main Explanation.

B. Diet modification

❌ Incorrect: Celiac disease is a malabsorption disorder in which there is abnormal small intestinal mucosa that improves when treated with a gluten-free diet. Some children with celiac disease may present with neurologic disorders (e.g., ataxia, neuropathy); however, this patient has no history of diarrhea, making this diagnosis less likely.

C. Hemin supplementation

❌ Incorrect: Acute intermittent porphyria (AIP) is a genetic condition caused by a defect in the heme synthesis pathway. Clinical manifestations of AIP include neurologic dysfunction (sensory, motor abnormalities), as well as intense abdominal pain, vomiting, and constipation. Treatment of patients includes supplementation with hemin. This patient has none of these additional features, and, in conjunction with his isoniazid treatment, he would benefit from another treatment.

D. Drinking filtered water

❌ Incorrect: Lead toxicity can occur after acute or chronic exposure and occurs especially in areas with unfiltered drinking water. The characteristic neurologic manifestations of lead poisoning range from developmental delay and loss of milestones to encephalopathy. Neuropathy can occur in some cases, which would present as distal ankle weakness with foot drop. However, this patient does not demonstrate other signs of lead toxicity (e.g., abdominal pain, cognitive impairment), and his current treatment with isoniazid suggests a different etiology for his symptoms.

E. Frequent insulin administration

❌ Incorrect: Peripheral neuropathy is a common complication of diabetes, likely caused by the effects of hyperglycemia on the peripheral nerve. Children with type I diabetes mellitus typically present with polydipsia (increased thirst), polyuria (increased urination), and weight loss. This patient does not demonstrate any of these symptoms, and his current treatment with isoniazid suggests a different etiology for his symptoms.

Explanation

This patient with peripheral neuropathy following isoniazid use has a presentation consistent with drug-induced pyridoxine (vitamin B6) deficiency.

Pyridoxine deficiency can occur due to inadequate dietary intake but is more commonly encountered with the use of drugs that interfere with its metabolism, such as isoniazid (INH), hydralazine, penicillamine and levodopa/carbidopa. Pyridoxine is converted to its active form pyridoxal phosphate, which acts as a cofactor in transamination reactions, decarboxylation reactions, and glycogen phosphorylase functions.

The mechanism of isoniazid-induced peripheral neuropathy involves interference of INH metabolites with the metabolism of vitamin B6 (pyridoxine), resulting in decreased amounts of biologically active vitamin B6. Most patients have large enough stores of pyridoxine to prevent deficiencies; however, patients who are malnourished or have certain comorbid illnesses (e.g. diabetes mellitus) are at increased risk of deficiency. Since pyridoxine is required as a vital cofactor in the synthesis of various neurotransmitters, deficiencies manifest with neurologic symptoms, such as numbness, tingling, and burning sensations.

 Clinical manifestations of pyridoxine deficiency include peripheral neuropathy, nonspecific glossitis, stomatitis, and hyperirritability. Complications include convulsions and sideroblastic anemia. The treatment and prevention of peripheral neuropathy caused by isoniazid is pyridoxine supplementation during treatment.

7. A 45-year-old man is brought to the emergency department by the local paramedics after he was found unconscious on the road side. The patient is covered in vomit, urine, and stool. The patient lives in a homeless shelter and has had several emergency department visits for alcohol intoxication. Past medical history is significant for chronic hepatitis C infection. Temperature is 37.2°C (99.0°F), pulse is 130/min, respirations are 19/min, and  blood pressure is 114/64 mmHg. Physical examination shows hepatomegaly and dry scaly skin. Eye examination findings are shown below:  

Reproduced from Flickr   

This patient’s eye examination findings are most likely related to the deficiency of which of the following?  

A. Vitamin A

✅ Correct: See Main Explanation

B. Vitamin B12

❌ Incorrect: Vitamin  B12 is a water-soluble vitamin and its intestinal absorption is not affected by fat malabsorption as seen in cystic fibrosis. Patients with vitamin B12  deficiency may present with paresthesias and subacute combined degeneration. 

C. Vitamin C

❌ Incorrect: Vitamin C  is a water-soluble vitamin and its intestinal absorption is not affected by fat malabsorption as seen in cystic fibrosis. Patients with vitamin C deficiency may present with signs of scurvy (e.g., swollen gums, easy bruising, poor wound healing). 

D. Vitamin D

❌ Incorrect: Vitamin D is a fat-soluble vitamin. However, its deficiency would present with rickets (in children) and osteomalacia (in adults). Bitot spots, xerosis, and night blindness are not associated with its deficiency.

E. Vitamin K

❌ Incorrect: Vitamin K is a fat-soluble vitamin. Its deficiency, however, would present with coagulopathy (bleeding diathesis) due to inadequate synthesis of vitamin K-dependent clotting factors (II, VII, IX and X).

Explanation

The patient is presenting with bitot spots and dry scaly skin on a physical examination, which is suggestive of vitamin A deficiency, most likely due to poor nutrition/low socioeconomic status and liver disorder in this case. Moreover, excess alcohol consumption can deplete vitamin A stores.  

Apart from poor nutrition (low socioeconomic status) and in liver disorders (e.g. cirrhosis), vitamin A deficiency is common in patients with malabsorptive conditions (e.g. celiac disease and giardiasis). Its deficiency can lead to the development of xerophthalmia, which presents with bitot spots (areas of abnormal squamous cell proliferation and keratinization of the conjunctiva), progressive corneal xerosis (dryness) and keratomalacia (corneal degradation). Vitamin A is a constituent of visual pigments, and its deficiency can also lead to night blindness and retinopathy. Dermatological manifestations include hyperkeratosis, follicular hyperkeratosis, and the destruction of hair follicles. Vitamin A is also vital for the humoral and cell-mediated immune system, and its deficiency can lead to immunosuppression and increase the susceptibility to developing infections.  

8. A 15-year-old boy is brought to the office by his parents for the evaluation of progressive gait instability, dysmetria and dysarthria for the past several years. The patient enjoys hockey but can no longer play due to his worsening symptoms. The review of systems is significant for chronic abdominal pain and fatty diarrhea. The patient is concerned that he is the shortest boy in his class. Family history is noncontributory. Physical examination shows a lean boy with mucosal pallor and reduced muscle mass. Skin examination reveals multiple tense, grouped blisters on the forearms as well as excoriations. Examination of lower extremities shows bilateral motor weakness and loss of deep tendon reflexes and loss of sensation to joint position and vibration. Laboratory results are shown below:  
 

Laboratory features
Laboratory value	Result
Hemoglobin	9 g/dL
Leukocyte count	8,000/mm3
Platelet count	230,000/mm3
Mean corpuscular volume	85/μm3
Reticulocyte count	4%

Peripheral blood smear is shown.

Reproduced from:Wikimedia Commons   

MRI of the brain and spine shows spinocerebellar and posterior column cells degeneration. Which of the following is the most likely cause of this patient’s condition?  

A. Vitamin B12 deficiency

❌ Incorrect: Vitamin B12 deficiency can present with neurological manifestations of spinocerebellar and posterior column degeneration (i.e. decreased position and vibration sense and ataxia). However, the absence of megaloblastic anemia and hypersegmented neutrophils on peripheral smear makes this diagnosis less likely.

B. Thiamine deficiency

❌ Incorrect: Thiamine deficiency can present with Wernicke encephalopathy which manifests with gait dysfunction, confusion, and oculomotor impairment. MRI shows demyelination of specific brain structures, such as the mammillary bodies and thalamus, not degeneration of the spinocerebellar and posterior column cells.

C. Tabes dorsalis

❌ Incorrect: Tabes dorsalis, caused by syphilis, is associated with damage to the dorsal column and dorsal nerve roots, which can manifest with loss of position and vibration sense, sensory ataxia, and paresthesia of lower extremities. However, it not affect the spinocerebellar tract.   

D. Amyotrophic lateral sclerosis

❌ Incorrect: Amyotrophic lateral sclerosis (ALS) manifests as progressive upper and lower motor neuron signs. Although the lateral corticospinal tract is often affected, the dorsal column and spinocerebellar tract are usually not involved. Moreover, affected patients present with asymmetric limb weakness, atrophy, and fasciculations due to anterior horn damage.

E. Vitamin E deficiency

✅ Correct: See Main Explanation.

Explanation

This patient’s neurological symptoms of gait instability, decreased position and vibration sense, and ataxia in combination with hemolytic anemia (normocytic anemia with acanthocytes in peripheral smear) is most likely indicative of vitamin E deficiency secondary to long-term fat malabsorption due to underlying celiac disease (fatty diarrhea, abdominal pain and reduced growth).  

Vitamin E is a fat-soluble vitamin that is widely available in the diet. Its deficiency is rare but can occur with fat malabsorption (e.g., cystic fibrosis, celiac disease) or abetalipoproteinemia (mutations in the microsomal triglyceride transfer protein). It is an antioxidant which protects the red blood cells and membranes from free radical damage. Therefore, its deficiency usually presents with hemolytic anemia, acanthocytosis and neurological manifestations including ataxia (due to spinocerebellar tract degeneration), loss of position and vibration sense (due to dorsal column degeneration) and loss of deep tendon reflexes (due to peripheral nerve degeneration). Other neurologic manifestations may include ophthalmoplegia, pigmented retinopathy, night blindness, dysarthria, dystonia, and tremor. Diagnosis is made by measuring ɑ-tocopherol levels (ɑ-tocopherol is another name for vitamin E) in the serum.  

Vitamin E deficiency should be differentiated from vitamin B12 deficiency, which presents with similar neurological symptoms but would instead show megaloblastic anemia and hypersegmented neutrophils on peripheral smear and elevated serum methylmalonic acid levels.  

9. A 73-year-old woman comes to a medical clinic for evaluation of easy bruising. The patient is currently undomiciled and frequently eats canned-goods for meals. The patient has a history of chronic alcohol use, intravenous drug use, and 20-pack-year smoking history. Temperature is 37.0 C (98.6°F), blood pressure is 110/70 mmHg, and pulse is 99/min. Mucous membranes are moist with evidence of swollen gums and multiple dental caries. There are scattered bilateral petechial lesions on the extremities and the trunk. There are 2 nonhealing ulcers over the sacrum that do not appear to be infected. Laboratory evaluation, including a complete blood count, is found to be within normal limits. Which of the following biochemical processes is most likely impaired in this patient? 

A. Hydroxylation of proline and lysine residues

✅ Correct: See Main Explanation.

B. DNA and methionine synthesis

❌ Incorrect: Vitamin B12 acts as a cofactor for the synthesis of methionine from homocysteine and for the synthesis of succinyl CoA from methylmalonyl CoA. Vitamin B12 deficiency would result in megaloblastic anemia and subacute degeneration of the spinal cord. Bleeding gums and petechiae are suggestive of another vitamin deficiency.

C. Decarboxylation of alpha keto acids

❌ Incorrect: Thiamine acts as a coenzyme and is responsible for the decarboxylation of alpha keto acids such as pyruvate and alpha ketoglutarate. Deficiency of thiamine can lead to Wernicke Korsakoff syndrome, which is characterized by confusion, ataxia and nystagmus. This patient’s bleeding gums and petechiae are suggestive of another vitamin deficiency.

D. Gamma carboxylation of coagulation factors

❌ Incorrect: Vitamin K is an essential cofactor for the gamma carboxylation of the coagulation factors II, VII, IX and X. Deficiency of vitamin K is typically seen in patients with fat malabsorption or those anticoagulant therapy (warfarin). This patient’s various mucosal bleedings, perifollicular hemorrhages, and gingival swelling, however, are suggestive of a different underlying vitamin deficiency.

E. Fatty acid oxidation

❌ Incorrect: Niacin is required for fatty acid oxidation, as it is required for the formation of NADP (nicotinamide adenine dinucleotide phosphate) and NAD (nicotinamide adenine dinucleotide). Niacin deficiency manifests with dermatitis (hyperpigmentation), dementia and diarrhea. Gingivitis and poor wound healing would be atypical.

Explanation

This patient with bleeding gums, petechial hemorrhage, and poor wound healing has typical features of scurvy. In the setting of malnutrition, chronic alcohol intake and advanced age, she most likely has vitamin C deficiency.

Vitamin C is obtained primarily from dietary sources, and deficiency results from inadequate dietary intake. Although inadequate dietary intake is uncommon in most developed countries, it is seen in elderly, institutionalized patients with a history of chronic alcohol use, poor nutritional status, or those with a history of psychiatric disorders.

Vitamin C acts as a reducing agent and hydroxylates proline and lysine residues within the structure of collagen during synthesis using the enzymes prolyl and lysyl hydroxylase. Failure of this step prevents cross linking of collagen fibrils and results in the formation of reduced collagen with decreased tensile strength.

The typical presentation of vitamin C deficiency indicates microvascular bleeding due to collagen defects in blood vessels and includes gingivitis (bleeding receding gums and dental caries), perifollicular hemorrhages, cutaneous hyperkeratosis, poor wound healing and increased susceptibility to infections. Deficient collagen formation also affects osteoblast and fibroblast function, manifesting as bone pain, myalgias and subperiosteal hematomas. 

10. An 11-year-old boy is brought in by his parent to the clinic when she noticed a skin rash over his chest and arms over the past 2 weeks. The boy has noticed that the rash becomes pruritic and painful to touch when he goes outside during recess at school. He also complains of diarrhea over the past several weeks. His parent states his developmental history has been unremarkable except for similar rashes when he was 5 years old that resolved spontaneously. He takes no medications and has not received treatment for any condition in the past. Temperature is 37.0°C (98.6°F), pulse is 72/min, respirations are 18/min, and blood pressure is 115/72 mmHg. BMI is 19 kg/m2. Physical examination reveals well-defined, hyperpigmented, hyperkeratotic, symmetrical, thick scaly plaques surrounded by erythema on the dorsa of the hands, arms, feet, up to the knees, and along the sides of the neck. Urine studies are shown below:

 

Urine
Erythrocytes	0/hpf
Leukocytes	10/hpf
Sediment	None
Urine chromatography	Neutral amino acids

Genetic testing is performed and the diagnosis is confirmed. Which of the following is the most likely pathological mechanism of this patient’s condition?  

A. Impaired synthesis of nitrogenous bases in DNA and RNA

❌ Incorrect: Folic acid is converted to tetrahydrofolic acid, which is essential for the synthesis of nitrogenous bases in DNA and RNA. Folate deficiency is not associated with dermatological changes and instead would present with hematological findings such as megaloblastic, macrocytic anemia and oral manifestations like glossitis.

B. Impaired transamination

❌ Incorrect: Pyridoxine is converted to pyridoxal phosphate, a cofactor used in transamination reactions. Pyridoxine is required for the synthesis of niacin, and a deficiency of pyridoxine can cause symptoms of pellagra. Isoniazid is used in the treatment of latent and active TB and can cause pyridoxine deficiency. However, pellagra following isoniazid use is not an inherited defect. Furthermore, this patient has not received treatment for pulmonary tuberculosis.

C. Impaired decarboxylation of alpha keto acids

❌ Incorrect: Thiamine is converted to its active form thiamine pyrophosphate, which is a cofactor for decarboxylation of alpha keto acids involved in glucose metabolism. Clinical manifestations of thiamine deficiency manifests as wet beriberi, dry beriberi, Wernicke encephalopathy, and Korsakoff syndrome. Dermatological findings as seen in this patient would be unlikely.

D. Impaired hydroxylation of proline and lysine 

❌ Incorrect: Collagen synthesis involves hydroxylation of proline and lysine, which is mediated by ascorbic acid. Deficiency of vitamin C results in bleeding gums, petechiae and subperiosteal hemorrhages. A photosensitive, hyperpigmented skin rash is not commonly associated with scurvy.

E. Defective intestinal absorption of amino acids 

✅ Correct: See Main Explanation.

Explanation

This patient has an inherited defect that has clinical manifestations which include photosensitive dermatitis and episodes of diarrhea. His presentation is consistent with niacin deficiency secondary to Hartnup disease.

Hartnup disease is an autosomal recessive condition that leads to an amino acid (tryptophan) deficiency due to defective membrane transport of tryptophan in proximal renal tubular cells and enterocytes. As a result, renal and intestinal absorption of tryptophan is impaired. Tryptophan serves as the precursor amino acid for the water-soluble vitamin niacin.

Defective absorption of tryptophan can result in niacin deficiency and pellagra-like symptoms. Symptoms include photosensitive, hyperpigmented, symmetric rash that worsens on sun exposure, gastrointestinal disturbances including vomiting and diarrhea, and, in severe cases, neurological changes such as ataxia, memory loss, nystagmus, tremors, headaches and intellectual disability. The diagnosis is confirmed by detecting neutral amino acids on urine chromatography, which differentiates it from patients with dietary pellagra. Treatment includes a high protein diet and niacin supplementation.    

11. A 2-week-old girl is brought to the clinic by her parents for a well-infant examination. She was born at 38 weeks gestation at a tertiary care hospital and weighed 3.2-kg (7-lb 1-oz) at birth. She has been exclusively breastfeeding with good latch, voiding appropriately, and stooling daily. Her mother consumes a well-balanced diet and does not consume alcohol or smoke tobacco. Vitals are within normal limits. Physical examination is unremarkable. At this time, supplementation with which of the following is most important in this infant?  

A. Vitamin A

❌ Incorrect: Although vitamin A levels are low in the infant’s liver at birth, its level increases rapidly due to large amounts in colostrum and milk.  

B. Folate

❌ Incorrect: Human breast milk contains an adequate amount of folate, and its supplementation is not required at this time.  

C. Iron 

❌ Incorrect: Breast milk is low in iron content, but iron bioavailability in breast milk is high and sufficient for infants up to 4 months of age. Iron supplementation is recommended for exclusively breastfed infants after 4 months of age until solid food intake provides adequate iron.  

D. Vitamin C

❌ Incorrect: A well-nourished mother with a healthy diet will have an adequate concentration of vitamin C in the breast milk for the infant, and its supplementation is not indicated at this time.  

E. Vitamin D

✅ Correct: See Main Explanation.

Explanation

Breast milk is the gold standard nutrition for an infant, as it contains adequate amounts of carbohydrates, proteins, fats, vitamins, and trace minerals. Although most of the vitamins are in sufficient amounts in breast milk, vitamin D and K are relatively insufficient even in vitamin D and K sufficient mothers. Vitamin K is supplemented at delivery via an intramuscular injection to prevent hemorrhagic disease of the newborn.  

Besides exclusive breastfeeding, other risk factors for vitamin D deficiency in an infant include absence of vitamin D exposure, maternal vitamin D deficiency, infants of dark skinned mothers (low vitamin D in breastmilk) or dark skinned infants (require more sunlight exposure to produce adequate vitamin D in skin). Prolonged vitamin D deficiency can lead to the development of rickets due to inadequate mineralization of bone and cartilage. Therefore, all exclusively breastfed infants should receive 400 international units (10 micrograms) daily of vitamin D supplements, beginning within a few days after birth. Supplementation should be continued until the infant is weaned and drinks at least 33 ounces (1 liter) of vitamin D-fortified formula or cow’s milk. Formula fed infants do not require vitamin D supplementation because formula is already fortified with sufficient vitamin D.   

12. A 56-year old woman presents to the clinic for loss of taste for the past 2 months. She states that she has been unable to taste or smell food so she has been eating much less than usual. She has also noticed that she has had hair thinning in the axillae and pubic area. Her past medical history is notable for alcoholic cirrhosis. Vitals are within normal limits. On physical exam, she has a sharply-demarcated red rash around the mouth and on the hands and buttocks. Which of the following nutrients is most likely deficient in this patient? 

A. Zinc

✅ Correct: See Main Explanation. 

B. Iodine

❌ Incorrect: As the body does not produce iodine, deficiency is caused by malnutrition. Iodine deficiency presents with goiter and hypothyroidism. In children, chronic deficiency can result in cretinism (permanent intellectual disability and developmental deficiency). Treatment is iodine supplementation through consumption of dairy, shellfish, saltwater fish, and eggs.  

C. Vitamin B12

❌ Incorrect: Patients present with macrocytic megaloblastic anemia, atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea, cognitive impairment, paresthesias, and gait disturbance. Deficiency can result from a number of issues including decreased intrinsic factor (such as in autoimmune gastritis), insufficient diet (such as in patients with chronic alcoholism), as well medications (such as metformin). Although this patient has a history of chronic alcohol use, her spectrum of symptoms (e.g., anosmia, hair loss) suggests another deficiency. 

D. Iron

❌ Incorrect: Iron deficiency results in a microcytic hypochromic anemia. Decreased iron stores can be caused by chronic bleeding, malnutrition, absorption disorders, GI surgery, or increased demand (pregnancy). Iron studies will show decreased iron, increased TIBC, decreased ferritin, and increased RDW. Patients will present with fatigue, conjunctival pallor, pica, spoon nails, glossitis, and cheilosis. Treatment is addressing the underlying condition and iron supplementation.   

E. Niacin

❌ Incorrect: Niacin (also known as vitamin B3) deficiency results in pellagra. Recall the 4 Ds of pellagra: dermatitis, diarrhea, dementia, and death. The dermatitis characteristically presents in sun-exposed areas. Patients will die in 4-5 years if left untreated. Patients have decreased levels of N-methylnicotinamide which is a niacin metabolism byproduct. The treatment is nicotinamide supplementation.  

Explanation

Zinc is the second-most abundant trace element in the body (after iron) and the most abundant intracellular one. Zinc is absorbed mainly in the duodenum and jejunum, and it is stored in the liver via the portal circulation. As the main organ involved in zinc metabolism, the liver plays an important role in maintaining systemic zinc homeostasis. Zinc is an essential mineral that is used by a wide variety of enzymes in the form of zinc fingers (transcription factor motifs). This role in gene transcription, therefore, makes it indispensable for growth and tissue maintenance, and its deficiency may present as growth failure, alopecia, and a decline in muscle growth. These various effects of zinc deficiency are likely caused by its suppression of IGF-1 and reduction in gene transcription. IGF-1 normally stimulates cellular proliferation and uptake of amino acids and glucose which are required by proliferating cells; therefore, in cases of zinc deficiency, rapidly proliferating cells (such as hair follicles and skin) are affected.  

Zinc deficiency results from malnutrition, malabsorption diseases, prolonged breastfeeding, and acrodermatitis enteropathica (autosomal recessive inherited intestinal zinc absorption defect). Since the liver plays an important role in zinc homeostasis, zinc deficiency is commonly associated with alcoholic cirrhosis. It typically presents with delayed wound healing, immunosuppression, male hypogonadism, alopecia, dysgeusia, anosmia, impaired night vision, depressed mental function, and rash around the mouth and buttocks and on acral surfaces. It can be diagnosed with red blood cell linoleic acid to dihomo-y-linolenic acid (LA:DLGA) ratios. The recommended treatment is zinc supplementation which can be achieved through consumption of fortified cereals, whole grains, nuts, oysters, beef, and lamb.  

13. A 65-year-old woman is brought to the clinic by her son for evaluation of generalized fatigue and unsteady gait for the past 2 months. The son states the patient has lived on her own for the past 15-years following the death of her husband. The patient complains of an inability to concentrate and reduced sleep and appetite. Medical conditions include hypertension, celiac sprue, Hashimoto thyroiditis, hypercholesterolemia and peripheral vascular disease. Current medications include levothyroxine, lisinopril, hydrochlorothiazide and atorvastatin. She follows a gluten-free diet and avoids red meat and eggs. She has been drinking 4-5 glasses of wine daily for the past 20 years. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 20/min, and blood pressure is 125/85 mmHg. BMI is 20 kg/m2. She is oriented to time, place, and person but is slow to respond to questions. Motor strength is 4/5 in bilateral lower limbs, and deep tendon reflexes are diminished at the ankles. Symmetrical “glove and stocking” distribution peripheral neuropathy with diminished perception to touch is present. Romberg sign is positive. Complete blood counts are shown below:

 

Laboratory value	Result
Complete blood count
Hemoglobin	9  g/dL
MCV	110 fL
Leukocyte count	6100 /mm3
Platelet count	90,000/mm3
TSH	1 mIU/L

 MRI of the spinal cord reveals degenerative changes in the dorsal columns of the spinal cord. CT scan of the brain appears normal. Which of the following is the most likely diagnosis?   

A. Pseudodementia

❌ Incorrect: Older patients who are depressed can develop cognitive impairments and diminished attention and concentration. Pseudodementia due to depression is a treatable and potentially reversible cause of cognitive impairment. However, physical examination and laboratory values in pseudodementia are typically normal; this patient’s clinical presentation and laboratory investigations include peripheral neuropathy and macrocytic anemia with involvement of the dorsal columns, which is unlikely to be found in pseudodementia.

B. Hypothyroid-induced cognitive impairment

❌ Incorrect: Hypothyroidism is a reversible cause of dementia resulting in deficits in short-term memory and concentration. Hypothyroidism can result in hypothyroid myopathy and can also be a cause of macrocytic anemia. Although this patient has a history of hypothyroidism, her current TSH levels are within normal limits, and MRI findings of degenerative changes in the dorsal columns suggest an alternative diagnosis.

C. Vascular dementia

❌ Incorrect: Vascular dementia results in a stepwise cognitive decline and is to be suspected in patients with a history of cerebrovascular disease, risk factors for thrombotic episodes, and imaging evidence of previous strokes. A negative history of strokes and a normal CT makes this diagnosis unlikely.

D. Tabes dorsalis

❌ Incorrect: Tabes dorsalis is a manifestation of late neurosyphilis affecting the posterior columns of the spinal cord. The most common presentations include sensory ataxia and lancinating pains involving the back, arms and face. This patient has a presentation that is more consistent with vitamin B12 deficiency.

E. Vitamin B12 deficiency

✅ Correct: See Main Explanation.

Explanation

This patient, who has a history of celiac disease, autoimmune disease (Hashimoto thyroiditis), and limited diet, is now presenting with signs and symptoms indicating dementia, ataxia, and peripheral neuropathy. This presentation is suggestive of vitamin B12 deficiency. Investigations including a complete blood count indicating macrocytic anemia, and MRI findings of subacute combined degeneration of the spinal cord further support this diagnosis.

Most of the vitamin B12 in the human body is stored in the liver. Most patients do not present with symptoms of a vitamin B12 deficiency until after several years of poor intake or inadequate absorption. Vitamin B12 is not endogenously synthesised and requires dietary supplementation. Dietary sources include animal products (e.g., milks, eggs, and meat); therefore, patients who follow vegan-based diets that avoid animal products are prone to becoming deficient in vitamin B12. Other causes of vitamin B12 deficiency include conditions that cause impaired absorption, such as celiac disease, enteritis, fish tapeworm infestation, achlorhydria, and excessive alcohol consumption. The lack of intrinsic factor, as seen in pernicious anemia, can impair the formation of the B12-intrinsic factor complex, which is required for absorption into the terminal ileum.

Vitamin B12 acts as cofactor for methionine synthase (homocysteine to methionine) and methylmalonyl-CoA mutase (converts methylmalonyl-CoA to succinyl-CoA). Vitamin B12 plays a crucial role in DNA synthesis, neuronal function, and hematopoiesis. In the absence of B12, excessive methylmalonic acid (MMA) levels can inhibit myelin synthesis, resulting in neurological signs.

Clinical manifestations of vitamin B12 deficiency can include dementia, peripheral neuropathy, anemia, oral manifestations of stomatitis and glossitis, and subacute combined degeneration of the spinal cord. The ascending tracts of the spinal cord include the spinocerebellar tract, corticospinal tracts, and dorsal column pathways. Degeneration would result in ataxic gait, reduced motor function, diminished propioception (e.g. positive Romberg sign) and impaired two-point discrimination.  

14. A 54-year-old man comes to the clinic with chronic fatigue and dyspnea on exertion over the last 2 months. He also reports 2 episodes of diarrhea and abdominal bloating. A week ago, he had a syncopal episode that was preceded by palpitations and lightheadedness while he was on a family vacation. He has had no chest pain, fevers, or cough. Past medical history is significant for hyperlipidemia managed with atorvastatin. His elder brother died of cirrhosis at the age of 50. The patient does not use tobacco, alcohol or illicit drugs. The patient started taking multiple high-dose vitamins daily in an effort to become “healthier.” He returned from a business trip to Brazil 2 months ago. Temperature is 37.0 C (98.6°F), blood pressure is 118/70 mmHg, and pulse is 90/min. On examination, his skin appears hyperpigmented. Hepatomegaly is noted on abdominal examination. Cardiac examination is normal. EKG shows sinus rhythm, and an echocardiogram reveals abnormal diastolic relaxation of the left ventricle with an ejection fraction of 50% and no wall motion abnormalities. Laboratory results are as follows:

 

Laboratory value	Result
Serum chemistries
Hemoglobin	14  g/dL
Platelet count	200,000/mm3
Leukocytes	6,500/mm3
Blood urea nitrogen	14 mg/dL
Creatinine	0.8 mg/dL
Fasting glucose	145 mg/dL
AST	120 U/L
ALT	98 U/L
Ferritin	1700 µg/L

Which of the following could be associated with this patient’s current clinical manifestations?

A. Vitamin C consumption

✅ Correct: See Main Explanation.

B. History of recent travel to South America

❌ Incorrect: Chagas disease results from a parasite-induced myocarditis, leading to dilated cardiomyopathy and a characteristic apical wall thinning of the left ventricle (apical aneurysm). Other manifestations include megaesophagus and megacolon. Skin hyperpigmentation, heart failure with diastolic dysfunction, elevated glucose levels and elevated ferritin levels in this patient are suggestive of an alternate diagnosis.

C. Episode of streptococcal pharyngitis

❌ Incorrect: Acute rheumatic fever from streptococcal pharyngitis can be followed by chronic cardiac inflammation and valvular heart disease. This patient’s skin hyperpigmentation, heart failure with diastolic dysfunction, diabetes, and elevated ferritin levels in this patient are suggestive of an alternate diagnosis.

D. History of Vibrio vulnificus gastrointestinal infection

❌ Incorrect: Patients with iron overload (elevated ferritin levels) are susceptible to rapidly progressive necrotizing fasciitis with hemorrhagic bullae when infected with Vibrio vulnificus, a Gram-negative bacterium found in salt water. In contrast, this patient’s excessive multivitamin intake is likely the cause of his worsening hereditary hemochromatosis.

E. Episode of viral upper respiratory infection

❌ Incorrect: Viral myocarditis can lead to dilated cardiomyopathy. Echocardiographic findings would include dilated ventricles with abnormal systolic ventricular function. Viral myocarditis would also, typically, be preceded by a symptomatic viral prodrome (fever, myalgias and sinus congestion).

Explanation

This patient with skin hyperpigmentation, diabetes mellitus, heart failure with diastolic dysfunction, hepatomegaly, and elevated iron stores most likely has hereditary hemochromatosis (HH). Hereditary homozygous hemochromatosis is an autosomal recessive condition that results in increased intestinal iron absorption leading to iron accumulation within visceral organs and eventual end-organ failure.

Typically, iron absorption is regulated by iron stores, the rate of erythrocyte production, and dietary intake. Vitamin C (ascorbic acid) converts ferric ions to ferrous ions and in turn aids in the mucosal uptake of iron. For the general population, an increase in vitamin C intake is not associated with an abnormal increase in iron absorption, as the process of iron absorption is well regulated. However, in patients diagnosed with HH, mutations affect the HFE protein, a protein that binds to transferrin and functions as a sensor of iron stores. Mutations cause the hepatocytes and the enterocytes to falsely detect a low level of iron stores; in response, the absorption of iron is expedited. In these patients, vitamin C supplementation can aid iron absorption and worsen the state of iron overload.

Ingestion of large amounts of vitamin C in HH can cause fatal arrhythmias resulting from myocardial damage and cardiac dysfunction due to iron overload. Cardiac manifestations include heart failure with diastolic dysfunction and ventricular arrhythmias. Similarly, patients diagnosed with sickle cell anemia and beta-thalassemia major have increased iron stores due to repeated blood transfusions or erythrocyte hemolysis. Therefore, the ingestion of vitamin C supplements is not advised in these patient subgroups.

Vitamin C toxicity is characterized by abdominal bloating and diarrhea. Vitamin C excess has been speculated to be associated with the occurrence of kidney stones; however, the evidence supporting this data is mixed and inconsistent. Men, particularly those at risk of oxalate stones, are advised to avoid vitamin C supplementation.

15. A 15-year-old boy is brought in by his parent to the clinic for evaluation of a skin rash over his chest and arms for the past 2 weeks. The patient has noticed that the rash becomes pruritic and painful to touch when he goes outside to play soccer. He also complains of loose stools over the last week. Three months ago, he was diagnosed with latent tuberculosis and was started on isoniazid. He and his family immigrated from India 9 months ago. Temperature is 37.0°C (98.6°F), pulse is 74/min, respirations are 16/min, and blood pressure is 115/75 mmHg. BMI is 20 kg/m2. Physical examination reveals scaly erythematous patches and hyperpigmentation of the arms, chest and skin below the knees. Motor strength is 5/5 in all four extremities. Sensation is intact throughout. Which of the following amino acids is a precursor of the vitamin that is most likely deficient in this patient?  

A. Histidine

❌ Incorrect: Histidine is converted to histamine with vitamin B6 as a cofactor. Pyridoxine deficiency manifests as peripheral neuropathy and dermatitis.

B. Glutamic acid

❌ Incorrect: Glutamic acid is the precursor amino acid for the neurotransmitter GABA. This conversion involves vitamin B6, also known as pyridoxine. Pyridoxine deficiency manifests as peripheral neuropathy and dermatitis.

C. Tryptophan

✅ Correct: See Main Explanation.

D. Methionine

❌ Incorrect: Methionine is involved in the synthesis of cysteine. It is not a precursor for niacin synthesis. Deficiency of methionine does not result in dermatitis or diarrhea, as seen in this patient.

E. Tyrosine

❌ Incorrect: Tyrosine is involved in the synthesis of neurotransmitters dopamine, norepinephrine, and epinephrine, in addition to melanin. Diseases like albinism and vitiligo can occur due to deficiencies or inadequate conversions of tyrosine to these end products.

Explanation

This patient with a photosensitive skin rash and diarrhea with a history of isoniazid use has a presentation suggestive of pellagra from niacin deficiency.

Niacin is a water-soluble vitamin that is formed from the precursor amino acid tryptophan. In patients with prolonged isoniazid use, symptoms of pellagra occur due to accelerated niacin depletion. Pyridoxine is utilized for the conversion of tryptophan to niacin. Isoniazid depletes stores of pyridoxal phosphate, accelerating tryptophan synthesis. Niacin is a component of NAD and NADP+ enzymes involved in redox reactions.

Clinical manifestations of pellagra can result from isoniazid use, bariatric surgery, anorexia nervosa or consumption of a diet deficient in niacin (corn/maize). Clinical features that are characteristic of pellagra include a symmetric hyperpigmented rash that involves sun-exposed areas of the skin particularly the neck (characteristically called a “Casal necklace”). Gastrointestinal disturbances include diarrhea and vomiting. In severe cases of prolonged deficiency, neurological symptoms include insomnia, dementia, encephalopathy, lapses in concentration and delusions.

 Symmetric photosensitive hyperpigmented skin rash seen in patients with niacin deficiency  
Reproduced from wikipedia.org

16. A 25-year-old woman comes to the clinic due to myalgia, loss of appetite and a skin rash.  She noticed a progressively worsening skin rash around her eyes, nose and mouth over the course of the last 4 weeks. She has not had a fever, and the rash is not painful or pruritic. Five months ago, she began an intense fitness regimen with a strict diet, which includes eating multiple egg whites everyday, as well as a protein shake every morning, in which she puts several raw eggs. Temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 20/min, and blood pressure is 125/85 mmHg. BMI is 19 kg/m2. Physical examination reveals macular patches around her eyes, nose and mouth. The physician suspects a nutritional deficiency. The cause of this patient’s symptoms is determined to be a vitamin deficiency that acts as a cofactor for the enzyme acetyl-CoA carboxylase. Which of the following additional biochemical processes uses the deficient vitamin as a cofactor? 

A. Branched chain amino acid degradation

✅ Correct: See Main Explanation.

B. Transamination

❌ Incorrect: Biotin does not act as a cofactor for enzymes involved in transamination reactions. Pyridoxal phosphate, the metabolically active form of pyridoxine (vitamin B6), acts as a cofactor for transamination reactions. Pyridoxine deficiency is characterized by peripheral neuropathy.

C. Glycolysis

❌ Incorrect: Biotin acts as a cofactor for enzymes involved in gluconeogenesis (pyruvate carboxylase converts pyruvate to oxaloacetate). It does not act as a cofactor for enzymes involved in glycolysis.

D. Citric acid cycle

❌ Incorrect: Succinyl-CoA is a product of odd chain fatty acid degradation (biotin is a cofactor of propionyl-CoA carboxylase) that can enter the citric acid cycle as succinate; however, biotin does not act as a cofactor for enzymes directly involved in the citric acid cycle.

E. Glycogenolysis

❌ Incorrect: Biotin is a cofactor for gluconeogenesis (pyruvate carboxylase converts pyruvate to oxaloacetate) and not glycogenolysis.

Explanation

Biotin deficiency is relatively rare and can have clinical manifestations including dermatitis, alopecia and enteritis. Neurologic symptoms including changes in mental status, lethargy and paresthesias have also been seen. Biotin deficiency can be caused by poor dietary intake, antibiotic use, or excessive ingestion of raw egg whites. Avidin, present in raw egg whites, binds to biotin, preventing its absorption.

Biotin is a cofactor for carboxylation enzymes including acetyl-CoA carboxylase, which converts acetyl-CoA to malonyl-CoA, the rate limiting step in fatty acid synthesis. Other biotin dependent carboxylases include pyruvate carboxylase (pyruvate to oxaloacetate; gluconeogenesis) and propionyl-CoA carboxylase (propionyl-CoA to methylmalonyl-CoA; branched chain amino acid degradation and degradation of odd chain fatty acids).

The disruption of fatty acid synthesis (inhibition of acetyl-CoA carboxylase) results in the dermatologic symptoms of biotin deficiency including alopecia and macular dermatitis, typically around the eyes, nose and mouth.  

17. A 28-year-old woman comes to the office because of a headache for the past 2 weeks. The patient reports that the headache is dull, intermittent, 5/10 in severity and is occasionally associated with nausea and vomiting. She has never had such a headache before. She denies fever or visual abnormalities. She states she has been eating multiple vitamins daily for the past 8 months in an effort to “become slimmer” and “build muscle.” Past medical history is significant for body dysmorphic disorder. Family history is not significant. Vitals are within normal limits. BMI is 19 kg/m2. Physical examination shows dry skin and hepatomegaly. Neurological examination is nonfocal and shows no meningeal signs. Fundoscopy reveals papilledema. MRI of the brain is unremarkable. Which of the following is the most likely cause of this patient’s condition?  

A. Folate deficiency

❌ Incorrect: Folate is important for DNA synthesis, and its deficiency can cause megaloblastic anemia and glossitis. No neurologic symptoms are seen in folate deficiency.  

B. Vitamin A excess

✅ Correct: See Main Explanation.

C. Vitamin E excess

❌ Incorrect: Vitamin E excess is rare and usually results from high-dose supplements. It may be asymptomatic or can present with muscle weakness, fatigue, nausea, and diarrhea. 

D. Vitamin D deficiency

❌ Incorrect: Severe vitamin D deficiency can cause bone demineralization leading to osteomalacia in adults and rickets in children. Headache with papilledema in this patient is instead indicative of vitamin A 1toxicity.  

E. Thiamine deficiency

❌ Incorrect: Thiamine deficiency is associated with the development of dry and/or wet beriberi and Wernicke-Korsakoff syndrome. These conditions result in distinct neurological manifestations (peripheral neuropathy, ataxia) which are not seen in this patient. 

Explanation

This patient’s headache with signs of increased intracranial pressure (bilateral papilledema) and a normal MRI  is suggestive of pseudotumor cerebri, most likely due to vitamin A toxicity. Unlike water-soluble vitamins, fat-soluble vitamins can build up in the body with excessive consumption, resulting in signs and symptoms of toxicity.  

While rare, vitamin A toxicity can be seen in patients who are consuming excessive amounts of vitamins, or in those who consume foods high in vitamin A, such as animal livers. Individuals who consume more than 10 times the Recommended Dietary Allowance (RDA) of vitamin A can develop toxicity. Vitamin A toxicity can be acute or chronic, and excess vitamin A can be teratogenic.

•  Acute toxicity can occur with a single high dose >660,000 international units (>200,000 micrograms) and typically presents with blurry vision, nausea, vomiting, and vertigo. 
•  Chronic toxicity (chronic ingestion of approximately 33,000 international units [10,000 micrograms] of retinol in adults) can present with hair loss, dry or peeling skin, hepatomegaly, arthralgias or pseudotumor cerebri. 
•  Teratogenicity: Retinoic acid is known to be teratogenic in the first trimester of pregnancy and can lead to spontaneous abortions and fetal malformations (e.g., microcephaly, cardiac anomalies). 

 

18. A 48-year-old man comes to the clinic with generalized fatigue, numbness, and weakness in his lower limbs over the last 2 weeks. Notable past medical history includes Crohn disease, for which he underwent an ileocecal resection 6 months ago and has been receiving total parenteral nutrition (TPN) since the procedure. He additionally has a history of chronic alcohol use and has been drinking 6-7 beers daily for the past 25 years. Temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 20/min, and blood pressure is 135/85 mmHg. BMI is 19 kg/m2. He is alert, cooperative, and oriented to time, place, and person. Neurological examination reveals symmetrical peripheral neuropathy in the upper and lower extremities with defective perception of touch and vibration sensation. Motor strength is 3/5 in the lower limbs and 5/5 in the upper limbs bilaterally. Symmetrical muscle wasting is noted on both lower limbs. Deep tendon reflexes are absent at the ankles bilaterally. Romberg test is negative. Laboratory investigations are shown below:

 

Laboratory value	Result
Complete blood count
Hemoglobin	12 g/dL
Hematocrit	40%
Leukocyte count	9,100/mm3
Platelet count	150,000/mm3
MCV	82 fL

This patient’s condition is most likely associated with which of the following additional findings?

A. Reduced erythrocyte transketolase activity

✅ Correct: See Main Explanation.

B. Reduced erythrocyte glutathione reductase activity 

❌ Incorrect: Erythrocyte glutathione reductase activity may be reduced in patients with a riboflavin (vitamin B2) deficiency, as the enzyme requires FADH2 (derived by riboflavin). Riboflavin deficiency is characterized by cheilosis and stomatitis. Peripheral neuropathy is unlikely.

C. Elevated serum methylmalonic acid level 

❌ Incorrect: Serum methylmalonic acid (MMA) is elevated in vitamin B12 deficiency, as B12 is necessary for the functioning of the enzyme methylmalonyl CoA mutase, which converts methylmalonyl CoA to succinyl CoA. Vitamin B12 deficiency can cause peripheral neuropathy in the setting of Crohn disease; however, megaloblastic anemia would be expected.

D. Reduced gamma carboxylation of glutamic acid residues

❌ Incorrect: Vitamin K is a fat soluble vitamin that is a cofactor for the gamma carboxylation of glutamic acid residues on clotting factors II, VII, IX, X and protein C & S. Symptoms include mucocutaneous, gastrointestinal and genitourinary bleeding.

E. Reduced hydroxylation of proline and lysine

❌ Incorrect: Vitamin C is a water-soluble vitamin that is involved in the hydroxylation of proline and lysine, a process essential for collagen synthesis. Patients with vitamin C deficiency can present with scurvy and poor wound healing. Peripheral neuropathy is not common.

Explanation

This patient has a history of an ileocecal resection due to severe Crohn disease, chronic alcohol use, and symptoms of peripheral neuropathy and weakness. Taking into consideration his history of prolonged total parenteral nutrition (TPN) supplementation, he most likely has a vitamin B1 deficiency (dry beriberi).

Thiamine is a water-soluble vitamin that acts as a cofactor for the conversion of pyruvate to acetyl CoA. It can present as wet/dry beriberi or can cause Wernicke-Korsakoff syndrome. Thiamine deficiency should be suspected in patients who have a history of heavy alcohol consumption and those with a prolonged history of receiving TPN. Dry beriberi is common in patients with a history of excessive alcohol intake and is characterized by distal peripheral neuropathy with a diminished perception of vibration and touch. Additionally, motor weakness and loss of deep tendon reflexes, particularly of the lower extremities, is also associated with dry beriberi. Wet beriberi includes cardiac involvement and manifests as cardiomegaly, cardiomyopathy, heart failure, peripheral edema, and tachycardia, in addition to neuropathy.

Diagnosis of dry beriberi can be made clinically in a case of high clinical suspicion (heavy alcohol intake and/or poor nutrition with concomitant peripheral neuropathy). However, confirmation of the diagnosis can be done by measuring serum thiamine levels or the activity of erythrocyte thiamine transketolase activity (ETKA). Transketolase is an enzyme involved in the HMP shunt pathway that uses thiamine as a cofactor. In thiamine deficiency, erythrocyte transketolase activity is reduced and improves after vitamin B1 administration, confirming the diagnosis. 

19. A 31-year-old man comes to the office for the evaluation of bleeding from the gums and easy bruising. The patient reports that even minor trauma causes a bruise, and he sometimes bleeds spontaneously from his gums. He also complains of frequent fatigue, generalized weakness, and poor appetite. Past medical history is significant for Crohn disease that required a partial small bowel resection a year ago. The patient has also been receiving oral antibiotic treatment for a perianal fistula for the past 3 months. Family history is noncontributory. Vitals are within normal limits. Physical examination shows multiple large ecchymoses of the lower extremities and trace bleeding from the gums. Laboratory results are shown.

 

Laboratory features
Laboratory value	Result
Platelet count	250,000/mm3
Bleeding time	5 minutes
Prothrombin time	29 seconds
Partial thromboplastin time	43 seconds
Bilirubin
Total	0.8 mg/dL
Direct	0.2 mg/dL
Alanine aminotransferase	15 U/L
Aspartate aminotransferase	17 U/L

Which of the following is the most likely cause of this patient’s presentation?  

A. Autoimmune hepatitis

❌ Incorrect: Autoimmune hepatitis is more often associated with ulcerative colitis than Crohn disease and tends to affect females rather than males. It can be asymptomatic or present with liver dysfunction (e.g., jaundice, hepatomegaly and ascites) including easy bruising and gastrointestinal bleeding due to coagulopathy. This patient’s liver function tests are within normal limits.

B. Factor VIII deficiency

❌ Incorrect: Factor VIII deficiency (hemophilia A) is an X-linked recessive disease leading to defective coagulation and typically manifests early in childhood. It commonly presents with easy bruising, hemarthrosis and prolonged bleeding after surgery. aPTT is significantly elevated in factor VIII deficiency, whereas PT is normal.

C. Immune thrombocytopenic purpura

❌ Incorrect: Immune thrombocytopenic purpura results from autoimmune destruction of platelets and is often associated with viral infections. Although patients usually present with petechial mucosal bleeding, the bleeding time is elevated and platelet count is decreased. PT and aPTT are normal in these patients.

D. Bile acid malabsorption

✅ Correct: See Main Explanation.

E. Leukocytoclastic vasculitis

❌ Incorrect: Leukocytoclastic vasculitis can be associated with a variety of risk factors, including the use of antibiotics; however, it usually presents with palpable purpura or non-blanching petechiae. Mucosal bleeding is usually not seen.

Explanation

This patient with a history of Crohn disease and partial small bowel resection is experiencing symptoms of vitamin K deficiency most likely due to bile acid malabsorption. Bile acids are required for the absorption of fats and other nutrients, which are normally reabsorbed in the terminal ileum (frequently affected in Crohn disease), recycled in the liver and then reused in the absorptive process. Resection or inflammation of the terminal ileum results in loss of bile acids in feces, leading to fat malabsorption and deficiency of fat-soluble vitamins.

Vitamin K is a fat-soluble vitamin which is an essential cofactor for gamma-glutamyl carboxylase, an enzyme responsible for the carboxylation of coagulation factors II, VII, IX and X. Its deficiency results in coagulation defects and presents with easy bruising, hematoma formation in bones and joints after minor trauma, or prolonged bleeding after surgery. Besides Crohn disease, other causes of vitamin K deficiency include other malabsorptive conditions like cystic fibrosis, primary sclerosing cholangitis, and celiac disease. Liver failure and medications (e.g., cephalosporins, warfarin) can also contribute to the development of vitamin K deficiency. Laboratory evaluation usually reveals a prolonged prothrombin time (PT), a mildly prolonged or normal partial thromboplastin time (PTT), and a normal bleeding time (BT), which indicates normal platelet function.  

20.  A 3-year-old boy in a refugee camp is brought to a volunteer clinic in sub-Saharan Africa with failure to thrive. His mother states he has been small since birth and has never seen a doctor. Height and weight are at the 5th percentile. On physical exam, he is very lethargic and severely emaciated with redundant skin folds. He is noted to have little subcutaneous fat. He is admitted for supportive treatment. Which of the following best describes the pathophysiology of this patient’s condition? 

A. Protein deficiency with adequate caloric intake

❌ Incorrect: Although Marasmus includes protein deficiency, this answer choice better describes Kwashiorkor, which is a severe protein deficiency in the setting of adequate calorie intake. These patients will present with bilateral pitting edema, abdominal distention, hepatomegaly, muscle wasting, hair thinning, dermatitis, skin/hair depigmentation, irritability, listlessness, and immunosuppression. Note that this patient does not have edema but rather severe muscle wasting, which suggests a different etiology.  

B. Vitamin B12 deficiency

❌ Incorrect: Patients with vitamin B12 deficiency present with macrocytic megaloblastic anemia, atrophic glossitis, angular stomatitis, anorexia, nausea, diarrhea, cognitive impairment, paresthesias, and gait disturbance. Deficiency can result from a number of issues including decreased intrinsic factor, insufficient diet, medications, and fish tapeworm infection.   

C. Global nutrient deficiency

✅ Correct: See Main Explanation. 

D. Iron deficiency

❌ Incorrect: Iron deficiency results in a microcytic hypochromic anemia. Decreased iron stores can be caused by chronic bleeding, malnutrition, absorption disorders, GI surgery, or increased demand (pregnancy). Iron studies will show decreased iron, increased TIBC, decreased ferritin, and increased RDW. Patients will present with fatigue, conjunctival pallor, pica, spoon nails, glossitis, and cheilosis. This patient from a resource-deprived region is presenting with severe muscle wasting and subcutaneous fat loss, suggesting a different cause to his condition. 

E. Niacin deficiency

❌ Incorrect: Niacin (also known as vitamin B3) deficiency results in pellagra. Recall the 4 Ds of pellagra: dermatitis, diarrhea, dementia, and death. The dermatitis characteristically presents in sun-exposed areas. Patients typically die in 4-5 years if left untreated. This patient from a resource-deprived region is presenting with severe muscle wasting and subcutaneous fat loss, suggesting a different cause to his condition. 

Explanation

This patient in a refugee camp that is likely resource-deprived is suffering from Marasmus. Marasmus is severe malnutrition disorder that results from overall inadequate calorie and nutrient intake. As this results in a chronic negative energy balance, the body compensates with decreased physical activity (lethargy), decreased basal metabolic rate, growth retardation, and weight loss. It presents with an emaciated appearance, disproportionately large head, severe muscle wasting, subcutaneous fat loss, irritability, weakness, and lethargy. Unlike Kwashiorkor, which is characterized by adequate caloric intake with severely deficient protein intake, Marasmus does not present with edema.   

Treatment includes prophylactic antibiotics, electrolyte correction, hydration, and gradual protein refeeding. Excessive rapid refeeding can lead to protein catabolism, which can cause urea accumulation that may overwhelm the liver and ultimately result in liver failure.  

Reproduced from: Wikimedia Commons

21. An 85-year-old man is brought in by his niece to the clinic after finding him confused outside his house. He denies the incident and says that he was “just walking his dog around the neighborhood” after having a meal with his friends. After the consultation, his niece states that “He doesn't own a dog, he lives alone, and most of his meals consist of reheating canned foods.” Past medical history includes hypertension, hypercholesterolemia and type 2 diabetes. Medications include hydrochlorothiazide, atorvastatin and metformin.  Family history is noncontributory. He has been drinking 5-6 beers daily for the past 30 years. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 17/min, and blood pressure is 135/85 mmHg. He is oriented to place and person but not time. Immediate and delayed memory recall is poor. Pupils are equal and reactive, and horizontal nystagmus is elicited on lateral gaze. Fundoscopy is normal. There is no nuchal rigidity on examination. Motor strength is 5/5 in the upper extremities and 2/4 in bilateral lower extremities. Deep tendon reflexes of the knee and ankle are 1+ bilaterally. MRI reveals necrosis in the mamillary bodies and medial thalamus. Which of the following is the most likely diagnosis?

A. Vascular dementia

❌ Incorrect: Vascular dementia is associated with a history of stroke/TIA. It is suspected in patients with significant risk factors for atherosclerotic disease, which include hypercholesterolemia, hypertension and type 2 diabetes mellitus. Symptoms expected include a stepwise deterioration of cognitive impairments and focal neurological deficits. This patient with a history of malnutrition, ophthalmoplegia, and an MRI showing degeneration of the mammillary bodies likely has another underlying condition.

B. Frontotemporal dementia 

❌ Incorrect: Frontotemporal dementia is characterized by personality changes, early loss of inhibitions, hyperorality and frontotemporal atrophy on radiological imaging. Opthalmoplegia, memory loss and degeneration of the mammillary bodies are not typical.

C. Alzeihmer dementia

❌ Incorrect: Radiological investigations in Alzheimer dementia can include widespread cortical atrophy, particularly in the area of the hippocampus. Insidious memory loss and impairment of visuospatial skills are typical of Alzheimer dementia. However, in the setting of chronic alcohol use, degeneration of the mammillary bodies, and observed ophthalmoplegia, thiamine deficiency is the most likely diagnosis.

D. Lewy body dementia

❌ Incorrect: Lewy body dementia typically presents with cognitive impairment, Parkinsonism features and visual hallucinations. This patient’s acute-onset confusion and ophthalmoplegia are suggestive of another condition.

E. Korsakoff syndrome

✅ Correct: See Main Explanation.

Explanation

This patient’s confusion and ophthalmoplegia, in the setting of chronic alcohol use, malnutrition, and MRI findings of degeneration of mammillary bodies, are consistent with a diagnosis of Korsakoff syndrome.

Korsakoff syndrome is a complication that results from thiamine (vitamin B1) deficiency. Thiamine deficiency should be suspected in patients with a history of chronic alcohol use, IBD, malnutrition, malabsorption syndromes, and those on prolonged total parenteral nutrition. Thiamine is a cofactor involved in the function of enzymes such as pyruvate dehydrogenase (links glycolysis to TCA cycle) and alpha ketoglutarate dehydrogenase (TCA cycle). These enzymes play a crucial role in glucose metabolism. In the absence of thiamine, glucose metabolism is impaired, which can lead to ATP depletion and result in neuronal dysfunction/death.

Korsakoff syndrome is characterized by anterograde (inability to form new memories) and retrograde amnesia. Confabulation is also commonly encountered, wherein patients create false stories to make up for the lapses in memory.  A clinical diagnosis is often sufficient to make a diagnosis. Radiological investigations, such as an MRI, can help differentiate causes of dementia that can mimic the presentation of Korsakoff syndrome. MRI scan will reveal necrosis or hemorrhage of the mammillary bodies and other periventricular regions including the anterior and dorsomedial thalamic nuclei. Laboratory investigations will reveal a reduced blood thiamine concentration. The memory deficit in Korsakoff syndrome is irreversible and generally permanent. Thiamine should be administered to all patients who present with Wernicke encephalopathy to prevent the irreversible neuronal damage that could result in Korsakoff syndrome. 

22. A 42-year-old man comes to the volunteer medical center of a large refugee camp with generalized fatigue and diarrhea over the past 2 days. He has also noticed increased hair loss in the last 2 months. He states he has had to frequently skip meals due to famine. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 20/min, and blood pressure is 135/85 mmHg. BMI is 18 kg/m2. He is alert, cooperative and oriented to time, place and person. Serum chemistry panel, complete blood count, and thyroid function tests are found to be normal. Further testing reveals a vitamin deficiency that leads to impaired production of coenzyme A and reduced fatty acid synthesis. Which of the following can be expected on further evaluation, considering the most likely diagnosis?

A. Peripheral neuropathy

✅ Correct: See Main Explanation.

B. Memory loss

❌ Incorrect: Korsakoff syndrome is a complication of thiamine deficiency that presents with loss of anterograde amnesia, retrograde amnesia, and confabulation. Thiamine pyrophosphate acts as a cofactor for decarboxylation of several alpha-keto acids involved in glucose metabolism. It is not a component of coenzyme A and is not involved in fatty acid synthesis.

C. Petechiae and bleeding gums

❌ Incorrect: Ascorbic acid plays an important role in collagen synthesis by inducing hydroxylation of proline and lysine. Deficiency of vitamin C results in bleeding gums, petechiae and subperiosteal hemorrhages. It is not a component of coenzyme A.

D. Diminished proprioception 

❌ Incorrect: Vitamin B12 acts as a cofactor for methionine synthase and methylmalonyl-CoA synthase. It plays a role in synthesis of DNA and RNA, methionine synthesis, and maintenance of myelin. It can cause subacute combined degeneration of the spinal cord affecting the dorsal column, resulting in peripheral neuropathy as well as a diminished sense of proprioception. However, vitamin B12 is not a component of coenzyme A and is not involved in fatty acid synthesis.

E. Subperiosteal hemorrhages

❌ Incorrect: Ascorbic acid plays an important role in collagen synthesis by inducing hydroxylation of proline and lysine. Deficiency of vitamin C results in bleeding gums, petechiae and subperiosteal hemorrhages. It is not a component of coenzyme A.

Explanation

This patient has generalized symptoms which include fatigue, diarrhea and alopecia. Vitamin B5, also known as pantothenic acid, is an essential component of coenzyme A (a cofactor for acyl transfers in the TCA cycle and fatty acid synthesis and breakdown) and fatty acid synthase. Vitamin B5 also plays a role in activation of many peptide hormones, including adrenocorticotropic hormone (ACTH). Coenzyme A plays an important role in the synthesis of fat-soluble vitamins (e.g., vitamins A, D), as well as the synthesis of steroids, carbohydrates, and proteins.

Pantothenic acid deficiency is uncommon, as it is readily available in most dietary sources including egg yolk, milk, whole grains, and meat. However, it can be encountered in patients with severe malnutrition, which can be seen in countries undergoing famine and/or war. Clinical manifestations of vitamin B5 deficiency include peripheral neuropathy  (paresthesias, tingling, numbness, dysesthesias), dermatitis, alopecia and enteritis. It can also cause adrenal insufficiency because of its vital role in synthesizing ACTH.

23. A 32-year-old woman comes to her primary care physician with worsening depression and frequent falls. She has had difficulty sleeping at night and has frequently been stumbling over herself while walking. The patient states “my legs feel numb all the time.” Her partner, who is also present during the visit, states that the patient has not been herself lately and has been eating less since her mother passed away. Past medical history is notable for Crohn disease, depression, and Graves disease. She drinks alcohol socially, occasionally smokes marijuana, and adheres to a vegan diet. Her temperature is 37.0°C (98.6°F), pulse is 67/min, respirations are 14/min, blood pressure is 110/74 mmHg, and O2 saturation is 98% on room air. Physical examination is notable for a sad affect, an ataxic gait, as well as paresthesias and hyperactive deep tendon reflexes in the lower extremities bilaterally. Laboratory testing reveals the following results:  

Laboratory Value	Result
Hemoglobin	10.5 g/dL
Leukocyte count	1,000/mm3
Platelet count	90,000/mm3
Mean corpuscular volume	115 μm3

Which of the following is the most likely etiology of this patient’s symptoms? 

A.  Cobalamin deficiency 

✅ Correct: See Main Explanation. 

B. Tertiary syphilis 

❌ Incorrect: Tabes dorsalis is caused by tertiary syphilis and arises due to degeneration and demyelination of the dorsal columns and roots. While tabes dorsalis may present with worsening ataxia, it also presents with absent deep tendon reflexes, as opposed to hyperactive reflexes. Furthermore, tabes dorsalis is commonly associated with pupils that display “light-near dissociation” or Argyll Robertson pupils.  

C. Acute inflammatory demyelinating polyneuropathy

❌ Incorrect: Guillain-Barre syndrome is characterized by demyelination due to autoimmune inflammation and is often triggered by infections. However, Guillain-Barre syndrome presents with only signs of lower motor neuron dysfunction, which would not account for this patient’s hyperreflexia. Moreover, Guillain-Barre syndrome may cause autonomic instability and respiratory difficulties. 

D.  Multiple sclerosis 

❌ Incorrect: This patient has a history of autoimmune conditions, which increases her risk of developing multiple sclerosis. However, this patient’s macrocytic anemia and depressive symptoms are more suggestive of vitamin B12 deficiency as the underlying etiology.   

E. Posterior spinal cord infarction

❌ Incorrect: An infarction of the posterior spinal cord would injure the dorsal column, resulting in symptoms of ataxia and proprioceptive disturbances. The condition can arise in the setting of vasculopathy or trauma. However, posterior spinal cord infarction is more likely to present with acute neurological findings.  

Explanation

This patient with a history of Crohn disease presents with findings of depression, ataxia, hyperreflexia, and paresthesias. She also consumes a vegan diet and is found to have a macrocytic anemia, thrombocytopenia, and leukopenia on her complete blood count. Together these findings are consistent with vitamin B12 deficiency and subsequent subacute combined degeneration of the spinal cord.    

Vitamin B12, or cobalamin, is a water-soluble vitamin essential for proper neuronal functioning. It may become deficient due to malabsorptive disease (e.g., Crohn disease, pernicious anemia), dietary restriction (e.g. veganism), or medications (e.g., metformin, proton pump inhibitors) that interfere with cobalamin absorption. When physiologic stores of vitamin B12 are low, levels of methylmalonic acid increase. This accumulation causes degeneration of the myelin sheath of the spinocerebellar, lateral corticospinal, and dorsal column pathways, resulting in subacute combined degeneration (SCD). SCD manifests with symptoms of gait ataxia, paresthesias, and impaired position/vibration sense. Furthermore, SCD can cause neuropsychiatric symptoms including worsening depression or signs of dementia.    

Additional signs of vitamin B12 deficiency include megaloblastic anemia, thrombocytopenia, and leukopenia, since vitamin B12 is essential for nucleotide synthesis and cell division.
 

24. A 29-year-old woman is brought to the emergency department by her partner for evaluation of progressive confusion. She also complains of nausea and vomiting for the past 24-hours. Past medical history is significant for asthma and a chronic cough for the past year. The patient has had 2 episodes of uveitis in the past 6 months treated with topical therapy. Current medications include vitamin supplementation and inhaled albuterol as needed. Family history is noncontributory. She does not use tobacco, alcohol, or illicit drugs. Temperature is 37.2 C (98.9 F), pulse is 98/min, respirations are 18/min and blood pressure is 100/60 mmHg. Physical examination shows dry mucous membranes and multiple tender pink-to-reddish nodules below the knee. Chest x-ray shows bilateral hilar lymphadenopathy. Laboratory studies are performed and shown below. Serum ACE levels are increased. HIV testing is negative. Which of the following serum substance levels is most likely to be increased in this patient?
 

Laboratory value	Result
Serum chemistry
Sodium	132 mEq/L
Potassium	4.2 mEq/L
Chloride	95 mEq/L
Calcium	11.8 mg/dL
Creatinine	0.8 mg/dL
Blood urea nitrogen	20 mg/dL

A. Retinol

❌ Incorrect: Retinol is a form of vitamin A, and its toxicity is rare even in patients taking vitamin A supplements, as its metabolism is highly-regulated. When acute toxicity does occur, it can cause yellow-tinged skin, nausea, vomiting, vertigo, and blurry vision. This patient’s presentation with hypercalcemia in the setting of likely sarcoidosis is suggestive of vitamin D toxicity.  

B. Lead

❌ Incorrect: Elevated serum lead levels can present with similar symptoms, but this patient’s hypercalcemia, increased ACE levels, and bilateral hilar lymphadenopathy are suggestive of vitamin D toxicity secondary to an underlying condition.  

C. 1,25-hydroxyvitamin D

✅ Correct: See Main Explanation.

D. Zinc

❌ Incorrect: Elevated serum zinc levels are rare even with the ingestion of excess zinc supplementation. If present, it can present with nonspecific gastrointestinal symptoms, including abdominal pain, diarrhea, nausea, and vomiting. This patient’s presentation is more likely suggestive of vitamin D toxicity due to granulomatous lung disease.  

E. Iron

❌ Incorrect: Elevated serum iron levels can occur in children with ingestion of iron tablets and presents with abdominal pain, vomiting, diarrhea, hematemesis, melena and lethargy. This patient’s presentation with hypercalcemia, increased ACE levels, and bilateral hilar lymphadenopathy is suggestive of vitamin D toxicity due to granulomatous lung disease.  

Explanation

This patient’s symptoms of confusion and gastrointestinal disturbances in the setting of elevated serum calcium levels, history of uveitis, erythema nodosum on lower extremities, and bilateral hilar lymphadenopathy is suggestive of hypercalcemia secondary to elevated 1,25-hydroxyvitamin D (1,25(OH)D) levels in sarcoidosis.   

Sarcoidosis is a granulomatous multisystem disease that can cause hypercalcemia due to the granulomatous activity of 1ɑ-hydroxylase in macrophages which increases the activation of vitamin D to 1,25-hydroxyvitamin D (i.e. the most active form of vitamin D) and thus increases intestinal calcium absorption. Besides sarcoidosis, other chronic granulomatous diseases (e.g. tuberculosis), lymphomas (e.g. Hodgkin lymphoma) and, less frequently, other illnesses characterized by granuloma formation (e.g. granulomatosis with polyangiitis (GPA)) can also cause vitamin D toxicity. Excess use of vitamin D supplements is another etiology.  

25. A 25-year-old primigravida at 40 weeks gestation comes to the emergency room in active labor. She received inconsistent prenatal care and did not take daily prenatal vitamins. Her past medical history includes rheumatoid arthritis managed with methotrexate, which she used throughout pregnancy. She did not smoke, consume alcohol or use illicit drugs during the course of her pregnancy. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 20/min, and blood pressure is 125/85 mmHg. She delivers a male infant with APGAR scores of 8 and 9 at 1 and 5 minutes respectively. Weight is 2.5 kg. Considering her past medical history, which of the following embryological defects is likely in this newborn? 

A. Failure of obliteration of the processus vaginalis

❌ Incorrect: Congenital hydrocoele results from failure of obliteration of the processus vaginalis. This condition is not associated with methotrexate use.

B. Failure of neural crest migration

❌ Incorrect: Hirschsprung disease results from the failure of neural crest migration to the sigmoid colon/rectum. It is associated with RET gene mutations. A history of methotrexate use throughout pregnancy does not increase the risk of developing Hirschsprung disease.

C. Displacement of tricuspid valve leaflets into right ventricle 

❌ Incorrect: Ebstein anomaly is characterized by displacement of the tricuspid valve leaflets into the right ventricle, resulting in atrialization of the ventricle. Exposure to lithium, a pharmacological agent used in the treatment of mood disorders, can cause Ebstein anomaly. This patient’s methotrexate use throughout pregnancy, however, puts the infant at increased risk of another condition.

D. Abnormal neural tube closure

✅ Correct: See Main Explanation.

E. Impaired recanalization of the duodenal lumen

❌ Incorrect: Duodenal atresia causes bilious emesis in a newborn and results from impaired recanalization of the duodenal lumen. This congenital anomaly is associated with Down syndrome. A history of methotrexate use does not increase the risk of developing Down syndrome. Instead, a history of previous trisomies or structural anomalies and advanced maternal age are risk factors for Down syndrome.

Explanation

This pregnant patient has a history of rheumatoid arthritis managed with methotrexate, and she received minimal prenatal care, including lack of prenatal vitamin use. Methotrexate is contraindicated in pregnancy as it inhibits dihydrofolate reductase, arresting DNA synthesis. This history puts the neonate at an increased risk of developing neural tube defects due to folate deficiency. Folic acid is a water-soluble vitamin that is converted to tetrahydrofolate (THF), which acts as a methylation donor for reactions that involve the synthesis of nitrogenous bases for DNA and RNA.

Pregnancy is a period of increased need for folate supplementation, as the requirements of folic acid increases. Supplemental folate administration is given to all women who are attempting conception or are capable of conception as a component of preconception counselling because the neural tube begins development as early as the third week of gestation. Offending medications that can impair folic acid synthesis, function, or absorption need to be stopped and switched to alternatives for the duration of pregnancy. In the absence of folate supplementation and use of offending medications that inhibit folic acid absorption or function (e.g., methotrexate, phenytoin, and carbamazepine), neurulation is impaired.

Neural tube defects are congenital anomalies that develop when the neural tube fails to close normally during the third and fourth weeks of gestation. Neural tube defects may be open (e.g., myelomeningocele, meningocele, encephalocele, and anencephaly) or closed (e.g., spina bifida occulta). Spina bifida is a group of neural tube defects that result from failure of posterior neural tube closure secondary to folate deficiency. Prenatal evaluation of all neural tube defects would reveal an increase in fetal alpha fetoprotein.

26. A 42-year-old woman comes to the clinic with generalized fatigue and a sore throat for the past week. She has a 15-year history of celiac disease that is poorly controlled with diet, and she frequently has large, bulky stools multiple times per day. Past medical history also includes seborrheic dermatitis. Temperature is 37.0°C (98.6°F), pulse is 96/min, respirations are 20/min, and blood pressure is 135/85 mmHg. BMI is 19 kg/m2. She is alert, cooperative, and oriented to time, place, and person. Oral examination reveals hyperemia of pharyngeal membranes, edema of mucous membranes, glossitis and stomatitis.

On cardiac auscultation, S1 and S2 are normal, and no murmurs or gallops are heard. Laboratory investigations are shown below:

 

Laboratory value	Result
Complete blood count
Hemoglobin	9 g/dL
Leukocyte count	5,000 /mm3
Platelet count	150,000/mm3
MCV	88 fL

An underlying water-soluble vitamin deficiency is suspected. Which of the following biochemical conversions are impaired, considering the most likely deficiency in this patient?

A. Histidine to histamine

❌ Incorrect: The conversion of histidine to histamine is a transamination reaction that involves the cofactor vitamin B6 (pyridoxine). Pyridoxine deficiency manifests as peripheral neuropathy and dermatitis.

B. Alpha ketoglutarate to succinyl-CoA

❌ Incorrect: The conversion of alpha ketoglutarate to succinyl-CoA requires the cofactor thiamine pyrophosphate. Thiamine deficiency can manifest as dry beriberi (peripheral neuropathy), wet beriberi (high-output congestive cardiac failure), or Wernicke-Korsakoff syndrome (confusion, memory loss, ophthalmoplegia, and ataxia). Oral manifestations alone would not indicate a thiamine deficiency.

C. Pyruvate to acetyl-CoA

❌ Incorrect: Pyruvate to acetyl-CoA is a dehydrogenase reaction that links glycolysis to the citric acid cycle. It requires thiamine as a cofactor. This patient has no signs of thiamine deficiency (peripheral neuropathy, cognitive dysfunction, ophthalmoplegia), making another vitamin deficiency more likely.

D. Succinate to fumarate

✅ Correct: See Main Explanation.

E. Methylmalonyl-CoA to succinyl-CoA

❌ Incorrect: Vitamin B12 is a cofactor for the conversion of methylmalonyl-CoA to succinyl-CoA involving the enzyme methylmalonyl-CoA synthase. Vitamin B12 causes megaloblastic anemia, subacute combined degeneration of the spinal cord, and peripheral neuropathy. This patient has predominantly oral manifestations and normocytic anemia, suggesting a different vitamin deficiency.

Explanation

This patient likely has a riboflavin deficiency, considering her history of active celiac disease and seborrheic dermatitis, with physical examination findings of stomatitis, glossitis and cheilitis.

Riboflavin is a water-soluble vitamin that is the precursor of coenzymes FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide). FAD is a known component of the succinate dehydrogenase complex that is involved in the conversion of succinate to fumarate, a step in the TCA cycle and a component of the electron transport chain. FMN is a component of complex I of the ETC that donates electrons and gets oxidized in the electron transport chain.

Patients with malabsorptive syndromes like active celiac disease, short bowel syndrome and anorexia nervosa are at an increased risk of developing riboflavin deficiency. Lactose intolerance and a diet deficient in dairy increases the risk of riboflavin deficiency, as dairy products are a rich source of vitamin B2. Clinical manifestations of riboflavin deficiency include stomatitis, cheilitis and hyperemia of pharyngeal mucous membranes. Laboratory findings typically reveal normocytic anemia.

27. A 45-year-old man goes to the clinic because of progressive gait instability, dysmetria and dysarthria for the past several months. He was a part of a local basketball team and had to quit recently because of his poor performance. Past medical history is significant for celiac disease, hypertension, diabetes, and atrial fibrillation. Current medication includes lisinopril, metformin, and warfarin.  Family history is noncontributory. Vitals are within normal limits. Physical examination shows mucosal pallor and reduced muscle mass. Examination of lower extremities show bilateral motor weakness and loss of deep tendon reflexes and sensation to joint position and vibration. Current INR is 2.5. Laboratory results are shown:  
 

Laboratory features
Laboratory value	Result
Hemoglobin	9 g/dL
Leukocyte count	8,000/mm3
Platelet count	230,000/mm3
Mean corpuscular volume	85/μm3
Reticulocyte count	4%

The patient is started on high-dose tocopherol supplementation. Which of the following complications is this patient at increased risk for due to this medication?

A. Hemorrhage

✅ Correct: See Main Explanation

B. Fragility fracture

❌ Incorrect: Although vitamin E toxicity can present with muscle weakness, fragility fractures are more commonly associated with vitamin D deficiency, which is required for bone mineralization.

C. Nephrolithiasis

❌ Incorrect: Nephrolithiasis is associated with large-doses of vitamin C. Oxalate is a metabolite of vitamin C, so high vitamin C intake could increase the risk of calcium oxalate kidney stones. Tocopherol does not increase the risk of nephrolithiasis.

D. Idiopathic intracranial hypertension

❌ Incorrect: Chronic vitamin A toxicity has been linked to the development of idiopathic intracranial hypertension. Tocopherol does not increase the risk of idiopathic intracranial hypertension.

E. Paraesthesias

❌ Incorrect: Vitamin B12 and vitamin E deficiency can cause demyelination of peripheral nerves and spinal tracts leading to paraesthesias. Tocopherol supplementation could improve these symptoms if they were due to vitamin E deficiency.

Explanation

This patient’s neurological symptoms of gait instability, decreased position and vibration sense, and ataxia in combination with hemolytic anemia (normocytic anemia with reticulocytosis) is most likely suggestive of vitamin E deficiency secondary to long-term fat malabsorption due to underlying celiac disease.  

Vitamin E is a fat-soluble vitamin that is widely available in the diet. Its deficiency is rare but can occur with fat malabsorption (e.g., cystic fibrosis and celiac disease) or abetalipoproteinemia (mutations in the microsomal triglyceride transfer protein). Its toxicity is rare but could result from high-dose supplements. Excess vitamin E may interfere with vitamin K metabolism and increase the anti-coagulation effects of warfarin, thus increasing the risk of bleeding and hemorrhage. Usually, elevated vitamin E levels have no symptoms, but they may cause muscle weakness, fatigue, nausea, and diarrhea.   

28. A 5-year old girl presents to the clinic for a well-child check. She was recently adopted from a refugee camp in Southeast Asia, and her biological family history is unknown. Her parents are concerned that she appears very thin but has a large protuberant abdomen. Temperature is 37°C (98.6°F), pulse is 90/min, respirations are 14/min and blood pressure is 110/70 mmHg. On physical exam, she appears irritable and minimally consolable by her mother. Examination reveals a distended abdomen, bilateral pitting edema, and muscle wasting. Laboratory results are significant for hypoalbuminemia, anemia, and hypophosphatemia. What is the most likely cause of edema seen in this patient’s condition? 

A. Decreased hydrostatic pressure in blood vessels

❌ Incorrect: Increased hydrostatic pressure results in edema. Per the Starling equation, when the hydrostatic pressure is greater in either the intravascular or interstitial space, the fluid will tend to move toward the area of lower pressure.  

B. Decreased plasma oncotic pressure

✅ Correct: See Main Explanation. 

C. Increased lipid absorption

❌ Incorrect: Edema would occur when lipid absorption is decreased, as there is less oncotic pressure inside the vessels to drive fluid inside. 

D. Increased liver protein synthesis

❌ Incorrect: Protein synthesis is decreased in Kwashiorkor, as it is a severe protein deficiency. Lack of protein leads to decreased intravascular oncotic pressure and therefore increased movement of fluid into the interstitial space. 

E. Increased lymphatic circulation

❌ Incorrect: Lymphatic circulation is impaired in Kwashiorkor. Since there is less lymphatic drainage, fluid will build up in the interstitial space leading to edema. Lymphatic obstruction can occur with infections, injury, radiation therapy, surgery, and tumors. 

Explanation

This patient is suffering from Kwashiorkor. Kwashiorkor is a severe protein deficiency in the setting of sufficient calorie intake. Patients present with bilateral pitting edema, abdominal distention, hepatomegaly, muscle wasting, hair thinning, dermatitis, skin/hair depigmentation, irritability, and immunosuppression.  

Laboratory studies may show hypoglycemia, decreased blood lipids, hypoalbuminemia, hypoproteinemia, anemia, as well as severe electrolyte derangements (e.g., hypophosphatemia, hypomagnesemia, hypokalemia). Treatment includes prophylactic antibiotics, electrolyte correction, hydration, and gradual protein refeeding. Excessive rapid refeeding can lead to protein catabolism, which can cause urea accumulation that may overwhelm the liver and ultimately result in liver failure.    

The movement of fluid is determined by Starling forces (or pressures). There are 2 types of forces acting within and outside of the capillaries that control the net movement of water in the vessels and tissues. For the purpose of this question, Kf and σ can be ignored.  

There are several main driving factors that contribute to edema seen in Kwashiorkor.  Children with Kwashiorkor have profoundly low levels of albumin due to decreased liver protein synthesis, and, as a result, become intravascularly depleted. This decreased oncotic pressure in blood vessels is the primary disturbance. Subsequently, antidiuretic hormone (ADH) increases in response to the severe hypovolemia, resulting in edema. Plasma renin also responds aggressively, causing sodium retention, worsening the edema.  

 An important distinction from Kwashiorkor is another condition seen in resource-deprived areas is Marasmus. While Kwashiorkor is a disease of edematous malnutrition (sufficient caloric intake with deficient protein intake), Marasmus is known as the wasting syndrome (deficient caloric intake and deficient protein intake). In contrast to Kwashiorkor, children with Marasmus do not have edema. Instead, children typically have a depletion of body fat stores, low weight for height, and reduced mid-upper arm circumference.

29. A 68-year-old woman comes to the clinic with generalized fatigue over the last 2 months. She has also noticed painful mouth ulcers. She states she has been consuming a “tea and toast” diet for the past 6 months in an effort to be “healthier.” Her other medical conditions include type 2 diabetes mellitus, hypertension, hypercholesterolemia and psoriasis. Her current medications include lisinopril, methotrexate, hydrochlorothiazide, NPH insulin and atorvastatin. Temperature is 37.0°C (98.6°F), pulse is 94/min, respirations are 18/min, and blood pressure is 135/95 mmHg. She is oriented to time, place and person. The patient has conjunctival pallor. Neurologic examination shows normal motor strength but decreased touch and pain sensation in the bilateral lower extremities. Complete blood count reveals a hemoglobin of 9 g/dL. HbA1c level is 9.4%. Thyroid function tests are within normal limits. Serum homocysteine levels are elevated, and serum methylmalonic acid levels are within normal limits. Peripheral smear reveals hypersegmented neutrophils and macrocytosis. A deficiency of which of the following vitamins are responsible for this patient’s symptoms?  

A. Cobalamin

❌ Incorrect: Cobalamin (vitamin B12) deficiency is one of the differentials for a peripheral smear that includes macrocytes and hypersegmented neutrophils, since its deficiency can inhibit DNA synthesis for hematopoietic cells. Clinical manifestations would include oral ulcers, peripheral neuropathy and anemia. However, methylmalonic acid (MMA) levels would be elevated, as B12 acts as a cofactor for methylmalonyl-CoA mutase. This patient’s distal neuropathy is likely due to her uncontrolled diabetes, as indicated by her elevated HbA1c levels.

B. Pyridoxine

❌ Incorrect: Pyridoxine (vitamin B6) deficiency manifests with peripheral neuropathy and oral manifestations. Since it is a cofactor for heme synthesis (ALA synthase), its deficiency can cause sideroblastic anemia, not macrocytosis and hypersegmented neutrophils, as seen on this patient’s peripheral smear.

C. Thiamine 

❌ Incorrect: Thiamine (vitamin B1) deficiency can cause dry beriberi (peripheral neuropathy) and signs of anemia. However, laboratory investigations would not reveal elevated homocysteine levels or megaloblastic anemia. Laboratory findings in thiamine deficiency may reveal decreased serum erythrocyte transketolase activity.

D. Folic acid 

✅ Correct: See Main Explanation.

E. Riboflavin

❌ Incorrect: Riboflavin deficiency can present with normocytic anemia and oral manifestations including aphthous ulcers, cheilosis and stomatitis. However, laboratory findings indicating macrocytic, megaloblastic anemia and raised homocysteine levels would be unlikely.

Explanation

This patient has a history of methotrexate use, restricted diet, symptoms of anemia (e.g., fatigue, tachycardia, pallor), and laboratory investigations indicating raised homocysteine levels and normal methylmalonic acid levels. This presentation is suggestive of a folate deficiency.

The timeline of symptom onset is important when distinguishing between folate deficiency and vitamin B12 deficiency, since both cases result in a macrocytic anemia. Most vitamin B12 reserves are stored in the liver, and unless dietary intake or absorption ceases, vitamin B12 deficiency will not develop for one to two years or longer. In contrast, folate stores can be depleted over weeks to months, especially in conditions that necessitate a higher folate requirement, such as pregnancy, or in patients taking antifolate medications (e.g., methotrexate, anticonvulsants).44

Macrocytic, megaloblastic anemia has a broad differential which includes folic acid and vitamin deficiencies. Folate and vitamin B12 play key roles in the synthesis of nitrogenous bases in DNA and RNA. A deficiency in either of these vitamins can impair hematopoietic cell synthesis and result in macrocytosis. Vitamin B12 deficiency is also more likely to be associated with neurological deficits including dementia, peripheral neuropathy and subacute combined degeneration, as it serves as a cofactor for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. In cobalamin’s absence, methylmalonic acid (MMA) accumulates and disrupts myelin synthesis. In this patient’s case, however, peripheral neuropathy is more likely to be a result of diabetic neuropathy, as suggested by her elevated HbA1c level, as opposed to a vitamin deficiency.

Laboratory investigations help differentiate vitamin B12 deficiency from folate deficiency. Serum methylmalonic acid levels and homocysteine levels would be elevated in vitamin B12 deficiency, whereas in folate deficiency although homocysteine levels are elevated, MMA levels would be normal.

30. A 32-year-old woman in the intensive care unit is brought to the attention of the on-call physician for acute mental status changes shortly after a nurse initiated dextrose supplementation. She was admitted to the hospital 1 week ago for severe acute pancreatitis. Past medical history includes anorexia nervosa and 2 hospital admissions in the past year for alcohol withdrawal. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 18/min, and blood pressure is 125/85 mmHg. BMI is 17.5 kg/m2. She is confused and disoriented to time, place and person. Pupils are equal and reactive, and horizontal nystagmus is elicited on lateral gaze. Fundoscopy is normal. Motor strength is 5/5 in the upper extremities and 2/4 in bilateral lower extremities. Deep tendon reflexes of the knee and ankle are 1+ bilaterally. Rapid glucose test is 70 mg/dL. Laboratory investigations are noncontributory. Which of the following enzymes is likely inhibited considering the most likely diagnosis in this patient?

A. Methionine synthase

❌ Incorrect: Methionine synthase is an enzyme that converts homocysteine to methionine and uses vitamin B12 as a cofactor for this conversion. Vitamin B12 deficiency is characterized by macrocytic, megaloblastic anemia and neurological symptoms like peripheral neuropathy and subacute combined degeneration of the spinal cord. Opthalmoplegia and acute confusion would be unlikely.

B. Methylmalonyl-CoA synthase

❌ Incorrect: Vitamin B12 deficiency inhibits the function of the enzyme of methylmalonyl-CoA synthase, which converts methylmalonyl-CoA to succinyl-CoA. Inhibition of this enzyme can result in irreversible nerve damage. In most cases, vitamin B12 deficiency presents with megaloblastic anemia and spinal cord involvement.

C. Pyruvate dehydrogenase

✅ Correct: See Main Explanation.

D. Pyruvate carboxylase

❌ Incorrect: Vitamin B7/biotin is a cofactor for the enzyme pyruvate carboxylase, which converts pyruvate to oxaloacetate in the TCA cycle. Biotin deficiency causes dermatitis, alopecia and enteritis. Neurological deficits are not commonly seen.

E. Succinate dehydrogenase

❌ Incorrect: Succinate dehydrogenase is an enzyme in the TCA cycle that requires cofactors such as FAD which are derived from vitamin B2/riboflavin. Riboflavin deficiency can cause cheilosis, stomatitis and corneal vascularisation. Ophthalmoplegia and confusion would be unlikely.

Explanation

This patient has symptoms of acute confusion and ophthalmoplegia in the setting of chronic malnutrition due to pancreatitis, chronic alcohol use, and anorexia nervosa. She most likely has Wernicke encephalopathy (WE). WE and thiamine deficiency should be considered in all patients with malnutrition and malabsorption, including patients with a history of chronic alcohol use, malabsorption syndromes, and those receiving total parenteral nutrition.

WE is an acute neurological condition resulting from thiamine deficiency and is characterized by a clinical triad of ophthalmoparesis with nystagmus, ataxia, and confusion. Thiamine is a crucial cofactor involved in the function of various enzymes, including:

•  pyruvate dehydrogenase, which is crucial in forming acetyl-CoA, which is then used in the citric acid cycle (TCA) 
•  alpha ketoglutarate dehydrogenase, which is used in the citric acid cycle 

In the absence of thiamine, these crucial biochemical processes are impaired, resulting in an accumulation of lactate and pyruvate, which can cause metabolic imbalances leading to neurologic complications including neuronal cell death. WE affects specific areas of the brain which include the brainstem, the cerebellum, and the mammillary bodies.

A diagnosis can be made based on clinical suspicion alone. However, confirmation with a decreased blood thiamine level, decreased erythrocyte transketolase activity, and degenerated mammillary bodies on MRI imaging can aid the diagnosis. WE is a reversible condition that requires a thiamine infusion. With a high glucose intake, the requirement for thiamine increases in order to assist in the breakdown of glucose through the Krebs cycle, and thus a glucose infusion can induce or worsen WE. If glucose (dextrose) is administered prior to thiamine replacement, it would be converted to lactic acid, and as a result, it would precipitate WE in susceptible populations such as those with chronic alcohol use and malnourished patients (e.g. anorexia nervosa).
 

31. A 45-year-old man comes to the clinic in winter for evaluation of recurrent pruritus, flushing and paraesthesias over his face and chest. He was diagnosed with hypertension and hypercholesterolemia last week, and he was started on hydrochlorothiazide and supplemental niacin. He states the symptoms typically occur 30 minutes after taking his medications at night. He does not have trouble breathing during these episodes. His past medical history includes seasonal rhinitis that is well managed with cetirizine. Temperature is 37.0°C (98.6°F), pulse is 82/min, respirations are 20/min, and blood pressure is 135/95 mmHg. BMI is 32 kg/m2. Physical examination is within normal limits. Which of the following is the most likely mechanism for this patient’s adverse reaction?  

A. T-cell release of inflammatory mediators

❌ Incorrect: Acute allergic contact dermatitis presents with vesicular, weeping erythematous lesions. It typically occurs after exposure to environmental toxins, such as urushiol from poison ivy or nickel found in watches and necklaces. This patient has facial flushing and pruritus, not formation of vesicular, erythematous lesions, that occurs daily shortly after taking medication, which suggests a different etiology.

B. IgE-dependent mast cell degranulation

❌ Incorrect: IgE-dependent mast cell degranulation is associated with type I hypersensitivity, which is commonly encountered with the use of beta lactam antibiotics such as cephalosporins and penicillins. Other triggers include environmental exposure to pollen, dust and other allergens, which are typically encountered in the spring and summer (and therefore, would be unlikely in the winter). Considering the acuity of these symptoms, in conjunction with the recent initiation of niacin, this is unlikely to be the pathogenic mechanism involved.

C. IgE-independent mast cell degranulation 

❌ Incorrect: Use of drugs such as opioids, vancomycin, and radiocontrast dyes can result in IgE-independent mast cell degranulation by activation of protein kinase A. This patient does not have a history of receiving these medications.

D. Prostaglandin-mediated vasodilation 

✅ Correct: See Main Explanation.

E. Inhibition of prostaglandin synthesis

❌ Incorrect: Patients with chronic idiopathic urticaria are prone to developing urticaria following aspirin or NSAID use, since these medications inhibit the prostaglandin pathways and promote leukotriene synthesis. This patient is not taking these medications, making this pathogenesis less likely.

Explanation

This patient with symptoms of flushing, paraesthesia and pruritus after initiation of a lipid-lowering agent (niacin) has a presentation consistent with niacin toxicity.

Niacin is a lipid-lowering agent that inhibits lipoprotein lipase in adipose tissue and reduces hepatic VLDL synthesis. However, its use is limited to those with intolerance to standard therapy with statins due to its poor side effect profile. Clinical features associated with niacin toxicity include flushing (erythema, itching, warmth) of the face, neck and chest, paresthesias and pruritus. Other symptoms include nausea, vomiting and diarrhea. Flushing is mediated by prostaglandin (PGD2) release resulting in vasodilation of skin arterioles, which commonly lasts up to 30 minutes after niacin administration. While the flushing can be concerning to the patient, it is self-limiting and does not require medication; however, it can typically be prevented by pretreatment with aspirin or other NSAIDs due to their anti-prostaglandin properties.

Niacin can also lead to hyperglycemia, glucose intolerance and insulin resistance, and therefore, its use is avoided in susceptible patients and those with overt diabetes mellitus. It can cause hyperuricemia and can precipitate acute gout flares in patients with a history of gouty arthritis. With prolonged use, niacin is also known to cause hepatotoxicity.  

32. A 56-year-old individual presents to the emergency department after being found wandering the streets aimlessly. According to emergency services, the patient was uttering “nonsense” to bystanders on the street who then proceeded to call an ambulance. Chart review demonstrates the patient has a history of recurrent presentations to the emergency department for alcohol intoxication. Vital signs are within normal limits. On physical examination, the patient appears disheveled and provides minimal responses when asked how they arrived at the emergency department. Gait examination is normal. A blood alcohol level is undetectable, and a urine drug screen is within normal limits. Head CT is noncontributory. Which of the following clinical manifestations is most characteristic of this condition? 

A. Anterograde amnesia 

✅ Correct: See Main Explanation. 

B. Unilateral paralysis

❌ Incorrect: Unilateral paralysis can be seen in patients with strokes. Strokes can also be an inciting cause of acute delirium; however, this patient’s negative CT scan and past medical history suggest a different etiology.  

C. Visual hallucinations

❌ Incorrect: Visual hallucinations are not characteristic of Korsakoff syndrome; they are more commonly observed in toxic ingestion, severe alcohol withdrawal, or delirium.  

D. Stereotyped vocal and motor tics

❌ Incorrect: Tourette syndrome is characterized by vocal and motor tics. Korsakoff syndrome is characterized by confabulation, memory impairment, and personality changes.  

E. Autonomic instability

❌ Incorrect: Autonomic instability is one of the hallmark symptoms of delirium tremens, the most severe form of alcohol withdrawal.  

Explanation

This patient with a history of alcohol intoxication presents for evaluation of confabulation and apathy with a negative blood alcohol level and negative urine drug screen. Together, these findings are concerning Korsakoff syndrome, which is often clinically characterized by severe memory impairment, most commonly anterograde amnesia.   

Korsakoff syndrome reflects an end-point of Wernicke encephalopathy, a syndrome caused by severe thiamine deficiency in the setting of chronic alcohol use and characterized by ophthalmoplegia, ataxia, and altered mental status. If untreated, this disease ultimately results in permanent damage to the anterior and dorsomedial nuclei of the thalamus, causing Korsakoff syndrome.  

This syndrome, which is chronic and irreversible, is characterized by severe and permanent memory impairment, confabulation, as well as personality changes. In addition, patients often have a lack of insight into their condition as well as minimal content in conversation.  

33. A 35-year-old woman comes to the office because of fatigue and generalized itching that has developed over the past year. There is no visible rash, and the review of systems is otherwise unremarkable. The patient has never sought medical care before. Family history is noncontributory. She does not use tobacco, alcohol, or illicit drugs. Vitals are within normal limits. Physical examination shows mild hepatomegaly and jaundice. Laboratory studies show significant elevations in alkaline phosphatase,  and bilirubin levels. Anti-mitochondrial antibody titers are elevated. This patient is at risk of developing which of the following complications?  

A. Seborrheic dermatitis

❌ Incorrect: Seborrheic dermatitis is an inflammatory skin condition that usually presents with accumulation of scaly, greasy skin on the face, scalp, ears and eyebrows. It is commonly associated with Parkinson disease and HIV but not cholestatic liver disease.  

B. Pathologic fractures

✅ Correct: See Main Explanation.  

C. Macrocytic anemia

❌ Incorrect: Atrophic gastritis can lead to loss of production of intrinsic factor, which is responsible for vitamin B12 absorption in the intestine. B12 deficiency can cause macrocytic anemia. However, vitamin B12 is a water-soluble vitamin, and malabsorptive syndromes do not affect its absorption.  

D. Pellagra

❌ Incorrect: Pellagra (diarrhea, dementia, and dermatitis) is the manifestation of severe niacin deficiency which can result from Hartnup disease, carcinoid syndrome, or isoniazid use. However, niacin is a water-soluble vitamin, and malabsorptive syndromes do not affect its serum levels.  

E. Cardiac dilation

❌ Incorrect: Cardiac dilation can occur in patients with thiamine deficiency, which is common in patients with alcohol abuse.  However, it is a water-soluble vitamin, and malabsorptive syndromes do not affect its serum levels or intestinal absorption.  

Explanation

This patient’s presentation with fatigue, pruritus and a significant elevation in alkaline phosphatase and bilirubin in combination with elevated anti-mitochondrial antibody levels is suggestive of cholestatic liver disease -- specifically, primary biliary cholangitis (PBC).  

When PBC is longstanding, the reduction in bile flow can impair the intestinal absorption of fats and fat-soluble vitamins, which require bile salts for absorption. Vitamin D is a fat-soluble vitamin, and its deficiency in this patient can lead to pathological fractures secondary to decreased bone mineralization and subsequent osteomalacia. Common causes and risk factors associated with vitamin D deficiency are as follows:  

 

Mild-to-moderate vitamin D deficiency can be asymptomatic, whereas long-standing vitamin D deficiency results in hypocalcemia accompanied by secondary hyperparathyroidism, impaired mineralization of the skeleton, and subsequent development of osteomalacia in adults and rickets in children. Additional symptoms may include bone pain and tenderness, muscle weakness, fractures, and difficulty walking. Rarely, it can present acutely with symptoms of hypocalcemia (e.g., numbness, tingling, seizures).  

34. A 56-year-old man comes to the clinic with generalized fatigue and dyspnea on exertion that he noticed over the past month. He now becomes breathless after walking up a flight of stairs. He has also noticed numbness in his lower limbs over the last 2 weeks. Past medical history includes chronic pancreatitis. He has been drinking a pint of vodka daily for the past 25 years. Temperature is 37.0°C (98.6°F), pulse is 92/min, respirations are 19/min, and blood pressure is 135/85 mmHg. BMI is 20 kg/m2. He is alert, cooperative, and oriented to time, place, and person. Neurological examination reveals symmetrical peripheral neuropathy in a “stocking and glove” distribution with defective perception of touch and vibration sensation. Motor strength is 3/5 in the lower limbs and 5/5 in the upper limbs bilaterally. Symmetrical muscle wasting is noted in both lower limbs. Deep tendon reflexes are absent at the ankles bilaterally. On cardiac auscultation, a 3rd heart sound is heard, and the apical impulse is displaced to the 6th intercostal space. Romberg sign is negative. Laboratory investigations are shown below:

 

Laboratory value	Result
Complete blood count
Hemoglobin	13 g/dL
Hematocrit	40%
Leukocyte count	5,000/mm3
Platelet count	150,000/mm3
MCV	88 fL

Serum methylmalonic acid levels are normal. This patient’s condition is most likely associated with which of the following impaired biological processes? 

A. Purine and thymidine synthesis

❌ Incorrect: Folate deficiency inhibits purine and thymidine synthesis, as folic acid is a component of tetrahydrofolate, a coenzyme essential for the synthesis of nitrogenous bases in DNA and RNA. Most patients present with signs and symptoms of anemia with megaloblastic features on a peripheral smear.

B. Transamination of amino acids

❌ Incorrect: Pyridoxine is converted to pyridoxal phosphate, which is a cofactor used in transamination reactions. Pyridoxine deficiency causes peripheral neuropathy and seborrheic dermatitis. Dilated cardiomyopathy, as seen in this patient, would be unlikely.

C. DNA and methionine synthesis

❌ Incorrect: Vitamin B12 is a cofactor for methionine synthase and for the formation of tetrahydrofolate (involved in the synthesis of nitrogenous bases in DNA and RNA). Vitamin B12 deficiency can cause megaloblastic anemia, subacute combined degeneration of the spinal cord, and peripheral neuropathy. Although vitamin B12 levels may also cause peripheral neuropathy, this patient’s serum MMA levels are normal.

D. Hydroxylation of proline and lysine

❌ Incorrect: Vitamin C is involved in the hydroxylation of proline and lysine in collagen synthesis. Symptoms of vitamin C deficiency include swollen gums and petechiae. Neuropathy and cardiac symptoms are unlikely.

E. Decarboxylation of alpha keto acids

✅ Correct: See Main Explanation.

Explanation

This patient with symptoms of peripheral neuropathy and dilated cardiomyopathy in the setting of chronic alcohol use and malnutrition (secondary to chronic pancreatitis) has a presentation strongly suggestive of thiamine deficiency. Thiamine deficiency can cause different clinical phenotypes which include dry beriberi, wet beriberi, Wernicke encephalopathy, and Korsakoff syndrome.

Beriberi can be classified as wet or dry beriberi:

•  Dry beriberi manifests with symmetrical peripheral neuropathy with loss of perception of touch and vibration. Motor involvement can occur, and deep tendon reflexes are frequently diminished.
• Wet beriberi includes additional cardiac involvement and typically presents with the signs and symptoms of dilated cardiomyopathy, which include progressive dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, a 3rd heart sound (suggestive of volume overload of the ventricles), and shift of the apical impulse (indicating cardiomegaly). High-output congestive heart failure due to thiamine deficiency is potentially reversible with thiamine infusions. 

Thiamine is a cofactor involved in the function of enzymes such as pyruvate dehydrogenase (links glycolysis to TCA cycle) and alpha ketoglutarate dehydrogenase (TCA cycle). These enzymes play a crucial role in glucose metabolism. In the absence of thiamine, glucose metabolism is impaired, which can affect cardiac, skeletal muscle and neural tissues.  Thiamine also plays an important role in the synthesis of glutamate and GABA, as well as myelin sheath maintenance. Impairment of these processes is the proposed mechanism for both dry and wet beriberi.

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