Module 1: Deck 5/Cards 34-

Question 1

A 56-year-old Caucasian man was seen in the hematology clinic for evaluation of anemia. He had a CBC showing hemoglobin 10.5, hematocrit 32.5, WBC 6800, platelet count of 3 25,000. He was diagnosed with a mild hemolytic anemia. He was noted to have tendon xanthomas and brought with him a lipid panel drawn by his primary care clinician. He reported that he had been diagnosed with high cholesterol 5 years ago and was started on a low-fat diet, with a marked improvement in his elevated LDL cholesterol. However, he gradually stopped following the recommended diet. He had not seen his primary care provider for the past 4 years, but a checkup done 3 months ago, at which time the above anemia was diagnosed, had a lipid panel that showed a total cholesterol of 320, HDL of 50, triglycerides of 100, and LDL of 250. He was started on atorvastatin 40 mg daily and a repeat lipid panel showed total cholesterol of 290, HDL of 54, triglycerides of 90, and LDL of 220. Although his dietary adherence was not good, it had not changed since he began the atorvastatin, and he reported that he had taken his atorvastatin every day since it was prescribed. He has no other medical problems and is taking no other medications. His exam was notable for tendon xanthomas. A mutation in which gene encoding which protein likely accounts for this patient’s clinical picture?

Answer 1

ABCG8

Question 2

A 56-year-old Caucasian man was seen in the hematology clinic for evaluation of anemia. He had a CBC showing hemoglobin 10.5, hematocrit 32.5, WBC 6800, platelet count of 3 25,000. He was diagnosed with a mild hemolytic anemia. He was noted to have tendon xanthomas and brought with him a lipid panel drawn by his primary care clinician. He reported that he had been diagnosed with high cholesterol 5 years ago and was started on a low-fat diet, with a marked improvement in his elevated LDL cholesterol. However, he gradually stopped following the recommended diet. He had not seen his primary care provider for the past 4 years, but a checkup done 3 months ago, at which time the above anemia was diagnosed, had a lipid panel that showed a total cholesterol of 320, HDL of 50, triglycerides of 100, and LDL of 250. He was started on atorvastatin 40 mg daily and a repeat lipid panel showed total cholesterol of 290, HDL of 54, triglycerides of 90, and LDL of 220. Although his dietary adherence was not good, it had not changed since he began the atorvastatin, and he reported that he had taken his atorvastatin every day since it was prescribed. He has no other medical problems and is taking no other medications. His exam was notable for tendon xanthomas. What is the diagnosed disorder for this patient?

Answer 2

sitosterolemia

Question 3

What is sitosterolemia?

Answer 3

An autosomal recessive disorder caused by mutation of the small intestinal efflux transporters, ABC G5 or G8.

Question 4

In normal individuals more than 99% of circulating sterols are accounted for by cholesterol. In patients with sitosterolemia, plasma levels of sitosterol are (1) more than 50 fold and about 50% of circulating sterols are derived from (2).

Answer 4

1. increased

2. plants and shellfish

Question 5

Sitosterolemia: presenting symptoms? 3

Answer 5

Bulky tendon xanthomas, premature ASCVD and aortic stenosis

Question 6

Sitosterolemia: Why can these patients present with low level hemolysis?

Answer 6

Presumed to be due to incorporation of plant sterols into red blood cell membranes.

Question 7

Sitosterolemia: how is the diagnosis made? 3

How do these patients respond to statins?
How do they respond to diet?
What is the treatment of choice?

Answer 7

1. gas liquid chromatography (GLC)
2. gas chromatography/mass spectometry (GC/MS)
3. high pressure liquid chromatography

• blunted
• excellent LDL lowering response to dietary cholesterol restriction
• ezetimibe

Question 8

Ezetimibe: MOA?

Answer 8

reduces small intestinal absorption of cholesterol and plant sterols.

Question 9

Sitosterolemia: What additional medication can be used for sitosterolemia for LDL-C lowering?

Answer 9

bile acid sequestrants.

Question 10

A 35-year-old woman is referred to you after having a large tendon xanthoma removed from her elbow. She had a cataract removed from her left eye two years ago. Her husband, who accompanied her, mentioned that her gait had been somewhat unsteady lately. Her lipid panel showed TC 180 mg/dL, HDL-C 55 mg/dL, TG 100 mg/dL and LDL-C 105 mg/dL. Her glucose, renal and hepatic studies, TSH, and hemoglobin A1C were normal.
Which of the following mutations is the most likely cause of her clinical presentation?

A. LDL receptor binding domain abnormality
B. Apo B R3500Q
C. PCSK9 gain of function
D. CYP27A1

Answer 10

CYP27A1

Cerebrotendinous xanthomatosis (CTX)

Question 11

What is the most common cause of tendon xanthomas?

Answer 11

LDL receptor mutations leading to familial hypercholesterolemia

( Less often apo B mutations (the most common of which is apo B R3500Q), and rarely gain-of-function mutations of PCSK9 are the pathophysiologic abnormality.)

Question 12

Cerebrotendinous xanthomatosis (CTX) is what?

Answer 12

a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene encodes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis.

Question 13

Cerebrotendinous xanthomatosis (CTX): mutations in this gene result in what?

Answer 13

high serum accumulation of cholestanol, with resultant metabolic consequences.

Question 14

Patients with CTX are most often about (1) years old at the time of diagnosis and may present with adult-onset what? 2(first has 7, second has 6)

Answer 14

1. 35

2. 
progressive neurological dysfunction 
-ataxia, 
-dystonia, 
-dementia, 
-epilepsy, 
-psychiatric disorders, 
-peripheral  neuropathy, and 
-myopathy) 

premature non-neurologic manifestations

• tendon xanthomas,
• childhood onset cataracts,
• infantile-onset diarrhea,
• premature atherosclerosis,
• osteoporosis, and
• respiratory insufficiency).

Question 15

Cerebrotendinous xanthomatosis (CTX): The laboratory abnormalities found in these patients are? 6

Answer 15

• High plasma and tissue cholestanol concentration (see table below).
• Normal to low plasma cholesterol concentration
• Markedly decreased formation of chenodeoxycholic acid resulting from impaired primary bile acid synthesis
• Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma (see table below).
• Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid (CSF) resulting from changes in the blood-brain barrier
• Increased plasma lactate concentration