WBR0421

Author	[[PageAuthor::Rim Halaby, M.D. [1], Alison Leibowitz [2] (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::Endocrine
Prompt	[[Prompt::A 17-year-old female presents to the emergency room with complaints of chest pain and shortness of breath at rest. The patient takes atorvastatin for hypercholesterolemia and multiple members of her family died at a young age from myocardial infarction. Upon physical examination, you note tendon xanthomas on the Achilles tendon and arcus senilis corneae on the outer margin of the iris. Vital signs illustrate a temperature of 37 °C, heart rate of 102 beats per minute, and blood pressure of 110/70 mmHg. An electrocardiogram (ECG) reveals ST-segment elevation in the anterior leads, elevation of tropnin I levels, and low density lipoprotein-cholesterol (LDL-C) levels of 980 mg/dL. Which of the following explains the pathogenesis of this patient’s disease?]]
Answer A	AnswerA::Increased hepatocyte production of LDL
Answer A Explanation	[[AnswerAExp::The increased hepatocytes production of LDL is not the pathogenesis of FH. LDL production is frequently increased secondary to insulin resistance, diabetes mellitus, renal disease, and in obese individuals.]]
Answer B	AnswerB::LDL-receptor overexpression
Answer B Explanation	[[AnswerBExp::LDL receptor over-expression, occurring upon statin therapy secondary to decreased production of cholesterol by inhibition of HMG-CoA reductase, results in a reduced risk of atherosclerosis.]]
Answer C	AnswerC::Deficiency of high density lipoprotein (HDL)
Answer C Explanation	[[AnswerCExp::Deficiency of HDL, frequently resulting from a genetic mutation of the ABC1 gene, may cause Tangier disease (TD) and some types of hypoalphalipoproteinemia (HA). HDL is considered an inverse predictor of atherosclerosis.]]
Answer D	AnswerD::Deficiency of LDL receptors on hepatocyte plasma membrane
Answer D Explanation	AnswerDExp::See explanation.
Answer E	AnswerE::
Answer E Explanation	[[AnswerEExp::Deficiency of lipoprotein lipase (LPL), characteristic of type I dyslipidemia (hyperchylomicronemia), manifests with elevated levels of circulating chylomicrons, resulting in elevated levels of triglycerides and cholesterol. A frequent complication of hyperchylomicronemia is recurrent pancreatitis, not myocardial infarction.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Familial hypercholesterolemia (FH), an autosomal dominant disease characterized by the deficiency of LDL receptors on the hepatocytes plasma membrane, results from a mutation of LDLR gene on chromosome 19. The mutation results in abnormally elevated amounts of serum LDL due to decreased clearance of LDL at the level of the liver. Affected patients are predisposed to accelerated atherosclerosis and an increased risk of cardiovascular diseases, such as myocardial infarction, and hypercholesterolemia manifesting upon physical exam as Achilles tendon xanthoma and arcus senilis corneae. FH occurs in both a homozygous and a heterozygous form. The homozygous form, which is more severe, often manifests with LDL levels approximately 1000 mg/dL that are often refractory to anti-lipidemic medications and cardiovascular complications that frequently occur during childhood. In the heterozygous form, LDL levels are classically lower than that of homozygous FH, ranging from 300-500 mg/dL. In patients with heterogeneous FH, who often do not display symptoms during childhood, the risk of atherosclerosis is elevated relative to the general population. Educational Objective: FH, an autosomal dominant disease resulting from a mutation of LDLR gene on chromosome 19, frequently leads to a deficiency or absence of LDL receptors on hepatocytes. FH manifest with both a heterozygous and a more severe homozygous form. FH may manifest with atherosclerosis in young individuals, as well as with signs of hypercholesterolemia, predisposing those affected to myocardial infarctions. References: Motulsky AG. Genetic aspects of familial hypercholesterolemia and its diagnosis. Arteriosclerosis. 1989; Jan-Feb;9(1 Suppl):I3-7]]
Approved	Approved::Yes
Keyword	WBRKeyword::LDL, WBRKeyword::familial hypercholesterolemia, WBRKeyword::myocardial, WBRKeyword::infarction, WBRKeyword::genetics, WBRKeyword::autosomal dominant, WBRKeyword::FH, WBRKeyword::inheritance
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::