WBR0421

Author	[[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry
Sub Category	SubCategory::Endocrine
Prompt	[[Prompt::A 38-year-old woman is brought to the emergency department for complaints of chest pain and shortness of breath at rest. She describes her pain as a crushing sensation in the middle of her chest that radiates to her left arm and is associated with nausea and cold sweats. The patient receives daily atorvastatin for hypercholesterolemia. She reports that multiple members of her family died at a young age from cardiovascular disease. On physical examination, the physician notes xanthomas on the Achilles tendon and arcus senilis corneae on the outer margin of the iris. In the ED, her temperature is 37.0 °C (98.6 °F), heart rate is 112/min, and blood pressure is 148/84 mmHg. An electrocardiogram (ECG) reveals ST-segment elevation in the anterior leads. Her lab work-up is remarkable for elevation of troponin I and low-density lipoprotein-cholesterol (LDL-C) concentration of 680 mg/dL. The physician suspects that the patient's condition may be caused by an inherited disease. Which of the following explains the pathogenesis of this patient’s inherited disease?]]
Answer A	AnswerA::Increased hepatocyte production of LDL-C
Answer A Explanation	[[AnswerAExp::The increased hepatocytes production of LDL-C 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 occurs following initiation of statin therapy secondary to decreased production of cholesterol by inhibition of HMG-CoA reductase.
Answer C	AnswerC::Deficiency of high density lipoprotein-cholesterol (HDL-C)
Answer C Explanation	[[AnswerCExp::Deficiency of HDL-C frequently results from a genetic mutation in the ABC1 gene and may cause Tangier disease (TD) and some types of hypoalphalipoproteinemia (HA). Classically, HDL-C concentration has been inversely associated with atherosclerosis, but more recently, the emphasis of cardiovascular risk reduction shifted from the numerical concentration of HDL-C towards the function of HDL-C and ApoA-I given their capacity of reverse cholesterol transport.]]
Answer D	AnswerD::Deficiency of LDL receptors on hepatocyte plasma membrane
Answer D Explanation	[[AnswerDExp::Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by the absence or deficiency of LDL receptors on the hepatocyte plasma membrane.]]
Answer E	AnswerE::Deficiency of lipoprotein lipase (LPL)
Answer E Explanation	[[AnswerEExp::Deficiency of lipoprotein lipase (LPL) is type I dyslipidemia, called hyperchylomicronemia, which is characterized by elevated concentration of circulating chylomicrons that result in high concentration of triglycerides and cholesterol. Although eruptive xanthoma may be present in hyperchylomicronemia, a classic complication of hyperchylomicronemia is usually recurrent pancreatitis (due to hypertriglyceridemia), not myocardial infarction.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by the absence or deficiency of LDL receptors on the hepatocyte plasma membrane commonly due to a mutation in LDLR gene in chromosome 19. The mutation results in abnormally elevated concentration of serum LDL-C due to decreased clearance of LDL-C at the level of the liver, which predisposes affected patients to accelerated atherosclerosis at a young age with an increased risk of early cardiovascular disease. Patients may present at young age (before the age of 50) with myocardial infarction along with signs of hypercholesterolemia on physical exam, such as Achilles tendon xanthoma and arcus senilis corneae, as described in the patient in this vignette. FH has a homozygous form and a heterozygous form. The homozygous form is more severe; it occurs among patients who have 2 mutated alleles of the LDLR gene. Classically, patients with homozygous mutation have LDL-C concentrations greater than 500 mg/dL that are often refractory to anti-lipidemic medications. These patients are also at high risk of early cardiovascular complications that may occur as early as adolescence or young adulthood. Heterozygous form develop when only 1 mutated allele is inherited. In the heterozygous form, LDL-C concentrations are classically lower than that of homozygous forms in the range of 300-500 mg/dL. In heterogeneous FH, cardiovascular disease may not manifest as early as homogeneous FH, but the risk of atherosclerosis is still high when compared with the general population. Educational Objective: Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by the absence or deficiency of LDL receptors on the hepatocyte plasma membrane commonly due to a mutation in LDLR gene in chromosome 19. Homozygous forms of FH may manifest with early atherosclerosis along with signs of hypercholesterolemia. References: Motulsky AG. Genetic aspects of familial hypercholesterolemia and its diagnosis. Arteriosclerosis. 1989;9(1 Suppl):I3-7. First Aid 2014 page 87, 118]]
Approved	Approved::Yes
Keyword	WBRKeyword::LDL, WBRKeyword::Familial hypercholesterolemia, WBRKeyword::Myocardial infarction, WBRKeyword::Autosomal dominant, WBRKeyword::FH, WBRKeyword::Inheritance, WBRKeyword::Hypercholesterolemia
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