WBR0096

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Cardiology
Prompt	[[Prompt::A 20-year-old man presents to the emergency department (ED) with an acute severe substernal chest pain at rest. The patient denies recent physical trauma or illicit drug use. His past medical history is unremarkable. His father died of cardiovascular disease at young age, and his mother was recently diagnosed with lung cancer. In the ED, the patient is afebrile, blood pressure is 175/90 mmHg, heart rate is 110/min, and respiratory rate is 22/min. His ECG shows ST-segment elevation in leads V1-V4. Laboratory values show elevated troponin, LDL-cholesterol of 840 mg/dL, and HDL-cholesterol of 30 mg/dL. Which of the following is most likely true of this patient’s condition?]]
Answer A	AnswerA::The disease follows autosomal recessive inheritance
Answer A Explanation	[[AnswerAExp::Familial hypercholesterolemia is caused by loss of function mutations in the LDL receptor and follows an autosomal dominant pattern of inheritance.]]
Answer B	AnswerB::The disease is associated with subcutaneous deposits
Answer B Explanation	[[AnswerBExp::Familial hypercholesterolemia causes an increase in LDL cholesterol, which leads to the formation of subcutaneous fatty xanthomas of the Achilles tendon and xanthelasmas on the eyelids.]]
Answer C	AnswerC::The disease is associated with hepatomegaly
Answer C Explanation	[[AnswerCExp::Hyperchylomicronemia, dyslipidemia type I, is associated with hepatomegaly.]]
Answer D	AnswerD::The disease is associated with increased chylomicrons
Answer D Explanation	[[AnswerDExp::This patient has familial hypercholesterolemia (type IIa dyslipidemia), which is associated with increased levels of cholesterol in the blood. Patients with hyperchylomycronemia (type I dyslipidemia) have increased levels of serum chylomicrons.]]
Answer E	AnswerE::The disease is caused by gain-of-function mutations in HMG-CoA reductase
Answer E Explanation	[[AnswerEExp::Familial hypercholesterolemia is caused by loss-of-function mutations in the LDL receptor and follows an autosomal dominant pattern of inheritance.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Familial hypercholesterolemia or familial dyslipidemia type IIa is an autosomal dominant genetic disorder characterized by high concentrations of total cholesterol and plasma low-density lipoprotein (LDL). Patients with the homozygous form typically have LDL concentration > 500 mg/dL, decreased plasma HDL concentration, and increased apoB turnover. Familial hypercholesterolemia is associated with early cardiovascular and peripheral vascular disease, starting in the first or second decade of life. Patients classically have mutations in the LDLR gene, which encodes the LDL receptor protein that normally eliminates LDL from the circulation. Heterozygous familial hypercholesterolemia is usually treated with statins, bile acid sequestrants, or other hypolipidemic agents that lower cholesterol concentration. Individuals with homozygous mutations are more difficult to treat as these individuals lack any functional LDL receptors, which statins could serve to upregulate. However, these patients may still be prescribed statins and other lipid-lowering agents, along with LDL apheresis. Lomitapide and mipomersen are two drugs recently approved for patients with homozygous familial hypercholesterolemia. Unlike statins, both drugs decrease LDL independently of LDL-receptor activity. Patients may eventually require liver transplantation. Yellow cholesterol deposits may be observed on the eyelids, leading to the formation of xanthelasma palpebrarum. Additionally, xanthomas are subcutaneous fatty deposits in the tendons of the hands, elbows, knees and feet, and characteristically at the distal one-third of the Achilles tendon. The eyes may also be involved in patients with familial hypercholesterolemia, showing arcus senilis corneae, a whitish arc at the edge of the cornea. Accelerated deposition of cholesterol in the walls of arteries leads to premature atherosclerosis, the underlying cause of early cardiovascular and peripheral vascular disease. Educational Objective: Familial hypercholesterolemia causes an increase in LDL cholesterol, which leads to the formation of subcutaneous fatty xanthomas of the Achilles tendon and xanthelasmas on the eyelids. References: France M, Schofield J, Kwok S, et al. Treatment of homozygous familial hypercholesterolemia. Clin Lipidol. 2014;9(1):101-18 Ziajka PE. Management of patients with homozygous familial hypercholesterolemia. Am J Manag Care. 2013;19(13 Suppl):s First Aid 2014 page 110, 118]]
Approved	Approved::Yes
Keyword	WBRKeyword::Familial hypercholesterolemia, WBRKeyword::Dysplipidemia, WBRKeyword::Lipids, WBRKeyword::Cholesterol, WBRKeyword::Heart, WBRKeyword::Cardiovascular, WBRKeyword::Genetics, WBRKeyword::Myocardial infarction, WBRKeyword::Atherosclerosis, WBRKeyword::WJG
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