View source for WBR0421

{{WBRQuestion
|QuestionAuthor={{Rim}}
|ExamType=USMLE Step 1
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|SubCategory=Endocrine
|MainCategory=Biochemistry
|MainCategory=Biochemistry
|SubCategory=Endocrine
|Prompt=A 17 year old female patient presents to the emergency department with chest pain and dyspnea at rest.  The patient explains he takes atorvastatin for hypercholesterolemia.  Her family history is notable for death of myocardial infarction in multiple members of her family at young age.  Vital signs show a temperature of 37 degrees C (98.6 degrees F), heart rate of 102 beats per minute, and blood pressure of 110/70 mmHg.  On physical examination, the physician notes tendon xanthomas on the Achilles tendon and arcus senilis corneae on the outer margin of the iris.  Work-up in the emergency department reveals an electrocardiogram (ECG) with 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?
|Explanation=[[Familial]] [[hypercholesterolemia]] (FH) is an autosomal dominant inherited disease characterized by the absence of deficiency of [[LDL]] receptors on hepatocytes plasma membrane due to 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; predisposing affected patients to accelerating [[atherosclerosis]] at a young age with increased risk of cardiovascular disease, such as [[myocardial]] [[infarction]], and signs of [[hypercholesterolemia]] on physical exam, such as [[Achilles tendon xanthoma]] and [[arcus senilis corneae]], as described in the patient in the vignette. 
FH has a homozygous form and a heterozygous form.  The homozygous form is more severe; it occurs in patients who have 2 mutated alleles of the gene.  Classically, patients with homozygous mutation have LDL levels approximately 1000 mg/dL that are often refractory to anti-lipidemic medications with cardiovascular complications that can occur as early as during childhood.  Heterozygous form occurs when 1 mutated allele is inherited.  In the heterozygous form, LDL levels are classically lower than that of homozygous FH, in the range of 300-500 mg/dL.  In heterogeneous FH, symptoms may not occur as early as homogeneous FH but the risk of atherosclerosis is still high when compared to the general population.
|AnswerA=Increased hepatocyte production of LDL
|AnswerAExp=Increased hepatocytes production of LDL is not the pathogenesis of FH.  LDL production is increased secondary to insulin resistance and diabetes mellitus, renal disease, and in obese individuals.
|AnswerB=LDL-receptor overexpression
|AnswerBExp=LDL receptor over-expression occurs with statin therapy secondary to decreased production of cholesterol by inhibition of HMG-CoA reductase.  In this case, the risk of atherosclerosis is expected to be reduced.
|AnswerC=Deficiency of high density lipoprotein (HDL)
|AnswerCExp=Deficiency of HDL is a genetic mutation of the ABC1 gene.  It might cause Tangier disease (TD) and some types of hypoalphalipoproteinemia (HA), both of which are characterized by low HDL.  HDL is considered an inverse predictor of atherosclerosis.  However, the patient’s work-up in the vignette showed abnormally elevated serum LDL levels, suggestive of FH.
|AnswerD=Deficiency of LDL receptors on hepatocyte plasma membrane
|AnswerDExp=FH is characterized by myocardial infarction at young age.  FH is caused by a mutation of the LDL receptor at the hepatocytes with abnormally elevated levels of circulating LDL.
|AnswerE=Deficiency of lipoprotein lipoprotein lipase (LPL)
|AnswerEExp=Deficiency of lipoprotein lipase (LPL) is type I dyslipidemia, called hyperchylomicronemia, which is characterized by elevated levels of circulating chylomicrons causing high levels of triglycerides and cholesterol.   Although eruptive xanthoma can be present in hyperchylomicronemia, a classic complication of hyperchylomicronemia is usually recurrent pancreatitis, not myocardial infarction.
|RightAnswer=D
|WBRKeyword=LDL, familial, hypercholesterolemia, myocardial, infarction
|Approved=No
}}