A 67-year-old man comes to the office due to increased fatigue and weight gain over the past 6 months. He has hypertension controlled with a calcium channel blocker. Two years ago, the patient's physical examination was unremarkable, and his blood tests, including a lipid panel, were normal. Blood pressure is 135/98 mm Hg, and pulse is 62/min. BMI is 28 kg/m². On physical examination, the thyroid appears to be mildly enlarged and is irregular and firm in consistency. Laboratory studies reveal elevated TSH, low free thyroxine (T4), high total and LDL cholesterol, and mildly elevated triglyceride levels. Which of the following is the most likely underlying mechanism for the elevated cholesterol in this patient?

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11ec160b_3cb3_cbf2_9249_e1fbf122d112_MD0001_00 This patient has primary hypothyroidism presenting with fatigue, weight gain, and goiter, along with elevated TSH and low free thyroxine (T4) levels. Hypothyroidism can cause a number of adverse effects on serum lipids, including elevating total cholesterol, LDL cholesterol, and triglyceride levels. Hypothyroidism causes decreased LDL receptor expression, leading to decreased clearance of LDL with resultant increased blood LDL levels. Hypothyroidism may also decrease LDL receptor activity and biliary excretion of cholesterol. Hypertriglyceridemia can occur in hypothyroidism due to decreased expression of lipoprotein lipase (Choice C). Along with effects on blood pressure (eg, hypertension due to increased peripheral vascular resistance), the adverse effects of hypothyroidism on lipid levels can increase the risk of coronary atherosclerosis. (Choice A) Peroxisome proliferator-activated receptor alpha (PPAR-α) stimulates fatty-acid uptake and beta oxidation; increased PPAR-α expression would cause a reduction in triglyceride levels. Decreased PPAR-α activity leads to hypertriglyceridemia and lipid accumulation within the liver (fatty liver disease) but is not associated with hypothyroidism. (Choice D) Hypothyroidism is associated with decreased activity of HMG-CoA reductase and therefore decreased de novo synthesis of cholesterol; however, patients still develop hyperlipidemia due to reduced LDL clearance. Thyroid hormone (not hypothyroidism) induces expression of HMG-CoA reductase. (Choice E) Similar to decreased LDL receptor expression, increased LDL receptor degradation leads to elevated blood LDL levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the degradation of hepatic LDL receptors; alirocumab, a monoclonal antibody against PCSK9, blocks this effect, leading to a reduction in LDL levels. However, hypothyroidism is not associated with increased LDL receptor degradation. Educational objective: Hypothyroidism causes decreased expression of LDL receptors in the liver, leading to decreased clearance of LDL and increased blood LDL levels. It also causes hypertriglyceridemia due to decreased expression of lipoprotein lipase. The adverse effects of hypothyroidism on lipid levels can increase the risk of coronary atherosclerosis. __________ References: Effects of thyroid dysfunction on lipid profile. (http://www.ncbi.nlm.nih.gov/pubmed/21660244)

A 67-Year-Old Man Comes to the Office Due to Increased