Endocrinology & anti-lipid drugs

A 53-year-old man comes to the physician for a follow-up visit after an acute myocardial infarction. His

medications include metoprolol and low-dose aspirin. He used to smoke 2 packs of cigarettes daily but quit after

his myocardial infarction. The patient's father has hypertension and his mother has type 2 diabetes mellitus. He

currently weighs 100 kg (220 lb) and is 178 cm (70 in) tall. Examination shows an obese male with no other

abnormalities. His total serum cholesterol level is 155 mg/dl, with an HDL level of 27 mg/dl and a triglyceride

level of 92 mg/dl. Which of the following lipid-lowering agents would be most effective for preventing future

cardiovascular events in this patient?

• A. Absorption inhibitor

• B. Cationic exchange resin

• C. Enzyme inhibitor

• D. Essential fatty acids

• E. Pharmacologic vitamin

Answer explanation

Patients with low high-density lipoprotein (HDL) levels (men <40 mg/dl, women <50 mg/dl) are at increased risk for cardiovascular disease. HDL is involved in reverse cholesterol transport; it helps to remove cholesterol from peripheral tissues and transports it to the liver for metabolism.

Nonpharmacologic measures such as exercise, weight loss, and smoking cessation help to raise HDL levels and

have significant cardiovascular benefits. In contrast, use of medications to raise HDL levels does not improve

cardiovascular outcomes. Pharmacologic treatment of patients with low HDL levels should focus on lowering LDL

cholesterol with HMG-CoA reductase inhibitors (statins), as these are the most effective lipid-lowering drugs for

preventing cardiovascular events. Statins are indicated for secondary prevention in all patients with known

atherosclerotic cardiovascular disease, regardless of baseline lipid levels.

A 48-year-old man comes to the office for a follow-up visit. He was diagnosed with hypercholesterolemia 6 months

ago and has been strictly following dietary and lifestyle modifications as advised. The patient has no other medical

problems. He does not use tobacco, alcohol, or illicit drugs. His father has diabetes mellitus and coronary artery

disease. The patient's blood pressure is 126/70 mm Hg and BMI is 33.1 kg/m2. Physical examination is normal.

Laboratory studies show a current LDL level of 190 mg/dl. Which of the following should be obtained before

starting statin therapy in this patient?

• A. Apolipoprotein-B level

• B. Complete blood count

• C. Lipoprotein lipase activity assay

• D. Liver transaminase levels

• E. Serum cortisol level

Answer explanation

This patient has a severe elevation in his LDL level. This degree of hyperlipidemia, especially with a family history of coronary artery disease, suggests familial hypercholesterolemia and confers a very high risk for cardiovascular

events. HMG-CoA reductase inhibitors (statins) are the first-line therapy for most patients with

hypercholesterolemia and have been proven to reduce the risk of cardiac events. The statins are structural analogs of HMG-CoA and competitively inhibit HMG-CoA reductase, the enzyme responsible for the rate-limiting

step in cholesterol synthesis.

Serious side effects of statins include myopathy and hepatitis. Liverfunction tests are recommended before starting statin therapy; otherwise, routine monitoring is not necessary unless symptoms of hepatic injury develop (eg, fatigue, malaise, anorexia).

A 63-year-old man comes to the office for a follow-up visit. Two months ago, he was hospitalized for chest pain

and was found to have a blockage in the left anterior descending artery. He had percutaneous coronary

intervention with placement of a drug-eluting stent, and was discharged on appropriate medical therapy. His other

medical problems include hypertension, type 2 diabetes mellitus, and degenerative joint disease. The patient has

been taking all his medications as prescribed. He has no chest pain but does have diffuse muscle aches and

cramps, especially after exercise. Physical examination is unremarkable. Laboratory testing reveals elevated

serum creatine kinase. The medication most likely responsible for this patient's current findings also causes which

of the following effects?

• A. Decreased gastric mucosa! prostaglandin synthesis

• B. Elevated plasma bradykinin level

• C. Impaired potassium entry into cells

• D. Increased hepatocyte LDL receptor recycling

• E. Increased renal calcium reabsorption

Answer explanation

This patient's symptoms are most likely due to statin-induced myopathy. Statins are an effective treatment for hypercholesteremia and are now routinely prescribed for all patients with symptomatic coronary artery disease,

regardless of baseline cholesterol levels. Myopathy is the most common complication of statin use, and symptomscan range from myalgia or myopathy, with or without myonecrosis (elevated serum creatine kinase), to frank rhabdomyolysis.

A 36-year-old man comes to the office after he was found to have an abnormal lipid panel during employee

wellness testing at his company. He has no prior medical problems and takes no medications. The patient is a software technician and has a sedentary lifestyle. He eats mostly fast foods, rarely exercises, and drinks 2-3 cans of beer daily. His BMI is 31 kg/m2. Physical examination is unremarkable. Results of laboratory studies performed in the office are as follows:

Total cholesterol 290 mg/dl

High-density lipoprotein 45 mg/dl

Low-density lipoprotein 110 mg/dl

Triglycerides 675 mg/dl

Lifestyle modification with a balanced diet, regular exercise, and reduced alcohol intake is advised. He is also started on fenofibrate therapy. This medication is most likely to help the patient by which of the following mechanisms?

• A. Blocking intestinal cholesterol absorption

• B. Decreasing hepatic cholesterol synthesis

• C. Increasing fecal loss of cholesterol derivatives

• D. Inhibiting LDL receptor degradation

• E. Reducing hepatic VLDL production

Answer explanation

This patient has a moderately elevated (>500 mg/dL) triglyceride level, which is associated with an increased risk of cardiovascular disease. Lifestyle modifications (increased aerobic exercise, decreased alcohol and total caloric intake) can decrease triglycerides, but moderate (or worse) hypertriglyceridemia usually requires pharmacologic therapy.

Fibrates (eg, gemfibrozil, fenofibrate) activate peroxisome

proliferator-activated receptor alpha (PPAR-a), which leads to decreased hepatic VLDL production and increased LPL activity. They are able to decrease triglyceride levels by 25%-50% and increase HDL by 5%-20%.

Fish oil supplements containing high concentrations of omega-3 fatty acids also decrease VLDL production, and

inhibit synthesis of apolipoprotein B as well. These supplements lower triglycerides and can be used as an

alternate treatment for patients with moderate hypertriglyceridemia.

A 57-year-old man is seen in the office after an episode of acute pancreatitis. Hospital evaluation found no

evidence of gallstones. The patient does not consume alcohol, but he does have a history of severe

hypertriglyceridemia. He was treated with a fibrate medication in the past but could not tolerate it due to liver

toxicity. He has no history of diabetes mellitus or hypertension. On examination, the patient has no abdominal

tenderness. Laboratory studies show normal hepatic and pancreatic enzyme levels, but the patient again has a

severely elevated triglyceride level. The physician prescribes the appropriate medications and explains that the

patient is likely to experience skin flushing and warmth after taking the pills. Which of the following is the primary agent mediating these side effects?

• A. Histamine

• B. Platelet-activating factor

• C. Prostaglandin

• D. Serotonin

• E. Substance P

Answer explanation

Nicotinic acid, or niacin, has been used in the treatment of hyperlipidemia for almost 4 decades. It is effective in raising HDL cholesterol levels, as well as lowering triglycerides and LDL levels.

Niacin's main side effects are cutaneous flushing, warmth, and itching; these are primarily mediated by release of prostaglandins (particularly PGD2 and PGE2). Aspirin, which inhibits prostaglandin synthesis, can significantly reduce these side effects if given 30-60 minutes before niacin administration.

A 33-year-old man comes to the office due to several months of episodic headaches accompanied by sweating and

feelings of anxiety that spontaneously resolve after 15-30 minutes. The patient has no other medical conditions

and takes no medications. His brother recently had surgery to treat hyperparathyroidism. Blood pressure is

180/110 mm Hg and pulse is 102/min. Laboratory results show normal serum electrolytes and renal function. CT

scan of the abdomen reveals a mass in the right adrenal gland. Which of the following cells have the same

embryologic origin as the tissue responsible for this patient's current condition?

• A. Capillary endothelial cells

• B. Cardiac myocytes

• C. Interstitial fibroblasts

• D. Melanin-producing cells

• E. Thyroid follicular cells

Answer explanation

Neural crest:

• Neural ganglia, adrenal medulla

• Schwann cells; pia & arachnoid mater

• Aorticopulmonary septum & endocardial cushions

• Branchial arches (bones & cartilage)

• Skull bones

• Melanocytes

This patient with hypertension; episodic headache, anxiety, and diaphoresis; and an adrenal mass on CT scan has a pheochromocytoma, a catecholamine-secreting tumor arising from the chromaffin cells of the adrenal medulla.

The chromaffin cells of the adrenal medulla are derived from neural crest cells, which are multipotent, migratory

cells that originate in the ectoderm at the margin of the neural tube and give rise to a diverse cell lineage. In

addition to the adrenal medulla, other important structures that arise from neural crest cells include melanocytes

(melanin-producing cells) and neural ganglia (eg, sympathetic and parasympathetic ganglia)

A 24-year-old postpartum woman comes to the office for fol low-up of gestational diabetes. The patient was

diagnosed with gestational diabetes mellitus during routine screening at 28 weeks gestation; she was treated with

dietary modification and exercise and required insulin briefly. Since delivery 12 weeks ago, she has continued to

follow dietary recommendations, and her blood glucose has been fairly well controlled without insulin. The patient

has fasting blood glucose levels of 100-120 mg/dl. Medical history is otherwise unremarkable. Family history is

significant for diabetes mellitus in her mother and gestational diabetes in her sister. Vital signs are within normal

limits. BMI is 22 kg/m2. Physical examination shows no abnormalities. Her gestational diabetes and fasting

hyperglycemia are suspected to be genetically predisposed. This patient's condition is most likely caused by

reduced activity of which of the following enzymes?

• A. Aldolase A

• B. Enolase

• C. Glucokinase

• D. Lactate dehydrogenase

• E. Phosphofructokinase

Answer explanation

Glucose-induced insulin release from pancreatic beta cells requires the following steps:

1. Glucose enters the beta cell through glucose transporter type 2 (GLUT-2).

2. Glucose is metabolized by glucokinase to glucose-6-phosphate.

3. Glucose-6-phosphate enters glycolysis to produce ATP.

4. Increased ATP levels causes closure of ATP-sensitive potassium (KATP) channels.

5. Depolarization of beta cells triggers opening of voltage-dependent calcium channels.

6. Influx of calcium causes insulin release.

Heterozygous mutations of the glucokinase gene that decrease the activity or affinity of the enzyme cause a decrease in beta cell glucose metabolism, leading to reduced ATP formation and insulin secretion at any given glucose level. Glucokinase mutations are one cause of maturity-onset diabetes of the young (MODY), an autosomal dominant disorder characterized by mild hyperglycemia that often worsens with pregnancy-induced insulin resistance

A 58-year-old man comes to the office for evaluation of a thyroid nodule. The patient first noticed a painless neck

lump 2 months ago, which has progressively enlarged. He has had no heat or cold intolerance, recent weight

changes, or difficulty breathing or swallowing. Medical history is notable for well-controlled hypertension. The

patient has no history of radiation exposure or family history of thyroid diseases. Physical examination shows a

firm, nontender nodule in the right thyroid lobe. Serum TSH level is normal, and ultrasonography shows a 4-cm

solid nodule in the right thyroid lobe. Fine-needle aspiration biopsy shows a large number of follicular cells

dispersed in clusters and microfollicles. The patient undergoes right thyroid lobectomy. Which of the following

histologic findings would confirm a diagnosis of follicular thyroid carcinoma in this patient?

• A. C-cell hyperplasia

• B. Cells with empty appearing nuclei

• C. Hurthle cells

• D. Lymphocytic germinal centers

• E. Tumor capsular invasion

Answer explanation

Most follicular thyroid neoplasms are benign follicular adenomas, but 15%-30% can be malignant fol licular carcinomas. Both types of follicular neoplasms have a similar appearance on ultrasound and FNA.

Differentiating between benign and malignant foll icular lesions can only be accomplished by histologic examination

of the entire tumor (eg, thyroidectomy).

• Follicular adenomas (the most common benign thyroid neoplasm) display numerous neoplastic follicular cells

and microfollicles on histology but are completely encapsulated.

• In contrast, follicular thyroid carcinomas are characterized by invasion of the tumor capsule and/or

surrounding blood vessels.

This propensity of fol licular thyroid carcinomas to invade surrounding blood vessels accounts for their tendency to

metastasize via hematogenous spread to distant tissues (eg, bone, lung).

A 21 -year-old man comes to the office due to recent weight loss and fatigue. The patient is a college athlete and

states, "My coach wants me to put on more weight, but I can't seem to do it. It doesn't matter how much I eat, I

keep losing weight. I've been really thirsty and drinking lots of water lately too, and it's causing me to use the

bathroom frequently during practice. I'm worried that I'm going to get dropped from the team if I don't get myself

together." He is sexually active and has 1 lifetime partner. The patient's father was diagnosed with colon cancer at

age 64. Which of the following studies would be the best next step to establish the diagnosis in this patient?

• A. Colonoscopy

• B. Hemoglobin A 1 c

• C. HIV testing

• D. Serum TSH level

• E. Urinalysis

A 58-year-old man comes to the office for evaluation of a foot wound. The patient noticed a small ulcer on the

bottom of his right foot a week ago but recalls no significant foot injury. He has been applying antiseptics, but the

wound has failed to heal. The patient has a 15-year history of type 2 diabetes mellitus and is nonadherent to

medical therapy. He has smoked a pack of cigarettes daily for 20 years. Temperature is 37.1 C (98.8 F), blood

pressure is 140/80 mm Hg, and pulse is 72/min. Right lower extremity examination shows a 1-cm (0.39-in) plantar

ulcer under the first metatarsal head. There are no other lesions, and the tibial and dorsalis pedis pulses are

normal. Which of the fol lowing is the strongest contributing factor underlying the development of this patient's foot

ulcer?

• A. Atherosclerotic disease

• B. Bacterial infection

• C. Irritant dermatitis

• D. Sensory impairment

• E. Systemic vasculitis

Answer explanation

This patient has a plantar ulcer under the first metatarsal head. In a patient with chronic, poorly controlled diabetes mellitus, this is likely a neuropathic ulcer due to underlying peripheral sensory neuropathy. Chronic

hyperglycemia promotes nerve injury and impairs nerve repair in distal sensory fibers, causing decreased sensation of pain, pressure, and proprioception.

Areas that are particularly susceptible are points of localized pressure created by a shoe or weightbearing

bones of the foot (eg, plantar surface of the first metatarsal head). A wound in this area often goes

unnoticed (due to lack of pain sensation and being hidden by socks or shoes) and can develop into a nonhealing

foot ulcer.