Diagnosis and Treatment of Dyslipidemia
1. A 46-year-old woman visits your office as a new patient. She has recently moved to town and wishes to establish new primary care. She has no complaint today. She is moderately obese, with central adiposity. She has moderate hypertension, for which she has been undergoing treatment with a thiazide diuretic. The rest of her medical history is unremarkable. Her laboratory data reveal that her renal function is normal. Her blood glucose level is in the normal range, but her triglyceride level is elevated, and her highdensity lipoprotein (HDL) cholesterol level is low. The rest of the physical examination is normal.
Which of the following statements regarding the metabolic syndrome is true?
A. An accumulation of visceral rather than subcutaneous fat has been observed in individuals with the metabolic syndrome
B. First-line therapy for treatment of the metabolic syndrome is highdose statin therapy
C. The lipid abnormalities associated with the metabolic syndrome are a very high total low-density lipoprotein (LDL) cholesterol level and normal HDL cholesterol and triglyceride levels
D. This patient should not be diagnosed as having metabolic syndrome because she meets only four of the five diagnostic criteria for that disorder
Key Concept/Objective: To know the characteristics of the metabolic syndrome
An accumulation of visceral rather than subcutaneous fat has been observed in individuals with the central body fat distribution characteristic of the metabolic syndrome. The lipid abnormalities associated with the metabolic syndrome are increased levels of triglyceride; increased numbers of small, dense LDL and apolipoprotein B particles; and decreased levels of HDL2 cholesterol. The National Cholesterol Education Program Adult Treatment Panel III has suggested five clinical variables as diagnostic criteria for the metabolic syndrome: (1) increased waist circumference, (2) increased triglyceride level, (3) decreased HDL cholesterol level, (4) increased blood pressure, and (5) elevated level of fasting plasma glucose. A diagnosis of the metabolic syndrome is made when three or more of these clinical variables are present. Aerobic exercise and a diet low in saturated fat are indicated as therapy for most people with the metabolic syndrome. More aggressive therapy is indicated if the metabolic syndrome is severe or if the patient has familial combined hyperlipidemia or type 2 diabetes mellitus. (Answer: A—An accumulation of visceral rather than subcutaneous fat has been observed in individuals with the metabolic syndrome)
2. A 28-year-old white man visits your office for a routine physical examination. He has had no medical problems, he exercises regularly, and his weight is very near his ideal body weight. His family history is significant in that his father and two uncles each had heart attacks and underwent revascularization procedures between the ages of 49 and 55 years. On physical examination, tendon xanthomas are noted on the Achilles tendons and the extensor tendons of the patient’s hands, and bilateral xanthelasma is present. The rest of the physical examination is normal.
Which of the following statements regarding familial hypercholesterolemia (FH) is true
A. It is inherited in an autosomal recessive fashion
B. It is atypical for this patient with heterozygous FH to have developed xanthomas at only 28 years of age
C. In patients with heterozygous FH, coronary artery disease develops early, with symptoms often manifesting in men in their fourth or fifth decade
D. Although tendon xanthomas do occur with this illness, the xanthelasmas are a highly specific finding, indicating FH in this patient
Key Concept/Objective: To understand the physical examination findings and medical implications of FH
FH is an autosomal dominant disorder caused by a mutation in the gene encoding the LDL receptor protein. Tendon xanthomas begin to appear by 20 years of age and may be present in up to 70% of older individuals. Xanthelasma (cutaneous xanthomas on the palpebra) and corneal arcus are common after 30 years of age. Tendon xanthomas are a highly specific sign of FH, but xanthelasma and corneal arcus may occur in normocholesterolemic persons. Coronary artery disease develops early, with symptoms often manifesting in men in the fourth or fifth decade. By 60 years of age, at least 50% of men with FH experience myocardial infarction; in women, symptoms tend to develop about 10 years later. (Answer: C—In patients with heterozygous FH, coronary artery disease develops early, with symptoms often manifesting in men in their fourth or fifth decade)
3. A 35-year-old male patient visits your office asking for information about his medical condition. He states that several years ago, his physician told him that on the basis of his cholesterol profile and the presence of characteristic skin lesions on his ankles and hands, he likely had FH. The patient chose to ignore his previous doctor’s advice regarding therapy, but he has now decided that he should seek medical attention. He asks you for general information regarding the treatment of his condition.
Which of the following statements regarding the treatment of heterozygous FH is true?
A. Because it is an acquired illness, the screening of first-degree relatives is not necessary
B. Aggressive diet therapy alone is adequate therapy for most patients with this illness
C. Despite appropriate therapy for this illness, tendon xanthomas will not regress
D. Effective treatment for this illness is possible with statins, intestinally active drugs, and nicotinic acid
Key Concept/Objective: To understand the appropriate therapy for patients with FH
FH is a primary cause of isolated, severely elevated cholesterol levels. The ability to diagnose FH is valuable because affected individuals will require drug therapy from a relatively young age. Careful attention to family members is mandatory; 50% of them will be affected and will require aggressive lipid-lowering therapy. In patients with heterozygous FH, it is possible to stimulate the one normal gene; in such patients, effective treatment is possible with statins, intestinally active drugs, and nicotinic acid. Because LDL cholesterol levels tend to be very high, combination therapy with two drugs is often required, and three drugs may be necessary. Although diet therapy alone is not sufficient for patients with heterozygous FH, reducing saturated fatty acid and cholesterol intake will lower LDL levels and reduce the amount of medication required. Tendon xanthomas have been shown to regress when LDL levels are maintained in a desirable range. (Answer: D—Effective treatment for this illness is possible with statins, intestinally active drugs, and nicotinic acid)
For more information, see Brunzell JD: 9 Metabolism: II Diagnosis and Treatment of Dyslipidemia. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, January 2004
The Porphyrias
4. A concerned young mother brings her 10-month-old son to your clinic for treatment of severe sunburn.
She recently took her son to the beach and noticed the rapid appearance of large blisters and erosions after only a short period in the sun. The mother reports that two uncles sunburned easily and had “blood problems.” You suspect congenital erythropoietic porphyria. Urinary, fecal, and erythrocyte porphyrin levels confirm the diagnosis.
Which of the following measures has NOT been shown to be helpful for patients with erythropoietic porphyria?
A. Bone marrow transplantation
B. Avoidance of sunlight
C. Vitamin B12 supplementation
D. Oral ß-carotene
Key Concept/Objective: To understand the treatment of congenital erythropoietic porphyria
Congenital erythropoietic porphyria is an autosomal recessive disorder that results from a deficiency of the uroporphyrinogen cosynthase enzyme. It typically presents in infancy; patients have photosensitivity, hypertrichosis, hemolytic anemia, and erythrodontia. Treatment is aimed at protection from sun damage, decreasing hemolysis, increasing red blood cell production, or curing the disorder. Avoidance of sunlight and administration of ß-carotene can help prevent photosensitivity reactions. Red blood cell transfusion has been helpful transiently in decreasing hemolysis and erythropoiesis, and bone marrow transplantation is curative. Vitamin B12 supplementation has not been successful in the treatment of congenital erythropoietic porphyria. (Answer: C— Vitamin B12 supplementation)
5. A 24-year-old woman with a history of acute intermittent porphyria (AIP) presents to the emergency department with diffuse abdominal pain, nausea, and vomiting of 24 hours’ duration. She states that her symptoms are identical to those she experiences during acute attacks of AIP.
Which of the following, if found, is NOT consistent with an acute attack of AIP?
A. Photosensitive rash
B. Hypertension
C. Peripheral neuropathy
D. Seizure
Key Concept/Objective: To know the symptoms of attacks of AIP
AIP is an autosomal dominant disorder caused by a deficiency in porphobilinogen deaminase. Its course tends to be marked by asymptomatic periods that are interrupted by acute attacks. These attacks are marked by severe abdominal complaints, including pain, which may be localized or generalized; nausea; vomiting, and bowel disturbances. Urinary complaints, tachycardia, hypertension, fever, and tremor are also common. Neurologic symptoms can include weakness, peripheral neuropathy, and seizure, particularly in patients with coexisting hyponatremia. In severe cases, the urine may be the color of port wine because of the accumulation of porphobilin. Unlike most other porphyrias, no cutaneous manifestations are associated with this enzyme deficiency. (Answer: A—Photosensitive rash)
6. A 26-year-old woman with known AIP is brought to the hospital with abdominal pain after using narcotic analgesics after a tooth extraction. On examination, she is found to have fever, tachycardia, hypertension, and tremor. Urinalysis shows the urine to be deep red in color; there is no evidence of red blood cells. Soon after admission to the hospital for treatment, the patient suffers a generalized tonic-clonic seizure.
Which of the following would NOT be expected to help in the treatment of this patient’s exacerbation of AIP?
A. Intravenous phenobarbital
B. Intravenous fluids with sodium chloride
C. Intravenous fluids with dextrose
D. Intravenous hematin
Key Concept/Objective: To understand the treatment of an attack of AIP
This patient appears to be suffering a severe attack of AIP. Treatment of her attack is aimed at eliminating or avoiding any inciting factors; achieving appropriate volume resuscitation with attention to sodium disorders; maintaining adequate nutrition, particularly carbohydrates; and temporarily blocking porphyrin synthesis. Thus, intravenous administration of fluid with both sodium chloride and dextrose is appropriate, as is identification and treatment of infection. Hematin, an inhibitor of porphyrin synthesis, is also effective in stopping acute attacks. However, phenobarbital is a potent inducer of the hepatic cytochrome P-450 system, which stimulates heme synthesis; this is a precipitating factor. (Answer: A—Intravenous phenobarbital)
7. A 45-year-old man with a long history of heavy alcohol ingestion presents with vesicles on sun-exposed areas of his body, particularly the dorsum of his hands. Some areas have become atrophic and hyperpigmented.
Which of the following laboratory findings would be consistent with a diagnosis of porphyria cutanea tarda (PCT) for this patient?
A. Normal serum ferritin level
B. Isocoproporphyrin in the stool
C. Normal plasma porphyrin level
D. Urinary fluorescence under infrared light
Key Concept/Objective: To understand the laboratory tests used to diagnose PCT
PCT is probably the most common of the porphyrias. It manifests as vesicle formation in sun-exposed areas, particularly the dorsum of the hands, followed by scarring and hyperpigmentation. It is frequently associated with liver abnormalities. PCT results from an inherited or acquired deficiency in uroporphyrinogen decarboxylase; the acquired form is frequently associated with excessive alcohol ingestion and iron overload. Therefore, the serum ferritin level is typically elevated. Plasma porphyrin levels are also elevated, as are urinary porphyrin levels, leading to urinary fluorescence under ultraviolet light. A finding that is virtually diagnostic of PCT is the presence of isocoproporphyrin in stool. (Answer: B—Isocoproporphyrin in the stool)
For more information, see Sassa S, Kappas A: 9 Metabolism: V The Porphyrias. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, December 2003
Diabetes Mellitus
8. A 38-year-old woman presents with symptoms of recurrent so-called yeast infection. Over the past 2 years, she has had repeated episodes of similar infections that have been only partially responsive to over-the-counter treatments. She has not seen a physician in the 10 years since her last pregnancy and denies knowledge of major medical illness. She has been moderately obese for most of her adult life; her maximal weight was 234 lb, although she recently lost 9 lb. She reports that she has had nocturia for the past several months. Physical examination is remarkable for a blood pressure of 145/92 mm Hg, obesity, and findings consistent with vaginal candidiasis.
Which of the following would be the most useful test for diagnosing diabetes in this patient?
A. Immediate measurement of blood glucose concentration
B. Determination of hemoglobin A1c (HbA1c) level
C. A 50 g oral glucose tolerance test
D. Measurement of blood glucose after an overnight fast
E. A 100 g oral glucose tolerance test
Key Concept/Objective: To understand that measurement of fasting blood glucose (FBG) is the preferred diagnostic test for patients suspected of having type 2 diabetes
The standard means of diagnosing diabetes is measurement of FBG; the measurement should be repeated if the value is greater than 110 mg/dl. The current criteria considered diagnostic of diabetes is the finding of an FBG level of 126 mg/dl on more than one occasion. It must be realized that this value is somewhat arbitrary, and FBG values are distributed along a continuum from normal to diabetic. An FBG of 110 to 126 mg/dl is indicative of abnormal glucose metabolism, with higher values indicating an increased likelihood of progression to diabetes. A determination of random blood glucose level is diagnostic if that level is greater than 200 mg/dl in a symptomatic patient. This woman’s nocturia and her recurrent vaginal candidiasis, which is a common correlate of hyperglycemia in women, are symptoms of diabetes. Random blood glucose values vary considerably more than do FBG values and so are not as reliable for establishing a diagnosis. The HbA1c level reflects glycosylation of red cell proteins and is proportional to the glucose concentration over the preceding 2 to 3 months. Although FBG measurements are very useful for monitoring the course of patients with an established diagnosis, standards have not been established to enable clinicians to effectively distinguish diabetes from less serious causes of abnormalities in glucose metabolism. Glucose tolerance tests are quite sensitive in the detection of diabetes, and the 50 g and 100 g tests have a clear place in the diagnosis of gestational diabetes. However, these tests are more expensive and inconvenient for patients than measurement of FBG, and their results are less reproducible. Because abnormalities in fasting and postprandial glycemia tend to progress in tandem, FBG measurement has supplanted the oral glucose tolerance test for the diagnosis of diabetes except during pregnancy. (Answer: D— Measurement of blood glucose after an overnight fast)
9. A 25-year-old woman with a 12-year history of type 1 diabetes presents with complaints of recurrent nocturnal hypoglycemia. She reports that she has had repeated episodes of early morning awakening, during which she has experienced confusion and profound diaphoresis. She also experiences midday hypoglycemia when she eats lunch later than usual. These symptoms developed coincidently with her joining a health club, at which she engages in an aerobic training program five afternoons a week. She has been on a regimen of twice-daily injections of 45 units of a fixed mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular insulin (she has followed this regimen since she was a teenager). Despite the more frequent hypoglycemia, her HbA1c level is 8.9%; evaluation of her home glucose monitoring results reveals morning fasting glucose levels that frequently exceed 250 mg/dl and afternoon values that average 185 mg/dl.
Which of the following steps is most appropriate for this patient?
A. Decreasing her evening insulin level by discontinuing the 70/30 insulin therapy and starting her on 12 U of regular insulin before dinner and 20 U of NPH insulin at bedtime
B. A thorough diagnostic evaluation of pituitary and adrenal function
C. Decreasing her evening insulin level by discontinuing the 70/30 insulin therapy and starting 12 U of lispro and 25 U of NPH insulin at dinner
D. Measurement of plasma glucagon and epinephrine after induction of hypoglycemia
E. Asking the patient to decrease the overall intensity of her physical training and to increase the amount of resistance training
Key Concept/Objective: To understand that twice-daily insulin regimens are often ineffective in the treatment of type 1 diabetes
This patient’s hypoglycemia has increased because of an increase in physical activity. It is not unusual for diabetic patients who require insulin to have delayed hypoglycemia in response to exercise. Her current regimen of NPH administered before dinner results in insulin action peaking in the early morning; because of her recent increase in daily glucose use with exercise, having insulin action peak at this time makes her susceptible to hypoglycemia. In addition, the poor overall glycemic control and the presence of fasting hyperglycemia indicate that she does not have effective overnight insulin action. Changing the time of administration of NPH from the evening to bedtime will shift the time of peak effect from between midnight and 3:00 A.M. to between 4:00 A.M. and 7:00 A.M.; this should result in a lower fasting glucose level as well as a decrease in the incidence of hypoglycemia. Increasing the number of insulin doses often results in better glycemic control, even when the total amount of insulin is decreased, because the timing of peak effects that results from increasing the number of doses is often more appropriate to the patient’s needs. The use of lispro insulin can provide increased flexibility for patients who require insulin because the period of action of lispro is much shorter than that of regular insulin. In this case, substituting lispro for regular insulin might decrease the early morning insulin action that is causing the hypoglycemia, but continuing to administer NPH before dinner would still likely cause problems. The new onset of unexplained hypoglycemia in persons with type 1 diabetes should always raise concern that adrenal or thyroid insufficiency or some other autoimmune disease has developed. However, in this patient, these relatively rare conditions can be dismissed unless the patient continues to have hypoglycemia after adjustments are made to her insulin regimen. There are no standardized values for plasma glucagon and epinephrine levels that reliably indicate alpha cell, or autonomic nervous system, dysfunction. Aerobic exercise is as beneficial for persons with type 1 diabetes as it is for nondiabetic individuals, and although it frequently requires vigilant glucose monitoring and insulin adjustment, it should be encouraged in most cases. (Answer: A—Decreasing her evening insulin level by discontinuing the 70/30 insulin therapy and starting her on 12 U of regular insulin before dinner and 20 U of NPH insulin at bedtime)
10. A 42-year-old man with long-standing type 1 diabetes presents with gastroenteritis that has been worsening for 5 days. His serum biochemistry values are consistent with diabetic ketoacidosis (DKA); his blood pressure is 90/55 mm Hg, and his heart rate is 135 beats/min. Other laboratory findings are as follows: blood glucose, 656 mg/dl; sodium, 127 mEq/L; potassium, 4.2 mEq/L; HCO3, 14 mEq/L; anion gap,
25; and pH, 7.05.
Which of the following would not be an appropriate step in the immediate treatment of this patient?
A. I.V. administration of 0.9% saline
B. Admission to the intensive care unit
C. I.V. administration of potassium chloride
D. I.V. administration of insulin
E. I.V. administration of sodium bicarbonate
Key Concept/Objective: To understand that in most cases, successful treatment of DKA does not require bicarbonate administration
This patient’s vital signs suggest moderate to severe dehydration, and volume replacement with normal saline is critical in the early management of his DKA. The severity of his metabolic derangements indicates that he should be treated in the intensive care unit. Insulin should be started immediately; the intravenous route is preferred because the rate of absorption of subcutaneous and intramuscular injections can vary in dehydrated individuals. The combination of volume expansion, diuresis, and insulin dependent glucose disposal will lower the blood glucose level at a modest rate. More important, insulin will inhibit lipolysis and ketogenesis, reducing the acidosis. This patient is likely to have a large deficit in total body potassium, and with hydration and insulin treatment, his serum potassium level will decrease. Failure to adequately replace potassium can have severe consequences in patients with DKA, and potassium should be started immediately unless urine output is compromised or hyperkalemia exists. Administration of bicarbonate is not generally required in most cases of DKA and is generally reserved for treatment of severe acidosis (pH < 7.0 or HCO3 < 10) or hemodynamic instability. Studies have indicated that the use of bicarbonate does not affect the course of most cases of DKA, and there is some theoretical rationale for not using bicarbonate unless clearly necessary. (Answer: E—I.V. administration of sodium bicarbonate)
11. A 49-year-old man was referred from a walk-in clinic when he was discovered to have a blood glucose level of 246 mg/dl during evaluation of an acute GI syndrome. Subsequently, a diagnosis of diabetes was confirmed by a finding of fasting blood glucose values of 190 mg/dl and 176 mg/dl, measured when the patient was not ill. Overall, this patient’s clinical picture is consistent with type 2 diabetes. He has not received medical treatment or been evaluated for many years but reports being in generally good health.
Which of the following is the most reasonable approach for evaluating this patient’s renal status?
A. Perform 24-hour urine collection, obtain an estimate of his creatinine clearance, and measure total protein excretion
B. Measure the albumin-creatinine ratio on a spot urine sample
C. Defer specific assessment because he has just been diagnosed, and diabetic nephropathy is unlikely to have developed
D. Measure serum BUN and creatinine concentrations
E. Perform renal ultrasound
Key Concept/Objective: To know that urinary albumin excretion is the most sensitive means of detecting early diabetic nephropathy
An abnormally high rate of albumin excretion is the earliest manifestation of diabetic nephropathy, and microalbuminuria can be detected well before changes in creatinine clearance and pathologic proteinuria occur. Microalbuminuria is predictive of the progression of renal disease in most cases, and its occurrence marks the point in the course of nephropathy at which treatment is most efficacious. Therefore, all patients who are diagnosed with diabetes should undergo screening for renal albumin excretion. For patients with type 1 diabetes, formal evaluation can be deferred for several years because the time of disease onset is generally clear, and abnormalities in renal function do not occur during the first 5 years after onset. Patients with type 2 diabetes should be screened at the time of diagnosis because the time of onset of type 2 diabetes is often hard to discern, and asymptomatic hyperglycemia may have been present for several years. Screening for microalbuminuria can be done with a 24-hour urine collection, an overnight collection, a 4-hour timed collection, or a spot collection with determination of albumin-creatinine ratio. All these measures require a specific assay for albumin because standard clinical laboratory measurements of urinary protein are not sensitive enough to detect microalbuminuria. Diabetic nephropathy is usually quite advanced before changes in the BUN and serum creatinine levels occur. Although one of the earliest renal manifestations of diabetes is transient kidney enlargement, renal ultrasound is not useful for screening for diabetic nephropathy. (Answer: B—Measure the albumincreatinine ratio on a spot urine sample)
For more information, see Genuth S: 9 Metabolism: VI Diabetes Mellitus. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, May 2004