H.U. Rehman, MB, FRCPC, FACP The work-up for mixed Department of Medicine, Regina Qu’Appelle Health Region, Regina General hyperlipidemia: A case study Hospital, Canada This case demonstrates that a history, physical exam, [email protected] The author reported no and laboratory studies are all needed to determine if the potential conflict of interest disorder is primary, secondary, or both. relevant to this article.
42-year-old man with type 2 diabe- Ask about alcohol intake and use of medi- tes mellitus and hypertension was cations including glucocorticoids and oral A referred to our clinic for assessment contraceptives. And explore the family his- of mixed hyperlipidemia found on routine tory, particularly for premature heart disease, investigation. Results of our physical exami- pancreatitis, and known lipid disorders. Epi- nation were unremarkable. The patient had demiologic studies have shown that higher- no xanthomatous deposits. His family history than-normal triglyceride levels increase the was strongly positive for type 2 diabetes. His risk of coronary artery disease (CAD), and medications included ramipril, glyburide, triglyceride levels greater than 500.44 mg/dL and hydrochlorothiazide. are associated with pancreatitis.1 In our further laboratory testing, a fasting z What to look for in the physical ex- blood sample revealed a grossly lipemic serum, amination. Measure body mass index (BMI), with a total cholesterol level of 536.34 mg/dL check blood pressure and carotid and periph- (normal range=146.94-201.08 mg/dL), to eral pulses, and palpate the liver and thyroid. tal triglyceride level of 5927.4 mg/dL Inspect palms, soles, extensor surfaces of the (normal=31.15-151.3 mg/dL), and high- arms, buttocks, and tendinous attachments density cholesterol (HDL-C) level of 23.4 mg/dL for xanthomatous deposits. (normal=35.1-93.6 mg/dL). His thyroid- z Lab work. Order a fasting glucose stimulating hormone (TSH) level was test, renal panel, thyroid function tests, and 0.94 mIU/L (normal=0.49-4.67 mIU/L). a liver panel to detect or rule out diabetes, Results were in the normal range for hypothyroidism, and renal and liver disease. urea, creatinine, electrolytes, bilirubin, alka- Typically, in dyslipidemia due to excessive line phosphatase, alanine aminotransferase, alcohol intake or estrogen use, HDL choles- and albumin. Hemoglobin A1c (HbA1c) was terol is disproportionately elevated (TABLE 1). 9.5%. Patients with hypertriglyceridemia may also present with acute pancreatitis and relatively low amylase levels, due to interference by Following clues triglyceride-rich lipoproteins that can show to an accurate diagnosis falsely low amylase levels. Removal of chy- When the lipid phenotype is a mixed hyper lomicrons from plasma by centrifugation lipidemia—a common disorder that becomes before laboratory testing can eliminate such more prevalent with increasing age—inves- artifacts.2 In addition, hypertriglyceridemia tigate potential underlying disorders such can interfere with biochemical measurement as diabetes mellitus, renal failure, hypothy- of glucose, leading to falsely normal levels in roidism, and chronic liver disease (TABLE 1). these patients.3 Continued
jfponline.com Vol 61, No 3 | MARCH 2012 | The Journal of Family Practice 133 TABLE 1 Secondary causes of hyperlipidemia
Underlying cause Chylomicrons VLDL LDL HDL IDL Lp(a)
Acromegaly + +
Acute intermittent + porphyria
Alcohol + +
Anorexia nervosa +
Autoimmune disease + +
Cushing’s disease +
Diabetes mellitus + + – (type 2)
When the lipid Glucocorticoids + phenotype is a mixed Hepatitis + hyperlipidemia, investigate Hypothyroidism + + + potential underlying Liver disease (severe) – disorders such Monoclonal + as diabetes gammopathies mellitus, renal failure, Multiple myeloma + hypothyroidism, and chronic Nephrotic syndrome + + liver disease. Obesity + –
Oral contraceptives + +
Renal failure + +
+, elevated; –, reduced. HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein a; VLDL, very low-density lipoprotein. Adapted from: Rader DJ, Hobbs HH. Harrison’s Principles of Internal Medicine. 2012.10
z To further refine the diagnosis, order hyperlipidemia most often have the type IV lipoprotein electrophoresis, which identi- variety, they can also have other types, includ- fies mixed hyperlipidemias according to the ing type V. In uncontrolled diabetes, increased Fredrickson classification (types I–V).4 lipid metabolism mobilizes fat stores and in- creases VLDL and chylomicrons in plasma. Li- poprotein lipase activity is insulin dependent Making sense of findings and is transiently reduced in insulin-deficient Although patients with type 2 diabetes and states, further increasing triglyceride levels.5
134 The Journal of Family Practice | MARCH 2012 | Vol 61, No 3 mixed hyperlipidemia
TABLE 2 Primary hyperlipidemia
Genetic disorder (Frederickson type) Typical clinical findings
Familial lipoprotein lipase deficiency Eruptive xanthomas, hepatosplenomegaly, (type I) pancreatitis
Familial apoprotein C-II deficiency Eruptive xanthomas, hepatosplenomegaly, (type I) pancreatitis
Familial combined hyperlipidemia Coronary or peripheral atherosclerosis (type IIb)
Familial dysbetalipoproteinemia Palmar and tuberous xanthomas, coronary (type III) or peripheral atherosclerosis
Familial hypertriglyceridemia Eruptive xanthomas (type V) (type IV or V)
Adapted from: Rader DJ, Hobbs HH. Harrison’s Principles of Internal Medicine. 2012.10 Patients with triglyceride Hypothyroidism is classically associated ondary dyslipidemia due to diabetes and levels above with elevated plasma LDL cholesterol, but metabolic syndrome. But patients with tri- 2001.77 mg/dL is also sometimes linked with high plasma glyceride levels above 2001.77 mg/dL almost almost always triglycerides. The elevated plasma LDL cho- always have both a secondary and a genetic have both a lesterol in hypothyroidism is due to reduced form of hyperlipidemia.9 My colleagues and I secondary and a expression of LDL receptors resulting in im- suspected Fredrickson’s type V hyperlipopro- genetic form of paired clearance of LDL.6 Elevated triglycer- teinemia because of the high triglycerides. hyperlipidemia. ides in hypothyroidism are due to decreased This was confirmed when the lipoprotein lipoprotein lipase activity.7 electrophoresis showed decreased alpha, in- z Suspect primary (familial) hyperlip- creased prebeta, and normal beta fractions idemia (TABLE 2) if blood test results exclude and chylomicronemia. such disorders as diabetes or hypothyroid- z Treatment. Therapy choices differ de- ism, and excessive alcohol intake and medi- pending on the type of mixed hyperlipidemia cation use have been ruled out. Some genetic a patient has. However, fibrates are usually causes of hyperchylomicronemia are rare and needed in addition to statins. (Of note: Statin- include familial lipoprotein lipase deficiency induced myopathy is more likely in patients and apoprotein C-II deficiency. The differen- who are also taking fibrates, so careful moni- tial diagnosis of mixed hyperlipidemia also toring is important.) includes familial combined hyperlipidemia I added fenofibrate, metformin, and ro- (FCHL), familial dysbetalipoproteinemia, suvastatin to the patient’s regimen, which and familial hypertriglyceridemia. included ramipril, glyburide, and hydro- FCHL can be difficult to differentiate chlorothiazide. I also recommended lifestyle from dyslipidemia of metabolic syndrome. A modifications and arranged a consultation dominant inheritance pattern favors a diag- with a dietician. nosis of FCHL, while environmental factors Four weeks later, his fasting lipid pro- are more important in dyslipidemia of meta- file had improved: Total serum choles- bolic syndrome.8 terol level was 213.45 mg/dL, triglyceride level was 825.5 mg/dL, and HDL-C level was 37.05 mg/dL. Apolipoprotein B100 was How my patient’s case resolved 2.54 g/L (normal=0.59-1.46 g/L). At fol- My patient’s case was consistent with sec- low-up 3 months later, the patient’s total
jfponline.com Vol 61, No 3 | MARCH 2012 | The Journal of Family Practice 135 CORRESPONDENCE cholesterol level was 145.9 mg/dL, triglycer- H.U. Rehman, MB, Clinical Associate Professor, Department ide level was 330.4 mg/dL, and HDL-C level of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, was 27.84 mg/dL. JFP Canada; [email protected]
References 1. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the thyroid states. Endocr Rev. 1985;6:590-607. risk of coronary heart disease. 10,158 incident cases among 7. Valdemarsson S, Hansson P, Hedner P, et al. Relations be- 262,525 participants in 29 Western prospective studies. tween thyroid function, hepatic and lipoprotein lipase activi- Circulation. 2007;115:450-458. ties, and plasma lipoprotein concentrations. Acta Endocrinol. 2. Chait A, Brunzell JD. Chylomicronemia syndrome. Adv Intern 1983;104:50-56. Med. 1992;37:249-273. 8. Cabezas MC, Rabelink TJ. Familial combined hyperlipidemia: 3. Rumbak MJ, Hughes TA, Kitabchi AE. Pseudonormoglyce- The case of triglycerides. In: Betteridge DJ, ed. Case Studies in mia in diabetic ketoacidosis with elevated triglycerides. Am J Lipid Management. London, England: Informa UK; 2007:85-93. Emerg Med. 1991;9:61-63. 9. Martin D, McCann E, Glynn P. Rheologic reflection in 4. Jialal I. A practical approach to the laboratory diagnosis of dys- hypertriglyceridemia-induced pancreatitis. South Med J. lipidemia. Am J Clin Pathol. 1996;106:128-138. 2009;102:1049-1051. 5. McLean AG, Petersons CJ, Hooper AJ, et al. Extreme diabetic 10. Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. lipaemia associated with a novel lipoprotein gene mutation. In: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Clin Chem Acta. 2009;406:167-169. Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th 6. Heimberg M, Olubadew JO, Wilcox HG. Plasma lipoproteins ed. New York, NY: McGraw-Hill Companies, Inc; 2012:3145- and regulation of hepatic metabolism of fatty acids in altered 3161.
In thIs IssuE Improving Medication Adherence
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