Secondary causes of dyslipidemia

INTRODUCTION — In many patients, hyperlipidemia is caused by some underlying "nonlipid" etiology rather than a primary disorder of lipoprotein metabolism. The secondary causes of dyslipidemia will be reviewed briefly here (table 1).

Primary lipid disorders are discussed separately. (See "Familial hypercholesterolemia in adults: Overview" and "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia" and "Hypertriglyceridemia in adults: Management".)

PREVALENCE — Dyslipidemia due to secondary causes is common. In a cohort of 824 new patients referred to a lipid clinic at an academic medical center in the United States, 28 percent had one or more potential causes of secondary dyslipidemia [1]. The most common conditions that were felt to be contributing to dyslipidemia were excessive alcohol intake (10 percent) and uncontrolled diabetes mellitus (8 percent).

DISEASE ASSOCIATIONS

Diabetes mellitus — Hyperlipidemia in association with insulin resistance is common in patients with type 2 diabetes mellitus [2,3]. Insulin resistance and the ensuing hyperinsulinemia are associated with hypertriglyceridemia, increased low-density lipoprotein (LDL), and low serum high-density lipoprotein (HDL) cholesterol concentrations. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Lipid management'.)

The lipoprotein abnormalities are related to the severity of the insulin resistance. A study that measured insulin sensitivity using a euglycemic clamp in patients with and without type 2 diabetes mellitus found that greater insulin resistance was associated with larger very low-density lipoprotein (VLDL) particle size, smaller LDL particle size, and smaller HDL particle size [4]. Additionally, the number of VLDL, intermediate-density lipoprotein (IDL), and LDL particles increase with increasing insulin resistance, while HDL particle concentration decreases.

Hypertriglyceridemia results both from increased substrate availability (glucose and free fatty acids) and from decreased lipolysis of VLDL triglyceride. Nicotinic acid can partially correct these disturbances but at the potential expense of increased insulin resistance and worse glycemic control. In one study, for example, nicotinic acid administration led to a 21 percent rise in hemoglobin A1c values [3]. (See "Hypertriglyceridemia in adults: Management".)

Cholestatic liver disease — Primary biliary cholangitis and similar disorders may be accompanied by marked hypercholesterolemia that results from an accumulation of lipoprotein-X and/or lipoprotein-Z [5]. Clinical stigmata include xanthomata striata palmare that may appear when the serum cholesterol concentration is 1400 mg/dL (36 mmol/L) or higher. Xanthomata appear on the extremities as well. Marked elevations in lipoprotein X has been associated with the hyperviscosity syndrome [5], but no clear association with coronary heart disease has been established [6]. (See "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)".)

Renal diseases

Nephrotic syndrome — Marked hyperlipidemia can occur in the nephrotic syndrome due primarily to high serum total and low-density lipoprotein (LDL) cholesterol concentrations. Increased hepatic production of lipoproteins (induced in part by the fall in plasma oncotic pressure) is the major abnormality, but diminished lipoprotein catabolism may play a contributory role. (See "Lipid abnormalities in nephrotic syndrome".)

Chronic renal disease — Dyslipidemia is less prominent in chronic kidney disease (CKD), but CKD is associated with elevations in low-density lipoprotein (LDL) cholesterol and triglycerides, and low levels of high-density lipoprotein (HDL) cholesterol; hypertriglyceridemia (type IV hyperlipoproteinemia) occurs in 30 to 50 percent of cases of CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia'.)

Hypothyroidism — Hypothyroidism is frequently associated with and is a common cause of hyperlipidemia. The relationship between hypothyroidism and hyperlipidemia is discussed separately. (See "Lipid abnormalities in thyroid disease".)

Thus, serum thyrotropin should be measured in all patients with dyslipidemia (see "Diagnosis of and screening for hypothyroidism in nonpregnant adults"). Reversal of the hypothyroidism with thyroid hormone replacement leads to correction of the hyperlipidemia.

Obesity — Obesity is associated with a number of deleterious changes in lipoprotein metabolism, including high serum concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides, and a reduction in serum high-density lipoprotein (HDL) cholesterol concentration of about 5 percent [7]. Loss of body fat can reverse the hypercholesterolemia and hypertriglyceridemia. However, improvement in serum total and HDL cholesterol, HDL2 cholesterol, and apolipoprotein A-I is primarily limited to patients with LDL subclass A; improvement occurs in only one-third of patients with LDL subclass B [8]. (See "Overweight and obesity in adults: Health consequences", section on 'Dyslipidemia'.)

LIFESTYLE FACTORS

Cigarette smoking — Smoking modestly lowers the serum high-density lipoprotein (HDL) cholesterol concentrations and may induce insulin resistance [9-11]. In the screening phase of the Bezafibrate Infarction Prevention Study Group, for example, the mean serum HDL cholesterol concentration was 40 mg/dL (1 mmol/L) in nonsmokers, 37 mg/dL (1 mmol/L) in former smokers, and 35 mg/dL (1 mmol/L) in current smokers with an intake of two packs per day or more [10]. Another report found that the effect of smoking was more prominent if adjusted for concomitant alcohol intake; in such patients, smoking was associated with a 5 to 9 mg/dL (0.1 to 0.2 mmol/L) decline in serum HDL cholesterol [11]. These effects are reversible within one to two months after smoking cessation [12-14]. In addition, cigarette smoking impairs HDL function by reducing antioxidant and antiinflammatory capacity and impeding cellular cholesterol efflux [15]. (See "Cardiovascular risk of smoking and benefits of smoking cessation".)

Excessive alcohol consumption — While moderate alcohol consumption generally has favorable effects on lipids (see "Cardiovascular benefits and risks of moderate alcohol consumption"), excessive alcohol consumption can raise triglyceride levels [16,17]. This is a particular concern in patients with severe hypertriglyceridemia at baseline and patients who have had triglyceride-associated acute pancreatitis.

MEDICATIONS — Some medications, including thiazide diuretics, beta blockers, and oral estrogens can cause modest changes in serum lipid concentrations (see "Antihypertensive drugs and lipids" and "Menopausal hormone therapy and cardiovascular risk" and "Combined estrogen-progestin contraception: Side effects and health concerns"). Some of the atypical antipsychotic agents, in particular clozapine and olanzapine, have been associated with weight gain, obesity, hypertriglyceridemia, and development of diabetes mellitus [18-21]. The mechanism(s) by which they cause the metabolic syndrome have not been defined.

Antiretroviral regimens used for human immunodeficiency virus (HIV) infection, and in particular the protease inhibitors, have been associated with abnormalities in lipids and glucose metabolism often as part of a lipodystrophy syndrome. (See "Lipodystrophic syndromes", section on 'Lipodystrophy associated with HIV therapy' and "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: High cholesterol and lipids (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)" and "Patient education: Losing weight (Beyond the Basics)" and "Patient education: High cholesterol and lipid treatment options (Beyond the Basics)")

SUMMARY

●Introduction – In many patients, hyperlipidemia may be caused by some "nonlipid" etiology (table 1).

●Disease associations

•Diabetes – In patients with type 2 diabetes mellitus, hyperlipidemia occurs in association with insulin resistance and frequently involves increased triglycerides and low serum high-density lipoprotein (HDL) cholesterol. (See 'Diabetes mellitus' above and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Lipid management'.)

•Liver disease – Primary biliary cholangitis and similar disorders may be accompanied by marked hypercholesterolemia that results from an accumulation of lipoprotein-X and lipoprotein-Z. (See 'Cholestatic liver disease' above and "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)".)

•Renal diseases

-Nephrotic syndrome – Marked hyperlipidemia can occur in the nephrotic syndrome due primarily to high serum total and low-density lipoprotein (LDL) cholesterol concentrations. (See 'Nephrotic syndrome' above and "Lipid abnormalities in nephrotic syndrome".)

-Chronic kidney disease (CKD) – Dyslipidemia is less prominent in CKD, but CKD is associated with elevations in LDL cholesterol and triglycerides, and low levels of HDL cholesterol; hypertriglyceridemia (type IV hyperlipoproteinemia) occurs in 30 to 50 percent of cases of CKD. (See 'Chronic renal disease' above and "Overview of the management of chronic kidney disease in adults", section on 'Dyslipidemia'.)

•Hypothyroidism – This is a common cause of hyperlipidemia, most typically raising LDL cholesterol, but hypertriglyceridemia can also be seen. We advise screening for hypothyroidism in all patients with dyslipidemia. (See 'Hypothyroidism' above and "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

•Obesity is associated with a number of deleterious changes in lipid metabolism, including high serum concentrations of total cholesterol, LDL cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides, and a reduction in serum HDL cholesterol concentration. (See 'Obesity' above and "Overweight and obesity in adults: Health consequences", section on 'Dyslipidemia'.)

●Lifestyle factors

•Cigarette smoking modestly lowers the serum HDL cholesterol concentrations and HDL atheroprotective properties. (See 'Cigarette smoking' above and "Cardiovascular risk of smoking and benefits of smoking cessation".)

•Excessive alcohol consumption can raise triglyceride levels. (See 'Excessive alcohol consumption' above and "Cardiovascular benefits and risks of moderate alcohol consumption".)

●Medications – A number of medications can affect serum lipid concentrations, either directly or through effects on weight or glucose metabolism. (See 'Medications' above.)