Secondary causes of dyslipidemia

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2017. | This topic last updated: Feb 10, 2016.

INTRODUCTION In many patients hyperlipidemia is caused by some underlying "nonlipid" etiology rather than a
primary disorder of lipid metabolism. The secondary causes of dyslipidemia will be reviewed briefly here; many of these
are discussed in more detail elsewhere:

Type 2 diabetes mellitus (DM)

Excessive alcohol consumption
Cholestatic liver diseases
Nephrotic syndrome
Chronic renal failure
Hypothyroidism
Cigarette smoking
Obesity
Drugs

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 DM (8 percent).

TYPE 2 DIABETES MELLITUS Hyperlipidemia in association with insulin resistance is common in patients with type 2
diabetes mellitus (DM) [2,3]. Insulin resistance and the ensuing hyperinsulinemia are associated with hypertriglyceridemia
and low serum high density lipoprotein (HDL) cholesterol concentrations.

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 DM found that greater insulin resistance was associated with
larger very low density lipoprotein (VLDL) particle size, smaller low density lipoprotein (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 "Treatment of lipids (including hypercholesterolemia) in secondary
prevention", section on 'Treatment in diabetes'.)

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 [5,6]. This is particular concern in patients with severe hypertriglyceridemia at baseline.
(See "Hypertriglyceridemia", section on 'Indications for drug therapy'.)

CHOLESTATIC LIVER DISEASES Primary biliary cholangitis and similar disorders may be accompanied by marked
hypercholesterolemia that results from an accumulation of lipoprotein-X. 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, but no clear association with coronary heart disease (CHD) has been established [7].
(See "Hypercholesterolemia and atherosclerosis in primary biliary cholangitis (primary biliary cirrhosis)".)

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 lipid catabolism may play a
contributory role. (See "Lipid abnormalities in nephrotic syndrome".)
CHRONIC KIDNEY 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 "Indications for statins in nondialysis chronic kidney disease".)

HYPOTHYROIDISM Hypothyroidism is frequently associated with and is a common cause of hyperlipidemia. The
relationship between hypothyroidism and hyperlipidemia can be illustrated by the following findings (see "Lipid
abnormalities in thyroid disease"):

In a study of 268 patients with primary hypothyroidism, hypercholesterolemia (type IIa hyperlipoproteinemia) was
present in 56 percent, hypercholesterolemia and hypertriglyceridemia (type IIb) in 34 percent, and
hypertriglyceridemia (type IV) in 1.5 percent; only 8.5 percent had a normal lipid profile [8].
The severity of the lipid abnormalities increases in a graded fashion with the severity of the hypothyroidism [9].
In a survey of 248 patients referred to a lipid disorders clinic, 2.8 percent had overt hypothyroidism and 4.4 percent
had subclinical hypothyroidism [10].

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.

CIGARETTE SMOKING Smoking modestly lowers the serum high density lipoprotein (HDL) cholesterol concentrations
and may induce insulin resistance [11-13]. 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 [12]. 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
[13]. These effects are reversible within one to two months after smoking cessation [14-16]. In addition, cigarette smoking
impairs HDL function by reducing antioxidant and anti-inflammatory capacity and impeding cellular cholesterol efflux [17].
(See "Cardiovascular risk of smoking and benefits of smoking cessation".)

OBESITY Obesity is associated with a number of deleterious changes in lipid 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 [18]. 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 [19].

DRUGS 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 "Risks and side effects associated with estrogen-progestin contraceptives"). Some of the atypical
antipsychotic agents, in particular, clozapine and olanzapine, have been associated with weight gain, obesity,
hypertriglyceridemia, and development of diabetes mellitus (DM) [20-23]. 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 6th 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 12th 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 (hyperlipidemia) (Beyond the
Basics)" and "Patient education: Diabetes mellitus type 2: Overview (Beyond the Basics)" and "Patient education:
Preventing complications in diabetes mellitus (Beyond the Basics)" and "Patient education: Weight loss treatments
(Beyond the Basics)" and "Patient education: High cholesterol treatment options (Beyond the Basics)")

SUMMARY In many patients, hyperlipidemia may be caused by some "nonlipid" etiology:

In patients with type 2 diabetes mellitus (DM), hyperlipidemia occurs in association with insulin resistance and
frequently involves increased triglycerides and low serum high density lipoprotein (HDL) cholesterol. (See 'Type 2
diabetes mellitus' above.)
Excessive alcohol consumption can raise triglyceride levels. (See 'Excessive alcohol consumption' above.)
Primary biliary cholangitis and similar disorders may be accompanied by marked hypercholesterolemia that results
from an accumulation of lipoprotein-X. (See 'Cholestatic liver diseases' above.)
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.)
Dyslipidemia is less prominent in chronic kidney disease (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 "Indications for statins in nondialysis chronic kidney disease".)
Hypothyroidism is a common cause of hyperlipidemia, most typically raising LDL cholesterol, but
hypertriglyceridemia can also be seen. We suggest screening for hypothyroidism in all patients with dyslipidemia.
(See 'Hypothyroidism' above and "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)
Smoking modestly lowers the serum HDL cholesterol concentrations and HDL atheroprotective properties.
(See 'Cigarette smoking' above.)
Obesity is associated with a number of deleterious changes in lipid metabolism, including high serum
concentrations of total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides, and a reduction in serum
HDL cholesterol concentration. (See 'Obesity' above.)
A number of medications can affect serum lipid concentrations, either directly or through effects on weight or
glucose metabolism. (See 'Drugs' above.)