L1. Obtain History, Physical Examination, and Laboratory Tests.  Assess for Secondary Causes, Familial Disorders, and Comorbidities

objective

Detect and if needed treat health disorders that present with an elevated LDL-C or TG, low HDL-C, or metabolic syndrome.

background

Several underlying conditions may influence lipid levels.  Addressing these underlying conditions can improve or normalize underlying lipid abnormalities.  Failure to address these can render therapy sub-optimal or ineffective.  When treating potential causes of secondary hyperlipidemia, the provider should follow up the lipid levels at a reasonable time, usually six to eight weeks, following correction of any such underlying disorder.  Even with successful treatment of a secondary cause of hyperlipidemia, intervention with appropriate pharmacologic agents to lower cholesterol and/or triglycerides TG levels may be required.  Initial laboratory tests will also provide the baseline values for any lipid lowering therapy that may be initiated.

recommendations

1. Adults with abnormal lipid profiles (dyslipidemia) should be assessed for secondary causes, familial disorders, and other underlying conditions that may influence lipid levels.  [I]
2. Assessment for secondary causes should be based on medical history, physical examination and laboratory tests:
1. Measurement of serum thyroid-stimulating hormone (TSH), BUN/creatinine, liver function tests (LFTs), and a dipstick urinalysis should be obtained to exclude hypothyroidism, chronic renal failure, obstructive liver disease, and nephrotic syndrome conditions.  [I]
2. If dipstick urine protein is >1+ (detected in two urine tests), nephrotic syndrome as a secondary cause of elevated LDL-C should be ruled out.  [I]
3. Serum lipids should be assayed six to eight weeks post-TSH normalization to determine the need for additional treatment.  [I]
4. Patients with hypertriglyceridemia should be evaluated for alcohol use, diabetes, and hypothyroidism.  Addressing these underlying conditions can improve or normalize triglyceride levels, and failure to address these can render therapy ineffective.  [I]
5. Lipid levels in patients treated for secondary hyperlipidemia should be repeated six to eight weeks post correction of the underlying disorder.
6. Family members of patients presenting with very severe hypercholesterolemia should be screened to detect other candidates for therapy.
7. Consider consulting with a specialist to assist the primary care clinician in co-managing patients with familial disorders who do not respond to therapy.  [I]

Table 1.  Secondary Causes of Lipid Abnormalities

Disorder/Patient Characteristic	Effect on Lipids	Laboratory Test for Diagnosis
Chronic renal failure/ Postrenal transplantation	TG, TC, HDL-C	SCr
DM	TG, TC, HDL-C	Glucose, HbA1c
Ethanol use	TG, HDL-C	--
HIV/AIDS Wasting	TG, TC, HDL-C, LDL-C	--
HIV/AIDS (HAART)	TG, TC, HDL-C	--
Hypothyroidism	TG, TC, LDL-C	TSH
Inactivity	HDL-C	--
Nephrotic syndrome	TC,LDL-C	Urinalysis, serum albumin
Obesity	TG, HDL-C	--
Obstructive liver disease	TC	LFTs (Alkaline phosphatase, total bilirubin)
Estrogen therapy	TG, LDL, HDL	--
Medications	Variable	--

AIDS = acquired immune deficiency syndrome; DM = diabetes mellitus; HAART =  highly active antiretroviral therapy; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; LFTs = liver function tests; SCr = serum creatinine; TC = total cholesterol; TG = triglycerides; TSH = thyroid-stimulating hormone

discussion

Consider and Treat Secondary Causes of Elevated LDL- C

Hypothyroidism raises serum LDL.  A normal serum TSH level adequately rules out the common condition of primary hypothyroidism. TSH alone cannot exclude the rare condition of secondary hypothyroidism (hypothalamic or pituitary insufficiency).  If there is any clinical suspicion of this condition, serum thyroxine (T4) should be measured.  Normal TSH and normal T4 effectively rule-out the possibility of secondary hypothyroidism.

Treatment of severe hypothyroidism (manifested by very high TSH and/or very low T4) with oral L-thyroxine replacement often lowers elevated LDL to the normal range; treatment of mild, or subclinical, hypothyroidism has considerably less impact on the serum LDL.  In either case, serum lipids should be assayed six to eight weeks after normalization of the serum TSH (or T4, in the case of secondary hypothyroidism) to see if any additional treatment is needed (Stone et al., 1997; NCEP III, 2002).

Nephrotic syndrome is a secondary cause of dyslipidemia (Stone et al., 1997; NCEP III, 2002).  Nephrotic syndrome is characterized by excessive urinary protein excretion, which may be detected by routine dipstick urine testing.  If the dipstick test is positive, then a spot urine-protein creatinine ratio should be obtained.  If an abnormal ratio (³3g/day) is discovered, referral to a nephrologist for further evaluation and management is appropriate.

Consider and Treat Secondary Causes of Hypertriglyceridemia

Hypertriglyceridemia can be caused by or exacerbated by an underlying medical disorder.  When secondary disorders of hyperlipidemia are appropriately treated, TG levels can greatly improve or, in some cases, even return to the normal range.  Hypertriglyceridemia has been associated with obesity and alcohol use/abuse.  The need to screen for underlying alcohol use, together with a critical review of dietary habits, cannot be overemphasized (Oberman et al., 1992).  Diabetes mellitus (especially suboptimally controlled), and hypothyroidism, have also been documented as potential causes for hypertriglyceridemia (See Table 1).

Consider Medication

Some medications can have an incidental negative impact on a patient’s lipid profile.  Progestins, estrogens, androgens, anabolic steroids, corticosteroids, cyclosporine, protease inhibitors, diuretics, and retinoids may raise cholesterol and/or TG levels.  A thorough review of the patient’s chart and previous lipid panels may support the possibility of a drug side effect as the etiology for the lipid abnormality, or a trial of the suspected agent may be required for confirmation.  Of note, oral estrogens have been associated with significant hypertriglyceridemia, which resolved with the discontinuation of the oral preparation.  Many of these patients appear to be able to tolerate estrogen patch therapy without recurrence of the TG elevations.  Progestins have been shown to decrease HDL, thereby counteracting the HDL-raising effects of estrogen therapy.

Familial Hypercholesterolemia

Most severe forms of hypercholesterolemia are the result of genetic disorders.  Hypercholesterolemia is characterized by severe elevations of LDL-C (>200 mg/dL), tendinous xanthomas and xanthelasmae on physical examinations, and premature CVD.  Familial combined hyperlipidemia is characterized by elevations of TC, TG, or both, in different members of the same family, and is associated with premature CVD.  Family members of patients presenting with very severe hypercholesterolemia should undergo screening to detect other candidates for therapy.  A consultation with a specialist is recommended to assist the primary care clinician in co-managing these patients.