Familial Hypercholesterolemia Clinical Presentation

Updated: Mar 07, 2017
  • Author: Mose July, MD, CCD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
  • Print
Presentation

History

Children with homozygous FH

These patients may have symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis. Such symptoms may be confused with conditions that are more benign unless the diagnosis of homozygous FH is considered.

Patients may have articular symptoms such as tendonitis or arthralgias.

Patients have a history of unusual skin lesions.

Because they are obligate heterozygous hypercholesterolemics, both parents must have severe elevations in LDLc; although they are often too young to have developed symptomatic CAD. Because each must have a parent with heterozygous FH, a history of significant hypercholesterolemia and premature CHD can be traced to the patient’s second degree relatives.

Children with heterozygous FH

Children with heterozygous FH do not have symptoms related to CHD.

One parent will have severe hypercholesterolemia and will probably have either a personal or family history for early CAD.

Statistically, because the gene for FH is dominant, 50% of the patient’s siblings will also have heterozygous FH.

Adults with homozygous FH

Most patients do not survive beyond age 30 years unless treated with unusual methods, such as liver transplantation, LDL apheresis, or ileal bypass surgery to dramatically lower their LDLc levels.

Their family history should be positive for severe hypercholesterolemia and premature CAD in both parental family lines.

Adults with heterozygous FH

These patients have a long-standing history of severe hypercholesterolemia dating back to childhood.

If an acute coronary event has not already occurred, symptoms consistent with ischemic heart disease are not uncommon, especially if other cardiovascular risk factors (especially smoking) are present.

Past or present symptoms of recurrent Achilles tendonitis or arthritic complaints may be present.

Premature CAD and severe hypercholesterolemia are present in one or more first-degree relatives.

If carefully questioned, patients with either homozygous or heterozygous FH may describe first-degree relatives who had visible tendon xanthomas on their hands.

Next:

Physical

The presence of tendon xanthomas is usually stated to be pathognomonic for FH, but that is not the case. As described in Causes, patients with familial ligand defective apoB-100 may have tendon xanthomas and elevated LDLc levels. 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. However, this rare disease causes other abnormalities (eg, dementia, ataxia, cataracts) with reference range cholesterol levels and, therefore, cannot be confused with FH. Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. Tendon xanthomas are present at an early stage although cholesterol levels are within the reference range or only mildly elevated. Uncommonly, patients with dysbetahyperlipoproteinemia have tendon xanthomas.

Homozygous FH

These patients may have cutaneous xanthomas at birth or by early childhood.

Several types of xanthomas are usually obvious in the first decade of life, and they include (1) planar xanthomas (on hands, elbows, buttocks, or knees), which are diagnostic for the homozygous state and are distinct from other cutaneous xanthomas because of their yellow-to-orange coloration; (2) tuberous xanthomas (on hands, elbows, or knees); and (3) tendon xanthomas (especially on extensor tendons of hands or Achilles tendon) will occur somewhat later.

Children may have corneal arcus, which is sometimes circumferential. While occasionally present in older adults with normal cholesterol levels, corneal arcus is highly unusual in children, and this finding should prompt a workup for homozygous FH.

The murmur of aortic stenosis may be heard.

Heterozygous FH

Most children with heterozygous FH do not develop tendon xanthomas or corneal arcus. By the third decade of life, more than 60% of patients with untreated FH develop tendon xanthomas as in the image below.

Metacarpophalangeal joint tendon xanthomas in a 45 Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.

Xanthomas are noted commonly on the Achilles tendons and metacarpal phalangeal extensor tendons of the hands.

The figures in many textbooks suggest that tendon xanthomas in heterozygous patients are readily apparent upon gross inspection. Unfortunately, this often is not the case. Careful palpation rather than simple inspection may be necessary for detection of Achilles tendon xanthomas. A diffusely thickened tendon or one with discreet irregularities is suggestive of a xanthoma.

Tendon xanthomas of the metacarpophalangeal joints may be seen by careful inspection and palpation. Slowly flexing and extending the digits and watching for nodules that move with the motion of the tendon make these xanthomas more noticeable and distinguish them from cutaneous or subcutaneous nodules.

Xanthelasmas may occur in older patients with normal cholesterol levels and this finding is, therefore, not specific for FH.

The presence of tendon xanthomas is often stated to be pathognomonic for FH but that is not the case.

As described below, patients with familial ligand defective apoB-100 may have tendon xanthomas and equivalent laboratory values.

27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. But this rare disease causes other abnormalities (dementia, ataxia, cataracts) with normal cholesterol levels and, therefore, cannot be confused with FH.

Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. [24, 26] Tendon xanthomas may be present though cholesterol levels are normal or only mildly elevated.

Uncommonly, patients with dysbetalipoproteinemia have tendon xanthomas.

Previous
Next:

Causes

A major change in the number or functional status of LDL receptors directly affects serum cholesterol levels. If the liver does not take up LDL particles, serum LDLc levels increase. Also, when LDL is not internalized by hepatocytes, hepatic synthesis of cholesterol is not suppressed. This leads to further cholesterol production despite high levels of circulating cholesterol. Therefore, circulating cholesterol levels are increased dramatically. The total and LDLc levels of infants and children with homozygous FH are higher than 600 mg/dL. In patients with heterozygous FH, half the LDL receptors are normal and half are rendered ineffective by the mutation. These patients' total cholesterol and LDLc levels are twice as high as the population average. LDLc levels of 200-400 mg/dL are common.

High levels of LDLc increase cholesterol uptake in nonhepatic cells that is independent of LDL receptors. These scavenger pathways allow cholesterol uptake by monocytes and macrophages, leading to foam cell formation, plaque deposition in the endothelium of coronary arteries, and premature CAD. Cholesterol also accumulates in other areas, particularly the skin, causing xanthelasmas and a variety of xanthomas. Early corneal arcus is frequent, and, in patients with the homozygous condition, valvular abnormalities, most frequently aortic stenosis, are common secondary to the deposition of cholesterol.

Several conditions other than FH cause severely elevated LDL levels, and each is caused by a single gene abnormality.

Familial ligand defective apoB-100

Familial ligand defective apoB-100 (FLDB), also called familial defective apoB-100, is responsible for a syndrome almost indistinguishable from heterozygous FH. Instead of an abnormal or absent LDL receptor, this syndrome is caused by an abnormality at the binding site of apoB-100, which impedes its role as a ligand for the receptor. ApoB-100 is a single polypeptide chain composed of 4536 amino acids. The gene resides on the short arm of chromosome 2 and the first described mutation was a substitution of glycine for arginine at the codon for amino acid 3500. Different mutations at the same and different codons have since been described.

Although the LDL receptors are normal in both number and function, LDL is taken up inefficiently, leading to elevated LDLc levels that can be indistinguishable from those associated with heterozygous FH. These patients can present with cutaneous manifestations and an increased risk of premature CAD similar to patients with heterozygous FH. Because LDL receptors function normally with respect to the apoE ligand, uptake of very low-density lipoprotein, very low-density lipoprotein remnants, and intermediate-density lipoprotein is normal. The consequence may be that patients with defective apoB-100 may have a clinically more benign course than patients with heterozygous FH. The finding that patients homozygous for familial defective apoB-100 are clinically similar to those with the heterozygous condition supports this supposition.

Autosomal recessive hypercholesterolemia

Another recently identified molecular defect that also causes severely elevated LDL levels is autosomal recessive hypercholesterolemia. These patients have LDLc levels that are higher than 400 mg/dL; however, heterozygous individuals have normal levels.

Previous