Familial Hypercholesterolemia (FH)

At a Glance

Familial hypercholesterolemia is the most common monogenic disorder of lipoprotein metabolism and may be encountered fairly frequently by physicians. Most FH cases are either undiagnosed or only diagnosed after the primary coronary event. A patient with very high plasma levels of low density lipoprotein-cholesterol (LDL-C), a strong family history of high LDL-C levels and/or heart attacks at an early age would be suspect for FH. Patients with FH usually have normal circulating levels of triglycerides and high-density lipoprotein cholesterol (HDL-C, which may be slightly lower in FH patients).

The clinical hallmark of FH is cholesterol ester accumulation in tissues manifesting as xanthomas over the elbows, knees, buttocks, tendons (e.g. Achilles), and around the cornea and ocular orbit. However, these clinical signs generally develop later in life and have variable manifestation. It is important to palpate for nodules and really feel the Achilles tendons to make sure that they are thickened, as this may not be apparent to the patient and is easy to miss. Patients may also present with angina and other signs of coronary heart disease (e.g. elevated plasma total cholesterol levels, increased carotid intima-media thickness).

LDL-derived cholesterol deposits may also occur in arterial plaques of FH patients, in which they are called atheromas. Less commonly, arteries of the brain may be affected and lead to transient ischemic attacks or, occasionally, strokes. Peripheral artery occlusive disease may occur in smokers who have FH; this can cause pain in the calf muscles during walking that wanes during rest and complications from decreased blood supply to the feet (e.g. gangrene).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

In FH, LDL particles contain greater-than-average quantities of cholesterol, but both LDL-C and ApoB concentrations are markedly elevated. Some FH cases also have elevated levels of Lp(a), another atherogenic lipoprotein, which will synergistically add to the increased cardiovascular risk. The most common cause of FH is an autosomal dominant genetic mutation in the LDL receptor (LDLR) gene on chromosome 19p13.2 that affects the structure or function of the LDL receptor, leading to plasma accumulation of cholesterol ester-laden LDL particles (LDL-P).

Patients with one abnormal copy of the LDLR gene (heterozygotes) may have premature cardiovascular disease at 30-50 years of age. These patients have two- to three-fold elevations in plasma LDL-C (200-350 mg/dL). Those with two abnormal copies (homozygotes) have LDL-C levels six- to 10-fold that of normal values (>600 mg/dL) and may suffer severe cardiovascular disease in childhood. Heterozygous FH has a population prevalence of approximately 1 in 500 in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Yet another recently discovered rare form of FH is due to gain-of-function mutations in the proprotein convertase sybtilisin/kexin type 9 (PCSK9) gene, also causing decreased clearance of LDL by novel mechanisms involving the hepatic LDLR endocytotic pathway. A recessive form of hypercholesterolemia is caused by very rare mutations in the low density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene.

It is important to identify the causative mutation to establish other affected family members at an early age, thus optimizing health benefits via early treatment. However, it is important to note that mutation detection rate in genetic screening programs of FH patients is only 75-85%, at best, owing to the genetic heterogeneity of the disorder (>1000 different mutations and many novel mutations yet to be discovered), with frequent occurrence of large gene rearrangements (DNA copy number variations, deletions and insertions). Selected populations exist in which the incidence of a particular mutant allele is high, owing to a founder effect (e.g., Quebec, Finland, Iceland, South Africa, Lebanon).

There are no universally adopted diagnostic criteria for FH. The Simon Broome Register criteria (UK), the Dutch Lipid Clinic Network Criteria (DLCNC) and the Make Early Diagnosis, Prevent Early Deaths (MEDPED) criteria (USA) are currently used. The latter is based on validated age- and sex-adjusted serum cholesterol cut-off points. (Table 1) (Table 2)

Table 1
Criteria Points
1 Family history
   First degree relative with known premature coronary and vascular disease 1
   First degree relative with known plasma LDL-C concentration greater than 95th percentile for age and sex in an adult relative 1
   First degree relative with known plasma LDL-C concentration greater than 95th percentile for age and sex in a relative <18 years 2
   First degree relative with known tendon xanthomata or corneal arcus 2
2 Clinical history
   Presence of coronary artery disease 2
   Presence of cerebral or peripheral vascular disease 1
3 Physical examination
   Presence of tendon xanthomata 6
   Presence of corneal arcus in a patient <45 years of age 4
4 LDL-cholesterol level (mmol/L)
       ≥ 8.5 (330 mg/dL) 8
       6.5–8.4 (250-329 mg/dL) 5
       5.0–6.4 (195-249 mg/dL) 3
       4.0–4.9 (155-194 mg/dL) 1
5 DNA analysis
   Functional mutation in the LDLR gene or other FH related gene 8
        Diagnosis Total points
        Definite FH > 8
        Probable FH 6–8
        Possible FH 3–5
Table 2
A Plasma cholesterol measurement of either:
   Total cholesterol >7.5 mmol/L (290 mg/dL; adult) or >6.7 mmol/L (260 mg/dL; child <16 years)
   LDL-cholesterol >4.9 mmol/L (190 mg/dL; adult) or >4.0 mmol/L (155mg/dL; child <16 years)
B Presence of tendon xanthomata in patient or in a first or second degree relative
C DNA-based evidence of a mutation in the LDLR or other FH related gene
D Family history of myocardial infarction in a second degree relative <50 years of age or in a first degree relative <60 years of age
E Family history of plasma total cholesterol of >7.5 mmol/L (290 mg/dL) in a first or second degree relative
   Diagnosis Criteria required
   Definite FH A + B OR C
   Probable FH A + D OR A + E

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Some medications or other conditions that might affect diagnosis using laboratory tests include:

Lipid-lowering drugs (e.g. statins, ezetimibe, fibrates, bile acid sequestrants) will lower LDL-C and total serum cholesterol levels.

Some glucorticoids (e.g. prednisone) may increase LDL-C levels.

Amiodarone, used to treat heart arrhythmias, can raise LDL-C levels.

Anabolic steroids may increase LDL-C levels.

Cyclosporine, used to suppress the immune system, can raise LDL-C levels.

Thiazide diuretics may increase LDL-C levels.

Ostrogen in oral contraceptives or hormone replacement therapy may lower LDL-C levels.

What Lab Results Are Absolutely Confirmatory?

FH needs to be distinguished from familial combined hyperlipidemia (FCH) and polygenic hypercholesterolemia (in which heredity plays a smaller role; the situation for most individuals with elevated LDL-C, due to feedback suppression of LDLR gene expression by high dietary intake of cholesterol and saturated fats and/or other modifying genetic variants). Heterozygotes with FH tend to have higher plasma LDL-C levels than those with FCH and do not usually have relatives with lipoprotein abnormalities of multiple types, which is characteristic of FCH.

Confirmation of FH diagnosis requires either the demonstration of a decrease in LDL receptor activity; detection of the causative genetic mutation in LDLR, PCSK9, or LDLRAP1 segregating within the family; elevated LDL-C and Lp(a) levels (with normal triglycerides and normal/slightly reduced HDL-C); or the presence of xanthomata. When either the plasma total cholesterol or LDL-C level is used as a genetic marker, FH is highly penetrant at all ages. Thus, more than 95% of people carrying an FH mutation have a total cholesterol value greater than the 95th percentile of the population. However, neither elevation is specific for FH. The finding of a plasma LDL-C level above 220 mg/dL in children, or above 290 mg/dL in adults, together with a normal triglyceride level in a first-degree relative of a subject with FH is 98% specific and 87% sensitive for the diagnosis of FH.

Premature atherosclerosis and xanthomas are also symptoms of two rare conditions: phytosterolemia and cerebrotendinous xanthomatosis. The latter may manifest with neurological/psychiatric symptoms, cataracts, diarrhea and normal LDL-C levels as distinguishing features. These disorders can be confirmed by testing plasma levels of phytosterols (for phytosterolemia) or cholestanol (for cerebrotendinous xanthomatosis).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Fasting (10-14 hours) measurement of plasma LDL-C, Lp(a), HDL-C, TG and follow-up of these biomarkers.

Genetic mutation screening for the LDLR, PCSK9 and LDLRAP1 genes can be done using DNA extracted from white blood cells and PCR-based techniques. If no mutation is found, screen for the Familial Defective Apolipoprotein B-100, which is clinically similar to heterozygous FH, APOB gene mutation (see Familial Defective Apolipoprotein B-100).

The presence of the prothrombin gene G20210A mutation may increase the risk of cardiovascular disease (CV) events in FH patients.

The two most discriminatory tests to quantify LDL receptor function in cultured skin fibroblasts are:

1. measurement of the rate of proteolytic degradation of 125I-labeled LDL.

2. measurement of the LDL-mediated stimulation of the incorporation of [14C]oleate into cellular cholesteryl [14C]oleate.

Together, these tests can distinguish FH affected and unaffected family members with 90% accuracy.The number of LDL receptors can also be quantified by immunoblotting techniques or immunoprecipitation. These two assays also permit the detection of qualitative defects in the LDL receptor.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Lipoprotein X (LpX), if present, will be measured as LDL-C and could lead to a false diagnosis of FH. LpX is a lipoprotein that accumulates in cholestatic liver disease. LpX cholesterol concentration can be elevated to levels consistent with heterozygous and homozygous FH and even higher. LDL-C, if determined using the friedewald equation, should be measured when the patient has fasted for 10-14 hours. The presence of chylomicrons and marked hypertriglyceridemia could lead to the underestimation of LDL cholesterol.