Type III hyperlipoproteinaemia
For a review of type III hyperlipoproteinaemia see references [Durrington, 1995a; Mahley, 1995].

What is the incidence?
Type III hyperlipoproteinaemia is a rare condition with several synonyms: broad beta disease, floating beta disease, dysbetalipoproteinaemia and remnant removal disease. It occurs in fewer than one in 5000 people, but has the distinction of being the first clinical syndrome associated with hyperlipoproteinaemia to be described (by Addison and Gull in 1851).

What is the lipoprotein phenotype?
Type III hyperlipoproteinaemia is caused by the presence in the circulation of increased amounts of chylomicron remnants and IDL, often collectively termed beta-VLDL. This is the result of decreased clearance of these lipoproteins by hepatic receptors. There is an increase in both the serum cholesterol and fasting triglyceride concentrations. Typical levels are 7-12 mmol/L (270-470 mg/dL) for cholesterol and 5-20 mmol/L (450-1800 mg/dL) for triglycerides. The molar concentrations of cholesterol and triglycerides are often similar, and this may be a clue that a patient has type III hyperlipoproteinaemia. Occasionally, the condition is associated with marked hypertriglyceridaemia owing to overwhelming chylomicronaemia.

Features of type III hypertriglyceridaemia

Xanthomata Xanthomata are present in more than half of the patients who have the type III lipoprotein phenotype, and striate palmar xanthomata and tuberoeruptive xanthomata are characteristic of the condition. Striate palmar xanthomata Striate palmar xanthomata may simply be an orange-yellow discoloration within the creases of the skin of the palms of the hands. Striate palmar xanthomata may, however, be more florid and appear as raised, seed-like lesions (sometimes even larger) in the skin creases of the palms, fingers and flexor surfaces of the wrists (see Figure 9a). Tuberoeruptive xanthomata Tuberoeruptive xanthomata are raised yellow lesions, usually on the elbows and knees (see Figure 9b). Tuberoeruptive xanthomata may be nodular or cauliflower-like, often surrounded by smaller satellites. Sometimes they may be found over other tuberosities, such as the heels and dorsum of the interphalangeal joints of the fingers, and they resolve entirely with successful treatment.

Figure 9. Xanthoma in type III hyperlipoproteinaemia

What is the occurrence of type III hyperlipoproteinaemia?
Type III hyperlipoproteinaemia is rare in women before the menopause, perhaps because hepatic remnant particle uptake is enhanced by oestrogen. It is also rare in childhood, but has a definite incidence in men by early adulthood.

What is the genetic basis?
Type III hyperlipoproteinaemia is generally an autosomal recessive condition with variable penetrance. In all cases there appears to be a mutation or polymorphism of the apo E gene, which impairs the receptor binding of apo E. The most common is a polymorphism, called apo E2, in which cysteine is substituted for arginine at position 158 of the amino acid sequence. At least 90% of patients with type III hyperlipoproteinaemia are homozygous for apo E2.

What other factors affect expression?
More often than not, however, apo E2 homozygosity (present in around 1% of the population) does not itself impose such a severe strain on lipoprotein metabolism that hyperlipoproteinaemia develops; a combination of apo E2 homozygosity with some other disorder, leading to overproduction of VLDL or some additional catabolic defect, is required. This explains the association of type III hyperlipoproteinaemia with diabetes and hypothyroidism. More often, however, the additional stimulus leading to hyperlipoproteinaemia is obesity or the co-inheritance of a polygenic tendency to hypertriglyceridaemia. More rare mutations of apo E have been described, which behave in a clinically similar way to apo E2 homozygosity.

Involvement of rarer apo E mutations
More severe are mutations leading to apo E deficiency, which in homozygotes do not require other factors for the expression of the type III phenotype. Heterozygous apo E deficiency finds little clinical expression, but, interestingly, mutations involving the receptor-binding domain of apo E (amino acids 124-150) directly produce the type III phenotype even in heterozygotes (dominant expression). This implies that such mutations are a greater handicap to receptor clearance than mutations in which one gene is not producing apo E.

Consequences of type III hyperlipoproteinaemia
Type III hyperlipoproteinaemia undoubtedly causes accelerated atherosclerosis in the coronary, femoral and tibial arteries leading to clinical manifestations. Intermittent claudication occurs at least as frequently as CHD, and the incidence of the latter is about the same as that in familial hypercholesterolaemia. It is of considerable interest that in familial hypercholesterolaemia, peripheral arterial disease is uncommon relative to CHD, indicating that the leg arteries are much more susceptible to the larger lipoprotein particles in type III hyperlipoproteinaemia.

Diagnosis
In the presence of typical xanthomata, the diagnosis of type III hyperlipoproteinaemia is not difficult. When these are absent, the diagnosis must be made in the laboratory. Type IIb or V hyperlipoproteinaemia can give similar serum lipid levels. Lipoprotein electrophoresis is still available in some hospital laboratories and, when it clearly shows separate pre-beta (VLDL) and beta (LDL) bands, is useful in establishing type IIb rather than type III hyperlipoproteinaemia. Frequently, however, the classical broad beta band associated with type III hyperlipoproteinaemia cannot be distinguished from a smear stretching from the origin into the pre-beta and sometimes beta region in the more severe type IIb or type V phenotype. Identifying apo E2 homozygosity (a test available in many specialised centres) in the presence of dyslipidaemia, however, makes type III hyperlipoproteinaemia virtually certain. Most commonly, apo E2 homozygosity is found when the diagnosis is type III hyperlipidaemia, but on rare occasions, when the patient clearly has the clinical syndrome, it is because an apo E mutation is the cause. The simplest way then to confirm the diagnosis is to send plasma to a centre that can provide ultracentrifugation to identify the cholesterol-rich VLDL (beta-VLDL) typical of type III hyperlipoproteinaemia. It is also important in these circumstances to exclude paraproteinaemia, which can produce both hyperlipoproteinaemia and hypolipoproteinaemia and can mimic type III hyperlipoproteinaemia.

What is the lipoprotein phenotype?
The common lipoprotein phenotype associated with a combined increase in serum cholesterol and triglycerides is IIb.

 

Features of type IIb hyperlipoproteinaemia

In the majority of people with the type IIb phenotype (in whom it is primary) the cause is probably best regarded as a polygenic tendency exacerbated by acquired nutritional factors such as obesity. A few patients will have tendon xanthomata, indicating familial hypercholesterolaemia (see earlier), but the majority will not. Cardiovascular risk is greater for any given level of cholesterol when the serum triglyceride concentration is also elevated. Often the HDL is low, which further compounds the risk. In addition, patients with hypertriglyceridaemia frequently have increased levels of cholesterol-depleted small dense LDL (discussed previously).