Analbuminaemia: clinical features and associated hypercholesterolaemia

In this journal, Caridi et al. ¹ report a case of analbuminaemia showing a novel splice mutation in the albumin gene associated with chromosome 4q 13.3. Although not the first report of mutations^2–4 in the albumin gene in this condition, this case highlights the clinical importance of analbuminaemia and the associated hypercholesterolaemia.

Analbuminaemia is very rare (estimated prevalence approximately one per million) and is usually an autosomal recessive condition. Albumin is the most expressed serum protein, with a molecular weight of about 65,000 Da and is synthesized by the liver albumin gene. The plasma half-life is normally about 20 days. Over 20 different molecular defects have been described in this condition. Most are nonsense mutations or mutations affecting splicing and frameshift/deletions.^2–5

Albumin is quantitatively the most important protein contributing to the plasma colloid osmotic pressure, thereby playing a key role in body fluid distribution. Albumin also acts to bind and transport many substances, for example, calcium, bilirubin and free fatty acids, with the albumin-bound fractions usually physiologically inactive. A marked reduction in plasma albumin, by reducing the binding capacity, may increase the plasma-free concentrations of substances, leading to potentially toxic effects. For example, many drugs, such as salicylates, penicillin, warfarin and sulphonamides, are albumin-bound.

Analbuminaemia is characterized by an extremely low serum albumin concentration (usually between 0.001 and 10 g/L). Protein electrophoresis shows a minimal albumin fraction and variable compensatory increases in serum globulins. ⁶ Pseudo-analbuminaemia needs to be excluded due, for example, to the presence of a slow albumin variant moving to the alpha-1 zone on serum protein electrophoresis. ⁷ There are many described causes of hypoalbuminaemia, ⁸ which may also need to be considered and excluded.

Analbuminaemia often presents in adulthood, with relatively innocuous clinical features, such as mild oedema, reduced blood pressure and fatigue. Some patients develop more serious clinical sequelae such as lower body lipodystrophy. Severe hypercholesterolemia with elevated serum low-density lipoprotein-cholesterol concentration and increased esterified cholesterol are frequently observed. In addition, free fatty acids and raised apolipoprotein B may occur as well as increases in serum high-density lipoprotein-3 and apolipoprotein A-I and A-II levels. The question of whether analbuminaemia is associated with premature atherosclerosis is unanswered on account of the rarity of the condition.^2–6

An important practical point is that many analbuminaemic individuals are treated with cholesterol-lowering drugs such as simvastatin, and may be more prone to side-effects due to reduced drug albumin binding, with significant increases in creatine kinase activity.^9,10 Other associated medical conditions with analbuminaemia include respiratory tract infections, hypercoagulability, cutaneous angiomata and osteoporosis.^2–6

At the other end of the clinical spectrum of severity, intrauterine death may occur with analbuminaemia, and in neonates the clinical course is far more severe, with marked oedema and even death, thus illustrating the major biological role albumin plays in the pre- and perinatal period.^11–15 In less severe presentations, the near-absence of serum albumin results in compensatory increases, e.g. apolipoproteins along with vascular and circulatory adaptations, which may help to explain the relative lack of serious clinical sequelae in adult life. Other compensatory increases are seen in immunoglobulins, sex hormone-binding globulin, thyroid-binding globulin, transferrin, fibrinogen, haptoglobin, prealbumin, complement, alpha-fetoprotein and ceruloplasmin.^11–15

Waldmann et al. ¹⁶ noted that albumin infusions in analbuminaemic patients help to reverse the abnormal lipid features. Interestingly, in another study, the cholesterol-lowering drug atorvastatin was associated with a decrease in oncotic pressure, due to reduced compensatory hypercholesterolaemia and severe lower limb oedema. The oedema was reversed by intravenous albumin infusions which also decreased the serum cholesterol. ¹⁷ This suggests that the severe hypercholesterolemia seen in analbuminaemia may be the result of a compensatory mechanism for the severe albumin deficiency and provides evidence for the possible role of serum albumin in controlling lipoprotein metabolism.^17–20

In summary, analbuminaemia is a very rare condition. Individuals show almost total absence of serum albumin and severe hypercholesterolaemia; whether this increases the risk of atherosclerosis in these patients is currently unknown. Earlier in life analbuminaemia can be fatal, but in adults compensatory production of other proteins including apolipoproteins attenuates the clinical complications.