Behaving Oddly- Hereditary Spherocytosis

Hereditary Spherocytosis (HS) is the commonest disorder of red cell membrane leading to haemolysis (incidence~500/million). It is inherited in an autosomal dominant manner in 75% of cases and recessively in the remaining quarter. Subjects with recessive inheritance tend to have more aggressive disease and present earlier in life, as with many other disorders with recessive inheritance.

HS has many odd, non-intuitive features. Newborn with HS do not have anaemia, but are diagnosed due to prolonged jaundice. Adults present with anaemia, jaundice and with bilirubin containing gallstones. Thus, recurrent gallstones with jaundice may not necessarily presage primary gallstone disease, but may indicate underlying HS. Anaemia may be mild or absent because of compensation by the marrow, thus leading to difficulty in diagnosis. The diagnosis is usually made by noticing spherocytes on the blood film. It is thought that because of defective anchoring of the red cell membrane to the underlying cytoskeleton, bits of the membrane are gradually lost, reducing the surface area to volume ratio, causing spherocytosis.

Oddly, subjects with HS may develop obstructive jaundice due to CBD stones in addition to underlying indirect hyperbilirubinaemia. When this happens, red cell survival is paradoxically increased. This is thought to be due to increase in the cholesterol content of the red cell membrane which increases its distensibility and thus reduces the propensity for lysis while passing through the splenic sinusoids.

As stated above, mild HS may not be associated with anaemia due to compensation by the bone marrow. The reticulocyte count will be raised in such subjects, but may return towards normal after splenectomy. An important clue to the diagnosis of HS, particularly in infants, is the presence of a high mean corpuscler haemoglobin concentration (MCHC). Normally, MCHC would be expected to be around 31. In HS, MCHC is 36 or higher. A combination of high MCHC (>35) and a high RDW (15 or higher), is virtually diagnostic of HS. I know of no other condition that lends itself to diagnosis by looking at the MCHC alone.

Subjects with HS have more porous red cell membrane. While this allows Na to enter freely, thus increasing the risk of osmotic haemolysis (exploited in the osmotic fragility test, now supplanted by more sensitive and specific tests such as EMA), it also leads to a leakage of K ions when blood is cooled after being drawn. This often leads to the finding of pseudohyperkalaemia in such subjects.

Other odd things happen in these subjects. While splenectomy imparts a lifelong higher risk of arterial and venous clots in HS, due to higher leucocyte, red cell, platelet and fibrinogen levels, non-splenectomised subjects with HS actually have a lower cardiovascular risk than their relatives. It is thought that higher serum bilirubin and lower serum cholesterol protects such subjects against cardiovascular events.