Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia

Abstract

Summary Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant‐derived cholesterol‐like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC‐MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

“…Abcg5-deficient mice showed severely decreased platelet counts and a grossly increased platelet size, implying that these mice suffer from macrothrombocytopenia analogous to the situation described recently in sitosterolemia patients (17,27). Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, as these cells were abundantly present in the bone marrow and spleens of Abcg5 Ϫ/Ϫ mice, presumably as a consequence of high TPO levels.…”

“…An obvious question is why platelet formation is so severely affected by plant sterols, whereas functional properties of red blood cells and their resistance to hemolytic stress are not or only mildly affected in mice because studies in humans (17,19) strongly emphasize the coexistence of platelet and red blood cell abnormalities in sitosterolemia. Whereas the underlying cause of this remarkable species difference remains unclear, it does demonstrate that platelet and red blood cell abnormalities represent independent features of this condition.…”

“…Interestingly, we observed that Abcg5 deficiency was associated with a strong bleeding tendency during surgery for gallbladder cannulation or jugular vein catheterization. To assess whether the hematological phenotype reported in patients with sitosterolemia (17,27) is also present in Abcg5 Ϫ/Ϫ mice, we analyzed several hematological parameters. Chow-fed Abcg5 Ϫ/Ϫ mice showed severe thrombocytopenia, as blood platelet counts were only 32% of those observed in wild-type littermates (Fig.…”

“…A number of associated features, including hemolysis, abnormal platelets, and iron deficiency, have occasionally been reported (12,15,16). Recently, a series of subjects with Mediterranean macrothrombocytopenia (low levels of abnormally large platelets) were identified as sitosterolemia patients (17), harboring different known and new mutations in ABCG5 or ABCG8. The mechanism(s) underlying this interesting link between defective sterol metabolism and hematological abnormalities have remained unexplained so far.…”

Clinical utility gene card for: Sitosterolaemia

“…5,6 In addition, some patients can present with haematological abnormalities including macrothrombocytopenia, stomatocytes, haemolytic anaemia and splenomegaly. 7,8 Very rare patients can present primarily with elevated plasma levels of lowdensity lipoprotein cholesterol and cutaneous xanthomas, expressing a phenotype that resembles heterozygous familial hypercholesterolaemia (FH), 9 and in severe cases, resembling homozygous FH, with coronary disease in childhood and adolescence. 10,11 The condition should be considered even when consumption of plant sterols has not commenced, as phytosterols can be found in breast milk.…”