R Khurana, P Kanvinde, M Desai, N Shah, A Swami, M Bodhanwala, S Mudaliar
Sitosterolemia is a rare autosomal recessive disease of plant sterol metabolism. Bhattacharyya and Connor first described this disease in 1974 (1). To date, there are only about 100 known cases worldwide (2).
We describe two patients diagnosed with Sitosterolemia at our centre. Patient A is a 12 year old male, presented with complaints of short stature, abdominal distension & gradually progressive paleness since 2 months. He had pallor, hemolytic facies and both weight (25kg) & height (130cm) were less than 3rd centile and had spleno-hepatomegaly.
His investigations (table1) were suggestive of a chronic hemolytic anemia. Since the child did not have spherocytes on peripheral smear & had giant platelets, diagnosis of hereditary spherocytosis seemed unconvincing. So genetic work up by next generation sequencing was done which revealed mutation in ABCG8 gene, suggestive of Sitosterolemia. On review, his peripheral smear showed some stomatocytes (figure1).
Patient B is a 12 year old child who was referred to us for splenectomy. Child had splenomegaly bicytopenia, diagnosed during work up for a short febrile illness. There were stomatocytes in his smear too & sterol levels were borderline high, hence genetic studies were sent, which revealed compound heterozygous variants in the ABCG5 gene, suggestive of Sitosterolemia type 2.
Both the patients are under regular follow up for monitoring diet, counts & changes of early atherosclerosis. If dietary changes are not adequate, we will consider ezitimibe for them.
Discussion
Patients with Sitosterolemia can have a variety of presentations like short stature, chronic abdominal discomfort, splenomegaly etc indicating a chronic hemolytic disease. Some may present with tendinous and cutaneous xanthomas, arthritis, and arthralgias. They have a strong propensity towards premature coronary atherosclerosis (3).
Laboratory features are suggestive of chronic hemolysis with presence of stomatocytic red cells and macrothrombocytopenia on blood films. Eosin 5’ maleimide test by flow cytometry (EMA) is usually abnormal. Plasma levels of plant sterols (sitosterol, cholestanol, and stigmasterol) measured by GC-MS (gas chromatography-mass spectrometry) are elevated. The identified homozygous or compound heterozygous mutations in ABCG5 and ABCG8 genes further confirm the diagnosis.
Treatment predominantly involves dietary changes & pharmacological adjuncts. All sources of vegetable fats like vegetable oils, nuts, seeds, olives, avocados etc. should be eliminated. Food derived from animal sources with cholesterol as the dominant source should be allowed (4). Bile acid resins like cholestyramine may be useful, statins have no role (5). Ezetimibe was US FDA approved in 2002 for use in patients with sitosterolemia. Ezetimibe alone or in combination with cholestyramine effectively reduces plant sterol levels by around 50%(6). Some patients may require surgical interventions like ileal bypass to effectively reduce sterol levels.
We feel that this condition is under reported as many may remain misdiagnosed as hereditary spherocytosis or hyperlipidemias. Measures as simple as dietary modification can control this condition & prevent a splenectomy(which will be detrimental in patients with Sitosterolemia). Hence, stomatocytes should be actively searched for in patients with large platelets and unexplained mild hemolysis. Consider early NGS to determine diagnosis.
References
  1. Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974;53(4):1033-1043.
  2. Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol. 2008; 61(5):588-594.
  3. Merkens LS, Myrie SB, Steiner RD, Mymin D. Sitosterolemia. GeneReviews [Internet]  Seattle (WA): University of Washington; 2016. [updated 2013 Apr 4].
  4. Escola­Gil JC, Quesada H, Julve J, Martin­Campos JM, Cedo L, Blanco­Vaca F. Sitosterolemia: diagnosis, investigation, and management. Curr Atheroscler Rep 2014;16:424.
  5. Parsons HG, Jamal R, Baylis B, Dias VC, Roncari D. A marked and sustained reduction in LDL sterols by diet and cholestyramine in beta­sitosterolemia. Clin Invest Med 1995;18:389­400.
  6. Lutjohann D, von Bergmann K, Sirah W, Macdonell G, Johnson­Levonas AO, Shah A, et al. Long­term efficacy and safety of ezetimibe 10 mg in patients with homozygous sitosterolemia: a 2­year, open­label extension study. Int J Clin Pract 2008;62:1499­510.