Rare Sterol Disorder Unmasked as Unexplained Cytopenias in Six Patients

When that transporter fails, the body absorbs plant sterols such as sitosterol and campesterol from the diet with unusual efficiency while excreting them poorly into bile. The sterols accumulate in blood and tissues, producing the classical textbook picture of tendon xanthomas, hypercholesterolemia, and accelerated atherosclerosis. What the classical picture often omits is that many patients instead arrive first in a hematology clinic, with low blood counts rather than visible cholesterol deposits as their initial complaint.

The new series is small but carefully assembled. The authors reviewed six consecutive patients seen between January 2024 and June 2026 who had clinical features suggestive of sitosterolemia together with molecular variants in ABCG5 or ABCG8; patients without genetic testing were excluded. The cohort comprised three men and three women with a median age of 40 years and a range of 22 to 55. All six presented with anemia, thrombocytopenia, and splenomegaly, and all had initially been labeled with more common conditions: immune thrombocytopenia, iron-deficiency anemia, megaloblastic anemia, Evans syndrome, or hereditary spherocytosis. Before the correct diagnosis, one patient had needed intermittent blood transfusions, one had been treated with the thrombopoietin receptor agonist eltrombopag, three had received corticosteroids, and every patient had at some point been treated for nutritional anemia.

Two morphological clues unified the group and, the authors argue, should serve as a warning sign for any hematologist. The combination of stomatocytic hemolytic anemia, macrothrombocytopenia, and splenomegaly, the paper explains, overlaps so closely with hereditary spherocytosis, immune thrombocytopenia, Evans syndrome, and bone marrow failure syndromes that patients are routinely misdirected toward immunosuppression or even splenectomy before anyone thinks of a sterol transporter defect.

The cellular mechanism behind these findings is now reasonably well understood. Plant sterols become incorporated into erythrocyte and platelet membranes, where they alter lipid composition, reduce membrane deformability, and drive the formation of stomatocytes and large platelets. These membrane abnormalities increase osmotic fragility, disturb erythrocyte hydration and calcium homeostasis, and accelerate splenic clearance of the damaged cells, producing the hemolytic anemia, thrombocytopenia, and enlarging spleen seen in the clinic. Work by Warang and colleagues cited in the paper adds an important nuance: in sitosterolemia, red cell injury is not solely a matter of altered membrane lipids. Those researchers found elevated intracellular calcium, enhanced calcium influx during osmotic stress, and increased reactive oxygen species in erythrocytes, suggesting that calcium dysregulation and oxidative stress also contribute to membrane instability and hemolysis.

Genetic analysis of the six patients revealed marked allelic heterogeneity, with a predominance of ABCG8 variants over ABCG5, a pattern consistent with previous reports. Three of the five distinct variants identified had been described before: the ABCG8 c.361C>T (p.Arg121Ter) and ABCG5 c.727C>T (p.Arg243Ter) variants, first reported by Lu and colleagues and listed as pathogenic in ClinVar, and the ABCG8 c.408del (p.Gln137SerfsTer8) variant, recently reported by Trehan and colleagues and classified as pathogenic or likely pathogenic, which appeared in three of the patients. The ABCG8 c.2T>C (p.Met1Thr) start-loss variant carries limited and conflicting evidence in ClinVar. Most intriguing was a homozygous ABCG5 c.1724T>G (p.Leu575Arg) variant that, to the authors’ knowledge, had never been reported in a patient with sitosterolemia and is currently classified as a variant of uncertain significance; the affected patient was homozygous and had clinical and hematologic findings suggestive of the disease, but functional studies and segregation analyses will be needed to settle its pathogenicity.

The genetics also exposed practical gaps in the diagnostic pathway. Several patients carried only a single heterozygous ABCG8 pathogenic variant, which would ordinarily be insufficient for an autosomal recessive diagnosis. Because copy-number analysis by multiplex ligation-dependent probe amplification, deep intronic sequencing, and segregation studies were not available at the center, a second undetected pathogenic allele could not be formally ruled out. The authors emphasize that the patients nevertheless had phenotypes highly suggestive of sitosterolemia, from the characteristic smear findings to a favorable response to treatment, and that genetic results must be interpreted alongside the clinical and hematologic picture rather than in isolation. Plasma sitosterol and campesterol measurements, normally the biochemical confirmation of choice, were simply not available, and the authors note that routine lipid profiles in the cohort were normal because standard enzymatic assays do not specifically measure phytosterols; sterol-specific chromatographic techniques are required.

Treatment followed the established logic of the disease: stop absorbing plant sterols and the accumulated membrane injury has a chance to resolve. Among the four patients with available follow-up data, hemoglobin, platelet count, and spleen size all improved over 4 to 12 months of follow-up, supporting earlier reports that early diagnosis and targeted therapy can reverse hematologic abnormalities and spare patients unnecessary immunosuppression or splenectomy. One patient was lost to follow-up and one had insufficient follow-up for outcome assessment, a reminder that the apparent benefit rests on a small, partially documented sample.

The evidence is not uniformly optimistic. Warang and colleagues reported persistent hemolysis and overhydrated erythrocytes despite a fall in plasma phytosterol levels after ezetimibe therapy, indicating that established membrane damage in mature red cells, which cannot repair their own membranes, may not be completely reversible. Microvesicle shedding and loss of membrane surface area may allow structural changes to persist and sustain hemolysis in some patients even after treatment begins. Those researchers have suggested that therapies targeting calcium homeostasis or oxidative stress might improve response in such cases, though that idea remains untested in clinical studies.

The authors propose a practical diagnostic approach built directly on their experience. Once more common causes have been excluded, any patient with unexplained cytopenias who shows stomatocytes, giant platelets, splenomegaly, or tendon xanthomas should be evaluated for sitosterolemia. Their suggested workup includes a reticulocyte count, direct antiglobulin test, liver function tests, lactate dehydrogenase, lipid profile, abdominal ultrasonography, osmotic fragility testing, paroxysmal nocturnal hemoglobinuria flow cytometry, and plasma phytosterol measurement, with ABCG5 and ABCG8 genetic testing where indicated. The study’s limitations deserve emphasis: it is retrospective and single-center, involves only six patients, lacked plasma phytosterol measurements and advanced genetic testing, and had incomplete follow-up with no functional erythrocyte studies.

Subject of Research: A retrospective case series describing hematologic presentations, genetic variants, and treatment outcomes in six patients with sitosterolemia.

Article Title: Sitosterolemia presenting as unexplained cytopenias: hematologic manifestations and genetic spectrum

Article References: Mishra, N., Gupta, N., Bansal, N., Verma, M., & Kotwal, J. (2026). Sitosterolemia presenting as unexplained cytopenias: hematologic manifestations and genetic spectrum. Blood Research, 61(1), Article 60. https://doi.org/10.1007/s44313-026-00176-9

Image Credits: AI Generated

DOI: 10.1007/s44313-026-00176-9

Keywords: sitosterolemia, ABCG5, ABCG8, cytopenias, stomatocytes, macrothrombocytopenia, ezetimibe, phytosterol-restricted diet, splenomegaly, variant of uncertain significance, hemolytic anemia, genetic testing