シトステロール血症

BACKGROUND: Sitosterolemia is a rare autosomal recessive lipid metabolism disorder caused by pathogenic variants in ABCG5 or ABCG8 genes. Although classically associated with xanthomas and premature atherosclerosis, some patients may predominantly present with hematologic manifestations, leading to significant diagnostic challenges. METHODS: We retrospectively analyzed seven genetically confirmed cases of sitosterolemia presenting primarily with hematologic abnormalities at a tertiary care hematology center. Clinical characteristics, hematologic parameters, peripheral smear findings, molecular genetic profile, treatment response, and long-term outcomes were evaluated. RESULTS: The median age at presentation was 15 years (range: 6-17 years). All patients presented with anemia and splenomegaly, while thrombocytopenia was observed in six patients. Peripheral blood smear examination demonstrated stomatocytes and/or macrothrombocytes in a majority of cases. None of the patients had tendon xanthomas or overt dyslipidemic manifestations at presentation. Genetic analysis revealed pathogenic or likely pathogenic variants involving ABCG5 and ABCG8 genes, including homozygous and compound heterozygous mutations. Ezetimibe therapy along with dietary plant sterol restriction resulted in clinical improvement with rise in hemoglobin levels and reduction in hemolytic manifestations on follow-up. CONCLUSION: Sitosterolemia is an underrecognized but treatable cause of hemolytic anemia with macrothrombocytopenia. Careful peripheral smear examination demonstrating stomatocytes and giant platelets can provide an important diagnostic clue. Early recognition and targeted therapy can significantly improve clinical outcomes.

BACKGROUND: Sitosterolemia (STSL) is a rare autosomal recessive disorder caused by mutations in ABCG5 or ABCG8, characterized by hemolytic anemia, xanthomas, and atherosclerosis. Nephronophthisis (NPHP), another autosomal recessive disorder, is characterized by its devastating progression toward renal failure. METHODS: We analyzed the clinical, laboratory, and genetic data of a Chinese boy with concurrent STSL and NPHP. Separately, we conducted a comprehensive review of the phenotypic and genotypic profiles of all previously reported STSL cases in China. RESULTS: The proband presented with recurrent fever, thrombocytopenia, splenomegaly, and renal dysfunction and was initially misdiagnosed with hemophagocytic lymphohistiocytosis. Genetic testing confirmed biallelic ABCG8 mutations (c.490C>T and c.323-1G>C) and a homozygous NPHP1 deletion. A comprehensive review of 131 Chinese STSL cases (130 from the literature) found that xanthomas, hypercholesterolemia, and elevated low-density lipoprotein cholesterol (LDL-C) were the most common manifestations (each with a prevalence of 82.4%), followed by splenomegaly (32.1%), thrombocytopenia (32.1%), and anemia (30.5%). Hypercholesterolemia and high LDL-C were more common in children, whereas hematologic abnormalities and organ damage were more prevalent in adults. Mutations in ABCG5 accounted for 77.1% of patients. CONCLUSIONS: Genetic testing is crucial when clinical findings conflict with the initial diagnosis. This study summarizes the largest cohort of Chinese STSL patients to date, which may aid in the early recognition and management of this condition.

BACKGROUND: Sitosterolaemia is a rare lipid disorder characterized by massive accumulation of phytosterols. Due to its non-specific clinical features and the lack of routine sterol quantification, diagnostic delays are common, leading to inappropriate dietary interventions that may paradoxically accelerate vascular damage. CASE SUMMARY: We herein describe the case of a 13-year-old boy with sitosterolaemia and early-onset atherosclerosis against a background of a 7-year diagnostic delay. Following the identification of a paradoxical pro-atherogenic effect of a standard lipid-lowering diet, treatment with a plant-oil-restricted diet and cholestyramine resulted in a 51.7% reduction in carotid plaque thickness. DISCUSSION: This case highlights the necessity of screening for sitosterolaemia in paediatric patients with unexplained carotid plaque. Plaque resolution was achieved only after replacing conventional lipid-lowering strategies with targeted phytosterol-lowering interventions and specialized dietary modifications.

Sitosterolemia is an autosomal recessive condition leading to increased absorption of plant sterols from the intestine. A woman in her first pregnancy presented with thrombocytopenia and a family history of sitosterolaemia. Genetic analysis confirmed an ABCG8 (G-ATP binding cassette transporters) mutation. She was started on ezetimibe and had no complications other than thrombocytopenia. She underwent an emergency cesarean delivery at 37 weeks of gestation. Post-operatively both the mother and the baby did well. While sitosterolaemia is not directly linked to pregnancy complications such as diabetes and pre-eclampsia, its impact on lipid metabolism can indirectly increase the risk. It is important to distinguish it from familial hypercholesterolemia as sitosterolemia responds better to ezetimibe and is relatively non-responsive to statins. This case report shows that sitosterolemia, though an uncommon diagnosis, can manifest in many ways, in this case being thrombocytopenia. With dietary modifications and appropriate therapy, these patients can have a normal pregnancy.

Several case reports and a meta-analysis have documented significant increases in cholesterol levels among individuals following a ketogenic diet. However, the mechanistic drivers of this phenotype remain incompletely understood. Here, we describe a retrospective case series of 14 patients with ketogenic diet-induced hypercholesterolemia who experienced larger-than-expected LDL-C reductions after ezetimibe therapy. In a subset of participants with available genetic data, no biallelic sitosterolemia-associated variants were identified in the loci assessed. We hypothesize that chronically low insulin levels may alter hepatic cholesterol homeostasis through changes in ACAT2-mediated cholesterol esterification and in NPC1L1/ABCG5/G8-mediated cholesterol handling. The magnitude of LDL-C reduction achieved with ezetimibe in this cohort suggests that altered cholesterol absorption may contribute importantly to this phenotype. This hypothesis-generating framework offers a plausible mechanistic explanation and supports further prospective study of precision lipid management in ketogenic diet-induced hypercholesterolemia.