phytosterols and Thrombocytopenia

Essentials Diagnosis of sitosterolemia, a rare recessive or syndromic disorder, is usually delayed. Peripheral blood smear is extremely useful for establishing the suspicion of sitosterolemia. High-throughput sequencing technology enables the molecular diagnosis of inherited thrombocytopenias. Accurate characterization of sitosterolemia helps us determine appropriate management.. Background Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis. Objectives To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL. Patient/Methods A 46-year-old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia-related xanthomas. Molecular analysis was performed with high-throughput sequencing. Plasma PS levels were evaluated with gas-liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974. Results A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities. Conclusions This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes in blood smears. The definitive diagnosis of STSL by measurement of serum PS levels and molecular analyses prompted the use of ezetimibe therapy.

Topics: Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 5; DNA Mutational Analysis; Ezetimibe; Female; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Middle Aged; Mutation; Phenotype; Phytosterols; Sitosterols; Spain; Thrombocytopenia; Xanthomatosis

Sitosterolemia is a rare autosomal recessively inherited disease caused by mutations affecting ABCG5 or ABCG8, which are located on human chromosome band 2p21. Around 100 cases have been reported in the literature. Sitosterolemic patients typically exhibit a 30-fold to 100-fold increase in plasma concentrations of plant sterols. The clinical manifestations include xanthomas, premature atherosclerosis, hemolytic anemia, and macrothrombocytopenia. It is noteworthy that abnormal hematological parameters may be the only clinical feature of sitosterolemic patients, suggesting that sitosterolemia may be more frequent than previously thought. Severe accumulation of plant sterols in mouse models of sitosterolemia induced complex cardiac lesions, anemia, and macrothrombocytopenia, disrupted adrenal and liver cholesterol homeostasis, and caused infertility and hypertriglyceridemia. It remains unclear whether all disease traits are present in sitosterolemic patients. The drug ezetimibe appears to be effective in reducing plasma plant sterol levels, promotes xanthoma regression, and improves the cardiovascular and hematological signs in sitosterolemic patients.

Topics: Anemia, Hemolytic; Animals; Anticholesteremic Agents; Atherosclerosis; Azetidines; Ezetimibe; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Mice; Phytosterols; Thrombocytopenia; Xanthomatosis

Topics: Anemia, Hemolytic; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Phytosterols; Thrombocytopenia

Sitosterolemia is a rare autosomal recessive hereditary disease caused by loss-of-function genetic mutations in either ATP-binding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8). Here, we investigate novel variants in ABCG5 and ABCG8 that are associated with the sitosterolemia phenotype. We describe a 32-year-old woman with hypercholesterolemia, tendon and hip xanthomas, autoimmune hemolytic anemia and macrothrombocytopenia from early life, which make us highly suspicious of the possibility of sitosterolemia. A novel homozygous variant in ABCG5 (c.1769C>A, p.S590X) was identified by genomic sequencing. We also examined the lipid profile, especially plant sterols levels, using gas chromatography-mass spectrometry. Functional studies, including western blotting and immunofluorescence staining, showed that the nonsense mutation ABCG5 1769C>A hinders the formation of ABCG5 and ABCG8 heterodimers and the function of transporting sterols. Our study expands the knowledge of variants in sitosterolemia and provides diagnosis and treatment recommendations.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily G, Member 5; Female; Humans; Hypercholesterolemia; Lipid Metabolism, Inborn Errors; Lipoproteins; Mutation; Phytosterols; Thrombocytopenia

谷固醇血症是一种罕见的常染色体隐性遗传脂质代谢异常疾病，其特征为血浆和组织中谷固醇的含量增高、蓄积。现报道1例以血小板减少和肝功能异常就诊，通过相关检查发现ABCG5基因突变确诊为谷固醇血症患儿，同时分析患儿的临床特征。.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; Child; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Liver; Mutation; Phytosterols; Thrombocytopenia

Topics: Blood Platelets; Child; Erythrocytes, Abnormal; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Phytosterols; Thrombocytopenia

Topics: Adolescent; Anemia, Hemolytic, Congenital; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Blood Platelets; Child; Female; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Mutation, Missense; Phytosterols; Thrombocytopenia

Sitosterolemia (phytosterolemia) is a rare inherited sterol storage disorder, characterized by significantly elevated plasma levels of plant sterols. The clinical features of sitosterolemia are xanthomas, premature atherosclerosis, arthritis, and, occasionally, liver function impair and hematologic abnormalities. This disorder is caused by mutations of ABCG5/ABCG8 genes. We report here the clinical, laboratory, and molecular genetic features of 13 patients with sitosterolemia from eight unrelated families who had specific hematologic problems of macrothrombocytopenia, hemolytic anemia, and splenomegaly besides the major clinical manifestations. The peripheral blood films showed some unique features: large platelets surrounded by a circle of vacuoles, and various abnormal erythrocyte shapes, especially stomatocyte. According to these distinct changes of blood cell morphology, we identified two sitosterolemia patients who lacked the classical clinical phenomena. All the patients had been misdiagnosed with immune thrombocytopenia (ITP), Evans syndrome, or secondary ITP with delay being 28.8 years between symptom onset and correct diagnosis. These results indicate that sitosterolemia is certainly not as rare as originally thought. The phenomena of macrothrombocytopenia/hemolysis might represent a new platelet disorder. Plasma plant sterols and ABCG5/ABCG8 genes should be analyzed when such hematologic abnormalities are unexplained.

Topics: Adult; Anemia, Hemolytic, Congenital; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Blood Platelets; Cell Shape; Cholesterol; Delayed Diagnosis; Diagnostic Errors; DNA Mutational Analysis; Erythrocytes, Abnormal; Exons; Female; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Middle Aged; Osmotic Fragility; Pedigree; Phenotype; Phytosterols; Prevalence; Purpura, Thrombocytopenic, Idiopathic; Splenectomy; Splenomegaly; Thrombocytopenia; Vacuoles; Xanthomatosis

Topics: Acid-Base Imbalance; Anemia, Hemolytic, Congenital; Erythrocytes, Abnormal; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Metabolism, Inborn Errors; Middle Aged; Phytosterols; Thrombocytopenia

Phytosterolemia is a rare autosomal recessive lipid storage disease. It is caused by mutations of ABCG5 and ABCG8 genes and characterized by the increased plasma levels of plant sterols. The common clinical manifestations include tendon and tuberous xanthomas and premature coronary heart disease; it has occasionally been associated with hematologic abnormalities.. We report a phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis and discuss its clinical significance.. The patient, aged 31 years, was born of a consanguineous marriage. He had epistaxis from childhood and underwent splenectomy because of thrombocytopenia, anemia and splenomegaly at the age of 9 years. His blood film showed prominent stomatocytes and macroplatelets. High performance liquid chromatography showed a grossly elevated level of phytosterols in the blood. The patient was confirmed to be a homozygote of missense mutation R419H in ABCG5.. We describe a phytosterolemia patient whose clinical manifestations were macrothrombocytopenia, stomatocytic hemolysis and splenomegaly, without the common features of this disorder. Our results suggest that blood cells could be a target for the toxic effect of plasma plant sterols, which should be measured in patients with unexplained stomatocytosis and/or macrothrombocytopenia in order to determine if they have phytosterolemia.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Blood Platelets; Cell Size; Consanguinity; Erythrocytes, Abnormal; Hemolysis; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Mutation, Missense; Phytosterols; Splenomegaly; Thrombocytopenia

To study the clinical features and ABCG5/ABCG8 gene mutations of three pedigrees of phytosterolemia presented with macrothrombocytopenia and hemolysis.. Erythrocyte and platelet morphology were examined under light microscope. Plasma sterol levels were measured by high pressure/performance liquid chromatography method. All of ABCG5 and ABCG8 exons and intron-exon boundaries were directly sequenced to identify mutations, the corresponding gene mutation sites of three families members and healthy individuals were detected.. All the patients presented macrothrombocytopenia, hemolysis, splenomegaly and xanthomas. The blood smears showed large platelets, some as large as erythrocytes, and abnormal erythrocyte shapes, such as stomatocytes. Plasma concentrations of phytosterols, especially sitosterol were markedly elevated (30 fold) in the affected patients. Four mutations were identified in these three pedigrees, ABCG5 C20896T (R446X) and A20883G, ABCG8 del43683-43724 and del1938C-1939G/ins1938T. The latter three were novel mutations reported for the first time.. Phytosterolemia associated with macrothrombocytopenia and hemolysis is a new subtype of this disease. Plasma phytosterols and related gene analysis should be performed when ever an unexplained macrothrombocytopenia, especially combined with haemolysis or/and stomatocytosis.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Blood Platelets; DNA Mutational Analysis; Erythrocytes, Abnormal; Female; Hemolysis; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Middle Aged; Mutation; Pedigree; Phytosterols; Platelet Count; Thrombocytopenia

The spontaneous mouse mutation "thrombocytopenia and cardiomyopathy" (trac) causes macrothrombocytopenia, prolonged bleeding times, anemia, leukopenia, infertility, cardiomyopathy, and shortened life span. Homozygotes show a 20-fold decrease in platelet numbers and a 3-fold increase in platelet size with structural alterations and functional impairments in activation and aggregation. Megakaryocytes in trac/trac mice are present in increased numbers, have poorly developed demarcation membrane systems, and have decreased polyploidy. The thrombocytopenia is not intrinsic to defects at the level of hematopoietic progenitor cells but is associated with a microenvironmental abnormality. The trac mutation maps to mouse chromosome 17, syntenic with human chromosome 2p21-22. A G to A mutation in exon 10 of the adenosine triphosphate (ATP)-binding cassette subfamily G, member 5 (Abcg5) gene, alters a tryptophan codon (UGG) to a premature stop codon (UAG). Crosses with mice doubly transgenic for the human ABCG5 and ABCG8 genes rescued platelet counts and volumes. ABCG5 and ABCG8 form a functional complex that limits dietary phytosterol accumulation. Phytosterolemia in trac/trac mice confirmed a functional defect in the ABCG5/ABCG8 transport system. The trac mutation provides a new clinically significant animal model for human phytosterolemia and provides a new means for studying the role of phytosterols in hematologic diseases and testing therapeutic interventions.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Bleeding Time; Cardiomyopathies; Cells, Cultured; Colony-Forming Units Assay; Crosses, Genetic; Disease Models, Animal; Female; Fetus; Lipid Metabolism, Inborn Errors; Lipoproteins; Liver; Male; Megakaryocytes; Mice; Mice, Inbred A; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Phytosterols; Sitosterols; Thrombocytopenia

Topics: Australia; Food Contamination; Humans; Mediterranean Sea; Olive Oil; Phytosterols; Plant Oils; Sitosterols; Thrombocytopenia

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.

Topics: Adolescent; Adult; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Blood Platelets; Child; Erythrocyte Membrane; Erythrocytes, Abnormal; Female; Hemolysis; Humans; Lipoproteins; Magnetic Resonance Spectroscopy; Male; Mutation; Pedigree; Phytosterols; Steroid Metabolism, Inborn Errors; Thrombocytopenia

Parenteral nutrition is associated with liver enzyme abnormalities. Until 1993 the incidence of icterus was low in both academic hospitals in Amsterdam, the Netherlands (Academic Medical Centre (AMC) and Academic Hospital of the Free University (AZVU)). In 1993 Intralipid in the nutrition was replaced by Endolipid in the home total parenteral nutrition programme (AMC) and by Lipofundin S in AZVU. Fifty per cent of the patients in the home programme developed severe fatigue, jaundice and thrombocytopenia. These signs and symptoms disappeared over months when parenteral nutrition without fat was given. After reintroduction of Intralipid these signs and symptoms never recurred. In AZVU the incidence of jaundice increased from 21% in 1992 to 79% in 1993 (p = 0.0002). After reintroduction of Intralipid in 1994 the incidence of jaundice decreased to 16%.. Although the lipid emulsions are equivalent according to the product specification, the described observation suggests that Lipofundin S and Endolipid cause more icterus than Intralipid, possibly caused bij an impurity in the fat emulsion.

Topics: Academic Medical Centers; Adult; Cause of Death; Fat Emulsions, Intravenous; Female; Humans; Incidence; Jaundice; Liver Failure; Liver Function Tests; Male; Middle Aged; Netherlands; Parenteral Nutrition; Phytosterols; Thrombocytopenia

Lipid emulsions used for parenteral nutrition (PN) contain phytosterols. Our hypothesis was that these phytosterols can accumulate and contribute to cholestatic liver disease and other complications of PN, e.g., thrombocytopenia (which occurs in hereditary phytosterolemia).. Using gas chromatography-mass spectrometry, plasma concentrations of sterols were measured in 29 children aged 2 months to 9 years receiving PN and in 29 age-matched controls. The children receiving PN fell into two subgroups: 5 with severe PN-associated cholestatic liver disease (bilirubin level, > 100 mumol/L; aspartate aminotransferase [AST] level, > 200 U/L) and 24 with a bilirubin level of < 100 mumol/L and/or AST level of < 200 U/L.. The 5 children with severe PN-associated liver disease had plasma concentrations of phytosterols and sitostanol that were as high as those seen in patients with hereditary phytosterolemia (total phytosterols 1.3-1.8 mmol/L). All 5 had intermittent thrombocytopenia. A reduction in intake of lipid emulsion to < 50 mL.kg-1.wk-1 was associated with a decrease in plasma phytosterol concentrations and an improvement in liver function tests and platelet counts in two patients. Children with less severe PN-associated liver disease had lower plasma phytosterol concentrations than the 5 with severe disease.. Children receiving PN who have high plasma phytosterol concentrations also have cholestatic liver disease and thrombocytopenia; phytosterolemia might contribute to the pathogenesis of complications of PN.

Topics: Aspartate Aminotransferases; Child; Child, Preschool; Cholestasis; Fat Emulsions, Intravenous; Gas Chromatography-Mass Spectrometry; Humans; Infant; Liver Diseases; Parenteral Nutrition; Phytosterols; Thrombocytopenia