Phytosterolemia in children with parenteral nutrition—Associated cholestatic liver disease

Clayton, Peter T.; Bowron, Ann; Mills, Kevin; Massoud, Ahmed; Casteels, Minne; Milla, Peter J.

doi:10.1016/0016-5085(93)91079-w

Cited by 232 publications

(172 citation statements)

References 26 publications

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“…Similar elevations are observed in children receiving TPN with severe liver dysfunction (Clayton et al 1993). Plasma cholesterol was 3.73mmol/L in this sample.…”

Section: Resultssupporting

confidence: 84%

See 1 more Smart Citation

Dihydropyridmidinase deficiency and congenital microvillous atrophy: Coincidence or genetic relation?

Assmann

Hoffmann

Wagner

et al. 1997

J of Inher Metab Disea

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“…Similar elevations are observed in children receiving TPN with severe liver dysfunction (Clayton et al 1993). Plasma cholesterol was 3.73mmol/L in this sample.…”

Section: Resultssupporting

confidence: 84%

“…The role of phytosterols (derived from intralipid infusions) in the development of cholestasis has not yet been completely elucidated (Clayton et al 1993), but 6 days of intralipid are not sufficient to cause cholestasis.…”

Section: Dihydropyrimidinase Deficiency and Microvillous Atrophy 685mentioning

confidence: 99%

Dihydropyridmidinase deficiency and congenital microvillous atrophy: Coincidence or genetic relation?

Assmann

Hoffmann

Wagner

et al. 1997

J of Inher Metab Disea

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“…However, polymorphisms in both ABCG5 and ABCG8 that do affect plasma plant sterol levels have been described (36), and in view of the present results, it may be prudent to check for potential consequences of increased dietary plant sterol intake on platelet morphology and function in these subjects as well as in obligate heterozygotes. High plasma plant sterol levels and thrombocytopenia have also been reported in patients receiving total parenteral nutrition (TPN) who developed liver dysfunction (37). TPN based on soybean oil is, by definition, rich in plant sterols (38), but not all TPN formulations share this feature.…”

Section: Discussionmentioning

confidence: 99%

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Kruit

Drayer

Bloks

et al. 2008

Journal of Biological Chemistry

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Mutations in either ABCG5 or ABCG8 cause sitosterolemia, an inborn error of metabolism characterized by high plasma plant sterol concentrations. Recently, macrothrombocytopenia was described in a number of sitosterolemia patients, linking hematological dysfunction to disturbed sterol metabolism. Here, we demonstrate that macrothrombocytopenia is an intrinsic feature of murine sitosterolemia. Abcg5-deficient (Abcg5 ؊/؊ ) mice showed a 68% reduction in platelet count, and platelets were enlarged compared with wild-type controls. Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, but defective megakaryocyte development with deterioration of the demarcation membrane system was evident. Lethally irradiated wild-type mice transplanted with bone marrow from Abcg5 ؊/؊ mice displayed normal platelets, whereas Abcg5 ؊/؊ mice transplanted with wild-type bone marrow still showed macrothrombocytopenia. Treatment with the sterol absorption inhibitor ezetimibe rapidly reversed macrothrombocytopenia in Abcg5 ؊/؊ mice concomitant with a strong decrease in plasma plant sterols. Thus, accumulation of plant sterols is responsible for development of macrothrombocytopenia in sitosterolemia, and blocking intestinal plant sterol absorption provides an effective means of treatment.Plant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24 (campesterol and sitosterol, respectively), in some cases with an additional double bond at C-22 (brassicasterol and stigmasterol, respectively). These structural differences appear to have a major impact on their handling in the body. Despite the fact that regular Western diets contain similar amounts of cholesterol and plant sterols (intakes of ϳ200 -400 mg/day for both) (1), plasma levels of plant sterols are Ͼ100 times lower than those of cholesterol in healthy individuals (2), indicating the presence of effective systems to prevent plant sterol accumulation in the human body. It has become clear that the ATPbinding cassette half-transporters ABCG5 and ABCG8, most abundantly present in intestine and liver, are critically involved herein. ABCG5 and ABCG8 function as an obligate heterodimer and mediate cholesterol and plant sterol transport out of intestinal and hepatic cells (3, 4). The functional heterodimer is present at the apical membranes of enterocytes and hepatocytes, where it transports (plant) sterols back into the intestinal lumen or bile, respectively (4, 5). Expression of ABCG5 and ABCG8 in other organs and tissues is relatively low (6 -8), and functionality at sites other than intestine and liver has not been reported.Mutations in either the ABCG5 or ABCG8 gene cause sitosterolemia (9, 10). Sitosterolemia is a relatively rare autosomal recessive disorder characterized by the accumulation of plant sterols in blood and tissues. Patients frequently develop tendon and cutaneous xanthomas and, most important, are at risk of developing premature coronary atherosclerosis (11)(12)(13)(14). A ...

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“…Scattered reports in the literature have linked PNAC to the vegetable sterol components of ILEs (1)(2)(3)(4)(5). Information on the sterol contents of ILEs, however, is currently scant and one of our previous purpose was to identify animal and plant sterols contained in the most representative ILEs.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, toxic substances such as phytosterols have been found in ILEs. Phytosterols have been related to a TPN-associated complication defined parenteral nutrition-associated cholestasis (PNAC) (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Phytosterols and Lack of Occurrence of Cholestasis in Rats Nourished Parenterally or Orally

Forchielli¹,

Bersani²,

Talà³

et al. 2012

Cholestasis

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Phytosterolemia in children with parenteral nutrition—Associated cholestatic liver disease

Cited by 232 publications

References 26 publications

Dihydropyridmidinase deficiency and congenital microvillous atrophy: Coincidence or genetic relation?

Dihydropyridmidinase deficiency and congenital microvillous atrophy: Coincidence or genetic relation?

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Phytosterols and Lack of Occurrence of Cholestasis in Rats Nourished Parenterally or Orally

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