Niemann‐pick Disease and Giant Cell Transformation of the Liver

Ashkenazi, A; Yarom, R.; Gutman, Alisa; Abrahamov, Ayala; Russell, Alex

doi:10.1111/j.1651-2227.1971.tb06658.x

Cited by 23 publications

(14 citation statements)

References 9 publications

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“…In most instances, a child undiagnosed with NPC1 disease may present with liver disease and be broadly diagnosed as having neonatal hepatitis with obstructive cholestasis, as evidence of having elevated bilirubin and alkaline phosphatase levels, in addition to having elevated ALT and AST enzyme levels [Ivemark et al, 1963;Jaeken et al, 1980;Semeraro et al, 1986]. A liver biopsy from such children has revealed the presence of pleomorphic, enlarged, and vacuolated hepatocytes containing numerous dense and membranous inclusions within the cytoplasm [Ashkenazi et al, 1971;Semeraro et al, 1986]. …”

Section: Discussionmentioning

confidence: 98%

Characterization of liver disease and lipid metabolism in the Niemann‐Pick C1 mouse

Garver

Jelínek

Oyarzo

et al. 2007

J of Cellular Biochemistry

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Niemann-Pick type C1 (NPC1) disease is an autosomal-recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. The NPC1 gene is expressed in every tissue of the body, with liver expressing the highest amounts of NPC1 mRNA and protein. A number of studies have now indicated that the NPC1 protein regulates the transport of cholesterol from late endosomes/lysosomes to other cellular compartments involved in maintaining intracellular cholesterol homeostasis. The present study characterizes liver disease and lipid metabolism in NPC1 mice at 35 days of age before the development of weight loss and neurological symptoms. At this age, homozygous affected (NPC1(-/-)) mice were characterized with mild hepatomegaly, an elevation of liver enzymes, and an accumulation of liver cholesterol approximately four times that measured in normal (NPC1(+/+)) mice. In contrast, heterozygous (NPC1(+/-)) mice were without hepatomegaly and an elevation of liver enzymes, but the livers had a significant accumulation of triacylglycerol. With respect to apolipoprotein and lipoprotein metabolism, the results indicated only minor alterations in NPC1(-/-) mouse serum. Finally, compared to NPC1(+/+) mouse livers, the amount and processing of SREBP-1 and -2 proteins were significantly increased in NPC1(-/-) mouse livers, suggesting a relative deficiency of cholesterol at the metabolically active pool of cholesterol located at the endoplasmic reticulum. The results from this study further support the hypothesis that an accumulation of lipoprotein-derived cholesterol within late endosomes/lysosomes, in addition to altered intracellular cholesterol homeostasis, has a key role in the biochemical and cellular pathophysiology associated with NPC1 liver disease.

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Section: Discussionmentioning

confidence: 98%

Characterization of liver disease and lipid metabolism in the Niemann‐Pick C1 mouse

Garver

Jelínek

Oyarzo

et al. 2007

J of Cellular Biochemistry

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“…Progressive neonatal liver failure and cholestasis have been described in neonatal NP-C disease in human patients (22-25). In one study of 52 children, 34 had cholestatic liver disease and approximately half of these children had persistent elevations of liver enzymes although neurological dysfunction remained the predominant disease manifestation (24).…”

Section: Discussionmentioning

confidence: 99%

Clinical, Electrophysiological, and Serum Biochemical Measures of Progressive Neurological and Hepatic Dysfunction in Feline Niemann-Pick Type C Disease

et al. 2008

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Niemann-Pick type C (NP-C) disease is a neurovisceral lysosomal storage disease characterized by neurological dysfunction, hepatosplenomegaly, and early death. Natural history studies are very difficult to perform due to the low incidence and high heterogeneity of disease in the human population. Sixteen cats with a spontaneously occurring missense mutation in NPC1 were evaluated over time to define the progression of neurological and hepatic disease. Affected cats had remarkably regular onsets of specific signs of cerebellar and vestibular system dysfunction with progressive severity of dysfunction quantified by post-rotatory nystagmus and brain stem auditory evoked response measures. NP-C disease cats also showed increasing serum activity of alanine aminotransferase, asparate aminotransferase, and cholesterol with advancing age. Affected cats lived to a mean age of 20.5 +/- 4.8 weeks. Central nervous system and hepatic lesions were similar to those described in human patients. These data are the first to document progressive hepatic disease in the feline model and demonstrate the importance of liver disease as part of the NP-C disease phenotype. Both neurological and hepatic measures of disease onset and severity can be used as a baseline with which to assess the efficacy of experimental therapies of NP-C disease in the feline model.

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“…trisomy E (Alpert et al, 1969), Niemann-Pick disease (Ivemark et al, 1963;Ashkenazi et al, 1971). It seems more reasonable to propose that most of the diseases listed in Table 7 act by nonspecifically increasing susceptibility to agents capable of causing hepatitis than to claim that each can specifically cause a liver lesion in an occasional baby.…”

Section: Discussionmentioning

confidence: 99%