Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indian childhood cirrhosis (ICC) is an almost uniformly fatal disease whose outcome may be modified with penicillamine if given at a sufficiently early stage. Twenty nine children with ICC seen in Pune, India, in 1980-7, who had survived at least five years from onset of penicillamine treatment, were reviewed aged 6.3 to 13 years. They were assessed clinically, biochemically, histologically, and by duplex Doppler ultrasound examination. None had symptoms suggestive of liver disease. There were no toxic effects of penicillamine other than asymptomatic proteinuria. Hepatosplenomegaly reduced significantly and liver function tests returned to normal in all. In four children, significant hepatosplenomegaly was associated with an abnormal duplex Doppler hepatic vein flow pattern and micronodular cirrhosis on biopsy. Clinical findings, growth and development, and ultrasound examination were normal in the remainder. Review of serial liver biopsy specimens showed a sequence of recovery from ICC through inactive micronodular cirrhosis to virtually normal histological appearances. The four children who still have micronodular cirrhosis beyond four years from onset remain on penicillamine treatment. In the others penicillamine was stopped after 1-7 (mean 3.5) years without relapse, strong evidence that ICC is not due to an inborn error of copper metabolism.
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PMID:Long term survival in Indian childhood cirrhosis treated with D-penicillamine. 866 42

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administered orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group, liver damage was established. In the combined group, liver injury was more frequent and more severe compared to the aflatoxin B1 group and biliary copper excretion was diminished compared with the copper group. Histologically, only the livers of this group exhibited degeneration, atrophy and steatosis of liver cells, inflammatory processes and a more or less prominent fibrosis. For childhood cirrhosis (ICC and ICT) a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.
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PMID:Experimental induction of liver fibrosis in young guinea pigs by combined application of copper sulphate and aflatoxin B1. 933 26

Of the cirrhoses that affect Indian children, Indian childhood cirrhosis (ICC) is a discrete clinical and histologic entity in which large amounts of copper are deposited in the liver. The evidence linking copper deposition to increased dietary copper intake in infancy was reviewed. Prevention of this feeding pattern prevents ICC, and the disease has now largely disappeared from many parts of India. Penicillamine, if given before the terminal clinical stage of ICC, reduces mortality from 92% to 53%. Long-term survivors show a sequence of histologic resolution, resulting either in inactive micronodular cirrhosis or in virtually normal histologic appearance. Twenty-nine treated ICC patients reexamined at 8.8 y of age (range: 6.3-13 y), 5-12 y after diagnosis, were well and had normal results from liver function tests. Clinical and epidemiologic evidence show that there must be excessive copper ingestion for ICC to develop, but the lack of an animal model, the inconstant relation between liver copper concentrations and liver damage, and the rarity of liver disease in adults suggests that other etiologic factors contribute. Two mechanisms are discussed: 1) that copper may be acting in synergy with a hepatotoxin, or 2) that there may be a genetic predisposition to copper-associated liver damage, as suggested recently for Tyrollean childhood cirrhosis. Although ICC is now rare, sporadic cases of an ICC-like disorder in infants continue to occur. There should be a greater awareness among pediatricians of this disease to enable early diagnosis. Penicillamine should be used early and adverse prognostic factors recognized as indications for early transplantation and unregulated water supplies should not be used to prepare infant feeds.
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PMID:Role of copper in Indian childhood cirrhosis. 958 55

Pathomorphology of the liver has been reviewed in 12 German infants with chronic exogenic copper intoxication. In 8 cases severe liver damage with diffuse accumulation of Mallory bodies and liver cell necrosis mimicking florid Indian childhood cirrhosis (ICC) was found. Seven of these children died because of liver failure. One child received liver transplantation at the age of 9 months. In contrast, 4 children with a stable clinical course had a complete micronodular cirrhosis in liver biopsy. The characteristic morphological features of ICC, especially ballooning of liver cells and accumulation of Mallory bodies, were only slightly expressed or even lacking. There was no correlation between the copper content of the liver and the severity of liver damage. The copper concentration varied between 541 micrograms/g dry weight (norm < 50 micrograms/g) and 2.154 micrograms/g dry weight in fatal cases. In surviving infants even higher concentrations of up to 698 micrograms/g fresh weight (norm < 5 micrograms/g), were found. The amount of free cytosolic copper varied between 900-4,900 ng/mg protein (13-70 times of normal). In conclusion, a spectrum of pathomorphological alterations exists in exogenic infantile copper disease which correlates with the clinical outcome in contrast to the copper content of the liver. Copper intoxication of the liver should be of diagnostic concern in any case of unclear micronodular cirrhosis in early infancy.
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PMID:Different pathomorphologic patterns in exogenic infantile copper intoxication of the liver. 968 45

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administrated orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group liver damage was established. In the combined group liver injury was more frequent and more severe compared to the aflatoxin B1 group. Compared with the copper group biliary copper excretion was diminished and the kidney copper content was elevated in the Afl. B1 + Cu group. While copper concentrations in bile and kidney correlated with other parameters, notably the pathological lesions of the liver, no such correlation was found for liver copper. Therefore in this experiment the degree of Cu accumulation was not decisive for the liver lesions. The livers' capacity for excreting Cu by bile seems to be a much more important factor. Histologically only the livers of the combined group exhibited degeneration, atrophy and steatosis of liver cells, and a fibrosis more or less pronounced. For childhood cirrhosis (ICC and ICT), a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.
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PMID:Liver fibrosis in guinea pigs experimentally induced by combined copper and aflatoxin application. 978 33

A novel copper-binding protein was identified in the liver supernatant (100,000 x g) of Indian childhood cirrhosis (ICC), purified to apparent homogeneity and characterized [corrected]. Purified major copper-binding protein (MCuBP) is solely responsible for binding about 35% of the total supernatant copper. Elution profile of ICC liver supernatant on Sephadex G-75 column chromatography showed three peaks. About 60% of the total supernatant copper was resolved in peak II, whereas zinc content was insignificant in this peak. But peak II was almost missing in a gel elution profile of control liver supernatant. The control group included cases of various liver diseases viz. neonatal hepatitis, septicemia, and mixed nodular cirrhosis. Copper-binding proteins of peak II further purified on ion-exchange chromatography and elution profile showed that peak II was a MCuBP with high copper-binding capacity (10 g atoms/mol of native protein). SDS-PAGE of this protein also revealed the existence of a single band with molecular mass of about 50 kD. UV spectra of MCuBP showed the maximal absorbance at 254 nm. Unlike the classical metallothionein, the amino acid composition of MCuBP revealed the presence of aromatic amino acids and higher content of glutamic acid and aspartic acid followed by glycine and serine. The ratio (0.3) of basic amino acids to acidic amino acids strongly indicates that it is an acidic protein. The cysteine content in this protein was insignificant, which further corroborates the possibility that the acidic amino acids might be prominent candidates for binding copper. Thus, the 50-kD MCuBP apparently makes a major contribution to the total copper-binding activity in ICC liver cytosol and may play a significant role in hepatic intracellular copper accumulation.
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PMID:Identification of a novel copper-binding protein from the liver of Indian childhood cirrhosis: purification and physicochemical characterization [corrected]. 980 48

Recently, 138 cases of infantile cirrhosis originating in several families in the Austrian province of the Tyrol were reported. This endemic Tyrolean infantile cirrhosis (ETIC) is indistinguishable from Indian childhood cirrhosis (ICC), idiopathic copper toxicosis (ICT), and resembles the early forms of Wilson's disease (WND). It has been argued that ETIC might represent an allelic variant of the WND gene, which is a copper transporting P-type ATPase (ATP7B). Assuming that ETIC results from a founder effect, a possible role for ATP7B in ETIC was investigated by association studies and haplotype sharing. Because of its lethality, the mapping of ETIC was focused on obligate gene carriers, i.e. the patients' parents. Our data indicate that ETIC is a separate genetic entity, distinct from WND.
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PMID:Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease. 988 82

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0.5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved.
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PMID:An animal model for copper-associated cirrhosis in infancy. 992 39

Pathomorphology of the liver has been reviewed in twelve German infants with chronic exogenic copper intoxication. Eight cases suffered from florid Indian childhood cirrhosis. Seven of these children died because of liver failure. One child received liver transplantation. In contrast, four children with a stable clinical course had a complete micronodular cirrhosis with only slight developed features of liver cell damage and stable clinical course. The copper content varied between 541 microg/g dry weight (norm <59 microg/g) and 698 microg/g fresh weight (norm <5 microg/g). There was no significant difference in the copper content between the children with florid Indian childhood cirrhosis and those with micronodular cirrhosis. The results show that there exists a spectrum of pathomorphological alterations in exogenic infantile copper disease correlating with the clinical outcome in contrast to the copper content of the liver. Copper intoxication of the liver should be of diagnostic concern in any unclear case of micronodular cirrhosis in early infancy.
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PMID:Pathomorphology of the liver in exogenic infantile copper intoxication in Germany. 1038 77

Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and idiopathic copper toxicosis (ICT), are clinically and pathologically indistinguishable liver disorders of infants and young children linked with exogenous copper and with increasing evidence for a genetic predisposition. North Ronaldsay sheep are a primitive breed which have adapted to a copper impoverished environment (<5 ppm) and display an abnormal sensitivity to copper poisoning when transferred to a copper replete (11 ppm) habitat. The aetiological parallels prompted a study of copper-associated liver disease in North Ronaldsay sheep (RCT) to see if the pathology could contribute to the understanding of the childhood disorder. A retrospective study was performed in which the livers of 22 mainland-bred North Ronaldsay sheep were compared with three island-bred sheep and categorized for liver copper content and pathomorphology. It was found that all the mainland sheep had accumulated liver copper (>300 microg/g), in contrast to the island sheep, although 10 sheep with increased liver copper (mean 600 SD 270 microg/g) showed no evidence of liver damage. A further 10 sheep with liver copper (mean 1276 SD 508 microg/g) exhibited periportal to panlobular histochemical copper retention, a periportal and/or panlobular pericellular fibrosis, a mixed inflammatory infiltrate and cholangioplasia. Steatosis was absent and regeneration was in abeyance. Finally, two sheep (liver copper >2000 microg/g) had a more active hepatitis with a florid pericellular, panlobular fibrosis and cirrhosis. Electron microscopy identified large numbers of collagen-producing hepatic stellate (Ito) cells in periportal regions. The pathological findings were sufficiently reminiscent of ICC, ETIC and ICT to warrant further exploration of RCT as a putative animal model. The North Ronaldsay sheep liver may be a useful tool for the investigation of copper-induced fibrogenesis.
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PMID:Copper-associated liver disease in North Ronaldsay sheep: a possible animal model for non-Wilsonian hepatic copper toxicosis of infancy and childhood. 1159 8


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