Liver disease in India.

Bhave, Sheila; Pandit, Anand; Pradhan, A M; Sidhaye, D G; Kantarjian, A.; Williams, Ashleigh; Talbot, I. C.; Tanner, M S

doi:10.1136/adc.57.12.922

Cited by 48 publications

(12 citation statements)

References 18 publications

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“…Indian childhood cirrhosis is hepatic disorder that has an undetermined genetic component, but is believed to be caused by the consumption of milk boiled in copper kettles. There are reported cases of hepatic copper concentrations in excess of 6 mg/g dry weight in children with this disorder 43.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Copper-Activated Transcription: Activation of AP-1, and the JNK/SAPK and p38 Signal Transduction Pathways

Mattie

McElwee

Freedman

2008

Journal of Molecular Biology

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Copper is an essential metal that is able to produce reactive oxygen species and induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress in various organisms and tissues, but few address the molecular mechanisms by which copper affects transcription. Our results demonstrated that in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to AP-1 and antioxidant response elements. The level of copperinducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways. The activation of these pathways resulted in a concomitant increase in c-Jun phosphorylation. We investigated the hypothesis that copper-induced oxidative stress leads to the formation of stable lipid peroxidation by-products, which activate MAPK pathways; ultimately affecting transcription. While exposure did result in the production of HNE, the timing of the increased levels of proto-oncogene mRNA, phosphorylation of c-jun, and phosphorylation and activation of MAPKs, as well as the inability of the lipophilic antioxidant vitamin E to abrogate MAPK phosphorylation suggests that the formation of stable lipid peroxidation by-products may not be the primary mechanism by which copper activates MAKKs. These results further elucidate the effects of copper on signal transduction pathways to alter gene expression.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Copper-Activated Transcription: Activation of AP-1, and the JNK/SAPK and p38 Signal Transduction Pathways

Mattie

McElwee

Freedman

2008

Journal of Molecular Biology

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“…It is now firmly established that ICC is associated with greatly increased hepatic Cu. Whereas, liver Cu in normal children is less than 50 µg/g, the values in ICC are usually over 1000 µg/g 12 . Serum, hair and urinary Cu are also raised in ICC 15 .…”

Section: Indian Childhood Cirrhosis: An Environmental Disease?mentioning

confidence: 95%

“…The characteristic, clinical and epidemiological features of ICC are: [11][12][13] 1. Specific age range of 6 months to 5 years with a mean of 18 months.…”

Section: Indian Childhood Cirrhosis: An Environmental Disease?mentioning

confidence: 99%

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Copper metabolic defects and liver disease: Environmental aspects

Pankit¹,

Bhave²

2002

J of Gastro and Hepatol

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Copper (Cu) is an essential trace element for many biological processes. Cu homeostasis is generally well maintained by inbuilt controls in intestinal absorption, biliary excretion and intrahepatic storage. Copper deficiency disorders are rare. Acute Cu toxicity occurs occasionally in accidental poisoning with Cu sulfate. Chronic Cu toxicity in the form of liver cirrhosis and damage to other organs is seen classically in Wilson's Disease (genetic abnormality of Cu metabolism) and in the presumed environmental disorder Indian Childhood Cirrhosis (ICC). The clinical, epidemiological and treatment aspects of ICC are described. The evidence linking ICC to environmental Cu is (i) greatly increased hepatic Cu; (ii) early introduction of Cu contaminated milk boiled or stored in brass vessels; (iii) dramatic decline in ICC throughout the country coincident with change in feeding vessels; and (iv) continued long-term remission in d-penicillamine-treated patients after withdrawal of the drug. The nature and role of a second factor in the causation of ICC remains unclear, although a genetic predisposition is strongly suspected. Scattered reports of an ICC-like illness from the West (Idiopathic Cu Toxicosis, Endemic Tyrolean Infantile Cirrhosis), suggest that different mechanisms (environmental, genetic or both) can lead to the same end stage liver disease-'ecogenetic' disorders.

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“…Indian childhood cirrhosis is remarkable similar to Tyrolean infantile cirrhosis [14][15][16][17][18][19]. It occurs in India in infants or very young children fed milk stored in brass or copper containers.…”

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confidence: 99%

Editorial: Is heterozygosity for a Wilson's disease gene defect an important underlying cause of infantile and childhood copper toxicosis syndromes?

Brewer

2000

J. Trace Elem. Exp. Med.

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In this editorial, I would like to provide basic information on two seemingly disparate topics, and then bring them together in a unifying hypothesis that claims one is an underlying cause of the other. The two topics are first, the heterozygous state for a Wilson's disease genetic defect, and second, the occurrence of infantile and early childhood cirrhosis due to copper toxicity. I hypothesize that the latter primarily occurs in the presence of heterozygosity for Wilson's disease, and that this heterozygosity is often an important causal factor.By way of background, Wilson's disease is an inherited disorder of copper metabolism in which there is a failure in biliary excretion of excess copper [1,2]. As a result, these patients are not able to eliminate the small excess of copper that is present in most human diets. This daily accumulation leads to the liver becoming excessively loaded with copper, and it is damaged early in childhood. At some point, patients may present with clinically obvious liver disease, while in others, the liver disease may remain subclinical. As the liver is increasingly unable to store the excess copper, levels build up elsewhere, and the brain is the next most sensitive organ. These patients develop neurologic symptoms of a movement disorder type and often psychiatric symptomatology as well. Fortunately, there are now good treatments for Wilson's disease, and if these patients are diagnosed and treated early enough, recovery is usually substantial, they can live a normal or near-normal life, and have a normal or near-normal life expectancy [1][2][3][4]. The disease is rather rare, with frequencies around the world estimated at about 1 in 40,000. This case frequency estimate leads to an estimated heterozygous carrier frequency of 1%.The gene responsible for Wilson's disease has been cloned [5][6][7]. It is called ATP7B and codes for a protein which has copper-and membrane-binding specificities, and ATPase activity. This protein is responsible in some manner for helping the

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Liver disease in India.

Cited by 48 publications

References 18 publications

Mechanism of Copper-Activated Transcription: Activation of AP-1, and the JNK/SAPK and p38 Signal Transduction Pathways

Mechanism of Copper-Activated Transcription: Activation of AP-1, and the JNK/SAPK and p38 Signal Transduction Pathways

Copper metabolic defects and liver disease: Environmental aspects

Editorial: Is heterozygosity for a Wilson's disease gene defect an important underlying cause of infantile and childhood copper toxicosis syndromes?

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