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Indian Childhood Cirrhosis

Cirrhosis Fam + Pulm Hyperten

Indian childhood cirrhosis is a liver disease caused by the toxic effects of copper overload that occurs in genetically susceptible infants and children. Although initially thought to only occur in Indian children, this disease has been documented in other ethnic groups, as well and is characterized by excess copper (with a higher level than those detectable in Wilson's disease) and Orcein stain positive copper binding protein. An autoimmune mechanism has also been postulated.


Presentation

Despite the fact that both Wilson's disease and Indian childhood cirrhosis are characterized by hepatic dysfunction induced by copper exposure, their clinical and histological traits do not overlap.

Indian childhood cirrhosis may become symptomatic between the ages of 6 months and 5 years, more commonly after the child is one to two years old [1]. Disease onset is often gradual, with nonspecific signs such as malaise, irritability, sleeplessness, lack of appetite, constipation or diarrhea, fever and abdominal distension due to hepatosplenomegaly, representing pre-cirrhotic findings [2]. These abnormalities, including an enlarged liver, may have multiple causes in children, therefore an early diagnosis is difficult to establish. In severe cases, a hepatic bruit may be noticed. The ponderal curve becomes flat. Abdominal palpation reveals a hard liver with a sharp inferior border localized 3 to 5 centimeters under the inferior rib cage border. Splenomegaly appears after the liver has become enlarged. By the time jaundice appears, the liver function is severely compromised and events like hepatocellular failure, ascites, bleeding due to esophageal varices leading to anemia, bacterial infection and death occur rapidly. In the preterminal phase, symptoms of cirrhosis become overt and include confusion due to hepatic encephalopathy, palmar erythema, spider nevi localized on the upper torso, portal hypertension and hepatic coma. At this point, a specific garlic odor may also be present, also a sign of severe hepatic dysfunction. Dyspnea and cyanosis on exertion are probably a consequence of severe anemia.

Disease onset may also be sudden, with fever, clay-like stools, jaundice or coma. Cholestasis is generally a late trait of this illness.

Easy Bruising
  • Cirrhosis can lead to Easy bruising or bleeding, or nosebleeds Swelling of the abdomen or legs Extra sensitivity to medicines High blood pressure in the vein entering the liver Enlarged veins called varices in the esophagus and stomach.[medlineplus.gov]
Fever
  • Disease onset may also be sudden, with fever, clay-like stools, jaundice or coma. Cholestasis is generally a late trait of this illness. Blood workup should include standard hepatic function tests.[symptoma.com]
  • Each had been well until progressive lethargy, abdominal swelling, jaundice, and fever developed four to seven months before death.[ncbi.nlm.nih.gov]
  • "The baby also had fever along with cough and had difficulty in breathing for six days prior to reaching the hospital," Dr Wadhwa said.[dailymail.co.uk]
  • ., worsening encephalopathy but no fever). Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines ( spontaneous bacterial peritonitis ).[gutenberg.us]
Non-Alcoholic Cirrhosis
  • Metabolism 44: 765–770 PubMed Google Scholar Crawford DH, Shepherd RW, Halliday JW et al. (1994) Body composition in non alcoholic cirrhosis: the effect of disease etiology and severity on nutritional compartments.[link.springer.com]
Loss of Appetite
  • Affected individuals can experience fatigue, weakness, loss of appetite, weight loss, nausea, swelling (edema), enlarged blood vessels, and yellowing of the skin and whites of the eyes (jaundice).People with cryptogenic cirrhosis may develop high blood[icdlist.com]
  • CLINICAL FEATURES • Discomfort in right upper quadrant due to mild hepatomegaly • Anorexia • Malaise • Weight loss • Loss of appetite • Jaundice • Ascites • Peripheral edema • Distended 32 Ramya Deepthi P 33.[slideshare.net]
  • -recommended as adjuvant: -Domestic: hepatitis, liver failure, gallstones, biliary dyskinesia, useful in the therapy of liver cirrhosis and chronic liver infections, loss of appetite, weight disorders, digestion difficult-adjuvant in cases of mushroom[farmaciaverde.util21.ro]
Jaundice
  • Disease onset may also be sudden, with fever, clay-like stools, jaundice or coma. Cholestasis is generally a late trait of this illness. Blood workup should include standard hepatic function tests.[symptoma.com]
  • Among children admitted to a further double blind trial who had ICC but who had not yet developed jaundice or ascites 10 treated with penicillamine and 10 treated with penicillamine plus prednisolone had a significantly improved survival.[ncbi.nlm.nih.gov]
  • Each had been well until progressive lethargy, abdominal swelling, jaundice, and fever developed four to seven months before death.[ncbi.nlm.nih.gov]
  • It typically presents with transient neonatal jaundice, in a child who is otherwise healthy, and progresses to biliary cirrhosis and portal hypertension.[ncbi.nlm.nih.gov]
  • "When the boy was three months old, doctors at his hometown noticed that the baby has progressive jaundice.[dailymail.co.uk]
Hepatomegaly
  • On examination, he had hepatosplenomegaly with firm hepatomegaly and a leafy border. There were no other signs of liver cell failure.[pediatriconcall.com]
  • May be asymptomatic or complain of fatigue, pruritus , and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin.[gutenberg.us]
  • Among patients with liver cirrhosis, 63% had hepatomegaly, 44% had splenomegaly and 56% had dilated superficial veins with upward flow in abdomen and chest wall.[tropicalgastro.com]
  • CLINICAL FEATURES • Discomfort in right upper quadrant due to mild hepatomegaly • Anorexia • Malaise • Weight loss • Loss of appetite • Jaundice • Ascites • Peripheral edema • Distended 32 Ramya Deepthi P 33.[slideshare.net]
  • Patients may be asymptomatic or have fatigue, pruritus , and non-jaundice skin hyperpigmentation with hepatomegaly.[en.wikipedia.org]
Hepatic Bruit
  • In severe cases, a hepatic bruit may be noticed. The ponderal curve becomes flat. Abdominal palpation reveals a hard liver with a sharp inferior border localized 3 to 5 centimeters under the inferior rib cage border.[symptoma.com]
Suggestibility
  • In earlier reports autosomal recessive (AR) mode of inheritance was suggested.[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]
  • This suggests that etiologies other than impaired MT production should be sought as the primary defect in these disorders.[ncbi.nlm.nih.gov]
  • Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect.[ncbi.nlm.nih.gov]
  • Total serum ALP isoenzyme and its heat-stable component progressively increased in concentration from early to advanced stages of the disease suggesting that the diseased liver in ICC is the source of the abnormal isoenzyme.[ncbi.nlm.nih.gov]

Workup

Blood workup should include standard hepatic function tests. Alanine transaminase and gamma glutamyl transpeptidase will be increased. A coagulation panel composed of bleeding and clotting time and prothrombin time should be obtained in order to further assess hepatic function and to prevent catastrophic bleeding following a liver biopsy. Ceruloplasmin and copper levels are within normal limits at first [3] [4]. Cupriuresis following d-penicillamine will be high.

Liver biopsy shows extensive hepatocyte damage, with liver cells appearing vacuolated, necrotic or ballooned. Histologic examination further describes the presence of inflammatory cells [5] and extensive pericellular intralobular fibrosis with poor regeneration, leading to a so- called "micro-micro nodular" cirrhosis [6] [7]. Hyaline inclusions, similar to those found in Wilson's disease or alcoholic liver disease have also been described. Fat deposits are small. However, there is one typical histological aspect of this disease, namely the presence of granules that color dark brown with orcein staining due to the fact that they consist of a copper-associated protein [8].

Enlargement of the Spleen
  • Other later symptoms, some due to complications, include: Reddened palms Loss of body hair Enlarged liver Enlarged spleen Appearance of thin, purplish-red, spidery looking blood vessels on the skin, especially around the navel Water retention and swelling[chp.edu]
  • Other findings suggestive of cirrhosis in imaging are an enlarged caudate lobe , widening of the liver fissures and enlargement of the spleen .[gutenberg.us]
  • Other liver findings suggestive of cirrhosis in imaging are an enlarged caudate lobe , widening of the fissures and enlargement of the spleen .[en.wikipedia.org]
Globulins Increased
  • Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone .[gutenberg.us]
  • Globulinsincreased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium – hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone .[en.wikipedia.org]

Treatment

  • The latter died within 185 (mean, 149) days of starting treatment. Nine receiving penicillamine died within 540 (mean, 338) days, but the remainder are well 5.1-9.3 years after commencing treatment.[ncbi.nlm.nih.gov]
  • The four children who still have micronodular cirrhosis beyond four years from onset remain on penicillamine treatment.[ncbi.nlm.nih.gov]
  • This report is the first documentation of the histologic sequence of changes in Indian childhood cirrhosis on d-penicillamine treatment.[ncbi.nlm.nih.gov]
  • Fourteen of 29 treated cases made a clinical recovery and were alive 489 to 1460 days from the start of treatment.[ncbi.nlm.nih.gov]
  • The latter died within 185 (mean, 149) days of starting treatment. Nine receiving penicillamine died within 540 (mean, 338) days, but the remainder are well 5.1–9.3 years after commencing treatment.[journals.lww.com]

Prognosis

  • "Indian childhood cirrhosis: clinical features, prognosis and treatment". Indian journal of pediatrics . 47 (389): 537–41. doi : 10.1007/BF02822546 . PMID 7262970 . Bavdekar, AR; Bhave, SA; Pradhan, AM; Pandit, AN; Tanner, MS (1996).[en.wikipedia.org]
  • Established cirrhosis has a 10-year mortality of 34–66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis.[gutenberg.us]
  • Prognosis • Patients without jaundice, Ascites or heatemesis and are abstainers from alcohol have 90% five year survival. • Cause of death in alcoholic cirrhosis could be due to –  Hepatic coma  Massive gastrointestinal bleeding  Infections  Hepatocellular[slideshare.net]
  • These also constitute the indications for liver transplantation as they predict poor prognosis. In HVCS these symptoms occur before the development of cirrhosis or during early liver cirrhosis.[tropicalgastro.com]

Etiology

  • This suggests that etiologies other than impaired MT production should be sought as the primary defect in these disorders.[ncbi.nlm.nih.gov]
  • We studied the clinical histories of four white American siblings who died at 41/2 to six years of age of an unknown form of cirrhosis, in an effort to identify the etiologic factors in this familial syndrome.[ncbi.nlm.nih.gov]
  • North American Indian childhood cirrhosis (CIRH1A, or NAIC), a severe autosomal recessive intrahepatic cholestasis described in Ojibway-Cree children from northwestern Quebec, is one of several familial cholestases with unknown molecular etiology.[ncbi.nlm.nih.gov]
  • The age range of the three male and two female children were from 1 ½ to 12 y and on clinical and investigational features all 5 cases were labeled as non-Wilsonian liver disease of uncertain etiology.[ncbi.nlm.nih.gov]
  • […] 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[ncbi.nlm.nih.gov]

Epidemiology

  • Indian Childhood Cirrhosis (ICC) is a unique syndrome with characteristic clinical, epidemiological and histopathological features which is a major cause of mortality in India in children 1 to 4 years of age.[ncbi.nlm.nih.gov]
  • Epidemiologically, copper intoxication of the drinking water was verified. The drinking water was obtained from wells via copper pipes.[ncbi.nlm.nih.gov]
  • Epidemiological investigations revealed an elevated copper concentration (8645 microg/l, normal: 2000) and a low pH value (6.3) of the drinking water supplied by copper pipes.[ncbi.nlm.nih.gov]
  • 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[ncbi.nlm.nih.gov]
  • The hypothesis that early introduction of copper contaminated animal milk is of aetiological importance explains many of the epidemiological features of ICC.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • Isolation of the NICC gene and defining its pathophysiology will significantly expand our insight into copper metabolism in man, which, at present, is largely limited.[ncbi.nlm.nih.gov]
  • NAIC has thus been proposed to be a primary ribosomal disorder (ribosomopathy); however, investigation of the pathophysiologic mechanism of this disease has been hindered by lack of an animal model.[ncbi.nlm.nih.gov]
  • Transplantation 27: 1760–1765 Google Scholar Roberts LR, Kamath PS (1996) Ascites and hepatorenal syndrome: pathophysiology and management.[link.springer.com]
  • Pathophysiology The liver plays a vital role in synthesis of proteins (e.g., albumin , clotting factors and complement ), detoxification and storage (e.g., vitamin A ). In addition, it participates in the metabolism of lipids and carbohydrates .[gutenberg.us]
  • Pathophysiology of disease : an introduction to clinical medicine (6th ed.). New York: McGraw-Hill Medical. pp. Chapter 14: Liver Disease. Cirrhosis. ISBN 978-0071621670 . Iredale JP (2003).[en.wikipedia.org]

Prevention

  • A common killer disease of the past, Indian childhood cirrhosis (ICC), which became preventable and treatable in the early 1990s, is now rare.[ncbi.nlm.nih.gov]
  • 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%.[ncbi.nlm.nih.gov]
  • It had a very high case fatality in the past [3] but has eventually become preventable, treatable and is now rare. [4] Variants [ edit ] North American Indian childhood cirrhosis [5] References [ edit ] Further reading North American Indian childhood[en.wikipedia.org]
  • ABSTRACT A common killer disease of the past, Indian childhood cirrhosis (ICC), which became preventable and treatable in the early 1990s, is now rare.[ajcn.nutrition.org]
  • A coagulation panel composed of bleeding and clotting time and prothrombin time should be obtained in order to further assess hepatic function and to prevent catastrophic bleeding following a liver biopsy.[symptoma.com]

References

Article

  1. Nayak N, Ramalingaswami V. Indian childhood cirrhosis. Clin Gastroenterol. 1975;4:333-349.
  2. Parekh S, Patel B. Epidemiological survey of Indian childhood cirrhosis. Indian Pediatr. 1972;9:431-439.
  3. Kapoor S, Singh M, Ghai OP. Study of serum copper oxidase in patients with Indian childhood cirrhosis. Indian J Med Res. 1971;59:115-121.
  4. Vij S, Vij A. Serum magnesium, copper, and iron levels in infantile cirrhosis. Indian Pediatr. 1975;12:411-413.
  5. Patel B, Parekh S, Chitale A. Histopathological evolution of Indian childhood cirrhosis with emphasis on criteria of early diagnoses. Indian Pediatr. 1974;11:19-28.
  6. Tanner M, Portmann B, Mowat A, et al. Indian childhood cirrhosis presenting in Britain with orcein-positive deposits in liver and kidney. Br Med J. 1978;ii:928-929.
  7. Nayak N, Ramalingaswami V. Indian childhood cirrhosis. Clin Gastroenterol. 1975;4:333-349.
  8. Salaspuro M, Sipponen P. Demonstration of an intracellular copper-binding protein by orcein staining in long standing cholestatic liver diseases. Gut. 1976;17:787-790.

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Last updated: 2018-06-21 21:18