Indian childhood cirrhosis

ICC is a chronic liver disease seen in pediatric age group and is unique to the Indian subcontinent
First reported at kolkatta in 1880 as “infantile cirrhosis” or “infantile childhood cirrhosis” and was published in 1930
Definite etiologic factor is not known.
Probable cause is Hepatic copper toxicosis
ICC should not be confused with North American Indian cirrhosis (or cholestasis) which is due to mutations in the CIRH1A gene, which codes for cirhin.
In India, ICC is one of the significant cause of morbidity and mortality among children below the age of 5 years
Sharp decline in incidence in India after recognition of the role of copper overload in its pathogenesis
Age
- The age range is from 6 months to 5 years (but can occur at later years also)
- Peak around 2 years
Clinical manifestations
- Three clinical stages of ICC have been recognized:
- (1) An early stage with an insidious onset characterized by disturbances of appetite and bowel movement, slight enlargement of the liver and occasional jaundice
- (2) An intermediate stage characterized by irritability, minimal jaundice, marked hepatomegaly, splenomegaly and occasionally, subcutaneous oedema, ascites and susceptibility to infection
- (3) A late stage with increasing jaundice, hepatosplenomegaly and progression to hepatic failure and death
Etiology –
Three possibilities have been proposed
- Firstly, ICC is simply due to excessive copper ingestion, siblings sharing the same diet and environment are equally likely to be affected.
- Secondly, ICC may be another inherited abnormality of copper metabolism but no clear pattern of inheritance is demonstrable and may be due to poor ‘penetrance’, either of the genotype in causing copper storage or of the copper storage in causing hepatic damage.
- Against this hypothesis is the geographical restriction of ICC to India, and its apparent absence in Indian expatriates in the UK, Africa, or North America.
- The third possibility is that both an inherited abnormality and an increased copper load are necessary to produce ICC.
Other causes
- Environmental factors must be at least partially responsible
- If children with ICC are genetically normal with respect to their copper metabolism, then it is related to other trace elements-such as zinc or molybdenum-which impair copper absorption.
- The ingestion of another agent might interfere with the hepatic excretion of copper. For example hepatotoxic effects of pyrrolizidine alkaloids of the plant Heliotropium europaeum
Copper (but not zinc) is avidly taken up from brass and bound to casein from which it is completely removable by picolinate chelation
Milk is an effective carrier of copper from a brass utensil to the infant enterocyte
Direct cytopathic effect of copper – Reversal by penicillamine therapy
Morphology
- Copper storage is directly responsible for the histopathological lesions in ICC
- The copper accumulates first in periportal hepatocytes and then extends towards the terminal hepatic venules
- Earliest changes :
  - Ballooning degeneration and focal necrosis
  - Formation of Mallory–Denk bodies
  - Neutrophilic satellitosis may be seen
  - Steatosis is conspicuously absent
- The mesenchymal reaction is characterized by inflammatory cell infiltration (lymphocytes, histiocytes, neutrophils and a few plasma cells)
- Variable periportal ductular reaction
- Progressive fibrosis
- Micronodular cirrhosis
- Regenerative activity appears absent

Ballooning degeneration

Neutrophilic satellitosis

micronodular cirrhosis

Investigations
- Ceruloplasmin levels are normal or low
- Demonstration of copper in liver biopsy by
  - Histochemical :stain Orcein for copper-binding protein
  - Rhodanine stain for copper
  Quantitative techniques :Atomic absorption spectrophotometer

Orcein stain

Incidence can be decreased by :
- Avoid the use of copper vessels for infants and young children
- Penicillamine therapy
Differential diagnosis
- Alcoholic liver disease
- Wilsons disease –
  - ICC commonly occurs in the age group of 4 months to 5 years, Cases of WD below 3 years are very rare and are generally asymptomatic. Features favoring ICC were normal serum ceruloplasmin levels, absence of neurological symptoms/KF rings, sharp liver margin on palpation, and rapidly progressive clinical course
  - The histological picture of panlobular copper deposits, pericellular fibrosis, sparse regenerative activity, and diffuse Mallory hyaline favored ICC. Steatosis, glycogenated nuclei, irregular copper distribution, macronodules, and associated hemosiderin deposition, features more characteristic of WD,

References

Richard K Gilroy, Rahil Shah. Wilson disease, practice essentials, background and etiology. Gastroenterology, Drugs and diseases: Medscape.
Indian childhood cirrhosis. Archives of Disease in Childhood, 1981, 56, 4-6.
Jaivinder yadav, Deepak Sharma, Suman Yadav, Swetha shastri. Indian childhood cirrhosis: Case report and pediatric diagnostic challenges. Int J Pediatr,2015;vol.3,N.5-1,serial No.21
Sriramachari S, editor. New Delhi: Indian Council of Medical Research; 2006. Indian Childhood Cirrhosis (ICC) – A Multicentre National Collaborative Study.

INDIAN CHILDHOOD CIRRHOSIS

ICC is a chronic liver disease seen in pediatric age group and is unique to the Indian subcontinent

First reported at kolkatta in 1880 as “infantile cirrhosis” or “infantile childhood cirrhosis” and was published in 1930

Definite etiologic factor is not known.

Probable cause is Hepatic copper toxicosis

ICC should not be confused with North American Indian cirrhosis (or cholestasis) which is due to mutations in the CIRH1A gene, which codes for cirhin.

In India, ICC is one of the significant cause of morbidity and mortality among children below the age of 5 years

Sharp decline in incidence in India after recognition of the role of copper overload in its pathogenesis

Age

The age range is from 6 months to 5 years (but can occur at later years also)

Peak around 2 years

Clinical manifestations

Three clinical stages of ICC have been recognized:

(1) An early stage with an insidious onset characterized by disturbances of appetite and bowel movement, slight enlargement of the liver and occasional jaundice

(2) An intermediate stage characterized by irritability, minimal jaundice, marked hepatomegaly, splenomegaly and occasionally, subcutaneous oedema, ascites and susceptibility to infection

(3) A late stage with increasing jaundice, hepatosplenomegaly and progression to hepatic failure and death

Etiology –

Three possibilities have been proposed

Firstly, ICC is simply due to excessive copper ingestion, siblings sharing the same diet and environment are equally likely to be affected.

Secondly, ICC may be another inherited abnormality of copper metabolism but no clear pattern of inheritance is demonstrable and may be due to poor ‘penetrance’, either of the genotype in causing copper storage or of the copper storage in causing hepatic damage.

Against this hypothesis is the geographical restriction of ICC to India, and its apparent absence in Indian expatriates in the UK, Africa, or North America.

The third possibility is that both an inherited abnormality and an increased copper load are necessary to produce ICC.

Other causes

Environmental factors must be at least partially responsible

If children with ICC are genetically normal with respect to their copper metabolism, then it is related to other trace elements-such as zinc or molybdenum-which impair copper absorption.

The ingestion of another agent might interfere with the hepatic excretion of copper. For example hepatotoxic effects of pyrrolizidine alkaloids of the plant Heliotropium europaeum

Copper (but not zinc) is avidly taken up from brass and bound to casein from which it is completely removable by picolinate chelation

Milk is an effective carrier of copper from a brass utensil to the infant enterocyte

Direct cytopathic effect of copper – Reversal by penicillamine therapy

Morphology

Copper storage is directly responsible for the histopathological lesions in ICC

The copper accumulates first in periportal hepatocytes and then extends towards the terminal hepatic venules

Earliest changes :

Ballooning degeneration and focal necrosis

Formation of Mallory–Denk bodies

Neutrophilic satellitosis may be seen

Steatosis is conspicuously absent

The mesenchymal reaction is characterized by inflammatory cell infiltration (lymphocytes, histiocytes, neutrophils and a few plasma cells)

Variable periportal ductular reaction

Progressive fibrosis

Micronodular cirrhosis

Regenerative activity appears absent

Investigations

Ceruloplasmin levels are normal or low

Demonstration of copper in liver biopsy by

Histochemical :stain Orcein for copper-binding protein

Rhodanine stain for copper

Quantitative techniques :Atomic absorption spectrophotometer

Incidence can be decreased by :

Avoid the use of copper vessels for infants and young children

Penicillamine therapy

Differential diagnosis

Alcoholic liver disease

Wilsons disease –

References

Richard K Gilroy, Rahil Shah. Wilson disease, practice essentials, background and etiology. Gastroenterology, Drugs and diseases: Medscape.

Indian childhood cirrhosis. Archives of Disease in Childhood, 1981, 56, 4-6.

Jaivinder yadav, Deepak Sharma, Suman Yadav, Swetha shastri. Indian childhood cirrhosis: Case report and pediatric diagnostic challenges. Int J Pediatr,2015;vol.3,N.5-1,serial No.21

Sriramachari S, editor. New Delhi: Indian Council of Medical Research; 2006. Indian Childhood Cirrhosis (ICC) – A Multicentre National Collaborative Study.