Indian J Med Res 128, August 2008, pp 93-96

Editorial
Indian childhood cirrhosis: Several dilemmas resolved

Indian childhood cirrhosis (ICC) is a chronic liver disease in 1-3 yr old children, unique to the Indian subcontinent. The Indian Council of Medical Research (ICMR) in 1983, set up a Multi-centric National Collaborative Study (MNCS) on ICC in six centres, except in Kolkata, its original home, due to total absence of cases for decades! Indeed after the 1980s there have been no cases of ICC any where in India, enhancing the erstwhile mystery. The MNCS Report on ICC1 was released in 2006, just when the disease was on the verge of extinction; in the process, apart from clarification of several longstanding dilemmas, the stage is set for the solution of the only remaining issue about its aetiology. In October 1887, Boyle Chunder Sen2 presented the first clinical account of this condition, attributing it to some inherited dyscrasia. In the very next year, Gibbons performed the first autopsy, soon followed by three more. He designated the disease Infantile Biliary Cirrhosis, due to the presence of proliferated bile ducts, and ascribed it to some endogenous chemical irritant3 which went unchallenged for over six decades. The detailed autopsy studies revealed several new and unique features4 like Peri-cellular fibrosis in the liver, and raised suspicions of congenital syphilis, but was ruled out on the basis of negative serology. Since cirrhosis was also accompanied by phlebosclerosis of some of the tributaries of the hepatic vein, the causative role of some exogenous plant toxins was invoked and a new termSub-acute toxic cirrhosis was introduced4. However in 1954, Bhende and Deoras described the presence of hyaline in autopsy liver samples and also designated the condition as Infantile cirrhosis5. To clarify the prevalent issues about this unique Indian disease, the ICMR constituted an Expert Committee under the Chairmanship of Dr Khanolkar, which proposed the term Infantile cirrhosis. The
93

presence of hyaline in liver biopsy samples was reinforced6. Incidentally, the current eponym Indian childhood cirrhosis, was actually introduced in 1957 by Jelliffe, et al7 and it acquired long lease subsequently following Achar et al8. The toxipathic significance of Mallorys hyaline in liver biopsy samples was glossed over for nearly 15 years. In brief, the WHO classification of cirrhosis reveals that, while the aetiology of ICC is unknown, the morphological picture is one of micro-nodular cirrhosis, for copper, and +ve for Mallorys hyaline9. Nayak and colleagues10,11 established its identity with Mallorys hyaline (MH) of alcoholic liver disease. Its possible role in the development of ICC as an inclusion criterion or a sine qua non of ICC was widely recognized12. Yet, the pathogenesis, and aetiology of ICC, remained enigmatic, several theories were postulated, such as familial and genetic factors13,14, community and caste-related nutritional deficiencies (vegetarianism) 15,16, microbial 17,18 and viral 15,19 infections and suspected toxins10,20. Investigations at Madras (now Chennai) established that successful therapeutic regimens like globulin and steroids on ICC patients led to long-term survival as well as improvement of hepatic lesions, as confirmed by repeat biopsies21. However, that ICC might be due to endemic non-A, non-B viral hepatitis, was not substantiated by later studies, employing sensitive techniques to detect hepatitis due to virus infections22. Thus the aetiology remained an open issue. Towards the end of 1970s, Tanner and associates modified the previous histochemical studies on ICC23, and reported an increase of Orcein +ve stainable hepatic Copper binding protein (CuBP)24. Finally in 1979, a new theory of dietary copper toxicity, based on elevated levels of hepatic copper, attributed to use of

94

INDIAN J MED RES, AUGUST 2008

copper yielding utensils was proposed25. Soon, the need to confirm the qualitative histochemical studies by quantitative elemental analyses was felt and so the standard Atomic Absorption Spectrometry (AAS) Chemical Analysis was carried out on liver biopsy samples25. Almost simultaneously, Popper with the help of Delhi group carried out AAS studies on three autopsy samples of ICC26. The Delhi group undertook in 1981, a histochemical study on a large and wide range of cases of ICC, their asymptomatic and non-diseased siblings and matched controls, and noted that, unlike regular ICC patients, some of the siblings had only mild to moderate increase of hepatic Cu and CuBP. The defective copper homeostasis was not accompanied by any significant organelle damage and seemed to be spontaneously corrected27. Later Sundaravalli and colleagues at Chennai28, who had originally contributed to Tanners studies, undertook an equally comprehensive study of the copper content of liver, skin, hair and nails of ICC patients, their siblings and normal and disease controls by employing the more reliable quantitative chemo-metric analyses by AAS technique. The changes were only in the liver of established cases of ICC28. But, there were genuine doubts whether such changes were the cause or consequence of the disease. The MNCS of ICMR set out to clarify all pending issues about the disease. The MNCS was based on comprehensive and mutually agreed objectives as per standardized epidemiological, clinical, laboratory and histopathological proformas. Possible pitfalls in clinical diagnosis were circumvented by strict adherence to a mutually agreed code of pathological classification. Stress was laid on the pivotal role of single or multiple liver biopsies and clinico-pathological follow up. Based on the large series of 748 cases, not only the early lesion, but the entire spectrum of histopathology of ICC was successfully delineated. The MNCS Report1 confirmed, with minor variations, most of the earlier epidemiological and clinical features of ICC. The clinical significance of pre-cirrhotic symptom complex (PCSC) advocated by investigators from Mumbai12 could not be substantiated. In the Madras Centre, a new feature of superimposition of keratomalacia was found in older children with ICC1,29. More importantly, the newly invoked theory of dietary copper toxicity was found to be virtually untenable. Thus, in four of the six Centres, use of copper yielding

utensils was reported in just 10 to 50 per cent of cases categorized as definitive ICC, a frequency not different from that in controls. In the remaining two Centres located in Mumbai, copper yielding utensils were not at all used for cooking and boiling or storing milk for any of the definitive ICC cases. Until they developed the disease, 9 children with definitive or florid ICC were found to be purely breast-fed without any supplementation by milk or weaning diets. All the other stages of ICC were also encountered in the total absence of use of copper yielding utensils for cooking the food of affected children. In the entire series of 748 cases, Cu and CuBP were positive histologically in 91.4 per cent of definitive ICC (with Mallorys hyaline), 24 per cent of probable ICC (without Mallorys hyaline) and 25 per cent of mixed micro-macro nodular cirrhosis. In the other two earlier stages, with non specific milder changes, Cu positivity was seen in an extremely insignificant percentage of cases. Thereby, the basic issue of dietary copper toxicity advocated by Tanner and associates25 was convincingly disproved. Yet another fact that emerged from the MNCS Report was the dynamic transitions in liver pathology that often occurred in several cases of ICC. Thus, adjacent biopsies showed variations from a histologically mild to more severe category and viceversa. There were also transformations amongst the three stages or sub-types of active cell damage and cirrhosis, with or without Mallory hyaline, as well as inactive cirrhosis of the micro nodular cirrhosis (mnc) type. The last type was more often found in older children with longer survival. After completion of the MNCS work, Sriramachari and associates, undertook fresh quantitative studies in ICC. Chemometric analysis of copper and zinc content of hepatic tissue was carried out by Graphite Furnace AAS technique in 156 biopsy samples (including ten MH +ve cases), drawn from Centres 4 and 6 under their purview. In general, the values of hepatic zinc were higher than that of copper at all stages. Variable degrees of increase of both elements were found to be directly related to the pathological severity of the hepatic lesions, especially the MH +ve state of florid ICC30. Similar trends were observed in metallothionein immuno-histochemistry31. The concurrent twin element response, including nontoxic zinc, appears to represent a metabolic tissue response or consequence. Had ICC been caused by

SRIRAMACHARI & NAYAK: INDIAN CHILDHOOD CIRRHOSIS

95

dietary copper toxicity, hepatic copper overload should have manifested at the initial stages of the disease, rather than towards the terminal phases. Lastly, in order to explore the nature of exogenous toxic factors, potential causative agent(s) of ICC, a series of pilot experiments were done on rats and mice fed a diet simulating poor quality Indian vegetarian food, supplemented with domestic post-puerperal therapeutic remedies that used to be given to mothers and infants in several Indian communities. Some of these animals have developed hepatic lesions similar to those encountered in different stages of ICC32. In conclusion, apart from bringing clarity to the century-old ICC, several misconceptions and controversies have been resolved. Establishing the early lesion, as well as the broad and dynamic pathological spectrum, with to-and-fro transitions are significant historical contributions by the MNCS. The presence of Mallory hyaline appears to be a late phenomenon, accompanied by accumulation of not only the incriminated Cu, but the non-toxic Zn as well. However, the causative role of Cu has been dispelled. In view of the subsequent disappearance of the disease in the affected castes (and communities), the hypothesis of inherited susceptibility of copper metabolism also does not appear to be valid. Instead, the possible hepato-toxic effects of post-puerperal domestic therapeutic remedies appear to be more plausible. The current efforts at identification of the incriminated compound(s) in specific herbal formulations, by appropriate animal experiment, will resolve the mystery of ICC. S. Sriramachari* & N.C. Nayak** * Institute of Pathology (ICMR) Safdarjung Hospital Complex, New Delhi 110 029 ** Department of Pathology Sir Ganga Ram Hospital New Delhi 110 060, India * For correspondence: ssriramachari@hotmail.com References
1. Indian childhood cirrhosis (ICC): A Multicentric National Collaborative Study, S.Sriramachari, Editor-in-Chief. 2006, Indian Council of Medical Research, New Delhi. Available at: http://www.icmr.nic.in. Sen B. Infantile cirrhosis. Indian Med Gaz 1887; 22 : 338-42. Gibbons J. Biliary Cirrhosis of the liver in children. Indian Med Gaz 1890; 25 : 119-23.

4. 5. 6.

Radhakrishna Rao MV. Histopathology of the liver in Infantile biliary cirrhosis. Indian J Med Res 1935; 23 : 69-90. Bhende YM, Deoras SM. Pathology of infantile cirrhosis of the liver. Indian J Med Sci 1954: 8 : 21-30. Khanolkar V, Achar S, Raju V, Aikat B.K, Kutumbiah P, Patwardhan VN, et al. Infantile cirrhosis of the liver in India (Synonym-Infantile biliary cirrhosis). Indian J Med Res 1955; 43 : 725-47. Jelliffe DB, Bras G, Mukherjee KL. Veno-occlusive disease of the liver and Indian childhood cirrhosis. Arch Dis Child 1957; 32 : 369-85. Achar ST, Balagopala Raju V, Sriramachari S. Indian Childhood Cirrhosis. J Pediatr 1960; 57 : 744-58. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978; 31 : 395-414.

7.

8. 9.

10. Nayak NC, Sagreiya K, Ramalingaswami V. Indian childhood cirrhosis. The nature and significance of cytoplasmic hyaline of hepatocytes. Arch Pathol 1969; 88 : 631-7. 11. Roy S, Ramalingaswami V, Nayak NC. An ultrastructural study of the liver in Indian childhood cirrhosis with particular reference to the structure of cytoplasmic hyaline. Gut 1971; 12 : 693-701. 12. Patel BD, Parekh SR, Chitale AR. Histopathological evolution of Indian childhood cirrhosis with emphasis on criteria of early diagnosis. Indian Pediatr 1974; 11 : 19-28. 13. Srivastava J. The genetic factor in infantile cirrhosis of liver: A preliminary report. Indian J Med Sci 1956; 10 : 191-6. 14. Aggarwal S, Lahiri UC, Mehta SK, Smith DG, Bajpai PC. Inheritance of Indian childhood cirrhosis. Hum Hered 1979; 29 : 82-9. 15. Kutumbiah P. Infantile biliary cirrhosis - A critical review of the literature on the subject. Antiseptic 1956; 53 : 643-64. 16. Sarma AVS. Infantile hepatic cirrhosis. Antiseptic 1946; 43 : 12-35. 17. Krishna Rao P. Infantile cirrhosis of the liver. Proc Indian Acad Sci 1942; 14 : 318-38. 18. Lahiri S. Role of infection in the etiology of infantile cirrhosis of the liver. Indian Med Gaz 1936; 71 : 313-9. 19. Srivastava J, Aikat, BK. Infantile cirrhosis of liver: A clinicopathological study. Indian J Med Sci 1954; 8 : 446-52. 20. Nayak NC, Sachdeva R, Dhar A, Seth HN. Demonstration of hepatitis B virus surface component in human hepatocellular cancer cells. Indian J Med Res 1979; 69 : 161-7. 21. Sundaravalli N, Raju, VB, Sriramachari S. Indian childhood cirrhosis past, present and future. Trop Gastroenterol 1981; 2 : 149-56. 22. Nayak NC, Visalakshi S, Singh M, Chawla V, Chandra RK, Ramalingaswami V. Indian childhood cirrhosis-a re-evaluation of its pathomorphologic features and their significance in the light of clinical data and natural history of the disease. Indian J Med Res 1972; 60 : 246-59.

2. 3.

96

INDIAN J MED RES, AUGUST 2008 28. Sundaravalli N, Meena S, Bhaskar Raju B. Copper studies in liver disorders. Indian Pediatr 1985; 22 : 195-9. 29. Sundaravali N, Chandy M, Raju VB. Serum retinol and albumin studies in Indian childhood cirrhosis. Mediscope 1977; 1 : 9-15. 30. Sriramachari S, Iyengar, B, Sundaravalli, N, Srivastava VK, Sindu JK, Jain AK, et al. Tissue trace element composition in ICC and allied disorders. Int J Toxico Occup Environ Health 1993; 2 : 85. 31. Sindhu JK, Jain, AK, Beena, KR, Sriramachari, S. An immunohistochemichal study of ICC. Annual Report, 2000 , New Delhi: Institute of Pathology, Indian Council of Medical Research; 2000. 32. Sriramachari S. Urgent need of experimental model for Indian childhood cirrhosis. Indian J Med Res 2007; 125 : 807-9.

23. Balasubrahmanyan M, Chopra HL. Histopathological demonstration of copper in the liver in different types of liver injury. Indian J Med Sci 1960; 14 : 351- 4. 24. Portman B, Movat AP, Tanner MS, Williams R. Orceinpositive liver deposits in Indian childhood cirrhosis. Lancet 1978; i : 1338-40. 25. Tanner MS, Portman B, Mowat AP, Williams R, Pandit AN, Mills CF, et al. Increased hepatic copper concentration in Indian childhood cirrhosis. Lancet 1979; i : 1203-5. 26. Popper H, Goldfischer S, Sternlieb I, Nayak NC, Madhavan TV. Cytoplasmic copper and its toxic effects: Studies in Indian childhood cirrhosis. Lancet 1979; i ; 1205-8. 27. Marwaha N, Nayak NC, Roy S, Kalra V, Ghai OP. The role of excess hepatic copper in the evolution of Indian childhood cirrhosis. Indian J Med Res 1981; 73 : 395-403.