93

Editorial

Indian childhood cirrhosis: Several dilemmas resolved

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

Indian childhood cirrhosis (ICC) is a chronic liverdisease in 1-3 yr old children, unique to the Indian sub-continent. The Indian Council of Medical Research(ICMR) in 1983, set up a Multi-centric NationalCollaborative Study (MNCS) on ICC in six centres,except in Kolkata, its original home, due to totalabsence of cases for decades! Indeed after the 1980sthere have been no cases of ICC any where in India,enhancing the erstwhile mystery. The MNCS Reporton ICC1 was released in 2006, just when the diseasewas on the verge of extinction; in the process, apartfrom clarification of several longstanding dilemmas, thestage is set for the solution of the only remaining issueabout its aetiology.

In October 1887, Boyle Chunder Sen2 presentedthe first clinical account of this condition, attributing itto some ‘inherited dyscrasia’. In the very next year,Gibbons performed the first autopsy, soon followed bythree more. He designated the disease ‘Infantile BiliaryCirrhosis’, due to the presence of proliferated bile ducts,and ascribed it to some ‘endogenous chemical irritant’3

which went unchallenged for over six decades. Thedetailed autopsy studies revealed several new andunique features4 like ‘Peri-cellular fibrosis’ in the liver,and raised suspicions of ‘congenital syphilis’, but wasruled out on the basis of ‘negative serology’. Sincecirrhosis was also accompanied by ‘phlebosclerosis’ ofsome of the tributaries of the hepatic vein, the causativerole of some exogenous ‘plant toxins’ was invoked anda new term‘Sub-acute toxic cirrhosis’ was introduced4.However in 1954, Bhende and Deoras described thepresence of ‘hyaline’ in autopsy liver samples and alsodesignated the condition as ‘Infantile cirrhosis’5.

To clarify the prevalent issues about this uniqueIndian disease, the ICMR constituted an ExpertCommittee under the Chairmanship of Dr Khanolkar,which proposed the term ‘Infantile cirrhosis’. The

presence of hyaline in liver biopsy samples wasreinforced6. Incidentally, the current eponym ‘Indianchildhood cirrhosis’, was actually introduced in 1957by Jelliffe, et al7 and it acquired long lease subsequentlyfollowing Achar et al8.

The ‘toxipathic significance’ of Mallory’s hyalinein liver biopsy samples was glossed over for nearly 15years. In brief, the WHO classification of cirrhosisreveals that, while the aetiology of ICC is unknown,the morphological picture is one of ‘micro-nodularcirrhosis’, ± for copper, and +ve for Mallory’s hyaline9.Nayak and colleagues10,11 established its identity with“Mallory’s 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 widelyrecognized12.

Yet, the pathogenesis, and aetiology of ICC,remained enigmatic, several theories were postulated,such as familial and genetic factors13,14, community andcaste-related nutritional deficiencies (vegetarian-ism)15,16, microbial17,18 and viral15,19 infections andsuspected toxins10,20. Investigations at Madras (nowChennai) established that successful therapeuticregimens like γ globulin and steroids on ICC patientsled to long-term survival as well as improvement ofhepatic lesions, as confirmed by repeat biopsies21.However, that ICC might be due to endemic non-A,non-B viral hepatitis, was not substantiated by laterstudies, employing sensitive techniques to detecthepatitis due to virus infections22. Thus the aetiologyremained an open issue.

Towards the end of 1970s, Tanner and associatesmodified the previous histochemical studies on ICC23,and reported an increase of Orcein +ve stainable hepaticCopper binding protein (CuBP)24. Finally in 1979, anew theory of ‘dietary copper toxicity’, based onelevated levels of hepatic copper, attributed to use of

94 INDIAN J MED RES, AUGUST 2008

‘copper yielding utensils’ was proposed25. Soon, theneed to confirm the qualitative histochemical studiesby ‘quantitative elemental analyses’ was felt and so thestandard Atomic Absorption Spectrometry (AAS)Chemical Analysis was carried out on liver biopsysamples25. Almost simultaneously, Popper with the helpof Delhi group carried out ‘AAS studies on threeautopsy samples of ICC26.

The Delhi group undertook in 1981, ahistochemical study on a large and wide range of casesof ICC, their asymptomatic and non-diseased siblingsand matched controls, and noted that, unlike regularICC patients, some of the “siblings” had only mild tomoderate increase of hepatic Cu and CuBP. Thedefective copper homeostasis was not accompanied byany significant organelle damage and seemed to bespontaneously corrected27. Later Sundaravalli andcolleagues at Chennai28, who had originally contributedto Tanner’s studies, undertook an equally comprehen-sive study of the copper content of liver, skin, hair andnails of ICC patients, their siblings and normal anddisease controls by employing the more reliablequantitative chemo-metric analyses by AAS technique.The changes were only in the liver of established casesof ICC28.

But, there were genuine doubts whether suchchanges were the “cause or consequence of the disease”.The MNCS of ICMR set out to clarify all pending issuesabout the disease. The MNCS was based oncomprehensive and mutually agreed objectives as perstandardized epidemiological, clinical, laboratory andhistopathological proformas. Possible pitfalls in clinicaldiagnosis were circumvented by strict adherence to amutually agreed code of pathological classification.Stress was laid on the pivotal role of single or multipleliver biopsies and clinico-pathological follow up.

Based on the large series of 748 cases, not onlythe early lesion, but the entire spectrum ofhistopathology of ICC was successfully delineated. TheMNCS Report1 confirmed, with minor variations, mostof the earlier epidemiological and clinical features ofICC. The clinical significance of pre-cirrhotic symptomcomplex (PCSC) advocated by investigators fromMumbai12 could not be substantiated. In the MadrasCentre, a new feature of superimposition ofkeratomalacia was found in older children with ICC1,29.More importantly, the newly invoked theory of ‘dietarycopper 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 casescategorized as definitive ICC, a frequency not differentfrom that in controls. In the remaining two Centreslocated in Mumbai, copper yielding utensils were notat all used for cooking and boiling or storing milk forany of the definitive ICC cases. Until they developedthe disease, 9 children with definitive or florid ICC werefound to be purely breast-fed without anysupplementation by milk or weaning diets. All the otherstages of ICC were also encountered in the total absenceof use of copper yielding utensils for cooking the foodof affected children.

In the entire series of 748 cases, Cu and CuBPwere positive histologically in 91.4 per cent of definitiveICC (with Mallory’s hyaline), 24 per cent of probableICC (without Mallory’s hyaline) and 25 per cent ofmixed ‘micro-macro nodular cirrhosis’. In the other twoearlier stages, with non specific milder changes, Cupositivity was seen in an extremely insignificantpercentage of cases. Thereby, the basic issue of ‘dietarycopper toxicity’ advocated by Tanner and associates25

was convincingly disproved.

Yet another fact that emerged from the MNCSReport was the dynamic transitions in liver pathologythat often occurred in several cases of ICC. Thus,adjacent biopsies showed variations from ahistologically mild to more severe category and vice-versa. There were also transformations amongst thethree stages or sub-types of active cell damage andcirrhosis, with or without Mallory hyaline, as well asinactive cirrhosis of the micro nodular cirrhosis (mnc)type. The last type was more often found in olderchildren with longer survival.

After completion of the MNCS work,Sriramachari and associates, undertook freshquantitative studies in ICC. Chemometric analysis ofcopper and zinc content of hepatic tissue was carriedout by Graphite Furnace AAS technique in 156 biopsysamples (including ten MH +ve cases), drawn fromCentres 4 and 6 under their purview. In general, thevalues of hepatic zinc were higher than that of copperat all stages. Variable degrees of increase of bothelements were found to be directly related to thepathological severity of the hepatic lesions, especiallythe MH +ve state of florid ICC30. Similar trends wereobserved in metallothionein immuno-histochemistry31.The concurrent ‘twin element response’, including non-toxic zinc, appears to represent a metabolic tissueresponse or consequence. Had ICC been caused by

SRIRAMACHARI & NAYAK: INDIAN CHILDHOOD CIRRHOSIS 95

dietary copper toxicity, hepatic copper overload shouldhave manifested at the initial stages of the disease, ratherthan towards the terminal phases.

Lastly, in order to explore the nature of exogenoustoxic factors, potential causative agent(s) of ICC, aseries of pilot experiments were done on rats and micefed a diet simulating poor quality Indian vegetarian food,supplemented with domestic ‘post-puerperal therapeuticremedies’ that used to be given to mothers and infantsin several Indian communities. Some of these animalshave developed hepatic lesions similar to thoseencountered in different stages of ICC32.

In conclusion, apart from bringing clarity to thecentury-old ICC, several misconceptions andcontroversies have been resolved. Establishing the earlylesion, as well as the broad and dynamic pathologicalspectrum, with to-and-fro transitions are significanthistorical contributions by the MNCS. The presence ofMallory hyaline appears to be a late phenomenon,accompanied by accumulation of not only theincriminated Cu, but the non-toxic Zn as well. However,the causative role of Cu has been dispelled. In view ofthe subsequent disappearance of the disease in theaffected castes (and communities), the hypothesis ofinherited susceptibility of copper metabolism also doesnot appear to be valid. Instead, the possible hepato-toxiceffects of post-puerperal domestic therapeutic remediesappear to be more plausible. The current efforts atidentification of the incriminated compound(s) inspecific herbal formulations, by appropriate animalexperiment, will resolve the mystery of ICC.

S. Sriramachari* & N.C. Nayak**

*Institute of Pathology (ICMR)Safdarjung Hospital Complex, New Delhi 110 029

**Department of PathologySir Ganga Ram Hospital

New Delhi 110 060, India*For correspondence:

ssriramachari@hotmail.com

References1. Indian childhood cirrhosis (ICC): A Multicentric National

Collaborative Study, S.Sriramachari, Editor-in-Chief. 2006,Indian Council of Medical Research, New Delhi. Availableat: http://www.icmr.nic.in.

2. Sen B. Infantile cirrhosis. Indian Med Gaz 1887; 22 : 338-42.3. Gibbons J. Biliary Cirrhosis of the liver in children. Indian

Med Gaz 1890; 25 : 119-23.

4. Radhakrishna Rao MV. Histopathology of the liver in Infantilebiliary cirrhosis. Indian J Med Res 1935; 23 : 69-90.

5. Bhende YM, Deoras SM. Pathology of infantile cirrhosis ofthe liver. Indian J Med Sci 1954: 8 : 21-30.

6. 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.

7. Jelliffe DB, Bras G, Mukherjee KL. Veno-occlusive diseaseof the liver and Indian childhood cirrhosis. Arch Dis Child1957; 32 : 369-85.

8. Achar ST, Balagopala Raju V, Sriramachari S. IndianChildhood Cirrhosis. J Pediatr 1960; 57 : 744-58.

9. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ,Sobin LH. The morphology of cirrhosis. Recommendationson definition, nomenclature, and classification by a workinggroup sponsored by the World Health Organization. J ClinPathol 1978; 31 : 395-414.

10. Nayak NC, Sagreiya K, Ramalingaswami V. Indian childhoodcirrhosis. The nature and significance of cytoplasmic hyalineof hepatocytes. Arch Pathol 1969; 88 : 631-7.

11. Roy S, Ramalingaswami V, Nayak NC. An ultrastructural studyof the liver in Indian childhood cirrhosis with particularreference to the structure of cytoplasmic hyaline. Gut 1971;12 : 693-701.

12. Patel BD, Parekh SR, Chitale AR. Histopathological evolutionof Indian childhood cirrhosis with emphasis on criteria of earlydiagnosis. 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 ofthe 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 IndianAcad Sci 1942; 14 : 318-38.

18. Lahiri S. Role of infection in the etiology of infantile cirrhosisof the liver. Indian Med Gaz 1936; 71 : 313-9.

19. Srivastava J, Aikat, BK. Infantile cirrhosis of liver: A clinico-pathological study. Indian J Med Sci 1954; 8 : 446-52.

20. Nayak NC, Sachdeva R, Dhar A, Seth HN. Demonstration ofhepatitis B virus surface component in human hepatocellularcancer cells. Indian J Med Res 1979; 69 : 161-7.

21. Sundaravalli N, Raju, VB, Sriramachari S. Indian childhoodcirrhosis 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-evaluationof its pathomorphologic features and their significance in thelight of clinical data and natural history of the disease. IndianJ Med Res 1972; 60 : 246-59.

23. Balasubrahmanyan M, Chopra HL. Histopathologicaldemonstration of copper in the liver in different types of liverinjury. Indian J Med Sci 1960; 14 : 351- 4.

24. Portman B, Movat AP, Tanner MS, Williams R. Orcein-positive liver deposits in Indian childhood cirrhosis. Lancet1978; i : 1338-40.

25. Tanner MS, Portman B, Mowat AP, Williams R, Pandit AN,Mills CF, et al. Increased hepatic copper concentration inIndian childhood cirrhosis. Lancet 1979; i : 1203-5.

26. Popper H, Goldfischer S, Sternlieb I, Nayak NC, MadhavanTV. Cytoplasmic copper and its toxic effects: Studies inIndian childhood cirrhosis. Lancet 1979; i ; 1205-8.

27. Marwaha N, Nayak NC, Roy S, Kalra V, Ghai OP. The role ofexcess hepatic copper in the evolution of Indian childhoodcirrhosis. Indian J Med Res 1981; 73 : 395-403.

28. Sundaravalli N, Meena S, Bhaskar Raju B. Copper studies inliver disorders. Indian Pediatr 1985; 22 : 195-9.

29. Sundaravali N, Chandy M, Raju VB. Serum retinol andalbumin studies in Indian childhood cirrhosis. Mediscope1977; 1 : 9-15.

30. Sriramachari S, Iyengar, B, Sundaravalli, N, Srivastava VK,Sindu JK, Jain AK, et al. Tissue trace element composition inICC and allied disorders. Int J Toxico Occup Environ Health1993; 2 : 85.

31. Sindhu JK, Jain, AK, Beena, KR, Sriramachari, S. An immuno-histochemichal study of ICC. Annual Report, 2000,New Delhi: Institute of Pathology, Indian Council of MedicalResearch; 2000.

32. Sriramachari S. Urgent need of experimental model for Indianchildhood cirrhosis. Indian J Med Res 2007; 125 : 807-9.

96 INDIAN J MED RES, AUGUST 2008