Childhood Cirrhosis Research Articles

Bile Decompression in Children with Histopathological Evidence of Pre-Existing Liver Cirrhosis

Although it is agreed upon by most that adequate and timely bile decompression can preserve or even improve existing liver function much debate centers on whether pre-existing liver cirrhosis can also be reversed. To help answer this question we analyzed data on 47 children with choledochal cyst disease (CD) who underwent simultaneous liver biopsy during bile decompression surgery. We collected data on two groups of children with CD spanning two different time periods: January 1985 through November 1994 (Group A) and June 1995 through November 1999 (Group B). In Group A 37 children (16 boys and 21 girls ages 5 days to 10 years) underwent simultaneous liver biopsy during elective definitive surgery for CD. In Group B ten children (five boys and five girls age one month to 7 years) underwent liver biopsy twice: first during initial cyst decompression for acute obstruction and second during elective definitive surgery after resolution of acute disease. Degree of liver cirrhosis was based on a modified World Health Organization classification system (0-IV). In Group A 15/37 (40.5%) had significant liver cirrhosis at time of biopsy (III or IV) with altered liver function in all cases; eight of nine had normal liver function on follow-up, six were lost to follow-up. In Group B seven of ten (70%) had less liver cirrhosis on pathology at second operation with three unchanged; nine of ten (90%) regained normal liver function. We conclude that bile duct obstruction is the main cause of liver cirrhosis in children with CD. Adequate and timely bile decompression can restore normal liver function and even reverse severe cirrhosis.

Lipid parameters in childhood cirrhosis and chronic liver disease

Alterations in lipid metabolism are well defined in liver disease. As there has not been an ample amount of work published regarding this topic in children, especially about apolipoprotein A-I (apo A-I) and apolipoprotein B (apo B), theoretical knowledge depends on adult studies. In this study, we investigated serum lipid parameters of children with chronic liver disease and cirrhosis. Serum triglyceride, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), plasma apo A-I and apo B levels of 82 children with chronic liver disease, 41 of whom had cirrhosis as well, were investigated. Twenty healthy children were selected as controls. While mean serum triglyceride and cholesterol levels were not different in chronic hepatitis, cirrhosis and healthy children, mean apo B level of cirrhotic group was higher than that of the control group (P < 0.05). Mean LDL and HDL values of children with chronic hepatitis were lower and mean apo B value was higher than those of the control group (P < 0.05, P < 0.05 and P < 0.001, respectively). Apolipoprotein A-I level was lower in cholestatic cirrhotic children than non-cholestatic children (P < 0.05). No statistical difference was detected in lipid parameters of children with or without malnutrition (P > 0.05). The mean HDL value of Child-Pugh B group was significantly lower when compared to Child-Pugh A group (P < 0.05). The mean apo A-I value of Child-Pugh A group was higher than those of Child-Pugh B and C groups (P < 0.05 and P < 0.001). Consequently, we found that among lipid parameters apo A-I was the most affected parameter in liver injury. Whether apo A-I level can be used as a prognostic criterion in childhood cirrhosis may require further study.

Coexpression and accumulation of ubiquitin +1 and ZZ proteins in livers of children with alpha(1)-antitrypsin deficiency.

The ZZ variant of alpha(1)-antitrypsin deficiency (AATD) is well known to cause liver damage and cirrhosis in some affected children. Ubiquitin abnormality was recently shown to be significant in AATD in childhood cirrhosis. Molecular misreading (MM), defined as faulty transcription of genomic information from DNA into mRNA, as well as its translation into mutant proteins, has been documented in many pathologic processes where aggregation of abnormal proteins occurs. The misread protein, ubiquitin-B(+1) (UBB(+1)), was recently identified in the hallmarks of various neurological disorders. The objective of this study was to determine whether MM of ubiquitin occurs in AATD. Twelve explanted liver specimens from AATD-affected children with cirrhosis were retrieved from archival sources, along with 10 control liver specimens obtained from autopsies of age-matched children with no clinical, gross anatomic, or histologic evidence of liver disease. Double immunofluorescence studies using rabbit polyclonal antibodies against UBB(+1) and AAT were performed on consecutively sectioned tissue. UBB(+1) immunoreactivity was colocalized with AAT in all cirrhotic AATD livers. The control livers were consistently negative. Ubiquitin MM is prominent in AATD-affected cirrhotic livers. This indicates that for children with AATD and cirrhosis, ubiquitin MM is a necessary cofactor to the aggregation of mutant ZZ isoform of AATD.

Copper-associated liver disease in North Ronaldsay sheep: a possible animal model for non-Wilsonian hepatic copper toxicosis of infancy and childhood.

Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and idiopathic copper toxicosis (ICT), are clinically and pathologically indistinguishable liver disorders of infants and young children linked with exogenous copper and with increasing evidence for a genetic predisposition. North Ronaldsay sheep are a primitive breed which have adapted to a copper impoverished environment (<5 ppm) and display an abnormal sensitivity to copper poisoning when transferred to a copper replete (11 ppm) habitat. The aetiological parallels prompted a study of copper-associated liver disease in North Ronaldsay sheep (RCT) to see if the pathology could contribute to the understanding of the childhood disorder. A retrospective study was performed in which the livers of 22 mainland-bred North Ronaldsay sheep were compared with three island-bred sheep and categorized for liver copper content and pathomorphology. It was found that all the mainland sheep had accumulated liver copper (>300 microg/g), in contrast to the island sheep, although 10 sheep with increased liver copper (mean 600 SD 270 microg/g) showed no evidence of liver damage. A further 10 sheep with liver copper (mean 1276 SD 508 microg/g) exhibited periportal to panlobular histochemical copper retention, a periportal and/or panlobular pericellular fibrosis, a mixed inflammatory infiltrate and cholangioplasia. Steatosis was absent and regeneration was in abeyance. Finally, two sheep (liver copper >2000 microg/g) had a more active hepatitis with a florid pericellular, panlobular fibrosis and cirrhosis. Electron microscopy identified large numbers of collagen-producing hepatic stellate (Ito) cells in periportal regions. The pathological findings were sufficiently reminiscent of ICC, ETIC and ICT to warrant further exploration of RCT as a putative animal model. The North Ronaldsay sheep liver may be a useful tool for the investigation of copper-induced fibrogenesis.

Plasma and liver carnitine status of children with chronic liver disease and cirrhosis.

Carnitine is an essential cofactor in the transfer of long-chain fatty acids across the inner mitochondrial membrane for oxidation. As its synthesis is performed in the liver, alterations in carnitine metabolism is expected in liver diseases, especially in cirrhosis. In this study, we investigated plasma and liver carnitine concentrations of 68 children with chronic liver disease, 36 of whom had cirrhosis as well. Carnitine level was determined by enzymatic method. Plasma and liver carnitine concentrations were not correlated. Mean plasma carnitine level of cirrhotic children was significantly lower than that of the control group (P<0. 0001). While there was no difference between liver carnitine concentrations of children with chronic liver disease and cirrhosis (P>0.05), mean plasma level of cirrhotics were lower (P<0.05). Plasma carnitine was correlated with albumin, triglyceride and gamma glutamyl transpeptidase (GGT) in patients with chronic liver disease (P<0.05). Liver carnitine was correlated with GGT in cirrhotic patients (P<0.005). Children with malnutrition had higher plasma and liver carnitine levels (P<0.05). The highest plasma and liver carnitine levels were detected in children with biliary atresia and criptogenic cirrhosis, respectively. Both the lowest plasma and liver carnitine levels were detected in Wilson's disease. Children with cirrhosis have low plasma carnitine concentrations. This finding is prominent in children with Wilson's disease. As carnitine is an essential factor in lipid metabolism, the carnitine supplementation for patients with cirrhosis in childhood, especially with Wilson's disease, seems to be mandatory.

North American Indian Cirrhosis in Children: A Review of 30 Cases

ABSTRACTBackgroundNorth American Indian childhood cirrhosis (NAIC) is a distinct, rapidly evolving form of familial cholestasis found in aboriginal children from northwestern Quebec. This is a retrospective review of the 30 patients treated in Quebec since the discovery of NAIC in 1970.MethodsThe clinical records and histologic samples from 30 patients were reviewed. Extensive metabolic, biochemical, viral, genetic, and radiologic studies were performed in most patients.ResultsGenetic analysis suggests autosomal recessive inheritance and a carrier frequency of 10% in this population. Gene mapping studies showed that the NAIC gene is located on chromosome 16q22. Typically, patients have neonatal cholestatic jaundice (70%) or hepatosplenomegaly (20%) with resolution of clinical jaundice by age 1 year but persistent direct hyperbilirubinemia. Portal hypertension was documented in 29 patients (91%). Variceal bleeding (15 patients, 50%) occurred as early as age 10 months. Surgical portosystemic shunting was performed in 13 of these 15 patients (87%); 4 (31%) rebled after 1 to 5 years. Fourteen patients died (47%). In 10 (71%), liver disease was the cause. Four children died of liver failure before liver transplantation became available. In transplanted livers, no recurrence of NAIC was observed after 1 to 10 years. Recognized infectious, metabolic, toxic, autoimmune, and obstructive causes of cirrhosis have been eliminated. The histologic features of NAIC show early bile duct proliferation and rapid development of portal fibrosis and biliary cirrhosis, suggesting a cholangiopathic phenomenon.ConclusionTogether with gene mapping studies showing that the NAIC gene is different from those of other familial cholestases, these observations suggest that NAIC is a distinct entity that could be classified as “progressive familial cholangiopathy.”

Localization of a Recessive Gene for North American Indian Childhood Cirrhosis to Chromosome Region 16q22—and Identification of a Shared Haplotype

North American Indian childhood cirrhosis (NAIC, or CIRH1A) is an isolated nonsyndromic form of familial cholestasis reported in Ojibway-Cree children and young adults in northwestern Quebec. The pattern of transmission is consistent with an autosomal recessive mode of inheritance. To map the NAIC locus, we performed a genomewide scan on three DNA pools of samples from 13 patients, 16 unaffected siblings, and 22 parents from five families. Analysis of 333 highly polymorphic markers revealed 3 markers with apparent excess allele sharing among affected individuals. Additional mapping identified a chromosome 16q segment shared by all affected individuals. When the program FASTLINK/LINKAGE was used and a completely penetrant autosomal recessive mode of inheritance was assumed, a maximum LOD score of 4.44 was observed for a recombination fraction of 0, with marker D16S3067. A five-marker haplotype (D16S3067, D16S752, D16S2624, D16S3025, and D16S3106) spanning 4.9 cM was shared by all patients. These results provide significant evidence of linkage for a candidate gene on chromosome 16q22.

Copper toxicity affects proliferation and viability of human hepatoma cells (HepG2 line).

In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability of the HepG2 cells they were cultured in 4-32 microM copper(II) sulphate (CuSO4)). These levels were comparable to the circulatory and tissue concentrations of copper recorded for these two diseases. Specific uptake comparable to levels of copper recorded in the livers of patients with Wilson's disease and ICC was measured in the HepG2 cells. After 48 h acid vesicle function increased from 4 to 32 microM Cu2+ but significantly declined at 64 microM compared to the controls. Lysosomal acid phosphatase showed a concentration dependent decline in activity at 72 h. Cellls exposed to 64 microM Cu2+ had a potential doubling time (Tpot) 21 h longer than the control cells due to a prolonged DNA synthesis phase. At 64 microM Cu2+, increases of necrosis up to 18% were seen whereas comparable levels of apoptotic and necrotic cells (<5%) were seen below this concentration. Chronic exposure over 8 weeks impaired colony-forming efficiency at concentrations of 16 microM Cu2+ and above. This study suggests that when liver cells sequester large amounts of copper, the toxic effects include delayed cell-cycle progression, a gradual loss of replicative capacity, and an increased incidence of cell death.

Studies on the influence of a Se-restricted diet on the effects of long-term increased copper intake in guinea pigs

Guinea pigs were exposed to Se-restriction/deficiency in combination with drinking water containing 200 or 300 mg Cu/l for 6-30 weeks. Under the influence of Se-restriction/deficiency Cu excretion by bile was diminished, the Cu content of the kidneys was increased and disturbances of liver function were seen in animals exposed for prolonged periods. Some parameters of the immune system, such as the phagocytic activity of peritoneal macrophages, mitogenicity of spleen lymphocytes and the amount of lymphatic spleen tissue were also adversely affected. These effects correlated in part with the liver damage and the copper content of the kidneys. Conclusion are drawn with respect to the Idiopathic Copper Toxicosis/Indian Childhood Cirrhosis.

Chronic Hepatitis C Virus Infection in Childhood and Early Cirrhosis: It Is Possible?

Chronic Hepatitis C Virus Infection in Childhood and Early Cirrhosis: It Is Possible?

Nasogastric feeding enhances nutritional status in paediatric liver disease but does not alter circulating levels of IGF-I and IGF binding proteins.

Complications of childhood cirrhosis include abnormal growth and malnutrition, associated with abnormalities in circulating IGFs and IGFBPs. Controlled studies suggest that intensive enteral feeding enhances nutritional status. The aim was to ascertain whether nasogastric feeding improves nutritional status in clinical practice and to assess the effect of feeding on serum IGF-I and IGFBPs. Thirty-three children (median age 0.6 years) with biliary atresia and failure to thrive who were treated with nasogastric feeding. Height, weight and triceps skin fold thickness were measured prior to feeding and regularly for 1 year or until feeding was stopped. Serum IGF-I and IGFBPs were measured by immunoassay at the same intervals. The median duration of feeding was 3.7 months. Twenty-two stopped feeding after liver transplantation, while 10 stopped electively and 1 boy died. Before feeding, the children were losing weight and height centile. Triceps skin fold thickness, weight and height SD scores improved with feeding. Baseline serum IGF-I and IGFBP-3 were low, while IGFBP-1 and IGFBP-2 were raised. IGF-I and IGFBP-1 did not change with feeding. IGFBP-2 fell and reached a nadir by 3 months, while IGFBP-3 rose temporarily for 4-6 weeks. Nasogastric feeding improves body composition in paediatric liver disease but circulating IGF-I and IGFBPs remain abnormal and do not play a major role in mediating these changes. This does not exclude a paracrine or autocrine effect of IGF-I.

Studies on the influence of the copper content in the drinking water on the newborn copper burden and transaminases activity

Introduction: Clinical parameters for the early diagnosis of a potential development of childhood cirrhosis are not available. A cross-section study was performed to investigate whether the serum copper content and the activities of the newborn's glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) may be associated with the copper contents of the drinking water and/or the maternal serum and thus could serve as early indicator of an elevated health hazard. Material and Methods: The serum concentration of copper was analyzed in samples of 141 mother-newborn pairs. Additionally, in umbilical cord serum the activities of the transaminases GOT and GPT were determined. Low molecular bound or free copper was quantified in 30 randomly chosen serum filtrates. According to questionnaire data, in 62 of the 141 households the drinking water installations consisted of copper. In these cases, the element was analyzed in drinking water. Results: The copper content of the drinking water was found ranging between 0.02 and 2.5 mg Cu/l (median 0.22 mg Cu/l), the maternal serum copper content ranged from 770–3720 μg Cu/l (median 2275 μg Cu/l), the neonatal serum from 220 to 1930 μg Cu/l (median 500 μg Cu/l), respectively. GOT (6–33 U/l); median 14 U/l) and GPT (3–21 U/l; median 6 U/l) activities could be judged as reference range data. In the statistical analysis, an association between the copper content of the drinking water and the maternal or neonatal serum copper content could not be found. Pearson regression analysis revealed slight, yet significant correlations of the neonatal GOT and GPT activities with the maternal serum copper content (GPT: r 2 = 0.06; p<0.05; GOT: r 2 = 0.05; p<0.05; each n = 139). In addition, the copper content of the mother's serum filtrates was correlated with the newborns' serum filtrates (Spearman: r = 0.61; p<0.001; n = 30). Conclusions: The prenatal copper exposure of the infant could be mainly determined by low molecular or free serum maternal copper, which seems to be able to penetrate the placental barrier easily. The association between maternal serum copper content and neonatal transaminases activity can be judged as clinically not relevant and might be a physiologic response.

Renal hemodynamic changes in children with liver cirrhosis.

To assess the sensitivity of duplex Doppler ultrasonography in detecting early impairment of renal function in childhood cirrhosis, intrarenal arterial pulsatility index (PI) and resistive index (RI) were measured in 10 ascitic and 11 non-ascitic children with liver cirrhosis and normal creatinine clearance and 10 age- and sex-matched controls. PI and RI were higher in ascitic than non-ascitic children [PI 1.54+/-0.4 vs. 1.1+/-0.2 (mean +/- SD), P=0. 006; RI 0.76+/-0.07 vs. 0.68+/-0.07, P=0.03). Non-ascitic patients had higher PI and RI than controls (P=0.002 and 0.0001, respectively). PI was inversely correlated with creatinine clearance (r=-0.54, P=0.01). A significant positive relationship was observed between both PI and RI and Child score (r=0.47, P=0.009; r=0.45, P=0. 01, respectively). However, no significant correlation was observed between PI and RI and portal hypertension. We conclude that renal vascular resistance indexes evaluated by duplex Doppler ultrasonography are increased in the non-ascitic phase of cirrhosis. Development of ascites is associated with a further increase in these indexes. The resistance indexes are best correlated with severity of hepatocellular dysfunction, assessed by Child score, but not with portal hypertension. Hence, monitoring these indexes, especially PI, is a non-invasive means of studying early renal hemodynamic alteration in childhood cirrhosis.

Pyrrolizidine alkaloids in human diet

Pyrrolizidine alkaloids are the leading plant toxins associated with disease in humans and animals. Upon ingestion, metabolic activation in liver converts the parent compounds into highly reactive electrophiles capable of reacting with cellular macromolecules forming adducts which may initiate acute or chronic toxicity. The pyrrolizidine alkaloids present a serious health risk to human populations that may be exposed to them through contamination of foodstuffs or when plants containing them are consumed as medicinal herbs. Some pyrrolizidine alkaloids (PA) adducts are persistent in animal tissue and the metabolites may be re-released and cause damage long after the initial period of ingestion. PAs are also known to act as teratogens and abortifacients. Chronic ingestion of plants containing PAs has also led to cancer in experimental animals and metabolites of several PAs have been shown to be mutagenic in the Salmonella typhimurium/mammalian microsome system. However, no clinical association has yet been found between human cancer and exposure to PAs. Based on the extensive reports on the outcome of human exposure available in the literature, we conclude that while humans face the risk of veno-occlusive disease and childhood cirrhosis PAs are not carcinogenic to humans.

Copper.

Copper is an essential trace element, which is an important catalyst for heme synthesis and iron absorption. Following zinc and iron, copper is the third most abundant trace element in the body. Copper is a noble metal, like silver and gold. Useful industrial properties include high thermal and electrical conductivity, low corrosion, alloying ability, and malleability. Most of the metallic copper appears in electrical applications. Copper is a constituent of intrauterine contraceptive devices and the release of copper is necessary for their contraceptive effects. The average daily intake of copper in the US is about 1 mg Cu with the primary source being the diet. The bioavailability of copper from the diet is about 65-70% depending on a variety of factors including chemical form, interaction with other metals, and dietary components. The biological half-life of copper from the diet is 13-33 days with bilary excretion being the major route of elimination. Copper sulfate is a gastric irritant that produces erosion of the lining of the gastrointestinal tract. Chronic copper toxicity is rare and primarily affects the liver. Wilson's disease and Indian childhood cirrhosis are examples of severe chronic liver disease that results from the genetic predisposition to the hepatic accumulation of copper. The serum copper concentration ranges up to approximately 1.5 mg/L in healthy persons. Gastrointestinal symptoms occur at whole blood concentrations near 3 mg Cu/L. Chelating agents (CaNa2EDTA, BAL) are recommended in severe poisoning, but there are little pharmacokinetic data to evaluate the effectiveness of these agents.

Identification of a novel copper-binding protein from the liver of Indian childhood cirrhosis: purification and physicochemical characterization [corrected

A novel copper-binding protein was identified in the liver supernatant (100,000 x g) of Indian childhood cirrhosis (ICC), purified to apparent homogeneity and characterized [corrected]. Purified major copper-binding protein (MCuBP) is solely responsible for binding about 35% of the total supernatant copper. Elution profile of ICC liver supernatant on Sephadex G-75 column chromatography showed three peaks. About 60% of the total supernatant copper was resolved in peak II, whereas zinc content was insignificant in this peak. But peak II was almost missing in a gel elution profile of control liver supernatant. The control group included cases of various liver diseases viz. neonatal hepatitis, septicemia, and mixed nodular cirrhosis. Copper-binding proteins of peak II further purified on ion-exchange chromatography and elution profile showed that peak II was a MCuBP with high copper-binding capacity (10 g atoms/mol of native protein). SDS-PAGE of this protein also revealed the existence of a single band with molecular mass of about 50 kD. UV spectra of MCuBP showed the maximal absorbance at 254 nm. Unlike the classical metallothionein, the amino acid composition of MCuBP revealed the presence of aromatic amino acids and higher content of glutamic acid and aspartic acid followed by glycine and serine. The ratio (0.3) of basic amino acids to acidic amino acids strongly indicates that it is an acidic protein. The cysteine content in this protein was insignificant, which further corroborates the possibility that the acidic amino acids might be prominent candidates for binding copper. Thus, the 50-kD MCuBP apparently makes a major contribution to the total copper-binding activity in ICC liver cytosol and may play a significant role in hepatic intracellular copper accumulation.

Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease.

Recently, 138 cases of infantile cirrhosis originating in several families in the Austrian province of the Tyrol were reported. This endemic Tyrolean infantile cirrhosis (ETIC) is indistinguishable from Indian childhood cirrhosis (ICC), idiopathic copper toxicosis (ICT), and resembles the early forms of Wilson's disease (WND). It has been argued that ETIC might represent an allelic variant of the WND gene, which is a copper transporting P-type ATPase (ATP7B). Assuming that ETIC results from a founder effect, a possible role for ATP7B in ETIC was investigated by association studies and haplotype sharing. Because of its lethality, the mapping of ETIC was focused on obligate gene carriers, i.e. the patients' parents. Our data indicate that ETIC is a separate genetic entity, distinct from WND.

An animal model for copper‐associated cirrhosis in infancy

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0·5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved. Copyright © 1998 John Wiley & Sons, Ltd.

An animal model for copper-associated cirrhosis in infancy.

In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0.5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved.

Liver fibrosis in guinea pigs experimentally induced by combined copper and aflatoxin application

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administrated orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group liver damage was established. In the combined group liver injury was more frequent and more severe compared to the aflatoxin B1 group. Compared with the copper group biliary copper excretion was diminished and the kidney copper content was elevated in the Afl. B1 + Cu group. While copper concentrations in bile and kidney correlated with other parameters, notably the pathological lesions of the liver, no such correlation was found for liver copper. Therefore in this experiment the degree of Cu accumulation was not decisive for the liver lesions. The livers' capacity for excreting Cu by bile seems to be a much more important factor. Histologically only the livers of the combined group exhibited degeneration, atrophy and steatosis of liver cells, and a fibrosis more or less pronounced. For childhood cirrhosis (ICC and ICT), a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.