A diversity of equations is available for the estimation of liver volume (LV), derived from studies in populations of ethnically homogeneous individuals and using a variety of methods of measurement. The aim of this study was to integrate all published pediatric data and to define a general equation for estimating LV from birth onward. Data were collated from 5,036 subjects (birth to 18 yr old). Equations were developed based on simple regression against body surface area (BSA) and multiple regression of LV with weight, height, BSA, age, gender, race, methodology, and year of publication as covariates. These equations, together with those reported in the literature, were compared for accuracy of prediction of LV from birth to 18 yr old. The most parsimonious equation to describe LV was selected according to the Akaike information criteria (AIC), precision and bias and following visual inspection of residual errors and observed vs. predicted plots: LV = 0.722 * BSA(1.176). The multiple regression models indicated that Japanese have up to 19% larger livers compared to Caucasians for a given body weight. Radiographic and ultrasonic measurements were associated with up to 8% lower estimates of liver size compared to measurements made at autopsy. There was no evidence that gender or the year in which a study was published (1933-1999) influenced the estimation of LV. The general equation was also applied to predict adult LV, and its precision and accuracy was found to be superior to those of 10/11 published adult models. In conclusion, we have developed a more general model to predict LV in pediatric populations and young adults, and have investigated a range of covariates.

Patients with Wilson's disease (WD), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT) develop severe liver disease morphologically characterized by ballooning of hepatocytes, inflammation, cytoskeletal alterations, and Mallory body (MB) formation, finally leading to mostly micronodular cirrhosis. The pathogenesis of MBs in copper toxicosis is still unresolved. Immunohistochemical analysis of MBs in different types of copper intoxication revealed that keratin, p62, and ubiquitin are integral components. Thus MBs associated with copper intoxication resemble those present in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). p62 is a multifunctional immediate early gene product that, on the one hand, is involved in stress-induced cell signaling (particularly that of oxidative stress) by acting as an adapter protein linking receptor-interacting protein (RIP) with the atypical protein kinase C. On the other hand, p62 binds with high affinity to polyubiquitin and ubiquitinated proteins. In conclusion, p62 accumulation in WD, ICC, and ICT and deposition in MBs indicates a central role of protein misfolding induced by oxidative stress in copper-induced liver toxicity. By sequestering potentially harmful misfolded ubiquitinated proteins as inert cytoplasmic inclusion bodies (e.g., as MBs), p62 may be a major player in an important cellular rescue mechanism in oxidative hepatocyte injury.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Background: Non-Wilsonian hepatic copper toxicosis includes Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and the non-Indian disease known as idiopathic copper toxicosis (ICT). These entities resemble the hepatic copper overload observed in livers of Bedlington terriers with respect to their clinical presentation and biochemical and histological findings. We recently cloned the gene causing copper toxicosis in Bedlington terriers, MURR1, as well as the orthologous human gene on chromosome 2p13-p16.Aim: To study the human orthologue of the canine copper toxicosis gene as a candidate gene for ICC, ETIC, and ICT.Methods: We sequenced the exons and the intron-exon boundaries of the human MURR1 gene in 12 patients with classical ICC, one patient with ETIC, and 10 patients with ICT to see whether these patients display any mutations in the human orthologue of the canine copper toxicosis gene.Results: No mutations in the MURR1 gene, including the intron-exon boundaries, were identified in a total of 23 patients with non-Wilsonian hepatic copper toxicosis.Conclusions: Our results demonstrate that copper toxicosis in Bedlington terriers is not an animal model for the non-Wilsonian hepatic copper toxicosis described in this study. (C) 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.

Hepatocyte injury and necrosis from many causes may result in pediatric liver disease. Influenced by other cell types in the liver, by its unique vascular arrangements, by lobular zonation, and by contributory effects of sepsis, reactive oxygen species and disordered hepatic architecture, the hepatocyte is prone to injury from exogenous toxins, from inborn errors of metabolism, from hepatotrophic viruses, and from immune mechanisms. Experimental studies on cultured hepatocytes or animal models must be interpreted with caution. Having discussed general concepts, this review describes immune mechanisms of liver injury, as seen in autoimmune hepatitis, hepatitis B and C infection, the anticonvulsant hypersensitivity syndrome, and autoimmune polyendocrinopathy. Of the monogenic disorders causing significant liver injury in childhood, alpha-1 antitrypsin deficiency and Niemann-Pick C disease demonstrate the effect of endoplasmic or endosomal retention of macromolecules. Tyrosinemia illustrates how understanding the biochemical defect leads to understanding cell injury, extrahepatic porphyric effects, oncogenesis, pharmacological intervention, and possible stem cell therapy. Pathogenesis of cirrhosis in galactosemia remains incompletely understood. In hereditary fructose intolerance, phosphate sequestration causes ATP depletion. Recent information about mitochondrial disease, NASH, disorders of glycosylation, Wilson's disease, and the progressive familial intrahepatic cholestases is discussed.

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 µ/g), in contrast to the island sheep, although 10 sheep with increased liver copper (mean 600 SD 270 µ/g) showed no evidence of liver damage. A further 10 sheep with liver copper (mean 1276 SD 508 µg/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 µg/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. Copyright © 2001 John Wiley & Sons, Ltd.

Jaundice persisting beyond the first 2 wk of life is often regarded as an indication for investigation to exclude cholestatic liver disease. Most babies with prolonged jaundice have breast milk‐related jaundice, which is a benign condition. Cholestatic liver disease is usually accompanied by pale stools and yellow or orange urine. A community programme was established to ascertain the incidence of prolonged jaundice and determine whether abnormal stool and urine colour could be used to assist primary care staff in referral decisions. Data were collected on normal stool and urine colour and used to devise a colour chart and information sheet for parents. Babies with prolonged jaundice were identified and referred for investigation. In all, 3661 babies were recruited into the study, of which 127 were jaundiced at 28 d of age. Of these, 125 were breastfed. The incidence of jaundice in breastfed babies at 28 d was 9.2% (95% CI 7.8%‐11.0%) Abnormal liver function tests (LFTs) were common, but no baby had abnormal stool or urine colour and none was found to have liver disease. Jaundiced breastfed babies who are well are unlikely to have serious disease. Elevated LFTs are compatible with a diagnosis of breast milk‐related jaundice. Prolonged jaundice in bottle‐fed babies, and persistent pallor of stools or yellow/orange urine, are rare and merit immediate referral. Parents and professionals can be advised to report pale stools without generating a large number of unnecessary referrals. Further work is needed to determine whether a colour chart reduces the mean age of referral and treatment of infants with cholestatic liver disease. □Breast milk jaundice, hyperbilirubinaemia, jaundice, liver function tests, stool colour

Several recent studies have indicated that an increased concentration of plasma homocysteine is an independent risk factor for the premature development of vascular disease. These important findings emphasize the need for careful selection of an appropriate analytical approach to diagnose and treat individuals who may be at risk. We compared the results obtained from the measurement of plasma total homocysteine (free + protein-bound fractions) by high-performance liquid chromatography (HPLC) with the measurement of plasma free homocystine (free fraction) by conventional ion-exchange chromatography in 10 patients with inherited defects of homocysteine metabolism and 13 obligate heterozygote individuals. This study can be used to formulate recommendations on the appropriate use of these assays in different clinical circumstances. Our results show that the concentration of total plasma homocysteine must exceed 60 mumol/L before plasma free homocystine becomes detectable by conventional ion-exchange chromatography. Similarly, assessment of the urinary excretion of homocysteine in these patients indicates that it may not become consistently detectable by conventional ion-exchange chromatography or HPLC until plasma total homocysteine exceeds 150 mumol/L. On this basis, while most patients with classical homocystinuria would be detected by analysis of plasma using conventional ion-exchange chromatography or by measurement of of the urinary homocysteine excretion, occasional patients would be missed. When monitoring patients receiving treatment for classical homocystinuria, in whom metabolic control is good, and when investigating individuals with a suspected inherited defect of cobalamin or folate metabolism, a method which measures plasma total homocysteine should be used. The identification of moderate hyperhomocysteinaemia of undefined cause investigated in relation to a history of early vacsular disease can only be identified by this approach.

Indian Childhood Cirrhosis (ICC) (Tanner 1997) and Tyrolean Childhood Cirrhosis (TCC) (Muller et al 1996) have both now virtually disappeared. In ICC, and putatively in TCC, greatly increased levels of ingested dietary copper in infancy were associated with greatly increased hepatic copper concentrations and, hence, cirrhosis. Cessation of this feeding habit has been associated with disappearance of the disease in each case.

Thirty-three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary orotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0μmol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0μmol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl-phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.

Journal of Inherited Metabolic DiseaseVolume 22, Issue 1 p. 88-89 Article Normal acylcarnitines in maternal urine during a pregnancy affected by glutaric aciduria type II N. J. Manning, N. J. Manning Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorJ. R. Bonham, J. R. Bonham Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. Downing, M. Downing Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorR. G. Edwards, R. G. Edwards Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorS. E. Olpin, S. E. Olpin Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorR. J. Pollitt, R. J. Pollitt Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. Pourfarzam, M. Pourfarzam Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorM. J. Sharrard, M. J. Sharrard Department of Paediatrics, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. S. Tanner, M. S. Tanner Department of Paediatrics, The Children's Hospital, Sheffield, UKSearch for more papers by this author N. J. Manning, N. J. Manning Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorJ. R. Bonham, J. R. Bonham Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. Downing, M. Downing Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorR. G. Edwards, R. G. Edwards Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorS. E. Olpin, S. E. Olpin Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorR. J. Pollitt, R. J. Pollitt Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. Pourfarzam, M. Pourfarzam Department of Child Health, The Royal Victoria Infirmary, Newcastle upon Tyne, UKSearch for more papers by this authorM. J. Sharrard, M. J. Sharrard Department of Paediatrics, The Children's Hospital, Sheffield, UKSearch for more papers by this authorM. S. Tanner, M. S. Tanner Department of Paediatrics, The Children's Hospital, Sheffield, UKSearch for more papers by this author First published: 01 February 1999 https://doi.org/10.1023/A:1005467803802Citations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume22, Issue1February 1999Pages 88-89 RelatedInformation

Of the cirrhoses that affect Indian children, Indian childhood cirrhosis (ICC) is a discrete clinical and histologic entity in which large amounts of copper are deposited in the liver. The evidence linking copper deposition to increased dietary copper intake in infancy was reviewed. 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%. Long-term survivors show a sequence of histologic resolution, resulting either in inactive micronodular cirrhosis or in virtually normal histologic appearance. Twenty-nine treated ICC patients reexamined at 8.8 y of age (range: 6.3-13 y), 5-12 y after diagnosis, were well and had normal results from liver function tests. 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 adults suggests that other etiologic factors contribute. 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. Although ICC is now rare, sporadic cases of an ICC-like disorder in infants continue to occur. There should be a greater awareness among pediatricians of this disease to enable early diagnosis. Penicillamine should be used early and adverse prognostic factors recognized as indications for early transplantation and unregulated water supplies should not be used to prepare infant feeds.

We previously demonstrated decreased metallothionein (MT) synthesis in cultured fibroblasts obtained from an American boy with findings typical of Indian Childhood Cirrhosis (ICC). We now report normal basal, copper-induced, and zinc-induced MT synthesis in the fibroblasts of two Indian boys and one Irish boy with typical ICC and one Indian boy with copper-associated childhood cirrhosis. This suggests that etiologies other than impaired MT production should be sought as the primary defect in these disorders.

Two fatal cases of invasive pneumococcal disease in the newborn are reported, both acquired from the maternal vagina. The rarity of vaginal carriage of pneumococcus suggests that this organism has a higher invasion to colonisation ratio than group B streptococcus and maternal carriage or neonatal colonisation should be more aggressively treated.