The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).

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. (Liver Transpl 2005;12:1481-1493.)

To assess the prevalence, demography, and clinical features of liver disease among patients with cystic fibrosis the case notes of 524 patients of ali ages who were attending the cystic fibrosis clinic were studied. Computer databases were used to establish the condition of the liver in a further 576 such patients. The overall prevalence of overt liver disease indicated by the presence of an enlarged liver or spleen (or both) was 4-2%. The age related prevalence rose to a peak in adolescence, and then feli in patients over 20 years old. The implied increase in mortality among those with liver disease was not explained by deaths from liver disease, which were rare. Male patients were significantly more affected than female, the ratio being 3:1 among adolescents. Increasing prevalence of liver disease in patients with cystic fibrosis is, therefore, not just a result of longevity.

Aims To investigate the effects of age and disease states on the expression and activity of intestinal CYP3A4 in a paediatric population. Methods Duodenal biopsies and surgical sections were collected from 104 paediatric patients (age range 2 weeks to 17 years) and from 11 foetuses. An S9 fraction was prepared in each case. CYP3A4 expression was assessed by Western blotting and by immunohistochemistry; activity was measured by the rate of formation of 6b-hydroxytestosterone from testosterone. Villin expression was used as a marker of enterocyte harvest to normalize CYP3A4 expression and activity data. Results In the 74 histologically normal paediatric biopsies there were statistically signi®cant increases in CYP3A4 expression (r 2 =0.19, P=0.001) and activity (r 2 =0.17, P=0.02) with age. CYP3A4 was practically absent in fetal duodenum and was expressed at relatively low levels in neonates (P<0.05 between neonates and children >5 years). Active coeliac disease resulted in signi®cant (P<0.001) decreases in CYP3A4 expression and activity. Conclusions Duodenal CYP3A4 is present at signi®cantly lower levels in neonates and in patients with active coeliac disease. This may have clinical signi®cance with respect to the oral bioavailability of CYP3A4 substrates.

Progressive familial intrahepatic cholestasis (PFIC; OMIM 211600) is the second most common familial cholestatic syndrome presenting in infancy. A locus has previously been mapped to chromosome 18q21-22 in the original Byler pedigree. This chromosomal region also harbors the locus for benign recurrent intrahepatic cholestasis (BRIC) a related phenotype. Linkage analysis in six consanguineous PFIC pedigrees from the Middle East has previously excluded linkage to chromosome 18q21-22, indicating the existence of locus heterogeneity within the PFIC phenotype. By use of homozygosity mapping and a genome scan in these pedigrees, a locus designated "PFIC2" has been mapped to chromosome 2q24. A maximum LOD score of 8.5 was obtained in the interval between marker loci D2S306 and D2S124, with all families linked.

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.

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