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Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we used data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA. In all, 289 infants who were enrolled in the prospective database prior to surgery at any of 15 participating centers were evaluated. Group 1 was nonsyndromic, isolated BA (without major malformations) (n = 242, 84%), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal, and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24%) anomalies; interestingly, this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%).This study identified a group of BA (Group 2) that differed from the classical syndromic and nonsyndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome.

Objectives To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. Study design Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB Results Fifty percent (68/137) of infants had TB P P P P P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P P Conclusions Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB Trial registration ClinicalTrials.gov: NCT00061828 and NCT00294684.

Elongated, enlarged mitochondria with crystalloid matrix arrays were discovered in periportal hepatocytes in 11 of 12 children (age 6 to 15 years) with portal hypertension, minimal alterations on light microscopy, and cavernous transformation of the portal vein. Eleven of the children were clinically well before onset of symptoms, one was anemic with megaloblastic bone marrow, and a second had undergone renal transplantation. Minimal findings by light microscopy included slight portal fibrosis (six cases), pericentral venular fibrosis (one case), mild, patchy sinusoidal sclerosis (one case), central venular and sinusoidal dilatation (two cases), and mild hepatocellular lipid accumulation (one case). Four were judged normal by routine histologic examination. Subtle depletion of periportal hepatocellular glycogen was present in six. In 10, subtle striation or granularity of periportal hepatocyte cytoplasm was visible with high-magnification light microscopy. Although similar mitochondria are seen sporadically in hepatocytes in diverse settings, enlarged mitochondria with crystalloid matrix inclusions have not been previously reported as a uniform feature in children with portal hypertension due to cavernous transformation of the portal vein and minimal other hepatic alteration. It is postulated that the mitochondria are adapting in response to an abnormal metabolic milieu created by hemodynamic alterations.

• Background.— Granuloma annulare is a common skin condition usually presenting as annular plaques composed of intradermal papules. Variants such as disseminated, subcutaneous, and perforating have been described. In this article, the clinical and histologic features of a distinct papular umbilicated form of granuloma annulare are described. Observations.— Four boys aged 5 to 9 years presented with papular, umbilicated, flesh-colored papules limited to the dorsa of the hands and fingers. Histologically there were unusually distributed but typical features of granuloma annulare, including well-demarcated areas of necrobiosis of collagen, localized beneath areas of epidermal thinning and parakeratosis. There was no perforation. Conclusions.— Papular umbilicated granuloma annulare appears to be a distinct variant that may be difficult to diagnose because of its unique clinical and histologic features. (Arch Dermatol.1992;128:1375-1378)