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OBJECTIVES: Describe clinical characteristics, management, and outcome in a cohort of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) patients. METHODS: We conducted a retrospective chart review of MMIHS patients followed at a large transplant and intestinal rehabilitation center over a period of 17 years. RESULTS: We identified 25 patients with MMIHS (68% girls, 13 transplanted). One transplanted and 1 nontransplanted patient were lost to follow-up. We estimated 100, 100, and 86% for 5-,10-, and 20-year survival, respectively, with only 1 death. Of the 22 patients alive at the time of study (11 transplanted, 11 nontransplanted), median age was 9.2 years (range 2.7–22.9 years). Longest posttransplant follow-up was 16 years. Seventeen patients had available prenatal imaging reports; all showed distended bladder. Eight had genetic testing (5, ACTG2; 2, MYH11; 1, MYL9). Almost all patients had normal growth with median weight z-score −0.77 (interquartile range −1.39 to 0.26), height z score −1.2 (−2.04 to −0.48) and body mass index z-score 0.23 (−0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients. All nontransplanted patients were on parenteral nutrition with minimal/no feeds, and all except 1 of the transplanted patients were on full enteral feeds. Recent average bilirubin, INR, albumin, and creatinine fell within the reference ranges. CONCLUSIONS: This is the largest single-center case series with the longest duration of follow-up for MMIHS patients. In the current era of improved intestinal rehabilitation and transplantation, MMIHS patients have excellent outcomes in survival, growth, and liver function. This observation contradicts previous reports and should alter counselling and management decisions in these patients at diagnosis.

Transplantation of the intestine in children has presented significant challenges even as it has become a standard to treat nutritional failure due to short gut syndrome. These challenges have been addressed in part by significant improvements in short and long-term care. Noteworthy enhancements include reduced need for intestine transplantation, drug-sparing immunosuppressive regimens, immune monitoring, and improved surveillance and management of PTLD and non-adherence.

Three distinct forms of familial intrahepatic cholestasis are the result of mutations in the ATP8B1, ABCB11, and ABCB4 genes. The pathophysiologies of the latter 2 of these diseases are well characterized and are the result of abnormalities in canalicular excretion of bile acids and phospholipids, respectively. The molecular pathophysiology of the systemic disease associated with mutations in ATP8B1 remains unclear. In all of these diseases, wide variations in clinical phenotypes have been observed. The variability can be ascribed at least in part to predicted genotype:phenotype correlations. Disease- and genotype-specific prognoses and therapeutic approaches may exist, although much more information needs to be ascertained before clinicians can confidently make decisions based on genetic information.

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.

Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21 , CCL5 , GNLY , SLAMF7 , TGFBR3 , NKG7 , SYNE1 , and GK5 . Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14 + monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5 + CD14 + monocytes and intragraft CD14 + monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154 + T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14 + monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14 + macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14 + macrophages may predict rejection events.

The nucleotide-binding oligomerization protein 2 (NOD2) gene single nucleotide polymorphisms (SNPs) associated with Crohn's disease were recently associated with severe rejection after small-bowel transplantation (SBTx). The purpose of this study was to re-test this association and explore whether deficient innate immunity suggested by the NOD2 SNPs predisposes to intestine failure requiring isolated SBTx or combined liver-intestine failure requiring combined liver-SBTx (LSBTx).Archived DNA from 85 children with primary isolated SBTx or LSBTx was genotyped with Taqman biallelic discrimination assays. To minimize confounding effects of racial differences in minor allele frequencies (MAFs), allelic associations were tested in 60 Caucasian recipients (discovery cohort). Replication was sought in an independent cohort of 39 Caucasian pediatric and adult SBTx patients.MAF for rs2066845 and rs2066847 was similar to that seen in 538 healthy North American Caucasians. In the discovery cohort, MAF for rs2066844 was significantly higher in LSBTx (13.5 vs. 3.6%, P=0.0007, Fisher's exact test), but not in isolated SBTx recipients (2.2 vs. 3.6%, P=NS), when compared with 538 healthy Caucasians. In addition, among LSBTx recipients who received identical immunosuppression, the minor allele of rs2066844 associated with early rejection in linear regression analysis (P=0.028) (all but one of the risk alleles were found in rejectors), decreased survival (P=0.015, log-rank, Kaplan-Meier analysis), and a 20-fold greater hazard of septic death in proportional hazard analysis (P=0.030). Steroid-resistant (severe) rejection and graft loss were associated with isolated SBTx (P=0.036 and 0.082, respectively), but not with NOD2 SNPs. The association between rs2066844 and combined liver-intestine failure requiring LSBTx was significant in the replication cohort (P=0.014), and achieved greater significance in the combined cohort (P=0.00006).The NOD2 SNP rs2066844 associates with combined liver and intestinal failure in subjects with short-gut syndrome, who require combined liver-intestine transplantation, and secondarily with early rejection and septic deaths.

Fulminant hepatic failure (FHF) accounts for 10-15% of pediatric liver transplants in the USA annually. Because the onset of FHF may be the first presentation of Wilson's disease (WD) and autoimmune hepatitis (AIH) in previously asymptomatic adolescents, determination of the etiology of FHF is critical as treatment and prognosis differ between these two entities. Patients with AIH may be salvaged by medical treatment. On the contrary, liver transplantation is currently the only life saving therapeutic option available for patients with WD who present with fulminant liver failure. To establish the diagnosis of WD and AIH in the setting of FHF remains challenging for diagnosticians and decisions regarding liver transplantation may be necessary before a diagnosis is firmly established. We report a previously asymptomatic patient who presented with FHF and clinical and laboratory features suggestive of both WD and AIH and who underwent successful therapeutic liver transplantation before the diagnosis of WD could be confirmed.