This is a comprehensive guidance on the diagnosis, evaluation, and management of ascites and hepatorenal syndrome in patients with chronic liver disease from the American Association for the Study of Liver Diseases (AASLD). It replaces the prior AASLD guideline on the same topic published in 2012 (1).This AASLD Guidance provides a data-supported approach to the management of ascites and hepatorenal syndrome. It differs from AASLD Guidelines, which are supported by systematic reviews of the literature, formal rating of the quality of the evidence and strength of the recommendations. In contrast, this Guidance was developed by consensus of an expert panel and provides guidance statements based on comprehensive review and analysis of the literature on the topics, with oversight provided by the AASLD Practice Guidelines Committee. The AASLD Practice Guidelines Committee chose to perform a Guidance on this topic because a sufficient number of randomized controlled trials were not available to support meaningful systematic reviews and meta-analyses. A. Introduction Burden of Cirrhotic Ascites and Hepatorenal SyndromeHepatic decompensation, defined by ascites, hepatic encephalopathy, and portal hypertensive gastrointestinal bleeding, is an important landmark in the natural history of cirrhosis (2). Ascites is commonly the first decompensation-defining event, with 5%-10% of patients with compensated cirrhosis developing ascites per year (3). The development of ascites is associated with a reduction in 5-year survival from 80% to 30% (4), which is due in part to patients with ascites being prone to additional complications such as bacterial infections, electrolyte abnormalities, hepatorenal syndrome (HRS) and nutritional imbalances, and consequently, further clinical decline (5). Patients with cirrhosis who develop clinically significant ascites and related complications should be considered for referral for liver transplantation (LT) evaluation and, where appropriate, palliative care (6).HRS is a late complication of cirrhosis that accounted for 3.2% of all hospital discharges related to cirrhosis according to a 2012 study based on a large inpatient health care database of patients representative of community hospitals in the United States (4). Moreover, the number of HRS discharges in the United States has increased significantly in the past 2 decades (7). HRS was also associated with high inpatient mortality (~46%), as well as longer lengths of stay and higher costs of hospitalizations, compared to cirrhosis discharges without HRS.

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12‐17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8‐16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon‐based regimens. The primary PK endpoint was steady‐state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on‐treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on‐treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

The need for a universal consensus on the definition of CFLD to clarify disease stage and to identify relevant biomarkers to assess disease severity was highlighted. A deeper understanding of the pathophysiology and prognostic factors for the long-term evolution of CFLD is fundamental to move forward and has a strong bearing on identifying potential treatments. Novel experimental models and new treatment options under investigation are discussed and offer hope for the near future of CFLD.

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A randomized, double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition, with particular reference to linear growth. One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka, Bangladesh, and randomly assigned to receive elemental zinc by mouth, 1.5 mg/kg for 15 d, 6.0 mg/kg for 15 d, or 6.0 mg/kg for 30 d, and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length, midupper arm circumference, subscapular and triceps skinfold thicknesses, and change in height-for-age, weight-for-age, and weight-for-height z scores. Higher zinc doses were not associated with significant change in any anthropometric measurement, but mortality was significantly greater in children who received high-dose zinc (6.0 mg/kg) initially as opposed to those who received low-dose zinc supplementation (1.5 mg/kg) (Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53; 95% CI: 1.09 < risk ratio < 18.8). We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children.

The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.