Parvathi Mohan

Pathology of chronic hepatitis C in children: Liver biopsy findings in the Peds‐C Trial

There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds‐C Trial, designed to test the efficacy and safety of peginterferon alfa‐2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment‐naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non‐overweight. In conclusion, in this cohort of HCV‐infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment‐naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors. (HEPATOLOGY 2007.)

The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C

BACKGROUND & AIMS Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C. METHODS HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy). RESULTS SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups. CONCLUSIONS The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.

Safety, efficacy and pharmacokinetics of peginterferon α2a (40 kd) in children with chronic hepatitis C

Chronic hepatitis C virus (HCV) infection in children is a problem affecting thousands of children worldwide. Although standard interferon (INF) has better efficacy in pediatric patients than in adults, results in children with genotype 1 are poor; response rates to combination treatment with standard INF and ribavirin are better but the treatment requires thrice-weekly injections. The improved antiviral efficacy of weekly pegylated interferons relative to standard interferons in adults with chronic HCV infection suggests that pegylated interferons may also improve antiviral efficacy in children. We therefore investigated the pharmacokinetics, efficacy and safety of peginterferon &agr;2a (pegINF-&agr;2a) (40 kd) in 14 children ages 2 to 8 years with chronic hepatitis C (13 genotype 1, 1 non-1 genotype). Drug dose was calculated from each patients body surface area (BSA) according to the formula BSA (m2)/(1.73 m2) × 180 &mgr;g, and patients were administered once-weekly subcutaneous injections for 48 weeks. Viral load and pharmacokinetic parameters were determined from blood drawn throughout the study and during follow-up. At week 24, the mean trough concentration was about 20% below values obtained from adults treated with pegINF-&agr;2a, and the area under the curve from 0 to 168 hours was about 20% above adult values, suggesting that drug doses calculated from BSA achieved therapeutically adequate concentrations. Six of 14 patients (43%), all infected with genotype 1, achieved a sustained virological response. Adverse events were those commonly associated with INF-based treatment, and none was deemed serious. In conclusion, our findings provide a basis for larger studies evaluating the efficacy and safety of pegINF-&agr;2a as monotherapy as well as in combination with ribavirin in pediatric patients with chronic hepatitis C.

Characteristics of Congenital Hepatic Fibrosis in a Large Cohort of Patients With Autosomal Recessive Polycystic Kidney Disease

BACKGROUND & AIMS Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patients height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.

Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C.

Hepatitis C virus (HCV) infection is a global health problem affecting 170 million individuals worldwide. In the United States, there are approximately 7 million adults and 100,000 children chronically infected with HCV (1,2). The importance of HCV infection stems from its proclivity to cause insidious liver damage over many years, including chronic hepatitis, cirrhosis, and liver cancer. In adults, HCV infection is a leading cause for liver cancer worldwide (3). The financial burden of this viral infection is staggering, with projected medical costs of

Choline intake in a large cohort of patients with nonalcoholic fatty liver disease

10.7 billion in adults from 2010 to 2019 and approximately

Pegylated interferon for chronic hepatitis C in children affects growth and body composition: results from the pediatric study of hepatitis C (PEDS-C) trial

426 million during the next 10 years in children (4,5). The epidemiology, clinical outcome, and risk factors associated with progression of HCV-related liver disease are fairly well characterized in adults. Although the natural history of childhood HCV infection is poorly defined, it appears to be an indolent disease in most children (6–13); however, progressive liver disease, including chronic hepatitis and cirrhosis necessitating liver transplantation, can occur in children (14,15). Unlike in adults, liver cancer, particularly hepatocellular carcinoma (HCC), is rare in children (16), but it was described in 2 young adults infected with HCV during childhood (17). Herein we extend these observations and present 2 children with chronic hepatitis C who developed HCC as adolescents. To our knowledge, they are the

Long-term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety

BACKGROUND There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency. OBJECTIVE We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features. DESIGN We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicines definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI. RESULTS Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women. CONCLUSION Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635.

Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: A retrospective study

Weight loss and changes in growth are noted in children treated with interferon alpha (IFN‐α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha‐2a (Peg‐IFN‐α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS‐C) trial underwent anthropometric measurements, dual‐energy X‐ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5‐unit decrement in height‐for‐age z (HAZ) score. Though weight‐for‐age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post‐therapy for the long‐treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat‐free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. Conclusions: Peg‐IFN‐α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV. (HEPATOLOGY 2012)