Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P ‫؍‬ .009), hepatocellular ballooning (P ‫؍‬ .0001), lobular inflammation (P ‫؍‬ .0001), fibrosis (P ‫؍‬ .0001), and the absence of lipogranulomas (P ‫؍‬ .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of >5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH." (HEPATOLOGY 2005;41:1313-1321

The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P ‫؍‬ .87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P ‫؍‬ .0001). An ␣-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < 6.5 cm, or < 3 nodules with the largest lesion < 4.5 cm and total tumor diameter < 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P ‫؍‬ .0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT. (HEPATOLOGY 2001;33:1394-1403.)Orthotopic liver transplantation (OLT) is a rational therapeutic option for patients with hepatocellular carcinoma (HCC), because it addresses the multifocal potential of HCC in many patients that limits the success and applicability of resection, and also treats the underlying liver disease. The early experience of OLT for HCC in unselected patients included those with extensive and bulky tumors, and was associated with a dismal outcome primarily as a result of aggressive tumor recurrence after OLT. 1,2 The observation that small HCC discovered incidentally at the time of pathologic examination of the explanted liver had a much lower recurrence rate after OLT 1,2 provided the impetus for subsequent studies evaluating OLT mainly for patients with small HCC. [3][4][5][6] In a study by Bismuth et al., 3 the subgroup of patients with no more than 3 tumor nodules and none greater than 3 cm in greatest diameter had a 3-year disease-free survival of 83% with OLT, compared with only 18% treated by resection. In a subsequent study by Mazzaferro et al., 5 35 patients with a solitary tumor not exceeding 5 cm or no more than 3 tumors with none greater than 3 cm had excellent overall and recurrence-free survival rates of 85% and 92%, respectively, at 4 years after OLT. In the report by Figueras et al.,6 the 5-year survival rate for OLT in 38 patients with small HCC not exceeding 5 cm in maximal diameter was 7...

No abstract

Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally-graded biopsies and temporally-related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with "more than mild" in adults were older age (P < 0.0001), female gender (P ‫؍‬ 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P ‫؍‬ 0.001), higher homeostasis model assessment of insulin resistance score (HOMA-IR) (P < 0.0001), and medications used for NAFLD (P ‫؍‬ 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). "More than mild" in the pediatric biopsies correlated with younger age (P ‫؍‬ 0.01), but not with body mass index, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with "more than mild" were steatosis amount (P ‫؍‬ 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, "more than mild" was associated with steatosis location (P ‫؍‬ 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009;49:809-820.)

BACKGROUND Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in HIV-infected patients due to reportedly poor outcomes. METHODS This prospective U.S. multicenter cohort study compared patient and graft survival in 89 HCV-HIV coinfected versus 2 different controls groups: 235 HCV monoinfected LT controls and all U.S. transplant recipients ≥65 years. RESULTS The 3-year patient and graft survival rates (95% CI) were 60% (47–71%) and 53% (40–64%) in HCV-HIV versus 79% (72–84%) and 74% (66–79%) in HCV recipients (both p<0.001) and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among HCV-HIV patients, older donor age (HR=1.3 per decade), combined kidney-LT (HR=3.8), HCV-positive donor (HR=2.5), and body mass index (BMI) less than 21 kg/m2 (HR=3.2) were independent predictors of graft loss. In patients without these latter 3 factors, patient and graft survival were similar to those in U.S. LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher in HCV-HIV versus HCV (log rank p=0.02) but cumulative incidence of severe HCV disease (29% versus 23% at 3 years, respectively) were not significantly different (p=0.21). CONCLUSIONS Patient and graft survival are lower in HCV-HIV compared to HCV alone LT patients. Importantly, rates of treated acute rejection but not HCV disease severity are significantly higher in HCV-HIV compared to HCV recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients but recipient and donor selection as well as management of acute rejection strongly influence outcomes.