The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and “not SH” in 22%. The NAS was ≥5 in 50% and ≤4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS ≥5, whereas 28% of borderline SH and 7% of “not SH” biopsies had NAS ≥5. Of biopsies with an NAS ≥5, 86% had SH and 3% “not SH”. NAS ≤4 did not indicate benign histology; 29% had SH and only 42% had “not SH.” Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome. Conclusion: The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account. (Hepatology 2011)

Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease (NAFLD) are measured. Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD, i.e. nonalcoholic steatohepatitis (NASH) and fibrosis. Included in the lesions of NAFLD are steatosis, lobular and portal inflammation, hepatocyte injury in the forms of ballooning and apoptosis, and fibrosis. However, patterns of these lesions are as distinguishing as the lesions themselves. Liver injury in adults and children due to NAFLD may have different histological patterns. In this review, the rationale for liver biopsy, as well as the histopathological lesions, the microscopically observable patterns of injury, and the differential diagnoses of NAFLD and NASH are discussed.

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.)

One hundred fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long‐term clinical follow‐up study; patients were followed for 5 years for liver‐related outcomes and evidence of biochemical or virologic relapse. Patients with stage 2 or greater fibrosis on pretreatment biopsy were invited to undergo a long‐term follow‐up biopsy after their fourth year of follow‐up. One hundred twenty‐eight patients (85%) were followed through their fourth year, and long‐term follow‐up biopsies were obtained from 60 patients (40%). Forty‐nine patients had paired pretreatment and long‐term follow‐up biopsies blindly rescored. Forty of these patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on long‐term follow‐up biopsy. Two patients with pretreatment cirrhosis developed hepatocellular carcinoma (HCC), and one died. All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long‐term follow‐up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase levels; two of these had new liver disease. Conclusion: In a cohort of 150 patients with SVR followed for 5 years, the majority of patients had good outcomes. Serum virologic relapse was not seen, but two patients with pretreatment cirrhosis developed HCC, and one died. In a blind rescoring of 49 paired pretreatment and long‐term follow‐up biopsies, 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver tissue on long‐term follow‐up biopsy. Patients with cirrhosis pretreatment are at a low but real risk of HCC after SVR. (HEPATOLOGY 2009.)