Hepatic steatosis, steatohepatitis, and chemotherapy-related liver injury

Fatty liver disease

NAFLD comprises nonalcoholic fatty liver (NAFL), also known as “simple steatosis,” and nonalcoholic steatohepatitis (NASH) (see Chapter 74 ). Grossly, a fatty liver is characterized by hepatomegaly, yellow appearance, and rounded edges ( Fig. 69.1A ). Hepatic steatosis is defined as abnormal macrovesicular or microvesicular triglyceride accumulation in at least 5% of hepatocytes diagnosed histologically or by radiologic imaging. NAFL was traditionally thought of as a benign condition with a low likelihood of progression to NASH and associated fibrosis. ^{, ,} However, several studies dispute whether NAFL and NASH represent a spectrum of FLD (i.e., progression from steatosis to steatohepatitis) or distinct diseases. Moreover, although progression is more rapid in NASH, patients with NAFL (including those with inflammatory components insufficient for a NASH diagnosis) can also experience fibrosis progression. ^{, ,}

NASH encompasses a pattern of injury characterized by hepatic steatosis, lobular inflammation, and hepatocyte ballooning with or without associated fibrosis ( Fig. 69.2A ). In adults, the initial injury usually occurs in the perivenular (zone 3) portion of the hepatic acinus, which is the least oxygenated and most prone to free radical–mediated injury. This is in contrast to other chronic liver diseases in which marked portal inflammation is observed early in the disease course. However, with worsening disease, the injury may progress to all zones. Ballooning injury, a requirement for the diagnosis of NASH, is a condition in which hepatocytes become enlarged and the cytoplasm becomes irregularly clumped with clear, nonvesiculated areas with or without residual fat droplets. ^, Borderline steatohepatitis includes some but not all of these features. The most common standardized method for evaluating NASH is a validated histologic scoring system developed by the Pathology Committee of the NASH Clinical Research Network. This NAFLD activity score (NAS) includes potentially reversible features of steatohepatitis, including steatosis (score 0–3), lobular inflammation (0–3), and hepatocyte ballooning (0–2). A total NAS of 5 or greater correlated with the diagnosis of steatohepatitis. ^, Importantly, NASH diagnosis should be made based on a recognized pattern of liver injury and not simply by a numerical score. Recent studies demonstrate that using a particular NAS threshold missed 40% to 45% of patients with steatohepatitis as diagnosed by experienced hepatobiliary pathologists and that NAS thresholds were not correlated with liver-related mortality.

Early liver fibrosis and cirrhosis is commonly associated with NASH (see Chapters 7 and 74 ). Early characteristic patterns of fibrosis that are due to NASH include delicate collagen strands that may isolate one or more hepatocytes (see Fig. 69.2B ) and perisinusoidal “chicken-wire” fibrosis. In more advanced stages, periportal fibrosis may occur with possible progression to bridging fibrosis. Of patients with NASH, 25% to 30% have advanced fibrosis on diagnosis, 10% to 15% of which have cirrhosis. Moreover, fibrosis progression has been noted on serial biopsies in 25% to 37% of cases with older age and greater body mass index (BMI) at diagnosis risk factors for this fibrosis progression. ^, Importantly, many of the histologic features of NASH disappear when advanced fibrosis or cirrhosis develops, a finding known as “burned out” NASH. ^{, ,} Given the similarities in the profile of metabolic syndrome elements observed in several studies between patients with NAFLD and cryptogenic cirrhosis, it is widely thought that as many as 50% to 70% of traditionally diagnosed cryptogenic cirrhosis can be ultimately traced back to NASH. ^{, , ,}

Importantly, FLD has many causes that may synergistically augment background liver injury. Potential risk factors include alcohol use, elements of the metabolic syndrome, hereditary disorders, and drug-induced injury, particularly from chemotherapeutics. There are few reliable, consistent histologic criteria that differentiate between causes of FLD. ^, For inclusion in clinical trials and cohort studies, the consumption threshold used to define the nonalcoholic nature of FLD is arbitrarily set at fewer than 21 and 14 drinks per week for men and women, respectively. Yet because patients often experience multiple insults, FLD should be considered one histopathologic injury with multiple nonexclusive causes that may synergistically augment liver injury.