Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging TreatmentHistopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Introduction
Chronic liver diseases and cirrhosis are the 12th leading cause of death in the United States [1]. Within this category, the subgroup of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing in the United States, as well as in the rest of the developed world, concurrent with the global rise in obesity and diabetes. NAFLD is an all-encompassing term for the spectrum of liver diseases linked by the common central feature of steatosis. In adults, NAFLD is typically classified into two categories: nonalcoholic steatohepatitis (NASH), a progressive liver disease characterized by a particular pattern of steatosis, inflammatory changes and hepatocellular injury and steatosis without features of NASH, which we term nonalcoholic fatty liver (NAFL) [2]. This latter category, often termed “simple steatosis”, may have inflammation and other features of injury. While NAFL has been generally considered a benign condition, NASH is a progressive disease that can advance to liver cirrhosis and hepatocellular carcinoma [3], [4], [5]. Nevertheless, it is likely that some cases of NAFL do progress to NASH and the risk factors for progress are incompletely understood [6], [7]. The classification of NAFL and NASH may seem straightforward, but there remains variation among pathologists when diagnosing NASH. The goal of this review is to provide information on histology, pathophysiology, and diagnostic clues for diagnosing NASH. Additionally, scoring tools for assessing the severity of NASH will be reviewed, as well as special situations in which the diagnosis may be especially problematic (e.g., pediatric cases).
Up until 1980, when Ludwig and colleagues originally coined the term nonalcoholic steatohepatitis (to differentiate it from alcoholic steatohepatitis) the pattern of liver injury in biopsies “caused clinicians to persevere unduly in their attempts to wrench from the patient an admission of excessive alcohol intake or to obtain a confirmation of such habits from relatives of the patient” [8]. They examined biopsies taken from 20 patients evaluated at the Mayo Clinic over a 10-year period. These patients had histologic evidence suggestive of alcoholic hepatitis on liver biopsy (i.e., steatosis, lobular inflammation, ballooning injury and Mallory-Denk bodies) but no history of alcohol abuse. Many of these patients were female (60%) and the majority were obese (90%). Since then, studies have shown that NASH is common disorder and an increasingly frequent reason for liver transplantation [9]. In addition to the liver disease itself, NASH is also strongly associated with coronary artery disease and metabolic syndrome (diabetes mellitus type 2, insulin resistance, central obesity, dyslipidemia, and hypertension) [10].
Section snippets
Histopathology
In most cases the histological features of NAFLD are indistinguishable from those of alcohol induced liver disease and so the pathologist must rely on the clinician to exclude alcohol use as an etiology. For diagnostic purposes, pathologists divide NAFLD into NAFL (predominantly macrovesicular steatosis with or without non-specific inflammation) and NASH. The histologic features of NASH include macrovesicular steatosis, ballooning degeneration of hepatocytes, scattered (mainly lobular)
Scoring, Staging and Grading
While making the diagnosis of steatohepatitis can be challenging at times, the grading and staging of NASH has also been problematic. Several systems have been proposed to address this situation and will be reviewed accordingly.
In 1999, Brunt et al. proposed a grading and staging system for NASH [36]. They incorporated histologic features, such as steatosis, ballooning degeneration, and inflammation to grade the disease and used patterns and location of fibrosis to stage it. The proposed system
Special Situations: Children, Bariatric Surgery, Lipodystrophy
While diagnosis of nonalcoholic fatty liver disease in adults continues to be intensely studied, there are some situations that deviate from established patterns and criteria, which may yield difficulties in diagnosis. Pediatric steatohepatitis can be challenging for pathologists, while fatty liver disease in bariatric surgery and lipodystrophy patients continues to be understudied. In this section we will briefly review the available data concerning these unusual situations.
Several studies
Summary
NAFLD is a complex liver disease, with several distinct manifestations. NASH is a subtype of NAFLD in which there is a specific injury pattern characterized by ballooning hepatocellular injury, in combination with macrovesicular steatosis and inflammation. Fibrosis and MDBs are also often seen, but not required for the diagnosis. Children, particularly prepubertal children, have a pattern of NAFLD characterized by a zone 1 distribution of steatosis, inflammation and fibrosis. Several scoring
Author Contributions
Drs Brown and Kleiner both contributed significantly to the main text of the manuscript. Dr Kleiner captured histopathologic images.
Conflicts of Interest
The authors have no financial conflicts of interest to disclose.
Acknowledgments
This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer institute.
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