Steatohepatitis with Cirrhosis Linda D. Ferrell University of California, San Francisco

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Clinical History A 37 year-old Caucasian woman was admitted with jaundice and asterixis for an expedited transplant evaluation for presumed end-stage liver disease with acute decompensation. The patient's history was remarkable for morbid obesity with a body mass index (BMI) of 59.4 three years ago. She then lost approximately 300 pounds after her Roux-en-Y gastric bypass procedure at a referring institution (no biopsy available for review) over a period of 2 years. Six months prior to this admission, she developed jaundice. She now presented with a BMI of 26.5, height 5'2", 145 pounds. Liver laboratory studies on admission at UCSF included total bilirubin of 28, AST: 105 (mildly elevated), ALT: 39 (normal), alkaline phosphatase: 124 (mildly elevated), low serum albumin, and INR of 2.4 (prolonged). Lipid studies included serum cholesterol: 74, triglycerides:102, LDL:41, HDL:13. HAV, HBV, HCV, and other viral markers (CMV, EBV, HIV) were negative; ANA, SMA, and LKM-1 antibodies were negative; ceruloplasmin and alpha-1-antitrypsin levels were within normal limits. Drug regimen had included omeprazole, spironolactone, Lasix, and lactulose. Ultrasound demonstrated hepatomegaly with fatty change, ascites, and splenomegaly. The patient had no history of diabetes, hypertension, alcohol or drug abuse. Her family history was unremarkable. Sample is from explant, performed 7 days after admission. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 10x. Portal area upper right, central zonal scar on left, and extensive intrasinusoidal scarring is also present. Inflammation is scant, and ductular reaction is present in lobular zone 1. (10x) Figure 2 Higher magnification (20x). The scar at the bottom of the photo is the residual centrizonal region (zone 3). Ductular metaplasia is present in zone 1 and 2, and ballooned hepatocytes are present near the centrizonal scar. Mild large droplet fat is present. Figure 3 40x. Ballooned hepatocytes and ductular metaplasia. Also note the sinusoidal pattern of scarring. Inflammation is mostly mononuclear but some neutrophils are also present. Focal large droplet fat is present on right. Figure 4 20x. Similar to figure 3, with ballooned hepatocytes, ductular metaplasia. The inflammatory infiltrate is more mixed than in fig 3. Mallory hyaline is present in ballooned hepatocytes (center, bottom center and bottom right). Figure 5 20x. Prominent ballooned hepatocytes, many which contain Mallory hyaline. Also note bile stasis/bile plugs. Metaplastic ductule is present on left. Figure 6 20x. Prominent ballooned hepatocytes, many with Mallory hyaline. Fatty change is scant but present. Figure 7 40x. Centrizonal scar, with adjacent ballooned hepatocyte that contains prominent Mallory hyaline. Figure 8 40x. Zone of prominent cholestasis. Large droplet fat is also present. Note sinusoidal fibrosis. Figure 9 Trichrome stain, 10x. Portal zone at bottom, centrizonal scar at top center. Note sinusoidal/centrizonal pattern of scarring. Fatty change can be identified. Figure 10 Trichrome stain, 10x. Portal zone on left, residual centrizonal area with scar on right. Sinusoidal and centrizonal pattern of scarring is prominent. Figure 11 Trichrome stain, 20x. Central vein with surrounding scar. Pericellular and sinusoidal scarring is prominent. Figure 12 Orcein stain, 20x. Central vein wall is outlined by the dark fibers in the center. The lumen of the vein is sclerosed and occluded. Diagnosis: Steatohepatitis with cirrhosis Objectives: To define the criteria for steatohepatitis, which includes ballooned hepatocytes, inflammation, fatty change, and centrizonal fibrosis Clinical Considerations Steatohepatitis is a term used to describe the necroinflammatory lesion of persistent hepatic steatosis, and accounts for the major way by which fatty livers progress to cirrhosis. Steatohepatitis can be caused by alcohol; however, the lesion frequently occurs in the absence of alcohol exposure, and so designated as "non-alcoholic steatohepatitis" (NASH). The lesion has been identified associated with a variety of conditions, many occurring in the setting of "metabolic syndrome". The primary associated entities are diabetes mellitus, obesity, and hyperlipidemia, but other processes also possibly associated with NASH or NASH-like lesions include accelerated weight loss, acute starvation, total parenteral nutrition, jejunoileal or jejunocolonic bypass, extensive small bowel resection, gastroplasty, biliopancreatic diversion, drug therapy (amiodarone, perhexiline maleate, synthetic estrogens, tamoxifen, nifedipine, corticosteroids), Weber-Christian disease, and abetalipoproteinemia. In spite of all these associated factors, many cases may still occur in the absence of any of the above clinical settings. Approximately 10-30% of patients with NASH may progress to cirrhosis, typically in a slow manner over a period of many years. A study from the Mayo clinic suggested that older age, obesity, presence of diabetes mellitus, and aspartate transaminase/alanine transaminase (AST/ALT) ratio greater than 1 were significant predictors of severe liver fibrosis (bridging fibrosis or cirrhosis). Iron accumulation in these cases is likely not associated with a poorer outcome. Diagnostic Considerations Steatohepatitis is defined histologically by most as a combination of steatosis (>5% of hepatocytes involved), hepatocyte necrosis or injury, and inflammatory infiltration, with or without fibrosis. The process typically begins in the centrilobular zone (acinar zone 3), and then extends over time to involve other zones, and in some cases, may progress to cirrhosis. The steatosis is essentially a universal finding in this lesion, and generally is of the macrovesicular type, both large and small droplets. True microvesicular fat (defined as very small droplets uniformly filling the hepatocyte without displacement of the nucleus) is uncommon, and when present, tends to be in small patches. Rarely, minimal or no steatosis may be seen in occasional cases, as may be noted in steatohepatitis that has already progressed to cirrhosis. The hepatocyte injury typically consists of enlarged, pale hepatocytes with some residual granular cytoplasmic material, so-called "ballooned" cells. These cells are generally seen near the fibrous septa, and are typically centrilobular in location in early lesions. Spotty hepatocyte necrosis (apoptosis) is often present. Mallory hyaline can be seen, but may not be as well-formed or as prominent as seen in alcoholic steatohepatitis, and may be highlighted on Masson's trichrome stain as grey to blue cytoplasmic bodies or identified by immunohistochemical stains for keratin or ubiquitin. The inflammatory infiltrate can be mixed, but the predominant inflammatory cell present in most cases of NASH is the lymphocyte, in contrast to alcoholic steatohepatitis, where neutrophils are often more commonly seen. Neutrophils, when present, tend to cluster around the injured hepatocytes as in alcoholic steatohepatitis. Macrophages, lipogranulomas, plasma cells and eosinophils can also be present. In later stages, portal inflammatory changes and bile ductular proliferation may become prominent. Early signs of fibrosis, when present, tend to be found in the centrilobular zone as a sinusoidal, pericellular deposition. Periportal fibrosis, if present, generally occurs later in the course of the disease, except that periportal fibrosis may be the earliest lesion (instead of centrizonal fibrosis) in many pediatric patients. This form of NASH with periportal fibrosis has been designated as type 2 NASH (Schwimmer, Behling, et al). Prominent cholestasis, Mallory hyaline formation, neutrophilic infiltrates, and central vein sclerosis are more commonly seen in alcoholic steatohepatitis and not as typical of NASH, except perhaps in rare instances of aggressive NASH with more rapid progression to liver failure (personal observations). In some of the drug-related forms of injury that cause a NASH-like histology, a phospholipidosis occurs that gives the hepatocytes a foamy or granular cytoplasmic appearance due to lysosomes filled with concentric laminated phospholipid. The drug commonly associated with this finding is amiodarone. In amiodarone-related lesions, fatty change is often only mild or minimal and Mallory hyaline is abundant. Grading and Staging for NASH Tables 1 and 2 contain a relatively simple system from Kleiner, Brunt et al., Hepatol 2005, for grading and staging NASH. Table 1: Grading for NASH Grade Steatosis Ballooning Inflammation, lobular 0 <5% 0 0 1 5- 33% Rare or few 1-2 foci per 20x field 2 34-66% Many 2-4 foci / 20x field 3 >66% Not applicable >4 foci / 20x field Table 2: Staging for NASH Stage Histologic Description 0 No fibrosis 1a Zone 3 sinusoidal fibrosis, requires trichrome stain to identify 1b Zone 3 sinusoidal fibrosis, seen easily on H&E 1c Periportal/portal fibrosis only 2 Zone 3 with portal/periportal fibrosis 3 As above with bridging fibrosis 4 Cirrhosis Take Home Messages Diagnostic highlights Ballooned hepatocytes: Active disease Centrizonal fibrosis: Chronic or remote Variant aggressive form may mimic alcoholic injury References Caldwell SH, Hespenheide EE. Subacute liver failure in obese women. Am J Gastroenterol 2002;97:2058-62. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterol 2004;127:S97-103. Caldwell SH, Oeisner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. 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