eration, and Mallory bodies disappear from a patient with cirrhotic NASH, it is impossible to diagnose. NASH, because the characteristic features of fibrosis.
J Gastroenterol 2004; 39:1215–1218 DOI 10.1007/s00535-004-1475-x
Case report Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH Yoko Yoshioka, Etsuko Hashimoto, Satoru Yatsuji, Hiroyuki Kaneda, Makiko Taniai, Katsutoshi Tokushige, and Keiko Shiratori Department of Internal Medicine and Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by the histological features of steatohepatitis in the absence of significant alcohol consumption. The natural history of NASH is poorly defined. Here we report our experience with a patient to illustrate the clinical course of cirrhotic NASH. A 67-yearold woman was admitted with hematemesis due to the rupture of esophageal varices. Her varices were treated by endoscopic ligation and endoscopic sclerotherapy. Her medical history was unremarkable. Both the patient and her family members were asked about alcohol intake several times during her illness, but all of them denied a history of alcohol intake. She had insulin resistance, as determined by homeostasis model assessment. Serological tests for viral hepatitis were all negative. Viral hepatitis, autoimmune liver disease, iron overload, and metabolic liver disorders were all excluded. Imaging tests failed to reveal any steatosis, because of the presence of severe fibrosis. Liver biopsy showed moderate steatosis, moderate inflammation, ballooning degeneration, and Mallory bodies. We diagnosed NASH associated with cirrhosis based on the clinicopathological features. Almost 2 years later, she developed hepatocellular carcinoma (HCC) and she died of multiple HCCs. At autopsy, tumor invasion was seen throughout liver segment 8. The noncancerous liver showed burnt-out NASH; the steatosis, necroinflammation, ballooning degeneration, and Mallory bodies had all disappeared. In Japan, the prevalence of nonalcoholic fatty liver disease will increase as obesity has been increasing, so it is important to understand how to diagnose NASH. When a patient has NASH, careful follow-up should be performed.
Received: February 3, 2004 / Accepted: April 30, 2004 Reprint requests to: E. Hashimoto
Key words: NASH, hepatocellular carcinoma, cryptogenic cirrhosis, burnt-out NASH, cirrhosis
Introduction Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by the histological features of steatohepatitis in the absence of significant alcohol consumption.1 NASH has generally been considered to be a mild condition, but it can progress to cirrhosis and hepatocellular carcinoma (HCC).2–5 The natural history of NASH is poorly defined, although its prevalence increases with the increasing prevalence of obesity.6–13 In 1990, Powell et al.14 reported that a patient with characteristic histological features of cirrhotic NASH showed complete loss of steatosis and inflammation in a subsequent liver biopsy, which showed only advanced cirrhosis. If steatosis, inflammation, ballooning degeneration, and Mallory bodies disappear from a patient with cirrhotic NASH, it is impossible to diagnose NASH, because the characteristic features of fibrosis (such as perivenular fibrosis) are difficult to identify after the liver architecture is disrupted. This is very important to remember when assessing liver-related morbidity and mortality due to cryptogenic cirrhosis, but there have only been two case reports illustrating this sequence.14–15 We previously reported six patients with NASH who developed HCC.16 Case 2 in that report was diagnosed as having cirrhotic NASH at age 67, and HCC was diagnosed almost 2 years later. She died within 4 years after the diagnosis of HCC. At autopsy, steatosis, inflammatory changes, ballooning degeneration, and Mallory bodies had all disappeared. Here, we report our experience with this patient to illustrate the clinical course of cirrhotic NASH; we also discuss a possible novel diagnostic approach to this liver disease.
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Case report A 67-year-old woman was admitted with hematemesis after the rupture of esophageal varices. Prior to the rupture of these varices, her medical history was unremarkable, without blood transfusion, injectable drug use, exposure to toxins, or alcohol intake. Both the patient and her family members were asked about alcohol intake several times during her illness (from presentation to death), but all of them denied a history of alcohol intake. She had never been overweight and had no symptoms of metabolic syndrome. There was no family history of liver disease. Her general status was as follows: her consciousness was clear, her height was 154.5 cm, her weight was 51.2 kg, and her body mass index was 21.4 kg/m2. Her blood pressure was 140/ 75 mmHg. There was mild conjunctive anemia. Vascular spider and palmar erythema were not observed. On examination of the abdomen, there was splenomegaly with mild ascites. Laboratory tests showed the following: serum aspartate aminotransferase, 45 IU/l (normal, ⬍31 IU/l); alanine aminotransferase, 33 IU/l (normal, ⬍31 IU/l); gamma-glutamic transpeptidase, 39 IU/l (normal, 7–28 IU/l); alkaline phosphatase, 163 IU/l (normal, 79–205 IU/l); total bilirubin, 0.6 mg/dl; albumin, 3.6 g/dl; white blood cells, 3590/µl; red blood cells, 4.22 ⫻ 106/µl; platelet count, 6.8 ⫻ 103/µl; prothrombin time, 93%; hyaluronic acid, 125 ng/ml (normal, ⬍50 ng/ml); fasting glucose, 101 mg/dl; fasting immunoreactive insulin, 24.1 µU/ml; homeostasis model assessment, 6.0; and HbA1C, 4.5%. She had insulin resistance, as determined by the homeostasis model assessment. Serological tests for viral hepatitis (hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis C virus antibody, and hepatitis C virus-RNA) were all negative. Antinuclear antibody was negative. Viral hepatitis, autoimmune liver disease, iron overload, and metabolic liver disorders were all excluded. Ultrasonography (US) and computed tomography (CT) failed to reveal any steatosis, because of the presence of severe fibrosis. Laparoscopy showed an early cirrhotic liver, with a yellowish surface. Liver biopsy revealed moderate steatosis, moderate inflammation, ballooning degeneration, Mallory bodies, and pericellular fibrosis (Fig. 1). Kupffer cell hemosiderosis was present, probably because of a blood transfusion after her admission. Although the biopsy specimen was too small to allow the detection of nodular regeneration, we diagnosed NASH associated with cirrhosis, based on the clinicopathological features. Her esophageal varices were treated by endoscopic ligation and endoscopic sclerotherapy, while the ascites resolved after treatment with diuretics. After discharge, she remained stable during follow up at our hospital. Almost 2 years later, at the age of 69 years, two hepatic tumors were diagnosed by
Y. Yoshioka et al.: NASH and cirrhosis
US, CT, and angiography. These tumors were 1.5 cm in diameter, located in liver segments 4 and 8, and showed features consistent with HCC. We confirmed the diagnosis by US-guided biopsy, which revealed a grade-2 HCC. She was treated by transarterial embolization. Recurrence of HCC was detected 3.5 years after the initial diagnosis of HCC, and variceal bleeding also recurred. She died of HCC on June 2, 2003. During her illness, she had not been treated with any medicine for NASH and her insulin resistance and body weight had not changed. At autopsy, tumor invasion was seen throughout segment 8. Histologically, the tumor was a grade-2 hepatocellular carcinoma with trabecular and solid patterns (Fig. 2). The noncancerous liver showed burnt-out NASH; the steatosis, ballooning degeneration, and Mallory bodies had all disappeared (Fig. 3).
Discussion This case may represent the typical clinical course of NASH accompanied by advanced cirrhosis; i.e., clinically silent until variceal rupture, steatosis undetectable by diagnostic imaging because of severe fibrosis, complication by HCC, and eventual loss of the histological characteristics of NASH. We believe that, in this patient, the histological consequences of steatohepatitis showed their natural course, because the patient had not received any drug treatment for NASH and her metabolic status had not changed. The detection of cirrhosis in NASH patients appears to be delayed compared with that in other chronic liver diseases, because there are no serum markers for NASH, and a definitive diagnosis requires liver biopsy, while aminotransferase levels are only slightly elevated. Moreover, nonalcoholic fatty liver disease (NAFLD), which comprises NASH and simple fatty liver, has been considered benign and has rarely been followed with detailed examinations such as liver biopsy, on endoscopy to check for esophageal varices. In Japan, NASH seems to be a common liver disorder, because NAFLD is found in 10%–20% of adults at annual health checks and it was reported that almost 10% of NAFLD patients have NASH rather than simple fatty liver.2,4,5,17 Thus, the prevalence of NASH can be calculated as 1%–2%, which is higher than that of hepatitis C. A diagnosis of NAFLD can be made by imaging tests, but a differential diagnosis between NASH and simple fatty liver requires liver biopsy.18 However, performing liver biopsies in all NAFLD patients is not practical. Therefore, we propose that a liver biopsy should be done for patients who show steatosis on imaging tests and have a low platelet count, high levels of fibrosis markers, or deterioration of liver function, as well as for patients with cryptogenic cirrhosis,
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b
a
Fig. 1a,b. Liver biopsy. a Steatohepatitis with zone-3 fibrosis. b Steatohepatitis with ballooning degeneration of hepatocytes in zone 3, Mallory bodies (arrowheads), and inflammatory infiltrates. a Reticulin silver stain, ⫻ 40; b H&E, ⫻ 100
Fig. 2. Autopsy specimen shows a grade-2 hepatocellular carcinoma with trabecular and solid patterns. H&E, ⫻ 50
Fig. 3. At autopsy, the noncancerous liver shows complete disappearance of steatosis, Mallory bodies, and ballooning degeneration; i.e., burnt-out nonalcoholic steatohepatitis (NASH). H&E, ⫻ 30
because these patients may have NASH with advanced fibrosis. Although there are no proven treatments, recommendations for patients with NASH include the avoidance of hepatotoxins and the aggressive management of associated conditions such as hypertriglyceridemia and type 2 diabetes mellitus. Moreover, these patients should be followed up regularly to assess liver function and to monitor for the development of portal hypertension or HCC. NASH rises to the top of the list of potential diagnoses in patients with cryptogenic cirrhosis because: (1) the characteristic features of NASH disappear after cirrhosis is advanced (i.e., burnt-out NASH), (2) patients with cryptogenic cirrhosis are more likely to have features of metabolic syndrome than patients with other
chronic liver diseases, and (3) there is a high prevalence of NAFLD after orthotopic liver transplantation for cryptogenic cirrhosis14,15,19–23 Nowadays, cryptogenic cirrhosis associated with metabolic syndrome is diagnosed as NASH in some reports.24–26 In Japan, the prevalence of NAFLD will increase in the future with increasing obesity, so it is important to understand how to diagnose NASH among so many patients with NAFLD and cryptogenic cirrhosis. When a patient has NASH and advanced fibrosis, careful follow up should be performed, with treatment for NASH and any associated metabolic syndrome. Acknowledgment. The authors thank Dr. Jurgen Ludwig for the histological diagnosis of NASH in this patient.
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