- Email: [email protected]
Disease Progression in a Patient with Nonalcoholic Steatohepatitis
CASE REPORT
Disease Progression in a Patient with Nonalcoholic Steatohepatitis Ping-Huei Tseng,1 Chun-Jen Liu,1 Jia-Horng Kao,1,2,3 Chia-Tung Shun,4 Pei-Jer Chen,1,2,3 Ding-Shinn Chen1,2,3* Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). The prevalence and clinical significance of NAFLD/NASH have been increasingly recognized in Western countries but much less known in Asian countries, including Taiwan. Here, we report the case of a 43-year-old man who had abnormal liver tests for 18 years. Retrospective evaluation of his initial clinical, laboratory and histologic findings indicated that the hepatic disorder was compatible with the diagnosis of NASH. Although his liver biochemical tests improved after taking lipid-lowering agents, a liver biopsy 17 years later demonstrated histologic progression of intralobular necroinflammation and perivenular fibrosis. These facts suggest that NASH, albeit mild and slowly progressive, indeed exists in Taiwan. After the control of chronic hepatitis B and C and westernization of the lifestyle in Taiwan, an increasing burden of NAFLD/NASH is anticipated and active prophylactic measures should be implemented. [J Formos Med Assoc 2008;107(10):816–821] Key Words: metabolic syndrome, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis
many Asian countries including Taiwan. However, the emergence of NAFLD and its clinical impact seems to have been overlooked in this region. Herein, we report a Taiwanese patient who had abnormal liver tests for 18 years, and paired liver biopsies performed 17 years apart confirmed the diagnosis and histologic progression of NASH.
Nonalcoholic fatty liver disease (NAFLD) represents a broad disease spectrum, ranging from simple steatosis without inflammation, to nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis and even cirrhosis in patients who deny alcohol abuse.1 Risk factors for the development of NAFLD include major components of the metabolic syndrome: obesity, type 2 diabetes, and dyslipidemia.2–5 NAFLD has been increasingly recognized as the most common liver disease in Western countries where the prevalence is estimated to be about 20–30%, while NASH affects about 2–3% of the general population.6,7 With the westernization of lifestyle and diet patterns in recent decades, the prevalence of obesity and overweight has been increasing in
Case Report A 43-year-old man was incidentally found to have elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in February 1987. He was referred to our hospital for further evaluation. He denied the history
©2008 Elsevier & Formosan Medical Association .
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Department of Internal Medicine, 2Hepatitis Research Center, 3Graduate Institute of Clinical Medicine, and 4 Department of Forensic Medicine and Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Received: May 9, 2007 Revised: June 27, 2007 Accepted: August 7, 2007
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*Correspondence to: Dr Ding-Shinn Chen, Hepatitis Research Center, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2008 • Vol 107 • No 10
Nonalcoholic steatohepatitis
A
B
Figure 1. First liver biopsy (August 1988) reveals diffuse micro- and macrovesicular fatty changes in the hepatocytes. (A) Mild mononuclear cell infiltrations in portal and lobular areas (black arrow; hematoxylin & eosin, 400×). (B) Focal mild perivenous fibrosis (white arrow; hematoxylin & eosin, 400×). The necroinflammatory activity is graded 1 and the fibrosis is staged 1 by Brunt et al’s criteria.8
of alcohol abuse, any drugs or toxin exposure, and blood transfusion. None of his family had history of chronic liver disease. At that time, his body weight was 77 kg and body height was 173.5 cm (body mass index [BMI], 25.6 kg/m2). Serum ALT level was 59 IU/L (upper limit of normal [ULN], < 37 IU/L) and serum AST level was 40 IU/L (ULN, < 37 IU/L). Blood pressure, blood sugar, serum albumin, globulin, bilirubin, alkaline phosphatase and γ-glutamyl transferase levels were all within normal limits. Serum total cholesterol (T-CHO) level was 233 mg/dL (ULN, < 220 mg/dL) and triglyceride (TG) level was 68 mg/dL (ULN, < 150 mg/dL). Hepatitis viral markers in February 1987 revealed that he was negative for both hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs), and positive for antibody against hepatitis B core antigen (anti-HBc). Antibody against hepatitis C virus (anti-HCV), performed in February 2000 when the assay was available, was also negative. Serological studies excluded the presence of autoimmune hepatitis and inherited/metabolic liver diseases. Abdominal ultrasonography showed a small hemangioma at the right lobe of the liver. His hepatic parenchyma was fine in echotexture and there was no evidence of fatty liver. Since viral hepatitis, drug-induced liver injury and autoimmune liver disease had been ruled out, the diagnosis of cryptogenic hepatitis was made. J Formos Med Assoc | 2008 • Vol 107 • No 10
Liver biopsy was performed after 18 months of persistently elevated serum ALT and AST. Histologic examination disclosed evidence of steatohepatitis: diffuse micro- and macrovesicular fatty changes in the hepatocytes; mild focal necrosis of the hepatocytes in the lobules, accompanied by mild mononuclear cell infiltration in portal and lobular areas; and mild focal perivenous fibrosis (Figure 1). Based on Brunt’s criteria, the necroinflammatory activity was grade 1 and the fibrosis was stage 1.8 Over the next 12 years, serum AST and ALT levels increased gradually to 6–8 × ULN. Hepatitis B and C viral serologic markers were repeatedly negative. Serum HBV DNA and HCV RNA were also undetectable by polymerase chain reaction assays when the techniques became available. Alcohol abuse and drugs or toxin exposure were denied. Evidence of autoimmune liver disease was not found during follow-up. Meanwhile, his body weight increased to 83 kg (BMI, 27.6 kg/m2) in 1999. Moreover, serum lipid profile revealed that T-CHO level was 344 mg/dL, TG level was 152 mg/dL, low-density lipoprotein (LDL) level was 273 mg/dL, and high-density lipoprotein (HDL) level was 40 mg/dL. Fasting serum glucose level was 83 mg/dL. Simvastatin was thus prescribed and his serum T-CHO decreased to 133 mg/dL in May 2001. Serum AST and ALT levels improved in parallel (AST, 46 IU/L; ALT, 817
P.H. Tseng, et al
AST/ALT (IU/L), T-CHO/TG (mg/dL)
500 450
1st liver biopsy
2nd liver biopsy
Simvastatin
400 350 AST
300
ALT
250
T-CHO
200
TG
150 100 50 0 1987 1988 1989 1999 2000 2001 2002 2003 2004 2005 Year 27.6 27.1 28.8 28.6 BMI (kg/m2) 25.6
Figure 2. Chronological profile of body mass index (BMI), serum aspartate aminotransferase (AST) level, serum alanine aminotransferase (ALT) level, serum total cholesterol (T-CHO) level, and serum triglyceride (TG) level during an 18-year follow-up.
89 IU/L). However, drug compliance was not satisfactory and his body weight increased gradually to 86.6 kg (BMI, 28.8 kg/m2) in December 2004, 17 years after his first visit to our hospital, accompanied by deterioration in serum AST and ALT levels. The chronological data of serum AST, ALT, TG and T-CHO levels, and BMI during follow-up are shown in Figure 2. Abdominal ultrasonography performed in May 2005 showed the presence of fatty liver of moderate degree in addition to a small hemangioma. In June 2005, his body height was 173.5 cm and body weight was 86.0 kg (BMI, 28.6 kg/m2). His waist circumference was 91 cm. The body temperature was 36.6°C, pulse rate was 72 per minute, respiratory rate was 20 per minute, and blood pressure was 106/70 mmHg. Other physical findings were unremarkable. The white blood cell count was 5850/mm3. Blood sugar level was 95 mg/dL before meal and 128 mg/dL 2 hours after meal. Serum AST and ALT levels were 56 IU/L and 119 IU/L, respectively. Serum lipid profile revealed that TCHO level was 306 mg/dL, TG level was 102 mg/ dL, LDL level was 242 mg/dL, and HDL level was 44 mg/dL. He received follow-up needle biopsy of the liver on July 14, 2005, 17 years after the first biopsy. Histologic features again disclosed 818
evidence of steatohepatitis: diffuse micro- and macrovesicular fatty changes of the hepatocytes; lymphocytic and occasional neutrophilic infiltration in portal and lobular areas; and fibrosis at the portal, perivenular and pericentral venous areas with septum formation, which was confirmed by Masson-Trichrome stain (Figure 3). The histology was therefore designated grade 1 necroinflammation and stage 2 fibrosis based on the same criteria of Brunt et al.8
Discussion We report a histologically proven case of NASH in a Taiwanese patient, who had metabolic derangements and a long-term follow-up for more than 18 years. This patient documented the existence of NAFLD/NASH in Taiwan with possible histologic progression. The development of NAFLD/NASH has been linked to insulin resistance and it is now considered a hepatic manifestation of the metabolic syndrome.3,9,10 However, the criteria for the diagnosis of metabolic syndrome are set according to studies in Western countries and may not be suitable for Asian populations.11 For example, recent J Formos Med Assoc | 2008 • Vol 107 • No 10
Nonalcoholic steatohepatitis
A
B
Figure 3. Second liver biopsy (July 2005) reveals diffuse micro- and macrovesicular fatty changes of the hepatocytes, accompanied by lymphocytic and occasional neutrophilic infiltrations in the portal and lobular areas. (A) Fibrosis at the portal area (black arrow; hematoxylin & eosin, 400×). (B) Fibrosis at the portal, perivenular and pericellular areas with septal formation (white arrow; Masson-trichrome stain, 200×). The necroinflammatory activity is graded 1 and the fibrosis is staged 2 by Brunt et al’s criteria.8
studies suggested that the risk of obesity in Asians may be higher than that of other ethnic groups using the same BMI cutoff values. Accordingly, the definition of overweight and obesity in Taiwanese may be better set as BMI > 24 kg/m2 and > 27 kg/m2, respectively. In the present case, if we used the modified criteria, he would already be overweight at the initial visit (BMI, 25.6 kg/m2) and obese at the last visit (BMI, 28.6 kg/m2). The presence of metabolic derangement most likely accounted for the development of NAFLD/NASH in this patient. The diagnosis of NAFLD and NASH relies on clinical suspicion and histopathologic findings. Mildly to moderately elevated serum aminotransferase levels are common. Imaging studies may provide evidence of fatty infiltration of the liver but cannot differentiate simple steatosis from NASH.12 Therefore, liver biopsy remains the definite diagnostic procedure.3 In the present case, initial abdominal ultrasonography did not show the typical features of liver brightness, blurring of vessel walls nor fat attenuation.13 However, the presence of diffuse steatosis was found by liver biopsy, which consistently supported the role of liver biopsy for accurate diagnosis. The pattern of steatosis in NASH/NAFLD is mostly macrovesicular and secondly mixed macrovesicular and microvesicular,8 as seen in the present case. J Formos Med Assoc | 2008 • Vol 107 • No 10
The pattern of true microvesicular steatosis, consisting of much smaller and uniform fat droplets dispersed throughout the hepatocyte, was not found in the pathologic examinations of the case. Furthermore, the possibility of toxin exposure, the most common cause of microvesicular steatosis, was also excluded by history. As to the management of NAFLD and NASH, currently, there is still no proven effective drug therapy. A recent study has revealed that aggressive body weight control was followed by improvement in the biochemical and histologic profiles of NASH patients.14 In our patient who had underlying obesity and hyperlipidemia, weight reduction was suggested and the lipid-lowering agent simvastatin was used. Interestingly, clinical improvement of both total cholesterol level and liver function test was documented, although only transiently due to his poor drug compliance and progressively increasing body weight. The natural history of NAFLD correlates with baseline histologic findings.15 Retrospective cohort studies suggested that patients with simple steatosis usually run a benign course with a negligible risk of developing cirrhosis over 15–20 years. In contrast, patients with NASH and fibrosis can progress to cirrhosis with a risk ranging from 0% to 12% over 5–8 years’ follow-up.1,16–18 Data on the prevalence and natural course in 819
P.H. Tseng, et al
Chinese populations are limited in the literature. Wong et al reviewed the clinical and histologic features of 42 patients with biopsy-proven NAFLD in Hong Kong.19 They found that most patients had features of metabolic syndrome. As high as 85.7% of NAFLD patients had evidence of steatohepatitis and 26.1% had fibrosis according to Brunt’s criteria. They further investigated the histologic progression in 17 Chinese patients with paired liver biopsy.20 Nine (53%) of them had a progressive disease with worsening of fibrosis score during a median histologic follow-up period of 6.1 years (range, 3.8–8.0 years). In our patient with a paired histologic follow-up of over 17 years, we also demonstrated the benign but slowly progressive course of NASH. In Taiwan, chronic viral hepatitis including hepatitis B and C is the most common cause of liver disease. However, with the control of chronic viral hepatitis by universal vaccination and effective antiviral therapies, NAFLD/NASH will become major liver diseases in the Taiwanese people. The prevalence of fatty liver was found to be around 40% by ultrasonography in a hospital-based health check-up series.21 NASH has been reported in morbidly obese patients in Taiwan with a prevalence of 33.8%.22 Nevertheless, the prevalence of NAFLD and NASH in the general population of Taiwan remains to be studied. From another aspect, whether NAFLD superimposed on patients with underlying chronic viral hepatitis contributes to the progression of liver diseases should also be seriously considered. In our retrospective studies, hepatic steatosis was found in 46% of patients with chronic hepatitis C, but steatohepatitis was uncommonly encountered (4%). Furthermore, the presence of steatosis might adversely affect the response to antiviral therapy.23,24 These findings indicate that correcting metabolic derangement might help to improve the response to antiviral therapies. In summary, we documented a case of NASH and showed progression of the disease in a Taiwanese man. NAFLD, a health burden in Western countries, will very likely prevail in Oriental countries in the near future. Clinicians in Taiwan 820
should become aware of the issues of NAFLD, apart from the well-known facts of chronic viral hepatitis B and C. The role of correcting metabolic derangement in preventing the progression of NAFLD and the impact of coexisting NAFLD on the natural history and antiviral treatment outcomes in patients with underlying chronic viral hepatitis merit further studies.
Acknowledgments This work was supported by grants from National Taiwan University Hospital, the Department of Health, the National Science Council, Executive Yuan, and the National Health Research Institutes, Taiwan.
References 1. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–9. 2. Ludwig J, Viaggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experience with an hitherto unnamed disease. Mayo Clin Proc 1980;55:434–8. 3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;16:1221–31. 4. Bellentani S, Saccoccio G, Masatti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112–7. 5. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–23. 6. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649–57. 7. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003;37:1202–19. 8. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467–74. 9. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844–50. 10. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006;43:S99–112. 11. Pei D, Kuo SW, Wu DA, et al. The relationships between insulin resistance and components of metabolic syndrome in Taiwanese Asians. Int J Clin Pract 2005;59:1408–16.
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12. Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–50. 13. Yang PM, Hung GT, Lin JT, et al. Ultrasonography in the diagnosis of benign diffuse parenchymal liver diseases: a prospective study. J Formos Med Assoc 1988;87: 966–77. 14. Dixon JB, Bhathal PS, Hughs NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647–54. 15. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology 2005;129: 375–8. 16. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–21. 17. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut 2004;53:750–5. 18. Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal
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study of 103 patients with sequential liver biopsies. J Hepatol 2005;42:132–8. Wong VW, Chan HL, Hui AY, et al. Clinical and histological features of non-alcoholic fatty liver disease in Hong Kong Chinese. Aliment Pharmacol Ther 2004;20:45–9. Hui AY, Wong VW, Chan HL, et al. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005;21:407–13. Lai SW, Tan CK, Ng KC. Epidemiology of fatty liver in a hospital-based study in Taiwan. South Med J 2002;11: 1288–92. Liew PL, Lee WJ, Lee YC, et al. Hepatic histopathology of morbid obesity: concurrence of other forms of chronic liver disease. Obes Surg 2006;16:1584–93. Liu CJ, Chen PJ, Jeng YM, et al. Serum adiponectin correlates with viral characteristics but not histologic features in patients with chronic hepatitis C. J Hepatol 2005;43:235–42. Liu CJ, Jeng YM, Chen PJ, et al. Influence of metabolic syndrome, viral genotype and antiviral therapy on superimposed fatty liver disease in chronic hepatitis C. Antivir Ther 2005;10:405–15.
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Disease Progression in a Patient with Nonalcoholic Steatohepatitis Ping-Huei Tseng,1 Chun-Jen Liu,1 Jia-Horng Kao,1,2,3 Chia-Tung Shun,4 Pei-Jer Chen,1,2,3 Ding-Shinn Chen1,2,3* Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). The prevalence and clinical significance of NAFLD/NASH have been increasingly recognized in Western countries but much less known in Asian countries, including Taiwan. Here, we report the case of a 43-year-old man who had abnormal liver tests for 18 years. Retrospective evaluation of his initial clinical, laboratory and histologic findings indicated that the hepatic disorder was compatible with the diagnosis of NASH. Although his liver biochemical tests improved after taking lipid-lowering agents, a liver biopsy 17 years later demonstrated histologic progression of intralobular necroinflammation and perivenular fibrosis. These facts suggest that NASH, albeit mild and slowly progressive, indeed exists in Taiwan. After the control of chronic hepatitis B and C and westernization of the lifestyle in Taiwan, an increasing burden of NAFLD/NASH is anticipated and active prophylactic measures should be implemented. [J Formos Med Assoc 2008;107(10):816–821] Key Words: metabolic syndrome, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis
many Asian countries including Taiwan. However, the emergence of NAFLD and its clinical impact seems to have been overlooked in this region. Herein, we report a Taiwanese patient who had abnormal liver tests for 18 years, and paired liver biopsies performed 17 years apart confirmed the diagnosis and histologic progression of NASH.
Nonalcoholic fatty liver disease (NAFLD) represents a broad disease spectrum, ranging from simple steatosis without inflammation, to nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis and even cirrhosis in patients who deny alcohol abuse.1 Risk factors for the development of NAFLD include major components of the metabolic syndrome: obesity, type 2 diabetes, and dyslipidemia.2–5 NAFLD has been increasingly recognized as the most common liver disease in Western countries where the prevalence is estimated to be about 20–30%, while NASH affects about 2–3% of the general population.6,7 With the westernization of lifestyle and diet patterns in recent decades, the prevalence of obesity and overweight has been increasing in
Case Report A 43-year-old man was incidentally found to have elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in February 1987. He was referred to our hospital for further evaluation. He denied the history
©2008 Elsevier & Formosan Medical Association .
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Department of Internal Medicine, 2Hepatitis Research Center, 3Graduate Institute of Clinical Medicine, and 4 Department of Forensic Medicine and Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Received: May 9, 2007 Revised: June 27, 2007 Accepted: August 7, 2007
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*Correspondence to: Dr Ding-Shinn Chen, Hepatitis Research Center, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2008 • Vol 107 • No 10
Nonalcoholic steatohepatitis
A
B
Figure 1. First liver biopsy (August 1988) reveals diffuse micro- and macrovesicular fatty changes in the hepatocytes. (A) Mild mononuclear cell infiltrations in portal and lobular areas (black arrow; hematoxylin & eosin, 400×). (B) Focal mild perivenous fibrosis (white arrow; hematoxylin & eosin, 400×). The necroinflammatory activity is graded 1 and the fibrosis is staged 1 by Brunt et al’s criteria.8
of alcohol abuse, any drugs or toxin exposure, and blood transfusion. None of his family had history of chronic liver disease. At that time, his body weight was 77 kg and body height was 173.5 cm (body mass index [BMI], 25.6 kg/m2). Serum ALT level was 59 IU/L (upper limit of normal [ULN], < 37 IU/L) and serum AST level was 40 IU/L (ULN, < 37 IU/L). Blood pressure, blood sugar, serum albumin, globulin, bilirubin, alkaline phosphatase and γ-glutamyl transferase levels were all within normal limits. Serum total cholesterol (T-CHO) level was 233 mg/dL (ULN, < 220 mg/dL) and triglyceride (TG) level was 68 mg/dL (ULN, < 150 mg/dL). Hepatitis viral markers in February 1987 revealed that he was negative for both hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs), and positive for antibody against hepatitis B core antigen (anti-HBc). Antibody against hepatitis C virus (anti-HCV), performed in February 2000 when the assay was available, was also negative. Serological studies excluded the presence of autoimmune hepatitis and inherited/metabolic liver diseases. Abdominal ultrasonography showed a small hemangioma at the right lobe of the liver. His hepatic parenchyma was fine in echotexture and there was no evidence of fatty liver. Since viral hepatitis, drug-induced liver injury and autoimmune liver disease had been ruled out, the diagnosis of cryptogenic hepatitis was made. J Formos Med Assoc | 2008 • Vol 107 • No 10
Liver biopsy was performed after 18 months of persistently elevated serum ALT and AST. Histologic examination disclosed evidence of steatohepatitis: diffuse micro- and macrovesicular fatty changes in the hepatocytes; mild focal necrosis of the hepatocytes in the lobules, accompanied by mild mononuclear cell infiltration in portal and lobular areas; and mild focal perivenous fibrosis (Figure 1). Based on Brunt’s criteria, the necroinflammatory activity was grade 1 and the fibrosis was stage 1.8 Over the next 12 years, serum AST and ALT levels increased gradually to 6–8 × ULN. Hepatitis B and C viral serologic markers were repeatedly negative. Serum HBV DNA and HCV RNA were also undetectable by polymerase chain reaction assays when the techniques became available. Alcohol abuse and drugs or toxin exposure were denied. Evidence of autoimmune liver disease was not found during follow-up. Meanwhile, his body weight increased to 83 kg (BMI, 27.6 kg/m2) in 1999. Moreover, serum lipid profile revealed that T-CHO level was 344 mg/dL, TG level was 152 mg/dL, low-density lipoprotein (LDL) level was 273 mg/dL, and high-density lipoprotein (HDL) level was 40 mg/dL. Fasting serum glucose level was 83 mg/dL. Simvastatin was thus prescribed and his serum T-CHO decreased to 133 mg/dL in May 2001. Serum AST and ALT levels improved in parallel (AST, 46 IU/L; ALT, 817
P.H. Tseng, et al
AST/ALT (IU/L), T-CHO/TG (mg/dL)
500 450
1st liver biopsy
2nd liver biopsy
Simvastatin
400 350 AST
300
ALT
250
T-CHO
200
TG
150 100 50 0 1987 1988 1989 1999 2000 2001 2002 2003 2004 2005 Year 27.6 27.1 28.8 28.6 BMI (kg/m2) 25.6
Figure 2. Chronological profile of body mass index (BMI), serum aspartate aminotransferase (AST) level, serum alanine aminotransferase (ALT) level, serum total cholesterol (T-CHO) level, and serum triglyceride (TG) level during an 18-year follow-up.
89 IU/L). However, drug compliance was not satisfactory and his body weight increased gradually to 86.6 kg (BMI, 28.8 kg/m2) in December 2004, 17 years after his first visit to our hospital, accompanied by deterioration in serum AST and ALT levels. The chronological data of serum AST, ALT, TG and T-CHO levels, and BMI during follow-up are shown in Figure 2. Abdominal ultrasonography performed in May 2005 showed the presence of fatty liver of moderate degree in addition to a small hemangioma. In June 2005, his body height was 173.5 cm and body weight was 86.0 kg (BMI, 28.6 kg/m2). His waist circumference was 91 cm. The body temperature was 36.6°C, pulse rate was 72 per minute, respiratory rate was 20 per minute, and blood pressure was 106/70 mmHg. Other physical findings were unremarkable. The white blood cell count was 5850/mm3. Blood sugar level was 95 mg/dL before meal and 128 mg/dL 2 hours after meal. Serum AST and ALT levels were 56 IU/L and 119 IU/L, respectively. Serum lipid profile revealed that TCHO level was 306 mg/dL, TG level was 102 mg/ dL, LDL level was 242 mg/dL, and HDL level was 44 mg/dL. He received follow-up needle biopsy of the liver on July 14, 2005, 17 years after the first biopsy. Histologic features again disclosed 818
evidence of steatohepatitis: diffuse micro- and macrovesicular fatty changes of the hepatocytes; lymphocytic and occasional neutrophilic infiltration in portal and lobular areas; and fibrosis at the portal, perivenular and pericentral venous areas with septum formation, which was confirmed by Masson-Trichrome stain (Figure 3). The histology was therefore designated grade 1 necroinflammation and stage 2 fibrosis based on the same criteria of Brunt et al.8
Discussion We report a histologically proven case of NASH in a Taiwanese patient, who had metabolic derangements and a long-term follow-up for more than 18 years. This patient documented the existence of NAFLD/NASH in Taiwan with possible histologic progression. The development of NAFLD/NASH has been linked to insulin resistance and it is now considered a hepatic manifestation of the metabolic syndrome.3,9,10 However, the criteria for the diagnosis of metabolic syndrome are set according to studies in Western countries and may not be suitable for Asian populations.11 For example, recent J Formos Med Assoc | 2008 • Vol 107 • No 10
Nonalcoholic steatohepatitis
A
B
Figure 3. Second liver biopsy (July 2005) reveals diffuse micro- and macrovesicular fatty changes of the hepatocytes, accompanied by lymphocytic and occasional neutrophilic infiltrations in the portal and lobular areas. (A) Fibrosis at the portal area (black arrow; hematoxylin & eosin, 400×). (B) Fibrosis at the portal, perivenular and pericellular areas with septal formation (white arrow; Masson-trichrome stain, 200×). The necroinflammatory activity is graded 1 and the fibrosis is staged 2 by Brunt et al’s criteria.8
studies suggested that the risk of obesity in Asians may be higher than that of other ethnic groups using the same BMI cutoff values. Accordingly, the definition of overweight and obesity in Taiwanese may be better set as BMI > 24 kg/m2 and > 27 kg/m2, respectively. In the present case, if we used the modified criteria, he would already be overweight at the initial visit (BMI, 25.6 kg/m2) and obese at the last visit (BMI, 28.6 kg/m2). The presence of metabolic derangement most likely accounted for the development of NAFLD/NASH in this patient. The diagnosis of NAFLD and NASH relies on clinical suspicion and histopathologic findings. Mildly to moderately elevated serum aminotransferase levels are common. Imaging studies may provide evidence of fatty infiltration of the liver but cannot differentiate simple steatosis from NASH.12 Therefore, liver biopsy remains the definite diagnostic procedure.3 In the present case, initial abdominal ultrasonography did not show the typical features of liver brightness, blurring of vessel walls nor fat attenuation.13 However, the presence of diffuse steatosis was found by liver biopsy, which consistently supported the role of liver biopsy for accurate diagnosis. The pattern of steatosis in NASH/NAFLD is mostly macrovesicular and secondly mixed macrovesicular and microvesicular,8 as seen in the present case. J Formos Med Assoc | 2008 • Vol 107 • No 10
The pattern of true microvesicular steatosis, consisting of much smaller and uniform fat droplets dispersed throughout the hepatocyte, was not found in the pathologic examinations of the case. Furthermore, the possibility of toxin exposure, the most common cause of microvesicular steatosis, was also excluded by history. As to the management of NAFLD and NASH, currently, there is still no proven effective drug therapy. A recent study has revealed that aggressive body weight control was followed by improvement in the biochemical and histologic profiles of NASH patients.14 In our patient who had underlying obesity and hyperlipidemia, weight reduction was suggested and the lipid-lowering agent simvastatin was used. Interestingly, clinical improvement of both total cholesterol level and liver function test was documented, although only transiently due to his poor drug compliance and progressively increasing body weight. The natural history of NAFLD correlates with baseline histologic findings.15 Retrospective cohort studies suggested that patients with simple steatosis usually run a benign course with a negligible risk of developing cirrhosis over 15–20 years. In contrast, patients with NASH and fibrosis can progress to cirrhosis with a risk ranging from 0% to 12% over 5–8 years’ follow-up.1,16–18 Data on the prevalence and natural course in 819
P.H. Tseng, et al
Chinese populations are limited in the literature. Wong et al reviewed the clinical and histologic features of 42 patients with biopsy-proven NAFLD in Hong Kong.19 They found that most patients had features of metabolic syndrome. As high as 85.7% of NAFLD patients had evidence of steatohepatitis and 26.1% had fibrosis according to Brunt’s criteria. They further investigated the histologic progression in 17 Chinese patients with paired liver biopsy.20 Nine (53%) of them had a progressive disease with worsening of fibrosis score during a median histologic follow-up period of 6.1 years (range, 3.8–8.0 years). In our patient with a paired histologic follow-up of over 17 years, we also demonstrated the benign but slowly progressive course of NASH. In Taiwan, chronic viral hepatitis including hepatitis B and C is the most common cause of liver disease. However, with the control of chronic viral hepatitis by universal vaccination and effective antiviral therapies, NAFLD/NASH will become major liver diseases in the Taiwanese people. The prevalence of fatty liver was found to be around 40% by ultrasonography in a hospital-based health check-up series.21 NASH has been reported in morbidly obese patients in Taiwan with a prevalence of 33.8%.22 Nevertheless, the prevalence of NAFLD and NASH in the general population of Taiwan remains to be studied. From another aspect, whether NAFLD superimposed on patients with underlying chronic viral hepatitis contributes to the progression of liver diseases should also be seriously considered. In our retrospective studies, hepatic steatosis was found in 46% of patients with chronic hepatitis C, but steatohepatitis was uncommonly encountered (4%). Furthermore, the presence of steatosis might adversely affect the response to antiviral therapy.23,24 These findings indicate that correcting metabolic derangement might help to improve the response to antiviral therapies. In summary, we documented a case of NASH and showed progression of the disease in a Taiwanese man. NAFLD, a health burden in Western countries, will very likely prevail in Oriental countries in the near future. Clinicians in Taiwan 820
should become aware of the issues of NAFLD, apart from the well-known facts of chronic viral hepatitis B and C. The role of correcting metabolic derangement in preventing the progression of NAFLD and the impact of coexisting NAFLD on the natural history and antiviral treatment outcomes in patients with underlying chronic viral hepatitis merit further studies.
Acknowledgments This work was supported by grants from National Taiwan University Hospital, the Department of Health, the National Science Council, Executive Yuan, and the National Health Research Institutes, Taiwan.
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