- Email: [email protected]
Nonalcoholic Fatty Liver Disease
Nonalcoholic Fatty Liver Disease LEON A. ADAMS, MBBS, AND KEITH D. LINDOR, MD
Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis not associated with a significant intake of ethanol. Insulin resistance is central to the pathogenesis of NAFLD; thus obesity, diabetes, and the metabolic syndrome are frequently associated with the disease. Consequently, as these metabolic conditions emerge as major health problems in Western society, it is now recognized that NAFLD is the most common chronic liver condition in the Western world. NAFLD is generally asymptomatic, although a minority of patients may present with evidence of progressive liver injury with complications of cirrhosis, liver failure, and hepatocellular carcinoma. Despite being common and potentially serious, relatively little is known about the natural history or prognostic significance of NAFLD. Although diabetes, obesity, and age are recognized risk factors for advanced liver disease, other significant factors leading to progressive liver injury remain to be identified. The treatment of NAFLD focuses upon modifying metabolic risk factors. Insulin-sensitizing and hepatoprotective drugs have been subjected to study trials, but as yet, no agent has conclusively been demonstrated to prevent disease progression. Management is further complicated by the inability to predict which patients will develop liver-related morbidity and thus benefit from treatment. Ann Epidemiol 2007;17:863–869. Ó 2007 Elsevier Inc. All rights reserved. KEY WORDS:
Nonalcoholic Fatty Liver, Steatohepatitis.
INVITED COMMENTARY INTRODUCTION The presence of nonalcoholic liver disease (NAFLD) is determined by the radiological or pathological confirmation of hepatic steatosis in association with the clinical exclusion of excessive alcohol intake (1). The definition of ‘‘excessive’’ alcohol intake is variable; however, 20 g/d is commonly accepted (1, 2). NAFLD occurs as a histological spectrum of disease and includes the subtypes of simple steatosis and nonalcoholic steatohepatitis (NASH). Simple steatosis describes hepatic steatosis in the absence of histological evidence of hepatocellular damage, whereas NASH refers to hepatic steatosis with associated inflammation and hepatocyte damage (1). Fibrosis may be present but is not necessary for the definition of NASH. NAFLD may be categorized as primary or secondary depending on the underlying pathogenesis (Table 1). Primary NAFLD occurs most commonly and is associated with insulin-resistant states, such as diabetes and obesity, and will be the focus of this review. Other conditions associated with insulin resistance, such as polycystic ovarian syndrome and hypopituitarism, have also been described in association with From the School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital Campus (L.A.A.) and the Division of Gastroenterology and Hepatology, Mayo Clinic and College of Medicine, Rochester, MN (K.D.L.). Address correspondence to: Professor Keith Lindor, Department of Gastroenterology and Medicine, Mayo Clinic, Rochester MN 55905. E-mail: [email protected]. Received April 9, 2007; accepted May 1, 2007. Ó 2007 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
NAFLD, although the exact prevalence and significance in these conditions remains unclear (3, 4). Distinction from secondary types is important as these have differing treatment and prognoses (5).
EPIDEMIOLOGY The prevalence of NAFLD varies according to the sensitivity of the instrument used to detect hepatic steatosis. Magnetic resonance spectroscopy (MRS) and liver biopsy are the most sensitive techniques at detecting hepatic steatosis, whereas the sensitivity of ultrasound varies between 49% and 94%, being less sensitive with milder degrees of hepatic steatosis or with higher levels of body mass index (BMI) (6, 7). Abnormal liver enzymes not due to alcohol, viral hepatitis, or iron overload are present in 2.8% to 5.5% of the U.S. general population and may be due to NAFLD in 66% to 90% of cases (8–11). However, raised liver enzymes are insensitive at detecting NAFLD, being normal in up to 78% of cases and thus are of limited value for determining prevalence (12). NAFLD is very common and occurs in persons of all ages and ethnic groups (Table 2). A large population-based study of 2287 adult subjects from the United States found the adjusted prevalence of hepatic steatosis as detected by MRS to be 34%, over 90% of which could be attributed to nonalcoholic causes (12). Overall, hepatic steatosis was slightly more common among males than females with a 1.1:1 ratio, although this increased to 1.8:1 among Caucasians. Potential living liver transplant donors undergoing work-up 1047-2797/07/$–see front matter doi:10.1016/j.annepidem.2007.05.013
864
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
Selected Abbreviations and Acronyms BMI Z body mass index FFA Z free fatty acid HCC Z hepatocellular carcinoma NAFLD Z non-alcoholic fatty liver disease NASH Z non-alcoholic steatohepatitis
with liver biopsy have a similar prevalence of hepatic steatosis of 33% (13). Other population-based studies have found the prevalence of hepatic steatosis or NAFLD to be between 13% and 26% (14–17). Potential reasons for the variable prevalence include the use of less sensitive imaging techniques and differences in ethnic composition and metabolic risk factors. Among Asian populations, the prevalence of NAFLD/fatty liver as detected by ultrasound is 14% to 16% (14, 16, 17). Using MRS, the prevalence of fatty liver is highest among Hispanic persons (45%) compared to Caucasians or African Americans (33% and 31%, respectively) (12). The prevalence of metabolic risk factors in these studies is generally lower among Asians compared with African Americans or Hispanics but similar to Caucasians. The importance of metabolic factors has been demonstrated in a population-based study from northern Italy (18) where the prevalence of NAFLD, as determined by ultrasound, increased from 16.4% among individuals of normal weight (BMI: !25 kg/m2) to 75.8% among obese persons (BMI O30 kg/m2). The prevalence among morbidly obese individuals undergoing bariatric surgery is up to 96% (19). Similarly, the prevalence of NAFLD rises with increasing degrees of hyperglycemia, being 27% among subjects with normal fasting glucose levels (!110 mg/dL) and rising to 43% among those with impaired fasting glycemia (110– 126 mg/dL) to 62% among patients with newly diagnosed diabetes (O126 mg/dL) (20). Among nonobese, nondiabetic individuals, other metabolic risk factors for NAFLD TABLE 1. Types of nonalcoholic fatty liver disease Type Primary Secondary Drugs
Viruses Metabolic conditions
Toxins Nutritional
Associations Obesity, glucose intolerance, hypertension, hypertriglyceridemia, low HDL cholesterol Corticosteroids, tamoxifen, diltiazem, aspirin, HAART, valproate, amiodarone, methotrexate, total parental nutrition Hepatitis C, human immunodeficiency virus Hypobetalipoproteinemia, lipodystrophy, hypopituitarism, hypothalamic obesity, WeberChristian syndrome, acute fatty liver of pregnancy, Reyes syndrome Organic solvents, mushroom toxins Rapid weight loss, intestinal bypass surgery, starvation
HAART Z highly active antiretroviral therapy.
AEP Vol. 17, No. 11 November 2007: 863–869
include impaired fasting glycemia (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.5–5.20), hypertriglyceridemia (OR 2.8, 95% CI 2.0–4.0]), hyperuricemia (OR 2.6, 95% CI 1.6–4.1), central obesity (OR 2.4, 95% CI 1.7– 3.4), hypertension (OR 1.7, 95% CI 1.2–2.4]) and low high-density lipoprotein (HDL) cholesterol levels (OR 1.4, 95% CI 1.0–2.0) (21). The prevalence of NAFLD increases with age with a peak prevalence of 25.6% in 40- to 49-year-olds recorded in Japan, whereas a peak of 21.9% was found among adults 65 years of age and older in China (16, 17). Similarly, another Chinese study found fatty liver to be most prevalent (28.4%) among 60- to 69-year-olds (14). The only population-based study among children documented a prevalence of 2.6%, as determined by ultrasound, among 4- to 12-year-olds, which increased to 22% in the presence of obesity (22). There are no population-based epidemiological studies examining the elderly, although a prevalence of NAFLD of 46% has been documented among hospitalized octogenarians (23). Determining the prevalence of the different subtypes of NAFLD is difficult as distinguishing between them requires histological examination of a liver biopsy specimen. An autopsy study of 351 individuals revealed NASH in 2.7% of normal-weight subjects, which increased to 18.5% among obese subjects (24). A history of type 2 diabetes was also associated with an increased prevalence of NASH (12.2% vs. 4.7%). Work-up of 100 potential living liver donors by means of liver biopsy revealed simple steatosis in 26% and mild NASH in 6% of this select group (13).
PATHOPHYSIOLOGY Accumulation of hepatic triglyceride results when lipid influx and de novo synthesis exceeds hepatic lipid export and utilization. Insulin resistance is an important driving force, which promotes lipolysis of peripheral adipose tissue which in turn increases free fatty acid (FFA) influx into the liver. Hyperinsulinemia and hyperglycemia also promote de novo lipogenesis as well as indirectly inhibit FFA oxidation (25, 26). Lipid export from the liver may also be impaired among individuals with NAFLD because of defective incorporation of triglyceride into apolipoprotein carrier proteins (27, 28). The steatotic liver appears to be susceptible to further hepatotoxic insults, which may lead to hepatocyte injury, inflammation, and fibrosis (29). The exact mechanisms promoting progressive liver injury are not well defined, although substrates derived from adipose tissue such as FFA, tumor necrosis factor alpha, leptin, and adiponectin have been implicated (30–35). Oxidative stress appears to be important, leading to subsequent lipid peroxidation, cytokine induction, and mitochondrial dysfunction. Microvascular
AEP Vol. 17, No. 11 November 2007: 863–869
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
865
TABLE 2. Prevalence of fatty liver disease among adults Prevalence (%) Year
Study
2005 2005 2005 2003 1988
Browning and Horton (25) Bedogni et al. (15) Fan et al. (14) Shen et al. (16) Nomura et al. (17)
Country USA Italy China China Japan
N
Diagnosis
Technique
2287 511 3175
Fatty liver NAFLD NAFLD NAFLD Fatty liver
MRS US US US US
2574
Overall
Males
Females
30.5 26.4 15.4 12.9 14.0
33.5 24.1 NA 15.8 13.6
27.8 30.1 NA 7.5 14.4
MRS Z magnetic resonance spectroscopy; NALFD Z nonalcoholic fatty liver disease; US Z ultrasound.
insufficiency has also been implicated in the exacerbation of liver injury (36). NATURAL HISTORY Since the first description of NASH, it has been recognized that hepatic fibrosis may be progressive and result in cirrhosis with complications of hepatocellular carcinoma (HCC), liver failure, and liver-related death (37, 38). Overall, NAFLD appears to be a slowly progressive, with diseaserelated morbidity and mortality occurring in a minority of subjects. There appears to be, however, considerable variation in the course of the disease with rapid progression to end-stage liver disease being reported among children, although it is unclear why this occurs (39). Recently it has also been acknowledged that a substantial proportion of patients with cryptogenic cirrhosis have previously unrecognized NAFLD (40). Subfulminant liver failure is a rare presentation of NAFLD, but has been reported in patients with presumed unrecognized cirrhosis who decompensate because of an unknown insult (41). Natural history studies of NAFLD have generally had limited numbers and follow-up or originate from tertiary referral centers, thus limiting the generalizability of their findings. Investigators have examined histological progression to advanced fibrosis as well as clinical progression to cirrhosis, liver failure, and death. Risk factors for advanced fibrosis in cross-sectional studies of patients with NAFLD include age, insulin resistance, and its clinical correlates of obesity, diabetes, and hypertriglyceridemia (19, 35, 42–45). The relationship between insulin resistance and advanced fibrosis may be confounded by the fact that cirrhosis leads to hyperinsulinemia and impaired insulin sensitivity (46). Therefore factors associated with advanced fibrosis in these crosssectional studies are not necessarily causative. A number of longitudinal studies have prospectively examined patients with serial liver biopsies to determine the progression of fibrosis in patients with NAFLD (Table 3) (38, 47–53). Progressive fibrosis appears to be more common among patients with NASH compared to those with simple steatosis. Approximately one third of patients with NASH
will have progressive fibrosis over 3 to 4 years, whereas over half will progress when followed up for 6 years. The small number of patients with simple steatosis studied has revealed progressive fibrosis in only zero to 8% of patients after a maximum of 16 years follow-up (48, 52). Diabetes and obesity are independent risk factors for progressive fibrosis among patients with NAFLD but appear to account for a small proportion of the risk (48, 49). Several studies have examined the clinical progression of NAFLD to cirrhosis, HCC, and liver-related death (38, 52– 57). Among patients with NAFLD from tertiary referral centers followed up for a mean of 8 years, the occurrence of cirrhosis is 20%, the incidence of HCC is 1%, and the incidence of liver-related death is 9% (55). Among community-based patients, the occurrence of cirrhosis, HCC, and liver-related death over a similar follow-up period is considerably lower at 5%, 0.5% and 3%, respectively, likely because of fewer selection biases (57). Importantly, NAFLD is associated with an increased risk of overall death compared to the general population (standardized mortality ratio 1.34), with diabetes and cirrhosis being risk factors for death (57). Liver disease was the third leading cause of death among NAFLD patients compared to the 13th leading cause among the general population, suggesting that liver-related mortality is responsible for a proportion of increased mortality risk among NAFLD patients.
TABLE 3. Histological progression of NAFLD
Author
Year
N
Diagnosis
Hui et al. (47) Adams et al. (48) Fassio et al. (49) Harrison et al. (50) Evans et al. (51) Teli et al. (52) Powell et al. (38) Lee (53)
2005 17 NAFLD 2005 103 NAFLD 2004 22 NASH 2003 22 NASH 2002 7 NASH 1995 12 Steatosis 1990 13 NASH 1989 13 NASH
NASH Z non-alcoholic steatohepatitis. *Mean.
Median follow-up, yr (range)
Progressive fibrosis (%)
6.1 (3.8–8.0) 9/17 (53) 3.2 (0.7–21.3) 37/103 (37) 4.3 (3.0–14.3) 7/22 (32) 5.7* (1.4–15.7) 7/22 (32) 8.2* (5.5–14.0) 4/7 (57) 11 (7.6–16.0) 1/12 (8) 4.3 (1.0–9.0) 4/13 (31) 3.2 (1.2–6.9) 5/13 (38)
866
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
Importantly, different histological subtypes of NAFLD have different clinical outcomes. Dam-Larsen and colleagues (54) followed up 109 patients with biopsy-proven hepatic steatosis without inflammation or fibrosis, for a median 16.7 years; only one patient developed cirrhosis and subsequently died of liver disease. Similarly, follow-up of 40 patients in the United Kingdom with simple steatosis for a median of 9.6 years revealed no progression to cirrhosis or liver-related deaths (52). Studies examining outcomes of patients with NASH have had relatively small patient numbers (32 to 42 subjects) and modest follow-up (3.8 to 5.9 years) (38, 53, 56). Among these patients who were recruited from tertiary hospital centers, the incidence of cirrhosis and liver-related death was 5% to 8% and 2% to 8%, respectively. In addition to leading to liver-related morbidity and mortality, there is some suggestion that NAFLD may exert metabolic effects. Although insulin resistance may lead to hepatic steatosis, the presence of hepatic fat worsens hepatic insulin resistance and thus may precipitate a vicious cycle (58). Supporting this hypothesis is a longitudinal cohort study which demonstrated that the development of obesity led to elevated hepatic aminotransaminases, which subsequently led to the development of glucose intolerance (59). Further studies are required to clarify the role of NAFLD in the development of metabolic diseases, such as diabetes.
NAFLD AND CRYPTOGENIC CIRRHOSIS An important observation by Powell and colleagues (38) was that patients with NAFLD may lose histological evidence of hepatic steatosis as the disease progresses to cirrhosis. Thus the histological picture may resemble one of cryptogenic cirrhosis. Subsequently, examination of metabolic risk factors among patients with cryptogenic cirrhosis revealed a similar prevalence of obesity and diabetes compared to patients with NASH, but a higher prevalence compared to patients with cirrhosis from other etiologies (60, 61). Furthermore, patients undergoing transplantation because of cryptogenic cirrhosis also tend to develop NAFLD after transplantation; one series demonstrated NAFLD in 52% of patients undergoing biopsy after transplantation (62).
NAFLD AND HCC The occurrence of HCC among patients with NAFLD appears to be relatively low, between zero and 2% (38, 63). However, as NAFLD may affect up to 1 in 3 persons, the potential disease burden may be considerable. Although HCC has been documented to rarely occur in NAFLD in the absence of cirrhosis (64), the risk appears predominantly in the
AEP Vol. 17, No. 11 November 2007: 863–869
presence of cirrhosis. The risk of HCC in patients with NASH-related cirrhosis is difficult to quantify because of the relatively low numbers of patients, inclusion of prevalent cases of HCC, lead-time bias, and patient populations including cryptogenic cirrhosis rather than NASH cirrhosis. In one Japanese referral center, 6 of 16 patients (38%) referred with NASH cirrhosis had a complicating HCC (65). In contrast, Hui et al (63) found no cases of HCC in 23 NASH patients with cirrhosis after a median follow-up of 5 years. The Japanese study included patients presenting with HCC at time of diagnosis of NASH-related cirrhosis and routinely screened their cirrhotic patients for HCC, potentially accounting for the difference between the two studies. As NAFLD may account for a substantial proportion of cases of cryptogenic cirrhosis, the occurrence of HCC among these patients has also been examined. The prevalence of obesity and diabetes is significantly higher in patients with HCC and cryptogenic cirrhosis compared to those with HCC and viral or alcohol-related cirrhosis, suggesting that NAFLD is the underlying etiology in many patients with cryptogenic cirrhosis complicated by HCC (66). A study from the United States found cryptogenic cirrhosis to be the second most common chronic liver disease associated with HCC, accounting for 29% (30/105) of all cases; approximately half of the cases of cryptogenic cirrhosis had histological or clinical features of NAFLD (67). In contrast, an Italian center found cryptogenic cirrhosis to account for only 7% (23/641) of HCC cases, which may reflect the higher prevalence of viral hepatitis in Italy; viral hepatitis accounted for 71% of all HCC cases (66). The risk of HCC among patients with cryptogenic cirrhosis is uncertain. One small retrospective analysis of obese patients with cryptogenic cirrhosis revealed HCC in 8 of 27 patients (30%), which was similar to the frequency among matched patients with hepatitis C (68).
TREATMENT Patients diagnosed with NAFLD should undergo evaluation and treatment of accompanying metabolic risk factors, such as obesity, glucose intolerance, and dyslipidemia in order to modify risk of morbidity and mortality from vascular disease. Treatment strategies specific for NAFLD aim to improve insulin sensitivity and modify underlying metabolic risk factors; these strategies may also be devised to protect the liver from oxidative stress and further insults. Liver transplantation may be required for patients with decompensated cirrhosis or liver cancer. Pharmacotherapy should probably be reserved for those patients at highest risk of developing cirrhosis, such as those with NASH, diabetes, and obesity. Definitive treatment recommendations regarding
AEP Vol. 17, No. 11 November 2007: 863–869
pharmacotherapy are difficult because of the lack of adequately powered randomized controlled trials of sufficient duration and with histological end points. Weight loss by dieting and exercise has been demonstrated to improve liver biochemistry and degree of hepatic steatosis (69). Uncontrolled series have shown improvement in liver histology with bariatric surgery (70), although very rapid weight loss can paradoxically worsen hepatic inflammation and fibrosis (69). Insulin-sensitizing agents, such as metformin, pioglitazone, and rosiglitazone, have been shown to improve histological features of NAFLD, although in the absence of comparative control groups (71–74). Vitamin E has not been shown to convincingly improve liver biochemistry or histology (50, 74). Other hepatoprotective and antifibrotic agents, such as betaine, pentoxifylline, and losartan, have shown promise in small pilot trials (69, 75).
CONCLUSIONS NAFLD is a common condition related to insulin-resistant states such as obesity and glucose intolerance. The individual risk of developing disease-related morbidity and mortality appears relatively low; however, the overall public health burden may be substantial, considering the high prevalence of the disease. Further natural history studies with adequate follow-up are required to clarify this further. In addition, research into disease pathogenesis will assist in identifying patients who are at greatest risk of progressive disease. This will also aid in the appropriate identification of which patients will require potentially long-term and expensive treatment. Leon Adams is sponsored by a Postgraduate Medical Research Scholarship (No. 353710) from the National Health and Medical Research Council as well as by the Athelstan and Amy Saw Postgraduate Medical Scholarship from The University of Western Australia.
REFERENCES 1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219. 2. Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–1725. 3. Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39:909–914. 4. Schwimmer JB, Khorram C, Chiu V, Schwimmer W. Abnormal aminotransferase activity in women with polycystic ovary syndrome. Fertil Steril. 2005;83:494–497. 5. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221– 1231. 6. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–637. 7. Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol. 2003;15:539–543.
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
867
8. Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–79. 9. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–967. 10. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. 1999;94:3010–3014. 11. Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001;35:195–199. 12. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387– 1395. 13. Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 2002;8:1114–1122. 14. Fan JG, Zhu G, Li XJ, Chen L, Li L, Dai F, et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol. 2005;43:508–513. 15. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52. 16. Shen L, Fan JG, Shao Y, Zeng MD, Wang JR, Luo GH, et al. Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol. 2003;9:1106–1110. 17. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med. 1988;27:142–149. 18. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–117. 19. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100. 20. Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005;22:1141–1145. 21. Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med. 2004;164:2169–2175. 22. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci. 1995;40:2002– 2009. 23. Kagansky N, Levy S, Keter D, Rimon E, Taiba Z, Fridman Z, et al. Nonalcoholic fatty liver diseaseda common and benign finding in octogenarian patients. Liver Int. 2004;24:588–594. 24. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106– 1110. 25. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152. 26. Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP1c) transcriptional activity in rat hepatocytes. Biochem J. 2000;350(Pt 2):389–393. 27. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology. 2002;35:898– 904.
868
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
AEP Vol. 17, No. 11 November 2007: 863–869
28. Letteron P, Sutton A, Mansouri A, Fromenty B, Pessayre D. Inhibition of microsomal triglyceride transfer protein: another mechanism for druginduced steatosis in mice. Hepatology. 2003;38:133–140.
49. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.
29. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842–845.
50. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.
30. Haque M, Sanyal AJ. The metabolic abnormalities associated with nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol. 2002;16:709–731. 31. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–443. 32. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185– 194. 33. Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122:274–280. 34. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–211. 35. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54. 36. McCuskey RS, Ito Y, Robertson GR, McCuskey MK, Perry M, Farrell GC. Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice. Hepatology. 2004;40:386–393. 37. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438. 38. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80. 39. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500–505. 40. Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol. 2004;40:578–584. 41. Caldwell SH, Hespenheide EE. Subacute liver failure in obese women. Am J Gastroenterol. 2002;97:2058–2062. 42. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–1362.
51. Evans CD, Oien KA, MacSween RN, Mills PR. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol. 2002;55:689–692. 52. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714– 1719. 53. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol. 1989;20:594–598. 54. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755. 55. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419. 56. Cortez-Pinto H, Baptista A, Camilo ME, De Moura MC. Nonalcoholic steatohepatitis–a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci. 2003;48:1909–1913. 57. Adams LA, Lymp J, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease:a population based cohort study. Gastroenterology. 2005;129:113–121. 58. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279:32345–32353. 59. Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology. 2005;41:64–71. 60. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology. 2000;32:689–692. 61. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–669. 62. Ong J, Younossi ZM, Reddy V, Price LL, Gramlich T, Mayes J, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl. 2001;7:797–801. 63. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et al. Longterm outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427.
43. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–1123.
64. Bullock RE, Zaitoun AM, Aithal GP, Ryder SD, Beckingham IJ, Lobo DN. Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma. J Hepatol. 2004;41:685–686.
44. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.
65. Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2002;37:154–160.
45. Bugianesi E, Manzini P, D’Antico S, Vanni E, Longo F, Leone N, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology. 2004;39:179–187.
66. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.
46. Petrides AS, Stanley T, Matthews DE, Vogt C, Bush AJ, Lambeth H. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology. 1998;28:141–149. 47. Hui AY, Wong WS, Chan HL, Liew CT, Chan JL, Chan FK, et al. Histological progression of nonalcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther. 2005;21:407–413. 48. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138.
67. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36:1349–1354. 68. Ratziu V, Bonyhay L, Di Martino V, Charlotte F, Cavallaro L, SayeghTainturier MH, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485–1493. 69. Angulo P. Current best treatment for non-alcoholic fatty liver disease. Expert Opin Pharmacother. 2003;4:611–623.
AEP Vol. 17, No. 11 November 2007: 863–869
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
869
70. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654.
73. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017.
71. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–1090.
74. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–1115.
72. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.
75. Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225.
Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis not associated with a significant intake of ethanol. Insulin resistance is central to the pathogenesis of NAFLD; thus obesity, diabetes, and the metabolic syndrome are frequently associated with the disease. Consequently, as these metabolic conditions emerge as major health problems in Western society, it is now recognized that NAFLD is the most common chronic liver condition in the Western world. NAFLD is generally asymptomatic, although a minority of patients may present with evidence of progressive liver injury with complications of cirrhosis, liver failure, and hepatocellular carcinoma. Despite being common and potentially serious, relatively little is known about the natural history or prognostic significance of NAFLD. Although diabetes, obesity, and age are recognized risk factors for advanced liver disease, other significant factors leading to progressive liver injury remain to be identified. The treatment of NAFLD focuses upon modifying metabolic risk factors. Insulin-sensitizing and hepatoprotective drugs have been subjected to study trials, but as yet, no agent has conclusively been demonstrated to prevent disease progression. Management is further complicated by the inability to predict which patients will develop liver-related morbidity and thus benefit from treatment. Ann Epidemiol 2007;17:863–869. Ó 2007 Elsevier Inc. All rights reserved. KEY WORDS:
Nonalcoholic Fatty Liver, Steatohepatitis.
INVITED COMMENTARY INTRODUCTION The presence of nonalcoholic liver disease (NAFLD) is determined by the radiological or pathological confirmation of hepatic steatosis in association with the clinical exclusion of excessive alcohol intake (1). The definition of ‘‘excessive’’ alcohol intake is variable; however, 20 g/d is commonly accepted (1, 2). NAFLD occurs as a histological spectrum of disease and includes the subtypes of simple steatosis and nonalcoholic steatohepatitis (NASH). Simple steatosis describes hepatic steatosis in the absence of histological evidence of hepatocellular damage, whereas NASH refers to hepatic steatosis with associated inflammation and hepatocyte damage (1). Fibrosis may be present but is not necessary for the definition of NASH. NAFLD may be categorized as primary or secondary depending on the underlying pathogenesis (Table 1). Primary NAFLD occurs most commonly and is associated with insulin-resistant states, such as diabetes and obesity, and will be the focus of this review. Other conditions associated with insulin resistance, such as polycystic ovarian syndrome and hypopituitarism, have also been described in association with From the School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital Campus (L.A.A.) and the Division of Gastroenterology and Hepatology, Mayo Clinic and College of Medicine, Rochester, MN (K.D.L.). Address correspondence to: Professor Keith Lindor, Department of Gastroenterology and Medicine, Mayo Clinic, Rochester MN 55905. E-mail: [email protected]. Received April 9, 2007; accepted May 1, 2007. Ó 2007 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
NAFLD, although the exact prevalence and significance in these conditions remains unclear (3, 4). Distinction from secondary types is important as these have differing treatment and prognoses (5).
EPIDEMIOLOGY The prevalence of NAFLD varies according to the sensitivity of the instrument used to detect hepatic steatosis. Magnetic resonance spectroscopy (MRS) and liver biopsy are the most sensitive techniques at detecting hepatic steatosis, whereas the sensitivity of ultrasound varies between 49% and 94%, being less sensitive with milder degrees of hepatic steatosis or with higher levels of body mass index (BMI) (6, 7). Abnormal liver enzymes not due to alcohol, viral hepatitis, or iron overload are present in 2.8% to 5.5% of the U.S. general population and may be due to NAFLD in 66% to 90% of cases (8–11). However, raised liver enzymes are insensitive at detecting NAFLD, being normal in up to 78% of cases and thus are of limited value for determining prevalence (12). NAFLD is very common and occurs in persons of all ages and ethnic groups (Table 2). A large population-based study of 2287 adult subjects from the United States found the adjusted prevalence of hepatic steatosis as detected by MRS to be 34%, over 90% of which could be attributed to nonalcoholic causes (12). Overall, hepatic steatosis was slightly more common among males than females with a 1.1:1 ratio, although this increased to 1.8:1 among Caucasians. Potential living liver transplant donors undergoing work-up 1047-2797/07/$–see front matter doi:10.1016/j.annepidem.2007.05.013
864
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
Selected Abbreviations and Acronyms BMI Z body mass index FFA Z free fatty acid HCC Z hepatocellular carcinoma NAFLD Z non-alcoholic fatty liver disease NASH Z non-alcoholic steatohepatitis
with liver biopsy have a similar prevalence of hepatic steatosis of 33% (13). Other population-based studies have found the prevalence of hepatic steatosis or NAFLD to be between 13% and 26% (14–17). Potential reasons for the variable prevalence include the use of less sensitive imaging techniques and differences in ethnic composition and metabolic risk factors. Among Asian populations, the prevalence of NAFLD/fatty liver as detected by ultrasound is 14% to 16% (14, 16, 17). Using MRS, the prevalence of fatty liver is highest among Hispanic persons (45%) compared to Caucasians or African Americans (33% and 31%, respectively) (12). The prevalence of metabolic risk factors in these studies is generally lower among Asians compared with African Americans or Hispanics but similar to Caucasians. The importance of metabolic factors has been demonstrated in a population-based study from northern Italy (18) where the prevalence of NAFLD, as determined by ultrasound, increased from 16.4% among individuals of normal weight (BMI: !25 kg/m2) to 75.8% among obese persons (BMI O30 kg/m2). The prevalence among morbidly obese individuals undergoing bariatric surgery is up to 96% (19). Similarly, the prevalence of NAFLD rises with increasing degrees of hyperglycemia, being 27% among subjects with normal fasting glucose levels (!110 mg/dL) and rising to 43% among those with impaired fasting glycemia (110– 126 mg/dL) to 62% among patients with newly diagnosed diabetes (O126 mg/dL) (20). Among nonobese, nondiabetic individuals, other metabolic risk factors for NAFLD TABLE 1. Types of nonalcoholic fatty liver disease Type Primary Secondary Drugs
Viruses Metabolic conditions
Toxins Nutritional
Associations Obesity, glucose intolerance, hypertension, hypertriglyceridemia, low HDL cholesterol Corticosteroids, tamoxifen, diltiazem, aspirin, HAART, valproate, amiodarone, methotrexate, total parental nutrition Hepatitis C, human immunodeficiency virus Hypobetalipoproteinemia, lipodystrophy, hypopituitarism, hypothalamic obesity, WeberChristian syndrome, acute fatty liver of pregnancy, Reyes syndrome Organic solvents, mushroom toxins Rapid weight loss, intestinal bypass surgery, starvation
HAART Z highly active antiretroviral therapy.
AEP Vol. 17, No. 11 November 2007: 863–869
include impaired fasting glycemia (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.5–5.20), hypertriglyceridemia (OR 2.8, 95% CI 2.0–4.0]), hyperuricemia (OR 2.6, 95% CI 1.6–4.1), central obesity (OR 2.4, 95% CI 1.7– 3.4), hypertension (OR 1.7, 95% CI 1.2–2.4]) and low high-density lipoprotein (HDL) cholesterol levels (OR 1.4, 95% CI 1.0–2.0) (21). The prevalence of NAFLD increases with age with a peak prevalence of 25.6% in 40- to 49-year-olds recorded in Japan, whereas a peak of 21.9% was found among adults 65 years of age and older in China (16, 17). Similarly, another Chinese study found fatty liver to be most prevalent (28.4%) among 60- to 69-year-olds (14). The only population-based study among children documented a prevalence of 2.6%, as determined by ultrasound, among 4- to 12-year-olds, which increased to 22% in the presence of obesity (22). There are no population-based epidemiological studies examining the elderly, although a prevalence of NAFLD of 46% has been documented among hospitalized octogenarians (23). Determining the prevalence of the different subtypes of NAFLD is difficult as distinguishing between them requires histological examination of a liver biopsy specimen. An autopsy study of 351 individuals revealed NASH in 2.7% of normal-weight subjects, which increased to 18.5% among obese subjects (24). A history of type 2 diabetes was also associated with an increased prevalence of NASH (12.2% vs. 4.7%). Work-up of 100 potential living liver donors by means of liver biopsy revealed simple steatosis in 26% and mild NASH in 6% of this select group (13).
PATHOPHYSIOLOGY Accumulation of hepatic triglyceride results when lipid influx and de novo synthesis exceeds hepatic lipid export and utilization. Insulin resistance is an important driving force, which promotes lipolysis of peripheral adipose tissue which in turn increases free fatty acid (FFA) influx into the liver. Hyperinsulinemia and hyperglycemia also promote de novo lipogenesis as well as indirectly inhibit FFA oxidation (25, 26). Lipid export from the liver may also be impaired among individuals with NAFLD because of defective incorporation of triglyceride into apolipoprotein carrier proteins (27, 28). The steatotic liver appears to be susceptible to further hepatotoxic insults, which may lead to hepatocyte injury, inflammation, and fibrosis (29). The exact mechanisms promoting progressive liver injury are not well defined, although substrates derived from adipose tissue such as FFA, tumor necrosis factor alpha, leptin, and adiponectin have been implicated (30–35). Oxidative stress appears to be important, leading to subsequent lipid peroxidation, cytokine induction, and mitochondrial dysfunction. Microvascular
AEP Vol. 17, No. 11 November 2007: 863–869
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
865
TABLE 2. Prevalence of fatty liver disease among adults Prevalence (%) Year
Study
2005 2005 2005 2003 1988
Browning and Horton (25) Bedogni et al. (15) Fan et al. (14) Shen et al. (16) Nomura et al. (17)
Country USA Italy China China Japan
N
Diagnosis
Technique
2287 511 3175
Fatty liver NAFLD NAFLD NAFLD Fatty liver
MRS US US US US
2574
Overall
Males
Females
30.5 26.4 15.4 12.9 14.0
33.5 24.1 NA 15.8 13.6
27.8 30.1 NA 7.5 14.4
MRS Z magnetic resonance spectroscopy; NALFD Z nonalcoholic fatty liver disease; US Z ultrasound.
insufficiency has also been implicated in the exacerbation of liver injury (36). NATURAL HISTORY Since the first description of NASH, it has been recognized that hepatic fibrosis may be progressive and result in cirrhosis with complications of hepatocellular carcinoma (HCC), liver failure, and liver-related death (37, 38). Overall, NAFLD appears to be a slowly progressive, with diseaserelated morbidity and mortality occurring in a minority of subjects. There appears to be, however, considerable variation in the course of the disease with rapid progression to end-stage liver disease being reported among children, although it is unclear why this occurs (39). Recently it has also been acknowledged that a substantial proportion of patients with cryptogenic cirrhosis have previously unrecognized NAFLD (40). Subfulminant liver failure is a rare presentation of NAFLD, but has been reported in patients with presumed unrecognized cirrhosis who decompensate because of an unknown insult (41). Natural history studies of NAFLD have generally had limited numbers and follow-up or originate from tertiary referral centers, thus limiting the generalizability of their findings. Investigators have examined histological progression to advanced fibrosis as well as clinical progression to cirrhosis, liver failure, and death. Risk factors for advanced fibrosis in cross-sectional studies of patients with NAFLD include age, insulin resistance, and its clinical correlates of obesity, diabetes, and hypertriglyceridemia (19, 35, 42–45). The relationship between insulin resistance and advanced fibrosis may be confounded by the fact that cirrhosis leads to hyperinsulinemia and impaired insulin sensitivity (46). Therefore factors associated with advanced fibrosis in these crosssectional studies are not necessarily causative. A number of longitudinal studies have prospectively examined patients with serial liver biopsies to determine the progression of fibrosis in patients with NAFLD (Table 3) (38, 47–53). Progressive fibrosis appears to be more common among patients with NASH compared to those with simple steatosis. Approximately one third of patients with NASH
will have progressive fibrosis over 3 to 4 years, whereas over half will progress when followed up for 6 years. The small number of patients with simple steatosis studied has revealed progressive fibrosis in only zero to 8% of patients after a maximum of 16 years follow-up (48, 52). Diabetes and obesity are independent risk factors for progressive fibrosis among patients with NAFLD but appear to account for a small proportion of the risk (48, 49). Several studies have examined the clinical progression of NAFLD to cirrhosis, HCC, and liver-related death (38, 52– 57). Among patients with NAFLD from tertiary referral centers followed up for a mean of 8 years, the occurrence of cirrhosis is 20%, the incidence of HCC is 1%, and the incidence of liver-related death is 9% (55). Among community-based patients, the occurrence of cirrhosis, HCC, and liver-related death over a similar follow-up period is considerably lower at 5%, 0.5% and 3%, respectively, likely because of fewer selection biases (57). Importantly, NAFLD is associated with an increased risk of overall death compared to the general population (standardized mortality ratio 1.34), with diabetes and cirrhosis being risk factors for death (57). Liver disease was the third leading cause of death among NAFLD patients compared to the 13th leading cause among the general population, suggesting that liver-related mortality is responsible for a proportion of increased mortality risk among NAFLD patients.
TABLE 3. Histological progression of NAFLD
Author
Year
N
Diagnosis
Hui et al. (47) Adams et al. (48) Fassio et al. (49) Harrison et al. (50) Evans et al. (51) Teli et al. (52) Powell et al. (38) Lee (53)
2005 17 NAFLD 2005 103 NAFLD 2004 22 NASH 2003 22 NASH 2002 7 NASH 1995 12 Steatosis 1990 13 NASH 1989 13 NASH
NASH Z non-alcoholic steatohepatitis. *Mean.
Median follow-up, yr (range)
Progressive fibrosis (%)
6.1 (3.8–8.0) 9/17 (53) 3.2 (0.7–21.3) 37/103 (37) 4.3 (3.0–14.3) 7/22 (32) 5.7* (1.4–15.7) 7/22 (32) 8.2* (5.5–14.0) 4/7 (57) 11 (7.6–16.0) 1/12 (8) 4.3 (1.0–9.0) 4/13 (31) 3.2 (1.2–6.9) 5/13 (38)
866
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
Importantly, different histological subtypes of NAFLD have different clinical outcomes. Dam-Larsen and colleagues (54) followed up 109 patients with biopsy-proven hepatic steatosis without inflammation or fibrosis, for a median 16.7 years; only one patient developed cirrhosis and subsequently died of liver disease. Similarly, follow-up of 40 patients in the United Kingdom with simple steatosis for a median of 9.6 years revealed no progression to cirrhosis or liver-related deaths (52). Studies examining outcomes of patients with NASH have had relatively small patient numbers (32 to 42 subjects) and modest follow-up (3.8 to 5.9 years) (38, 53, 56). Among these patients who were recruited from tertiary hospital centers, the incidence of cirrhosis and liver-related death was 5% to 8% and 2% to 8%, respectively. In addition to leading to liver-related morbidity and mortality, there is some suggestion that NAFLD may exert metabolic effects. Although insulin resistance may lead to hepatic steatosis, the presence of hepatic fat worsens hepatic insulin resistance and thus may precipitate a vicious cycle (58). Supporting this hypothesis is a longitudinal cohort study which demonstrated that the development of obesity led to elevated hepatic aminotransaminases, which subsequently led to the development of glucose intolerance (59). Further studies are required to clarify the role of NAFLD in the development of metabolic diseases, such as diabetes.
NAFLD AND CRYPTOGENIC CIRRHOSIS An important observation by Powell and colleagues (38) was that patients with NAFLD may lose histological evidence of hepatic steatosis as the disease progresses to cirrhosis. Thus the histological picture may resemble one of cryptogenic cirrhosis. Subsequently, examination of metabolic risk factors among patients with cryptogenic cirrhosis revealed a similar prevalence of obesity and diabetes compared to patients with NASH, but a higher prevalence compared to patients with cirrhosis from other etiologies (60, 61). Furthermore, patients undergoing transplantation because of cryptogenic cirrhosis also tend to develop NAFLD after transplantation; one series demonstrated NAFLD in 52% of patients undergoing biopsy after transplantation (62).
NAFLD AND HCC The occurrence of HCC among patients with NAFLD appears to be relatively low, between zero and 2% (38, 63). However, as NAFLD may affect up to 1 in 3 persons, the potential disease burden may be considerable. Although HCC has been documented to rarely occur in NAFLD in the absence of cirrhosis (64), the risk appears predominantly in the
AEP Vol. 17, No. 11 November 2007: 863–869
presence of cirrhosis. The risk of HCC in patients with NASH-related cirrhosis is difficult to quantify because of the relatively low numbers of patients, inclusion of prevalent cases of HCC, lead-time bias, and patient populations including cryptogenic cirrhosis rather than NASH cirrhosis. In one Japanese referral center, 6 of 16 patients (38%) referred with NASH cirrhosis had a complicating HCC (65). In contrast, Hui et al (63) found no cases of HCC in 23 NASH patients with cirrhosis after a median follow-up of 5 years. The Japanese study included patients presenting with HCC at time of diagnosis of NASH-related cirrhosis and routinely screened their cirrhotic patients for HCC, potentially accounting for the difference between the two studies. As NAFLD may account for a substantial proportion of cases of cryptogenic cirrhosis, the occurrence of HCC among these patients has also been examined. The prevalence of obesity and diabetes is significantly higher in patients with HCC and cryptogenic cirrhosis compared to those with HCC and viral or alcohol-related cirrhosis, suggesting that NAFLD is the underlying etiology in many patients with cryptogenic cirrhosis complicated by HCC (66). A study from the United States found cryptogenic cirrhosis to be the second most common chronic liver disease associated with HCC, accounting for 29% (30/105) of all cases; approximately half of the cases of cryptogenic cirrhosis had histological or clinical features of NAFLD (67). In contrast, an Italian center found cryptogenic cirrhosis to account for only 7% (23/641) of HCC cases, which may reflect the higher prevalence of viral hepatitis in Italy; viral hepatitis accounted for 71% of all HCC cases (66). The risk of HCC among patients with cryptogenic cirrhosis is uncertain. One small retrospective analysis of obese patients with cryptogenic cirrhosis revealed HCC in 8 of 27 patients (30%), which was similar to the frequency among matched patients with hepatitis C (68).
TREATMENT Patients diagnosed with NAFLD should undergo evaluation and treatment of accompanying metabolic risk factors, such as obesity, glucose intolerance, and dyslipidemia in order to modify risk of morbidity and mortality from vascular disease. Treatment strategies specific for NAFLD aim to improve insulin sensitivity and modify underlying metabolic risk factors; these strategies may also be devised to protect the liver from oxidative stress and further insults. Liver transplantation may be required for patients with decompensated cirrhosis or liver cancer. Pharmacotherapy should probably be reserved for those patients at highest risk of developing cirrhosis, such as those with NASH, diabetes, and obesity. Definitive treatment recommendations regarding
AEP Vol. 17, No. 11 November 2007: 863–869
pharmacotherapy are difficult because of the lack of adequately powered randomized controlled trials of sufficient duration and with histological end points. Weight loss by dieting and exercise has been demonstrated to improve liver biochemistry and degree of hepatic steatosis (69). Uncontrolled series have shown improvement in liver histology with bariatric surgery (70), although very rapid weight loss can paradoxically worsen hepatic inflammation and fibrosis (69). Insulin-sensitizing agents, such as metformin, pioglitazone, and rosiglitazone, have been shown to improve histological features of NAFLD, although in the absence of comparative control groups (71–74). Vitamin E has not been shown to convincingly improve liver biochemistry or histology (50, 74). Other hepatoprotective and antifibrotic agents, such as betaine, pentoxifylline, and losartan, have shown promise in small pilot trials (69, 75).
CONCLUSIONS NAFLD is a common condition related to insulin-resistant states such as obesity and glucose intolerance. The individual risk of developing disease-related morbidity and mortality appears relatively low; however, the overall public health burden may be substantial, considering the high prevalence of the disease. Further natural history studies with adequate follow-up are required to clarify this further. In addition, research into disease pathogenesis will assist in identifying patients who are at greatest risk of progressive disease. This will also aid in the appropriate identification of which patients will require potentially long-term and expensive treatment. Leon Adams is sponsored by a Postgraduate Medical Research Scholarship (No. 353710) from the National Health and Medical Research Council as well as by the Athelstan and Amy Saw Postgraduate Medical Scholarship from The University of Western Australia.
REFERENCES 1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219. 2. Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–1725. 3. Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology. 2004;39:909–914. 4. Schwimmer JB, Khorram C, Chiu V, Schwimmer W. Abnormal aminotransferase activity in women with polycystic ovary syndrome. Fertil Steril. 2005;83:494–497. 5. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221– 1231. 6. Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–637. 7. Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gastroenterol Hepatol. 2003;15:539–543.
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
867
8. Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–79. 9. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–967. 10. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol. 1999;94:3010–3014. 11. Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001;35:195–199. 12. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387– 1395. 13. Ryan CK, Johnson LA, Germin BI, Marcos A. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl. 2002;8:1114–1122. 14. Fan JG, Zhu G, Li XJ, Chen L, Li L, Dai F, et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol. 2005;43:508–513. 15. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52. 16. Shen L, Fan JG, Shao Y, Zeng MD, Wang JR, Luo GH, et al. Prevalence of nonalcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol. 2003;9:1106–1110. 17. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med. 1988;27:142–149. 18. Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med. 2000;132:112–117. 19. Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100. 20. Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005;22:1141–1145. 21. Kim HJ, Lee KE, Kim DJ, Kim SK, Ahn CW, Lim SK, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med. 2004;164:2169–2175. 22. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci. 1995;40:2002– 2009. 23. Kagansky N, Levy S, Keter D, Rimon E, Taiba Z, Fridman Z, et al. Nonalcoholic fatty liver diseaseda common and benign finding in octogenarian patients. Liver Int. 2004;24:588–594. 24. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106– 1110. 25. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152. 26. Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP1c) transcriptional activity in rat hepatocytes. Biochem J. 2000;350(Pt 2):389–393. 27. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology. 2002;35:898– 904.
868
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
AEP Vol. 17, No. 11 November 2007: 863–869
28. Letteron P, Sutton A, Mansouri A, Fromenty B, Pessayre D. Inhibition of microsomal triglyceride transfer protein: another mechanism for druginduced steatosis in mice. Hepatology. 2003;38:133–140.
49. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.
29. Day CP, James OF. Steatohepatitis: a tale of two ‘‘hits’’? Gastroenterology. 1998;114:842–845.
50. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2003;98:2485–2490.
30. Haque M, Sanyal AJ. The metabolic abnormalities associated with nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol. 2002;16:709–731. 31. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–443. 32. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185– 194. 33. Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122:274–280. 34. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–211. 35. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54. 36. McCuskey RS, Ito Y, Robertson GR, McCuskey MK, Perry M, Farrell GC. Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice. Hepatology. 2004;40:386–393. 37. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438. 38. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80. 39. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143:500–505. 40. Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol. 2004;40:578–584. 41. Caldwell SH, Hespenheide EE. Subacute liver failure in obese women. Am J Gastroenterol. 2002;97:2058–2062. 42. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–1362.
51. Evans CD, Oien KA, MacSween RN, Mills PR. Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol. 2002;55:689–692. 52. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714– 1719. 53. Lee RG. Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol. 1989;20:594–598. 54. Dam-Larsen S, Franzmann M, Andersen IB, Christoffersen P, Jensen LB, Sorensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755. 55. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419. 56. Cortez-Pinto H, Baptista A, Camilo ME, De Moura MC. Nonalcoholic steatohepatitis–a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci. 2003;48:1909–1913. 57. Adams LA, Lymp J, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease:a population based cohort study. Gastroenterology. 2005;129:113–121. 58. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279:32345–32353. 59. Suzuki A, Angulo P, Lymp J, St Sauver J, Muto A, Okada T, et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology. 2005;41:64–71. 60. Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology. 2000;32:689–692. 61. Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–669. 62. Ong J, Younossi ZM, Reddy V, Price LL, Gramlich T, Mayes J, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl. 2001;7:797–801. 63. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, et al. Longterm outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427.
43. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–1123.
64. Bullock RE, Zaitoun AM, Aithal GP, Ryder SD, Beckingham IJ, Lobo DN. Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma. J Hepatol. 2004;41:685–686.
44. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.
65. Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2002;37:154–160.
45. Bugianesi E, Manzini P, D’Antico S, Vanni E, Longo F, Leone N, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology. 2004;39:179–187.
66. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.
46. Petrides AS, Stanley T, Matthews DE, Vogt C, Bush AJ, Lambeth H. Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology. 1998;28:141–149. 47. Hui AY, Wong WS, Chan HL, Liew CT, Chan JL, Chan FK, et al. Histological progression of nonalcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther. 2005;21:407–413. 48. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138.
67. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36:1349–1354. 68. Ratziu V, Bonyhay L, Di Martino V, Charlotte F, Cavallaro L, SayeghTainturier MH, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485–1493. 69. Angulo P. Current best treatment for non-alcoholic fatty liver disease. Expert Opin Pharmacother. 2003;4:611–623.
AEP Vol. 17, No. 11 November 2007: 863–869
Adams and Lindor NONALCOHOLIC FATTY LIVER DISEASE
869
70. Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654.
73. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017.
71. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–1090.
74. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–1115.
72. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196.
75. Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225.