Journal of Gastroenterology and Hepatology (2002) 17 (Suppl.

) S186–S190

QUADRENNIAL REVIEW

Non-alcoholic fatty liver disease
PAUL ANGULO AND KEITH D LINDOR

Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America

Abstract Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects a high proportion of the world’s population. Insulin resistance and oxidative stress play a critical role in the pathogenesis of NAFLD. Clinical, biochemical and imaging studies are of value in the diagnostic evaluation of patients with NAFLD, but liver biopsy remains the most sensitive and specific means of providing important diagnostic and prognostic information. Simple steatosis has the best prognosis within the spectrum of NAFLD, but NAFLD has the potential to progress to steatohepatitis, fibrosis and even cirrhosis. No effective medical therapy is currently available for all patients with NAFLD. In patients with diabetes mellitus and hyperlipidemia, appropriate metabolic control is always recommended, but rarely effective in resolving the liver disease. Weight reduction, when achieved and sustained, may improve the liver disease, although the results with weight loss have been inconsistent. Pharmacological therapy aimed at the underlying liver disease holds promise. Several medications with different mechanisms of action and potential benefit are currently being evaluated in clinical trials. Liver transplantation is a lifeextending therapeutic alternative for patients with end-stage NAFLD, but NAFLD may recur after liver transplantation. © 2002 Blackwell Science Asia Pty Ltd

INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized clinicopathological condition that may progress to end-stage liver disease. The pathological picture resembles alcohol-induced liver injury, but occurs in patients who deny alcohol abuse. Nonalcoholic fatty liver disease comprises a wide spectrum of liver damage ranging from simple, uncomplicated steatosis to steatohepatitis to advanced fibrosis and cirrhosis. Non-alcoholic steatohepatitis (NASH) represents a stage within the spectrum of NAFLD and it is defined histologically by the presence of steatosis along with necroinflammatory activity mostly of lobular distribution regardless of the presence of fibrosis or Mallory’s hyaline.1,2 Non-alcoholic fatty liver disease must be differentiated from the steatosis with or without hepatitis resulting from secondary causes such as drugs, hepatotoxins, gastrointestinal surgery and some metabolic/genetic conditions. The diagnosis of NAFLD also requires the exclusion of other liver diseases that

may present with steatosis such as viral, autoimmune and metabolic/hereditary liver disease along with a thorough effort to exclude alcohol abuse.The clinical implications of NAFLD are derived mostly from its common occurence in the general population as well as its potential to progress to cirrhosis and liver failure.

EPIDEMIOLOGIC FEATURES
Obesity, type 2 (non-insulin dependent) diabetes mellitus and hyperlipidemia, alone or in combination, are comorbid conditions frequently associated with NAFLD.3 There is a direct correlation between the degree of obesity and prevalence and severity of NAFLD. The prevalence of NAFLD increases by 4.6fold in obese people.4 With any degree of obesity, type 2 diabetes mellitus significantly increases the prevalence and severity of NAFLD.5,6 Truncal obesity seems to be an important risk factor for NASH even in subjects with

Correspondence: Dr KD Lindor, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN, USA. Email: lindor.keith@mayo.edn

The prevalence of NAFLD. Mild to moderate elevation of serum aminotransferases (ALT. Mallory’s hyaline and fibrosis are typically concentrated in acinar zone 3. Severe hepatic fibrosis (septal/cirrhosis) is found in 25%11. mostly in the form of triglycerides. Hepatic iron index and hepatic iron concentration. however.1. Furthermore. AST) is the most common and often the only laboratory abnormality found in patients with NAFLD. it is possible that unrecognized NAFLD has led to cirrhosis in a substantial proportion of patients that have been diagnosed with cirrhosis of obscure cause.11 Hypoalbimunemia. but it could potentially result from insulin resistance and alterations in the uptake. The presence of fibrosis is a concerning histologic finding because it suggests a more advanced and severe liver injury. LIVER HISTOLOGY Non-alcoholic fatty liver disease is histologically indistinguishable from the liver damage resulting from alcohol abuse. increases significantly to 57. is a prerequisite for the development of NASH. Progressive injury in NAFLD results in portal fibrosis. The cross sectional imaging studies. Insulin resistance represents the most reproducible factor for the development of NAFLD.11 In a recent population-based study among patients who were found with fatty liver on an ultrasound survey. glycogen nuclei. Fibrosis was found in 67% of patients with NAFLD at the time of diagnosis.1.17 Most patients with NAFLD have an AST/ALT ratio of less than one. and in the perisinusoidal region. many patients who lack these associated risk factors are increasingly diagnosed with this condition: 29% of our 144 patients with liver biopsy-proven NASH were non-obese and non-diabetic and also had normal lipid profiles.11.7 NAFLD may affect any age group and has been described in most racial groups. are usually in the normal range. as well as necroinfammatory injury.4% had none of these comorbid conditions. The presence of these histologic features. There is not consensus on what are the minimal histologic features required for the diagnosis of NASH. A high proportion of patients with cryptogenic cirrhosis share many of the clinical and demographic features of patients with NAFLD.5–52. are useful in the diagnosis of fatty liver.4 S187 Half of all patients with NASH have elevated serum ferritin levels whereas increased transferrin saturation is found in 6–11% of patients. NAFLD is the cause of asymptomatic elevation of aminotransferases in 42–90%14 of cases once other causes of liver disease are excluded and represents a common explanation for abnormal liver tests in blood donors. synthesis. CLINICAL FEATURES Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis. This has . although the AST/ALT ratio increases as the liver disease progresses to cirrhosis. is not well understood. PATHOGENESIS A net retention of lipids within hepatocytes. however. and hepatocyte ballooning and spotty necrosis are the most common lesions required for the histologic diagnosis of NASH. elevated serum bilirubin and prolonged prothrombin time suggest advanced disease. mixed inflammatory cell infiltration.8–10 Furthermore.5.6 Similarly. ultrasonography and computed tomography. Most patients with NASH will show some degree of fibrosis.27–29 The steatotic liver may then be vulnerable to further injury when challenged by additional insults. hepatocyte ballooning and necrosis. however. Collagen is first laid down in the pericellular space around the central vein. the features of steatosis and necroinflammatory activity may no longer be present. and the disease is increasingly diagnosed in children and adolescents.18–25 The pattern of fibrosis in NAFLD is a characteristic feature. Mallory’s hyaline and fibrosis. central-portal and portal-portal septum formation and eventually cirrhosis. but others have shown a significantly greater prevalence of NAFLD in males than females. Liver biopsy features include steatosis. Steatosis.25 of patients at the time of diagnosis.18–26 In patients with cirrhosis. These figures. 16.8%12 in the obese child population. alone or in combination leads to a wide spectrum of non-alcoholic fatty liver disease.6% of children10 and this figure increases to 22.19–23. The AST/ALT ratio is useful in differentiating NAFLD from alcoholic liver disease.Non-alcoholic fatty liver disease normal body mass index. it has been estimated that steatosis affects over two-thirds of the obese population.16 Thus. Most series characterize a NAFLD patient as a middleaged woman.5–74%4. NAFLD affects 2.9 in obese individuals. however. about one-third of the USA population who suffer from type 2 diabetes mellitus have NAFLD.15 In the USA. The primary metabolic abnormality leading to lipid accumulation (steatosis).11. whereas Mallory’s hyaline may or may not be present. it is possible that the prevalence of NASH in the USA and other developed countries has increased over the past 10–15 years paralleling the marked increment of obesity and diabetes that has occurred among all age groups. degradation or secretory pathways of hepatic lipid metabolism. since many patients with this liver condition are non-obese and non-diabetic. Magnetic resonance imaging is useful for differentiating focal fatty infiltration or focal sparing from liver metastasis. clearly underestimate the real prevalence of NAFLD. whereas well-established cirrhosis is found in 14% of patients. However. whereas NASH is found in 19% of these obese individuals. mixed mononuclear and/or polymorphonuclear cell infiltration. the combination of steatosis. PREVALENCE NAFLD affects 10–24% of the general population from different countries. predominantly as large droplets or macrovesicular fat. losing its diagnostic accuracy in the cirrhotic stage of NAFLD.

Furthermore.25 These factors can help to identify the NASH patient expected to derive the most benefit from liver biopsy and enrollment into therapeutic trials. In patients with diabetes mellitus or hyperlipidemia. Nevertheless. the disease progresses to cirrhosis and its complications. radiological findings of fatty liver or unexplained persistent hepatomegaly.21. once other liver diseases have been excluded.11 In the subgroup of patients with NASH who are overweight or obese. Fifty-four out of 257 patients with non-alcoholic fatty liver reported in five different series20–23. PROGNOSIS DIAGNOSIS The diagnosis of NAFLD is usually suspected in individuals found with asymptomatic elevation of aminotransferases. Of these patients. In patients with NAFLD. uncomplicated steatosis to steatohepatitis to advanced fibrosis results from two operating ‘hits’. However. The presence of cirrhosis on liver biopsy would dictate the need for periodic endoscopic surveillance for gastroesophageal varices. but also the most sensitive and specific means of providing important prognostic information.38.S188 led investigators to presume that progression from simple. Thus.34 to more advanced fibrosis20. in some others. liver biopsy remains not only the best diagnostic tool for confirming NAFLD. presence of obesity or type 2 diabetes mellitus and an AST/ALT ratio greater than one are noteworthy indicators of advanced liver fibrosis. cytokine production and Fas ligand induction.25 had subsequent liver biopsies performed during an average follow-up of 3. Thus.25 or cirrhosis20–22. Patients with pure steatosis on liver biopsy seem to have the best prognosis within the spectrum of NAFLD.39 after weight reduction. two of them were liver-related including one patient who developed hepatocellular cancer. The diagnosis of NASH implies a thorough effort to exclude alcohol abuse as the cause of liver disease. P Angulo and KD Lindor tologic damage.23.3 years and exceeded only by cancer-related deaths. A total of 26 deaths occured during follow-up.21.25 progression of liver fibrosis occured only in patients with necroinflammation on liver biopsy. no clinical or biochemical abnormalities permit an accurate diagnosis of NAFLD.23 whereas features of steatohepatitis or more advanced fibrosis are associated with a worse prognosis. the clinical diagnosis and values of liver tests have a poor predictive value for making the diagnosis32.25 has been recognized in several cases.34–37 and children11. Although the AST/ALT ratio helps in differentiating alcoholic from non-alcoholic fatty liver disease. good metabolic control is always recommended.33 and for differentiating simple steatosis from NASH. and higher levels of ALT and triglycerides are also indicators of more advanced liver fibrosis. However. Prognosis in NAFLD is being defined. it is clear that some patients with non-alcoholic fatty liver follow a relatively benign course whereas. the clinical suspicion of NAFLD can only be confirmed with a liver biopsy. whereas 13% showed resolution or improvement of liver injury. older age. Progression from steatosis to steatohepatitis8. it may be reasonable to exclude alcohol abuse as the cause of the liver disease in patients who deny ingestion of these or greater doses of alcohol. higher BMI.31 Oxidative stress and lipid peroxidation are key factors in the development and progression from steatosis to more advanced stages of liver damage. age older than 45 years. Imaging studies. there has been a reasonable hesitation to perform liver biopsy with the simple purpose of confirming the diagnosis. Thus. liver biopsy is the best specific means of determining the effect of medical treatment given the uncertain correlation between improvement of liver tests or imaging studies with his- MANAGEMENT OF ASSOCIATED CONDITIONS Treatment of patients with NAFLD has typically been focused on the management of associated conditions as well as discontinuation of potentially hepatotoxic drugs known to produce NAFLD. It has been estimated in the general population that a daily dose of alcohol as low as 20 g in females and 30 g in males may be hepatotoxic. the use of medications that improve insulin sensitivity and increase antioxidant chemical species may be of potential benefit in the treatment of patients with NASH. Some histologic features have been recognized as useful in determining the risk of progression to more advanced liver disease. and possibly screening for liver cancer. There was a trend for more liver-related deaths among patients with NASH than in those without NASH. In another study.26 ROLE OF LIVER BIOPSY Examination of a liver biopsy by an experienced pathologist is an essential diagnostic complement. given the lack of effective medical treatment for patients with NAFLD. but rarely effective in reversing NAFLD.26 liver-related deaths in patients with NAFLD were the second most common cause of death after a mean follow-up of 8. 59% remained essentially unchanged. and the second (mostly reactive oxygen species) leading to lipid peroxidation. 28% had progression of liver damage.30 the first (mainly insulin resistance) leading to accumulation of fat within hepatocytes. The degree of .5–11 years. Hence. Improvement in serum levels of aminotransferases is almost universal in obese adults9.25. but it seems to be greatly determined by the severity of liver damage found on liver biopsy. although useful in determining the presence and amount of fatty infiltration of the liver. although this difference can also be explained by the significantly greater proportion of patients with cirrhosis among those with NASH.26 In one study. cannot be used to determine accurately the severity of liver damage.

42: 1438–2. Powell LW. Proc. 27: 142–9. J. 12 Franzese A. The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients.40 Hence. Med. 42: 548–51. 11 Angulo P. Cryptogenic cirrhosis. 11: 74–80. Blumenkehl M. 94: 3010–14. Hayashi J. Kajiyama W. 1980. Prevalence of fatty liver in a general population of Okinawa. 15 Bizzaro N. J. Oelsner DH. 3 James O.42. Vasudevan G. These medications however. T. Searle J. Hepatology 1999. Argenziano A et al. Bennett MK. 1999. Wang J. 22 Bacon BR. . Saccoccio G. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. use of medications that can directly reduce or reverse liver damage independent of weight loss is a reasonable alternative. Hepatology 1990. The increased attention to this condition in recent years in this area has led to a greater understanding and awareness of NAFLD. Lindor KD. Clinical characterization and risk factors for underlying disease. N-acetylcysteine. Prevalence of fatty liver in Japanese children and relationship to obesity. Sci. J. Future work is required to better define its natural history. 1986. Tani S. Hum. 4 Ballentani S. Goodman Z. Vajro P. 2000. betaine. Hepatology 1995. Int. Gastroenterol. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. although the degree of necroinflammation and fibrosis may worsen. Schaffner F. 22: 1714–19. Mayo Clinic experience with a hitherto unnamed disease. Tremolada F. as usually happens in most obese patients as well as for patients who lack risk factors or associated conditions such as those who are non-obese and non-diabetic. Kashiwagi S. alcohol intake and obesity. Prevalence of and risk factors for hepatic steatosis in northern Italy. 2 Schaffner F. Lindor KD. 1997. Janney CG. Cooksley GE. 18 Adler M. liver transplantation is a life-extending therapeutic alternative. 1999. Med. In patients with end-stage NAFLD. Monitoring liver injury during treatment with weight reduction cannot be fully accomplished without careful analysis of the effects on liver histology. Liver involvement in obese children. Ital. Alcohol-like liver disease in non-alcoholics. 1988.39. Scan.8. Liver abnormalities in severely obese subjects. Ishak G. Hepatology 1999. Non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis: Another disease of affluence. Am. Hanson R. MaGill DB. Non-alcoholic fatty liver disease. vitamin E (alphatocopherol) and insulin-sensitizer drugs (thiazolidinedione. Long S et al. Day C. Farahvash MJ. 6 Silverman JF. 353: 1634–6. Bodemar G. Ma CK. often progressive. O’Brien KF. Obes. Pathol. Gastroenterol. J. PHARMACOLOGIC THERAPY Because rapid weight loss may worsen NASH. James OFW. Keach JC. Iezzoni JC. Burt AD. Lentz JS.34. 55: 434–8.36. Pharmacological therapy directed specifically at the liver disease has only recently been evaluated in patients with NAFLD. ursodeoxycholic acid. extended follow up and include clinically relevant end points. NeuschwanderTetri BA. 30: 1356–62.Viggiano TR. Metabolism 1993. Lancet 1999. Body fat topography as an independent predictor of fatty liver. the improvement or normalization of serum aminotransferase levels and degree of fatty infiltration on imaging studies are poor indicators of worsening of liver damage that may occur during uncontrolled weight loss. 1979. Am. 94: 1018–22. Batts KP. 8: 283–6. Battle EH.Non-alcoholic fatty liver disease fatty infiltration usually improves with weight loss in most patients.. 1992. disease. Hespendheide EE. Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis. 1998. Gastroenterology 1994. Liver pathology in morbidly obese patients with and without diabetes. Med. 132: 112–7. Intern. Dig. 29: 664–9. REFERENCES 1 Ludwig J. The natural history of non-alcoholic fatty liver: a followup study. 107: 1103–9. Sci. Am. Pierson RN Jr. Halliday JW. Ben-Menachem. Dis. 7 Kral JG. Hepatology 1990. Masutti F et al. Japan. S189 5 Wanless IR. 20: 594–8. Pharmacologic therapy may be of particular benefit for patients who do not lose weight or cannot maintain long-term weight reduction. Foberg U. effect of drastic weight loss after gastroplasty. 9 Luyckx FH. 19 Diehl AM. Ann. 24: 237–41. Fatty liver hepatitis and cirrhosis in obese patients. Franzen LE. 34: 85–91. Driscoll CJ. 40: 2002–9.43 CONCLUSIONS Non-alcoholic fatty liver disease is an increasingly important chronic liver disease. Gastroenterol. Kurata JH. elucidate the pathogenesis and develop effective treatment options for this. 23 Teli MR. Desaive C. 22: 222–6. Serum alanine aminotransferase levels among volunteer blood donors: Effect of sex. Boynton J. metformin). Am. The natural history of non-alcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Jpn J. 21 Powell EE. Gastroenterol. Non-alcoholic steatohepatitis: an expanded clinical entity. Thiry A et al. 8 Nomura H. 85: 1349–55.37. 1995. J. 1990. Day CP. 1989. 14 Daniel S. Schaffner F. Chen YK et al. A study of 49 patients. 10 Tominaga K. Casarin C et al. Gastroenterol. J. Non-alcoholic steatohepatitis. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. 20 Lee RG. must be evaluated in carefully controlled clinical trials that must have enough power. 17 Sorbi D. Thaler H. 12: 1106–10. 13 Mathiesen UL. Dis. 16 Caldwell SH. 95: 1056–62. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating non-alcoholic steatohepatitis from alcoholic liver disease. Goto M. Prog. J. Mayo Clin. Dig. Fryden A.41 Encouraging results have been reported with pilot studies evaluating gemfibrozil. Gastroenterology 1988. Liver Dis. but NAFLD may recur early after liver transplantation with a rapid progression from steatosis to steatohepatitis. 1999. 67: 811–16. Ott BJ.

Campbell-Sargent C. Am. Mansouri A. 41 Angulo P. Scand. 12: 198–208. 39 Vajro P. 27 Angulo P. 43 Contos MJ. Perna C. 1989. J. Recurrence of non-alcoholic steatohepatitis following liver transplantation. Bondesson L. Mirshahi F et al. 32 Van Ness MM. Diehl AM. Sci. 30 Day CP. a tale of two ‘hits’? Gastroenterology 1998. 1991. Mitochondria in steatohepatitis. 9: 193–7. 29 Sanyal AJ. Insulin resistance and mitochondrial abnormalities in NASH. Non-alcoholic steatohepatitis. 7: 363–73. Steers JL. Hepatol. 27: 103–7. Sem. Porayko MK. 1994. in obese patients with fatty liver. 114: 842–5. J. Am. 12: 224–9. Baptista A. James OFW. 26 Matteoni CA. 40 Rozental P.S190 24 Cortez-Pinto E. Charlotte F et al. J. Liver Dis. Franzmann MB. 62: 1802–5. 120: 1281–5. Liver Transpl. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Liver fibrosis in overweight patients. Non-alcoholic fatty liver disease. 120: 1183–92. Gastroenterology 2001. 1967. Zimmerman HJ. Acta Med. 35 Palmer M. De Vincenzo A. 220: 83–8. 38 Rashid M. Therapeutic effects of restricted diet and exercise. Sugawara H. 30: 48–53. Dis. 21: 81–8. 33 Hay JE. Camilo ME. J. Hepatol. Liver morphology and function tests in obesity and during total starvation. Pediatr. Boparai N. Transplantation 1996. Dig. JPGN 2000. Effect of weight reduction on hepatic abnormalities in overweight patients. Orso G. Intern. Steatohepatitis. Association of non-alcoholic fatty liver disease with insulin resistance. Gastroenterology 2001. Morselli-Labate AM et al. Gludd C. Fromenty B. Nonalcoholic steatohepatitis. Roberts EA. 21: 57–70. 1999. Valente A. Dig. Hepatology 1989. Christofferesen P. Med. Ludwig J. Lindor KD. Wiesner RH. 118: 1117–23. Eriksson KF. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients. Hepatic effect of dietary weight loss in morbidly obese patients. 1996. McCullough AJ. 2001. Poterucha JJ. Sujaku K et al. 25 Ratziu V. Sem Liver Dis 2001. Tedesco M. 28 Marchesini G. 31 Pessayre D. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes? Ann. Liu YC. Rakela J. Younossi ZM. Gastroenterology 2000. 107: 450–5. Carniero de Maura M. A spectrum of clinical and pathological severity. . 99: 1408–13. J. Dis. Sterling RK et al. Gramlich T. Giral P. Development of non-alcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Biava C. Gastroenterology 1990. P Angulo and KD Lindor 34 Andersen T. Med. Fontanella A. Spencer H. Lindor KD. Czaja AJ. Treatment of non-alcoholic fatty liver: present and emerging therapies. Berson A. association of insulin resistance and mitochondrial abnormalities. A cool look into a burning issue. Saragoca A. 42 Kim WR. 2001. Cales W. 37 Ueno T. 116: 1413–19. A persistent aminotransferasemia resolving after weight reduction of children. 41: 172–9. 1997. 125: 239–41. Dickson ER. Non-alcoholic steatohepatitis in children. Gastroenterology 1999. 111: 473–8. 1986. Brizi M. Schaffner F. Non-alcoholic steatohepatitis in obesity: a reversible condition. 36 Eriksson S.

Sign up to vote on this title
UsefulNot useful