Aliment Pharmacol Ther 2003; 17: 977–986.

doi: 10.1046/j.0269-2813.2003.01493.x

Review article: non-alcoholic fatty liver disease
L. M. A LBA & K. LIN DOR Division of Gastroenterology and Hepatology, Mayo Clinic Foundation, Rochester, MN, USA
Accepted for publication 20 December 2002

SUMMARY

Non-alcoholic fatty liver disease is a clinicopathological condition that comprises a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Non-alcoholic steatohepatitis represents only a stage within the spectrum of non-alcoholic fatty liver disease and is defined pathologically by the presence of steatosis together with necro-inflammatory activity. The true prevalence of non-alcoholic fatty liver disease is unknown, but it is estimated that it affects 10–24% of the general population in different countries. The diagnosis of non-alcoholic fatty liver disease is based upon convincing evidence of absent or minimal alcohol consumption, compatible histological changes in liver

biopsy and the exclusion of other liver diseases. The natural history of non-alcoholic fatty liver disease remains to be defined. Patients with pure steatosis on liver biopsy follow a relatively benign course, whereas patients with histological necro-inflammatory changes and/or fibrosis may progress to end-stage liver disease. An initial step in the treatment of non-alcoholic fatty liver disease is the management of associated conditions, such as obesity, diabetes mellitus and hyperlipidaemia. Non-alcoholic fatty liver disease patients with steatohepatitis and/or fibrosis on liver biopsy may benefit from investigational pharmacological therapy. Patients with decompensated cirrhosis from non-alcoholic fatty liver disease may be candidates for liver transplantation.

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition that comprises a wide spectrum of liver damage, ranging from steatosis alone to steatohepatitis, advanced fibrosis and cirrhosis. The pathological picture resembles alcohol-induced liver injury, but NAFLD occurs in patients who do not consume significant amounts of alcohol. Non-alcoholic steatohepatitis represents only a stage in the spectrum of NAFLD and is defined pathologically by the presence of steatosis together with necro-inflammatory activity, mostly of lobular distribution, with or without Mallory’s hyaline or fibrosis.1, 2 The clinical implications of
Correspondence to: Dr K. Lindor, Division of Gastroenterology and Hepatology, Mayo Clinic Foundation, 200 First Street SW, Rochester, MN, USA. E-mail: lindor.keith@mayo.edu Ó 2003 Blackwell Publishing Ltd

NAFLD are derived mostly from its potential to progress to end-stage liver disease, whereas simple uncomplicated steatosis follows a relatively benign course in most patients.3–7
EPIDEMIOLOGICAL FEATURES

NAFLD may affect any age group and has been described in most racial groups. The true prevalence of NAFLD is unknown, but it is estimated that it affects 10–24% of the general population from different countries. The prevalence of NAFLD is higher in patients with obesity (60–95%), type 2 diabetes mellitus (28–55%) and hyperlipidaemia (20–92%).1, 3–9 Most series characterize a patient with NAFLD as a middle-aged woman, but others have shown a greater prevalence of NAFLD in males than females.10–12 Furthermore, many patients
977

paralleling the marked increases in obesity and diabetes that have occurred in all age groups. losing its diagnostic accuracy in cirrhotic stage NAFLD. (iii) the exclusion of other forms of liver disease. DIAGNOSIS such as macrovesicular steatosis. The estimated prevalence of NAFLD is about 2–3% in lean individuals. alone or in combination. presence of obesity or type 2 diabetes mellitus. Hence. but cannot accurately determine the presence of liver inflammation and/or fibrosis. advanced fibrosis and cirrhosis. in a prospective study.21.12 NAFLD affects 2. and an AST/ALT ratio greater than unity are noteworthy indicators of advanced liver fibrosis. 23 These factors can help to identify the NAFLD patient expected to have the most likely chance of clinically severe disease.20 (ii) liver biopsy showing characteristic features.19 however. Some factors can help to identify the sub-group of patients in whom liver biopsy may provide the most prognostic information. even in subjects with a normal body mass index. found that the level of alcohol intake above which the relative risk for developing liver disease was significantly greater than unity was 84–156 g alcohol/week for women and 168–324 g alcohol/week for men. higher levels of ALT and triglycerides. mostly of lobular distribution. but increases to 19% in the obese population. are usually in the normal range. it is not routinely performed due to the current lack of effective medical therapy for this condition. however.15. the clinical suspicion of NAFLD can only be confirmed with a liver biopsy.8%14 in the obese child population. When symptoms are present. ALBA & K. necro-inflammatory activity.17 The predominant laboratory abnormality in patients with NAFLD is mild to moderate elevation of serum aminotransferases. 22 and for differentiating between simple steatosis and steatohepatitis.18 Most patients with NAFLD have an AST/ALT ratio of less than unity. 977–986 The diagnosis of NAFLD is based on the following features: (i) convincing evidence of absent or minimal alcohol consumption: £ 20 g alcohol/day for women and £ 30 g alcohol/day for men. once other liver diseases have been excluded. Mallory’s hyaline.13 and this figure increases to 22. fibrosis or cirrhosis.978 L. ranging from steatosis alone or in combination with Ó 2003 Blackwell Publishing Ltd. although the AST/ALT ratio increases as the liver disease progresses to cirrhosis. however. they are variable. The hepatic iron index and hepatic iron concentration. Aliment Pharmacol Ther 17. whereas increased transferrin saturation is found in 6–11% of patients. Non-invasive imaging studies are useful in determining the presence and amount of fatty infiltration of the liver. 16 It is possible that the prevalence of NAFLD in the USA and other Western countries has increased over the past 10–15 years. liver biopsy is the only means to determine the severity of liver damage and to obtain important prognostic information. Nevertheless. and may prompt these patients towards enrollment into therapeutic trials.20 Clinical findings and liver test values have a poor predictive value for making a diagnosis. Hepatomegaly is the most common physical sign. Liver histology The histological features of NAFLD are indistinguishable from those of alcohol-induced liver disease. malaise and right upper quadrant discomfort. CLINICAL FEATURES Most patients with NAFLD are asymptomatic. but are less frequent.6. Role of liver biopsy Although a liver biopsy is the best diagnostic tool for confirming NAFLD. One-half of patients with NAFLD have elevated serum ferritin levels. NAFLD includes a wide spectrum of histological features. Splenomegaly and stigmata of cirrhosis can be present. 8 Truncal obesity seems to be a significant risk factor for NAFLD. LINDOR with NAFLD are non-obese and non-diabetic and have normal liver tests and lipid profiles. Many cases are diagnosed after finding elevated liver biochemistries during ‘routine’ laboratory testing. An age of 45 years or more. its current role as a diagnostic test for NAFLD has not been defined.8 The ratio of desialated transferrin to total transferrin has been suggested to be useful in distinguishing patients with NAFLD from those with alcoholic liver disease. Becker et al. and include fatigue. The aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is useful in differentiating NAFLD from alcoholic liver disease.6% of children. The minimal amount of alcohol considered to be excessive to fit the definition of NAFLD has not been determined. M.8. .5%13 to 52.

may be beneficial. The presence of fibrosis is a concerning histological finding because it suggests a more advanced and severe liver injury.30 Another end-product of lipid peroxidation. presumably favouring the development of systemic endotoxaemia and the release of pro-inflammatory cytokines. alteration of hepatocyte adenosine triphosphate stores and cytochrome P450 Cyp2E1/Cyp4A enzyme activity may play a role in the genesis and progression of NAFLD. 9. 23 whereas wellestablished cirrhosis is found in 14%.35.32.37 The messenger RNA of interferon-c. is reduced. treatment efforts primarily directed towards protecting hepatocyte adenosine triphosphate stores might be potentially beneficial in patients with NAFLD. More recently. Furthermore.5. whereas Mallory’s hyaline may or may not be present. 8. in part. such as tumour necrosis factor-a and interleukin-8. 33. however. 42 Studies of larger patient populations with non-alcoholic steatohepatitis. 4-hydroxynonenal. probably. Aliment Pharmacol Ther 17.31 and may also increase cytochrome P450 Cyp2E1/Cyp4A activity. 3–6. Mallory’s hyaline and pericentral perisinusoidal fibrosis. an end-product of lipid peroxidation. progression of NAFLD. whereas the messenger RNA of interleukin-10. and some derived from studies in animal models of fatty liver. is over-expressed. activates hepatic stellate cells. is a strong chemo-attractant for neutrophils.1. bacterial toxins. as shown in a rat model of NAFLD using a diet deficient in methionine–choline. cytochrome P450 Cyp2E1/Cyp4A activity may contribute to hepatotoxicity in mice and humans with NAFLD. Non-alcoholic steatohepatitis represents only a stage within the spectrum of NAFLD and is defined histologically by the presence of steatosis together with lobular inflammatory infiltrate and hepatocellular ballooning. 23–25 Severe hepatic fibrosis (septal/cirrhosis) is found in 25% of patients at the time of diagnosis. Based on the fact that metronidazole and polymixin B may prevent the development of NAFLD in obese patients undergoing intestinal bypass. 36 a role of endotoxin/cytokine-mediated injury has been suggested as a contributing factor to the development of NAFLD. 33 This evidence suggests that oxidative stress and lipid peroxidation may. the risk factors for the development of NAFLD. 43 PROGNOSIS The prognosis of NAFLD is still controversial. have shown that this is not always the case. The adenosine triphosphate stores in hepatocytes of mice38 and humans39 with steatosis seem to be potentially vulnerable to depletion. In this model.8. Lipid peroxidation seems to increase with the severity of steatosis.3–6. hepatocyte ballooning and necrosis. albeit still inconclusive. 8. such as dietary modifications (fat-reduced diet). overproduction of tumour necrosis factor-a. 6 PATHOGENESIS The pathogenesis of NAFLD is still unclear.41. compared with those of non-obese controls. it has been shown that genetically obese mice are very sensitive to the effect of lipopolysaccharide in developing NAFLD. Similarly. stimulating collagen production and fibrogenesis. Some lines of evidence. mainly because the natural history of the disease remains to be . Malondialdehyde may also contribute to inflammation by activating nuclear factor-jB (NF-jB). the phagocytic activity of Kupffer cells is reduced. Hence. 40 Treatment strategies to limit its activity.REVIEW: NON-ALCOHOLIC FATTY LIVER DISEASE 979 mixed inflammatory cell infiltration. which regulates the expression of pro-inflammatory cytokines. 23. 24 In patients with cirrhosis.34 and in rats receiving total parenteral nutrition. mainly of triglycerides. Many patients with NAFLD will have some degree of fibrosis. Hepatic steatosis is due to lipid accumulation.32. the features of steatosis and necroinflammatory activity may no longer be present. lead to increased circulating levels of free fatty acids with enhanced concentration in the liver. 3–9. within hepatocytes. be critical factors involved in the genesis and. Anecdotal reports suggest that increased iron stores might lead to more severe liver disease in patients with non-alcoholic steatohepatitis. but it could potentially result from insulin resistance26–28 and decreased disposal of fatty acids from impaired mitochondrial b-oxidation or deficient production of very low density lipoprotein. Free fatty acids per se are potentially cytotoxic. which is inhibitory to tumour necrosis factor-a effects. suggest that oxidative stress/lipid peroxidation. glycogen nuclei.29 Malondialdehyde. Fibrosis is found in 67% of patients with NAFLD at the time of diagnosis. namely obesity with rapid weight loss and type 2 Ó 2003 Blackwell Publishing Ltd. 977–986 diabetes mellitus. The role of iron in the pathogenesis of NAFLD remains uncertain. which sensitizes hepatocytes to tumour necrosis factor-a toxicity. The mechanisms leading to lipid accumulation are not completely understood.1.

Semin Liver Dis 2001. in patients with a high degree of fatty infiltration. * Inherited lipid storage disease. nifedipine) Chloroquine Oestrogens Perhexiline maleate Tamoxifen Tetracycline Valproic acid Other Environmental hepatotoxins Inflammatory bowel disease Human immunodeficiency virus infection Jejunal diverticulosis with bacterial overgrowth Modified from Angulo P. Conditions associated with non-alcoholic fatty liver disease Metabolic Obesity Diabetes mellitus type 2 Total parenteral nutrition Rapid weight loss Hyperlipidaemia Abetalipoproteinaemia Copper-associated liver diseases (including Wilson’s disease) Iron storage disorders Lypodystrophy Acute fatty liver of pregnancy Systemic carnitine deficiency* Weber–Christian disease Surgical Extensive small bowel resection Gastroplasty (for morbid obesity) Biliopancreatic diversion Jejuno-ileal bypass Drugs Amiodarone Corticosteroids Calcium channel blockers (diltiazem. but potentially serious.54 It remains Table 1.52 and have failed treatment with a conventional diet.53 These medications are associated with rare. Ó 2003 Blackwell Publishing Ltd. 23 Therefore. 977–986 Currently. weight loss of about 0. and should be encouraged to undergo liver biopsy. ALBA & K.44. and (iii) pharmacological therapy in patients at ‘high risk’ for developing advanced liver disease. It is speculated that the accumulation of hepatic triglycerides probably sensitizes patients in a particular clinical context to further insults that result in disease progression.5 kg/week can be expected in obese adults. Presents in childhood with a clinical picture resembling Reye’s syndrome. i.1. including pulmonary hypertension. LINDOR defined. bile stasis and focal necrosis. Lindor K. (ii) discontinuation of potentially hepatotoxic drugs. the management of NAFLD is focused in the following areas: (i) management of associated conditions (Table 1). it seems reasonable to start initially by decreasing the daily intake to 500–1000 kcal below the caloric intake required for weight maintenance. patients with NAFLD who were older. M. rapid weight loss may promote portal inflammation and fibrosis. . The rate and degree of weight loss required for the normalization of liver histology have not been established. An appropriate diet and exercise programme are important. Previous studies have shown that gradual weight loss may lead to an improvement in liver biochemistries and liver histology. Large epidemiological studies with decades of follow-up are needed. 23 The reasons for the different course in patients suffering from apparently the same condition remain to be defined.8 This sub-group of patients may benefit from investigational medical therapy. Weight loss. Medications used to reduce appetite will result in weight reduction in many patients. in addition to the management of associated conditions (weight loss. Very-low-calorie diets may be tried. Management of associated conditions Obesity. 3–8. 50 Therefore.3. control of diabetes). patients older than 45 years with diabetes and steatohepatitis. 44–51 However. Hepatic steatosis is a prominent feature. Aliment Pharmacol Ther 17. With this regimen.e. sideeffects. Treatment of nonalcoholic fatty liver: present and emerging therapies. 21: 81–8. obese and diabetic were at greatest risk of progressing to cirrhosis. 7. In the Mayo series.980 L. diabetes mellitus type 2 and hyperlipidaemia are major predisposing factors leading to the development of NAFLD.14. and further studies are needed to determine the most appropriate diet programme to be recommended for obese patients with NAFLD. it is reasonable to suggest that the prevention and appropriate management of these conditions will lead to the improvement of liver disease. THERAPY particularly for those patients who are more than 30% overweight. It has been recognized that some patients with NAFLD will follow a relatively benign course. 7 whereas others will progress to end-stage liver disease.5.

The mechanisms implicated in the genesis of liver damage.59 The ALT level was normalized in seven patients.61 In a recent study. In another report.11 Although proximal gastric bypass seems to be a safer procedure. choline.35. Diabetes and hyperlipidaemia control.and macrovesicular steatosis and steatohepatitis. but has been abandoned because of the high frequency of severe NAFLD followed by liver failure. such as type 2 diabetes and truncal obesity. in patients on long-term total parenteral nutrition can be divided into patient-dependent factors and total parenteral nutrition-dependent factors. Cavicchi et al. There are still insufficient data in humans to support a direct toxic effect of total parenteral nutrition. troglitazone (400 mg/day for 3–6 months) was given to 10 female patients. no significant benefit in liver tests or hepatic histology was found. In patients with diabetes and hyperlipidaemia. In a pilot study.63 short bowel syndrome64 and bacterial overgrowth. Insulin-sensitizing medications may benefit liver disease in patients with associated insulin-resistance conditions. and patients undergoing gastric bypass are not exempt from the risk of developing liver failure. 36 Total parenteral nutrition-dependent factors include the duration of total parenteral nutrition. Aliment Pharmacol Ther 17. cyclic administration of the formula. clofibrate (2 g/day) was evaluated in the treatment of a patient with NAFLD. Lipid-lowering agents have been employed.64 Long-term total parenteral nutrition with 20% fat emulsions high in x-6 polyunsaturated fatty acids may induce phospholipidosis and microvesicular steatosis in both hepatocytes and Kupffer cells. probably via reduced hepatic expression of tumour necrosis factora. Fatty liver may result from the inability of the reticulo-endothelial system to clear the exogenous lipid load. Bariatric surgery has been used. metformin was proven to be effective at reversing hepatomegaly. Jejuno-ileal bypass was a popular weight-reducing surgical procedure in the 1960s and 1970s. steatosis and liver test abnormalities. but is not always effective in reversing NAFLD.REVIEW: NON-ALCOHOLIC FATTY LIVER DISEASE 981 to be proven whether the risk-to-benefit ratio of appetite-suppressing medications justifies their use in patients with NAFLD. Patients receiving metformin also had a significant decrease in hepatic volume and body weight. but this was associated with an increase in lobular inflammation. Patient-dependent factors include a lack of enteral stimulation. metformin (500 mg three times daily for 4 months) was administered to 14 patients with NAFLD. however. including NAFLD. the severity of liver injury seems to be linked to the rapidity of weight loss rather than to the type of surgery. necro-inflammatory features of NAFLD were present in all seven patients. however. 46 patients with NAFLD were randomized to receive treatment with gemfibrozil (600 mg/day for 4 weeks) or no treatment. In a pilot study. Patients with insulin-dependent diabetes mellitus and hepatomegaly will show improvement in the symptoms of hepatomegaly when appropriate control of hyperglycaemia is achieved. Troglitazone can induce idiosyncratic hepatocellular injury.65. found that the risk of severe total parenteral nutrition-related liver disease was increased when the daily parenteral lipid intake was more than 1 g/kg. In adults. total parenteral nutrition-associated liver disease presents predominantly with both micro.55. 977–986 patients with non-alcoholic steatohepatitis. excessive intravenous lipids have also been implicated in the development of fatty liver. In ob/ob mice. good laboratory control is always recommended. 56 Luyckx et al.57 After 1 year of treatment. Insulin resistance represents the most reproducible predisposing factor for NAFLD.60 and is no longer available in the USA.62 The metformin-treated group showed significant improvement in liver tests and insulin sensitivity. Alterations to total parenteral nutrition formula. described the histological characteristics before and after gastroplasty in morbidly obese patients. Metformin is an antidiabetic medication that improves hepatic insulin sensitivity. The degree of steatosis improved after weight loss. Unfortunately. but this improvement did not occur in the untreated group. clinical and experimental evidence from total parenteral nutrition . 66 glutamine and lipid content and continuous vs. on follow-up biopsy. post-treatment liver biopsies were not performed. In a series of patients with permanent intestinal failure receiving long-term parenteral nutrition. although the grade of necro-inflammation improved in four of the seven. if the improvement of liver disease was because of weight loss or due to metformin. Other safer thiazolidinedione agents are currently available and may warrant further evaluation in Ó 2003 Blackwell Publishing Ltd. It is uncertain.67 Although the addition of lipids to total parenteral nutrition formulations appears to be beneficial in reducing liver fatty change.58 A significant improvement in aminotransferase levels was noted in the gemfibrozil group.

10 mg/kg/day 10 mg/kg/day 1 g/day 20 g/day 400–1200 IU/day 300 mg/day Duration 4 weeks 12 months 3–6 months 4 months 12 months 6–12 months 6 months 6 months 3 months 12 months 4–10 months 12 months NP. open-label. Recommendations to improve non-alcoholic fatty liver disease in patients requiring long-term total parenteral nutrition Encourage enteral nutrition63. pilot studies have evaluated the therapeutic benefit of ursodeoxycholic acid in patients with NAFLD. with the non-hepatotoxic ursodeoxycholic acid. not performed. their withdrawal. Post-treatment liver biopsies were performed in only one of these studies. 67 Cyclic total parenteral nutrition63. some of which may be hepatotoxic. steatohepatitis and even cirrhosis (Table 1). and only a few of them have evaluated the effect of treatment on liver histology (Table 3).982 L. steatosis. A careful interview to obtain a complete list of medications used by the patient. a-tocopherol and betaine.d. Although the liver condition resulting from these secondary causes differs strikingly from NAFLD in pathogenesis and outcomes.s. Drugs believed to be hepatoprotective. Ursodeoxycholic acid is the epimer of chenodeoxycholic acid and appears to replace endogenous bile acids.57. which have been evaluated for the treatment of NAFLD. liver tests significantly improved when compared with baseline. Pharmacological therapy Pharmacological therapy directed specifically at the liver disease has only recently been evaluated in patients with NAFLD.35 metronidazole36 Choline supplementation65. the degree of hepatic Table 2. 977–986 .d. * Study performed in children. Aliment Pharmacol Ther 17. Drugs evaluated in the treatment of non-alcoholic fatty liver disease Transaminase improvement Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Histological improvement NP No Yes NP Yes No NP NP NP Yes NP Yes  Drug Lipid-lowering Gemfibrozil58 Clofibrate57 Insulin-sensitizing Troglitazone59 Metformin62 Hepatoprotective UDCA57 UDCA70 UDCA + diet68 UDCA + diet69 N-Acetylcysteine73 Betaine72 Vitamin E74 a-Tocopherol75 Patients (n) 46 16 10 14 24 24 24 31 11 8 11* 22 Dose 600 mg/day 2 g/day 400 mg/day 500 mg t. 67 Antibiotics: polymixin B. 13–15 mg/kg/day 250 mg t. 68–70 In all four studies. open-label. Drugs and hepatotoxins Several drugs and environmental exposure to some hepatotoxins have been recognized as potential causes of fatty liver. ALBA & K. 66 Table 3. UDCA. include ursodeoxycholic acid.s. Table 2 summarizes recommendations for improving NAFLD in patients receiving long-term total parenteral nutrition. ursodeoxycholic acid. Most of these studies have been uncontrolled. usually leads to the resolution of liver disease. pilot studies lasting 1 year or less. when possible. is of paramount importance. as well as a thorough occupational history. 67 Reduce lipid intake to less than 1 g/kg of x-6-rich long-chain triglycerides64 Avoid excess carbohydrate59. M.   Liver biopsy performed in nine patients post-treatment. Four. N-acetylcysteine. LINDOR points to the possible role of nutrient deficiencies and caloric imbalances as important factors in the development of fatty liver. Ó 2003 Blackwell Publishing Ltd. The use of lipid-lowering agents and agents that increase insulin sensitivity has been discussed above (see ‘Management of associated conditions’).

other studies have not confirmed this observation. 43 Nevertheless. Future directions Based on our current knowledge of the pathogenesis of NAFLD. Betaine.8. whereas the degree of steatosis. betaine. necro-inflammatory activity and fibrosis improved or remained unchanged in all patients.41.73 Treatment was well tolerated and was associated with a significant improvement in aminotransferase levels at the end of treatment. ursodeoxycholic acid therapy also improved several markers of fibrogenesis. 40 Dietary modifications (fat-reduced diet) that reduce enzyme activity may be beneficial. 977–986 The encouraging results of pilot studies with gemfibrozil. may warrant further evaluation for the treatment of NAFLD. (e) Reduction of hepatic iron content.REVIEW: NON-ALCOHOLIC FATTY LIVER DISEASE 983 steatosis significantly improved when compared with baseline. ursodeoxycholic acid. Liver transplantation NAFLD may recur early after liver transplantation with rapid progression from steatosis to steatohepatitis. If excessive iron and perhaps also the HFE gene mutation are found. N-acetylcysteine and a-tocopherol in the treatment of NAFLD (Table 3) suggest that these agents deserve further evaluation in carefully controlled clinical trials that have appropriate statistical power and include clinically relevant end-points. the potential benefit of intestinal decontamination and the administration of soluble cytokine receptors and neutralizing anti-cytokine antibodies. as well as drugs such as oxpentifylline (pentoxifylline) and anti-tumour necrosis factor-a antibodies. A recent uncontrolled trial in 11 children with NAFLD reported significant improvement in serum aminotransferases after treatment with vitamin E.78–80 . future therapeutic strategies that may be of potential benefit and deserve further evaluation are as follows. a normal component of the metabolic cycle of methionine. Aliment Pharmacol Ther 17. a-Tocopherol had no effect on the serum ALT level in patients with NAFLD. a-tocopherol (300 mg/day for 1 year) was given to 12 patients with liver biopsy-proven non-alcoholic steatohepatitis and to 10 non-biopsied patients with NAFLD. Some reports have associated iron overload with accelerated hepatic fibrosis in NAFLD patients. Seven patients were able to complete treatment.32.70 Based on these promising results. betaine (20 g/day for 12 months) was given to 10 patients with NAFLD.76. insulin-sensitizing drugs (thiazolidenedione. serum iron studies should always be performed in patients with NAFLD. 33. increases S-adenosylmethionine levels. (c) Protection of hepatocyte adenosine triphosphate stores.37 If this concept is valid.69.38. 11 patients with NAFLD were treated with N-acetylcysteine (1 g/day for 3 months). (a) Inhibition of lipid peroxidation and oxidative stress mechanisms.57 Normalization or improvement in liver tests was significantly more common in patients treated with ursodeoxycholic acid plus diet than in those treated with diet alone.. Vitamin E (a-tocopherol) is known for its antioxidant properties. serial phlebotomies. metformin).72 N-Acetylcysteine is an antioxidant that increases glutathione levels in hepatocytes.74 In another study.71 In a recent pilot study. Plasma levels of transforming growth factor-b1 in patients with non-alcoholic steatohepatitis were reduced significantly by a-tocopherol. two patients were lost to follow-up and one patient received treatment for 6 months. 42 However. placebo-controlled trial of ursodeoxycholic acid in NAFLD patients is now underway.75 Ó 2003 Blackwell Publishing Ltd. inflammation and fibrosis improved or remained unchanged in the nine patients with non-alcoholic steatohepatitis for whom post-treatment liver biopsy was performed. 70 In the study by Holoman et al. Recently. 400–1200 IU/day. The plasma transforming growth factor-b1 level in patients with non-alcoholic steatohepatitis was significantly elevated compared with that in those with NAFLD and in healthy controls. and an iron stain with quantification of hepatic iron is also recommended in those patients with abnormal serum iron studies. The degree of steatosis. (b) Inhibition and/or neutralization of endotoxin/cytokine-mediated injury. S-adenosylmethionine has been shown to protect against triglyceride deposition and liver injury in ethanol-fed rats.75 Liver tests improved significantly in patients with non-alcoholic steatohepatitis. 39 (d) Down-regulation of Cyp2E1/Cyp4A enzyme activity. a large-scale. 77 may be a therapeutic option.29 Both silymarin and a-tocopherol are well-known antioxidants that deserve to be evaluated in large controlled trials. which may improve liver biochemistries. Betaine was well tolerated and led to a significant improvement in serum aminotransferase levels. for 4–10 months.

McGill DB. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. For those patients with NAFLD and decompensated cirrhosis. Hepatology 1996. Fatty liver hepatitis and cirrhosis in obese patients. 11 Luyckx FH. Aliment Pharmacol Ther 17. Hayashi J. 27: 142–9. Hepatology 1989. Semin Liver Dis 1999. Hum Pathol 1989. 15 Wanless IR. Ó 2003 Blackwell Publishing Ltd. Deis A. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. 22: 222–6. Diehl AM. et al. 23: 1025–9. Halliday JW. Hepatology 1995. Batts KP. The natural history of nonalcoholic fatty liver: a follow up study. Non alcoholic steatohepatitis. sex and age: a prospective population study. Tani S. Nonalcoholic fatty liver disease. Schaffner F. 67: 811–6. Argenziano A. Japan. Kashiwagi S. 3 Teli MR. 16 Silverman JF. In a 6-year study at a large transplant centre. alcoholic disease (15%) and hepatitis C (15%). 19: 221–7. Frank steatohepatitis recurred in approximately one-third of transplant recipients with NAFLD. 10 Nomura H. 42: 548–51. Dig Dis Sci 1997. 30: 1356–62. Rakela J. Thiry A. James OFW. Am J Gastroenterol 1990. Liver pathology in morbidly obese patients with and without diabetes. Janney CG. M. Lindor KD. et al. Jpn J Med 1988. with progression to cirrhosis in 12. Long S. Liver involvement in obese children. Farahvash MJ. 85: 1349–55. Day CP. A study of 49 patients. Kajiyama W. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Prevalence of fatty liver in the general population of Okinawa. Hepatology 1990. Am J Gastroenterol 1999. ALBA & K. 111: 473–8. Kurata JH. Liver fibrosis in overweight patients. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Czaja AJ. Nonalcoholic fatty liver disease. Cooksley GE. 20: 594–8.984 L. Gastroenterology 1999. et al. Wang J. Kwoh-Gain L. Metabolism 1993. Prediction of risk of liver disease by alcohol intake. et al. 118: 1117–23. 9: 193–7. A spectrum of clinical and pathological severity. O’Brien KF. These measures may be all that is required for patients with pure uncomplicated steatosis. Searle J. Gastroenterology 1994. Sorensen TI. 14 Franzese A. 107: 1103–9. 12: 1106–10. 23 Ratziu V. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. McCullough AJ. Ludwig J. LINDOR 7 Matteoni CA. Powell LW. 17 Diehl AM.80 CONCLUSIONS In summary. Giral P. Liu YC. Appropriate control of glucose and lipid levels should always be sought.7% and 81. Younossi ZM. Neuschwander-Tetri BA. initial useful steps in the treatment of NAFLD include the management of associated conditions. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients. Gradual weight loss may improve the liver condition.2%. 4 Lee RG.78 Post-transplant steatosis was higher in patients with NAFLD (60%) than in those with cholestatic disease (5%). 13: 455–9. Alcohol like liver disease in nonalcoholics. 18 Sorbi D. Dig Dis Sci 1995. Boparai N. 22: 1714–9. 116: 1413–9. 22 Hay JE. Ishak G. 11: 74–80. Nonalcoholic steatohepatitis: an expanded clinical entity. et al. Lentz JS. Prog Liver Dis 1986. comparable with the patient survival rates after transplantation for other causes of liver disease. et al. NAFLD was the primary cause of decompensated cirrhosis in 16 of the 546 (2. 4: 2002–9. 42: 1438–2. Goodman Z. Gramlich T. Ott BJ. Hanson R. Bennet MK. Body fat topography as an independent predictor of fatty liver. Am J Med 1979. 13 Tominaga K. Charlotte F. et al. Shaffner F. Int J Obes 1998. Markers of chronic alcohol ingestion in non-alcoholic steatohepatitis: an aid to diagnosis. respectively. Thaler H. Chen YK. Viggiano TR. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes? Ann Intern Med 1989. 21 Van Ness MM. Pierson RN Jr. et al. Burt JA. NAFLD patients with steatohepatitis and/or fibrosis on liver biopsy should be offered enrolment in well-controlled clinical trials evaluating the potential benefit of promising medications. Independent predictors of liver fibrosis in patients with non-alcoholic steatohepatitis.5%. 6 Bacon BR. Goto M. A clinical and histological comparison with alcohol induced liver injury. Hepatology 1999. such as obesity. REFERENCES 1 Ludwig J. 5 Powell EE. Desaive C. Hepatology 1991. Nonalcoholic steatohepatitis. Powell E. 20 Becker U.9%) patients who underwent liver transplantation. Vajro P. Prevalence of fatty liver in Japanese children and relationship to obesity. 94: 1018–22. Gastroenterology 2000. 2 Schaffner F. 55: 434–8. 8: 283–6. 24 Adler M. 19 Fletcher LM. 977–986 . liver transplantation is a potential life-extending therapeutic alternative. 95: 1056–62. Boyton J. 12 Kral JG. 9 Diehl AM. 8 Angulo P. but total starvation and very-low-calorie diets should be avoided. Keach JC. Mayo Clin Proc 1980. Gastroenterology 1988.80 Oneand 3-year patient survival rates were 93. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Hepatology 1990. diabetes mellitus and hyperlipidaemia.

Camilo ME. MacDonald GA. Hepatology 1996. Hepatic effect of dietary weight loss in morbidly obese patients. Eriksson KF. 47 Ueno T. 20: 119–31. Biava C. Liddle C. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. Hepatology 1999. TNF production and hepatic steatosis during total parenteral nutrition in rat. N Engl J Med 1998. Morselli-Labate AM. 335: 609–16. In: Blackburn GL. et al. Effect of weight reduction on hepatic abnormalities in overweight patients. Acta Med Scand 1986. 23: 1464–7. Kanders BS. 30 Jaeschke H. et al. 38 Chavin KD. 94: 2557–62. Brenot F. Jejunoileal bypass as a treatment of morbid obesity. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. Injury produced by free fatty acids to lysosomes and mitochondria in cultures of heart muscle and endothelial cells. Chatham J. 55 DeWind LT. 59 Caldwell SH. Gludd C. Prevention and reversal by metronidazole. 24: 200–8. Hall P. J Surg Res 1991. Psychology and Treatment. J Hepatol 1996. Johnson D. Tedesco M. Intestinal bypass surgery for morbid obesity. 51 Drenik EJ. Farrell GC. 137: 602–10. et al. Hepatology 1996. Orso G. et al. Drug Safety 1999. A possible beneficial effect of metronidazole in reducing TPN-associated liver function derangements. Bondesson L. 33 Weltman MD. Proc Natl Acad Sci USA 1997. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. Goldwurm S. J Hepatol 1997. Very-low calorie diets for the treatment of obesity. J Clin Invest 2000. Acbay O. Farrel GC. et al. et al. 111: 1645–53. Simmons F. Lin HZ. Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. troglitazone. 114: 311–8. 52 Kanders BS. Fontanella A. Roberts EA. 977–986 . 34 Drenick EJ. et al. 50 Rozental P. Ó 2003 Blackwell Publishing Ltd. Chacko VP. Brizi M. 41: 172–9. et al. Redick JA. J Am Med Assoc 1976. reducing diets. Campbell-Sargent C. 125: 239–41. 27: 128–33. 44 Andersen T. Polimixin B reduces cecal flora. Sujaku K. N Engl J Med 1970. 82: 535–48. N Engl J Med 1996. Dig Dis Sci 1996. 31 Acosta D. 12: 224–9. Field J. Christofferesen P. New York: Chapman & Hall. Lane MD. 20: 417–26. Hepatic iron and nonalcoholic fatty liver disease. Jawaid Q. 60 Watkins PB. Payne JH. Schaffner F. Hung TK.REVIEW: NON-ALCOHOLIC FATTY LIVER DISEASE 25 Cortez-Pinto E. A risk benefit assessment of anti-obesity drugs. 105: 1067–75. 99: 1408–13. 30: 847–50. 56 Campbell JM. A pilot study. Murphy J. J Pediatr Gastroenterol Nutr 2000. 338: 908–9. Nonalcoholic steatohepatitis in children. J Biol Chem 1999. 51: 106–12. 32 Weltman MD. et al. 57 Laurin J. et al. Wang Y. 29 Letterson P. Lindor KD. and small bowel bypass. Wenzel DG. Association of nonalcoholic fatty liver disease with insulin resistance. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Alterations in liver ATP homeostasis in human nonalcoholic steatoheaptitis. Hepatology 1998. Moride Y. Am J Dig Dis 1967. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. 58 Besaranoglu M. 35 Pappo I. Perna C. 41 George DK. 31: 384. Gastroenterology 2001. Arch Intern Med 1977. A controlled trial of gemfibrozil in the treatment of patients with non-alcoholic steatohepatitis. Yang SQ. Whitcomb RW. Tortorelli K. J Am Med Assoc 1999. Reactive oxygen species activate the transcription factor NF-kB in the liver by induction of lipid peroxidation [Abstract]. Crippin JS. Sugawara H. et al. Hepatic dysfunction associated with troglitazone. et al. J Hepatol 1999. Lindor KD. eds. Long term results. 107: 450–5. 43 Younossi ZM. Aliment Pharmacol Ther 17. 120: 1183–92. 54 Abenhaim L. Franzmann MB. Atherosclerosis 1974. 12: 198–208. A pilot study of thiazolidinedione. 46 Eriksson S. Blackburn GL. 1994: 197–215. 282: 1659–64. 38: 356–3. Mirshahi F. 220: 83–8. 27: 103–7. J Pediatr 1994. Obesity: Pathophysiology. irrespective of protein-calorie malnutrition. Terris B. et al. 27 Marchesini G. et al. Fisler J. 36 Freud HR. Spencer H. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Gastroenterology 1990. Gastroenterology 1998. et al. Gastroenterology 2001. Lin HZ. Nonalcoholic steatohepatitis in obesity: a reversible condition. et al. Farrell GC. Hespenheiden EE. Essani NA. 37 Yang SQ. Gastroenterology 1996. Bacovier H. 53 Kolanowski J. 236: 2298–301. Baptista A. LaFrance R. De Vincenzo A. Gramlich T. 30: 48–53. 40 Leclercq IA. et al. Insulin resistance and mitochondrial abnormalities in NASH: a cool look into a burning issue. J Surg Res 1985. Am J Gastroenterol 2001. A persistent aminotransferasemia resolving after weight reduction of children. et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Bacon BR. Effect on hepatic morphology of treatment of obesity by fasting. Ursodeoxycholic acid or clofibrate in the treatment of non-alcoholic induced steatohepatitis: a pilot study. Non-alcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Liver morphology and function tests in obesity and during total starvation. Berry EM. 49 Vajro P. Gastroenterology 1982. in non-alcoholic steatohepatitis. 282: 829–34. Karam JH. Muggia-Sullan M. Hepatic steatosis after intestinal bypass. 985 42 Boncovsky HL. J Hepatol 1999. Am J Med 1999. 24: 238A. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. 45 Palmer M. 120: 1281–5. Fromenty B. 274: 5692–700. 48 Rashid M. 31: 421–9. J Hepatol 1991. 96: 519–25. et al. 28 Sanyal AJ. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. Zimmerman HJ. 39 Cortez-Pinto H. Sonsuz A. 26 Angulo P. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine non-alcoholic steatohepatitis.

Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. Jenden D. Glasa J. Yoneda M. Aliment Pharmacol Ther 17. Ursodeoxycholic acid in the treatment of nonalcoholic steatohepatitis: results of a prospective clinical controlled trial [Abstract]. 358: 893–4. 12: 191–8. 67 Fleming CR. Metformin reverses fatty liver disease in obese. et al. et al. 68 Guma G. et al. Correlation to liver morphology and effect of therapy. Messing B. Marsch MN. Recurrence of nonalcoholic steatohepatitis following liver transplantation. Treatment on nonalcoholic steatohepatitis with N-acetylcysteine [Abstract]. et al. Angulo P. Phlebotomy reduces transaminase levels in patients with non-alcoholic steatohepatitis [Abstract]. Hepatobiliary complications in adults receiving nutrition support. Chuckaree C. 118: A1474(Abstract). 104: 286–301. 61 Lin HZ. Dickson ER. Jackson FW. et al. et al. 73 Gulbahar O. 80 Charlton M. Bianchi G. 6: 998–1003. Aliment Pharmacol Ther 2001. 28: 386A. Markin RS. Brizi M. Transplantation 1996. Thome M. 64 Cavicchi M. Beau P. Hepatology 1995. Lecithin increases plasma free choline and decreases hepatic steatosis in longterm total parenteral nutrition.986 L. 72 Abdelmalek M. LINDOR 71 Barak AJ. Cales W. et al. Shaffer JL. Lancet 2001. Dig Dis 1994. Effect of phlebotomy on non-alcoholic steatohepatitis (NASH) [Abstract]. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. 66 Buchman AL. Crenn P. 118: A1444(Abstract). et al. 70 Holoman J. Liver Transpl 2001. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Plasma transforming growth factor-b1 level and efficacy of a-tocopherol in patients with non-alcoholic hepatitis: a pilot study. 7: 608–14. et al. et al. 22: 1390–403. 7: 363–73. J Pediatr 2000. 62: 1802–5. Junnila M. 132: 525–32. Kasparova P. Serum markers of liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). 62 Marchesini G. et al. Dubin MD. Ann Intern Med 2000. 136: 734–8. Ersoz G. Gastroenterology 2000. Hepatology 1998. Viola L. Ó 2003 Blackwell Publishing Ltd. Steers JL. Weston S. 977–986 . 32: 210. et al. ALBA & K. Sterling RK. Jorgensen RA. Beckenhauer HC. Karasu ZA. Nakamura K. Mourkarzel AA. Gastroenterology 1992. Morini L. Hepatology 1998. Poterucha JJ. Gastroenterology 1993. Dubin M. leptin deficient mice. Yang SQ. M. Nature Med 2000. Wiesner RH. et al. Gastroenterology 2000. Effect of ursodeoxycholic acid plus diet in patients with non-alcoholic steatohepatitis [Abstract]. Liver Transpl 2001. Kasar J. 26: 387A. 118: A975(Abstract). 63 Quigley EM. 79 Contos MJ. et al. 74 Lavine JE. Alcohol Clin Exp Res 1993. 102: 1363–70. 15: 1667–72. Allen ML. 76 Desai TK. Degott C. J Hepatol 2000. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for criptogenic cirrhosis. Am J Gastroenterol 2001. 77 Nitecki J. Metformin in nonalcoholic steatohepatitis. 69 Ceriani R. Bunati S. Porayko MK. Dietary betaine promotes generation of hepatitic S-adenosylmethionine and protects the liver from ethanol-induced fatty infiltration. Betaine. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. 75 Hasewaga T. 78 Kim WR. Gastroenterology 2000. 65 Buchman AL. a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. 96: 2711–7. Hepatobiliary complications of total parenteral nutrition. 17: 552–5.