Aliment Pharmacol Ther 2003; 17: 977986.

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 brosis and cirrhosis. Non-alcoholic steatohepatitis represents only a stage within the spectrum of non-alcoholic fatty liver disease and is dened pathologically by the presence of steatosis together with necro-inammatory activity. The true prevalence of non-alcoholic fatty liver disease is unknown, but it is estimated that it affects 1024% 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 dened. Patients with pure steatosis on liver biopsy follow a relatively benign course, whereas patients with histological necro-inammatory changes and/or brosis 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 brosis on liver biopsy may benet 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 brosis and cirrhosis. The pathological picture resembles alcohol-induced liver injury, but NAFLD occurs in patients who do not consume signicant amounts of alcohol. Non-alcoholic steatohepatitis represents only a stage in the spectrum of NAFLD and is dened pathologically by the presence of steatosis together with necro-inammatory activity, mostly of lobular distribution, with or without Mallorys hyaline or brosis.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 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.37
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 1024% of the general population from different countries. The prevalence of NAFLD is higher in patients with obesity (6095%), type 2 diabetes mellitus (2855%) and hyperlipidaemia (2092%).1, 39 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.1012 Furthermore, many patients
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with NAFLD are non-obese and non-diabetic and have normal liver tests and lipid proles.6, 8 Truncal obesity seems to be a signicant risk factor for NAFLD, even in subjects with a normal body mass index.12 NAFLD affects 2.6% of children,13 and this gure increases to 22.5%13 to 52.8%14 in the obese child population. The estimated prevalence of NAFLD is about 23% in lean individuals, but increases to 19% in the obese population.15, 16 It is possible that the prevalence of NAFLD in the USA and other Western countries has increased over the past 1015 years, paralleling the marked increases in obesity and diabetes that have occurred in all age groups.
CLINICAL FEATURES

Most patients with NAFLD are asymptomatic. Many cases are diagnosed after nding elevated liver biochemistries during routine laboratory testing. When symptoms are present, they are variable, and include fatigue, malaise and right upper quadrant discomfort. Hepatomegaly is the most common physical sign. Splenomegaly and stigmata of cirrhosis can be present, but are less frequent.17 The predominant laboratory abnormality in patients with NAFLD is mild to moderate elevation of serum aminotransferases. The aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is useful in differentiating NAFLD from alcoholic liver disease.18 Most patients with NAFLD have an AST/ALT ratio of less than unity, although the AST/ALT ratio increases as the liver disease progresses to cirrhosis, losing its diagnostic accuracy in cirrhotic stage NAFLD.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;19 however, its current role as a diagnostic test for NAFLD has not been dened. One-half of patients with NAFLD have elevated serum ferritin levels, whereas increased transferrin saturation is found in 611% of patients. The hepatic iron index and hepatic iron concentration, however, are usually in the normal range.
DIAGNOSIS

such as macrovesicular steatosis, necro-inammatory activity, mostly of lobular distribution, Mallorys hyaline, brosis or cirrhosis; (iii) the exclusion of other forms of liver disease. The minimal amount of alcohol considered to be excessive to t the denition of NAFLD has not been determined; however, in a prospective study, Becker et al. found that the level of alcohol intake above which the relative risk for developing liver disease was signicantly greater than unity was 84156 g alcohol/week for women and 168324 g alcohol/week for men.20 Clinical ndings and liver test values have a poor predictive value for making a diagnosis,21, 22 and for differentiating between simple steatosis and steatohepatitis, advanced brosis and cirrhosis. Non-invasive imaging studies are useful in determining the presence and amount of fatty inltration of the liver, but cannot accurately determine the presence of liver inammation and/or brosis. Hence, once other liver diseases have been excluded, the clinical suspicion of NAFLD can only be conrmed with a liver biopsy. Role of liver biopsy Although a liver biopsy is the best diagnostic tool for conrming NAFLD, it is not routinely performed due to the current lack of effective medical therapy for this condition. Nevertheless, liver biopsy is the only means to determine the severity of liver damage and to obtain important prognostic information. Some factors can help to identify the sub-group of patients in whom liver biopsy may provide the most prognostic information. An age of 45 years or more, presence of obesity or type 2 diabetes mellitus, higher levels of ALT and triglycerides, and an AST/ALT ratio greater than unity are noteworthy indicators of advanced liver brosis.8, 23 These factors can help to identify the NAFLD patient expected to have the most likely chance of clinically severe disease, and may prompt these patients towards enrollment into therapeutic trials. Liver histology The histological features of NAFLD are indistinguishable from those of alcohol-induced liver disease. NAFLD includes a wide spectrum of histological features, ranging from steatosis alone or in combination with
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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;20 (ii) liver biopsy showing characteristic features, alone or in combination,

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mixed inammatory cell inltration, hepatocyte ballooning and necrosis, glycogen nuclei, Mallorys hyaline and pericentral perisinusoidal brosis. Non-alcoholic steatohepatitis represents only a stage within the spectrum of NAFLD and is dened histologically by the presence of steatosis together with lobular inammatory inltrate and hepatocellular ballooning. Many patients with NAFLD will have some degree of brosis, whereas Mallorys hyaline may or may not be present. The presence of brosis is a concerning histological nding because it suggests a more advanced and severe liver injury. Fibrosis is found in 67% of patients with NAFLD at the time of diagnosis.1, 36, 8, 9, 2325 Severe hepatic brosis (septal/cirrhosis) is found in 25% of patients at the time of diagnosis,36, 8, 23 whereas wellestablished cirrhosis is found in 14%.1, 39, 23, 24 In patients with cirrhosis, the features of steatosis and necroinammatory activity may no longer be present.5, 6
PATHOGENESIS

The pathogenesis of NAFLD is still unclear. Hepatic steatosis is due to lipid accumulation, mainly of triglycerides, within hepatocytes. The mechanisms leading to lipid accumulation are not completely understood, but it could potentially result from insulin resistance2628 and decreased disposal of fatty acids from impaired mitochondrial b-oxidation or decient production of very low density lipoprotein. Some lines of evidence, albeit still inconclusive, and some derived from studies in animal models of fatty liver, suggest that oxidative stress/lipid peroxidation, bacterial toxins, overproduction of tumour necrosis factor-a, alteration of hepatocyte adenosine triphosphate stores and cytochrome P450 Cyp2E1/Cyp4A enzyme activity may play a role in the genesis and progression of NAFLD. Lipid peroxidation seems to increase with the severity of steatosis.29 Malondialdehyde, an end-product of lipid peroxidation, activates hepatic stellate cells, stimulating collagen production and brogenesis. Malondialdehyde may also contribute to inammation by activating nuclear factor-jB (NF-jB), which regulates the expression of pro-inammatory cytokines, such as tumour necrosis factor-a and interleukin-8.30 Another end-product of lipid peroxidation, 4-hydroxynonenal, is a strong chemo-attractant for neutrophils. Furthermore, the risk factors for the development of NAFLD, namely obesity with rapid weight loss and type 2
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diabetes mellitus, lead to increased circulating levels of free fatty acids with enhanced concentration in the liver. Free fatty acids per se are potentially cytotoxic,31 and may also increase cytochrome P450 Cyp2E1/Cyp4A activity, as shown in a rat model of NAFLD using a diet decient in methioninecholine.32, 33 This evidence suggests that oxidative stress and lipid peroxidation may, in part, be critical factors involved in the genesis and, probably, progression of NAFLD. Based on the fact that metronidazole and polymixin B may prevent the development of NAFLD in obese patients undergoing intestinal bypass,34 and in rats receiving total parenteral nutrition,35, 36 a role of endotoxin/cytokine-mediated injury has been suggested as a contributing factor to the development of NAFLD. More recently, it has been shown that genetically obese mice are very sensitive to the effect of lipopolysaccharide in developing NAFLD.37 The messenger RNA of interferon-c, which sensitizes hepatocytes to tumour necrosis factor-a toxicity, is over-expressed, whereas the messenger RNA of interleukin-10, which is inhibitory to tumour necrosis factor-a effects, is reduced. In this model, the phagocytic activity of Kupffer cells is reduced, presumably favouring the development of systemic endotoxaemia and the release of pro-inammatory cytokines. The adenosine triphosphate stores in hepatocytes of mice38 and humans39 with steatosis seem to be potentially vulnerable to depletion, compared with those of non-obese controls. Hence, treatment efforts primarily directed towards protecting hepatocyte adenosine triphosphate stores might be potentially benecial in patients with NAFLD. Similarly, cytochrome P450 Cyp2E1/Cyp4A activity may contribute to hepatotoxicity in mice and humans with NAFLD.32, 33, 40 Treatment strategies to limit its activity, such as dietary modications (fat-reduced diet), may be benecial. The role of iron in the pathogenesis of NAFLD remains uncertain. Anecdotal reports suggest that increased iron stores might lead to more severe liver disease in patients with non-alcoholic steatohepatitis.41, 42 Studies of larger patient populations with non-alcoholic steatohepatitis, however, have shown that this is not always the case.8, 43
PROGNOSIS

The prognosis of NAFLD is still controversial, mainly because the natural history of the disease remains to be

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dened. Large epidemiological studies with decades of follow-up are needed. It has been recognized that some patients with NAFLD will follow a relatively benign course,3, 7 whereas others will progress to end-stage liver disease.5, 7, 23 The reasons for the different course in patients suffering from apparently the same condition remain to be dened. 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. In the Mayo series, patients with NAFLD who were older, obese and diabetic were at greatest risk of progressing to cirrhosis.8 This sub-group of patients may benet from investigational medical therapy, in addition to the management of associated conditions (weight loss, control of diabetes), and should be encouraged to undergo liver biopsy.
THERAPY

particularly for those patients who are more than 30% overweight,52 and have failed treatment with a conventional diet. The rate and degree of weight loss required for the normalization of liver histology have not been established, and further studies are needed to determine the most appropriate diet programme to be recommended for obese patients with NAFLD. Medications used to reduce appetite will result in weight reduction in many patients.53 These medications are associated with rare, but potentially serious, sideeffects, including pulmonary hypertension.54 It remains

Table 1. 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 Wilsons disease) Iron storage disorders Lypodystrophy Acute fatty liver of pregnancy Systemic carnitine deciency* WeberChristian disease Surgical Extensive small bowel resection Gastroplasty (for morbid obesity) Biliopancreatic diversion Jejuno-ileal bypass Drugs Amiodarone Corticosteroids Calcium channel blockers (diltiazem, nifedipine) Chloroquine Oestrogens Perhexiline maleate Tamoxifen Tetracycline Valproic acid Other Environmental hepatotoxins Inammatory bowel disease Human immunodeciency virus infection Jejunal diverticulosis with bacterial overgrowth
Modied from Angulo P, Lindor K. Treatment of nonalcoholic fatty liver: present and emerging therapies. Semin Liver Dis 2001; 21: 818. * Inherited lipid storage disease. Presents in childhood with a clinical picture resembling Reyes syndrome. Hepatic steatosis is a prominent feature. 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 977986

Currently, the management of NAFLD is focused in the following areas: (i) management of associated conditions (Table 1); (ii) discontinuation of potentially hepatotoxic drugs; and (iii) pharmacological therapy in patients at high risk for developing advanced liver disease, i.e. patients older than 45 years with diabetes and steatohepatitis. Management of associated conditions Obesity, diabetes mellitus type 2 and hyperlipidaemia are major predisposing factors leading to the development of NAFLD.1, 38, 23 Therefore, it is reasonable to suggest that the prevention and appropriate management of these conditions will lead to the improvement of liver disease. Weight loss. 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.14, 4451 However, in patients with a high degree of fatty inltration, rapid weight loss may promote portal inammation and brosis, bile stasis and focal necrosis.44, 50 Therefore, it seems reasonable to start initially by decreasing the daily intake to 5001000 kcal below the caloric intake required for weight maintenance. With this regimen, weight loss of about 0.5 kg/week can be expected in obese adults. Very-low-calorie diets may be tried,

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

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points to the possible role of nutrient deciencies and caloric imbalances as important factors in the development of fatty liver. Table 2 summarizes recommendations for improving NAFLD in patients receiving long-term total parenteral nutrition. Drugs and hepatotoxins Several drugs and environmental exposure to some hepatotoxins have been recognized as potential causes of fatty liver, steatosis, steatohepatitis and even cirrhosis (Table 1). A careful interview to obtain a complete list of medications used by the patient, as well as a thorough occupational history, is of paramount importance. Although the liver condition resulting from these secondary causes differs strikingly from NAFLD in

pathogenesis and outcomes, their withdrawal, when possible, usually leads to the resolution of liver disease. Pharmacological therapy Pharmacological therapy directed specically at the liver disease has only recently been evaluated in patients with NAFLD. Most of these studies have been uncontrolled, open-label, pilot studies lasting 1 year or less, and only a few of them have evaluated the effect of treatment on liver histology (Table 3). The use of lipid-lowering agents and agents that increase insulin sensitivity has been discussed above (see Management of associated conditions). Drugs believed to be hepatoprotective, which have been evaluated for the treatment of NAFLD, include ursodeoxycholic acid, N-acetylcysteine, a-tocopherol and betaine. Ursodeoxycholic acid is the epimer of chenodeoxycholic acid and appears to replace endogenous bile acids, some of which may be hepatotoxic, with the non-hepatotoxic ursodeoxycholic acid. Four, open-label, pilot studies have evaluated the therapeutic benet of ursodeoxycholic acid in patients with NAFLD.57, 6870 In all four studies, liver tests signicantly improved when compared with baseline. Post-treatment liver biopsies were performed in only one of these studies; the degree of hepatic

Table 2. Recommendations to improve non-alcoholic fatty liver disease in patients requiring long-term total parenteral nutrition Encourage enteral nutrition63, 67 Cyclic total parenteral nutrition63, 67 Reduce lipid intake to less than 1 g/kg of x-6-rich long-chain triglycerides64 Avoid excess carbohydrate59, 67 Antibiotics: polymixin B,35 metronidazole36 Choline supplementation65, 66

Table 3. 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 Gembrozil58 Clobrate57 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.d.s. 1315 mg/kg/day 250 mg t.d.s. 10 mg/kg/day 10 mg/kg/day 1 g/day 20 g/day 4001200 IU/day 300 mg/day

Duration 4 weeks 12 months 36 months 4 months 12 months 612 months 6 months 6 months 3 months 12 months 410 months 12 months

NP, not performed; UDCA, ursodeoxycholic acid. * Study performed in children. Liver biopsy performed in nine patients post-treatment. 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 977986

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steatosis signicantly improved when compared with baseline.57 Normalization or improvement in liver tests was signicantly more common in patients treated with ursodeoxycholic acid plus diet than in those treated with diet alone.69, 70 In the study by Holoman et al., ursodeoxycholic acid therapy also improved several markers of brogenesis.70 Based on these promising results, a large-scale, placebo-controlled trial of ursodeoxycholic acid in NAFLD patients is now underway. Betaine, a normal component of the metabolic cycle of methionine, increases S-adenosylmethionine levels. S-adenosylmethionine has been shown to protect against triglyceride deposition and liver injury in ethanol-fed rats.71 In a recent pilot study, betaine (20 g/day for 12 months) was given to 10 patients with NAFLD. Seven patients were able to complete treatment, two patients were lost to follow-up and one patient received treatment for 6 months. Betaine was well tolerated and led to a signicant improvement in serum aminotransferase levels, whereas the degree of steatosis, necro-inammatory activity and brosis improved or remained unchanged in all patients.72 N-Acetylcysteine is an antioxidant that increases glutathione levels in hepatocytes. Recently, 11 patients with NAFLD were treated with N-acetylcysteine (1 g/day for 3 months).73 Treatment was well tolerated and was associated with a signicant improvement in aminotransferase levels at the end of treatment. Vitamin E (a-tocopherol) is known for its antioxidant properties. A recent uncontrolled trial in 11 children with NAFLD reported signicant improvement in serum aminotransferases after treatment with vitamin E, 4001200 IU/day, for 410 months.74 In another study, 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.75 Liver tests improved signicantly in patients with non-alcoholic steatohepatitis. a-Tocopherol had no effect on the serum ALT level in patients with NAFLD. The degree of steatosis, inammation and brosis improved or remained unchanged in the nine patients with non-alcoholic steatohepatitis for whom post-treatment liver biopsy was performed. The plasma transforming growth factor-b1 level in patients with non-alcoholic steatohepatitis was signicantly elevated compared with that in those with NAFLD and in healthy controls. Plasma levels of transforming growth factor-b1 in patients with non-alcoholic steatohepatitis were reduced signicantly by a-tocopherol.75
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The encouraging results of pilot studies with gembrozil, insulin-sensitizing drugs (thiazolidenedione, metformin), ursodeoxycholic acid, betaine, 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. Future directions Based on our current knowledge of the pathogenesis of NAFLD, future therapeutic strategies that may be of potential benet and deserve further evaluation are as follows. (a) Inhibition of lipid peroxidation and oxidative stress mechanisms.29 Both silymarin and a-tocopherol are well-known antioxidants that deserve to be evaluated in large controlled trials. (b) Inhibition and/or neutralization of endotoxin/cytokine-mediated injury.37 If this concept is valid, the potential benet 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, may warrant further evaluation for the treatment of NAFLD. (c) Protection of hepatocyte adenosine triphosphate stores.38, 39 (d) Down-regulation of Cyp2E1/Cyp4A enzyme activity.32, 33, 40 Dietary modications (fat-reduced diet) that reduce enzyme activity may be benecial. (e) Reduction of hepatic iron content. Some reports have associated iron overload with accelerated hepatic brosis in NAFLD patients.41, 42 However, other studies have not conrmed this observation.8, 43 Nevertheless, serum iron studies should always be performed in patients with NAFLD, and an iron stain with quantication of hepatic iron is also recommended in those patients with abnormal serum iron studies. If excessive iron and perhaps also the HFE gene mutation are found, serial phlebotomies, which may improve liver biochemistries,76, 77 may be a therapeutic option. Liver transplantation NAFLD may recur early after liver transplantation with rapid progression from steatosis to steatohepatitis.7880

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7 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: 14139. 8 Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver brosis in patients with non-alcoholic steatohepatitis. Hepatology 1999; 30: 135662. 9 Diehl AM, Goodman Z, Ishak G. Alcohol like liver disease in nonalcoholics. A clinical and histological comparison with alcohol induced liver injury. Gastroenterology 1988; 95: 105662. 10 Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Tani S, Goto M. Prevalence of fatty liver in the general population of Okinawa, Japan. Jpn J Med 1988; 27: 1429. 11 Luyckx FH, Desaive C, Thiry A, et al. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes 1998; 22: 2226. 12 Kral JG, Schaffner F, Pierson RN Jr, Wang J. Body fat topography as an independent predictor of fatty liver. Metabolism 1993; 42: 54851. 13 Tominaga K, Kurata JH, Chen YK, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. Dig Dis Sci 1995; 4: 20029. 14 Franzese A, Vajro P, Argenziano A, et al. Liver involvement in obese children. Ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci 1997; 42: 14382. 15 Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12: 110610. 16 Silverman JF, OBrien KF, Long S, et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol 1990; 85: 134955. 17 Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999; 19: 2217. 18 Sorbi D, Boyton J, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999; 94: 101822. 19 Fletcher LM, Kwoh-Gain L, Powell E, et al. Markers of chronic alcohol ingestion in non-alcoholic steatohepatitis: an aid to diagnosis. Hepatology 1991; 13: 4559. 20 Becker U, Deis A, Sorensen TI, et al. Prediction of risk of liver disease by alcohol intake, sex and age: a prospective population study. Hepatology 1996; 23: 10259. 21 Van Ness MM, Diehl AM. Is liver biopsy useful in the evaluation of patients with chronically elevated liver enzymes? Ann Intern Med 1989; 111: 4738. 22 Hay JE, Czaja AJ, Rakela J, Ludwig J. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients. Hepatology 1989; 9: 1937. 23 Ratziu V, Giral P, Charlotte F, et al. Liver brosis in overweight patients. Gastroenterology 2000; 118: 111723. 24 Adler M, Shaffner F. Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 1979; 67: 8116.

In a 6-year study at a large transplant centre, NAFLD was the primary cause of decompensated cirrhosis in 16 of the 546 (2.9%) patients who underwent liver transplantation.78 Post-transplant steatosis was higher in patients with NAFLD (60%) than in those with cholestatic disease (5%), alcoholic disease (15%) and hepatitis C (15%). Frank steatohepatitis recurred in approximately one-third of transplant recipients with NAFLD, with progression to cirrhosis in 12.5%.80 Oneand 3-year patient survival rates were 93.7% and 81.2%, respectively, comparable with the patient survival rates after transplantation for other causes of liver disease.80
CONCLUSIONS

In summary, initial useful steps in the treatment of NAFLD include the management of associated conditions, such as obesity, diabetes mellitus and hyperlipidaemia. Gradual weight loss may improve the liver condition, but total starvation and very-low-calorie diets should be avoided. Appropriate control of glucose and lipid levels should always be sought. These measures may be all that is required for patients with pure uncomplicated steatosis. NAFLD patients with steatohepatitis and/or brosis on liver biopsy should be offered enrolment in well-controlled clinical trials evaluating the potential benet of promising medications. For those patients with NAFLD and decompensated cirrhosis, liver transplantation is a potential life-extending therapeutic alternative.
REFERENCES
1 Ludwig J, Viggiano TR, McGill DB, Ott BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 4348. 2 Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Prog Liver Dis 1986; 8: 2836. 3 Teli MR, James OFW, Burt JA, Bennet MK, Day CP. The natural history of nonalcoholic fatty liver: a follow up study. Hepatology 1995; 22: 17149. 4 Lee RG. Non alcoholic steatohepatitis. A study of 49 patients. Hum Pathol 1989; 20: 5948. 5 Powell EE, Cooksley GE, 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: 7480. 6 Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 11039.

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