Nutritional aspects of non-alcoholic steatohepatitis treatment.

Abstract

Objective and design: The aim of the present study is to review literature associated with the nutritional aspect of the treatment of non-alcoholic steatohepatitis (NASH).

Subjects and setting: The studies reviewed used small numbers of subjects and the majority of the studies were retrospective reviews and case series, not randomised controlled trials. The duration of the studies ranged from seven weeks to two years.

Main outcome measures: Almost all of the studies demonstrate improvement

in liver function tests, with weight loss combined with exercise beneficially reversing fatty liver. Omega-3 fatty acid supplementation suggests positive effects in triglycerides level reduction by its role in suppression of sterol regulatory element binding protein-1, whereas vitamin E supplementation reduces serum transaminase. Nutritional treatment in NASH is directed at its risk factors. Some studies give useful information regarding the importance of the nutritional aspects of treatment of the NASH patient, and almost all of the studies provide positive results although in some regimens the results are inconsistent.

Conclusion: Well-designed trials (in terms of numbers of subjects, with valid outcome measures) are needed to determine the efficacy of each strategy.

Key words: antioxidants, lifestyle, metabolic syndrome, non-alcoholic steatohepatitis, nutrition, omega-3 fatty acids.

INTRODUCTION

Non-alcoholic steatohepatitis (NASH) is a condition characterised by liver injury, resembling alcoholic hepatitis, in the absence of significance alcohol consumption. (1-24) Although data regarding NASH prevalence is still scarce, it is thought that NASH prevalence has been increasing along with the trend of increasing risk factors. (1) Syndrome 'X' or metabolic syndrome is the term used to denote the cluster of abnormalities: insulin resistance, obesity, type 2 diabetes mellitus, hypertension and hyperlipidaemia, which are associated with NASH risk factors. (3,4) NASH is a part of the liver disorder known as non-alcoholic fatty liver disorder (NAFLD) ranging from simple steatosis, NASH, fibrosis to cirrhosis. (5) Liver biopsy is the only way to distinguished NASH from the liver disorders within the NAFLD spectrum. (12) NASH may be asymptomatic for a long period of time; however, recent evidence has shown that NASH may develop into advanced liver disease (fibrosis, cirrhosis). (25-27) Despite the fact that there is no evidence-based treatment for NASH yet, an appropriate intervention is needed among people with high-risk factors to prevent disease progression. (25) There has not been any large-scale randomised clinical trial for NASH treatment to date. (7) Key management for NASH is to treat related conditions. (28-32) Some studies have shown that NASH management involving nutritional aspects such as gradual weight loss and nutritional supplements such as long-chain fatty acids and antioxidants are providing beneficial results for the NASH patient. (32-48) Currently in Australia, recruitment of subjects in a longitudinal study is underway at Westmead Hospital, Royal Prince Alfred Hospital and the Western Sydney Division of General Practice to examine the nutritional aspects of NASH treatment.

DEFINITION

In 1980, Ludwig et al. introduced the term NASH for the first time to describe liver injury in the absence of significant alcohol consumption. NASH is similar to alcoholic hepatitis. (1) Non-alcoholic fatty liver disease (NAFLD) is a term used to refer to conditions ranging from simple steatosis, NASH, fibrosis to cirrhosis. (1-11) Therefore, NASH is a stage of advanced disease within NAFLD category. (24)

PATHOGENESIS

Pathogenesis of NASH is increasingly important in view of its relationship with NASH management. (3) Other important factors with regard to NASH pathogenesis are conditions associated with NASH, which have become more prevalent in last two decades. Some evidence has shown that NASH may progress to advanced liver disease. (25-27) Day proposed the 'two hits' concept for NASH pathogenesis in 2002. (7,21) This concept suggests a close relationship between obesity, insulin resistance, hyperlipidaemia and NASH. The 'first hit' is the result of the development of steatosis, which sensitises the liver to a 'second hit' from further oxidative stress. The presence of factors associated with syndrome X such as obesity and insulin resistance may increase the degree of steatosis and thus the progression of fibrosis. (7,21) Elevated insulin levels promote lipolysis, which leads to free fatty acid transported to the liver. Increasing free fatty acid supply results in fat in the form of triglycerides accumulating in the liver. (49-51) Oxidative stress in the 'second hit' triggers the development of conditions, which range from simple steatosis to NASH and advanced liver disease. (21) Fatty acid oxidation produces oxidative stress. Free fatty acids in the liver that are metabolised within hepatic mitochondria activate reactive oxygen species. (16,17,26)

Lipid peroxidation induced by reactive oxygen species activation, releases tumour necrosis factor alpha (TNF-[alpha]) as a consequence. A study by Crespo et al. has demonstrated that the degree of NASH severity is equal to the serum TNF-[alpha]. (18) Oxidative stress activates hepatic stellate cells, therefore creating extracellullar matrix proteins, which are then responsible for liver fibrosis. (14-21)

CLINICAL FEATURES AND DIAGNOSTIC TEST

Most patients (45-100%) with NASH develop no specific symptoms. (5) Hepatomegaly is present in 75% of patients. NASH is often diagnosed incidentally when liver enzymes are further investigated by liver biopsy, leading to a NASH diagnosis. (3,12,14,16,17,25-37) In 65-90% of cases, a ratio of less than 1 of the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) helps to differentiate between NASH and alcoholic hepatitis. (49-52) A personal history including alcohol consumption, and all underlying conditions related to NASH should be investigated initially. Ultrasound and computer tomographic scans are only able to show hepatic steatosis. Liver biopsy is the only way to diagnose NASH accurately. (53-55) As NASH is thought to be responsible for two-thirds of cryptogenic cirrhosis, there is some evidence that NASH may progress to liver cancer. (56) Hepatocellular carcinoma (HCC) usually develops in the cirrhotic liver and any form of cirrhosis predisposes to HCC, although the relative risk varies between causative factors. (57) The relative risk is highest for hepatitis B, haemochromatosis and hepatitis C and intermediate level for alcohol and metabolic related diseases. (56) Diagnostic tests become very important tools in gathering prognostic information for an early intervention to be made. (56) Liver biopsy is required for a diagnosis of NASH, in the presence of chronic elevation of serum transaminase and the other NASH risk factors. (52-54) Ratziu et al. performed an evaluation by giving one score for each variable proposed body mass index (BMI) (weight in kilograms divided by height in metres squared) (BMI > 28 kg/[m.sup.2] or age > 50 years, ALT level (twice the normal level) and triglycerides > 1.7 mmol/L). (52) Existence of more than one factor indicates a risk of liver fibrosis. (52,53) A study by Marchesini et al. demonstrated that the relationship between obesity, type 2 diabetes mellitus and advancing age was associated with the increased development of liver fibrosis. (3) Therefore, individuals with abnormal liver enzyme test results and a combination of risk factors should endeavour to modify lifestyle factors for three to six months. If this strategy is unsuccessful, a liver biopsy should be performed to determine the extent of the diagnosis of NASH. (54)

RISK FACTORS

Non-alcoholic fatty liver disorder has been closely related to insulin resistance syndrome. Currently, NAFLD is a common condition; however, in the near future an increased incidence of NASH can be expected. Some recent studies suggest that NAFLD may be responsible for approximately 80% of cases of abnormal persistence of liver enzymes. In the majority of cases NAFLD is a benign condition and it has little chance of progression to advanced liver disease. However, in the 20-30% of cases this entity can develop into NASH. (3-10,13-17,19-22,47-63) A study of NASH patients has shown that insulin resistance is present in a high proportion of NASH patients. (52,58-68) Evidence demonstrated that high concentrations of insulin levels could cause a blockage in mitochondrial fatty acid oxidation pathway. (5,7,9,11,22) This might also cause high concentrations of intracellular fatty acids that may trigger oxidative stress. (7) Another study proposed that cryptogenic cirrhosis may be the result of 'burnt out NASH'. (21) This is more likely because NASH is closely associated to obesity, type 2 diabetes and hyperlipidaemia. (14) Clearly, NASH cannot be categorised as a primary liver disease, because NASH is part of a multifactorial metabolic syndrome. (68)

OVERWEIGHT AND OBESITY

Body mass index calculated as weight in kilograms divided by height in metres squared is a strong predictor of fibrosis in overweight patients. In a series of case studies, approximately 40% of the subjects were found to be obese or overweight (Table 1). The overall prevalence of NASH in obese patients (using autopsy data) was at least six times more frequent than in lean individuals. (53) Other data have demonstrated that NASH occurs in approximately 15-20% of obese people. (2) The International Obesity Task Force proposed a classification standard for Asian adults in which the overweight classification was a BMI of 23-24.9 and the obese classification was a BMI of [greater than or equal to]25 kg/[m.sup.2]. (20,55) Some ethnic groups have been associated with higher insulin resistance due to increased visceral adiposity. (9,20) The greater fat mass releases substances such as TNF-[alpha], leptin and free fatty acids, which eventually lead to insulin resistance. (18) Fat accumulation within hepatocytes occurs as a result of insulin resistance, liver cells are then more susceptible to the 'second hit'. (7,21) The other concerns about NASH in the obese are the increased risk of developing cryptogenic cirrhosis (Tables 2 and 3). A study conducted by Browning et al. from 1990 to 2001 using 41 subjects reports that cryptogenic cirrhosis was found in 46% of obese subjects. (11) That study was consistent with the results from two previous studies investigating the cause of cryptogenic cirrhosis conducted by Poonawala et al. (25) and Caldwell et al. (26) They found that obesity was present in 47% and 73%, respectively, of their subjects. Furthermore, Ratziu et al. in 2002 investigated survival, liver failure and HCC incidence in obesity-related cryptogenic cirrhosis, which revealed that the short-term survival rate was shorter in people with obesity-related cryptogenic cirrhosis when compared with hepatitis C-related cirrhosis (Table 3). (57)

TYPE 2 DIABETES MELLITUS

Type 2 diabetes mellitus is a condition that has been closely linked with NASH, especially in obese patients. Obesity is an independent risk factor for NASH. (25,49,52,64-69) Marchesini et al. demonstrated that people with insulin resistance and hyperinsulinaemia are at a greater risk for NAFLD. (49) Dixon et al. investigated the relationship of insulin resistance in 26 NASH patients. (68) Results of that study revealed that some of the subjects were diabetic after several normal fasting blood glucose levels. A similar mechanism was evident in obese people in which the cytokine TNF-[alpha] played an important role in the mechanism of the development of insulin resistance in people with type 2 diabetes mellitus. (18) A study conducted by Silverman et al. demonstrated that increasing liver pathology was found to correlate with the subject's glycaemic state. (65) Marceau et al. verified the results of the study by Silverman et al. in that people with impaired glucose tolerance or diabetes were seven times more likely to develop fibrosis. (67) A study conducted in India recently reported that the duration of diabetes plays an important role in NASH progression; this was mainly due to prolonged insulin resistance and fatty oxidation abnormalities. (52) Furthermore, a large cohort in the Verona study demonstrated that liver cirrhosis was the second most frequent cause of death in people with type 2 diabetes mellitus. (69) Poonawala et al. found that cryptogenic cirrhosis occurred in 47% of subjects with type 2 diabetes. (25) Hence it is very important for people with NASH to undergo glucose challenge test to exclude diabetes diagnosis, as diabetes often occurs asymptomatically in NASH patients and this may worsen the liver prognosis. Weight loss is the most effective treatment strategy to date. (28,29)

HYPERLIPIDAEMIA

Hyperlipidaemia (hypertriglyceridaemia, hypercholesterolaemia) as a cause of insulin resistance is often evident in patients with NAFLD and NASH. (17) Diehl et al. found that one-fifth of NASH and NAFLD patients developed hyperlipidaemia. (58) Another study reported that hyperlipidaemia occurred in 21-83% of NASH patients. (25) However, compared with hypercholesterolaemia, hypertriglyceridaemia is thought to increase the risk of development of fatty liver. (28) Te Sligte et al. summarised some factors that may contribute to fat accumulation in NASH patients. (19) High intake of saturated fatty acids and cholesterol results in increasing plasma triglycerides and free fatty acids. The diminishing insulin sensitivity suppresses lipolysis and increases hyperinsulinaemia and TNF-[alpha] release. (19)

OTHER CONDITIONS ASSOCIATED WITH NASH

Although insulin resistance is strongly associated with NASH, there are some other conditions that also relate to NASH. These conditions vary from surgical procedures such as jejunoileal bypass and intestinal resection, rapid weight loss, drugs, total parenteral nutrition to metabolic disorders. (52,70-72)

PROGNOSIS

It is obvious that NASH may progress to advanced liver disease especially in those individuals who carry a predisposing factor. (70) One retrospective study demonstrated that 25% of patients with NASH die from a liver-related cause. (72) Furthermore, Hui et al. found that people with NASH had similar health risks to those with untreated chronic hepatitis C (HCV). Liver failure is the main cause of morbidity and mortality in cirrhosis associated with NASH in Australia and the cumulative probability of overall survival was 95%, 90% and 84% in one, three and 10 years, respectively. (72) Furthermore, Chitturi et al. found that patients with NASH have similar health risks to those with untreated HCV. (20) Dutta et al. observed in Australia a 2% annual incidence of HCC in patients aged over 40 years with HCV. Malnourished patients with a previous exposure to HBV have the highest risk of developing HCC. (73) Two Japanese studies reported HCC incidence in NASH patients as sufficiently common to warrant screening. (74,75)

LIFESTYLE INTERVENTION AND NUTRITIONAL ASPECT OF TREATMENT OF NASH

At present there are no evidence-based guidelines that can be used in NASH treatment. (47,52,63-68) Although a number of drugs have been used in clinical trials and several have been used in practice for NASH treatment, the best practice evidence remains to be elucidated. (33,61) The management of NASH currently is more focused on the underlying disease. Lifestyle and nutrition intervention, which promote gradual weight loss; dietary supplementation in the form of long-chain polyunsaturated fatty acids (with proven ability to reduce hyperlipidaemia risk) and antioxidant supplements are beneficial. (28-48) Improvement is not only evident in liver function tests, but also confirmed through further examination using ultrasound or computer tomographic scan and histological findings in a follow-up liver biopsy. (34,44,46,47) It appears that nutritional interventions assist in the treatment of NASH and help to control predisposing factors or putative underlying diseases. (30-37) However, literature research has revealed that studies of nutritional intervention in NASH patients are still very limited and these strategies are yet to be incorporated into clinical practice. It is hoped that the study to commence at Westmead, Royal Prince Alfred Hospital and Western Division of General Practice will clarify this situation. Fortunately, a system of staging and grading of histological changes has been developed to identify the changes that take place in the development of NASH. (76,77) Ratziu et al. developed a clinicobiological score combining BMI, age, ALT and triglyceride levels to improve the selection process of patients for liver biopsy. (52)

LIFESTYLE INTERVENTION--WEIGHT LOSS

A number of studies have demonstrated that weight loss improves NASH and to date, this is considered to be current best practice, (28-37) although to this date no randomised controlled trial has been conducted with regard to weight loss. Eleven studies used weight loss in NASH and NAFLD treatment with different approaches to weight loss, such as diet restriction, combination between diet restriction and exercise, gastric banding and drugs. (28-37,63) The measurement outcomes demonstrated significant improvements after weight loss are serum transaminase and the reduction of the degree of steatosis. Limitations found in the studies overall were the lack of liver histology as only three studies performed liver biopsies (33,35,36) and one study used computer tomographic scan to measure the degree of steatosis. (31) These studies did demonstrate a reduction in the degree of fibrosis. Hickman et al. demonstrated in the HCV setting that weight loss was associated with a decrease in fibrous scores and a reduction in activated stellate cells. (37) Liver histology outcomes are necessary in these studies to establish the degree of weight loss needed to bring liver back to normal, and none of the studies offered this information. A recent study by Huang et al. demonstrated that one year of intense nutritional counselling is effective in achieving histological improvement. (78) One study conducted by Andersen et al. reported that rapid weight loss in people with severe fatty liver would exacerbate the degree of fibrosis and inflammation. (79) Therefore, gradual weight loss is recommended as a treatment in NASH patients particularly those who are 30% overweight. Weight reduction around 500 g-1 kg per week appears to be considered safe and effective. (47,48,78-80)

PHYSICAL ACTIVITY

The effect of physical activity alone on hepatic steatosis has not been studied in humans. In animal studies, physical activity was found beneficial in preventing the development of diet-induced steatosis in high fat fed rats. (81) In rats with already established steatosis, eight weeks of physical training provided significant improvement in plasma concentrations of triaclyglycerol compared with untrained rats; however, there was no change in hepatic steatosis. (82) Two studies conducted in Japan using a combination of diet restriction and exercise produced a more beneficial effect using this strategy. (34,35) A study by Ueno et al. demonstrated that energy restriction (25-30 kcal/kg ideal body weight/day) combined with exercise each day for three months would improve NASH patients' status. (34) This finding was confirmed with a measurement of some parameters such as BMI (P < 0.05), liver function test (P < 0.001), blood glucose level (P < 0.05), total cholesterol (P < 0.05) along with histological data from liver biopsy (degree of steatosis P < 0.005). A study by Hickman et al. conducted over 12 months supported the Ueno findings that improvement was achieved in biochemical and histological data after following a restricted diet and exercise programme (Table 4). (36)

NUTRITIONAL ASPECTS OF TREATMENT OF NASH--OMEGA 3 FATTY ACID

Supplementation with n-3 long-chain polyunsaturated fatty acids suggests some promising results; however, it is not currently recommended as best practice. Gradual weight loss, although requiring more clinical trials, is considered in the literature as best practice (28,29,36,37) Six studies investigated the association between omega-3 supplementation and the reduction of risk factors for NASH. Three studies were conducted in animals (39-41) and three studies were conducted in humans. (35,83,84) The majority of the studies examined the anti-obesity effect of omega-3 supplementation through different aspects. Browning investigated the antiobesity-related effect of omega-3 supplementation through different aspects. Browning investigated the antiobesity-related effect of omega-3 supplementation (1.3 g eicosapentaenoic acid and 2.9 g docosahexaenoic acid) in two groups of women with different inflammatory status (measured by sialic acid). (83) The results demonstrated that the group with the higher inflammatory status had a significant improvement in insulin sensitivity (P < 0.05). One study conducted in humans compared the effect of omega-3 fatty acids with atorvastatin and orlistat. (84) Although the orlistat group demonstrated a greater improvement in steatosis when compare with other groups, omega-3 fatty acids proved to be more effective in reducing AST. Furthermore, that study demonstrated that the omega-3 group had the highest reduction in triglyceride levels. In the three animal studies, two were controlled suggesting that fish oil administration would suppress sterol regulatory element binding protein-1 (SREBP-1), which is predominantly located in the liver. (39-41) SREBP-1 is responsible for the regulation of synthesis and storage of triglycerides in the liver. Disruption in mature SREBP-1 could improve hepatic steatosis. Although significant reduction of AST and ALT levels was not observed in these studies, one study decreased levels of triglycerides and postprandial blood glucose. (40) Promising data from clinical and animal studies without histological end points can be misleading. Hatzitolios et al. (84) demonstrated that n-3 long-chain polyunsaturated fatty acids supplementation reduced triglyceride levels; however, given the mechanism of the development of triglyceridaemia in NASH patients it is not yet clear how significant this effect is (Table 5). (52,60,84)

ANTIOXIDANTS

Antioxidant therapy is not recommended as part of clinical practice even though the research appears to be promising. At present there is a lack of strong evidence to support the supplementation of vitamin E to boost serum antioxidant levels in NASH patients. This therapy is based on the fact that oxidative stress is one of the most important factors in the promotion of NASH pathogenesis. (41) Four studies varying in length from 12 weeks to 12 months investigated the therapeutic use of vitamins in the treatment of NASH patients (Table 6). Lavine demonstrated in a pilot study of children aged less than 16 years that the supplementation with vitamin E 400-1200 IU/day resulted in the normalisation of ALT. (43) In a 12-month pilot study of NASH patients receiving dietary advice for six months and vitamin E supplementation for 12 months (at a rate of 300 mg/day), a majority of liver biopsy patients had improved histological scores. (44) In a 6-month prospective, double-blind study, 45 patients were randomised to receive 1000 IU/day of vitamin E and 1000 mg/day of vitamin C or placebo together with dietary counselling and a low-fat diet. There was a statistically significant improvement in fibrous score (P = 0.002), but not inflammation. (45) Kugelmas et al. conducted a pilot study of 16 NASH patients in which the effect of a low-fat diet and aerobic exercise with or without 800 IU of vitamin E daily on cytokine and liver enzyme levels was investigated. (46) Lifestyle modifications were associated with improvement in cholesterol and liver enzyme status. Cytokines were not decreased significantly with weight loss in either the supplemented or the unsupplemented groups. It is clear that a larger, multicentre, longer-term antioxidant supplementation study is warranted.

CONCLUSION

There is a need to develop a better understanding of the pathogenesis and natural history of NASH. Many patients do not progress to advanced liver disease; however, it would be of benefit to clinicians to be able to identify the subset of patients who are at risk of this progression. Treatment has been focused on the management of risk factors such as obesity, type 2 diabetes mellitus and hyperlipidaemia. NASH associated with obesity may be resolved by gradual weight loss, although some results are not consistent. Control of glucose and lipid levels is an appropriate strategy, but this does not always reverse the condition. Some medications have the potential to benefit patients as do nutritional supplements; however, dose-responses remain to be elucidated. Therefore, further research involving well-reasoned study design is needed to develop a wider range of treatment strategies to benefit NASH patients.

ACKNOWLEDGEMENT

The present research was conducted as partial fulfilment of Diah Yunianingtias' Master of Nutrition and Dietetics degree at the University of Sydney, under the supervision of Dianne Volker.

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57 Ratziu V, Bonyhay L, Di Martino V et al. Survival, liver failure and hepatocelullar carcinoma I obesity related cryptogenic cirrhosis. Hepatology 2002; 35: 1485-93.

58 Diehl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol induced liver injury. Gastroenterology 1988; 95: 1056-62.

59 Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow up study of forty-two patients for up to 21 years. Hepatology 1990; 11: 74-80.

60 Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Teri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103-9.

61 Pinto HC, Baptista A, Camilo ME, Valente A, Saragoca A, De Moura MC. Nonalcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci 1996; 41: 172-9.

62 Laurin J, Lindor KD, Crippin JS et al. Ursudeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996; 23: 1464-7.

63 Knobler H, Schattner A, Zhornicki T et al. Fatty liver--an additional and treatable feature of the insulin resistance syndrome. QJM 1999; 92: 73-9.

64 Sorrentino P, Tarantino G, Conca P et al. Silent nonalcoholic fatty liver disease--a clinical histological study. J Hepatol 2004; 41: 751-7.

65 Silverman JF, O'Brien KF, Long S et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol 1990; 85: 1349-55.

66 Luyckx FH, Desaive C, Thiry A et al. Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord 1998; 22: 222-6.

67 Marceau P, Biron S, Hould FS et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84: 1513-17.

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69 de Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Study. Diabetes Care 1999; 22: 756-61.

70 Allard JP. Other disease associations with non-alcoholic fatty liver disease (NAFLD). Best Pract Res Clin Gastroenterol 2002; 16: 783-95.

71 Day CP. NASH-related liver failure: one hit too many? Am J Gastroenterol 2002; 97: 1872-4.

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Diah YUNIANINGTIAS and Dianne VOLKER

Human Nutrition Unit, School of Molecular and Microbial Biosciences, University of Sydney, Chippendale, New South Wales, Australia

Correspondence: D. Volker, Suite 1, 3 Banksia Avenue, Dudley, NSW 2290, Australia. Email: [e-mail]

D. Yunianingtias, BMed, Student

D. Volker, PhD, APD, Senior Lecturer 

Table 1 Risk factor association in non-alcoholic steatohepatitis/
non-alcoholic fatty liver disorder

Reference                                                       Obesity
no.        Study                     n    Type of study         (%)

 1         Ludwig et al. (1980)       20  Retrospective review   90
26         Caldwell et al. (1999)     50  Retrospective review   64
53         Wanless et al. (1990)     351  Case series (a)        18.5
58         Diehl et al. (1988)        39  Retrospective review   71
59         Powell et al. (1990)       42  Prospective review     93
60         Bacon et al. (1994)        33  Retrospective review   39
61         Pinto et al. (1996)        32  Retrospective review   47
62         Laurin et al. (1996)       40  Intervention study     70
63         Knobler et al. (1999)      48  Prospective review     64
64         Sorrentino et al. (2004)   58  Retrospective review  100

Reference  Diabetes  Hyperlipidaemia
no.        (%)       (%)

 1         25        67
26         42        NA
53         NA        NA
58         55        NA
59         36        81
60         21        21
61         34        28
62         28        NA
63         44        73
64         93.1      77.5

(a) Autopsy
Table adapted from the study by Youssef et al. (47)
NA = not applicable.

Table 2 Non-alcoholic steatohepatitis (NASH) incidence in obese patients

                          Obese
Reference                 patients  Mean BMI                       NASH
no.        Study          (n)       (kg/[m.sup.2])  Type of study  (%)

29         Dixon et al.    36       NA              Retrospective  64
             (2004)                                   study
30         Spaulding et    48 (a)   51              Retrospective  56
             al. (2003)                               study
65         Silverman et   100       NA              Retrospective  66
             al. (1990)                               study
66         Luyckx et al.  528 (b)   43 [+ or -] 7   Retrospective  10
             (1998)                                   study
67         Marceau et     551 (c)   47 [+ or -] 9   Retrospective  24
             al. (1999)                               study
52         Ratziu et al.   93       29.1            Retrospective  30
             (2000)                                   study
68         Dixon et al.   105 (d)   NA              Retrospective  26
             (2001)                                   study

(a) Patients underwent Roux-en-Y gastric bypass for morbid obesity.
(b) Patients underwent bariatric surgery.
(c) Patients underwent biliopancreatic diversion for severe obesity.
(d) Patients underwent liver biopsy in obesity surgery.
BMI = body mass index; NA = not applicable.

Table 3 Incidence of cryptogenic cirrhosis in metabolic syndrome
patients

Reference
no.        Study                    n   Type of study

11         Browning et al. (2004)   41  Retrospective review
25         Poonawala et al. (2000)  49  Retrospective review
26         Caldwell et al. (1999)   70  Retrospective review

           Type 2                 Morbid   Obese +
Reference  diabetes      Obesity  Obesity  diabetes  Hyperlipidaemia
no.        mellitus (%)  (%)      (%)      (%)       (%)

11         53            46       NA       68        NA
25         47            47       22       23        21
26         53            47       NA       NA        NA

NA = not applicable.

Table 4 Weight loss in non-alcoholic steatohepatitis treatment

Ref.
no.   Study    n    Duration     Control       Intervention type

29    Dixon     36  9-51 months  No control    Gastric band
      et al.
      (2004)
31    Nomura    24  3 months     No control    Low-calorie diet (25-30
      et al.                                   cal x IBW in kg/day)
      (1987)
32    Park et   25  1 year       No weight     1. Low-calorie diet
      al.                        reduction     (25-30 cal/kg IBW/day)
      (1995)                                   2. Low impact aerobic
                                               exercise
34    Ueno et   25  3 months     No treatment  1. Low-energy diet (25
      al.                                      cal/kg IBW/day)
      (1997)                                   2. Exercise--walking and
                                               jogging
35    Okita     28  24 weeks     Non-obese     Moderate energy
      et al.                     healthy       restriction (25 kcal/kg
      (2001)                     adults        of IBW) and diet rich in
                                               fish, green vegetables,
                                               and low in meat were
                                               recommended
36    Hickman   14  15 months    Steatosis     1. 3 months: dietitian/
      et al.                     from HCV      week
      (2004)                                   2. 1 year: dietitian/
                                               month
                                               3. Exercise: 150 min/week
                                               aerobic
38    Kral et  689  44 months    No control    Biliopancreatic diversion
      al.           and 101                    surgery
      (2004)        months
63    Knobler   48  24 months    No control    1. Diet intervention
      et al.                                   2. Those who failed diet
      (1999)                                   intervention were given
                                               lipid-lowering drugs

Ref.
no.   Outcome Measurement           Results

29    1. Weight, BMI, W : H ratio   All parameters demonstrated an
      2. Lipid profile (TC,         improvement after weight loss
      fasting TG, HDL, LDL) HbAlc,
      insulin sensitivity, HOMA%
31    1. Laboratory tests of serum  SGPT value was reduced 61%, body
      glutamic-pyruvate             weight was reduced 5.7%, and
      transaminase                  increasing CT number of attenuation
      2. Body weight                up to 13.9%
      3. CT attenuation value of
      four liver segments.
32    1. Liver function tests       Significant decrease of liver
      (AST, ALT)                    function tests and total cholesterol
      2. TC                         in 'weight reduction' group whereas
                                    there was a significant increase of
                                    liver function tests and total
                                    cholesterol in 'non-weight
                                    reduction' group
34    1. Blood biochemistry         Significant reduction of blood
      2. BMI                        biochemistry values, BMI and degree
      3. Liver biopsy               of steatosis in treatment group
                                    (except TG slightly decreased)
35    1. BMI, body fat ratio,       Treated group had significant
      waist circumference           reduction in BMI, waist
      2. LFT (AST, ALT)             circumference, AST and ALT level. No
      3. TG                         significant change in male body fat
                                    ratio and tryacylglycerol level
36    1. BMI                        Weight loss in both subjects and
      2. LFT                        controls.
      3. Fasting BGL and HOMA       Patients with HCV lower decrease in
                                    fasting insulin compared with
                                    non-HCV.
                                    ALT improved in both groups at 3 and
                                    15 months.
                                    Liver biopsy (n = 14) improved
                                    steatosis. Stage of fibrosis (n = 7)
                                    improved
38    1. BMI and weight             There were significant improvements
      2. LFT                        in TC and TG levels (P < 0.01) as
      3. Fasting BGL                well as weight reduction in short-
      4. Lipid profile              and long-term follow up for all
      5. Liver biopsy (n = 104)     patients, severe fibrosis decreased
                                    (n = 28)
63    1. LFT                        LFTs were improved in 96% of
      2. Weight                     patients, weight loss was achieved
      3. Lipid profile              in 79% of patients (mean loss 3.7
                                    kg). Fasting BGL decreased.
                                    Lipid profiles decreased

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BGL =
blood glucose level; BMI = body mass index; CT = computer tomography;
HbAlc = glycosylated haemoglobin Alc test; HCV = hepatitis C virus;
HOMA = homeostasis model assessment; IBW = ideal body weight; LFT =
liver function tests; lipid profile = total cholesterol, high-density
lipoprotein, low-density lipoprotein, triglyceride levels; SGPT = serum
glutamic-pyruvic transaminase; TC = total cholesterol; TG =
triglycerides; W : H = waist to hip ratio.

Table 5 n-3 PUFA in relation to risk factors reduction

Ref.               Animal     Type of
no.   Study        type/n     study         Time         Control

39    Nakatani et  Mice       Intervention  1-13 weeks   No control
      al. (2003)              study
40    Sekiya et    Ob/ob      Intervention  7 days       1. HC fat-free
      al. (2003)   mice       study                      diet
                                                         supplemented
                                                         with 15%
                                                         triolein.
                                                         2. 15% triolein
                                                         and 5% EPA
                                                         ethyl ester
41    Levy et al.  F344 rats  Intervention  4 weeks      1. HC, low fat
      (2004)                                             (5.1% energy)
                                                         2. Lard (45%
                                                         energy)
35    Okita et     14         Intervention  8 weeks      No control
      al. (2001)              study         (short
                                            term) 24
                                            weeks (long
                                            term)
83    Browning     63 in two  Controlled    12 weeks     Placebo: five
      (2003)       groups     intervention  each         capsules/day
                   based on   study         treatment    2.8 g LA and
                   sialic                   with 4 week  1.4 g oleic
                   acid                     washout
                   content
84    Hatzitolios  88         Intervention  24 weeks     1. Atorvastatin
      et al.                  study                      2. Orlistat
      (2004)

Ref.                  Outcome
no.   Intervention    measurement    Result

39    Mice in seven   Body weight,   Reduction in weight and parametrial
      groups with     parametrial    WAT were observed in mice fed with
      different       WAT, SREBP-1   40-60% energy from fish oil in
      amount of fish  expressions    comparison with 0% energy from fish
      oils. Group 1                  oil after 1 and 13 weeks. Liver
      was given 0%                   weight was significantly increased
      fish oil and                   in 20% energy fish oil and above
      then fish oil                  groups. Liver damage accompanied
      concentrations                 with increasing AST or ALT was not
      were increased                 observed in 60% energy fish oil
      incrementally                  group.
      10% for the
      next each
      group
40    20% fish oil    Liver lipid    Mice fed fish oil showed reduction
                      content (TG),  in mature SREBP-1 up to 3x compared
                      SREBP-1        with those fed with HC diet. While
                      expression,    mice fed with oleat did not show
                      ALT IRS-2      any reduction of mature SREBP-1. TG
                      analysis       levels decreased significantly in
                                     mice fed with HC diet and mice fed
                                     with fish oil. No significant
                                     different for ALT levels in each
                                     group. However, elevated ALT level
                                     was decreased in test group.
41    Rats fed 45%    1. Body        FO fed rats ingested more energy in
      energy from     weight and     the first three weeks with less
      omega PUFA      body fat       weight gain. TG levels lower in FO
                      2. PP lipid    rats. PP-BGL and PP insulin levels
                      profile        lower in FO rats, insulin
                      3. BGL         sensitivity higher. Fasting SREBP
                      4. QUICKI      was similar in all groups, PP-SREBP
                      5. mRNA of     was 5x HC rats, 3x lard rats and no
                      PPAR-[alpha]   increase in FO rats.
                      6. SREBP-1
35    Diet            1. BMI         LFT decreased significantly after 8
      modification    2. Waist       and 24 weeks. Positive correlation
      (low energy)    circumference  between ALT level and Omega-3 PUFA
      with high       3. LFT         (P < 0.05).
      omega PUFA      4. Leucocytes
                      and PG
83    1.3 g EPA and   GTT            Improvement in insulin sensitivity
      2.9 g DHA                      noted in patients with higher
                                     sialic acid receiving n-3 PUFA (P <
                                     0.05).
84    Omega-3 PUFA 5  1. BMI         AST decreased significantly in all
      mL/day          2. LFTs        groups. Hierarchy of AST reduction
                      3. Lipid       was orlistat, omega-3 and
                      profile        atorvastatin group. Omega-3 group
                      4. Ultrasound  had greatest reduction in TG
                                     compared with other groups and
                                     orlistat group demonstrated greater
                                     improvement in ultrasound results.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BGL =
blood glucose level; BMI = body mass index; DHA = docosahexaenoic acid;
EPA = eicosapentaenoic acid; FO = fish oil; GTT = glucose tolerance
test; HC = high carbohydrate; IRS = insulin receptor substrate; lipid
profile = total cholesterol, high-density lipoprotein, low-density
lipoprotein, triglyceride levels; LFT = liver function tests; PG =
prostaglandins; PP = postprandial; PPAR = peroxisome proliferator-
activated receptor; PUFA = polyunsaturated fatty acids; QUICKI =
Quantitative Insulin Check Index; SREBP = sterol regulatory element
binding protein; TG = triglycerides; WAT = white adipose tissue.

Table 6 Antioxidants and non-alcoholic steatohepatitis (NASH)

Ref.
no    Study     n         Type of study       Time         Control

43    Lavine    11        Open-label pilot    4-10 months  No control
      (2000)              study
44    Hasegawa  12 NASH   Pilot study         1 year       No control
      et al.    10 NAFLD
      (2001)
45    Harrison  45        Prospective,        6 months     Placebo
      et al.              double-blind,
      (2003)              randomised,
                          placebo-controlled
46    Kugelmas  16 NASH   Pilot study         12 weeks     No control
      et al.
      (2003)

Ref.                  Outcome
no    Intervention    measurement    Result

43    Vitamin E 400   1. BMI         After treatment LFTs were reduced
      and 1200 IU/    2. LFTs        to normal level from 2.3 times and
      day                            3.9 times upper normal value before
                                     the treatment. No significant
                                     different found in BMI.
44    Dietary         1. BW          In all groups body weight was
      therapy (30     2. Lipid       reduced significantly. LFT tests
      kcal/kg BW)     profile        were reduced in both groups but
      for 6 months,   3. LFTs        NASH patients had non-significant
      and Vitamin E   4. Liver       reduction. After alpha tocopherol
      300 mg/day for  biopsy only    administration LFTs in NASH
      12 months       in NASH group  patients had further significant
                                     reduction (approximately 79%). Nine
                                     patients underwent liver biopsy,
                                     five demonstrated improvements in
                                     fibrosis and inflammation.
45    Vitamin E 1000  1. BMI         No clinically significant
      IU + Vitamin C  2. LFT         difference in BMI for each group
      1000 mg         3. Liver       after treatment. ALT level was
                      biopsy         improved in placebo group.
                                     Improvement of fibrosis in 47.8% of
                                     subject from test group.
46    Vitamin E 800   1. BW          All parameters were decreased
      IU/day and      2. BMI         significantly in the test group.
      diet as         3. LFT         AST decreased by week 6 and
      American Heart  4. Lipid       remained on the same level up to
      Association     profile        week 12.
      recommendation  5. Liver
                      histology
                      6. Ultrasound

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI =
body mass index; BW = body weight; lipid profile = total cholesterol,
high-density lipoprotein, low-density lipoprotein, triglyceride levels;
LFT = liver function tests; NAFLD = non-alcoholic fatty liver disorder.