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315

REVIEW

Treatment of non-alcoholic fatty liver disease

L A Adams, P Angulo
...............................................................................................................................

Postgrad Med J 2006;82:315322. doi: 10.1136/pgmj.2005.042200

Non-alcoholic fatty liver disease (NAFLD) is common and NAFLD and has been identified as a therapeutic
target for antioxidants. Injury by secondary
may progress to cirrhosis and its complications. The insults leads to the generation of pro-inflamma-
pathogenesis of steatosis and cellular injury is thought to be tory cytokines such as tumour necrosis factor a,
related mostly to insulin resistance and oxidative stress. which are targeted by hepatoprotective agents
such as pentoxifylline. Hyperinsulinaemia and
Therefore, management entails identification and treatment hyperglycaemia may also upregulate pro-fibro-
of metabolic risk factors, improving insulin sensitivity, and genic cytokines and thus provide a rational for
increasing antioxidant defences in the liver. Weight loss insulin sensitising agents such as metformin and
the thiozoladinediones to prevent progressive
and exercise improve insulin sensitivity. Bariatric surgery liver damage.7
may improve liver histology in patients with morbid
obesity. Insulin sensitising drugs showed promise in pilot NATURAL HISTORY
trials as have a number of hepatoprotective agents. Further NAFLD exists as a histological spectrum of
changes; simple steatosis refers to .5% hepatic
randomised, well controlled trials are required to steatosis in the absence of significant inflamma-
determine the efficacy of these drugs. tion and hepatocellular damage whereas non-
........................................................................... alcoholic steatohepatitis (NASH) demonstrates
inflammation and hepatocellular damage and
sometimes fibrosis.8 NAFLD may be progressive

N
on-alcoholic fatty liver disease (NAFLD) resulting in cirrhosis that may be complicated by
occurs across all age groups and ethni-
hepatocellular carcinoma and liver failure.
cities and is recognised to occur in 14%
Overall, about 5% of patients with NAFLD
30% of the general population.1 2 Primary NAFLD
develop cirrhosis over an average of a seven year
is related to insulin resistance and thus fre-
period with 1.7% dying from complications of
quently occurs as part of the metabolic changes
liver cirrhosis.9 The high prevalence and chronic
that accompany obesity, diabetes, and hyperlipi-
nature NAFLD subsequently translates to a
daemia. However, it is important to exclude
significant health burden for the general com-
secondary causes of hepatic steatosis (table 1) by
munity. In addition, subjects with a diagnosis of
clinical assessment. Treatment of these condi-
NAFLD have a higher risk of all cause mortality
tions differs and revolves around correcting the
than the general population.9 This may be partly
underlying cause.3
related to an increased risk of liver related death,
but may also be related to death from vascular
PATHOGENESIS disease as a result of underlying metabolic
The pathogenesis of NAFLD is not fully under- abnormalities and insulin resistance. Thus treat-
stood, however the finding that not all patients ment of patients with NAFLD should aim to
with steatosis develop hepatic inflammation and identify and treat associated metabolic factors
hepatocellular damage has led to the hypothesis such as obesity, glucose intolerance, dyslipidae-
that different pathogenic factors lead firstly to mia, and hypertension. Secondly, treatment
hepatic steatosis and secondly to hepatic damage aimed at preventing progressive liver injury
(the second hit).4 Accumulation of hepatic fat should be offered to those considered to be at
is closely linked to insulin resistance, which risk. Diabetes mellitus and obesity are risk
increases lipolysis of peripheral adipose tissue factors for progressive hepatic fibrosis,10 11 and
with resultant increased fat influx into the liver diabetes is also a risk factor for death in patients
in the form of free fatty acids. Furthermore, with NAFLD.9 12 Histological features also assist
See end of article for insulin resistance promotes de novo triglyceride in stratifying patient risk of progressive liver
authors affiliations synthesis within the liver and inhibits fatty acid disease. Simple steatosis is comparatively benign
....................... oxidation thereby promoting triglyceride accu- with a 0%4% risk of developing cirrhosis over a
Correspondence to: mulation.5 Therefore, improving insulin sensitiv- one to two decade period.1315 In contrast, 5%8%
Dr P Angulo, Division of ity has been a key strategy in the treatment of of patients with NASH may develop cirrhosis
Gastroenterology and NAFLD. over approximately five years.1618 Assessment of
Hepatology, Mayo Clinic
College of Medicine, 200 It is unknown what second hit leads to the fibrosis stage is also valuable in prognosticating
First Street SW, Rochester, development of liver damage, although several risk of developing liver related morbidity, with
MN 55905, USA; angulo- factors have been implicated including oxidative patients with advanced fibrosis (bridging fibrosis
hernandez.paul@mayo. stress, mitochondrial abnormalities, and hormo- and cirrhosis) at most risk. Although these
edu
nal disturbances involving leptin and adiponec-
Submitted 9 October 2005 tin.6 In particular, oxidative stress with Abbreviations: NAFLD, non-alcoholic fatty liver disease;
Accepted3December2005 subsequent lipid peroxidation and generation of ALT, alanine aminotransferase; AST, aspartate
....................... reactive oxygen species seems to be prominent in aminotransferase; NASH, non-alcoholic steatohepatitis

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316 Adams, Angulo

Table 1 Causes of non-alcoholic fatty liver disease glucose intolerance (fasting glucose >6.10 mmol/l), hyper-
triglyceridaemia (.1.70 mmol/l), low HDL cholesterol
Primary Obesity, glucose intolerance, hypertriglyceridaemia, low (,1.30 mmol/l in women, ,1.03 mmol/l in men), and
HDL cholesterol, hypertension hypertension (>135/80 mm Hg) are associated with cardio-
Nutritional Protein-calorie malnutrition, rapid weight loss,
gastrointestinal bypass surgery, total parental nutrition
vascular morbidity and mortality.23 24 These features are
Drugs Glucocorticoids, oestrogens, tamoxifen, amiodarone, commonly present in subjects with NAFLD, with 67%71%
methotrexate, diltiazem, zidovudine, valproate, aspirin, being obese, 12%37% having impaired fasting glycaemia,
tetracycline, cocaine 57%68% having disturbed lipid profiles, and 36%70% being
Metabolic Lipodystrophy, hypopituitarism,
hypertensive.1 9 25 Therefore, patients with newly diagnosed
dysbetalipoproteinaemia, Weber-Christian disease
Toxins Amanita phalloides mushroom, phosphorus poisoning, NAFLD should be screened for these conditions and appro-
petrochemicals, bacillus cereus toxin priate treatment instituted in an effort to ameliorate the
Infections Human immunodeficiency virus, hepatitis C, small bowel vascular risk as well as to improve NAFLD.
diverticulosis with bacterial overgrowth

WEIGHT LOSS AND EXERCISE

Moderate amounts of weight loss as well as exercise are
associated with improvement in insulin sensitivity and thus
features aid in stratifying patients at risk, a significant are logical treatment modalities for patients with NAFLD
proportion of patients will have all of these adverse who are overweight or obese.26 27 Weight reduction may be
prognostic markers but will not develop liver related achieved by caloric restriction from dieting, physical exercise,
morbidity or mortality. Thus accurate prediction of those and/or pharmacotherapeutic agents as well as bariatric
patients who will benefit most from treatment is difficult. surgery in those patients with morbid obesity who are
candidates for bariatric surgery.
DIAGNOSIS Trials examining the effect of diet and exercise are non-
The diagnosis of NAFLD requires confirmation of hepatic randomised, of short duration with limited numbers of
steatosis by imaging or liver biopsy with clinical exclusion of participants (table 2).2832 Liver biochemistry and hepatic
excessive (.20 g/day) alcohol ingestion.8 Ultrasound, com- steatosis seem to improve, however, improvement in hepatic
puted tomography, or magnetic resonance studies can inflammation and fibrosis has not been seen, although this
confirm the presence of hepatic steatosis with a compara- may be attributable to the lack of statistical power and
tively high degree of accuracy.19 Ultrasound is comparatively inadequate treatment duration. It should be noted however,
cheap and readily available but is less sensitive at detecting that rapid weight loss induced by very low energy diet
minimal (,30%) steatosis or among obese patients.20 Thus a (388 kcal/day) is associated with increased portal inflamma-
negative ultrasound does not necessarily exclude NAFLD. tion and serum bilirubin levels and thus should be avoided.28
Liver biopsy is the gold standard for diagnosis and is the only Energy restriction of about 2530 kcal/kg/day seems reason-
investigation able to distinguish between simple steatosis able with a target weight loss of about 10% of bodyweight
and NASH or stage the degree of fibrosis.21 The decision to over six months.30 32
perform a liver biopsy must be individualised and may be The optimal diet to treat NAFLD is not known. Patients
useful when there is diagnostic uncertainty (for example, in with NAFLD seem more likely to have a diet high in saturated
the presence of raised iron parameters, auto-antibodies, or fats and cholesterol and low in fibre and antioxidants.33
suspected coexisting drug toxicity) or to provide prognos- Mono and poly-unsaturated fats may potentially improve
itication regarding outcome. Liver biopsy may also be insulin resistance and may be beneficial in improving hepatic
performed in patients with risk factors of advanced fibrosis steatosis.34 One small pilot trial of 23 NAFLD patients with
(diabetes, obesity, age .45, AST:ALT.1)22 where a diagnosis hypertriglyceridaemia noted improvement of ALT levels with
of cirrhosis has implications for screening for varices and omega-3 fatty acid supplementation over six months,
hepatocellular carcinoma. although effect on histology was not assessed.35 Most trials
have used a diet similar to that recommended by the
TREATMENT American Heart Association with energy restriction and
Treatment strategies for NAFLD have revolved around (1) energy intake composed of 40%50% carbohydrates, 15%
identification and treatment of associated metabolic condi- 20% protein, and 25%40% predominately unsaturated
tions such as diabetes and hyperlipidaemia; (2) improving fats.29 30 32 The effect of low (5%10%) carbohydrate (Atkins
insulin resistance by weight loss, exercise, or pharmacother- diet) compared with standard (40%60%) carbohydrate diet
apy; (3) using hepato-protective agents such as antioxidants on NAFLD is unknown. Degree of weight loss is similar
to protect the liver from secondary insults (fig 1). Many between diets after 12 months, although the low carbohy-
agents have shown promising results in preliminary pilot drate diet is associated with lower serum levels of triglyceride
trials, however, there have been few treatment modalities and higher HDL cholesterol levels.36 37 It should be noted that
examined in rigorous randomised double blind placebo even under trial conditions and with frequent dietary
controlled trials with adequate statistical power. assessments, compliance is poor with 30%41% of partici-
Furthermore, interpretation of trials using biochemical pants dropping out emphasising the difficulty of maintaining
markers of liver injury (for example, hepatic aminotransa- weight loss through lifestyle change.29 36 37
minases) as treatment end points needs to be done In an effort to assist weight loss, various pharmacother-
cautiously, particularly in the absence of a control group. apeutic agents have been evaluated. Orlistat is a lipase
The natural history of patients with NAFLD and raised inhibitor that reduces fat absorption and promotes weight
aminotransaminases is characterised by improvement of loss. A small pilot study showed improvement in amino-
aminotransferases regardless of whether hepatic fibrosis transaminases with a mean 10 kg weight loss after six
improves or worsens.10 11 months of orlistat.38 A non-significant reduction in steatosis
was seen. Anorectic drugs such as fenfluramine and
TREATMENT OF ASSOCIATED METABOLIC phentermine in addition to dietary and behavioural mod-
CONDITIONS ifications were reported to improve aminotransaminase levels
The metabolic syndrome and its features of central obesity in 11 obese patients,39 but these drugs may induce cardio-
(waist circumference >94 cm for men, >80 cm for women), vascular and lung toxicity and they have been withdrawn

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Non-alcoholic fatty liver disease 317

Figure 1 Treatment algorithm for

Diagnosis of NAFLD NAFLD.

Exclude secondary NAFLD Consider liver biopsy if at risk of

advanced fibrosis
Diabetes
Obese
Evaluate and treat metabolic risk factors Age > 50
obesity AST/ALT > 1
hypertension
dyslipidaemia
glucose intolerance
Screen for HCC and varices if
cirrhosis present

Improve insulin sensitivity Avoid excessive

weight loss alcohol ingestion
exercise
consider bariatric surgery
if morbidly obese

Enrol in clinical trial if available

from the market. More recently, sibutramine was associated lobular hepatitis, although this has not been a universal
with weight loss and improvement in alanine aminotransfer- experience.43 47
ase (ALT) and aspartate aminotransferase (AST) over six Several studies have examined weight loss in obese
months in 13 patients.40 Histology was not assessed, however, children with NAFLD. Diet and exercise leading to roughly
regression of hepatic steatosis as determined by ultrasound, 500 g/week weight loss in nine children, led to improvement
occurred in 11 patients. The same series found similar in aminotransaminases and hepatic steatosis as determined
improvements in 12 patients who were assigned to orlistat. by ultrasound.48 Similarly, weight loss from diet (1200
Among morbidly obese patients, several observational 1400 calories/day) and exercise (at least six hours/week) was
studies have shown consistent improvement in aminotran- evaluated in 33 obese children aged between 4 and 16 years.49
saminase levels and degree of hepatic steatosis after bariatric Weight loss was associated with normalisation of liver tests
surgery.4144 The effect on hepatic inflammation and fibrosis and improvement or normalisation of hepatic steatosis on
has been more variable. Malabsorptive bariatric procedures ultrasound. Improvement in aminotransaminases has also
such as biliopancreatic diversion and jejenoileal bypass are been reported in a series of six children with NAFLD, with
associated with an increase in hepatic fibrosis with cases of fluctuating liver enzymes reported in those unable to lose
cirrhosis and liver related death reported after the latter weight.50
procedure.42 45 46 In addition, rapid weight loss associated In summary, the evidence of efficacy of diet and exercise in
with gastric banding has been associated with an increase in patients with NAFLD is surprisingly scant. However, as it is

Table 2 Effect of weight loss in non-alcoholic fatty liver disease in adults

Histology
Duration
Author Intervention Number Study Type Comparison (months) ALT Steatosis Inflammation Fibrosis
32
Ueno Diet/exercise 25 Open label, non- No treatment 3 Improved Improved No change No change
randomised
29
Huang Diet/exercise 23 Pilot trial Baseline 12 No change No change No change No change
28
Andersen Diet 41 Case series Baseline 6 Improved Improved No change* No change
Okita30 Diet 14 Pilot trial Baseline 6 Improved NA NA NA
Palmer31 Diet 39 Case series Baseline Improved NA NA NA
38
Harrison Orlistat 10 Pilot trial Baseline 6 Improved No change No change No change
HatzitoliosA35 Orlistat 21 Pilot trial Baseline 6 Improved NA NA NA
40
Sabuncu Orlistat 12 Pilot trial Baseline 6 Improved Improved NA NA
Sibutramine 13 Pilot trial Baseline 6 Improved Improved NA NA
Dixon41 Gastric banding 36 Pilot trial Baseline 26 Improved Improved Improved Improved
44
Silverman Gastro-jejenostomy 91 Case series Baseline 18 No change Improved No change Improved
Luyckx43 Gastric banding 69 Case series Baseline 27 Improved Improved Worse No change
Kral42 Biliopancreatic 104 Case series Baseline 74 Improved Improved No change Worse`
diversion
Clark JM92 Reux-en Y gastric 16 Case series Baseline 10 No change Improved Improved Improved
bypass

NA, not assessed. *No change in lobular inflammation, but significant worsening of portal inflammation; as assessed by ultrasound; `significance level
p = 0.053.

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318 Adams, Angulo

comparatively safe, inexpensive, and has other health Lactic acidosis is a feared complication of metformin
benefits, it should remain the first line among patients with therapy, although it is rare and primarily seen among
NAFLD and increased BMI. Patients with NAFLD and normal patients with renal or cardiac failure.59 However, the risk
BMI still have some degree of insulin resistance; physical among patients with advanced liver fibrosis has not been well
exercise in itself improves insulin resistance and thus NAFLD studied. In the few studies to date, 0%7% of patients taking
among subjects who are not obese or overweight based on metformin therapy had increased lactate levels but not
BMI measurements. Some patients with normal BMI and acidosis.54 5658 Very few patients taking metformin had
NAFLD meet criteria for central obesity, and thus, waist cirrhosis and thus it remains unclear whether it is safe to
circumference needs to be recorded in all patients with prescribe metformin in these patients.
NAFLD regardless of BMI. Rapid weight loss attributable to The thiozoladinediones bind to the peroxisome proliferator
very low calorie dieting or bariatric surgery risks exacerbation activated receptor c (PPAR) resulting in improved insulin
of liver injury and should be avoided. The risk/benefit of long sensitivity and redistribution of adipose tissue.60 In animal
term drugs for weight loss has not been clarified. models, PPARc agonists also have a protective effect against
liver fibrosis by inhibiting activation of hepatic stellate
INSULIN SENSITISING DRUGS cells.61 62 Troglitazone showed promising results in a pilot
It is well established that insulin resistance is a common trial63 before being removed from the market because of
association with patients with NAFLD and plays an impor- idiosyncratic liver toxicity.64 The second generation glita-
tant part in lipid accumulation within the liver and perhaps zones rosiglitazone and pioglitazone are structurally differ-
its progression to NASH.7 51 In keeping with this, insulin ent to troglitazone and seem to be safer.65
resistance is predictive of the necroinflammatory form of Two well designed pilot trials using pioglitazone (30 mg
NAFLD and conditions associated with insulin resistance daily) and rosiglitazone (4 mg twice daily) showed improve-
such as obesity and diabetes are associated with the presence ment in ALT, hepatic steatosis, and features of hepatic
of advanced fibrosis among subjects with NASH.22 47 This had inflammation compared with baseline.66 67 Pioglitazone but
provided the impetus to trial insulin sensitising drugs such as not rosiglitazone was associated with improvement in the
metformin and the thiozoladinediones in NAFLD. overall fibrosis stage. A randomised trial of 20 non-diabetic
Metformin is a biguanide antihyperglycaemic agent whose patients with NASH comparing pioglitazone (30 mg/day)
mechanism of action is not well understood.52 In animal plus vitamin E (400 IU/day) with vitamin E (400 IU/day)
models of fatty liver, metformin improved hepatic steatosis, alone, found both groups improved hepatic steatosis grade
which was accompanied by down-regulation of TNFa and compared with baseline, although the degree of improvement
lipid transcription factors.53 Several small pilot trials of four to with pioglitazone was greater; features of hepatic inflamma-
six months duration using doses of 11.5 g/day, have tion also improved in the pioglitazone group compared with
showed improvement in ALT levels compared with baseline baseline.68 Comparing treatments at the end of the study
(table 3).5456 Interestingly, a longer pilot trial using up to 2 g/ however, found no difference in ALT, steatosis grade, or
day found no difference in ALT levels after 12 months fibrosis stage between groups, although hepatic inflamma-
treatment despite initial improvement at three months.57 Ten tion were significantly less in the pioglitazone group.
patients in this trial underwent biopsies at the end of Interpretation of these studies without a placebo group is
treatment; improvement in steatosis was seen in one third of difficult, as ALT levels, hepatic steatosis, and inflammation
patients, inflammation in 20%, and fibrosis in 10%. A larger tend to improve over time as fibrosis progresses in
open label study from Italy randomised non-diabetic subjects NAFLD.10 11 Weight gain with fat redistribution from the
to 2 g/day metformin (n = 55), diet (n = 27), or 800 IU/day central/truncal area to the lower body was the most common
vitamin E (n = 28).58 Significantly more subjects taking side effect occurring in 67%72% of subjects taking pioglita-
metformin had normalisation of ALT levels compared with zone or roziglitazone.66 67 Of concern, 1 of 30 subjects in the
those taking vitamin E or diet treatment. Follow up liver rosiglitazone trial and 1 of 10 patients taking pioglitazone
biopsy was performed in 17 of the 55 subjects assigned to were withdrawn because of hepatotoxicity.66 68 Although
metformin therapy; significant improvements were seen in definitive cause-effect was not proved, potential hepatotoxi-
steatosis, inflammation, and fibrosis compared with baseline. city in the setting of liver disease remains a concern.
Although encouraging, these results need to be reproduced in
larger and well controlled clinical trials before assuming ANTIOXIDANTS
metformin is an effective and safe treatment for patients with Subjects with NAFLD exhibit increased levels of oxidative
NAFLD. stress and lipid peroxidation that may play a part in disease

Table 3 Insulin sensitising agents in the treatment non-alcoholic fatty liver disease
Histology
Duration
Author Intervention Number Study type Comparison (months) ALT Steatosis Inflammation Fibrosis
55
Magalotti Metformin 11 Pilot trial Baseline 6 Improved NA NA NA
Schwimmer56 Metformin 10 Pilot trial Baseline 6 Improved Improved* NA NA
57
Nair Metformin 15 Pilot trial Baseline 12 No change No change No change No change
54
Marchesini Metformin 14 Pilot trial Baseline 4 Improved NA NA NA
Bugianesis58 Metformin 110 Open label, Vitamin E or 12 Improved NA NA NA
randomised diet
67
Promrat Pioglitazone 18 Pilot trial Baseline 11 Improved Improved Improved Improved
Bajaj93 Pioglitazone 11 Pilot trial Baseline 4 NA Improved* NA NA
94
Shadid Pioglitazone 5 Pilot trial Baseline 4 Improved NA NA NA
Neuschwander- Rosiglitazone 30 Pilot trial Baseline 11 Improved Improved Improved No change
Tetri66
68
Sanyal Pioglitazone + 20 Open label, Vitamin E 6 No difference No difference Improved No
vitamin E randomised difference

*Determined by magnetic resonance spectroscopy; improvement seen in zone 3 fibrosis but not overall fibrosis score.

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Non-alcoholic fatty liver disease 319

progression.69 70 Vitamin E is a potent antioxidant and has the angiotensin II receptor that improved aminotransami-
been evaluated among paediatric and adult patients with nases, serum markers of fibrosis, and levels of profibrotic
NAFLD (table 4). Two small pilot trials have shown reduction cytokine transforming growth factor b1 in a pilot trial of
of ALT levels among adult and paediatric patients with seven subjects with NASH.80 Significant histological improve-
NASH. Subsequently, two small randomised controlled trials ment was not seen, although this may have been because of
have failed to show any benefit of vitamin E on ALT levels; lack of power.
one study randomised 16 adult subjects to vitamin E (800 IU/ Ursodeoxycholic acid (UDCA) has anti-inflammatory,
day) or no treatment over three months71; the other trial immune modulating, and antiapoptotic properties and is
consisted of 28 obese children taking vitamin E (400 mg/ widely used in chronic cholestatic liver diseases. After
daily for two months, 100 mg/daily for three months) or promising results from several pilot studies, a large rando-
placebo.72 In the only randomised study assessing histology, mised placebo controlled study recently found no effect on
Harrison and colleagues randomised 45 patients to vitamins liver biochemistry or histology.8183 In that study81 a sig-
E (1000 IU/day) and C (1000 mg/day) or placebo for six nificant improvement in the liver enzymes and degree of
months.73 Vitamin treatment significantly improved hepatic steatosis was found at two years of treatment as compared
inflammation and fibrosis compared with baseline. However, with baseline; this significant improvement in liver enzymes
the comparison of changes between placebo and vitamin E/C and steatosis was also seen in the placebo group. The
groups occurring with treatment at the end of the study improvement seen with UDCA treatment was not signifi-
showed no differences in ALT, hepatic inflammation or cantly better than that seen in the placebo group.81 Based on
fibrosis. Recent evidence has also suggested that vitamin E this study, UDCA is not recommended for the treatment of
supplementation may not be innocuous but may be NAFLD.
associated with an increased risk of death and heart failure.74 Intestinal derived bacterial endotoxin seems to sensitise
Therefore in the absence of convincing evidence of benefit animal model fatty livers to the effects of TNFa with
and the possible spectre of harm, vitamin E cannot be subsequent liver damage.84 Consequently, probiotics have
recommended for treatment of NAFLD outside of clinical been shown to ameliorate liver injury in these models.85
trials. Administration of the probiotic VSL no 3 to 22 NAFLD
Probucol is a lipid lowering antioxidant, which after patients over three months improved ALT levels as well as
showing promise in a pilot trial,75 improved ALT levels markers of lipid peroxidation.86 Effects on histology are
compared with placebo in a six month randomised trial.76 unknown.
However, probucol is not universally available and has been
withdrawn from Australia and the USA after concern LIPID LOWERING DRUGS
regarding its pro-arrhythmic potential. As hypertriglyceridaemia and low HDL cholesterol levels are a
manifestation of insulin resistance and common among
OTHER HEPATO-PROTECTIVE AGENTS subjects with NAFLD, several investigators have used lipid
A variety of hepato-protective agents used in other liver lowering drugs to treat NAFLD (table 5). The use of statin
disease have been evaluated in patients with NAFLD (table 5). drugs is currently contraindicated in the presence of active
Pentoxifylline inhibits TNFa and has been shown to improve liver disease or persistent unexplained increases of amino-
short term survival in severe alcoholic hepatitis. Early pilot transaminases. Recent evidence, however, shows that
trials have shown improvement in aminotransaminases in patients with raised liver enzymes may not be at increased
NAFLD patients with 12001600 mg/daily of pentoxifyl- risk of serious hepatotoxicity with standard doses of these
line.77 78 Similarly, betaine, a methyl donor that protects drugs.87 Subsequently two small pilot trials have shown
against hepatic lipid accumulation, lowered aminotransami- improvement of liver enzymes with atorvastatin.35 81 In
nase levels and also improved steatosis, inflammation, and addition, pravistatin 20 mg given for six months normalised
liver fibrosis in a pilot trial of 10 patients.79 liver enzymes and improved hepatic inflammation among
Angiotensin II promotes insulin resistance and hepatic five patients with NASH.88 Two small trials have also
fibrosis in animal models. Losartan is an antagonist against examined the fenofibrates; one 12 month trial of clofibrate

Table 4 Hepatoprotective agents in the treatment of non-alcoholic fatty liver disease

Histology
Duration
Author Intervention Number Study type Comparison (months) ALT Steatosis Inflammation Fibrosis
82
Laurin UDCA 24 Pilot trial Baseline 12 Improved Improved No change No change
Kiyici81 UCDA 17 Pilot trial Baseline 6 Improved NA NA NA
95
Vajro UCDA 31 Open label, Diet 6 No difference NA NA NA
randomised
Lindor83 UDCA 166 Blinded RCT Placebo 24 No difference No difference No difference No difference
79
Abdelmalek Betaine 10 Pilot trial Baseline 12 Improved Improved No difference Improved
Merat75 Probucol 17 Pilot trial Baseline 6 Improved NA NA NA
76
Merat Probucol 30 Blinded RCT Placebo 6 Improved NA NA NA
78
Adams Pentoxifylline 20 Pilot trial Baseline 12 Improved NA NA NA
Satapathy77 Pentoxifylline 18 Pilot trial Baseline 6 Improved NA NA NA
86
Loguercio VSL no 3 22 Pilot trial Baseline 3 Improved NA NA NA
80
Yokohama Losartan 7 Pilot trial Baseline 11 Improved No change No change No change
Hasegawa96 Vitamin E 22 Pilot trial Baseline 12 Improved No change No change No change
71
Kugelmas Vitamin E + diet 16 Open label, Diet and 3 No difference NA NA NA
and exercise randomised exercise
Vajro72 Vitamin E 28 Blinded RCT Placebo 5 No difference No difference* NA NA
73
Harrison Vitamin E + C 45 Blinded RCT Placebo 6 No difference NA No difference No difference
Lavine97 Vitamin E 11 Pilot trial Baseline 5 Improved NA NA NA

No change if no statistically significant change reported. *Assessed by ultrasound; fibrosis score improved compared with baseline but not in comparison with
placebo at end of treatment.

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320 Adams, Angulo

Table 5 Lipid lowering drugs in the treatment of non-alcoholic fatty liver disease
Histology
Duration
Author Intervention Number Study type Comparison (months) ALT Steatosis Inflammation Fibrosis
88
Rallidis Pravistatin 5 Pilot trial Baseline 6 Improved No change Improved No change
81
Kiyici Atorvastatin 27 Pilot trial Baseline 6 Improved NA NA NA
Hatzitolios35 Atorvastatin 28 Pilot trial Baseline 6 Improved NA NA NA
Omega-3 fatty acids 23 Pilot trial Baseline 6 Improved NA NA NA
82
Laurin Clofibrate 16 Pilot trial Baseline 12 No change No change No change No change
Basaranoglu89 Gemfibrozil 46 RCT Control group 1 Improved NA NA NA

2 g/day showed no improvement in liver enzymes or morbidity and mortality in a subset of people, particularly
histology,82 whereas gemfibrozil 600 mg/day improved ALT those who are obese, diabetic, and who have NASH.
levels compared with no treatment over four weeks of However, a better understanding of the natural history of
treatment.89 NAFLD will permit better identification of at risk patients
who should be targeted for long term and potentially
FUTURE DIRECTIONS expensive treatment.
Increased understanding of the pathogenesis of NAFLD and Treatment of NAFLD should begin with screening and
particularly the factors responsible for progressive liver managing metabolic risk factors that may modify the risk of
injury, will permit better targeting of therapeutic agents. liver disease as well as non-liver related disease such as
Adiponectin is a hormone secreted by adipose tissue that has ischaemic heart disease. First line treatment should consist of
insulin sensitising as well as apparent hepatoprotective lifestyle change with weight loss and exercise to improve
effects and thus may play a part in hepatic fat accumulation insulin sensitivity. However, because of long term compliance
as well as liver injury in patients with NAFLD. difficulties, pharmaceutical agents aimed at reducing insulin
Supplementation of adiponectin led to improvement in resistance or protecting the liver from additional insults are
hepatic steatosis and ALT levels to animal models of needed.
NAFLD.90 Human studies have not been performed. Many pilot trials have shown promising initial results in
Agonists of PPARc (thioglitazones) and PPARa (fibrates) improving liver enzymes or features of liver histology.
act to improve insulin sensitivity and up-regulate hepatic However, the efficacy of these agents still remains in
FFA oxidation thus decreasing hepatic steatosis. Both types question, and none of them can yet be recommended outside
of agonists have shown promising results in pilot trials in of clinical trials. Furthermore, the cost effectiveness of
NAFLD. Combination dual PPAR c and a agonists (mur- pharmacological therapy of NAFLD has to be defined. Some
aglitazar, tesaglitazar) would therefore seem to be attractive randomised, double blind, placebo controlled trials evaluat-
candidates for treatment of NAFLD. Phase 2 clinical trials are ing pioglitazone, metformin, vitamin E, betaine, and sily-
currently underway examining the influence of these agents marin are currently in progress, in both adults and children.
on cardiovascular risk factors.91 These trials will hopefully provide new therapeutic options
for the clinician in the near future.
CONCLUSIONS
NAFLD is now acknowledged to be the commonest liver MULTIPLE CHOICE QUESTIONS (TRUE (T)/FALSE (F);
condition in the western world, largely because of the ANSWERS AT END OF REFERENCES)
considerable increase in metabolic diseases such as obesity 1. Treatment of nonalcoholic fatty liver disease (NALFD)
and diabetes. It is clear that NAFLD leads to liver related should be aimed at preventing its progression to the
following complications;

Learning points (A) cirrhosis

(B) hepatocellular carcinoma
Metabolic risk factors for NAFLD (C) liver failure
N Central obesity (waist circumference >94 cm for men, (D) liver abscess
>80 cm for women)
N Impaired fasting glycaemia (>6.1 mmol/l) 2. The following are adverse prognostic indicators among
N Hypertriglyceridaemia (.1.70 mmol/l), patients with NAFLD;
N Low HDL-cholesterol (,1.30 mmol/l in women,
(A) obesity
,1.03 mmol/l in men)
(B) cirrhosis
N Hypertension (>135/>80 mm Hg)
(C) raised aminotransaminases
Treatment recommendations for NAFLD (D) diabetes
N Exclude secondary causes of hepatic steatosis
3. The following treatments should be routinely recom-
N Screen for metabolic risk factors
mended for patients with NAFLD;
N Avoid hepatotoxins such as alcohol excess
N Regular exercise (A) weight loss if obese
N Weight loss if centrally obese (B) exercise
N Consider bariatric surgery if morbidly obese (C) reduction of excessive alcohol ingestion
(D) thiozoladinediones

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Non-alcoholic fatty liver disease 321

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(D) the available antiobesity drugs have shown to prevent all-cause and cardiovascular mortality in the San Antonio heart study.
Circulation 2004;110:12517.
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.....................
steatohepatitis: a pilot study. Am J Gastroenterol 2005;100:107281.
Authors affiliations 30 Okita M, Hayashi M, Sasagawa T, et al. Effect of a moderately energy-
L A Adams, School of Medicine and Pharmacology, University of restricted diet on obese patients with fatty liver. Nutrition 2001;17:5427.
Western Australia, Fremantle Hospital, Perth, Australia 31 Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in
P Angulo, Division of Gastroenterology and Hepatology, Mayo Clinic overweight patients. Gastroenterology 1990;99:140813.
32 Ueno T, Sugawara H, Sujaku K, et al. Therapeutic effects of restricted diet and
College of Medicine, Rochester, USA
exercise in obese patients with fatty liver. J Hepatol 1997;27:1037.
Funding: LA is sponsored by a Postgraduate Medical Research 33 Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to
Scholarship (no 353710) from the National Health and Medical insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis.
Research Council as well as by the Athelstan and Amy Saw Hepatology 2003;37:90916.
34 Fernandez MI, Torres MI, Gil A, et al. Steatosis and collagen content in
Postgraduate Medical Scholarship from The University of Western experimental liver cirrhosis are affected by dietary monounsaturated and
Australia. polyunsaturated fatty acids. Scand J Gastroenterol 1997;32:3506.
Conflicts of interest: none declared. 35 Hatzitolios A, Savopoulos C, Lazaraki G, et al. Efficacy of omega-3 fatty
acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with
dyslipidemia. Indian J Gastroenterol 2004;23:1314.
36 Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate
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77 Satapathy SK, Garg S, Chauhan R, et al. Beneficial effects of tumor necrosis (A) T, (B) T, (C) T, (D) F; 4. (A) T, (B) F, (C) T, (D) F; 5. (A)
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Treatment of non-alcoholic fatty liver disease

L A Adams and P Angulo

Postgrad Med J 2006 82: 315-322

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