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Shyangdan D, Clar C, Ghouri N, et al. Insulin Sensitisers in the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review. Southampton (UK): NIHR Journals Library; 2011 Nov. (Health Technology Assessment, No. 15.38.)

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Insulin Sensitisers in the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review.

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1Introduction

What is non-alcoholic fatty liver disease?

‘Non-alcoholic fatty liver disease’ (NAFLD) is a term used for a group of inter-related chronic liver disorders causing a wide spectrum of liver damage associated with increased fat content in the liver in the absence of increased alcohol intake [< 10 g of alcohol per day for women, < 20 g per day for men (around 9–18 units of alcohol per week, respectively)].1,2 By definition, to have NAFLD, > 5% of the liver weight must be due to accumulation of fat.2 NAFLD has become recognised as an important problem only recently and was relatively unknown prior to 1980.3,4 Population-based screening studies suggest that the prevalence of NAFLD is in the region of 17–33% in the Western world.5 The prevalence of non-alcoholic steatohepatitis (NASH) is not known because it currently requires a liver biopsy to confirm the diagnosis, but it has been estimated to be around 3% in the total population.5

The spectrum of potentially progressive liver damage can include:

  • simple (hepatic) steatosis (fatty accumulation in the liver, also known as ‘fatty liver’)
  • NASH
  • advanced fibrosis
  • cirrhosis
  • hepatocellular carcinoma (HCC), hepatoma, liver cancer.

The term ‘NASH’ is sometimes used to describe the three subsequent stages after hepatic steatosis,6 but in this report will be used only for the inflammatory stage that follows simple steatosis.

Non-alcoholic fatty liver disease is the most common cause of abnormal blood tests of liver function.7 The liver damage seen in NAFLD is similar to the changes seen in alcohol-related liver disease,3 but, by definition, individuals with NAFLD do not consume increased quantities of alcohol.

Not every individual who develops simple steatosis (which is asymptomatic) progresses to the subsequent stages of liver damage, but some will progress to chronic liver failure (inability of the liver to fulfil its role in detoxifying the blood and synthesising various compounds necessary for the body to function) with potential subsequent acute decompensation. Chronic liver failure is associated with a very poor prognosis.8 Finally, some individuals can go on to develop HCC after reaching the cirrhotic stage.9 Data on disease progression are reviewed later in the chapter.

Although more cases of cirrhosis are due to alcohol than to NAFLD,10 more people have some form of NAFLD than alcohol-related fatty liver disease (ALD).11 NAFLD is strongly linked to insulin resistance, and thus associated with conditions such as type 2 diabetes mellitus (T2DM) and obesity. Therefore, as the prevalence of these two conditions increases, it is likely that there will be a marked rise in NAFLD, making NAFLD a growing issue for health-care providers. NAFLD is also a risk factor for the development of T2DM.5

What causes non-alcoholic fatty liver disease and its progression?

The key feature in NAFLD is the accumulation of fat in the liver. As mentioned above, simple fat deposition occurs at the beginning and is relatively benign; however, this can progress to inflammatory change (steatohepatitis, NASH), with the possible formation of scar tissue (fibrosis) and further structural change associated with the reduction in liver function (cirrhosis).

The accumulation of liver fat

Hepatic steatosis (accumulation of fat within liver cells) is the first stage of NAFLD. There is no single mechanism leading to hepatic steatosis, but rather the combination of a number of pathologies that ultimately disrupt normal lipid [fat-rich products, mainly triglycerides (TGs) – fatty acid molecules] movement through the liver cell and cause lipid accumulation. The fat in the liver can be traced to three sources – dietary intake, de novo synthesis and circulating non-esterified fatty acids (NEFAs) derived from body fat stores.5 It is known that high-fat diets can lead to hepatic steatosis, but it appears that NEFAs are the main source of liver fat, with 60% in individuals with NAFLD who have a normal fat-containing diet.12

The body's resistance to the effects of the hormone insulin (required for the uptake of glucose – the main sugar derived from dietary carbohydrate by liver, fat and muscle cells) is thought to play a key role in increasing levels of NEFAs, particularly the insulin resistance shown by fat and muscle cells (Figure 1). Once lipid starts to accumulate in the liver this can, in fact, worsen the body's insulin resistance, reducing the beneficial effects of insulin, leading to a vicious cycle.1315

FIGURE 1. The effects and potential clinical indicators of accumulating liver fat.

FIGURE 1

The effects and potential clinical indicators of accumulating liver fat. The presence of ectopic fat in the liver cell leads to hepatic insulin resistance following the accumulation of intracellular lipid by-products, which leads to disturbed glucose (more...)

Inflammation of the fatty liver – non-alcoholic steatohepatitis

McCullough16 has reviewed the pathophysiology of NASH. Hepatic steatosis is considered to have a benign course in most cases.17 This may be because of associated counter-regulatory protective mechanisms, which means that liver tissue changes (other than steatosis) and liver function may remain normal. NASH represents the stage when the fatty liver starts to show inflammatory change. It is the development of NASH and progression to fibrosis and cirrhosis that is responsible for the liver-specific morbidity and mortality of NAFLD.

It is unclear why only approximately 25–30% of patients with simple steatosis develop NASH.16 The counter-regulatory processes occurring as a means to maintain liver cell (hepatocyte) health forms the basis of the older ‘two-hit’ theory in the development of NASH. A newer theory suggests that NASH occurs by liver fat directly causing inflammation.

In the two-hit theory, the first hit refers to the accumulation of liver fat. It has been proposed the hepatocytes act, in addition, as a reservoir of toxic agents and are most susceptible to a ‘second hit’ – oxidative stress18,19 – caused by endogenous compounds within liver cells and by environmental toxins.20,21 The cells in the body constantly react with inhaled oxygen, producing energy – oxidation. As a consequence of this activity, highly reactive molecules (free radicals) are produced. Free radicals interact with other molecules within cells. This can cause damage – oxidative stress – to proteins, membranes and genes. Patients with NASH have increased levels of oxidative stress when compared with patients with steatosis alone.22,23

In addition to endogenous toxins, three factors have been proposed as potential causative mechanisms for producing this oxidative stress: increased insulin levels, lipid peroxidation and liver iron content (Figure 2).

FIGURE 2. The two-hit theory of NASH.

FIGURE 2

The two-hit theory of NASH. This involves insulin resistance, which causes hepatic steatosis, a process enhanced by obesity and/or T2DM. Once developed, hepatic steatosis may remain in a benign state or progress to NASH via the mechanisms discussed. Reproduced (more...)

Insulin may injure the liver both directly and indirectly.24,25 The indirect effects are related to the hyperinsulinaemic state increasing liver fat accumulation, as described earlier. The direct effect may be due to insulin's ability to generate oxidative stress.25 It also appears to have direct effects by stimulating scar tissue formation, especially in the presence of increased glucose levels.26 This may explain the observation that NAFLD patients with T2DM have a particularly poor prognosis.17,27 Insulin may be directly involved in causing stress on parts of the liver cell that lead to cell death (apoptosis). This, in itself, may exacerbate insulin resistance.28

Increased lipid peroxidation (breakdown of NEFAs, causing oxidative stress) has been demonstrated in patients with NAFLD.22,23,2931 As previously described, patients with NAFLD have increased breakdown of fat stores and increased delivery of NEFAs to the liver.22,32 The products of NEFA oxidation are capable of generating oxidative stress and subsequent lipid peroxidation, setting up a vicious cycle.

In response to oxidative stress, there is usually an increased synthesis of antioxidants. However, NAFLD patients have decreased antioxidants (glutathione).33 Therefore, patients with NAFLD have an impaired ability to produce sufficient antioxidants. A deficiency in antioxidants is also supported by a preliminary report that demonstrated that betaine (a naturally occurring antioxidant) improved the microscopic images of liver tissue and liver function tests (LFTs) in patients with NAFLD.34

The role of iron as a pro-oxidant in NASH is unclear. In McCullough's review,16 there is mention of patients with NAFLD having increased ferritin levels, and a relationship between hepatic iron and insulin resistance. However, there is acknowledgement that there is no strong evidence associating iron overload with NAFLD. Therefore, for now, iron is likely to be important in only a minority of patients with NASH and more research is required on iron as a pathophysiological factor.

There is also good evidence to support a one-hit theory of liver fat causing chronic inflammation directly, leading to direct NAFLD progression.5 A key player in steatosis formation appears to be nuclear factor-κB (NF-κB). This is a transcription factor – an intracellular protein required for the transcription of deoxyribonucleic acid to form proteins. In animal models it has been shown that a high-fat diet with resultant hepatic steatosis leads to increased NF-κB signalling in the liver.35 This then induces the production of chemicals involved with causing inflammation, which may play a role in the progression of NAFLD. The transcription factor also leads to activation of specific cells (Kupffer cells and macrophages) within liver tissue, which are known to cause further damage to liver tissue. In the same study35 there is evidence that inflammation, in the form of isolated increased NF-κB expression in rat liver, can lead directly to insulin resistance.35

Another factor that may be involved in the process is adiponectin, a polypeptide produced in adipocytes (fat cells) and which may be protective via an insulin-sensitising effect in the liver. Polyzos et al.36 reviewed the evidence on the role of adiponectin and noted that it was reduced in NAFLD and NASH, and increased by most interventions which improved NAFLD, including weight loss, bariatric surgery and pioglitazone, but not metformin. However, formal interventions and links to adiponectin genotypes would be required to prove a causal relationship.

The advanced stages – fibrosis and cirrhosis

As NAFLD progresses, more advanced forms can occur – fibrosis and cirrhosis. Liver fibrosis is the formation of excess fibrous tissue in the liver37 and is a reparative or reactive process, as a result of NASH,38 or, in a few cases, direct progression from simple steatosis.39 Liver fibrosis can lead to loss of function.

Cirrhosis of the liver is advanced fibrosis associated with regenerative nodules (an attempt at repair).40 Cirrhosis is associated with variable and usually irreversible loss of liver function. When liver function is minimally or not significantly compromised clinically, it is often termed ‘compensated cirrhosis’; however, when there is clinical evidence that the cirrhotic liver is unable to function properly, it is termed ‘decompensated cirrhosis’. Whereas decompensation can be reversible if due to an acute insult (e.g. infection), decompensation is often progressive, resulting in liver failure and death. Hui et al.41 in their prospective cohort study followed up 23 patients with NASH-associated cirrhosis for a mean duration of 84 months (range 5–177 months) and found that 9 out of 23 cases developed liver-related morbidity (eight developed ascites and/ or encephalopathy, one developed variceal bleeding). The authors then found that probability of complication-free survival was 83%, 77% and 48% at 1, 3 and 10 years, respectively, and the cumulative probability of overall survival at 1, 3 and 10 years was 95%, 90% and 84%, respectively.41

Other conditions associated with non-alcoholic fatty liver disease

As described above, other diseases and physiological states are associated with the development, severity and progression of NAFLD. The main ones are diabetes mellitus (particularly T2DM42), insulin resistance, obesity or overweight, and increased levels of TGs in the blood (hypertriglyceridaemia).7 Insulin resistance, obesity and hypertriglyceridaemia are key components of the (multiply defined) topical metabolic syndrome,43 a ‘syndrome’ associated with increased cardiovascular events.44 A substantial number of studies have shown the increased prevalence of these three conditions in patients with NAFLD, and some data are summarised in Table 1.45 More data relating to these conditions and NAFLD will be commented on in the next section.

TABLE 1. Type 2 diabetes mellitus, obesity and hypertriglyceridaemia in NAFLD.

TABLE 1

Type 2 diabetes mellitus, obesity and hypertriglyceridaemia in NAFLD.

Although all three conditions are associated with the development of NAFLD, it is also likely that NAFLD, associated with elevations in liver enzymes, has a causal role in development of T2DM,4649 as previously highlighted in Figure 1.

Prevalence and natural history of non-alcoholic fatty liver disease

Estimates of prevalence are variable, because of differences in the method used to diagnose the various stages of NAFLD and the variation in sample selection and size. As the histological (microscopic tissue) features of NAFLD may be indistinguishable from those of alcoholic liver disease, the diagnosis requires the exclusion of known excessive alcohol intake.

International data

As previously mentioned, screening studies using serum liver tests and ultrasonography (USG) suggest that the prevalence of NAFLD ranges from 17% to 33% in the general population of the Western world.50 Imaging using magnetic resonance spectroscopy (MRS) gives NAFLD a prevalence of 34%.51 The prevalence of NASH is less well known, as a liver biopsy is required to confirm the diagnosis. Estimates of the prevalence are in the range of approximately 3% in the general population and higher among obese persons.52 The average age at diagnosis lies between 45 and 55 years,45 and has a slight female preponderance.45

Natural history

Good long-term data (including UK data) on the natural history of NAFLD from simple steatosis to more advanced stages are lacking, for a number of reasons. NAFLD has only recently been characterised in detail. There are few long-term follow-up studies of well-defined patient cohorts, and follow-up liver biopsies have been performed in only a limited number of patients. The diagnostic method for fatty liver – blood tests ± ultrasound ± liver biopsy (the current gold standard)50 – is not uniform, and studies using ultrasound to diagnose steatosis will give higher numbers than liver biopsy. Furthermore, it is possible that the long-term complications of NAFLD may be under-recognised and under-reported, as the characteristic features of fatty liver, such as steatosis, may disappear in the late stages of the disease, leading to a picture of ‘bland’ cirrhosis, frequently described as ‘cryptogenic’, rather than NAFLD-related cirrhosis, which is now recognised as the most common cause of cryptogenic cirrhosis.53 Finally, most studies to date that have studied the natural history of NAFLD have been retrospective analyses (e.g. clinical follow-up from cohort studies) or case series in which selected patients with a diagnosis of NASH underwent subsequent liver biopsies.6

Despite these limitations, the following diagrams indicate the current thinking on the prevalence and progression of NAFLD (Figures 3 and 4).

FIGURE 3. The natural history of NAFLD. Adapted from Preiss and Sattar.

FIGURE 3

The natural history of NAFLD. Adapted from Preiss and Sattar. a, Matteoni et al., Day; b, Fassio et al., McCullough.

FIGURE 4. The natural history and clinical outcomes of NASH.

FIGURE 4

The natural history and clinical outcomes of NASH. OLTX, orthotopic liver transplantation. Reproduced with permission from AJ McCullough. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006;40(Suppl. 1):17–29.

Hence, it is difficult to determine what proportion of an unselected population will develop NAFLD-related cirrhosis and subsequent HCC. One study estimated that 7% of cases of HCC were related to underlying NAFLD or cryptogenic cirrhosis but such data are, at best, approximates.9

UK data

The UK data on NAFLD are limited, with no nationwide data. The incidence of NAFLD in a hepatology catchment area in England of 200,000 residents, based on referrals to a secondary care setting, was calculated at 29 per 100,000 population.55 This was subdivided into 23.5 per 100,000 population for non-cirrhotic NAFLD and 5.5 per 100,000 population for cirrhotic NAFLD. There are no satisfactory prevalence data.

Associations with type 2 diabetes mellitus and obesity

Numerous studies have reported the increased prevalence of NAFLD in individuals with T2DM,56 and increased risk and severity of NAFLD in T2DM.5759 In 939 randomly selected people with T2DM in Edinburgh, ultrasound-detected steatosis was present in 73.9% of subjects.60 A recent study in the USA reported the prevalence of ultrasound-determined NAFLD to be 69.5%.56 The prevalence of NAFLD in obese individuals (ultrasound determined) has been estimated to be high as 80%.50 One thing is certain – as the incidence and prevalence of obesity and T2DM increase,61 the incidence and prevalence of fatty liver, and hence NASH and more severe forms of NAFLD, are also likely to increase.

Cardiovascular risk

In addition to the organ-specific related morbidity and mortality of NAFLD, NAFLD has also been linked with increased cardiovascular risk, largely through the components of the metabolic syndrome. A detailed review in 2007 on NAFLD and cardiovascular risk62 showed that this increased risk was related to the presence of known cardiovascular risk factors, several of which (insulin resistance, obesity and dyslipidaemia/hypertriglyceridaemia) are also well associated with NAFLD.63

Similar conclusions were reached in a more recent review by Ghouri et al.,64 who concluded that the presence of NAFLD was an indication for screening for T2DM, but that it did not add useful data on CVD risk compared with traditional risk factors.

Hence, it appears that NAFLD itself is not an independent contributor to CVD risk, but that it is associated with adverse risk factors.

A more recent review by Targher et al.65 also addressed the question of whether or not NAFLD increased the risk of cardiovascular disease, independent from its association with traditional risk factors. They concluded that:

Although additional research is required to draw a definite conclusion, these observations raise the possibility that NAFLD – especially its necroinflammatory variant, NASH – not only is a marker of cardiovascular disease but may also be involved in its pathogenesis. This process may occur through the systemic release of pro-atherogenic mediators from the steatotic and inflamed liver or through the contribution of NAFLD itself to insulin resistance and atherogenic dyslipidaemia.

One key issue noted by Targher et al.65 is that cardiovascular disease is a greater threat to people with NAFLD than liver disease.

Associations with type 1 diabetes

A recent study66 has reported a high prevalence of NAFLD in 202 patients with type 1 diabetes in Italy. NAFLD was diagnosed by history and liver ultrasound. Over half of the group were classed as having NAFLD. Those who did were older, had suffered from diabetes longer and had higher body mass indices (BMIs) than those who did not.

Clinical features of non-alcoholic fatty liver disease

Given that NAFLD is a spectrum of (often progressive) liver damage, the clinical presentation can vary depending on the stage of presentation. Simple hepatic steatosis or fatty liver is often asymptomatic and is picked up only following investigations of abnormal blood LFTs. Symptoms, when present, may include fatigue and right upper quadrant pain and the most commonly reported clinical finding is hepatomegaly (enlarged liver on examination).67 Often these features are more apparent in individuals with NASH or early cirrhosis. If advanced cirrhosis eventually develops prior to diagnosis, presentation is similar to that of cirrhosis from other causes, with clinical signs including ascites (fluid collecting in the abdomen), variceal haemorrhage (bleeding from large veins in the gastrointestinal tract), splenomegaly (enlarged spleen on examination), bruising and eventual jaundice.

As mentioned above, NAFLD is associated with several other metabolic disorders, and therefore people with NAFLD can exhibit clinical features of these conditions as well. It is beyond the scope of this report to go into this aspect in detail.

Diagnosis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease can be reasonably accurately diagnosed from clinical history and ultrasound. However, staging is more difficult, and the current consensus is that NASH can be diagnosed only after liver biopsy. This could be a major hindrance to any trials that need to recruit large number of patients. Liver biopsy can have complications, such as bleeding.

For detecting liver fibrosis, various non-invasive alternatives to liver biopsy have been suggested, including combinations of blood tests (‘serum marker panels’) and either transient or real-time elastography (a form of ultrasound). For detecting NAFLD, ultrasound and magnetic resonance imaging (MRI)/MRS have been suggested.

The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme is commissioning a full review of evidence on non-invasive methods for the assessment and monitoring of liver fibrosis and cirrhosis (HTA no. 09/07),68 and so this review does not duplicate that. However, we review the diagnosis of lesser degrees of liver damage in Chapter 3.

Biochemical picture associated with non-alcoholic fatty liver disease

Table 2 summarises the biochemical pattern in NAFLD, and has been compared with ALD, the other most common cause of liver problems.5

TABLE 2. Biochemical profile associated with NAFLD.

TABLE 2

Biochemical profile associated with NAFLD.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [and sometimes gamma-glutamyl transferase (GGT)] are components of the broader group of liver function blood tests known as the LFTs. It should be noted that the AST concentration can be higher than ALT in cirrhosis, and thus in individuals with known NAFLD a rising AST concentration (and reversal of the ALT/AST ratio) is potentially a bad prognostic sign, suggesting necrosis (liver cell death associated with inflammation).5

Predicting non-alcoholic fatty liver disease

There are published algorithms that have attempted to detect individuals with a higher likelihood of NASH.69,70 Factors such as age (> 50 years), BMI (> 28 kg/m2), hypertriglyceridaemia and elevated ALT level were risk factors that were independently associated with liver fibrosis. A scoring system combining these factors could reduce the number of patients requiring liver biopsy.69

Treatment of non-alcoholic fatty liver disease

There is currently no approved treatment (medical or surgical) for NAFLD. Given that NAFLD is a group of inter-related progressive liver disorders, the aim and type of treatment will depend on the stage at which the diagnosis is made. There is no available prospective evidence showing the outcome of any form of treatment on important long-term outcomes, such as the development of cirrhosis or HCC. Treatment is aimed at reducing future risk of diabetes, or optimising control in patients with diabetes, treating obesity and reducing cardiovascular risk. Interventional studies have tended to use improvements in LFTs and liver histology as surrogate end points, based on the assumption that these will reflect subsequent reductions in morbidity from NAFLD.

Lifestyle changes

Reduced calorie intake and increased physical activity are viewed as logical methods to reduce liver fat content. Two studies have shown that a reduction in weight by 10% significantly reduced elevated LFTs compared with subjects with NAFLD who did not lose as much weight.71,72 Park et al.72 from Republic of Korea reported a marked reduction in liver enzymes (AST and ALT) in those who lost weight, but not in those who did not. Ueno et al.73 from Japan reported that effects of intensive lifestyle modification over a 3-month period in overweight patients with NAFLD produced an improvement in the microscopic changes in liver tissue, but such changes did not attain significance.73 However, a reduction of three units in BMI normalised previously elevated AST and ALT levels.

Weight loss drugs

Published pilot data on orlistat, a weight loss drug that reduces fat absorption, have shown improvements in LFTs, ultrasound findings and microscopic changes in liver tissue.74,75 A further small study76 compared orlistat with another drug – sibutramine, an appetite suppressant – and the results showed an improvement in LFTs and reduced liver fat on ultrasound in both groups.

In a detailed review of the effects of lifestyle modification with and without the use of weight loss drugs in patients with steatosis and NASH, Harrison and Day77 concluded that a weight loss of 10% of body weight not only improved the biochemical measures seen in NAFLD, but also improved the histological changes seen in NASH. They also concluded that the evidence from a number of studies suggested that physical activity alone, or with only modest (3%) weight loss, was also effective in improving insulin sensitivity.

More recently, a high-quality systematic review by Musso et al.78 reviewed all treatments for NAFLD. The authors also concluded that weight loss improved or reversed NASH, but that it appeared from two randomised controlled trials (RCTs) that weight loss had to be at least 7% or 9% for histological features to measurably improve. Musso et al.78 came to the same conclusion as Harrison and Day77 (but based on different studies) – that the evidence suggested that physical activity improved NAFLD independently of weight loss. These data, in turn, concur with evidence for an independent association of higher activity levels, albeit assessed by questionnaire, with lower GGT levels in a cohort study of British women.79

Drugs that control blood glucose levels

Trials using drugs that improve the body's sensitivity to the effects of insulin have been performed in individuals with NAFLD. Two main drugs – metformin and thiazolidinediones (TZDs) (glitazones) – have been investigated. Metformin reduces glucose production in the liver and improves the uptake of circulating glucose in the blood by fat and muscle, whereas the glitazones improve the uptake of circulating glucose in the blood and are also believed to redistribute fat away from ectopic sources (particularly the liver) to subcutaneous areas, often with an overall increase in weight (substantial in some individuals).80

The glitazones have adverse effects, including oedema, higher risk of fracture and in addition the development and worsening of heart failure;81,82 and rosiglitazone moderately increases cardiovascular risk83,84 and has recently been suspended in Europe.

The evidence on metformin and the glitazones is reviewed in Chapter 2.

Non-alcoholic fatty liver disease and other drugs

Patients with NAFLD are likely to be considered for lipid-lowering statin therapy owing to their elevated lipid levels and increased cardiovascular risk. Statin therapy in NAFLD certainly appears safe and should not be avoided because of mildly abnormal LFTs.85 There is also some evidence of improvement in liver histology on statin therapy from a small placebo-controlled study that was recently published.86 Other drugs studied have included vitamin E and fibrates. Vitamin E therapy has produced variable results87,88 and fibrate therapy has not shown benefit thus far.89 In the only placebo-controlled studies so far, combination therapy with the bile component ursodeoxycholic acid (UDCA) with vitamin E for 2 years resulted in a significant reduction in steatosis.90 UDCA therapy alone did not improve changes in liver tissue, although there was an improvement in LFTs. In two small studies, treatment with the angiotensin II blocker, losartan, also led to improvements in liver histology.91,92

A review of all drugs for NAFLD was not in our remit, but we note the findings of the recent review by Musso et al.,78 who found that:

  • There is some evidence of benefit from treatment with polyunsaturated fatty acids. Trials are in progress.
  • Fibrates had no effect.
  • The evidence on statins was sparse, but there was some evidence of benefit from atorvastatin.
  • The lipid-lowering drug probucol lowered ALT, but also high-density lipoprotein (HDL), which might increase cardiovascular risk.
  • UDCA had little or no effect.
  • There were mixed results with antioxidants.
  • Pentoxifylline appeared to be of benefit; two RCTs are under way.
  • Telmisartan (an angiotensin receptor blocker) appeared to reduce fibrosis, the only drug to do that. It improved steatosis, ballooning and lobular inflammation. It led to a reduction in insulin resistance, and TG and total cholesterol (TC) levels. It is noteworthy that the effects of valsartan were less despite similar blood pressure effects. The liver effects of telmisartan may be related to its peroxisome proliferators-activated receptor (PPAR) gamma activity.
  • There was some evidence of benefit for l-carnitine.
  • Orlistat added to diet resulted in little difference – weight loss of 8% instead of 6% on diet alone.

Surgery

Recently, data on surgery for morbid obesity with 18- to 24-month follow-up have been published. There are two main types of surgery for obesity. One procedure, gastric bypass surgery, in essence involves reducing the size of the stomach, by bypassing a large section of the stomach and connecting it to the small intestine, and this can be done laparoscopically (keyhole surgery). The second procedure is adjustable gastric banding, and involves placing an adjustable band over the top part of the stomach, creating a pouch that reduces the size of the stomach, and is also done laparoscopically. Studies have shown improvement of NAFLD staging or even complete disease resolution following surgery. Mummadi et al.93 carried out a systematic review to explore effectiveness of bariatric surgery in patients with NAFLD and found that the procedure was safe, with resolution of steatosis in 91.6% of patients, improvement of steatohepatitis and fibrosis in 81.3% and 65.5% of patients, respectively, and resolution of NASH in 69.5%.93

The effects of bypass surgery and concomitant weight loss (mean loss 50 kg), evaluated by liver biopsy, found considerable improvements in the prevalence of steatosis (90% preoperatively to 2.9% post-operatively), hepatocellular ballooning (swelling of liver cells: 58.9% preoperatively to 0% post-operatively) and fibrosis (50% down to 25%).94 In a similar study,95 there were similarly impressive reductions in steatosis, fibrosis and hepatocellular ballooning. In this latter study on a group of 18 patients, NASH resolved in 84% of patients and steatosis in 75%. Laparoscopic adjustable gastric banding with resultant weight loss has also led to promising improvements in liver histology.96,97 As obesity surgery is relatively novel, long-term outcome data are still limited, but should become more available as more of these procedures are performed.

Musso et al.78 concluded that the RCTs of surgery had insufficient follow-up as yet, noting that liver enzymes fluctuated and did not always correlate with fibrosis and NASH. However, a review of bariatric surgery by Kushner and Noble98 noted that two studies had shown resolution or improvement in NASH and fibrosis after bariatric surgery.

Conclusion

In summary, NAFLD is a chronic liver condition with a spectrum from simple steatosis to liver failure, associated with metabolic disturbances that result in organ-specific and cardiovascular morbidity and mortality. It appears to be increasing in prevalence. Unless this trend is reversed, this is likely to lead to increased demands on NHS resources in the years to come.

Decision problems

The HTA commissioning brief for this review identified the main issues as being the clinical effectiveness and cost-effectiveness of the insulin sensitisers in NAFLD, with the expectation that a trial might be required.

The first aim of this review is therefore to assess the current evidence base, with possible outcomes as follows:

  • There may be enough evidence to show that these drugs are effective, and that a further trial is not necessary. Alternatively, there may be sufficient evidence to show that, though effective, the effect size is too small to make them worth pursuing as a therapy for NAFLD.
  • There may be insufficient evidence for use in therapy, but enough to justify a large trial.

If there were to be a large trial, one problem would be how to identify eligible patients. It would be impractical to carry out liver biopsies on large numbers of people, so we would need a noninvasive screening test. Possible options are reviewed in Chapter 3.

Another consideration, which is outwith the scope of this review, is whether or not other drugs might be better options. The number of drugs that have been used suggests that none has been strikingly effective. Chekhov's comment may be relevant: ‘When a lot of remedies are suggested for a disease, that means it can't be cured’.99

However, the evidence suggests that NAFLD can be cured by sufficient weight loss. Unfortunately, adherence to lifestyle change is frequently poor.

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