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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

Background

Non-alcoholic fatty liver disease (NAFLD) is an umbrella term, which encompasses simple steatosis and non-alcoholic steatohepatitis (NASH). The entire spectrum of NAFLD has been associated with metabolic syndrome. NASH is associated with increased mortality compared with that of the general population. Many therapeutic options for NASH have been studied. However, there is very little evidence supporting the efficacy of most regimens for the treatment of NASH.

Aim

To provide a review focusing on the current therapeutic options available for patients with NASH as well as to briefly introduce possible future interventions.

Methods

A MEDLINE, Pubmed and Cochrane Review database search using a combination of keywords, which included non-alcoholic fatty liver disease, non-alcoholic hepatic steatosis, NAFLD, NASH, treatment, therapeutics, vitamin E, orlistat and bariatric surgery. An overall summary of the articles was developed for each section of discussion in this review.

Results

NASH associated with metabolic syndrome can progress advanced fibrosis and cirrhosis. Weight loss and lifestyle modification have been shown to improve NASH. Other medications used for weight loss and metabolic syndrome have been evaluated, such as orlistat, metformin and thiazolidinediones. Alternative regimens using ursodeoxycholic acid, statins and probiotics as well as bariatric surgery have been evaluated, but have not been recommended as first-line treatment for NASH. Vitamin E for NASH patients without diabetes seems to be promising. The lack of effective treatment for NASH suggests the heterogeneity of patients presenting with the NASH phenotype. The best treatment strategy for these patients may be to identify their pathogenic target and develop personalised treatment protocols.

Conclusions

Currently, there are few options available for the management of NASH. Future targeted treatment strategies based on the pathogenic pathways may be needed to develop effective treatment for patients with NASH.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

NAFLD is a general diagnosis that histologically includes both ‘simple’ steatosis and steatohepatitis. The term non-alcoholic fatty liver (NAFL or simple steatosis) and non-alcoholic steatohepatitis (NASH) denotes absence of secondary causes of fatty liver that may have been induced by excessive alcohol use, medications or precipitated by a hereditary disorder, such as Wilson's disease or lipodystrophy. Simple steatosis or NAFL is defined by fatty infiltration without evidence of inflammation, hepatocyte damage or fibrosis.[1-5] NASH is characterised by steatosis as well as presence of inflammation and hepatocellular ballooning or other evidence of hepatocyte injury. The histology seen in NASH is similar to that of alcoholic steatohepatitis and can progress to fibrosis and eventually cirrhosis. Patients with simple steatosis have a much better liver-related prognosis than those with NASH.[1-6]

The prevalence of NAFLD is not well known; however, it is estimated to be between 6.3 and 33% worldwide. In North America, the prevalence of NAFLD is estimated to around 20%. On the other hand, the prevalence of its more progressive subtype or NASH is around 2-3%. These rates are much higher in diabetics or patients undergoing weight reduction surgery.[1-4]

As previously noted, NASH is the only subtype of NAFLD that can potentially progress. Although we will primarily focus on patients with NASH, it is important to note that both NASH and NAFLD can present clinically in a similar fashion. Clinically, NASH is frequently diagnosed incidentally and can be associated with components of metabolic syndrome or associated diseases processes, such as polycystic ovary syndrome and obstructive sleep apnoea. Also, NASH can be seen with other diseases, such as hypopituitarism, hypogonadism and hypothyroidism.[1-7, 60-73] It is important to note that NASH can be seen in patients who are lean and have no identifiable risk factors.[8] In fact, most NASH patients tend to be relatively asymptomatic. Symptoms such as fatigue or mild right upper quadrant pain may be noted, but are not common.[1-5, 7] Patients with NASH may present with liver enzyme values that range from normal to five times the upper limit of normal. The ratio of AST to ALT in advanced NASH is generally, less than 1.[1-5, 7] Other laboratory abnormalities may include elevated gamma-glutamyltransferase (GGT), hyperlipidaemia or hyperglycaemia.[1-5, 7]

A few studies have suggested that patients with NAFLD have increased mortality compared with the general population, with the most common cause of death being cardiovascular disease.[1] Nevertheless, most data suggest that only patients with NASH, especially those with significant fibrosis, are at an increased risk of cirrhosis and hepatocellular carcinoma (HCC).[1-5] There is increasing evidence that fibrosis progression in NASH is seen in those with more severe insulin resistance and type 2 diabetes as well as in those with persistently elevated liver enzymes.[7]

It is becoming increasingly clear that a number of pathways are involved in the pathogenesis of NASH, and its progression to advanced stages of liver disease. These pathways may be diverse in different cohorts of patients with NASH. Understanding of which pathways play a role in the development of NASH will be critical before launching treatment modalities. There are several reviews, including a recent NAFLD guideline that the reader can refer to for obtaining in-depth information about pathogenesis of NAFLD and NASH.[2, 9-11, 69-73] However, we are providing a brief overview of the pathogenesis of NASH in preparation for the discussion of the current therapeutic options for treatment of NASH.

There are several pathways that may lead to the accumulation of hepatic fat. These include increased hepatic lipogenesis, decreased excretion of hepatic lipid stores and/or diminished oxidation of free fatty acids in the liver.[1-5, 7, 8] These processes promote lipid deposition within the hepatocyte, leading to the development of macrovesicular steatosis. This process of hepatic steatosis alone is not enough to cause progressive liver injury. The damage is brought about by subsequent oxidative stresses, which encourage lipid peroxidation in the cell membrane.[1-5, 7, 8] The damage to the hepatocytes activates inflammation and leads to the release of cytokines, which, over time, can lead to fibrosis. Although, oxidative stress may be an important pathway, other processes may serve as additional insult in the pathogenesis of NASH, including adipokines, endoplasmic reticulum stress, pro-inflammatory and pro-apoptotic factors associated with insulin resistance. In fact, several adipokines and cytokines associated with visceral adiposity are thought to play a pro-inflammatory role in the pathogenesis of NASH and its progression to fibrosis.[1-5, 7, 8]

It is important to remember that even though patients may share risk factors for the first insult to the liver, patient cohorts may have distinctly different second or subsequent insults. These different processes lead to a single phenotypic manifestation into a pathological picture of ‘steatohepatitis’. This pathogenesis-based approach to treatment may be the most optimal approach to treat patients with NASH. Nevertheless, in the next few pages, we will describe the results of clinical trials of different regimens that have been used for treatment of NASH.

Methods/Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

To evaluate the specific treatment of NASH, a search of the following databases was conducted: MEDLINE, PubMed and Cochrane Review Database using a combination of keywords, which included non-alcoholic fatty liver disease, non-alcoholic hepatic steatosis, NAFLD, NASH, treatment, therapeutics, vitamin E, orlistat, coffee and bariatric surgery. Approximately 300 articles were identified, but only those that reported original study data results with clear, concise methodology conducted between the years of 2008 and 2013 were included. In addition, we included articles from earlier publication dates, which were considered critical to the summary of treatment of NASH. Finally, we used the AASLD, AGA and ACG NAFLD Guideline and a few recent review articles to identify other relevant articles related to the treatment of NASH. The use of these criteria narrowed our search to 91 relevant articles to be included in our final report. Each article was then abstracted and summaries were integrated throughout this review.

General issues related to treatment of NASH

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

There are four important considerations prior to treating patients with NASH. First, general lifestyle modifications through dietary changes and increased activity may help primarily cardiovascular risk factors that are commonly seen in patients with NASH. Nevertheless, some benefit from the liver standpoint may also be accomplished with adequate weight loss. Second, treatment regimens for liver disease should be focused on those NAFLD patients with histologically proven NASH due to the potentially progressive course of this type of chronic liver disease. Third, treatment regimens must target the pathogenic pathway that is prominent in the specific patient with NASH. Fourth, prior to carrying out a clinical trial for treatment of NASH, it must be clearly stated what the outcomes will be and the importance of each outcome both from efficacy and safety standpoints.

Obviously, the most important clinical outcome for patients with NASH is improving their survival. Given the very slow progressive nature of NASH, only surrogate markers of this important clinical outcome can be used. There has been a great deal of debate and confusion about the validity and appropriateness of different surrogate markers in predicting the long-term survival of patients with NASH. In fact, clinical data and laboratory tests (such as aminotransferases) may have very limited utility in predicting liver-related mortality. These clinical and laboratory tests may have better utility for predicting advanced hepatic fibrosis, but not mortality.[12] Histological stage of hepatic fibrosis may be a better predictor of mortality. In a recent study, after considering clinical and pathological parameters, only histological fibrosis was the best predictor of liver-related mortality.[13] Studies have also shown that liver enzymes, presence of insulin resistance (IR) as well as histological ballooning of hepatocytes are associated with NASH-related fibrosis.[12, 14-16] Grade of hepatic steatosis by radiological modalities or pathology has not been, predictive of this important clinical outcome.[17, 18]

Over the past two decades, a large number of clinical trials have been carried out to treat NASH.[8, 11, 19-37] Except for a few recent studies, most did not follow these basic design requirements for clinical trials of NASH. The results of these studies have been quite disappointing and have not led to a clear recommendation of a single strategy to treat patients with NASH. In the following paragraphs, we will summarise the results of some of these different modalities used for treatment of patients with NASH and NAFLD.

Specific strategies to treat NASH

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

Weight loss and lifestyle modification

Past studies investigating lifestyle modifications (diet, exercise, behaviour modification) found that programmes that lead to a significant weight loss (5–10% of total body weight) improved steatosis.[9-11] Greater weight loss of at least 10% has also been shown to improve inflammation. Recently, Eckard and group recently completed a lifestyle modification study, noting the impact exercise and diet had on histopathological changes. A total of 56 participants, broken into four groups based on different diet components and length of exercise regimens, were included in the study. They found that many of the lifestyle modifications made a significant difference to the histopathological profile further studies with larger group sizes will be needed to determine any difference between the subgroups.[38] However, it is important to note that adherence to lifestyle interventions can be problematic. In several studies, only 15% of patients achieved a weight loss ≥10% and most of them regained their weight, with the best average weight loss among participants being 3–4 kg at 2 and 4 years.[39-42]

On the other hand, studies that investigated exercise only without dietary modification reported that exercise alone reduced hepatic fat, but had variable effect on hepatic inflammation.[9-11, 41-45, 47] However, there are potential barriers to exercise. One study found that, although NASH patients knew that exercise was important, they lacked confidence in the performance of the exercises, citing things such as afraid of falling, which was directly proportional to the degree of difficulty performing the exercise.[46]

In addition, another factor that impairs a patient with NASH in performing exercise is fatigue, one of the most prevalent and pervasive symptoms in people with NASH.[48, 49] A multivariate analysis showed that increased cognitive difficulty, age, fatigue, lower albumin and bilirubin were all independently associated with functional difficulty in patients with NASH. Fatigue has been shown to interfere with daily routines, including work, school, social, household and leisure activities. These potential contributors should be evaluated prior to prescribing an exercise plan because they are likely to influence the exercise prescription and contribute to whether an individual will respond to exercise.[48, 49] With these factors in mind, there are no recommended guidelines for an exercise programme specifically designed for patients with NASH. However, many practitioners follow the American College of Sports Medicine's protocols for setting exercise goals and establishing a starting point.[50]

The second part of ‘lifestyle modification’ is dietary changes. In their recent meta- analysis, Musso and colleagues determined that caloric restriction is the most important goal for patients with NASH to improve hepatic steatosis, but depending on the patient, diets of different composition may bring even greater benefits, i.e. diabetic patients had improved hepatic insulin sensitivity when placed on a low-carbohydrate diet and for those with cholesterol issues, a low-fat diet served them better by improving the LDL-C and HDL-C.[51]

Other investigators determined that avoiding drinks and food high in fructose and trans fats is essential.[51-53] Fructose and trans fats are associated with insulin resistance and the development of hepatic steatosis is thought to occur as a consequence ATP depletion, lipotoxicity and tumour necrosis factor (TNF) expression. Therefore, current recommendations for patients with NASH are to avoid drinks with fructose and foods high in trans fat and seek out foods high in polyunsaturated fats.[53, 54]

Finally, ingestion of coffee may be very beneficial for patients with NASH as well.[55-64] Although some findings of coffee consumption are contradictory, overall, drinking coffee (but not expresso) has been found to have a protective effect in NASH as well as in biopsy-proven NASH through the reduction of hepatic inflammation and fibrosis.[59-61] The exact mechanism of how coffee exerts its anti-inflammatory/fibrotic effect is still under investigation, but investigators now believe another mechanism related to UDP glucuronosyltransferases may also be involved.[56, 63-65]

In summary, the current evidence suggests that significant weight loss and possibly dietary change may positively impact surrogate markers of NASH. Nevertheless, the impact on the most important clinical outcomes is not available. On the other hand, data showing the efficacy of exercise in modifying outcomes of NASH are even less compelling. In 2013, weight loss, dietary changes and exercise should be recommended for all patients with NASH, primarily to modify their cardiovascular risks rather than liver-related risks.

Orlistat for treatment of NASH

Orlistat is a drug that inhibits enteric lipid absorption and has been promoted as a weight-loss aid. Orlistat, in addition to lifestyle modification, was evaluated as a potential therapy for NASH.[19, 20] Although ALT levels were significantly decreased in both groups, the orlistat group showed a larger reduction. There was also a reduction in fatty liver by ultrasound in the orlistat group. However, this finding could not be confirmed by biopsy due to lack of follow-up.[19] In another trial, calorie-restricted patients were asked to take vitamin E and then were randomly assigned to either a placebo group or a group that was administered orlistat. Patients taking orlistat did not benefit from significant weight loss or histological improvement compared with the placebo group. If there was any histological improvement, the improvement was proportional to weight loss and not attributed specifically to orlistat.[20]

Harrison and group conducted a randomised control study to investigate the effects of orlistat.[20] They determined that orlistat was safe and well tolerated; however, the ingestion of orlistat did not add any further cardio-metabolic or histological changes over lifestyle modification alone.[20] Based on these data, the evidence supporting the efficacy of orlistat in patients with NASH is lacking, hence this regimen cannot be highly recommended as a potential therapy for patients with NASH.[19, 20]

Treatment of insulin resistance associated with NASH and liver fibrosis

Metformin

Metformin, a drug well known for its effect on insulin resistance, has also been investigated regarding its use in patients with NASH.[21] Although many of the studies showed an improvement in liver enzymes while taking metformin, not all studies have reported the same results.[21-24] Improvement in histology has also been evaluated with variable results. One small trial, looking at patients with NASH, concluded that the modest decrease in ALT levels and histology probably reflected effects from weight loss in general and not effect of metformin.[21] Another small, open-label trial noted a decrease in ALT and AST; however, this was not sustainable and, after 3 months, the liver enzymes increased. In addition, there was only a minimal improvement in histology.[23] Metformin was also investigated in a trial that placed nondiabetic NASH patients on a diet and exercise programme vs. metformin patients on a diet and exercise programme plus a placebo. The results of this study demonstrated that the metformin had little effect on the liver histology or on aminotransferases.[24] Furthermore, another small randomised clinical trial placed patients on metformin for 6 months and found no improvement in histology.[22] Finally, a recent randomised study of metformin, the TONIC trial, compared metformin with vitamin E and placebo in children with NASH.[18] Again, there was no significant reduction in ALT compared with placebo in the metformin group and, with the exception of hepatocellular ballooning, there was no significant change in histology.[25] Based on these study results and others, the current NAFLD guidelines do not recommend metformin as a treatment for NAFLD.[21-28] Although metformin can be used for diabetic patients with NASH, there is no evidence to support its efficacy solely from the standpoint of NASH.

Thiazolidinediones

The majority of the studies examining thiazolidinediones (TZDs), medications known to enhance insulin sensitivity, which prevents the activation of adiponectin thus impairing adipocyte storage of triglycerides,[65] involve pioglitazone and rosiglitazone.[26-30] Rosiglitazone has been shown to decrease aminotransferases and improve histological inflammation, but not fibrosis.[26, 27] Subsequent studies have confirmed the improvement in the liver enzymes, but did not show histological improvement.[28]

In addition to rosiglitazone, pioglitazone has also been investigated for treatment of NASH.[29-31] A recent randomised clinical trial assessed the efficacy of pioglitazone vs. a placebo in patients with NASH. In this study, patients receiving pioglitazone showed improved histology and fibrosis.[30] On the other hand, the PIVENS trial randomly assigned 247 nondiabetic patients with NASH to one of three groups: pioglitazone, vitamin E or placebo group.[29] Liver biopsy results were assessed after 96 weeks of therapy. Although improvement was noted in both the vitamin E and pioglitazone groups, the rate of improvement in the pioglitazone did not meet the predetermined histological criteria. It is important to note that both Vitamin E and pioglitazone were associated with a decrease in liver enzymes as well as with improvement in steatosis and lobular inflammation. Although histological improvement was noted in the pioglitazone group, the improvement in the vitamin E group was greater, 34% vs. 43%, reaching the primary end point of histological improvement respectively. Nevertheless, neither group showed improvement in hepatic fibrosis.[31] Of note, the patients in the pioglitazone group gained more weight than those taking placebo or vitamin E. A limitation of the PIVENS study may have been related to the use of pioglitazone in nondiabetic NASH patients whose underlying liver disease may not have been primarily related to this pathway. Another limitation of PIVENS was that some of these patients did not have true NASH, therefore underpowering the study. It is possible that the predominant pathogenic pathway for this cohort may have been related to oxidative stress, favouring vitamin E as antioxidant. Although vitamin E can be recommended as a first-line treatment for NASH patients without diabetes, the long-term safety remains an issue (see next section). On the other hand, safety of pioglitazone in nondiabetics with NASH has not been established as TZDs have been associated with weight gain (average is 8.8 lbs), congestive heart failure, bone loss with increased risk of fractures and an increase in bladder cancers. In addition, the durability of response on TZD therapy is questionable, as Lutchman and colleagues noted in their study on the effects of discontinuing pioglitazone in patients with NASH. They noted that, after the discontinuation of TZD, there was an increase in aminotransferases, an increase in HOMA after 1 year and a recurrence of steatohepatitis.[66] These findings have called into question the duration of therapy. Therefore, careful consideration must be given to the risks and benefits for each patient before administering a TZD as a treatment option for diabetic patients with NASH.[67-71]

Antioxidants and cytoprotective agents

Vitamin E

Vitamin E is thought to decrease inflammation by acting as an antioxidant, thus decreasing oxidative cell damage. Although a number of open-label clinical trials have suggested the potential efficacy of vitamin E, the best evidence comes from the PIVENS trial.[25, 32, 74] As noted previously, the PIVENS trial showed a greater histological improvement in inflammation, but not in fibrosis, in nondiabetic patients taking vitamin E compared with those taking placebo and those taking pioglitazone.[31] Although a larger proportion of patients showed histological improvement in the vitamin E group, it is important to note that less than half of all the patients had any improvement.[31] Another smaller randomised trial published a year later, dubbed the TONIC trial, compared vitamin E with metformin in paediatric patients with biopsy-proven NASH.[25] The primary outcome was reduction in alanine aminotransferase (ALT), the secondary outcome was improvement in histology and resolution of NASH. Compared with placebo, neither intervention demonstrated significant, sustained reductions in ALT levels.[25] Of note, initially, there was a greater reduction in ALT levels in those children taking Vitamin E; however, the findings were not sustained over time. Interestingly, in the children taking vitamin E, there was a significant improvement noted in hepatocellular ballooning, NAFLD activity score and resolution of NASH in patients with borderline NASH. It is important to mention that there has been some concern with the long-term use of Vitamin E. In fact, a meta-analysis has reported an increase in all-cause mortality in patients using vitamin E for cardiovascular conditions.[32] The recent NAFLD guideline recommends Vitamin E as a first-line treatment for nondiabetic patients with only biopsy-proven NASH. On the other hand, Vitamin E is not recommended for NASH patients with diabetes due to lack of data on long-term safety and efficacy.[69-71]

Ursodeoxycholic acid (UDCA)

Ursodeoxycholic acid therapy decreases the cholesterol secretion into bile, as indicated by a decline in the cholesterol fraction of biliary lipids. UDCA exerts its action(s) in liver through multiple possibly interrelated pathways, including alterations of bile acid pool, choleresis, immune modulation effects and cytoprotection mechanism.[68-70] Although UDCA was initially suggested as a promising drug for the treatment of NASH, literature does not support its use.[33, 68] In fact, in a randomised controlled trial, 166 NASH patients were randomised to UDCA vs. placebo for 2 years. Of 166 patients enrolled, 126 patients completed the study; however, only 107 patients had pre- and post-treatment liver biopsies available. The biopsies available showed no significant difference in histology between the two groups.[33] Only the study by Dufour et al. observed a significant improvement of NASH with the combination of UDCA and Vitamin E when compared with a placebo therapy.[35] The administration of only UDCA was not as effective in the treatment of NASH, although there was much heterogeneity among the three other studies. Therefore, at the current time, evidence to support the use of UDCA is lacking, and its use cannot be recommended.

Statins

Although there are number of open-label trials suggesting improvement in liver enzymes, no convincing histological data are available. Therefore, statins are not currently recommended to treat patients with NASH for their liver disease.[71-73] On the other hand, statins are safe to use for the purpose of treating hyperlipidaemia in these individuals who also have cardiovascular disease, and the primary indication for use of statins is as an anti-cholesterol agent.[71-73] Therefore, clinicians treating hyperlipidaemia in NASH patients should not rule out the use of statins in treating hyperlipidaemia and should be considered as part of their therapeutic armamentarium.

Other treatment regimens

Other regimens such as omega-3 fatty acids, pentoxifylline, probiotics and traditional Chinese medicine such as Hawthorn fruit have been studied for treatment of NASH.[72-74] Parker and colleagues conducted a meta-analysis on the use of omega 3 polyunsaturated fatty acid (PUFA) on NASH.[75] The primary outcome measures of interest were liver fat and liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase (AST). There were nine eligible studies involving 355 individuals in the meta- analysis. There were beneficial changes in liver fat for those receiving PUFA treatment as well as an observed reduction in AST and a trend towards favouring PUFA treatment on ALT. Despite the heterogeneity of the studies, the pooled data suggested that omega-3 PUFA supplementation may decrease liver fat; however, the optimal dose is not currently known.[75]

Pentoxifylline is considered as anti-TNF compound. It decreases the inflammation associated with NASH. Although one study suggested improvement in steatosis, improvement in other important laboratory and histological outcomes was lacking.[76]

Probiotics, in theory, offer an interesting approach to NASH.[32] Gut flora is hypothesised to play a role in energy regulation and therefore adiposity. Also, endotoxins from the gut flora can get to the liver through portal blood system and could represent a second hit. In fact, probiotics have been suggested to be beneficial in NASH by augmenting the microbial environment in the intestine. In addition, they may provide anti-inflammatory protection. Despite early studies, no well-designed clinical trial data are available to provide evidence to support the use of any of these regimens for patients with NASH.[77]

Shi and colleagues conducted a meta-analysis on the use of traditional Chinese herbal medicines (TCM's) compared with the western medications, including placebo, ursodeoxycholic acid, insulin sensitisers, lipid-lowering drugs or antioxidants. Five thousand nine hundred and four patients from 62 RCTs were included for the meta-analysis and 25 661 patients from 419 clinical studies were included for TCM formulation analysis.[74] These investigators found that, when compared with western medicines, TCMs had a better effect on the normalisation of alanine aminotransferase and the disappearance of radiological steatosis in the treatment of NAFLD. There were 246 kinds of Chinese herbs that were included in the study, with an average of 10 herbs (range 1–31) in each formulation. Hawthorn Fruit (321 times in 17 670 patients) was the most often used herb in the treatment of NAFLD. They concluded that TCM is of modest benefit in the treatment of NAFLD.[74]

Although there are some promising results with these therapeutic medications, without further well-controlled randomised studies, omega-3 fatty acids, pentoxifylline, probiotics and traditional Chinese medicine such as Hawthorn fruit cannot be recommended as first-line therapeutic agents to treat NASH. It is also important to emphasize that consideration of safety of herbal supplements is critical and must be carefully assessed.

Bariatric surgery

The impact that bariatric surgery has on NAFLD has been assessed with liver enzymes and histology. In a number of studies, aminotransferases and GGT levels, as surrogate markers of liver histology, have shown some improvement.[78-88] One study found improvement in histology and fibrosis score 1 year post-operatively,[79] whereas others have shown improvement in histology, but not necessarily in fibrosis.[34, 76] A meta-analysis reviewed 15 studies and compiled results for improvement in steatosis, steatohepatitis and fibrosis as well as a mean reduction in body mass index.[80] The study concluded that steatosis, steatohepatitis and fibrosis all improved and, in some cases, resolved after weight loss associated with bariatric surgery.[80] A prospective trial performed in 2009 followed severely obese patients for 5 years post-bariatric surgery.[84] The overall percentage of biopsies of patients with steatosis was lower at 5 years. Conversely, 5 years after surgery, the level of fibrosis increased significantly. Levels of insulin resistance were independently predictive of steatosis and ballooning at the 5-year mark.[81] A randomised, nonblinded clinical trial was published in 2012 comparing bariatric surgery with intensive medical therapy in obese patients with diabetes.[82] Although the study did not include liver histology as primary or secondary end point, bariatric surgery was more effective at controlling glucose levels than medical therapy alone in these patients.[82]

As diabetes and obesity are strong risk factors for the development of NASH,[1-8] one can assume that better regimen for sustained weight loss and glycaemic control could potentially improve NASH outcomes. In fact, recent studies investigating the surgical management of patients with morbid obesity and NASH found that weight loss following conventional nonmalabsorptive bariatric-metabolic procedures reduces steatosis and lobular inflammation, but may not have a consistent effect on liver fibrosis. However, rapid weight loss, especially with malabsorptive procedures, may actually produce a transient or prolonged increase in liver disease, and therefore; patients need careful monitoring to make sure their weight loss occurs over time. It can be concluded that bariatric-metabolic surgery in patients with compensated cirrhosis is not established, but is definitely contraindicated in decompensated cirrhosis.

Given the lack of strong published evidence, the NAFLD guideline does not formally recommend bariatric surgery for treatment of NASH.[69, 72, 73] On the other hand, it is important to note that bariatric surgery is not contraindicated in NASH patients without cirrhosis. Additional well-designed studies are needed to assess the efficacy of this important treatment modality for obese-diabetic patients with NASH.

Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

As summarised, it has been over three decades since the original description of NASH by Ludwig et al.[90] Despite dozens of clinical trials of different agents, investigators have failed to identify effective treatment for patients with NASH. In reviewing the literature, there are two important considerations:

First, the designs of clinical trials of different regimens for treating NASH have been suboptimal. Until recently, there were no clear inclusion histological criteria for the clinical trials. In fact, studies have enrolled patients with NASH while also enrolling patients with simple steatosis. Second, the outcomes used to follow these patients were not very robust. Patients were followed with liver enzymes or fatty liver by ultrasound. Third, the studies were designed as open-label without the rigour of randomised clinical trials. Fourth, the duration of treatment was relatively short, lasting from 6 to 12 months. As NASH is the hepatic manifestation of metabolic syndrome, it should be treated like other complications of metabolic syndrome such as hypertension and hyperlipidaemia, i.e. long-term treatment. Finally, investigators paid little attention to the pathogenic pathway that may be the underlying cause for the specific cohort of NASH patients being considered for treatment. In fact, NASH patients enrolled in trials of insulin sensitiser may or may not have had insulin resistance or diabetes mellitus.

Due to the flaws of the study design, one can argue that ‘the classic’ clinical trials of NASH may not be appropriate to determine the right therapeutic option for an individual patient. Different pathogenic pathways may be involved in the development of NASH; many patients presenting with the NASH phenotype will be dissimilar in regard to their underlying pathogenic pathway leading to the development of NASH. Therefore, using a single treatment to treat all these NASH phenotypes will probably fail. In this context, it may be important to consider the development of a targeted treatment using a personalised medicine approach. Using this approach, patients with NASH can be categorised for treatment based on their pathogenic pathways, clinical markers, prognostic biomarkers and/or genomics biomarkers to clarify their pathogenic pathway. Some of the preliminary genomic tests that may be useful specific targets are listed in Table 1.[91] After identifying the specific pathway responsible for NASH, one can recommend a targeted treatment. Nevertheless, validated tests such as CK-18 and others may provide a simple initial step to classify these patients. Although quite exciting, further work in this area is needed to provide diagnostic, prognostic biomarkers and therapeutic targets for the treatment of NASH based on their pathogenic and clinical characteristics.

Table 1. Pathogenic pathways
GeneReference SNP IdNucleotide change (G = Guanine, A = Adenine, C = Cytosine, T = Thymine)Amino acidFunctional changePhenotypic association
HFE rs1800562G > ACysteine-to-tyrosine substitution at the amino acid 282Impairs association with β2-microglobulin and thus cell surface expression, resulting in increased iron absorption[1]Conflicting. Association with steatosis and inflammation
 rs1799945C > GHistidine-to-aspartate change at the amino acid 63Prevents association with transferrin receptor allowing the transferrin receptor to interact with transferrin and store iron[2] 
 rs1800730T > ASerine-to-cysteine change at amino acid 65Prevents association with transferrin receptor[3] 
ADIPOQ rs2241766T > GGlycine-to-Glycine change at amino acid 15NASeverity of hepatic fibrosis (but not steatohepatitis)
 rs1501299G > TIntron regionNA[4]
 rs266729C > GPromoter regionNo effect on promoter activity[4, 5] 
 rs17300539G > APromoter regionImpedes the DNA/adipocyte nuclear protein interaction and has increased transcription[4] 
LEPR rs1137100A > GLysine-to-arginine change at amino acid 109NASeverity of hepatic steatosis and insulin resistance
 rs1137101A > GGlutamine-to-arginine change at amino acid 223Impaired leptin-binding activity based on soluble leptin receptor levels 
MTP rs1800804T > CPromoter regionBasal transcription reduced[9]Conflicting. Association with histological steatosis and steatohepatitis
 rs1800591T > GPromoter regionBasal transcription reduced[10, 11] 
PNPLA3 rs738409G > CIsoleucine-to-methionine change at amino acid 148MNonfunctional protein affecting triglyceride hydrolysis[13]Severity of histological steatohepatitis and fibrosis
APOC3 rs2854116G > TPromoter regionLoss of insulin regulation[14]Association with steatosis
 rs2854117A > GPromoter regionLoss of insulin regulation[14] 
PPARGC1A rs1800206C > GLeucine-to-Valine change at amino acid 162Loss of function[15]Conflicting. Association with severity of steatosis
 rs2290602T > GIntron regionNA 
PPARg rs1801282C > GProline-to-alanine change at amino acid 12Loss of function[16]Associated with lipid-induced insulin resistance and steatosis.
ADRB2 rs1042714C > GGlutamine-to-glutamate change at amino acid 27Resistant to downregulation by agonist probably due to altered degradation of receptor protein[17]Associated with steatosis and hypertriglyceridaemia
MTHFR rs1042713G > AArginine-to-glycine change to amino acid 16Reduced downregulation by agonist probably due to altered degradation of receptor protein[17]Associated with steatosis and NASH
 rs1801133C > TAlanine-to-valine change at amino acid 222Thermolabile enzyme with reduced activity[18] 
 rs1801131A > CGlutamate-to-alanine change at amino acid 429Reduced activity[19] 

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

NAFLD is an umbrella term that encompasses the spectrum of liver disease from NAFL to NASH. NASH is associated with inflammation, ballooning of hepatocytes and thus a worse prognosis, given the faster progression to fibrosis and cirrhosis. The pathogenesis is thought be related to fatty accumulation within hepatocytes as the first hit with a number of different pathways leading to second or third hit, all manifesting as histological steatohepatitis and fibrosis. Currently, there are very few options available for treatment of patients with NASH (weight loss, exercise and, possibly, Vitamin E for nondiabetics with NASH). Given the pathogenic heterogeneity of patients presenting with NASH phenotype, future targeted treatment strategy may provide better options for patients with NASH.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References

Guarantor of the article: Z. M. Younossi.

Author contributions: Zobair Younossi, MD, guarantees that all authors participated in the creation of this manuscript and have read a final version of the manuscript before submission. Zobair Younossi developed, wrote and revised the manuscript. MJ Reyes was an active writer of the beginning manuscript. A Mishra helped to develop the manuscript. L Henry helped to write and revise the manuscript. All authors approved the final version of the manuscript.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods/Results
  5. General issues related to treatment of NASH
  6. Specific strategies to treat NASH
  7. Failure of clinical trials to provide treatment for patients with NASH: a case for personalised medicine
  8. Summary
  9. Authorship
  10. Acknowledgements
  11. References
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