Review of current and potential future pharmacological treatments in nonalcoholic steatohepatitis

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

Adipo‐IR

adipose tissue insulin resistance

NAFLD

nonalcoholic fatty liver disease

NAS

NAFLD activity score

NASH

nonalcoholic steatohepatitis

RCT

randomized controlled trial

TZD

thiazolidinedione

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of histopathological findings in the liver, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. In NASH, along with hepatic steatosis, liver injury takes the form of lobular inflammation and hepatocyte ballooning.1, 2 NAFLD has a reported prevalence rate in the general population of approximately 10% to 30% and increases to 57.5% to 74% in obese populations, whereas NASH is estimated to occur in 3% of the general population and up to 37% of morbidly obese persons.3, 4, 5, 6, 7 NASH is estimated to progress to cirrhosis in up to 20% of patients.8

NAFLD most commonly arises in the setting of metabolic syndrome.1 The pathogenesis of NASH is thought to be multifactorial, with insulin resistance and oxidative stress contributing to hepatic injury. Given the close association of NAFLD with obesity and metabolic syndrome, lifestyle modifications and weight loss achieved through diet and exercise regimens are the starting point of all therapy for patients with NAFLD or NASH.

Even in the absence of overt diabetes, many patients with NAFLD will have insulin resistance. Agents that improve insulin resistance such as metformin, thiazolidinendiones (TZDs) such as rosiglitazone and pioglitazone, and antioxidants such as vitamin E have been studied in trials to determine their efficacy in improving anthropometric measures and liver histology in individuals with NASH. Current pharmacological interventions for NASH have demonstrated conflicting evidence of efficacy. This article offers a brief review of current pharmacotherapy for patients with NASH, as well as potential future treatments.

Metformin

Pilot studies of metformin in NAFLD have demonstrated improvement in liver enzymes and histology.4, 9 An open‐label study conducted by Bugianesi et al.10 showed that nondiabetic subjects with NAFLD who received metformin for 12 months had significant improvement in both aminotransferase levels and hepatic steatosis compared with diet alone. Garinis et al.9 and Idilman et al.4 demonstrated that metformin therapy in nondiabetic subjects was associated with improvement or resolution of hepatic steatosis and aminotransferase levels compared with baseline. However, Idilman et al.4 showed histological improvement when compared with baseline did not reach statistical significance. Metformin significantly improved metabolic parameters including insulin resistance, whereas diet alone did not.9

However, a randomized, double‐blind, placebo‐controlled trial with metformin treatment for 6 months in diabetic patients with NAFLD showed no significant difference between groups in liver aminotransferases, hepatic steatosis, or insulin resistance.3 Similarly, other randomized controlled trials (RCTs), including some in pediatric and adolescent subjects, have failed to show a benefit of metformin in treatment of NAFLD.11 Furthermore, a systematic review of 6 to 12 months of therapy using metformin did not demonstrate a significant improvement in aminotransferases or histology when compared with lifestyle intervention alone.12 Because of conflicting results, especially of larger studies, along with uncertain long‐term efficacy, metformin cannot be recommended as a specific agent for treating NAFLD at this time.

Thiazolidinediones

A pilot study of nondiabetic NASH patients treated with pioglitazone showed a significant improvement in liver aminotransferases and the histological NAFLD activity score (NAS)13 (Table 1). A randomized, placebo‐controlled trial demonstrated nondiabetic patients with NASH treated with pioglitazone had significant improvement in alanine aminotransferase along with hepatocyte injury and fibrosis when compared with placebo.14 However, there was no statistical difference between the two groups with analysis of the homeostasis model assessment‐insulin resistance (HOMA‐IR) score or regarding histological evaluation of lobular inflammation and steatosis.14 Perhaps the most famous RCT, known as the PIVENS study, randomized 247 nondiabetic patients with NASH to one of three groups: pioglitazone, vitamin E, or placebo.2 Pioglitazone demonstrated a statistically significant improvement in the NAS score after 96 weeks of therapy when compared with placebo; however, there was no significant improvement in fibrosis.2 In addition, subjects who received pioglitazone gained more weight than those who received vitamin E or placebo.2

Table 1.

Histological NAFLD Activity Score

Pathology	Gradea
Steatosis	<5% (0)	5%‐33% (1)	>33%‐66% (2)	>66% (3)
Lobular inflammation	No foci (0)	<2 foci/200× (1)	2–4 foci/200× (2)	>4 foci/200× (3)
Hepatocyte ballooning	None (0)	Rare or few (1)	Many (2)

^aTotal NAS score (0–8) represents the sum of steatosis, lobular inflammation, and hepatocyte ballooning. The score for each grade is indicated by the number within the parentheses.

In a trial of diabetic NASH patients treated with pioglitazone for 6 months, the relationship between adipose tissue insulin resistance (Adipo‐IR) and liver histology was investigated.15 When compared with placebo, pioglitazone‐treated NASH patients demonstrated significant reduction in Adipo‐IR levels, which strongly correlated to improved liver histology, specifically necroinflammation and steatosis score, but no effect on fibrosis was observed.15

In summary, in larger RCTs, TZDs have been consistently associated with improvements in necroinflammatory scores (ballooning, steatosis, and lobular inflammation) compared with placebo, whereas fibrosis has not improved.2, 15 In the only head‐to‐head trial, pioglitazone was not superior to vitamin E in alleviating fibrosis or hepatocyte ballooning and only marginally superior in improving steatosis and lobular inflammation.2

The most common adverse effects of pioglitazone therapy are edema and weight gain. In a meta‐analysis of patients with type 2 diabetes, pioglitazone therapy has been associated with increased incidence of congestive heart failure compared with control subjects.16 In addition, bone loss and bladder cancer have been associated with long‐term use.17 Another TZD, rosiglitazone, which has demonstrated similar efficacy to pioglitazone,18 has been restricted in its use because of concerns related to increased acute coronary events.1, 19

In recognition of this contradictory evidence of efficacy and safety, pioglitazone received the following recommendation in the 2012 guideline of the American Association for the Study of Liver Diseases (AASLD):

• Pioglitazone can be used to treat steatohepatitis in patients with biopsy‐proven NASH. However, it should be noted that majority of the patients who participated in clinical trials that investigated pioglitazone for NASH were non‐diabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established. (Strength – 1, Evidence – B)1

Vitamin E

In addition to insulin resistance, oxidative stress can potentially catalyze the progression of fatty liver disease to NASH.20 Along with the insulin‐sensitizing agents previously mentioned, vitamin E has also been proposed as a potential agent for patients with NASH given its antioxidant properties. Studies using vitamin E in patients with NASH have typically shown a decrease in aminotransferases and improvement in liver histology other than fibrosis. In the pivotal PIVENS RCT mentioned previously, nondiabetic NASH patients who were treated with 800 IU/day vitamin E for 96 weeks showed statistically significant improvement in steatosis, hepatocellular ballooning, and lobular inflammation without improvement in fibrosis.2 In addition, the total NAS decreased significantly when compared with placebo. Along with improvement in histology, vitamin E therapy also showed significant improvement in aminotransferases when compared with placebo.

Current studies with vitamin E therapy have primarily focused on treatment of nondiabetic patients with NASH, and further data involving diabetic NASH patients are necessary to determine its overall efficacy. Similar to other agents, long‐term safety and efficacy in NASH have not been reported. Enthusiasm for the use of vitamin E in NAFLD has waned, particularly with recent data showing increased risk for prostate cancer with long‐term vitamin E supplementation21 and cardiovascular safety of vitamin E still in question.22 Nevertheless, in 2012, the AASLD guidelines regarding vitamin E were as follows:

• Vitamin E (α‐tocopherol) administered at daily dose of 800 IU/day improves liver histology in non‐diabetic adults with biopsy‐proven NASH and therefore it should be considered as a first‐line pharmacotherapy for this patient population. (Strength – 1, Quality – B)1

• Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. (Strength – 1, Quality – C)1

Obeticholic Acid

Obeticholic acid is a semisynthetic bile acid analogue that is a potent farnesoid X receptor agonist. It has been shown to increase insulin sensitivity and exert anti‐inflammatory and antifibrotic effects in the liver.23 A recent phase 2 placebo‐controlled trial assessed the treatment for 72 weeks of low‐dose obeticholic acid in both nondiabetic and diabetic patients with NASH.24 When compared with placebo, 45% of obeticholic‐treated patients displayed improved liver histology characterized by statistically significant improvement in steatosis, hepatocellular ballooning, inflammation, fibrosis, and NAS.24 Secondary outcomes demonstrated significant reductions in aminotransferases over the first 36 weeks of treatment with obeticholic acid, which reverted to an indistinguishable difference compared with placebo 24 weeks after discontinuation.24 The main adverse effects of obeticholic acid observed in this study were pruritus and changes in serum cholesterol. Phase 3 trials are now under way to investigate the efficacy and safety of this agent for NASH.

Other Agents

Probiotics have also been recently studied as an intervention for NASH, although limited by the absence of RCTs. A Cochrane review of two pilot studies demonstrated probiotics may have a role in improving liver chemistries and decrease markers of lipid peroxidation.25

The recent AASLD guidelines advise against using ursodeoxycholic acid or omega‐3 fatty acids for the specific treatment of NAFLD or NASH.1 Although there is insufficient evidence to advise the use of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase inhibitors (“statins”) for treatment of NAFLD, they should not be withheld from hypercholesterolemic patients on the grounds of concurrent NAFLD.1