REVIEW URRENT C OPINION
State of the art: treatment of nonalcoholic steatohepatitis Michelle Pearlman a and Rohit Loomba a,b
Purpose of review Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in Western countries, and consists of a spectrum of histopathological changes that range in severity from simple steatosis to steatohepatitis to cirrhosis. The use of pharmacological agents as adjunctive therapy to lifestyle modification is crucial, because weight loss is often difficult to achieve and maintain. The purpose of this review is to analyze the most recent literature pertaining to current therapies for nonalcoholic steatohepatitis (NASH), as there are currently no Food and Drug Administration-approved medications. Recent findings Recent studies suggest that vitamin E may improve liver histology in NASH without affecting insulin resistance; however, long-term risks remain to be studied. Pioglitazone is beneficial in improving liver histology and insulin resistance, but is associated with weight gain. Emerging data suggest that pentoxifylline may also be beneficial in improving serum aminotransferase and liver histology in patients with biopsy-proven NASH. Summary Ongoing research evaluating potential pharmacological agents for NASH is critical, because these patients are at an increased risk for cirrhosis and hepatocellular carcinoma. The current therapies being used for the treatment of NASH include the use of vitamin E and pioglitazone, in addition to dietary counseling and regular exercise. Keywords nonalcoholic fatty liver disease, pentoxifylline, pioglitazone, vitamin E
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of disease states including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD varies dramatically depending on the study population and the mode of diagnosis [1 ]. NAFL is nonprogressive whereas NASH can advance to cirrhosis and hepatocellular carcinoma [2,3]. NASH-induced cirrhosis is the third leading cause of liver transplantation in the United States [4] and is associated with high liver-related morbidity and mortality [3]. Furthermore, patients with NASH have an increased risk of developing fibrosis if they gain more than 5 kg, have significant insulin resistance, or exhibit profound hepatic fatty infiltration [5]. With the continued rise in obesity in the United States, the prevalence of NAFLD has followed a &&
similar trend. NAFLD is associated with central obesity, dyslipidemia, hypertension, and insulin resistance; a constellation of diseases that comprise metabolic syndrome [6,7 ]. It is imperative to manage these comorbidities, as the most common cause of death in this patient population is cardiovascular disease [5]. Additionally, elderly patients with NAFLD are more likely to develop NASH and advanced &
a Division of Gastroenterology, Department of Medicine and bDivision of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
Correspondence to Rohit Loomba, MD, MHSc, Division of Gastroenterology, Department of Medicine; Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, UC 303 (MC 0063), La Jolla, CA 92093-0063, USA. Tel: +1 858 534 2624; fax: +1 858 534 3338; e-mail: roloomba @ucsd.edu; http://fattyliver.ucsd.edu/ Curr Opin Gastroenterol 2014, 30:223–237 DOI:10.1097/MOG.0000000000000060
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Liver
KEY POINTS Lifestyle modification to induce weight loss with regular aerobic exercise and/or resistance training is required and caloric restriction is essential in halting the progression of NASH, and thereby to increase the likelihood of reversal of NASH. It is important to manage cardiovascular risk factors in patients with NAFLD including low-density lipoprotein, BMI, triglycerides, and diabetes mellitus 2 because cardiovascular disease is the most common cause of mortality in this patient population. Pioglitazone 30 mg/day may be considered in patients with biopsy-proven NASH with type 2 diabetes, who do not have congestive heart failure, or increased risk of fracture, although long-term effects have not yet been established. Vitamin E 800 IU/day may be considered as the firstline treatment for biopsy-proven NASH in nondiabetic patients without evidence of cirrhosis, although optimal duration of treatment and specific formulation remain to be studied. Both vitamin E and pioglitazone can reverse NASH.
treatment options are of particular importance in this patient population. The diagnosis of NAFLD is made in a patient without a history of significant alcohol use, after other causes of liver disease or hepatic steatosis have been excluded [9]. The definitive diagnosis for NAFLD is by liver biopsy, with histopathology exhibiting macrovesicular hepatic steatosis predominantly in zone 3 with varying degrees of lobular inflammation, and balloon degeneration, with or without perisinusoidal fibrosis [10]. Some of these histopathological changes including steatosis (grade 0–3), lobular inflammation (grade 0–3), and ballooning (grade 0–2) are used to calculate the NAFLD activity score (NAS with a total summary score of 8), which is used for research purposes to determine the response to therapy in a more objective manner [1 ]. The treatment approach for NAFLD and NASH begins with an exercise program and a calorie restricted diet to achieve a normal weight in a gradual manner. We usually recommend a goal of 1–2 lb weight/week to have a gradual weight reduction. The use of pharmacological agents as adjunctive therapy is often necessary, however, as lifestyle modification and weight loss are difficult to maintain ([11 ], Table 1). This review article will examine the most current literature (Table 2) [12 –14 ,15, 16 ,17,18 ,19,20 ,21] regarding the treatment of NASH and is based on both the current American &&
&
fibrosis compared with nonelderly patients with NAFLD [5,8 ]. Given the growing elderly population, knowledge of the natural history and available &
&
&
&
&
&
Table 1. Management of nonalcoholic fatty liver disease: The University of California San Diego Approach (1) Patients with NAFLD and no evidence of NASH or fibrosis on liver biopsy (a) Recommend lifestyle modification (i) Discuss importance of limiting fat and simple carbohydrate intake and consider referral to nutritionist (ii) Weight assessment: If BMI is either overweight or obese then patient is counseled on initiating a weight loss diet (see i) and starting a regular exercise program if they are otherwise fit to do so. Regimen includes aerobic (and/or resistance) exercise 3–5 days/week for 20–30 min/session to aid in weight reduction (b) Assess cardiovascular risk factors (i) Obtain LDL, HDL, and TG and treat based on Adult Treatment Panel III of the National Cholesterol Education Program guidelines (ii) Screen for diabetes, and prediabetes and treatment based on American Diabetes Association guidelines (c) Perform detail medicine reconciliation and try to eliminate medications that have the potential to worsen hepatic steatosis: medications include amiodarone, MTX, systemic steroids, tetracyclines, tamoxifen, estrogens, and valproic acid (2) Patients with NASH based on liver biopsy with or without fibrosis (a) Lifestyle modification, assess cardiovascular risk factors, medication reconciliation all mentioned above (b) Initiate medical therapy if no absolute contraindications (i) Vitamin E 800 IU/day for nondiabetic patients (ii) Pioglitazone with or without metformin in diabetic patients (3) Patients with NASH cirrhosis (a) Lifestyle modification, assess cardiovascular risk factors, medication reconciliation all mentioned above (b) Screen for esophageal varices (c) Screen for hepatocellular carcinoma (d) Referral to transplant center for evaluation when deemed appropriate &
Reproduced from [11 ]. HDL, high-density lipoprotein; IU, international unit; LDL, low-density lipoprotein; MTX, methotrexate; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglycerides.
224
www.co-gastroenterology.com
Volume 30 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
RCT
RCT
Sanyal et al. [15]
Sanyal et al. [15]
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
RCT
RCT
RCT
RCT
Bell et al. [14 ]
Pietu et al. [18 ]
Zein et al. [19]
Zein et al. [20 ]
Van Wagner et al. [21]
www.co-gastroenterology.com Pentoxifylline 1200 mg/day
Pentoxifylline 1200 mg/day
Pentoxifylline 1200 mg/day
Vitamin E 500 IU/day with UDCA
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Pioglitazone 30 mg/day
30
47
55
101
246
173
247
247
247
246
66
334
No. of patients
Placebo
Placebo
Placebo
Placebo
Pioglitazone 30 mg/day
Metformin 1000 mg/day and placebo
Placebo
Pioglitazone and placebo
Vitamin E and placebo
Vitamin E 800 IU/day
Silymarin and metformin
Placebo
Compared with
1 year
1 year
1 year
4 years
96 weeks
96 weeks
96 weeks
96 weeks
96 weeks
96 weeks
8 weeks
6 months
Treatment duration
Improvement in hepatocellular ballooning and steatosis when compared to baseline but no significant different between treatment group and placebo
Improvement in lobular inflammation and fibrosis based on reduction in plasma levels of certain oxidation products that have a strong correlation with liver histology
Significant reduction in steatosis, lobular inflammation, fibrosis score and resolution of NASH. No change in hepatocellular ballooning or fibrosis
Yes, improvement in NAS
No reduction in Adipo-IR score at 16 or 96 weeks but did show improvement in hepatocellular ballooning, fibrosis and NAS
Yes, improvement in hepatocellular ballooning and NAS
N/A
Yes, reduction in hepatic steatosis and lobular inflammation, no change in fibrosis score
Yes, reduction in hepatic steatosis and lobular inflammation, no change in fibrosis score
Yes at 16 weeks, not persistent at 96 weeks based on Adipo-IR score
N/A
Improvement in hepatocellular ballooning, lobular inflammation and steatosis, analysis of pioglitazone alone showed improvement in fibrosis
Histology improvement
Yes when compared to baseline but no significant difference compared to placebo
N/A
N/A
Yes
Yes
No
Yes
N/A
N/A
Yes
Yes
Yes
ALT improvement
Adipo-IR, adipose tissue insulin resistance; IU, international unit; N/A, not applicable; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; RCT, randomized control trial; UDCA, ursodeoxycholic acid.
&
&
RCT
Lavine et al. [17]
&
RCT
RCT
Hoofnagle et al. [16 ]
&
RCT
Bell et al. [14 ]
Pioglitazone 30 mg/day
Pioglitazone 15 mg/day
RCT
Hajiaghamohammadi & et al. [13 ]
&
Pioglitazone, varying doses
Meta-analysis using four RCTs
&
Boettcher et al. [12 ]
Drug/dose
Type of study
References
Table 2. Most recent studies of vitamin E, pioglitazone, and pentoxifylline in adult patients with nonalcoholic fatty liver or nonalcoholic steatohepatitis
Treatment of nonalcoholic steatohepatitis Pearlman and Loomba
225
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Liver
Association for the Study of Liver Disease (AASLD) practice guidelines published in 2012 and the practical approaches utilized at UCSD NAFLD clinic [1 ]. The studies chosen for this review were found on PubMed using search terms NASH, pioglitazone, pentoxifylline, vitamin E, and only include human participants with NAFL or NASH. The effects of surgical weight loss therapies have been discussed elsewhere and are beyond the scope of this review [1 ,22]. All studies used a P 0.05 to denote statistical significance. &&
&&
We generally emphasize that total caloric intake should be closely scrutinized by the patients. Patients should avoid large meals and dietary plans should be tailored based on whether they are normoglycemic, prediabetic, or diabetic with NAFLD.
LIFESTYLE MODIFICATION: THE ROLE OF WEIGHT LOSS &
Weight loss through calorie restriction [25 ], and/or regular exercise [23 ,24 ], has been shown to alter the progression of fatty liver disease. The AASLD guidelines [1 ] recommend a 3–5% reduction in body weight; however, other studies suggest >7% reduction is associated with improvement in hepatic steatosis and liver histology [28–30]. &
&
&&
LIFESTYLE MODIFICATION: THE ROLE OF EXERCISE There is no consensus regarding the intensity, duration, and types of exercise that are optimal for patients with NAFLD. Sullivan et al. [23 ] analyzed the effect on magnetic resonance spectroscopy intrahepatic triglyceride content (IHTG) in 18 obese participants with NAFLD. After 16 weeks of 150–300 min of moderate-intensity endurance exercise each week, there was a mild, although significant, reduction in IHTG content independent of weight loss (P < 0.05). Most recently, Bacchi et al. [24 ] compared the effects of aerobic exercise versus anaerobic resistance training on hepatic fat content after 4 months. On the basis of the magnetic resonance spectroscopy, there was a significant reduction in hepatic fat content in both the groups (P < 0.001), as well as an improvement in insulin sensitivity, BMI, and adipose tissue. We generally recommend that patients initiate an exercise program that is based on their current activity level. Most patients are able to initiate a moderate-intensity exercise program, initially aerobic for at least 30 min for 3 to 5 times a week. We emphasize that sustained activity and having a consistent weekly exercise regimen program is beneficial. However, the differential effect between the types of exercises in improving liver histology is currently not known. &
&
ROLE OF PIOGLITAZONE Thiazolidinediones (TZDs) have been studied as treatment options for NASH. Pioglitazone is a TZD, which improves insulin sensitivity by activating nuclear peroxisome proliferator activated-receptor-gamma, thereby upregulating gene transcription for several proteins involved in glucose and lipid metabolism [31]. Rosiglitazone, a different TZD, is not widely studied because of its association with ischemic stroke and heart failure [32 ]. Promrat et al. [33] conducted a pilot study in 18 nondiabetic, biopsy-proven NASH patients. This study showed that 30 mg/day of pioglitazone for 48 weeks led to a significant reduction in transaminases, as well as a significant improvement in histological parameters, including steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis (P < 0.05). A recent meta-analysis including four randomized controlled trials (RCTs) published between 2006 and 2010 suggested patients treated with either pioglitazone or rosiglitazone (n ¼ 169) had significant reductions in ballooning degeneration, lobular inflammation, and steatosis, whereas only pioglitazone led to improvement in fibrosis (n ¼ 137) [12 ,15,34–36]. In particular, the pioglitazone versus vitamin E versus placebo in nonalcoholic steatohepatitis (PIVENS) trial showed a significant improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST) (P < 0.001), hepatic steatosis (P < 0.001), and lobular inflammation (P ¼ 0.004) after treatment with pioglitazone 30 mg/day (n ¼ 80) for 96 weeks. However, no significant change in fibrosis was observed (P ¼ 0.12) [15]. Hajiaghamohammadi et al. [13 ] compared the effects of metformin 500 mg/day (n ¼ 22), pioglitazone 15 mg/day (n ¼ 22), and silymarin 140 mg/day (n ¼ 22). After 8 weeks, pioglitazone led to a significant improvement in AST and ALT and, out of the three therapies, was associated with the most &
&
LIFESTYLE MODIFICATION: THE ROLE OF NUTRITION Evidence-based dietary recommendations for patients with NAFLD are lacking. The American Diabetes Association [25 ] has published similar recommendations to those proposed by the AASLD [1 ], which include a low-carbohydrate (40–45% of daily calories (kcal) or low-fat diet (
State of the art: treatment of nonalcoholic steatohepatitis Michelle Pearlman a and Rohit Loomba a,b
Purpose of review Nonalcoholic fatty liver disease is the most common cause of chronic liver disease in Western countries, and consists of a spectrum of histopathological changes that range in severity from simple steatosis to steatohepatitis to cirrhosis. The use of pharmacological agents as adjunctive therapy to lifestyle modification is crucial, because weight loss is often difficult to achieve and maintain. The purpose of this review is to analyze the most recent literature pertaining to current therapies for nonalcoholic steatohepatitis (NASH), as there are currently no Food and Drug Administration-approved medications. Recent findings Recent studies suggest that vitamin E may improve liver histology in NASH without affecting insulin resistance; however, long-term risks remain to be studied. Pioglitazone is beneficial in improving liver histology and insulin resistance, but is associated with weight gain. Emerging data suggest that pentoxifylline may also be beneficial in improving serum aminotransferase and liver histology in patients with biopsy-proven NASH. Summary Ongoing research evaluating potential pharmacological agents for NASH is critical, because these patients are at an increased risk for cirrhosis and hepatocellular carcinoma. The current therapies being used for the treatment of NASH include the use of vitamin E and pioglitazone, in addition to dietary counseling and regular exercise. Keywords nonalcoholic fatty liver disease, pentoxifylline, pioglitazone, vitamin E
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of disease states including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD varies dramatically depending on the study population and the mode of diagnosis [1 ]. NAFL is nonprogressive whereas NASH can advance to cirrhosis and hepatocellular carcinoma [2,3]. NASH-induced cirrhosis is the third leading cause of liver transplantation in the United States [4] and is associated with high liver-related morbidity and mortality [3]. Furthermore, patients with NASH have an increased risk of developing fibrosis if they gain more than 5 kg, have significant insulin resistance, or exhibit profound hepatic fatty infiltration [5]. With the continued rise in obesity in the United States, the prevalence of NAFLD has followed a &&
similar trend. NAFLD is associated with central obesity, dyslipidemia, hypertension, and insulin resistance; a constellation of diseases that comprise metabolic syndrome [6,7 ]. It is imperative to manage these comorbidities, as the most common cause of death in this patient population is cardiovascular disease [5]. Additionally, elderly patients with NAFLD are more likely to develop NASH and advanced &
a Division of Gastroenterology, Department of Medicine and bDivision of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
Correspondence to Rohit Loomba, MD, MHSc, Division of Gastroenterology, Department of Medicine; Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, UC 303 (MC 0063), La Jolla, CA 92093-0063, USA. Tel: +1 858 534 2624; fax: +1 858 534 3338; e-mail: roloomba @ucsd.edu; http://fattyliver.ucsd.edu/ Curr Opin Gastroenterol 2014, 30:223–237 DOI:10.1097/MOG.0000000000000060
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-gastroenterology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Liver
KEY POINTS Lifestyle modification to induce weight loss with regular aerobic exercise and/or resistance training is required and caloric restriction is essential in halting the progression of NASH, and thereby to increase the likelihood of reversal of NASH. It is important to manage cardiovascular risk factors in patients with NAFLD including low-density lipoprotein, BMI, triglycerides, and diabetes mellitus 2 because cardiovascular disease is the most common cause of mortality in this patient population. Pioglitazone 30 mg/day may be considered in patients with biopsy-proven NASH with type 2 diabetes, who do not have congestive heart failure, or increased risk of fracture, although long-term effects have not yet been established. Vitamin E 800 IU/day may be considered as the firstline treatment for biopsy-proven NASH in nondiabetic patients without evidence of cirrhosis, although optimal duration of treatment and specific formulation remain to be studied. Both vitamin E and pioglitazone can reverse NASH.
treatment options are of particular importance in this patient population. The diagnosis of NAFLD is made in a patient without a history of significant alcohol use, after other causes of liver disease or hepatic steatosis have been excluded [9]. The definitive diagnosis for NAFLD is by liver biopsy, with histopathology exhibiting macrovesicular hepatic steatosis predominantly in zone 3 with varying degrees of lobular inflammation, and balloon degeneration, with or without perisinusoidal fibrosis [10]. Some of these histopathological changes including steatosis (grade 0–3), lobular inflammation (grade 0–3), and ballooning (grade 0–2) are used to calculate the NAFLD activity score (NAS with a total summary score of 8), which is used for research purposes to determine the response to therapy in a more objective manner [1 ]. The treatment approach for NAFLD and NASH begins with an exercise program and a calorie restricted diet to achieve a normal weight in a gradual manner. We usually recommend a goal of 1–2 lb weight/week to have a gradual weight reduction. The use of pharmacological agents as adjunctive therapy is often necessary, however, as lifestyle modification and weight loss are difficult to maintain ([11 ], Table 1). This review article will examine the most current literature (Table 2) [12 –14 ,15, 16 ,17,18 ,19,20 ,21] regarding the treatment of NASH and is based on both the current American &&
&
fibrosis compared with nonelderly patients with NAFLD [5,8 ]. Given the growing elderly population, knowledge of the natural history and available &
&
&
&
&
&
Table 1. Management of nonalcoholic fatty liver disease: The University of California San Diego Approach (1) Patients with NAFLD and no evidence of NASH or fibrosis on liver biopsy (a) Recommend lifestyle modification (i) Discuss importance of limiting fat and simple carbohydrate intake and consider referral to nutritionist (ii) Weight assessment: If BMI is either overweight or obese then patient is counseled on initiating a weight loss diet (see i) and starting a regular exercise program if they are otherwise fit to do so. Regimen includes aerobic (and/or resistance) exercise 3–5 days/week for 20–30 min/session to aid in weight reduction (b) Assess cardiovascular risk factors (i) Obtain LDL, HDL, and TG and treat based on Adult Treatment Panel III of the National Cholesterol Education Program guidelines (ii) Screen for diabetes, and prediabetes and treatment based on American Diabetes Association guidelines (c) Perform detail medicine reconciliation and try to eliminate medications that have the potential to worsen hepatic steatosis: medications include amiodarone, MTX, systemic steroids, tetracyclines, tamoxifen, estrogens, and valproic acid (2) Patients with NASH based on liver biopsy with or without fibrosis (a) Lifestyle modification, assess cardiovascular risk factors, medication reconciliation all mentioned above (b) Initiate medical therapy if no absolute contraindications (i) Vitamin E 800 IU/day for nondiabetic patients (ii) Pioglitazone with or without metformin in diabetic patients (3) Patients with NASH cirrhosis (a) Lifestyle modification, assess cardiovascular risk factors, medication reconciliation all mentioned above (b) Screen for esophageal varices (c) Screen for hepatocellular carcinoma (d) Referral to transplant center for evaluation when deemed appropriate &
Reproduced from [11 ]. HDL, high-density lipoprotein; IU, international unit; LDL, low-density lipoprotein; MTX, methotrexate; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglycerides.
224
www.co-gastroenterology.com
Volume 30 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
RCT
RCT
Sanyal et al. [15]
Sanyal et al. [15]
0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
RCT
RCT
RCT
RCT
Bell et al. [14 ]
Pietu et al. [18 ]
Zein et al. [19]
Zein et al. [20 ]
Van Wagner et al. [21]
www.co-gastroenterology.com Pentoxifylline 1200 mg/day
Pentoxifylline 1200 mg/day
Pentoxifylline 1200 mg/day
Vitamin E 500 IU/day with UDCA
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Vitamin E 800 IU/day
Pioglitazone 30 mg/day
30
47
55
101
246
173
247
247
247
246
66
334
No. of patients
Placebo
Placebo
Placebo
Placebo
Pioglitazone 30 mg/day
Metformin 1000 mg/day and placebo
Placebo
Pioglitazone and placebo
Vitamin E and placebo
Vitamin E 800 IU/day
Silymarin and metformin
Placebo
Compared with
1 year
1 year
1 year
4 years
96 weeks
96 weeks
96 weeks
96 weeks
96 weeks
96 weeks
8 weeks
6 months
Treatment duration
Improvement in hepatocellular ballooning and steatosis when compared to baseline but no significant different between treatment group and placebo
Improvement in lobular inflammation and fibrosis based on reduction in plasma levels of certain oxidation products that have a strong correlation with liver histology
Significant reduction in steatosis, lobular inflammation, fibrosis score and resolution of NASH. No change in hepatocellular ballooning or fibrosis
Yes, improvement in NAS
No reduction in Adipo-IR score at 16 or 96 weeks but did show improvement in hepatocellular ballooning, fibrosis and NAS
Yes, improvement in hepatocellular ballooning and NAS
N/A
Yes, reduction in hepatic steatosis and lobular inflammation, no change in fibrosis score
Yes, reduction in hepatic steatosis and lobular inflammation, no change in fibrosis score
Yes at 16 weeks, not persistent at 96 weeks based on Adipo-IR score
N/A
Improvement in hepatocellular ballooning, lobular inflammation and steatosis, analysis of pioglitazone alone showed improvement in fibrosis
Histology improvement
Yes when compared to baseline but no significant difference compared to placebo
N/A
N/A
Yes
Yes
No
Yes
N/A
N/A
Yes
Yes
Yes
ALT improvement
Adipo-IR, adipose tissue insulin resistance; IU, international unit; N/A, not applicable; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; RCT, randomized control trial; UDCA, ursodeoxycholic acid.
&
&
RCT
Lavine et al. [17]
&
RCT
RCT
Hoofnagle et al. [16 ]
&
RCT
Bell et al. [14 ]
Pioglitazone 30 mg/day
Pioglitazone 15 mg/day
RCT
Hajiaghamohammadi & et al. [13 ]
&
Pioglitazone, varying doses
Meta-analysis using four RCTs
&
Boettcher et al. [12 ]
Drug/dose
Type of study
References
Table 2. Most recent studies of vitamin E, pioglitazone, and pentoxifylline in adult patients with nonalcoholic fatty liver or nonalcoholic steatohepatitis
Treatment of nonalcoholic steatohepatitis Pearlman and Loomba
225
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Liver
Association for the Study of Liver Disease (AASLD) practice guidelines published in 2012 and the practical approaches utilized at UCSD NAFLD clinic [1 ]. The studies chosen for this review were found on PubMed using search terms NASH, pioglitazone, pentoxifylline, vitamin E, and only include human participants with NAFL or NASH. The effects of surgical weight loss therapies have been discussed elsewhere and are beyond the scope of this review [1 ,22]. All studies used a P 0.05 to denote statistical significance. &&
&&
We generally emphasize that total caloric intake should be closely scrutinized by the patients. Patients should avoid large meals and dietary plans should be tailored based on whether they are normoglycemic, prediabetic, or diabetic with NAFLD.
LIFESTYLE MODIFICATION: THE ROLE OF WEIGHT LOSS &
Weight loss through calorie restriction [25 ], and/or regular exercise [23 ,24 ], has been shown to alter the progression of fatty liver disease. The AASLD guidelines [1 ] recommend a 3–5% reduction in body weight; however, other studies suggest >7% reduction is associated with improvement in hepatic steatosis and liver histology [28–30]. &
&
&&
LIFESTYLE MODIFICATION: THE ROLE OF EXERCISE There is no consensus regarding the intensity, duration, and types of exercise that are optimal for patients with NAFLD. Sullivan et al. [23 ] analyzed the effect on magnetic resonance spectroscopy intrahepatic triglyceride content (IHTG) in 18 obese participants with NAFLD. After 16 weeks of 150–300 min of moderate-intensity endurance exercise each week, there was a mild, although significant, reduction in IHTG content independent of weight loss (P < 0.05). Most recently, Bacchi et al. [24 ] compared the effects of aerobic exercise versus anaerobic resistance training on hepatic fat content after 4 months. On the basis of the magnetic resonance spectroscopy, there was a significant reduction in hepatic fat content in both the groups (P < 0.001), as well as an improvement in insulin sensitivity, BMI, and adipose tissue. We generally recommend that patients initiate an exercise program that is based on their current activity level. Most patients are able to initiate a moderate-intensity exercise program, initially aerobic for at least 30 min for 3 to 5 times a week. We emphasize that sustained activity and having a consistent weekly exercise regimen program is beneficial. However, the differential effect between the types of exercises in improving liver histology is currently not known. &
&
ROLE OF PIOGLITAZONE Thiazolidinediones (TZDs) have been studied as treatment options for NASH. Pioglitazone is a TZD, which improves insulin sensitivity by activating nuclear peroxisome proliferator activated-receptor-gamma, thereby upregulating gene transcription for several proteins involved in glucose and lipid metabolism [31]. Rosiglitazone, a different TZD, is not widely studied because of its association with ischemic stroke and heart failure [32 ]. Promrat et al. [33] conducted a pilot study in 18 nondiabetic, biopsy-proven NASH patients. This study showed that 30 mg/day of pioglitazone for 48 weeks led to a significant reduction in transaminases, as well as a significant improvement in histological parameters, including steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis (P < 0.05). A recent meta-analysis including four randomized controlled trials (RCTs) published between 2006 and 2010 suggested patients treated with either pioglitazone or rosiglitazone (n ¼ 169) had significant reductions in ballooning degeneration, lobular inflammation, and steatosis, whereas only pioglitazone led to improvement in fibrosis (n ¼ 137) [12 ,15,34–36]. In particular, the pioglitazone versus vitamin E versus placebo in nonalcoholic steatohepatitis (PIVENS) trial showed a significant improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST) (P < 0.001), hepatic steatosis (P < 0.001), and lobular inflammation (P ¼ 0.004) after treatment with pioglitazone 30 mg/day (n ¼ 80) for 96 weeks. However, no significant change in fibrosis was observed (P ¼ 0.12) [15]. Hajiaghamohammadi et al. [13 ] compared the effects of metformin 500 mg/day (n ¼ 22), pioglitazone 15 mg/day (n ¼ 22), and silymarin 140 mg/day (n ¼ 22). After 8 weeks, pioglitazone led to a significant improvement in AST and ALT and, out of the three therapies, was associated with the most &
&
LIFESTYLE MODIFICATION: THE ROLE OF NUTRITION Evidence-based dietary recommendations for patients with NAFLD are lacking. The American Diabetes Association [25 ] has published similar recommendations to those proposed by the AASLD [1 ], which include a low-carbohydrate (40–45% of daily calories (kcal) or low-fat diet (
