Treatment of NASH: What Helps Beyond Weight Loss?

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1 THE RED SECTION 821 see related editorial on page x Treatment of NASH: What Helps Beyond Weight Loss? Bubu A. Banini, MD, PhD1 and Arun J. Sanyal, MBBS, MD1 Am J Gastroenterol 2017; 112: ; doi: /ajg ; published online 11 April 2017 THE BIG PICTURE Nonalcoholic fatty liver disease (NAFLD) is an increasingly common indication for referral to gastroenterology. NAFLD encompasses two histologically distinct disease subtypes: nonalcoholic fatty liver (NAFL), defined by the presence of hepatic steatosis (fat accumulation in >5% of hepatocytes) without hepatocellular injury; and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and hepatocellular injury with or without fibrosis ( Figure 1 ). NASH is especially worrisome as it may progress to cirrhosis and/or hepatocellular cancer (HCC). Due to the presumably indolent disease course and asymptomatic status of most NAFLD patients, as well as the emerging nature of NAFLD therapeutics, many clinicians are uncertain as to how to monitor and treat patients with the disease. Below, we discuss pragmatic approaches to managing those with suspected NAFLD, incorporating best evidence with our own experience in managing this increasingly prevalent disease. INITIAL ASSESSMENT OF SUSPECTED NAFLD There are three important steps in assessing a patient with suspected NAFLD: confirming the diagnosis; determining the patient s risk of liver-related outcomes (cirrhosis, HCC); and formulating a monitoring and/or treatment plan based on the patient s metabolic risk profile and risk for liver-related outcomes. NAFLD should be suspected in individuals with risk factors (overweight or obese, type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome), hepatic steatosis on imaging, and abnormal liver enzymes without a competing etiology for liver disease (such as viral hepatitis, Wilsons disease or alcoholic liver disease (ALD)). While clinical trials use alcohol intake less than 20 grams per day for women and 30 grams per day for men as threshold for ruling out ALD, we do not find this threshold useful in clinical practice due to lack of well-validated methods to assess this metric. Clinicians should ascertain the amount of alcohol ingested, the frequency of ingestion, and the consequences of alcohol consumption. Risky drinking behavior can be assessed by asking a few simple questions (1 ) (Table 1 ). Even in the absence of criteria outlined in Table 1, patients may be indulging in alcohol consumption that places them at risk for liver damage. Patients who report levels or patterns of alcohol intake likely to cause end-organ damage ( 2 ) should be counseled on abstinence or at least responsible alcohol consumption. In our view, labeling individuals who have moderately increased alcohol intake creates a stigma, reduces the likelihood of follow-up and adherence to medical care. Rather, noting their alcohol consumption as one of several factors, putting them at risk for liver disease (assuming they have additional risk factors) reduces stigmatization and its attendant consequences. CONFIRMATION OF NAFLD AND DISEASE PROGNOSTICATION Having established the nonalcoholic or multifactorial nature of a patient s liver disease, confirming the presence of steatosis or steatohepatitis and risk stratification are undertaken simultaneously. Several imaging modalities, including sonography, computed tomography (CT) scan and magnetic resonance imaging (MRI) can provide proof of hepatic steatosis but do not provide prognostic information. Prognostication relies on assessing the risk of progression to cirrhosis, inferred from disease activity and stage. Disease activity refers to the pathophysiological engine driving the disease towards cirrhosis, whereas disease stage refers to how far the disease has progressed towards cirrhosis. Disease activity is traditionally inferred from the presence of steatohepatitis and assessment of NAFLD activity score (NAS), which can only be determined with a liver biopsy. Disease stage is reliably measured by the fibrosis stage, which ranges from F0 (normal liver) through F4 (cirrhosis) ( 3 ). The need for a liver biopsy to make these assessments is a major barrier to the evaluation and management of NAFLD patients and has fueled great interest in alternate approaches. Disease stage can be assessed using vibration-controlled transient elastography (VCTE), which is relatively inexpensive compared to magnetic resonance elastograstography (MRE) and is widely available at many academic medical centers and large 1 Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. Correspondence: Arun J. Sanyal, MBBS, MD, Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, MCV Box , Richmond, Virginia , USA. arun.sanyal@vcuhealth.org 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

2 822 THE RED SECTION a b c d e PT Figure 1. Hematoxylin-eosin stain of tissue sections from normal human liver ( a ), nonalcoholic fatty liver (NAFL) ( b ), nonalcoholic steatohepatitis (NASH) ( c ), NASH with fibrosis ( d ), and NASH with cirrhosis ( e ). Black arrows indicate steatosis; white arrows show ballooned hepatocytes, a key feature of steatohepatitis; and black arrowheads indicate fibrosis. PT, portal tract. Table 1. Assessment of risky drinking behavior Questions refer to the last 12-month period 1. Recurrent drinking in hazardous situations a. More than once driven a car or other vehicle while drinking or after having had too much to drink? b. More than once gotten into situations while drinking or after drinking that increased your chances of getting hurt (such as swimming, using machinery, walking in a dangerous area or around heavy traffic, or having unsafe sex)? 2. Continued use despite recurrent interpersonal or social problems a. Continued to drink even though it was causing you trouble with family or friends? b. Gotten into physical fi ghts while drinking or right after drinking? c. Given up or cut back on activities that were important or interesting to you, in order to drink? 3. Failure to fulfi ll major role obligations at work, school, or home a. Had a period when your drinking - or being sick from drinking- often interfered with taking care of home or family? Caused job troubles? School problems? 4. Recurrent legal problems related to alcohol a. Gotten arrested, been held at a police station, or had any other legal problems because of drinking? 5. Health problems a. Found that when the effects of alcohol were wearing off, you had withdrawal symptoms, such as trouble sleeping, shakiness, restlessness, nausea, sweating, a racing heart, or a seizure? Or sensed things that were not there? b. Continued to drink even though it was making you feel depressed or anxious or adding to another health problem? Or after having had a memory blackout? Interpretation: even one or two of the above symptoms could be a reason for concern and would warrant counselling and intervention. Reproduced with modifi cation from the National Institute of Alcohol Abuse and Alcoholism ( 1 ). private practices. It provides liver stiffness measurement (LSM), a surrogate for hepatic fibrosis. It also provides the continuous attenuation parameter (CAP), a surrogate for hepatic steatosis. Other measures of disease stage include Fibrosis-4 (FIB4) index, NAFLD fibrosis score (NFS), and aspartate aminotransferase (AST) to platelet ratio index (APRI) ( 4 ). A FIB4<1.45 or NFS< can identify those without fibrosis and thus at very low risk of liverrelated outcomes ( 5,6 ). On the other hand, an AST/alanine aminotransferase (ALT) ratio>1, platelet count <150,000/mm 3, and LSM>14 kappa can identify cirrhotic subjects with a high positive predictive value ( 7 ). For those with intermediate results on noninvasive testing, a case-by-case decision has to be made to either wait and monitor or perform a liver biopsy to determine disease activity and stage. TREATMENT OPTIONS Risk category 1: low-risk subjects Subjects at low risk for liver-related outcomes (obesity without additional features of metabolic syndrome, age<40 years, FIB4<1.3, APRI<0.5, NFS< 1.455, and LSM<5 kappa) should be managed by interventions with a similarly low-risk profile ( Table 2 ). The cornerstone of treatment consists of a hypocaloric diet and exercise to create a calorie deficit of 500 1,000 cals per day. A 3 5% decrease in body weight generally improves hepatic steatosis, whereas a 7 10% weight decrease improves hepatic necroinflammation ( 8 ). Bariatric surgery has been shown to improve NAFLD ( 9 ), hence patients who meet criteria ( 10 ) should be referred for surgical evaluation. The principal causes of mortality in this population are cardiovascular disease and cancer ( 11 ), therefore, optimizing cardiovascular risk profile and adherence to cancer screening guidelines are essential. While statins and metformin are not indicated for the treatment of NASH per se, they are effective and recommended for patients who have NAFLD The American Journal of GASTROENTEROLOGY VOLUME 112 JUNE

3 THE RED SECTION 823 Table 2. Classification and management of patients with nonalcoholic fatty liver disease Risk category Characteristics Cutoff values Management Frequency of monitoring Low risk Intermediate risk High risk Overweight/obese but without T2DM or metabolic syndrome Age<40 years Multiple features of the metabolic syndrome Age>40 years Multiple features of the metabolic syndrome AST>ALT Platelets<150,000 FIB-4<1.30 NFS< APRI<0.5 LSM<5 kpa FIB to 2.67 NFS to APRI 0.5 to 1.5 LSM 6 to 11 kpa FIB-4>2.67 NFS>0.675 APRI>1.5 LSM>1 kpa Vitamin E; pioglitazone; pentoxifylline; liraglutide a Screening for varices and HCC 1 2 years 6 months 1 year At least every 3 6 months ALT, alanine aminotransferase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; CM, cardiometabolic; FIB-4, fi brosis 4 index; HCC, hepatocellular cancer; LSM, liver stiffness measurement; NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis; NFS, NAFLD fibrosis score; T2DM, type 2 diabetes mellitus. a Off-label pharmacological agents for NASH. Vitamin E and pioglitazone are typically used as fi rst-line agents, while pentoxifylline and liraglutide are used as second line. together with dyslipidemia or T2DM, respectively. Typically, we perform VCTE and FIB4 together with NFS or APRI biennially for those with NAFL and annually for those with low-risk NASH. Interval progression of liver disease necessitates a re-assessment of metabolic risk factors and likelihood of liver-related outcomes to determine the need to escalate treatment. Risk category 2: Intermediate-risk subjects For those with intermediate-risk (hepatic fibrosis but without cirrhosis), treatment is mainly directed towards reducing disease activity with pharmacological agents. Off-label drugs that have been shown to reduce disease activity are vitamin E (RRR-α -tocopherol) and pioglitazone, typically used as first-line agents; and liraglutide and pentoxifylline, which are used as second-line agents. Vitamin E increases resolution of steatohepatitis and improves disease activity, but does not decrease fibrosis or progression to cirrhosis ( 12 ). Although some studies suggested an association between treatment with vitamin E and increased risk of prostate cancer and all-cause mortality ( 13 ), these observations have been challenged and not supported by subsequent studies ( 14 ). NASH patients who lose weight and normalize their ALT on Vitamin E have a high likelihood of histological response ( 15 ). Pioglitazone is effective in improving liver histology and may even improve fibrosis ( 16 ). However, its use is limited by weight gain, fluid retention, increased heart failure, osteopenia, and risk of fractures. The risk of bladder cancer with pioglitazone and other thiazolidinediones appears to have been overestimated in prior studies ( 17 ). Given these data, together with evidence documenting an improvement in cardiovascular risk and all-cause mortality with pioglitazone in subjects with T2DM, pioglitazone is an attractive option in biopsy-proven NASH patients with T2DM. The decision to use pioglitazone should include a frank discussion of its pros and cons with the patient. Small pilot studies provide support for the use of sodium-glucose transporter (SGLT) 1/2 inhibitors, or combining vitamin E with exenatide or pentoxifylline. Due to the paucity of the published human data at this time, these agents should be used mainly as second-line agents, if at all. There are several agents, including cenicriviroc, elafibranor and obeticholic acid that are currently in advanced stage clinical trials for NASH ( 18 ). Patients in the intermediate-risk category should be monitored for disease progression on an annual basis using a combination of imaging and non-invasive indices of disease stage (FIB4, APRI, NFS). Risk category 3: High-risk subjects Careful management of high-risk NASH patients (bridging fibrosis or NASH-related cirrhosis) is of utmost importance. There are no completed clinical trials to demonstrate efficacy of any pharmacological agents in this population. The use of vitamin E, pioglitazone, pentoxifylline and other agents are completely experimental in this population. Given the potential for severe liver failure from drug-induced liver injury in those with cirrhosis, it is advisable to either refer such patients for clinical trials or await the results of such trials before recommending pharmacological treatment. Carefully-selected high-risk subjects with morbid obesity may be referred for surgical evaluation at centers well experienced in bariatric surgery in cirrhotic patients ( 19 ). Recently developed endoscopic techniques for weight loss appear to be attractive in those with established cirrhosis and morbid obesity, although the impact of these endoscopic techniques on NASH remains to be demonstrated in large studies. Patients in the high-risk category should be seen at least every 3 6 months, with close attention to modulating metabolic and inflammatory risk factors and screening for disease complications ( 8 ). Non-cirrhotic NASH patients with advanced fibrosis should undergo semi-annual HCC screening with ultrasound, since these patients are at increased risk of HCC. Cirrhotic patients should undergo HCC as well as variceal screening. All patients with high-risk NASH should be referred to transplant centers for stabilization of end-organ status and consideration for liver transplant by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 824 THE RED SECTION SUMMARY The appropriate monitoring and treatment strategy for a patient with NAFLD depends on the individual s metabolic risk profile and their risk of liver-related outcomes. Weight loss through diet and exercise remains the cornerstone of treatment; bariatric surgery should be considered in patients who meet criteria. Management of cardiometabolic risk and adherence to cancer screening guidelines are essential. Given the currently available data, vitamin E and pioglitazone, typically used as first-line agents, should be reserved for those with intermediate-risk NASH. The pharmacological treatment of NASH is evolving, with several agents currently in the pipeline for testing. ACKNOWLEDGMENTS We thank Dr Marcus R. Winkler from the Virginia Commonwealth University Department of Pathology, who assisted in obtaining liver biopsy images. CONFLICT OF INTEREST Guarantor of the article : Arun J. Sanyal, MBBS, MD. Specific author contributions : Developed the structure and arguments for the manuscript, wrote the first draft of the manuscript, made critical revisions to manuscript, and approved the final draft submitted: Bubu A. Banini, Arun J. Sanyal. Financial support : This manuscript was supported by a training grant T32 DK from NIH NIDDK to Dr Arun J Sanyal. Potential competing interests : Arun J. Sanyal: ICMJE COI form submitted separately (see attached). The remaining author declares no conflict of interest. DISCLAIMER The funding source had no role in manuscript content, design, writing, or approval. REFERENCES 1. NIH NIoAAaA. Alcohol use disorder. Available at: drinking.niaaa.nih.gov/how-much-is-too-much/whats-the-harm/what-are- Symptoms-Of-An-Alcohol-Use-Disorder.aspx (accessed September 2016). 2. Ekstedt M, Franzen LE, Holmqvist M et al. Alcohol consumption is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol 2009 ;44 : Angulo P, Kleiner DE, Dam-Larsen S et al. L ive r fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015 ;149 : e Sha h AG, Lyd e cke r A, Mu r r ay K et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009 ; 7 : Usluer G, Erben N, Aykin N et al. Comparison of non-invasive fibrosis markers and classical liver biopsy in chronic hepatitis C. Eur J Clin Microbiol Infect Dis 2012 ;31 : Arora A, Sharma P. Non-invasive diagnosis of fibrosis in non-alcoholic fatty liver disease. J Clin Exp Hepatol 2012 ; 2 : Friedrich-Rust M, Ong MF, Martens S et al. Performance of transient elasto graphy for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008 ;134 : Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012 ;55 : Tait ano A A, Markow M, F i nan J E et al. Bariatric surgery improves histological features of nonalcoholic fatty liver disease and liver fibrosis. J Gastrointestin Surg 2015 ;19 : ; discussion Gastrointestinal surgery for severe obesity. Proceedings of a National Institutes of Health Consensus Development Conference. March 25-27, 1991, Bethesda, MD. Am J Clin Nutr 1992 ; 55 ( 2 Suppl ): 487S 619S. 11. Adams LA, Lymp JFSt, Sauver J et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005 ;129 : Sanyal AJ, Chalasani N, Kowdley KV et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010 ;362 : Miller ER 3rd, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005 ;142 : Abner EL, Schmitt FA, Mendiondo MS et al. Vitamin E and all-cause mortality: a meta-analysis. Curr Aging Sci 2011 ;4 : Hoofnagle JH, Van Natta ML, Kleiner DE et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2013 ;38 : Boettcher E, Csako G, Pucino F et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012 ;35 : Lewis JD, Habel LA, Quesenberry CP et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 2015 ;314 : Banini BA, Sanyal AJ. Nonalcoholic fatty liver disease: epidemiology, pathogenesis: natural history, diagnosis, and current treatment options. Clin Med Insights Ther 2016 ;2016 : Jan A, Narwaria M, Mahawar KK. A Systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg 2015 ; 25 : The American Journal of GASTROENTEROLOGY VOLUME 112 JUNE

5 GASTROENTEROLOGY ARTICLE OF THE WEEK September 28, 2017 Banini BA, Snayal AJ. Treatment of NASH What helps beyond weight loss? Am J Gastroenterology 2017;112: Which of the following patients should undergo a liver biopsy a. Metabolic syndrome, AST/ALT ratio >1, platelet count 95,000, elastography 18 kpa b. Obesity, hyperlipidemia, insulin resistance without diabetes, AST/ALT ratio 0.5, platelet count of 295,000; elastography 3.5kPa, FIB-4 0.7, NFS c. No metabolic syndrome, fatty liver on ultrasound, ALT 110, platelet count 198,000, FIB d. Metabolic syndrome, age 30, platelet count 165,000, FIB-4 1.3, elastography 10.2, NFS True or False 2. Patients with NAFLD cirrhosis should be aggressively treated with either vitamin E, pioglitazone or SGLT ½ inhibitors 3. NAFLD patients that should be treated with liver-related therapy are those with advanced fibrosis but no cirrhosis 4. The main cause of mortality in patients with NAFLD and no fibrosis is cardiovascular disease 5. Routine imaging modalities such as CT, US and MRI may detect steatosis and do not provide prognostic information 6. Weight loss of 3-5% will result in improvement in hepatic necroinflammation 7. Highest likelihood of histologic improvement in response to vitamin E is in those patients that lose weight and normalize ALT levels 8. Cirrhosis is a contraindication to bariatric surgery