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Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation

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Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation GUIDELINES UPDATE YOUNOSSI Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation Zobair M. Younossi 1,2 1Betty and Guy Beatty Center for Integrated Research, Inova Health System and 2Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA Nonalcoholic fatty liver disease (NAFLD), a common cause of chronic liver disease (CLD), has a global prevalence of 25%.(1) Its progressive form, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplantation (LT) in the United States.(2,3) As a result, specialty societies, including the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver, have developed guidance on the epidemiology, diag- nosis, and treatment of NAFLD and NASH.(4,5) Therefore, the transplant team must be well versed in the state of cur- rent knowledge about NAFLD and transplant-specific issues for this increasingly important indication for LT. Liver Transplantation 24 166–170 2018 AASLD. Received December 20, 2017; accepted December 20, 2017. or radiologic assessment, the diagnosis of the NAFLD Epidemiology of NAFLD subtype of NASH requires a liver biopsy with strict patho- and NASH logic criteria. The term “nonalcoholic” denotes exclusion of excessive alcohol consumption and other causes of liver NAFLD spans a clinic-pathologic spectrum character- disease. In recent NAFLD studies, this threshold is >21 ized by hepatic steatosis with or without other pathologic and >14 standard drinks per week for men and women, features and in the absence of other specific causes of fatty respectively.(4) liver.(4,6) Although NAFLD is diagnosed by liver biopsy There is evidence that the NAFLD prevalence in the US population is approximately 23.5%, with NASH prevalence estimated between 1.5% and 6.5%.(1,7) The Abbreviations: AASLD, American Association for the Study of Liver pooled estimated incidence rates for NAFLD from Asia Diseases; CI, confidence interval; CKD, chronic kidney disease; CLD, and the West are 52.3 per 1000 person-years (95% con- chronic liver disease; CVD, cardiovascular disease; ELF, enhanced fidence interval [CI], 28.3-96.8) and 28 per 1000 liver fibrosis; FDA, Food and Drug Administration; GLP-1, gluca- (1,4) gon-like peptide-1; HCC, hepatocellular carcinoma; LT, liver trans- person-years (95% CI, 19.3-40.6), respectively. plantation; MRE, magnetic resonance elastography; NAFLD, The majority of NAFLD and NASH patients have nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; metabolic comorbidities (ie, obesity, type 2 diabetes NFS, nonalcoholic fatty liver disease fibrosis score; T2DM, type 2 diabetes mellitus. mellitus [T2DM], and dyslipidemia), whereas a small proportion have “lean” NAFLD. In the United States, Address reprint requests to Zobair M. Younossi, M.D., M.P.H., F.A.A.S.L.D., Betty and Guy Beatty Center for Integrated Research, the prevalence of lean NAFLD was reported to be 7%, Inova Health System, Inova Fairfax Hospital, Claude Moore Health whereas in rural areas of some Asian countries, it can Education and Research Building, 3300 Gallows Road, Falls be as high as 25%.(1,8,9) Church, VA 22042. Telephone: 703-776-2540; FAX: 703-776- 4386; E-mail: [email protected] The majority of NAFLD worldwide is related to metabolic comorbidities, suggesting this association is Copyright VC 2017 by the American Association for the Study of Liver Diseases. bidirectional. Metabolic comorbidities are risk factors for NAFLD and NASH, whereas the prevalence of View this article online at wileyonlinelibrary.com. NAFLD and NASH is high in patients with meta- DOI 10.1002/lt.25003 bolic comorbidities. In a recent meta-analysis of pa- Potential conflict of interest: Nothing to report. tients with diabetes, the prevalence of NAFLD was 57.8% (95% CI, 53.9%-61.6%), whereas the 166 | GUIDELINES UPDATE LIVER TRANSPLANTATION, Vol. 24, No. 2, 2018 YOUNOSSI prevalence of NASH was 65.3% (95% CI, 51.7%- prognosis, similar or worse than NASH cirrhosis.(17) 76.7%), and the prevalence of advanced fibrosis In clinical practice, all these patients with advanced (fibrosis F3) was 15.1% (95% CI, 8.2%-26.1%).(10) In fibrosis should be considered in a similar fashion. addition to T2DM, most morbidly obese patients under- going bariatric surgery have NAFLD, 20%-30% have NASH, and 10% have advanced fibrosis.(11) Diagnostics and Treatment In the United States, there is some impact of ethni- of NASH city on the prevalence and progressiveness of NAFLD. In this context, Hispanics have a higher prevalence of Liver biopsy remains the most accurate technique for NAFLD, whereas African Americans have lower identifying steatohepatitis and fibrosis staging, albeit prevalence rates, potentially due to the genetic variation limited by cost, sampling error, and procedure-related in the patatin-like phospholipase domain-containing 3 morbidity and mortality.(4,6,7,17) Noninvasive tests like gene.(4,6) serum aminotransferase and routine imaging modali- ties such as ultrasound, computerized tomography, and magnetic resonance imaging cannot distinguish Progression of NAFLD NASH from non-NASH, nor stage hepatic fibro- (4,6,7,17) Patients with histologic NASH, especially those with sis. Other methods including clinical prediction some degree of fibrosis, are at greatest risk for progres- rules (eg, nonalcoholic fatty liver disease fibrosis score sion to cirrhosis and liver-related mortality.(6) The [NFS], FIB-4 index, aspartate aminotransferase-to- most common cause of death in NAFLD and NASH platelet ratio index), noninvasive serum-based tests (eg, patients, however, is cardiovascular disease (CVD) enhanced liver fibrosis [ELF] panel, Fibrometer, with liver-related mortality among the top 3.(4,6) To FibroTest, Hepascore), or image-based tests (eg, tran- quantify liver-related and overall mortality rates, a sient elastography, magnetic resonance elastography meta-analysis suggested these rates among NAFLD [MRE], acoustic radiation force impulse imaging, and NASH to be 0.8 per 1000 (range, 0.3-1.8) and supersonic shear wave elastography) are used to stage 11.8 per 1000 (range, 7.1-19.5) person-years and 15.4 the severity of liver disease.(4,6,17) A noninvasive test per 1000 (range, 11.7-20.3) and 25.6 per 1000 (range, with optimal receiver operating curve is not available, 6.3-103.8) person-years, respectively.(1) so a combination of these noninvasive biomarkers can With an increasing number of patients with cirrho- increase the predictive performance of these algo- sis, NAFLD has become one of the most common rithms.(6,17) Among these tests, NFS, ELF, and MRE underlying causes of hepatocellular carcinoma (HCC) provide the most valuable tools in clinical practice. and the second/third most common indication for Nevertheless, in 2017, the Food and Drug Adminis- LT.(4) These data reflect the role of progressive tration (FDA) still requires histologic end points for NAFLD (NASH) in the increase in patients with clinical trials.(17) Given that this is a dynamic field, HCC and those listed for LT.(2,3) there is a rush to identify and validate a noninvasive Despite this progressive potential, progression of test for NASH or NASH with fibrosis(4,6,7,17) for NASH is nonlinear with some progressing and others FDA approval. spontaneously regressing.(6) This complex pattern At present, interventions for NAFLD have focused requires diagnostic and prognostic noninvasive bio- on mitigating the associated metabolic comorbid- markers that can help clinicians identify patients who ities.(4,7,17) The AASLD guidance document suggests are at the highest risk for progressive liver disease. that weight loss can be best achieved through a combi- Clinically, NAFLD patients with components of nation of a low-calorie (500-1000 kcal) diet and metabolic comorbidities are at greatest risk for progres- moderate-intensity exercise. A 3%-5% weight loss is sion.(10,12-14) Additionally, patients whose liver biop- necessary to improve steatosis, but a 7%-10% weight sies show fibrosis stage 2 are especially at risk for loss is necessary to improve histopathologic features of liver-related mortality.(15,16) NASH, including fibrosis. Exercise alone in NAFLD Some patients with metabolic comorbidities may can improve or prevent hepatic steatosis, but the not meet the pathologic criteria for NASH such as impact of exercise on hepatic necroinflammation or those with cryptogenic cirrhosis or those with severe fibrosis is not well studied.(4,7,17) steatofibrosis.(4,17) Both groups are excluded from Lifestyle modifications are recommended for all NASH clinical trials while experiencing poor longterm NAFLD patients due to cardio-metabolic benefits, but GUIDELINES UPDATE | 167 YOUNOSSI LIVER TRANSPLANTATION, February 2018 treatment with drugs should be limited to those with progressive liver disease such as steatohepatitis and/or LT in Patients with NASH fibrosis. Given the association of NASH with insulin Over the past two decades, there has been an increas- resistance, metformin, pioglitazone, and glucagon-like ing recognition that cryptogenic cirrhosis in the United peptide-1 (GLP-1) agonists have received more atten- States represents burnt-out NASH.(1-3) In this context, tion. Currently, the evidence does not support the use NASH and cryptogenic cirrhosis have been increas- (4,6) of metformin for treating NASH. Although piogli- ingly seen among patients awaiting LT.(2,3) Transplant tazone does improve liver histology in patients with candidates with NASH typically have several metabolic biopsy-proven NASH, its use should be limited to dia- comorbidities added to the complexity of managing betic patients with NASH whose risks and benefits the complications of CLD. Obesity increases the risk (18) have been explored. The AASLD guidance docu- of decompensation while awaiting LT and can present ment indicates that it is premature to use GLP-1 ago- a surgical technical challenge(4) although an upper limit (4) nists to treat NASH.
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