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Who Should Treat Fatty : Primary Care or ? Danielle Brandman, M.D., M.A.S.

Nonalcoholic fatty (NAFLD) is a major pub- NAFLD, although it is impractical to apply to the large at- lic health problem worldwide, affecting 25% of the pop- risk NAFLD population due to cost and risk for morbidity. ulation.1 It is well established that the leading causes of Noninvasive assessment of stage may be done by death in patients with NAFLD include cardiovascular dis- the primary care provider (PCP) using clinical prediction ease, malignancy, and liver disease.2 NAFLD is often sus- rules (e.g., NAFLD Fibrosis score [FIB-4]) and/or imaging pected in the primary care setting, although the diagnostic (ultrasound- or magnetic resonance–based elastogra- testing and management are typically performed by the phy),2 but ultimately, the hepatologist may be key in rec- hepatologist. Care by both fields is necessary for these pa- onciling discordant results and performing or interpreting tients, although the specific role of each should be better . defined.

Monitoring for Disease Progression NAFLD MANAGEMENT: THE CASE FOR THE The optimal method of monitoring for disease progres- HEPATOLOGIST sion has not been determined. NAFL is thought to have rel- Initial Diagnosis/Classification and Staging atively low risk for fibrosis progression, but several studies Nonalcoholic (NASH) and nonalco- have demonstrated that NAFL does not necessarily follow holic fatty liver (NAFL) are distinct categories of NAFLD an uneventful course. Meta-analysis of paired biopsy stud- with different natural histories; the hepatologist plays ies have shown that 11% of patients with NAFL at baseline an important role in disease classification. Liver biopsy is went on to experience development of advanced fibrosis, considered to be the gold standard for classification of with a fibrosis progression rate of 14.3 years to worsen

Abbreviations: CKD, chronic kidney disease; EASL, European Association for the Study of the Liver; HCC, ; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic ; NASH, nonalcoholic steatohepatitis; PCP, primary care provider. From the Division of , Department of , University of California San Francisco, San Francisco, CA. Potential conflict of interest: Nothing to report. Received June 29, 2018; accepted September 22, 2018.

View this article online at wileyonlinelibrary.com © 2019 by the American Association for the Study of Liver

158 | Clinical Liver Disease, VOL 13, NO 6, JUNE 2019 An Official Learning Resource of AASLD Review NAFLD: Disease of Primary Care or Hepatology? Brandman by one stage,3 although it remains unclear which patients NAFLD MANAGEMENT: THE CASE FOR THE were at risk for development of advanced fibrosis. Because PCP of this uncertainty with regard to disease progression, it Initial Disease Recognition may be difficult to completely release patients who “only” Patients with NAFLD are first typically recognized by the have NAFL from the hepatology unless there is as- PCP through routine or symptom-directed assessments surance for adequate liver-related monitoring by the PCP. with blood tests and/or abdominal imaging. Although NASH is associated with more rapid rates of fibrosis not yet recommended to routinely screen all at-risk pa- progression, taking 7 years to progress by one stage,3 so tients for NAFLD, patients with diabetes may warrant a definitive fibrosis reassessment with repeat liver biopsy higher index of suspicion for NAFLD.1 Once NAFLD is sus- may be indicated at some point after initial fibrosis classifi- pected, referral to hepatology should be placed to help cation.2,4 Patients with NASH are five times more likely to better characterize stage of disease, particularly if there die of liver disease than those with NAFL.5 Even at early fi- is suspicion for NASH and/or if noninvasive tools suggest brosis stages (F0–2), NASH has a 2-fold greater risk for liver significant fibrosis.2,4 mortality when compared with NAFL.5 In patients who ex- perience (up to 20% of patients with NASH), the Monitoring for Disease Progression 6 risk for decompensation may be as high as 45%. Ongoing The optimal method of monitoring for disease progres- hepatology care for patients to monitor for disease com- sion has not been determined. NAFL is thought to have plications such as , varices, and hepatocellular carci- relatively low risk for fibrosis progression, but several stud- noma (HCC) should be done in accordance with standard ies have demonstrated that NAFL does not necessarily fol- of care for patients with cirrhosis due to other causes. low an uneventful course. Meta-analysis of paired biopsy studies have shown that 11% of patients with NAFL at baseline went on to experience advanced fibrosis, with a Treatment of NAFLD fibrosis progression rate of 14.3 years to worsen by one 3 Ultimately, our goal in treating NAFLD is to prevent pro- stage, although it remains unclear which patients were at gression of cirrhosis and its complications, end-stage liver risk for development of advanced fibrosis. Because of this disease and HCC, recognizing that liver disease is the third uncertainty with regard to disease progression, it may be leading cause of death in these patients.7 Several studies difficult to completely release patients who “only” have have demonstrated that fibrosis stage is the most impor- NAFL from the hepatology clinic, but given the burden of tant predictor of liver-related mortality.8 early-stage disease within the large NAFLD population, the majority of these patients are likely best suited for moni- Currently, the most universally accepted treatment toring in the primary care setting. It is imperative that ad- of NAFLD among gastroenterology and hepatology sci- equate liver-related monitoring is performed by the PCP. entific societies is lifestyle modification with a goal of weight loss9; certainly this could be (and is) done by PCPs on a routine basis. However, liver-specific treat- Comorbidity Diagnosis and Management ment for patients with NASH should be handled by the A major focus in primary care for patients with NAFLD hepatologist. American Association for the Study of Liver should be diagnosis and management of metabolic syn- Diseases and European Association for the Study of the drome and prevention of end-organ damage. Because Liver (EASL) guidelines recommend that only patients several studies have demonstrated that NAFLD is associ- with biopsy-proven NASH receive pharmacotherapy, ated with increased risk for subsequent development of with vitamin E and pioglitazone being the only available diabetes, patients should be screened by the PCP annually. medications that have been shown to be of significant Cardiovascular disease is a leading cause of death in pa- benefit on liver histology in select patients.2,4 Many tients with NAFLD. Several studies have also demonstrated drugs targeting a variety of mechanisms are currently an association between presence of NAFLD and prevalent in development, and the hepatologist is best suited to subclinical signs of cardiovascular disease.10 Progression help identify patients appropriate for these clinical trials of coronary artery calcium may be faster in patients with that are investigating medications in a wide spectrum of NAFLD, particularly those with advanced fibrosis, as iden- NASH disease severity. tified through clinical prediction rules such as the NAFLD

159 | Clinical Liver Disease, VOL 13, NO 6, JUNE 2019 An Official Learning Resource of AASLD Review NAFLD: Disease of Primary Care or Hepatology? Brandman

Fibrosis Score.11 A meta-analysis that included 16 studies demonstrated that NAFLD was associated with incident fatal and nonfatal cardiovascular events, with more severe forms of NAFLD (e.g., higher fibrosis stage, higher liver ) having even greater risk for these events.12 It is imperative that comorbidities be appropriately managed by the PCP to try to help mitigate some of this risk. EASL guidelines recommend referral to a diabetologist for those with diabetes (or at risk for diabetes), but such an approach may not be feasible in the United States because of challenges in insurance approval, as well as availability of providers. and , key medications in management of hyperlipidemia and diabetes, respectively, should not be avoided, as they are safe for use in the setting of NAFLD.1,2,4 Use of GLP-1 agonists is also attractive for di- FIG 1 Proposed algorithm for NAFLD management with abetes management, not only for their potential cardiopro- definition of Hepatology and primary care roles. tective effects and weight reduction, but also for potential favorable hepatic effects in patients with NASH13; however, these findings have not yet been further validated in larger REFERENCES cohorts or GLP-1 agonists other than liraglutide. Chronic kidney disease (CKD) is also an important cause of morbid- 1) Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiol- ity in this patient population, with NASH being associated ogy of nonalcoholic fatty liver disease-meta-analytic assess- 14 ment of prevalence, incidence, and outcomes. Hepatology with greater risk for incident CKD than NAFL. Whether 2016;64:73-84. these patients warrant more aggressive risk modification compared with the general CKD population is not known. 2) Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and man- agement of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. NAFLD MANAGEMENT: THE CASE FOR Hepatology 2018;67:328-357. COLLABORATIVE CARE 3) Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonal- coholic fatty liver vs nonalcoholic steatohepatitis: a systematic re- It is premature for hepatologists to turn all patients with view and meta-analysis of paired-biopsy studies. Clin Gastroenterol NAFLD over to primary care and vice versa. The PCP must Hepatol 2015;13:643-654. help identify at-risk patients and refer to hepatology for fur- 4) European Association for the Study of the Liver (EASL); European ther risk stratification, although the optimal strategy for this Association for the Study of Diabetes (EASD); European Association is still not clear. Many patients with early-stage disease may for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. be able to return to primary care, provided that the PCP is J Hepatol 2016;64:1388-1402. vigilant in monitoring for signs of more advanced disease. Hepatologists must focus on the monitoring of disease pro- 5) Musso G, Gambino R, Cassader Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic gression in high-risk patients and assessing for liver-related accuracy of non-invasive tests for liver disease severity. Ann Med complications. Hepatology and primary care must then 2011;43:617- 649. partner to manage the patient as a whole, each providing 6) Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences care for liver disease and/or metabolic syndrome (Fig. 1), in outcomes of cirrhosis due to nonalcoholic steatohepatitis and with an ultimate goal of reducing the risk for morbidity and C. Hepatology 2006;43:682-689. mortality caused by hepatic and extrahepatic disease. 7) Adams LA, Lymp JF, St. Sauver J, et al. The natural history of non- CORRESPONDENCE alcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-121. Danielle Brandman, M.D., M.A.S., Division of Gastroenterology, Department of Medicine, University of California San Francisco, San 8) Ekstedt M, Hagstron H, Nasr P, et al. Fibrosis stage is the Francisco, CA 94143. E-mail: [email protected] strongest predictor for disease-specific mortality in NAFLD

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after up to 33 years of follow-up. Hepatology 2015;61: 12) Targher G, Byrne CD, Lonardo A, et al. Non-alcoholic fatty liver 1547-1554. disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 2016;65:589-600. 9) Nascimbeni F, Pais R, Bellentani S, et al. From NAFLD in clinical practice to answers from guidelines. J Hepatol 2013;59:859-871. 13) Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a 10) Mellinger JL, Pencina KM, Massaro JM, et al. Hepatic and multicenter, double-blind, randomized, placebo-controlled phase 2 cardiovascular disease outcomes: an analysis of the Framingham study. Lancet 2016;13:679-690. Heart Study. J Hepatol 2015;63:470-476. 14) Musso G, Gambino R, Taibibian JH, et al. Association of 11) Sinn DH, Kang D, Chang Y, et al. Non-alcoholic fatty liver disease non-alcoholic fatty liver disease with chronic kidney disease: and progression of coronary artery calcium score: a retrospective a systematic review and meta-analysis. PLoS Med 2014;11: cohort study. 2017;66:323-329. e1001680.

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