Who Should Treat Fatty Liver Disease: Primary Care or Hepatology?

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Abbreviations

CKD

chronic kidney disease

EASL

European Association for the Study of the Liver

HCC

hepatocellular carcinoma

NAFL

nonalcoholic fatty liver

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

PCP

primary care provider

Nonalcoholic fatty liver disease (NAFLD) is a major public health problem worldwide, affecting 25% of the population.1 It is well established that the leading causes of death in patients with NAFLD include cardiovascular disease, malignancy, and liver disease.² NAFLD is often suspected in the primary care setting, although the diagnostic testing and management are typically performed by the hepatologist. Care by both fields is necessary for these patients, although the specific role of each should be better defined.

NAFLD Management: The Case for the Hepatologist

Initial Diagnosis/Classification and Staging

Nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL) are distinct categories of NAFLD with different natural histories; the hepatologist plays an important role in disease classification. Liver biopsy is considered to be the gold standard for classification of NAFLD, although it is impractical to apply to the large at‐risk NAFLD population due to cost and risk for morbidity. Noninvasive assessment of fibrosis stage may be done by the primary care provider (PCP) using clinical prediction rules (e.g., NAFLD Fibrosis score [FIB‐4]) and/or imaging (ultrasound‐ or magnetic resonance–based elastography),2 but ultimately, the hepatologist may be key in reconciling discordant results and performing or interpreting liver biopsy.

Monitoring for Disease Progression

The optimal method of monitoring for disease progression has not been determined. NAFL is thought to have relatively low risk for fibrosis progression, but several studies have demonstrated that NAFL does not necessarily follow an uneventful course. Meta‐analysis of paired biopsy studies have shown that 11% of patients with NAFL at baseline went on to experience development of advanced fibrosis, with a fibrosis progression rate of 14.3 years to worsen by one stage,3 although it remains unclear which patients were at risk for development of advanced fibrosis. Because of this uncertainty with regard to disease progression, it may be difficult to completely release patients who “only” have NAFL from the hepatology clinic unless there is assurance for adequate liver‐related monitoring by the PCP.

NASH is associated with more rapid rates of fibrosis progression, taking 7 years to progress by one stage,3 so definitive fibrosis reassessment with repeat liver biopsy may be indicated at some point after initial fibrosis classification.2, 4 Patients with NASH are five times more likely to die of liver disease than those with NAFL.5 Even at early fibrosis stages (F0–2), NASH has a 2‐fold greater risk for liver mortality when compared with NAFL.5 In patients who experience cirrhosis (up to 20% of patients with NASH), the risk for decompensation may be as high as 45%.6 Ongoing hepatology care for patients to monitor for disease complications such as ascites, varices, and hepatocellular carcinoma (HCC) should be done in accordance with standard of care for patients with cirrhosis due to other causes.

Treatment of NAFLD

Ultimately, our goal in treating NAFLD is to prevent progression of cirrhosis and its complications, end‐stage liver disease and HCC, recognizing that liver disease is the third leading cause of death in these patients.7 Several studies have demonstrated that fibrosis stage is the most important predictor of liver‐related mortality.8

Currently, the most universally accepted treatment of NAFLD among gastroenterology and hepatology scientific 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 treatment for patients with NASH should be handled by the hepatologist. American Association for the Study of Liver Diseases and European Association for the Study of the Liver (EASL) guidelines recommend that only patients with biopsy‐proven NASH receive pharmacotherapy, with vitamin E and pioglitazone being the only available medications that have been shown to be of significant benefit on liver histology in select patients.2, 4 Many drugs targeting a variety of mechanisms are currently in development, and the hepatologist is best suited to help identify patients appropriate for these clinical trials that are investigating medications in a wide spectrum of NASH disease severity.

NAFLD Management: The Case for the PCP

Initial Disease Recognition

Patients with NAFLD are first typically recognized by the PCP through routine or symptom‐directed assessments with blood tests and/or abdominal imaging. Although not yet recommended to routinely screen all at‐risk patients for NAFLD, patients with diabetes may warrant a higher index of suspicion for NAFLD.1 Once NAFLD is suspected, referral to hepatology should be placed to help better characterize stage of disease, particularly if there is suspicion for NASH and/or if noninvasive tools suggest significant fibrosis.2, 4

Monitoring for Disease Progression

The optimal method of monitoring for disease progression has not been determined. NAFL is thought to have relatively low risk for fibrosis progression, but several studies have demonstrated that NAFL does not necessarily follow 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 fibrosis progression rate of 14.3 years to worsen by one stage,3 although it remains unclear which patients were at risk for development of advanced fibrosis. Because of this uncertainty with regard to disease progression, it may be difficult to completely release patients who “only” have NAFL from the hepatology clinic, but given the burden of early‐stage disease within the large NAFLD population, the majority of these patients are likely best suited for monitoring in the primary care setting. It is imperative that adequate liver‐related monitoring is performed by the PCP.

Comorbidity Diagnosis and Management

A major focus in primary care for patients with NAFLD should be diagnosis and management of metabolic syndrome and prevention of end‐organ damage. Because several studies have demonstrated that NAFLD is associated with increased risk for subsequent development of diabetes, patients should be screened by the PCP annually. Cardiovascular disease is a leading cause of death in patients with NAFLD. Several studies have also demonstrated an association between presence of NAFLD and prevalent subclinical signs of cardiovascular disease.10 Progression of coronary artery calcium may be faster in patients with NAFLD, particularly those with advanced fibrosis, as identified through clinical prediction rules such as the NAFLD 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 enzymes) having even greater risk for these events.12 It is imperative that metabolic syndrome 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. Statins and metformin, 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 diabetes management, not only for their potential cardioprotective 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 cohorts or GLP‐1 agonists other than liraglutide. Chronic kidney disease (CKD) is also an important cause of morbidity in this patient population, with NASH being associated with greater risk for incident CKD than NAFL.14 Whether these patients warrant more aggressive risk modification compared with the general CKD population is not known.

NAFLD Management: The Case for Collaborative Care

It is premature for hepatologists to turn all patients with NAFLD over to primary care and vice versa. The PCP must help identify at‐risk patients and refer to hepatology for further risk stratification, although the optimal strategy for this is still not clear. Many patients with early‐stage disease may be able to return to primary care, provided that the PCP is vigilant in monitoring for signs of more advanced disease. Hepatologists must focus on the monitoring of disease progression in high‐risk patients and assessing for liver‐related complications. Hepatology and primary care must then partner to manage the patient as a whole, each providing care for liver disease and/or metabolic syndrome (Fig. 1), with an ultimate goal of reducing the risk for morbidity and mortality caused by hepatic and extrahepatic disease.

Figure 1.

Proposed algorithm for NAFLD management with definition of Hepatology and primary care roles.

Potential conflict of interest

Nothing to report.