Nonalcoholic Fatty Liver Disease: Evidence-Based Management and Early Recognition of Nonalcoholic Steatohepatitis

      Highlights

      • Patients with nonalcoholic steatohepatitis (NASH) are at a higher risk for the progression of hepatic fibrosis.
      • Metabolic syndrome and obesity are risk factors associated with the development of nonalcoholic fatty liver disease (NAFLD).
      • Nurse practitioners can use diagnostic tools to assess if a patient is at a higher risk for NASH.
      • Patients with NAFLD should be counseled on weight loss and the management of medical comorbidities.

      Abstract

      Nonalcoholic fatty liver disease is the most prevalent liver disease in the world. Metabolic syndrome and obesity are associated risk factors. The inflammatory subtype, nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis, is predicted to become the primary indication for liver transplantation within the next decade. Although there are no approved medications for NASH, there are ongoing multicenter trials aimed at targeting aspects of fat accumulation, inflammation, and fibrosis throughout the disease process. Nurse practitioners should focus on identifying patients at risk for NASH, while using guidelines for the management of nonalcoholic fatty liver disease and the comorbidities contributing to disease progression.

      Keywords

      American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hours, including 0.15 hours of pharmacology credit, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.
      Nonalcoholic fatty liver disease (NAFLD) is the aggregate term defining the disease state that encompasses 1) nonalcoholic fatty liver (NAFL), or ≥ 5% of steatosis (fat) in the hepatocytes, 2) nonalcoholic steatohepatitis (NASH), or fatty infiltration with inflammation and hepatocyte ballooning present with or without fibrosis, and 3) NASH cirrhosis, or end-stage fibrosis of the liver independent of alcohol use or other factors associated with hepatic steatosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      NAFLD has become the most prevalent liver disease in the world and is predicted to become the main indication for liver transplantation within the next decade.
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      Patients with NASH are at greater risk of developing hepatic fibrosis over time, a precursor for cirrhosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Metabolic syndrome and obesity are the main risk factors that contribute to the development of this disease.
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      Patients with metabolic syndrome have 3 or more of the following abnormal measurements: an elevated waist circumference (in men > 40 inches and in women > 35 inches), elevated triglycerides over 150 mg/dL, an elevated systolic blood pressure over 130 mm Hg or an elevated diastolic blood pressure over 85 mm Hg, and/or elevated fasting glucose levels above 100 mg/dL.
      American Heart Association. About metabolic syndrome.
      The Food and Drug Administration has not yet approved any pharmacotherapies with an indication for the treatment of NASH; however, several multicenter trials are ongoing with early data supporting promising agents for this patient population.
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      These agents target the processes underlying fat accumulation, inflammation, and fibrosis associated with NASH at various points of the disease progression.
      • Filozof C.
      • Chow S.C.
      • Dimick-Santos L.
      • et al.
      Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: facilitating development approaches for an emerging epidemic.
      Current clinical guidelines published by the American Association for the Study of Liver Diseases encourage nurse practitioners (NPs) to focus identifying patients at high risk for NASH and the prevention of the progression of fibrosis in these patients through the treatment of liver disease and a patient’s metabolic comorbidities.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

      Presentation

      It is estimated that 25% of the adult population has NAFLD, and 5% to 6% of these patients hold a diagnosis of the inflammatory subtype, NASH (Figure 1).
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      A large percentage of NAFLD patients will present with medical comorbidities that increase the risk of the disease including obesity, diabetes, and metabolic syndrome. Regarding patient demographics, the overall incidence of NAFLD and the stage of liver fibrosis increase with age.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      NAFLD prevalence is estimated to be 2 times greater among the male population in comparison with the female population.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Early analysis of the ethnic differences among this population revealed an increased prevalence of NAFLD among Hispanic individuals in comparison with non-Hispanic whites and an even lower prevalence in the non-Hispanic black population.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      As the field of genomic medicine continues to expand, data suggest genetic differences may play a greater role than previously suspected.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Patients with polymorphisms in genes such as PNPLA3 and TM6SF2 have been found to have a greater incidence of NAFLD, including progressive disease such as liver cancer.
      • Dongiovanni P.
      • Anstee Q.M.
      • Valenti L.
      Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment.
      Because of the high prevalence of this disease, NPs practicing in all clinical settings will treat patients with NAFLD.
      Figure thumbnail gr1
      Figure 1NAFLD spectrum.
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      Patients can be characterized on the NAFLD spectrum based on the presence of steatosis, inflammation, ballooning, and hepatic fibrosis.
      • Calzadilla Bertot L.
      • Adams L.A.
      The natural course of non-alcoholic fatty liver disease.
      These characteristics influence a patient’s clinical course and presentation. Patients with steatosis without inflammation (non-NASH NAFL) generally follow a benign hepatic clinical course, are often asymptomatic, and are at increased risk for diabetes and cardiovascular outcomes.
      • Calzadilla Bertot L.
      • Adams L.A.
      The natural course of non-alcoholic fatty liver disease.
      In comparison, patients with NASH may experience symptoms and complications of liver disease with the progression of fibrosis (Figure 2).
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Studies estimate one third of NAFL and NASH patients will have disease progression, advancing from one stage of fibrosis to the next at a rate of 7.7 years.
      • Calzadilla Bertot L.
      • Adams L.A.
      The natural course of non-alcoholic fatty liver disease.
      Although this rate appears relatively slow, the rate of progression in NASH patients is twice as high, with data showing a subset of NASH patients moving from no fibrosis to advanced fibrosis within a 6-year period on average.
      • Calzadilla Bertot L.
      • Adams L.A.
      The natural course of non-alcoholic fatty liver disease.
      Over time, a subgroup of NASH patients will progress to cirrhosis and liver decompensation.
      Figure thumbnail gr2
      Figure 2Stages of fibrosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

      Diagnosis and Evaluation

      In addition to considering a patient’s metabolic risk factors, there are 2 common clinical scenarios that typically increase a provider’s suspicion for NAFLD: 1) the patient presents with abnormal imaging results with evidence of increased echogenicity or hepatic steatosis or 2) the patient has abnormal liver enzymes, particularly aminotransferases (aspartate transaminase [AST] or alanine transaminase [ALT]).
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      If an NP encounters a patient with chronically elevated aminotransferases, other potential causes of elevated liver enzymes must be considered. If a patient has a single abnormal laboratory test, the test can be repeated for confirmation.
      Non-NASH NAFL can be diagnosed by evidence of hepatic steatosis on imaging.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      If NAFLD is suspected in a patient with abnormal liver tests, an abdominal ultrasound is recommended as the initial cost-effective imaging modality used to evaluate the liver parenchyma for chronic changes, assess hepatic vasculature, and confirm hepatic steatosis (Figure 3).
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Abdominal ultrasound and computed tomographic scans detect steatosis in patients with moderate to massive steatosis and are less specific in detecting NAFLD in a patient with mild steatosis.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Magnetic resonance imaging has been found to have a greater specificity in detecting steatosis but is not recommended as an initial imaging modality for the evaluation of NAFLD and remains costly.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Ultrasound, computed tomographic scanning, and general magnetic resonance imaging may reveal steatosis but are limited in accurately detecting hepatic fibrosis.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Figure thumbnail gr3
      Figure 3NAFLD algorithm.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      It is also important to note during the initial workup that although serum aminotransferases (AST and ALT) have often been used by providers to evaluate for NASH, they cannot be used alone to diagnosis NASH or the stage of a patient’s liver disease. Aminotransferases remain poor predictors of hepatic fibrosis because a subset of the NASH population with advanced fibrosis/cirrhosis has aminotransferases characterized within the normal range.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      After hepatic steatosis is confirmed, NPs must complete a thorough history and physical assessment to further differentiate if the steatosis (fat) present is caused by NAFLD or another etiology. Taking a detailed alcohol history is imperative. If a patient has had a history of significant alcohol intake either in the past or present (> 14 drinks per week for a female and > 21 drinks per week for a male), alcoholic liver disease should be a clear differential diagnosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      This patient is more likely to have alcohol-related fatty liver disease and should be counseled on alcohol cessation. It is also important to inquire about any family or personal history of obesity, metabolic or liver diseases, diabetes, hyperlipidemia, and sedentarism because these increase suspicion for NAFLD.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      In addition, patients must be screened for contributing chronic liver diseases and medications associated with hepatic steatosis. There are several medications that contribute to hepatic steatosis such as, but not limited to, amiodarone, corticosteroids, methotrexate, tamoxifen, antiretroviral medications, and valproic acid.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      The National Institutes of Health’s Clinical and Research Information on Drug-Induced Liver Injury website (livertox.nih.gov) provides a helpful search engine to review hepatotoxicity and data on various prescription medications and supplements.
      National Institutes of Health
      LiverTox.
      With any potential offending medication, an NP must outweigh the risk of the medication with the patient’s overall disease and mortality risk. For example, although statins would not contribute to steatosis, providers often discontinue or avoid prescribing statins to patients with elevated aminotransferases. However, most statins are considered beneficial for patients with NAFLD because this population’s most common cause of death remains cardiovascular disease, with liver-related mortality following.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      This example highlights the importance of an accurate diagnosis of elevated liver tests, specialty consultation if uncertainty persists, and the proper management of NAFLD risk factors.
      NPs also must consider each patient’s risk factors for viral hepatitis and screen as indicated. For example, hepatitis C genotype 3 can contribute to hepatitis steatosis.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      If the patient was born between 1945 and 1965, the Centers for Disease Control and Prevention recommends screening for hepatitis C in this patient population because they are 5 times more likely to have the disease.
      Centers for Disease Control and Prevention
      Testing recommendations for hepatitis c virus infection.
      Other liver diseases that may also contribute to hepatic steatosis should be considered as differential diagnoses including Wilson disease, hemochromatosis, Reye syndrome, and inherited metabolic diseases such as familial hyperlipidemias.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Consideration of a patient’s ethnicity, age, and background provide guidance and direction for NPs when evaluating differential diagnoses in a patient with hepatic steatosis.
      After collecting a detailed health history, the NP should perform a physical assessment. NAFLD patients are more likely to have an elevated body mass index, elevated waist and/or neck circumference, and visceral adiposity.
      • Diehl A.M.
      • Day C.
      Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.
      Acanthosis nigricans may be evident in the insulin-resistant population.
      • Rodriguez-Gutierrez R.
      • Salcido-Montenegro A.
      • Gonzalez-Gonzalez J.G.
      Early clinical expressions of insulin resistance: the real enemy to look for.
      In younger patients especially, neurologic findings may prompt a more detailed workup for Wilson disease.
      • Wattacheril J.
      • Shea P.R.
      • Mohammad S.
      • et al.
      Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease.
      Lean NAFLD patients are a unique subpopulation of patients who have a normal body mass index and develop the disease.
      • Wattacheril J.
      • Sanyal A.J.
      Lean NAFLD: an underrecognized outlier.
      These patients are challenging because they do not have the typical clinical presentation, and a genetic component may be a significant contributor to the development of NAFLD in this population.
      • Wattacheril J.
      • Sanyal A.J.
      Lean NAFLD: an underrecognized outlier.
      Traditional lifestyle change recommendations (caloric restriction to achieve weight loss) is not appropriate for this subgroup. It is important to note that visceral adiposity is more typical for patients even with lean NAFLD although they have a normal body mass index.
      • Wattacheril J.
      • Sanyal A.J.
      Lean NAFLD: an underrecognized outlier.
      Lastly, as mentioned previously, patients often develop their first symptoms of liver disease in the later stages of fibrosis, cirrhosis, and decompensated liver disease. Symptoms of liver disease include fatigue, abdominal pain, nausea, pruritus, or changes in mental status.
      The National Institute of Diabetes and Digestive and Kidney Diseases
      Symptoms and causes of cirrhosis.
      Signs include jaundice, ascites, hepatomegaly, splenomegaly, lower extremity edema, ascites, vomiting, hematemesis, and melena.
      The National Institute of Diabetes and Digestive and Kidney Diseases
      Symptoms and causes of cirrhosis.
      If an NP evaluates a patient with cirrhosis on imaging or symptoms of advanced liver disease or liver decompensation on examination, the patient should immediately be referred to a gastroenterologist or hepatologist.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Patients with cirrhosis must be screened for esophageal varices with endoscopy and imaging for hepatocellular carcinoma.
      • Berzigotti A.
      Advances and challenges in cirrhosis and portal hypertension.
      Consideration for liver transplantation is appropriate for patients with decompensated liver disease.

      Diagnosis of Non-NASH NAFLD versus NASH

      Although a diagnosis of NAFL can be made based on hepatic steatosis on imaging and the exclusion of other causes of hepatic steatosis, a definitive diagnosis of NASH is made by liver biopsy alone.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Risk factors such as uncontrolled diabetes, metabolic syndrome, and obesity place patients at a higher risk for the development of NASH. NPs should use noninvasive methods such as fibrosis scores to determine if a patient is at risk for NASH and refer high-risk patients for a specialist evaluation with a gastroenterologist or hepatologist.
      The NAFLD fibrosis score includes serum aminotransferases (AST and ALT), a diagnosis of diabetes or insulin resistance, age, body mass index, platelet count, and albumin to calculate a patient’s risk for developing fibrosis.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      The NAFLD fibrosis score had a 67% sensitivity and 97% specificity in predicting advanced fibrosis (patients with a score > 0.676) in a meta-analysis of over 3,000.
      • Musso G.
      • Gambino R.
      • Cassader M.
      • Pagano G.
      Meta-analysis: natural history of non alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
      The Fibrosis-4 calculator is a similar index that incorporates a patient’s platelet count, AST, ALT, and age into a general score for assessing risk for fibrosis.
      • Cleveland E.
      • Bandy A.
      • VanWagner L.B.
      Diagnostic challenges of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      These calculators are accessible online to NPs at no cost, and although helpful in determining patients at a higher risk for fibrosis, the calculation alone is insufficient to diagnose or predict NASH.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Validated serum-based biomarkers are a current area of unmet need and are currently under systematic review as well.
      • Ratziu V.
      • Goodman Z.
      • Sanyal A.
      Current efforts and trends in the treatment of NASH.
      Patients with elevated fibrosis scores and NASH risk factors should be referred for specialty evaluation. In addition to the fibrosis scoring tools, specialists use magnetic resonance elastography (MRE) and vibration-controlled elastography assessments for hepatic fibrosis. An MRE scan generates waves throughout the liver creating elastograms, or maps of tissue stiffness.
      • Hoodeshenas S.
      • Yin M.
      • Venkatesh S.K.
      Magnetic resonance elastography of liver: current update.
      The MRE will define areas of the hepatic fibrosis based on stiffness with no liver fibrosis (stage 0), mild fibrosis (stage 1), mild to moderate (stage 2), moderate to advanced (stage 3), and advanced fibrosis/cirrhosis (stage 4).
      • Hoodeshenas S.
      • Yin M.
      • Venkatesh S.K.
      Magnetic resonance elastography of liver: current update.
      A second noninvasive tool to assess liver stiffness is through a vibration-controlled transient elastography scan (FibroScan; Echosens, Paris, France).
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      This technology measures shear wave velocity through the liver via the use of an ultrasound probe. The scan detects steatosis and fibrosis, providing a score for both assessments.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      MRE and vibration-controlled elastography are useful noninvasive methods to assess for fibrosis; however, cost and accessibility to centers with this technology remain a barrier for many patients.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      After using noninvasive methods, patients at higher risk for NASH are appropriate to undergo a liver biopsy to confirm the diagnosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      A liver biopsy will provide the grade of inflammatory activity and stage of fibrosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Patients with NASH will have steatosis, hepatocyte ballooning, and lobular inflammation with or without fibrosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      The NAFLD activity score quantifies biopsy findings based on those 3 categories and has been mostly used to characterize biopsies for clinical trials.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

      Treatment

      Pharmacotherapy

      Current guidelines do not recommend any pharmacologic intervention for patients with non-NASH NAFLD because hepatic steatosis largely occurs in individuals who would be managed with lifestyle management. Vitamin E is the only antioxidant supplement recommended for a subpopulation of patients with biopsy-proven NASH, which targets the oxidative stress that can contribute to hepatic injury.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Vitamin E is contraindicated in patients with NASH with a diagnosis of diabetes or patients with NASH cirrhosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      A prescribed daily dosage of 800 IU in total per day is recommended.
      • Xu R.
      • Tao A.
      • Zhang S.
      • Deng Y.
      • Chen G.
      Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis.
      With the expanding NASH population, there is an unmet need for pharmacotherapies with an indication to treat this disease and prevent the disease progression. Patients with a diagnosis of NASH frequently pursue opportunities to participate in their care. If a patient meets the inclusion criteria for a study, clinical trials can provide patients with the opportunity to advance research. There are several clinical sites participating in clinical trials for potential agents with an indication for the treatment of NASH. NPs can use https://clinicaltrials.gov/ as a resource to search for accessible trials for NASH patients.
      National Institutes of Health
      Clinicaltrials.gov.
      The off-label use of any medication being studied for NASH is not recommended because of the lack of data analysis to prove efficacious as well as concern for patient safety.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

      Lifestyle Intervention

      To prevent the progression of hepatic steatosis and fibrosis, all patients with NAFLD should be counseled on therapeutic lifestyle interventions such as weight loss and the management of medical comorbidities including, but not limited, to insulin resistance, dyslipidemia, and hypertension. Weight loss remains the most effective way to reverse steatosis in the liver and prevent the progression of hepatic fibrosis.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Weight loss of 3% to 5% of a patient’s body weight reduces steatosis within the liver, and weight loss of 7% to 10% has been shown to decrease necroinflammation in patients with NASH.
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      In addition to improving outcomes among patients with mild to moderate fibrosis, weight loss can decrease portal hypertension in patients with NASH cirrhosis. Portal hypertension remains the greatest indicator for liver disease–associated mortality among this population and can be decreased by weight loss.
      • Berzigotti A.
      Advances and challenges in cirrhosis and portal hypertension.
      Clinical guidelines recommend patients achieve weight loss goals through a hypocaloric diet (reduction by 500-1,000 calories daily) and participation in moderate-intensity exercise.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      It is important to encourage patients to lose weight and assess each patient based on his or her ability, resources, and motivation. Encouraging patients to set weekly sustainable weight loss goals, a nutritionist referral, structured weight loss programs, and establishing care with a certified medical weight loss clinic are all helpful strategies for weight loss. In addition to participating in cardiovascular physical activity, resistance exercises help patients decrease liver fat and improve glucose control and insulin sensitivity.
      • Ratziu V.
      • Goodman Z.
      • Sanyal A.
      Current efforts and trends in the treatment of NASH.
      Bariatric surgery may also be a very effective option for NAFLD patients with excessive weight gain.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      However, bariatric surgery may be contraindicated in NASH cirrhosis patients with portal hypertensive because of the risk of decompensated liver disease.
      Patients with NAFLD should be screened for insulin resistance and cardiovascular disease and treated accordingly.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      To test for insulin resistance, providers can use a fasting or random blood glucose, hemoglobin A1c, or oral glucose tolerance testing.
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      Insulin resistance can be assessed in patients without a prior diagnosis of diabetes through the homeostatic model assessment of insulin resistance.
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease.
      This score is calculated by multiplying a patient’s random glucose level by random insulin with this result divided by 22.5.
      • Salgado A.L.
      • Carvalho L.
      • Oliveira A.C.
      • Santos V.N.
      • Vieira J.G.
      • Parise E.R.
      Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals.
      A calculation suggesting significant insulin resistance can favor a diagnosis of a patient with insulin-resistant NAFLD; early intervention in these patients with modest weight reduction may reduce the lifetime risk of diabetes.
      • Vilar-Gomez E.
      • Martinez-Perez Y.
      • Calzadilla-Bertot L.
      • et al.
      Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis.
      Patients with diabetes can be treated with oral hypoglycemic medications including metformin, insulin secretagogues, incretins, sodium-glucose cotransporter-2 inhibitors, and/or insulin to manage blood glucose.
      American Diabetes Association
      Standards of medical care in diabetes–2018.
      Although insulin resistance and diabetes remain associated risks for this disease, NASH is not a complication of diabetes, and there is a subset of patients with NASH without this risk factor.
      • Ratziu V.
      • Goodman Z.
      • Sanyal A.
      Current efforts and trends in the treatment of NASH.
      Several studies have investigated insulin sensitizers and their ability to treat NASH.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Unless a patient has a diagnosis of diabetes or prediabetes, metformin has not improved liver histology and is not recommended to be prescribed to treat NASH alone.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Studies on pioglitazone found an improvement of liver histology in patients with diabetes and biopsy-proven NASH; however, data were lacking to recommend the safe use of the medication in NAFLD patients without NASH.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      In summary, insulin resistance remains a significant NAFLD risk factor and should be appropriately managed if the workup indicates this condition. If a goal hemoglobin A1c has not been reached, a referral to endocrinology should be discussed with the patient.
      In addition to insulin resistance, NAFLD is associated with cardiovascular disease and increased cardiovascular mortality. Patients with hypertension should be managed based on evidence-based standard guidelines. Patients with hyperlipidemia should be managed similarly to patients with cardiovascular disease or a diagnosis of diabetes mellitus. Statin medications are generally thought to be safe and recommended in patients with NAFLD who would benefit from a cardiovascular risk profile including patients with NASH cirrhosis, but current guidelines recommend caution in decompensated cirrhotic patients.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.

      Conclusion

      NAFLD is the most prevalent chronic liver disease worldwide.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      The spectrum of NAFLD ranges from hepatic steatosis to patients with NASH cirrhosis. NPs can expertly use various clinical tools to assess if a patient is at greater risk for NASH. Research continues to search for more accurate and cost-effective biomarkers to diagnose NASH; however, liver biopsy remains the only diagnostic modality at this time.
      • Ratziu V.
      • Goodman Z.
      • Sanyal A.
      Current efforts and trends in the treatment of NASH.
      Patients with biopsy-proven NASH can be considered for pharmacotherapy or clinical trials.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      All patients with NAFLD, with or without NASH, should be counseled on weight loss and the management of any other existing comorbities.
      • Chalasani N.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      Addressing the primary risk factors for NASH, including obesity and the management of metabolic syndrome, requires regular follow-up and provider dedication. The percentage of NPs practicing within primary care continues to grow as the health care system is faced with a shortage of skilled clinicians within this setting.
      Primary care NPs can make the greatest positive impact within this population through longitudinal management of medical comorbidities and recognizing patients at risk for NASH. In addition to primary care, NPs in all settings should be aware of this disease process. Collaboration of an interdisciplinary team consisting of but not limited to primary care, endocrinology, cardiology, gastroenterology, and hepatology will lead to the best patient outcomes.

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      Biography

      Nicole Kelly, DNP, AGPCNP-BC, is a nurse practitioner at the Center for Liver Disease and Transplantation, Columbia University, NY Presbyterian Hospital in New York, NY, and can be contacted at [email protected]
      Julia Wattacheril, MD, MPH, is the director of the Nonalcoholic Fatty Liver Disease Program and an assistant professor of medicine with the Center for Liver Disease and Transplantation, Columbia University, NY Presbyterian Hospital.