How to Approach the Silent Epidemic of NAFLD and NASH

In a perfect world, we find the hidden answers to difficult questions and solve puzzles that have previously had no solution. Included in this scenario, is finding treatment options for worsening disease states that have no known cure such as, Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).

NAFLD and NASH have reached epidemic proportions, continuing to worsen over time given its close association with Type 2 Diabetes (T2D) and obesity. It has also become a major public health issue due to a combination of increasing disease burden, limited disease awareness, and an incomplete understanding of the natural history of this disease. While our “imperfect world” has yet to solve the conundrum that is NAFLD and NASH, the medical research being conducted by integrated research providers, such as ObjectiveHealth, are inching us closer to a medical therapy for this disease process.

According to the American Liver Foundation, it is estimated that NAFLD affects up to 25% of Americans, and 12-14% of these will get some degree of NASH. Despite this prevalence, awareness remains limited, with less than 5% of NAFLD patients are aware of their disease.

To further raise awareness of impending gastrointestinal disease states, Cusi et al. outlined guidelines regarding the diagnosis and management of NAFLD and NASH early. These guidelines will be key to identifying high-risk patients early at the primary-care level:

Adult Diagnosis of NAFLD/NASH

  1. High risk patients with clinically significant fibrosis scores (F2-F4) and cirrhosis need to be identified. Risk factors include obesity and diabetes and features of the metabolic syndrome (MS). This comprises some or all the following: hypertension, obesity, glucose intolerance, and hyperlipidemia, pre-diabetes or T2D, those with hepatic steatosis on any imaging study and/or persistent aminotransferase elevation (greater than 6 months). All such patients should be screened for NAFLD/NASH. Patients undergoing bariatric surgery should be evaluated for the presence and severity of NASH, and a liver biopsy should be considered at the time of surgery.
  2. Biomarkers/liver fibrosis predictors. The preferred test is the FIB-4 (calculated using age, AST, ALT and platelet number). Those with elevated or indeterminate FIB-4 scores should have a further workup with LSM (liver stiffness measurement) or ELF test (blood test calculated using levels of metalloproteinase I, aminoterminal propeptide III, procollagen, and hyaluronic acid).
  3. Best imaging studies for NAFLD/NASH include vibration controlled transient elastography, which is the best non-invastive validated test to identify advanced disease and predict liver related outcomes. Alternative approaches could include shear wave elastography and magnetic resonance elastography (most accurate but high cost and limited availability). Consider input from a gastroenterologist or hepatologist for patients with indeterminate results and those who have evidence of advanced disease.

Screening and Triage in NAFLD/NASH

  1. All previously identified high risk patients should be screened for clinically significant fibrosis.
  2. All T2D patients should be screened using FIB-4, even if they have normal liver related enzymes.
  3. Type 1 diabetics should be screened using FIB-4 only if there are risk factors such as obesity, features of the metabolic syndrome, elevated aminotransferases, or hepatic steatosis on imaging.
  4. Patients with persistently elevated aminotransferases and/or hepatic steatosis on imaging and indeterminate risk or high risk (FIB-4, LSM, or ELF) should be referred to a gastroenterologist or hepatologist for further assessment which may include a liver biopsy. Clinicians should refer patients with evidence of advanced liver disease (ascites, hepatic encephalopathy, esophageal varices, or evidence of hepatic synthetic dysfunction) to a gastroenterologist or hepatologist for further management.

Management in Adults with NAFLD/NASH

  1. All patients with NAFLD/NASH that are obese, have characteristics of the MS, prediabetes, T2D, dyslipidemia, hypertension, and cardiovascular disease should be aggressively managed based on the current standards of care. This strategy will hopefully mitigate cardiometabolic risk and extrahepatic complications.
  2. Clinicians should recommend lifestyle modifications in patients with obesity and NAFLD/NASH, with a goal of at least 5%, preferrable greater than 10% weight loss (more weight loss associated with greater histologic and cardiometabolic benefit). Participation in a structured weight loss program should be encouraged.
  3. Dietary modification in NAFLD/NASH patients with adoption of healthy eating patterns, such as the Mediterranean diet should be recommended. Reduction of dietary macronutrient content to induce an energy deficit, with restriction of saturated fats, starch, and added sugar, is a sound strategy.
  4. In NAFLD/NASH patients, clinicians must encourage physical activity that improves body composition and cardiovascular health. Participation in a structured regimen should be recommended. Any program should be tailored to the patient’s lifestyle and personal needs.

Medications Proven Effective for Treating Hepatic and Cardiometabolic Conditions Associated Conditions Associated with NAFLD/NASH

  1. Poiglitazone and GLP-1 RAs may be recommended in patients with T2D and biopsy proven NASH
  2. Clinicians may consider treating T2D patients with Poiglitazone and/or GLP-1 RAs when there is an increased likelihood of having NASH based on elevated plasma aminotransferase levels and non-invasive tests.
  3. In patients with T2D and NASH, clinicians may consider treatment with GLP-1 RAs, Poiglitazone, or SGLT2 inhibitors. This strategy is likely to offer cardiometabolic benefit, but there is no benefit for the treatment of steatohepatitis with SGLT2 inhibitors.
  4. Metformin, acarbose, dipeptidyl peptidase IV inhibitors, and insulin are not recommended for the treatment of steatohepatitis (no benefit on hepatocyte necrosis or inflammation).
  5. Vitamin E therapy may be considered for the treatment of NAFLD/NASH in patients without T2D, but there is not enough evidence presently to recommend for patients with T2D or advanced fibrosis.

Obesity Pharmacotherapy of Benefit in NAFLD/NASH Patients

  1. Obesity pharmacotherapy should be recommended as adjunctive to lifestyle modifications in obese NAFLD/NASH patients. Weight loss goal should be at least 5% of total body weight, with preferrable 10% or greater being ideal.
  2. For weight management in patients with a BMI of greater than 27 kg/m2 and NAFLD/NASH, clinicians may consider semaglutide 2.4 mg per week (best evidence) or liraglutide 3 mg per day.
  3. The rationale for above therapeutic recommendations as adjunctive therapy to lifestyle modifications is to promote cardiometabolic health and treat or prevent T2D, CVD, and other end-stage manifestations of obesity.

Bariatric Surgery in NAFLD/NASH Patients

  1. Clinicians may consider bariatric surgery as an option to treat NAFLD/NASH and improve cardiometabolic health in patients with a BMI greater than or equal to 35 kg/m2 (32.5 kg/m2 in Asian populations) especially if T2D is present. This should also be a consideration in those with a BMI 30kg/m2 to 35 kg/m2 (27.5 to 32.5 in Asian populations).
  2. For patients with NASH and compensated cirrhosis, caution should be exercised in recommending bariatric surgery, which should be highly individualized if prescribed, and performed only at specialized centers.
  3. In patients with decompensated cirrhosis, bariatric surgery should not be recommended due to limited evidence and the potential for harm.
  4. Endoscopic bariatric and metabolic therapy and orally digested devices should not be recommended in NAFLD/NASH patients due to insufficient evidence.

These guidelines will facilitate the necessary first steps in identifying this exploding patient population, and “guiding” the group to the proper resources for management. Publishing guidelines is a critical step in increasing awareness and demonstrating the public health threat of NAFLD/NASH.

It is important that awareness must also increase at the primary-care level, as well as every endocrinology clinic given that T2D is such a dominant risk factor in the NASH/NAFLD landscape.

When T2D became an established epidemic, medical science responded with an exponential increase in pharmacological research that has yielded an abundance of new medical therapy for the disease. The treatment of T2D in the last decade has undergone a “renaissance”, with millions of patients benefitting. We need a similar game plan for NAFLD/NASH.

ObjectiveHealth has committed itself to cutting edge research using proprietary technology to identify and stratify patients at risk for NASH for clinical trials, further advance medical science. There has been much time and effort put into NAFLD/NASH research, with 8 completed NASH trials, and many ongoing trials. Many new medications have shown great promise in phase 2 and 3 clinical trials with work spearheaded by ObjectiveHealth, and there will be many more to come. NAFLD/NASH is still very much a conundrum, but in time there will be effective pharmacologic agents to help us in the quest to address this growing epidemic.


  1. American Association of Clinical Endocrinology Clinic Practice Guidelines for the Diagnosis and Management of NAFLD in Primary Care and Endocrinology Clinical Settings

Dr. Kenneth Cusi et al

Endocrine Practice 28 (2022) 528-562