The Pivotal Role of Gastroenterologists in NASH Care

Increasing Prevalence of Nonalcoholic Fatty Liver Disease

Together, nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), have reached epidemic proportions in the United States, with grave consequences for patients, clinicians, and healthcare systems.¹ The pooled prevalence of NAFLD in North America is approximately 31%, and NASH prevalence is approximately 5%.² By 2030, if current trends are left unchecked, NAFLD prevalence in the United States is projected to increase about 21%, and NASH prevalence is projected to increase by about 63%.^1,3

Need for a Unified Healthcare Strategy

Patients seen in primary care, endocrinology, and gastroenterology settings who may have NAFLD typically have obesity, diabetes, or metabolic syndrome.⁴ Thus, a unified strategy among healthcare providers is critical to identify, screen, diagnose, refer, and treat patients across the continuum of the disease.⁴ Alignment of primary care providers, endocrinologists, obesity medicine specialists, gastroenterologists, and hepatologists is key to identify patients with NAFLD, detect those with clinically significant fibrosis, and engage patients in care to improve their outcomes.⁴

NASH as a Progressive Disease

Early diagnosis of NAFLD is a key step in preventing progression to NASH.⁵ Clinicians need to initiate a care plan once any stage of the disease is detected.⁶ Without intervention, about 25% of patients who have NAFLD will develop NASH.⁵ Patients who have NASH are at risk for developing advanced fibrosis or cirrhosis.⁵ Furthermore, patients who have cirrhosis may develop hepatic carcinoma or liver failure and need liver transplantation.⁵

The NAFLD Clinical Care Pathway

A multidisciplinary panel of experts developed a Clinical Care Pathway that provides explicit guidance on the screening, diagnosis, and treatment of NAFLD.⁷ The Pathway is applicable in any setting where care for patients who have NAFLD is provided, including primary care, endocrinology, obesity medicine, gastroenterology practices, or other settings.⁷ The Pathway helps clinicians identify, test, and stratify patients into low-, intermediate-, or high-risk categories and determine how best to manage their care.⁷

Steps in the Pathway

Hepatic fibrosis is the most important determinant of liver and non-liver outcomes in patients with NAFLD.⁷ Therefore, Step 1 of the Pathway is effective screening and timely diagnosis of fibrosis to prevent disease progression in key risk groups.⁷ The 3 groups known to be at greatest risk of NAFLD/NASH-related fibrosis are: patients with type 2 diabetes; patients with 2 or more metabolic risk factors (eg, hypertension, dyslipidemia, or obesity); and patients with an incidental finding of hepatic steatosis or elevated aminotransferase levels.⁷ Of note, hepatic steatosis is sometimes detected in patients undergoing thoracic and abdominal imaging for reasons other than liver symptoms, signs, or abnormal liver biochemistry.⁷

Step 2 is to screen all at-risk patients identified in Step 1 for alcohol use and perform liver tests (or a comprehensive metabolic panel) and a complete blood count.⁷ Other forms of chronic liver disease need to be excluded, and patients need to be evaluated for liver masses.⁷

With the results from standard laboratory tests, clinicians can risk stratify patients for fibrosis using the Fibrosis-4 (FIB-4).⁷ The FIB-4 score is calculated from 4 variables: patient age, platelet count, and aspartate transaminase (AST) and alanine transaminase (ALT) results.⁷

Patients with scores <1.3 are at low risk for advanced fibrosis however, the FIB-4 should be repeated in 2 to 3 years.^7,8 A FIB-4 score >2.67 indicates a high risk for advanced fibrosis and the need to refer the patient to a hepatologist.⁷ For patients who have an intermediate score, the next step is to perform a secondary noninvasive test, typically a liver stiffness measurement (LSM).⁷ If this test is not available, clinicians should consider a liver biopsy, magnetic resonance elastography, or some other type of evaluation to obtain secondary risk stratification.⁷

Liver Stiffness Measurement

Transient elastography (FibroScan) is now widely used across the United States to obtain the LSM (liver stiffness measurement). The score, measured in kilopascals (kPa), reflects risk for clinically significant fibrosis.⁷ The methodology uses a shear wave, which is introduced through the skin, travels through the liver, and is then retrieved back to the transducer.⁹ An LSM  ( kPa)  <8 indicates that a patient is at low risk for significant fibrosis. A kPa of ≥12 indicates the patient is likely to have very significant fibrosis.⁷ Patients who have scores between 8 and 12 have intermediate risk and are likely to have stage 2 or higher fibrosis.⁷

Managing Patient Care

At this time, the U.S. Food and Drug Administration (FDA) has not approved any of the medications being investigated in clinical trials specifically for treatment of NASH. However, structured lifestyle interventions and medications for the management of comorbidities can have positive effects, and clinicians can help patients with NASH improve their health outcomes.⁴

Lifestyle Interventions and Investigational Drugs

Lifestyle interventions for NASH do work, but they can be difficult for patients to adopt.^10-14 Among patients with histologically proven NASH who participated in a study to assess the effects of weight loss on their disease, the more lifestyle-induced weight loss the patients achieved, the greater their improvement in histologic features of NASH.¹⁰ Rates of NASH reduction, NASH resolution, and fibrosis regression were highest among patients who lost ≥10% of their body weight.¹⁰

The FDA has issued guidance about the endpoints required for the approval of medications to treat patients who have NASH.^15,16 The primary efficacy endpoints that have been used in phase 2b and phase 3 clinical trials of drug treatment for patients with NASH are resolution of steatohepatitis on the overall histopathologic reading and no worsening of fibrosis.¹⁷ The secondary endpoint is improvement of 1 or more fibrosis stages with no worsening of steatohepatitis.¹⁷

Both endpoints—NASH resolution and fibrosis improvement—were achieved in MAESTRO-NASH (NCT03900429), a phase 3 trial of resmetirom.¹⁷ NASH resolution with no worsening of fibrosis was achieved in 26% and 30% of patients treated with resmetirom 80 mg and 100 mg, respectively, vs 10% in the placebo group. At least a 1-point fibrosis improvement with no worsening of NASH was achieved in 24% and 26% of patients treated with resmetirom 80 mg and 100 mg, respectively, vs 14% in the placebo group. Finally, the interim analysis reported achievement of a key secondary endpoint with a mean reduction in low-density lipoprotein cholesterol at week 24 of –12% and –16% in patients treated with resmetirom 80 mg and 100 mg, respectively, vs 1% in the placebo group .¹⁷ In addition, the study investigators noted a favorable impact on trial participants’ lipid profiles.¹⁷ 

The investigational drug lanifibranor was studied in the phase 2b trial NATIVE (NCT03008070).^16,17 NASH resolution with no worsening of fibrosis was achieved in 49% and 39% of patients treated with lanifibranor 1200 mg and 800 mg, respectively, vs 22% in the placebo group.^17,18 Improvement in the fibrosis stage of at least 1 point with no worsening of NASH was achieved in 48% and 34% of patients treated with lanifibranor 1200 mg and 800 mg, respectively, vs 29% in the placebo group.^17,18

A phase 2b study of semaglutide (NCT02970942) involving patients with NASH showed that a significantly higher percentage of those treated with semaglutide had NASH resolution at 72 weeks compared with the placebo group.¹⁹ However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage.¹⁹ Various doses of semaglutide were used, (0.1 mg, 0.2 mg, and 0.4 mg), and resolution of NASH with no worsening of fibrosis was seen in the population of patients who received semaglutide at the 0.4-mg dose.¹⁹

Conclusion

Noninvasive tests are available to aid clinicians in risk stratification of the large numbers of patients who have NAFLD and to identify those who likely have NASH, fibrosis, and more progressive disease. Current options available to manage patients with NAFLD or NASH target weight loss through lifestyle interventions or bariatric surgery. There are several investigational drugs in development for patients with NASH that are showing promising results in late-phase clinical trials.

References

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15. U.S. Food and Drug Administration. Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. December 2018. Accessed November 16, 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/noncirrhotic-nonalcoholic-steatohepatitis-liver-fibrosis-developing-drugs-treatment
16. U.S. Food and Drug Adminstration. Technical specifications for submitting clinical trial data sets for treatment of noncirrhotic nonalcoholic steatohepatitis (NASH) guidance for industry technical specifications document. January 2022. Accessed November 16, 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/technical-specifications-submitting-clinical-trial-data-sets-treatment-noncirrhotic-nonalcoholic
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19. Newsome PN, Buchholtz K, Cusi K, et al; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395