Nonalcoholic Fatty Liver Disease: A Disease that Is Difficult to Treat

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver, accumulation that is not related to excessive alcohol use.[1] Some people with NAFLD develop a form of the disease known as nonalcoholic steatohepatitis (NASH), which is associated with inflammation of the liver. Liver damage from inflammation can lead to scarring (fibrosis and cirrhosis) and liver failure, with its many complications including fluid buildup in the abdomen, esophageal bleeding and liver cancer. The leading cause of death associated with NAFLD is cardiovascular disease. Experts are uncertain why some people with NAFLD develop NASH and others do not. There are no medications that have been approved by the U.S. Food and Drug Administration (FDA) to treat either NAFLD or NASH.

The prevalence of NAFLD in the United States is approximately 20% and the prevalence of NASH is approximately 3%-5%.[2],[3] Most patients are diagnosed with NAFLD when they are 40 to 60 years of age.[4] In patients undergoing gastric bypass surgery for obesity, 71% to 88% were found to also have NAFLD.[5] In the United States, the prevalence of NAFLD has increased over time. Specifically, one study indicated that, in 1994, the prevalence was 6%. By 2008, it was 11%.[6]

Etiology, diagnosis, and treatment

The cause of NAFLD is not well understood. The disease is linked to a variety of metabolic (energy use) conditions including being overweight, as well as to high levels of sugar (hyperglycemia), cholesterol or fats (especially triglycerides) in the blood.[7],[8],[9] One study of 120 NASH patients without overt diabetes found that 88% had substantial metabolic illness.[10] Notably, foie gras (fatty liver meat) is an animal model of NAFLD, as the fatty liver is cultivated by inducing the disease in ducks via forced feeding to promote rapid and excessive weight gain.[11] NAFLD is also linked to polycystic ovary syndrome, sleep apnea and decreased activity of the thyroid and pituitary glands.[12] The cause or causes of NASH are even less well understood than the causes of NAFLD.

NAFLD is often first detected with blood tests that assess liver function, ordered during a medical checkup.[13] Although clinicians may use non-invasive imaging (ultrasound or magnetic resonance imaging [MRI]) to assess the presence of NAFLD, a definitive diagnosis may require microscopic examination of a liver tissue sample obtained via a needle biopsy through the abdomen. A recent UpToDate article on diagnosing NAFLD underscored the uncertainty of the diagnostic process. The article noted that computerized tomography (CT) and MRI imaging are “not sufficiently sensitive” to liver inflammation and fibrosis, and that presently “[t]here is no clear consensus about which patients require a liver biopsy.”[14]

The recommended treatment for NAFLD is weight loss through diet and exercise.[15] Weight loss can reduce liver fat, inflammation and fibrosis. Other recommendations are to eliminate alcohol consumption, be up to date on hepatitis vaccinations and to avoid or lower the dose of medications that can be toxic to the liver.[16] A Worst Pills, Best Pills News article from 2020 notes that more than 1,000 drugs and supplements can be toxic to the liver.[17] These medications include tamoxifen (SOLTAMOX) for breast cancer, amiodarone (PACERONE) for abnormal heart rhythm, methotrexate (TREXALL,XATMEP)[18] for cancer and rheumatoid arthritis and acetaminophen (TYLENOL) for pain relief. For some patients with progressive disease, liver transplantation may become necessary.

Given that weight loss is important to treating NAFLD, bariatric surgery is a potential approach for obese patients.[19] A recent randomized clinical trial of 288 patients that was conducted in Italy found that surgery was more effective than lifestyle changes and regular medical care at resolving NASH after a one-year of follow-up. The trial, however, was not blinded (patients and researchers knew who received the surgery). Severe adverse events occurred in 10 (6%) of those receiving surgery and in none of those in the lifestyle group. The role of bariatric surgery in treating patients with NASH requires further study.

No medications for NAFLD or NASH are FDA-approved

Although medications for NAFLD and NASH are being studied, as of December 2023, none had been approved by the FDA.[20] Below is a summary of some of those drugs.

The diabetes drugs known as glucagon-like peptide-1 (GLP-1) agonists have received considerable attention as weight-loss drugs.[21] Data, however, are lacking about a possible role for GLP-1 agonists in treating NAFLD or NASH.[22] Concerns about this class of medication include the fact that they need to be used lifelong to prevent weight regain and that they increase the risks for pancreatitis as well as pancreas and thyroid cancers.[23]

For patients with NASH and substantial fibrosis, but without diabetes, vitamin E in high doses has been suggested. The data, however, are mixed and unconvincing. Moreover, there are concerns that vitamin E supplementation above 400 international units per day may increase the risk of death.[24]

In NASH patients with type 2 diabetes, pioglitazone (ACTOS) has been suggested.[25],[26] Pioglitazone is one of a class of drugs known as thiazolidinediones, which are believed to act by increasing the body’s sensitivity to insulin. The drug, however, is associated with an increased risk of weight gain (which is not good for patients with NASH), heart failure and bone fracture, among others concerns. Public Citizen’s Health Research Group has classified pioglitazone as a Do Not Use drug.[27]

Obeticholic acid (OCALIVA), a bile acid analogue, was approved by the FDA in 2016 for the treatment of certain adult patients with primary biliary cholangitis (autoimmune-triggered degradation of the bile ducts that run through the liver). Obeticholic acid has demonstrated limited effectiveness in reducing fibrosis in NASH, but not in resolving NASH.[28] In May 2023, the FDA convened its Gastrointestinal Drugs Advisory Committee to discuss accelerated approval of the drug for the treatment of NASH with fibrosis. At the public hearing of the advisory committee meeting, Public Citizen’s Health Research group argued against accelerated approval because the treatment did not resolve NASH, and because treatment with obeticholic acid, as compared to placebo, increased the risk for adverse effects including pruritus (itching) and drug-induced liver disease.[29] We agreed with the FDA reviewers that the clinical efficacy of obeticholic acid is unknown. The advisory committee voted 15-1 against accelerated approval.[30]

What You Can Do

If you suspect you have NAFLD or have been diagnosed with NAFLD or NASH, you should discuss the best approach with your clinician. The cornerstone of therapy is dietary modifications and physical activity to support sustained weight loss. Although it may eventually be established that medications to support weight loss or medications to treat NAFLD or NASH directly have a role in treatment, at present there are no medications that are FDA-approved for either condition. In individuals, the progression of NAFLD remains uncertain as data compiled across 11 studies indicates that fibrosis worsens in approximately 34% of patients diagnosed through a liver biopsy, stabilizes in 43% and improves in 22% of confirmed cases.[31] This same compilation of evidence further estimated that the average rate at which fibrosis worsens in NAFLD was by 1 stage (range from 0 [no fibrosis] to 4 [severe, cirrhosis]) every 14 years, and by 1 stage every seven years for those with NASH.
 

References

[1] Mayo Clinic. Non-alcoholic liver disease. Overview. September 22, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567. Accessed September 27, 2023.

[2] Antunes C, Azadfard M, Hoilat GJ, et al. Fatty liver. [Updated 2023 Jan 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

[3] Sheth SG, Chopra S. Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults. UpToDate. November 7, 2022.

[4] Ibid. p. 3

[5] Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;25(8):883-9.

[6] Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9(6):524-530.e1.

[7] Mayo Clinic. Non-alcoholic liver disease. Overview. September 22, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567. Accessed September 27, 2023.

[8] Antunes C, Azadfard M, Hoilat GJ, et al. Fatty Liver. [Updated 2023 Jan 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

[9] Tendler DA. Pathogenesis of nonalcoholic fatty liver disease. UpToDate. August 23, 2022.

[10] Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917-23.

[11] Wikipedia. Fatty liver disease. https://en.wikipedia.org/wiki/Fatty_liver_disease#In_animals. September 9, 2023. Accessed September 27, 2023.

[12] Mayo Clinic. Non-alcoholic liver disease. Overview. September 22, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567. Accessed September 27, 2023.

[13] Mayo Clinic. Non-alcoholic liver disease. Diagnosis and Treatment September 21, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/diagnosis-treatment/drc-20354573. Accessed September 12, 2023.

[14] Sheth SG, Chopra S. Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults. UpToDate. November 7, 2022.

[15] Antunes C, Azadfard M, Hoilat GJ, et al. Fatty Liver. [Updated 2023 Jan 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

[16] Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate. June 26, 2023.

[17] Drug-Induced Liver Injury. Worst Pills Best Pills News. May 2020. https://www.worstpills.org/newsletters/view/1328. Accessed September 27, 2023.

[18] Antunes C, Azadfard M, Hoilat GJ, et al. Fatty Liver. [Updated 2023 Jan 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

[19] Verrastro O, Panunzi S, Castagneto-Gissey L, et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet. 2023;401(10390):1786-1797.

[20] Mayo Clinic. Non-alcoholic liver disease. Diagnosis and Treatment September 21, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/diagnosis-treatment/drc-20354573. Accessed September 27, 2023.

[21] Drug-Induced Liver Injury. Worst Pills Best Pills News. May 2020. https://www.worstpills.org/newsletters/view/1328. Accessed September 22, 2023.

[22] Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate. June 26, 2023.

[23] Antunes Ibid.

[24] Chopra S, Lai M. Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate. June 26, 2023.

[25] Mayo Clinic. Non-alcoholic liver disease. Diagnosis and Treatment September 21, 2021. https://www.mayoclinic.org/diseases-conditions/nonalcoholic-fatty-liver-disease/diagnosis-treatment/drc-20354573. Accessed September 12, 2023.

[26] Leung PB, Davis AM, Kumar S. Diagnosis and Management of Nonalcoholic Fatty Liver Disease. JAMA. 2023 Oct 16. doi: 10.1001/jama.2023.17935.

[27] Chopra S, Lai M. Management of nonalcoholic fatty liver disease in adults. UpToDate. June 26, 2023.

[28] Lee KC, Wu PS, Lin HC. Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis. Clin Mol Hepatol. 2023;29(1):77-98.

[29] Public Citizen’s Health Research Group. Inadequate evidence, and safety concerns for accelerated approval for NDA# 212833 (obeticholic scid; intercept pharmaceuticals) for the treatment of nonalcoholic steatohepatitis with fibrosis. Testimony before the Food and Drug Administration’s Gastrointestinal Drugs Advisory Committee. May 19, 2023. https://www.citizen.org/wp-content/uploads/2658.pdf. Accessed September 27, 2023.

[30] Food and Drug Administration, Center for Drug Evaluation and Research. Final minutes summary for the Gastrointestinal Drugs Advisory Committee Meeting. June 16, 2023. https://www.fda.gov/media/169627/download. Accessed September 27, 2023.]

[31] Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-54.e1-9.