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Non-alcoholic fatty liver disease natural history, complications and prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2] Parth Vikram Singh, MBBS[3]

Overview

If left untreated non-alcoholic fatty liver disease may progress to fibrosis and, later cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. Common complications of NAFLD include fibrosis, cirrhosis, internal bleeding, encephalopathy. The presence of fibrosis and cirrhosis associated with a particularly poor prognosis among patients with NAFLD.

Natural History, Complications and Prognosis

See also: Non-alcoholic fatty liver disease Noninvasive scores

Natural History

  • The symptoms of NAFLD usually develop in the 40th decade of life, and usually asymptomatic at first.
  • After following NAFLD patients for long-term the outcome of the disease is as follows
    • 1) Patients with NAFLD has overall high morbidity and mortality rate and the common cause of death in NAFLD patients is cardiovascular disease.
    • 2) Patients with NASH has more liver-related mortality rate
  • Approximately 15% to 40% of patients with isolated hepatic steatosis progress to MASH. Fibrosis progression is usually slow, with progression of approximately 1 fibrosis stage over 14 years among patients with isolated steatosis and approximately 1 fibrosis stage over 7 years among patients with MASH. More advanced fibrosis is the strongest risk factor for progression to cirrhosis, hepatic decompensation, and liver-related mortality.[1]
  • In a systematic review and meta-analysis of patients with histologically confirmed MASLD, 2% to 3% of patients with isolated steatosis developed advanced fibrosis over 15 to 20 years, while approximately 25% to 30% of patients with MASH developed advanced fibrosis within 8 to 10 years. Among patients with biopsy-confirmed MASH and F3 fibrosis, 22% progressed to cirrhosis over 2 years.
  • Cirrhosis is associated with hepatic decompensation events, including ascites, hepatic encephalopathy, and variceal bleeding, which occur at rates of about 10% annually. Up to nearly 2.5% of patients with cirrhosis develop incident hepatocellular carcinoma annually.
  • If left untreated, patients with NAFLD may progress to develop hepato-cellular carcinoma (HCC). But it is directly propotional to the degree of fibrosis and advanced cirrhosis
  • Children who are positive with NAFLD are also prone to short lifespan when compared to general population.[2]

Patients progress about 1 stage per 7 years[3].

NAFLD with normal liver enzymes

Two cohort studies suggest no increased risk of cirrhosis among patients with steatosis by imaging but normal liver transaminases”

  • NAFLD with normal liver enzyme levels (n = 41,461) after 6 years of monitoring.[4]
  • NAFLD with normal liver enzyme levels (n = 3,522) after 8 years of monitoring[5].

NAFLD with high FIB-4

In a cohort study of uncertain duration, 8% of patients had a high FIB-4 and 3% had one of cirrhosis, hepatocellular carcinoma, and liver transplantation[6].

NAFLD and fatty liver index

The fatty liver index (FLI) is based on the following findings from a cohort study[7]:

Parameters of the fatty liver index[7]
Parameter Regression coefficient]
Loge (triglycerides, mg*dL-1) 0.953
BMI (kg*m2-1) 0.139
Loge (GGT, U*L-1) 0.718
Waist circumference (cm) 0.053
Constant -15.745

This leads to the equation: FLI = (e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference – 15.745) / (1 + e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference – 15.745) * 100

Or the equation may be expressed as:

  • ey / (1 + ey) × 100
  • Note that in both the numerator and denominator the exponent is: y = 0.953 × ln(triglycerides, mg/dL) + 0.139 × BMI + 0.718 × ln (GGT, U/L) + 0.053 × waist circumference, cm – 15.745

This equation has been used to prognosticate[8].

Online calculators are available:

  • Diagnosis of fatty liver. MDCALC
  • Distinguishing alchoholic and nonalcoholic fatty liver disease, Mayo Clinic

NAFLD with any fibrosis

The NIH Cohort found that any state of Fibrosis increases overall mortality or liver transplantation[9].

NAFLD imaging

Elastography can help determine prognosis[10].

Complications

  • Other complications of MASLD include hepatocellular carcinoma, cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers.

Non-alcoholic fatty liver disease, especially if with cirrhosis, may be associated with thrombocytopenia[13][14].

Prognosis

  • Cardiovascular disease is the leading cause of death in patients with noncirrhotic MASLD, followed by extrahepatic cancer and liver-related complications. In patients with MASLD-related cirrhosis, liver-related and cardiovascular disease-related deaths are the predominant causes of mortality.[15]
  • In a cohort study of patient who had biopsy-proven NAFLD, 6% developed death, hepatocellular carcinoma, or death with 5 years[16].

In a cohort of patients with steatosis by imaging but did not have liver biopsies, after 8 years of follow-up, liver function tests predicted clinical outcomes only if LFTs abnormal[5].

  • The rate of ESLD (fibrosis stage 3/4 with symptoms) among patients with fibrosis stage 1/2 over 20 years is per Nasr et al[17]:
    • 11% (6 of 53) (Supplementary table 1)
    • 25% (4 of 16) (Supplementary table 1)
  • Histology is the most reliable means to grade the severity of the disease and thus estimate prognosis.
    • Fibrosis stage is the strongest prognostic factor for liver-related morbidity and mortality. Compared with patients with no fibrosis, patients with cirrhosis have substantially higher risks of liver-related events, liver-related mortality, liver transplantation, and all-cause mortality.
    • The presence of fibrosis and cirrhosis is associated with a particularly poor prognosis among patients with NAFLD. [18]
    • Depending on the extent of the fibrosis and cirrhosis at the time of diagnosis, the prognosis may vary.[19]

A simulation study has estimated prognoses[20]

Prognosis estimated based on treatment

Randomized controlled trials have been executed of:

  • Semaglutide[21]:
    • “An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48)” over 6 years of treatment.

Assuming that

  • The 14% improvement above found be Newsome et al[21] would be significant in larger trials
  • An improvement in fibrosis state has the same clinical significance as regression from advanced fibrosis (stage 3 or 4) to non-advanced fibrosis (Stage 1 or 2)

The reduction in progression to end-stage liver disease (ESLD; fibrosis stage 3 or 4 with symptoms) by treating is 1.4% over twenty years. The estimate is based on: 

10% (the absolute reduction in advanced fibrosis due to treatment according to Newsome et al[21])
 x 
14% (approximate absolute increase in risk of ESLD from fibrosis 3/4 versus fibrosis 1/2 per Nasr et al[17])

Thus, the number needed to treat (NNT) is about 70 (100/1.4).

References

  1. ↑ Tilg H, Petta S, Stefan N, Targher G (January 2026). “Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review”. JAMA. 335 (2): 163–174. doi:10.1001/jama.2025.19615. PMID 41212550 Check |pmid= value (help).
  2. ↑ Calzadilla Bertot L, Adams LA (2016). “The Natural Course of Non-Alcoholic Fatty Liver Disease”. Int J Mol Sci. 17 (5). doi:10.3390/ijms17050774. PMC 4881593. PMID 27213358.
  3. ↑ Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R (2015). “Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies”. Clin Gastroenterol Hepatol. 13 (4): 643-54.e1-9, quiz e39-40. doi:10.1016/j.cgh.2014.04.014. PMC 4208976. PMID 24768810.
  4. ↑ Huang YH, Chan C, Lee HW, Huang C, Chen YJ, Liu PC; et al. (2023). “Influence of Nonalcoholic Fatty Liver Disease With Increased Liver Enzyme Levels on the Risk of Cirrhosis and Hepatocellular Carcinoma”. Clin Gastroenterol Hepatol. 21 (4): 960–969.e1. doi:10.1016/j.cgh.2022.01.046. PMC 9349477 Check |pmc= value (help). PMID 35124270 Check |pmid= value (help).
  5. ↑ 5.0 5.1 Natarajan Y, Kramer JR, Yu X, Li L, Thrift AP, El-Serag HB; et al. (2020). “Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes”. Hepatology. 72 (4): 1242–1252. doi:10.1002/hep.31157. PMC 8318072 Check |pmc= value (help). PMID 32022277 Check |pmid= value (help).
  6. ↑ Schreiner AD, Zhang J, Moran WP, Koch DG, Livingston S, Bays C; et al. (2023). “Real-World Primary Care Data Comparing ALT and FIB-4 in Predicting Future Severe Liver Disease Outcomes”. J Gen Intern Med. 38 (11): 2453–2460. doi:10.1007/s11606-023-08093-8. PMID 36814048 Check |pmid= value (help).
  7. ↑ 7.0 7.1 Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A; et al. (2006). “The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population”. BMC Gastroenterol. 6: 33. doi:10.1186/1471-230X-6-33. PMC 1636651. PMID 17081293.
  8. ↑ Kim KS, Hong S, Han K, Park CY (2024). “Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study”. BMJ. 384: e076388. doi:10.1136/bmj-2023-076388. PMC 10862140 Check |pmc= value (help). PMID 38350680 Check |pmid= value (help).
  9. ↑ Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P; et al. (2015). “Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease”. Gastroenterology. 149 (2): 389–97.e10. doi:10.1053/j.gastro.2015.04.043. PMC 4516664. PMID 25935633.
  10. ↑ Lin H, Lee HW, Yip TC, Tsochatzis E, Petta S, Bugianesi E; et al. (2024). “Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease”. JAMA. doi:10.1001/jama.2024.1447. PMID 38512249 Check |pmid= value (help).
  11. ↑ Chacko KR, Reinus J (2016). “Extrahepatic Complications of Nonalcoholic Fatty Liver Disease”. Clin Liver Dis. 20 (2): 387–401. doi:10.1016/j.cld.2015.10.004. PMID 27063276.
  12. ↑ Vanni E, Marengo A, Mezzabotta L, Bugianesi E (2015). “Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander”. Semin Liver Dis. 35 (3): 236–49. doi:10.1055/s-0035-1562944. PMID 26378641.
  13. ↑ Rivera-Álvarez M, Córdova-Ramírez AC, Elías-De-La-Cruz GD, Murrieta-Álvarez I, León-Peña AA, Cantero-Fortiz Y; et al. (2021). “Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia”. Hematol Transfus Cell Ther. doi:10.1016/j.htct.2021.06.004. PMID 34312112 Check |pmid= value (help).
  14. ↑ Panke CL, Tovo CV, Villela-Nogueira CA, Cravo CM, Ferreira FC, Rezende GFM; et al. (2020). “Evaluation of thrombocytopenia in patients with non-alcoholic fatty liver disease without cirrhosis”. Ann Hepatol. 19 (1): 88–91. doi:10.1016/j.aohep.2019.05.011. PMID 31575467.
  15. ↑ Tilg H, Petta S, Stefan N, Targher G (January 2026). “Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review”. JAMA. 335 (2): 163–174. doi:10.1001/jama.2025.19615. PMID 41212550 Check |pmid= value (help).
  16. ↑ Mózes FE, Lee JA, Vali Y, Alzoubi O, Staufer K, Trauner M; et al. (2023). “Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis”. Lancet Gastroenterol Hepatol. doi:10.1016/S2468-1253(23)00141-3. PMID 37290471 Check |pmid= value (help).
  17. ↑ 17.0 17.1 Nasr P, Ignatova S, Kechagias S, Ekstedt M (2018). “Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies”. Hepatol Commun. 2 (2): 199–210. doi:10.1002/hep4.1134. PMC 5796332. PMID 29404527.
  18. ↑ Jepsen P, Grønbæk H (2011). “Prognosis and staging of non-alcoholic fatty liver disease”. BMJ. 343: d7302. doi:10.1136/bmj.d7302. PMID 22102440.
  19. ↑ Suman, A.; Khullar, V.; Limaye, A. (2016). “Complications of Non-Alcoholic Fatty Liver Disease”. Journal of Hepatology. 64 (2): S473. doi:10.1016/S0168-8278(16)00798-4. ISSN 0168-8278.
  20. ↑ Chhatwal J, Dalgic OO, Chen W, Samur S, Bethea ED, Xiao J; et al. (2022). “Analysis of a Simulation Model to Estimate Long-term Outcomes in Patients with Nonalcoholic Fatty Liver Disease”. JAMA Netw Open. 5 (9): e2230426. doi:10.1001/jamanetworkopen.2022.30426. PMC 9471976 Check |pmc= value (help). PMID 36098969 Check |pmid= value (help).
  21. ↑ 21.0 21.1 21.2 Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V; et al. (2021). “A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis”. N Engl J Med. 384 (12): 1113–1124. doi:10.1056/NEJMoa2028395. PMID 33185364 Check |pmid= value (help).

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