The role of liver fibrosis in the new onset of metabolic comorbidities in patients with NAFLD

29 Jul 2020

Non Alcoholic Fatty Liver Disease (NAFLD) is the most common liver disease in the Western countries1.  Even it is often considered the hepatic manifestation of the metabolic syndrome,  it is a matter of debate if NAFLD could precede the development of some metabolic disturbances, such as type 2 Diabetes Mellitus (T2DM), Arterial Hypertension (AHT) and dyslipidemias2,3.
The Spanish investigators of the Hepamet Registry recently published a multicenter longitudinal study in which they included 178 biopsy proven NAFLD patients without T2DM, AHT, hypertriglyceridemia and dyslipidemia at the baseline, while 40% of patients had a BMI >30 kg/m2 at the time of liver biopsy4.

The overall population were follow-up until the development of metabolic comorbidities. Patients who had significant fibrosis at the baseline (n=35, F2-F4 vs. F0-F1)5 were older in age, they had significantly higher insulin resistance (HOMA-IR), lower platelet count and they were more frequently obese. 37.1% of patients developed one or more metabolic disturbances during a mean follow-up of 5.6 ± 4.4 years.

The annual incidence rate of T2DM and AHT resulted four times higher in patients showing significant fibrosis compared to those with mild fibrosis, and the combination of significant fibrosis and obesity showed the highest annual incidence for T2DM and AHT, while fibrosis was not related to the occurrence of dyslipidemia. At multivariate analysis significant fibrosis, assessed by liver biopsy, predicted the incidence of T2DM (together with age, glucose, and BMI) and AHT (with age, glucose, BMI and platelets), while any significant association was found between liver steatosis or NASH and the occurrence of T2DM and AHT, as previously reported.

Among non-invasive blood tests calculated at the baseline (Hepamet Fibrosis Score,  Fibrosis-4 and NAFLD fibrosis Score) only Hepamet Fibrosis Score (HFS) >0.12 predicted the occurrence of T2DM, a result that could be explained by the inclusion of HOMA-IR in HFS.

The study conclusions were that the metabolically healthy patients with NAFLD-related significant fibrosis were at greater risk of developing T2DM and AHT; therefore, patients with intermediate-to-high risk of significant fibrosis should be more strictly monitored for the new onset of metabolic comorbidities.

Even if the study definition of “metabolically healthy patients” did not include the presence of BMI alterations and insulin resistance, the results of this study should be considered another step forward in demonstrating the importance of early detection of liver fibrosis in patients with NAFLD.


  1. Sanyal AJ. Past, present and future perspectives in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2019;16:377–386.
  2. Ma J, Hwang S-J, Pedley A, Massaro JM, Hoffmann U, Chung RT, et al. Bidirectional analysis between fatty liver and cardiovascular disease risk factors. J Hepatol 2017;66:390–397.
  3. Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 2017;66:1138–1153.
  4. Ampuero J, Aller R, Gallego-Durán R, HEPAmet Registry. Significant fibrosis predicts new-onset diabetes mellitus and arterial hypertension in patients with NASH. J Hepatol. 2020 Jul;73(1):17-25.
  5. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–1321.