Diabetes Impacts Prediction of Cirrhosis and Prognosis by Non-invasive Fibrosis Models in Non-alcoholic Fatty Liver Disease

Luis C. Bertot; Gary P. Jeffrey; Bastiaan de Boer; Gerry MacQuillan; George Garas; Justin Chin; Yi Huang; Leon A. Adams


Liver International. 2018;38(10):1793-1802. 

In This Article

Abstract and Introduction


Background & Aims: Non-alcoholic fatty liver disease (NAFLD) patients with diabetes are at increased risk of cirrhosis and liver-related death, and thus accurate fibrosis assessment in these patients is important. We examined the ability of non-invasive fibrosis models to determine cirrhosis and outcomes in NAFLD patients with and without diabetes.

Methods: Non-alcoholic fatty liver disease patients diagnosed between 2006 and 2015 had Hepascore, NAFLD fibrosis score (NFS), APRI and FIB-4 scores calculated at baseline and were followed up for outcomes of overall and liver-related mortality/liver transplantation, hepatic decompensation and hepatocellular carcinoma (HCC). Model accuracy was determined by Harrell's C-index and by Kaplan-Meier analysis.

Results: A total of 284 patients (53% diabetic, 15% cirrhotic) were followed up for a median of 51.4 months, (range 6.1–146). During follow-up, diabetic patients had a greater risk of liver-related death/transplantation, HR 3.4 (95% CI 1.2–9.1) decompensation, HR 4.7 (95% CI 2.0–11.3) and HCC, HR 2.9 (95% CI 1.2–7.3). Among 241 subjects with a baseline liver biopsy, the accuracy of Hepascore, APRI and FIB-4 for predicting cirrhosis was lower amongst diabetics compared to non-diabetics (P < .005 for all). Model accuracy apart from Hepascore, was also significantly lower for predicting liver death/transplantation in patients with diabetes. No patient with a low fibrosis score and without diabetes developed liver decompensation or HCC, whereas up to 21% of diabetic patients with a low fibrosis score developed liver decompensation and up to 27% developed HCC at 5 years.

Conclusions: Non-invasive scoring systems are less accurate at predicting cirrhosis and liver-related outcomes in patients with NAFLD and diabetes.


Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world.[1] Due to the global epidemic of obesity and diabetes, NAFLD is projected to become the leading cause of liver related morbidity and mortality in the next 20 years and is estimated to be the leading indication for liver transplantation in the next few years.[2,3]

Nevertheless, only a minority of patients with NAFLD will develop end-stage liver disease or die of complications related to liver disease. Subsequently, identifying patients at greatest risk of developing liver related complications remains a key clinical need to prioritize treatment, eligibility for clinical trials and monitoring.

Type 2 diabetes has emerged as a consistent risk factor for the development of cirrhosis, liver decompensation and death among patients with NAFLD.[4–7] The prevalence of advanced fibrosis in patients attending diabetes clinics is 7%–10%[8,9] and the risk of liver-related related death is more than twice as likely in individuals in the general population with diabetes than those without.[10] Thus, the presence of diabetes identifies an "at risk" sub-population of NAFLD patients, however, is not sufficiently sensitive or specific to predict cirrhosis or outcomes. Accurate determination of cirrhosis and prediction of future liver related outcomes in NAFLD patients with diabetes is therefore important and directly influences clinical decision making regarding surveillance for HCC, oesophageal varices, need for pharmacotherapy as well as ongoing monitoring and follow-up..[11]

The degree of hepatic fibrosis is currently the strongest predictor of long-term clinical outcomes in NAFLD patients including liver related mortality, decompensation and hepatocellular carcinoma (HCC).[12,13] Although liver biopsy remains the gold standard investigation for assessing stage of disease, its invasive nature makes it impractical for wide-spread use as a prognostic tool.[11] Serum-based panel tests are attractive alternatives due to their wide-spread availability, ease of use, cost and patient acceptability. Several non-invasive panels including APRI, FIB-4, Hepascore and the NAFLD fibrosis score (NAFLD FS) have demonstrated a good degree of accuracy and high negative predictive value's (NPV) to exclude advanced fibrosis.[14–16] In addition to being reliable predictors of advanced hepatic fibrosis, several serum-based panels have been demonstrated to predict liver related and/or overall mortality in patients with NAFLD.[17,18]

Despite the incorporation of non-invasive fibrosis assessment into clinical practice, it is clear that these measures can be influenced by patient factors that may reduce accuracy and limit interpretation.[19,20] One factor among patients with NAFLD may be the presence of type 2 diabetes, with the accuracy of the BARD score for determining advanced fibrosis noted to be significantly less in patients with type 2 diabetes.[21] This finding has not been confirmed and it remains unknown whether diabetes is associated with reduced accuracy or impaired prognostic ability in other fibrosis models. We aimed to examine the impact of diabetes on four non-proprietary algorithms (NAFLD fibrosis score, Hepascore, APRI and FIB-4) for firstly, the determination of cirrhosis and secondly, for the prediction of overall mortality, liver related events and HCC in NAFLD patients.