From fatty liver to end-stage liver disease through type 2 diabetes

The past decades have seen a marked increase in the incidence of type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). Epidemiological studies have clearly demonstrated that there is an association between type 2 diabetes and NAFLD. Further, it has been established that patients with type 2 diabetes are at an increased risk of severe liver disease. While liver biopsy remains the gold standard for diagnosing NAFLD, it is not clear how - and if - the histological features of NAFLD are associated with an increased risk of type 2 diabetes. It is unclear how to identify the subset of patients with type 2 diabetes that have the highest risk of severe liver disease. Likewise, it is not known how the currently practiced treatment strategies for type 2 diabetes affect the progression of NAFLD. Finally, the risk of cancer in the broader population of patients with NAFLD is not well known.

In the first paper, we investigated the risk of type 2 diabetes in a cohort of patients with biopsy-proven NAFLD and found that higher stages of fibrosis were associated with an increased risk of type 2 diabetes. In patients with small amounts of fibrosis, the amount of steatosis on biopsy was associated with an increased risk of type 2 diabetes. These results indicate that fibrosis and simple steatosis are useful histological variables when estimating risk of type 2 diabetes in patients with NAFLD.

In the second paper, we assessed the risk of severe liver disease (defined as a composite outcome of diagnoses correlated to cirrhosis) in a population-based cohort of patients with type 2 diabetes. We observed type 2 diabetes to be associated with an increased risk of severe liver disease compared to controls free of diabetes, and identified several risk factors for severe liver disease in patients with type 2 diabetes. These results motivate further studies to better characterize the patients with type 2 diabetes that are at a high risk of severe liver disease.

In the third paper, we studied how a personalized 4-day treatment program for type 2 diabetes currently used in clinical practice at the Karolinska University Hospital in Stockholm affects the progression of NAFLD. Patients were examined with transient elastography at baseline and at a follow-up visit after three months. The prevalence of NAFLD and increased liver stiffness was high. Improved glycemic control seen after the treatment program was associated with a reduction in hepatic steatosis in patients with NAFLD at baseline. These results indicate that improving glycemic control in type 2 diabetes per se can also be effective in treating NAFLD.

In the fourth paper, we examined the risk of cancer in a population-based cohort of patients with NAFLD compared to matched reference individuals. We observed an association between NAFLD and a slightly increased risk of any cancer. Of the specific types of cancer we investigated, the strongest association was found between NAFLD and risk of HCC. A slightly increased risk was also observed for bladder, kidney and uterine cancer. Further, male patients with NAFLD had a slightly increased risk of colorectal cancer. These results do not motivate general screening for cancer in patients with NAFLD.

List of scientific papers

I. Karl Björkström, Per Stål, Rolf Hultcrantz, Hannes Hagström. Histologic Scores for Fat and Fibrosis Associate With Development of Type 2 Diabetes in Patients With Nonalcoholic Fatty Liver Disease. Clinical Gastroenterology and Hepatology. 2017;15:1461–1468.
https://doi.org/10.1016/j.cgh.2017.04.040

II. Karl Björkström, Stefan Franzén, Björn Eliasson, Mervete Miftaraj, Soffia Gudbjörnsdottir, Ylva Trolle-Lagerros, Ann-Marie Svensson, Hannes Hagström. Risk Factors for Severe Liver Disease in Patients With Type 2 Diabetes. Clinical Gastroenterology and Hepatology. 2019;17:2769–2775.
https://doi.org/10.1016/j.cgh.2019.04.038

III. Karl Björkström, Per Stål, Magnus Holmer, Bonnie Bengtsson, Johan Hoffstedt, Hannes Hagström. A personalized treatment program in persons with type 2 diabetes is associated with a reduction in liver steatosis. European Journal of Gastroenterology & Hepatology. August 10, 2020. [Accepted]
https://doi.org/10.1097/MEG.0000000000001882

IV. Karl Björkström, Linnea Widman, Hannes Hagström. Risk of hepatic and extra-hepatic cancer in NAFLD - a population-based cohort study. [Manuscript]