Diabetes mellitus – risk factor and potential future target for hepatic encephalopathy in patients with liver cirrhosis?

Abstract

Hepatic encephalopathy (HE) is one of the major complications of cirrhosis, and its presence is associated with poor survival. Several risk factors for HE are well established, including age, history of HE, portosystemic shunts, or poorer liver function. In recent years, diabetes mellitus (DM) has emerged as another potential risk factor for the development of HE. This may be important for many patients, as the incidence of type 2 DM (T2DM) is increasing worldwide and, consequently, the incidence of NAFLD-related cirrhosis is rising simultaneously. In addition, DM is a critical factor in the progression of other liver diseases, such as alcohol-related liver disease. Thus, the number of patients with cirrhosis and comorbid T2DM will also increase. To date, the prevalence of DM already ranges between 22 - 40% in patients with cirrhosis. DM-associated factors that may influence the risk of HE include systemic inflammation, insulin resistance with increased muscle protein breakdown as well as autonomic dysfunction with prolonged intestinal transit time and small intestinal bacterial overgrowth. Currently, the evidence for an association between DM and both minimal and overt HE is weak and it seems likely that only poor glycemic control has an impact on HE risk. In addition, there are some early signs indicating that DM may impair the response of patients with HE to pharmacological therapies such as rifaximin. Thus, improvements in the management of glycemic control may be a candidate future target to reduce the risk of HE. In this concise review, we summarize the current evidence on the association between DM and HE and its potential future implications.

Rifaximin plus lactulose versus lactulose alone for reducing the risk of HE recurrence

“…Diabetes is a common condition in cirrhosis and can affect HE therapy efficacy. 5 , 10 However, the current results indicate that the efficacy of rifaximin plus lactulose for reducing the risk of OHE recurrence is not affected by comorbid diabetes; however, hemoglobin A1c levels were not collected during the trials. Rifaximin plus lactulose therapy should be considered for adults with cirrhosis and a history of OHE, including those with comorbid diabetes or ascites and those being discharged from an inpatient setting after a recurrent OHE episode.…”

Empagliflozin attenuates liver fibrosis in high‐fat diet/streptozotocin‐induced mice by modulating gut microbiota

“…21 At present, NAFLD has gradually become a global health problem, especially because its interaction with DM and other metabolic diseases increases the intractability of NAFLD. 3,22 Therefore, an effective strategy that can simultaneously improve glucose metabolism and slow down the progression of NAFLD, such as SGLT2 inhibitors, has a good therapeutic prospect. 23 Since 2015, the anti-liver fibrosis effect of SGLT2 inhibitors has been gradually confirmed.…”

Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease

“…Diabetes may increase venous plasma ammonia levels by autonomic dysfunction, extended gastrointestinal transit times, and bacterial overgrowth as well as increased protein catabolism and accelerated muscle-breakdown. 23 Even in earlier stages of fibrosis in individuals with NAFLD/metabolic-associated fatty liver disease (MAFLD), deficiencies in urea synthesis (in part caused by impaired liver-α-cell axis with glucagon resistance and impaired ureagenesis 24 ), microglial activation, astrocyte swelling, and possibly even neurodegenerative changes and brain atrophy – all caused by elevated ammonia levels – have been reported. 25 , 26 …”