Clinical implications of diabetes in chronic liver disease: Diagnosis, outcomes and management, current and future perspectives

Abstract

Diabetes mellitus (DM) is common in liver cirrhosis (LC). The pathophysiological association is bidirectional. DM is a risk factor of LC and LC is a diabetogenic condition. In the recent years, research on different aspects of the association DM and LC has been intensified. Nevertheless, it has been insufficient and still exist many gaps. The aims of this review are: (1) To discuss the latest understandings of the association of DM and LC in order to identify the strategies of early diagnosis; (2) To evaluate the impact of DM on outcomes of LC patients; and (3) To select the most adequate management benefiting the two conditions. Literature searches were conducted using PubMed, Ovid and Scopus engines for DM and LC, diagnosis, outcomes and management. The authors also provided insight from their own published experience. Based on the published studies, two types of DM associated with LC have emerged: Type 2 DM (T2DM) and hepatogenous diabetes (HD). High-quality evidences have determined that T2DM or HD significantly increase complications and death pre and post-liver transplantation. HD has been poorly studied and has not been recognized as a complication of LC. The management of DM in LC patients continues to be difficult and should be based on drug pharmacokinetics and the degree of liver failure. In conclusion, the clinical impact of DM in outcomes of LC patients has been the most studied item recently. Nevertheless many gaps still exist particularly in the management. These most important gaps were highlighted in order to propose future lines for research.

Keywords: Clinical implications; Diabetes mellitus; Hepatogenous diabetes; Liver cirrhosis; Therapy.

Figure 1

Pathophysiology of hepatogenous diabetes in cirrhotic liver. Hepatogenous diabetes develops directly from insulin resistance in the liver, and indirectly from impaired glucose metabolism due to insulin resistance in muscle. Hyperinsulinemia can result from reduced insulin clearance by the damaged liver and the presence of portosystemic shunts. With progression of diabetes, there is a reduction in the sensitivity of pancreatic b cells due to glucotoxicity, and reduced production of insulin. IGF: Insulin-like growth factor.

Figure 2

The pathophysiological relationship between diabetes mellitus and nonalcoholic fatty liver disease. This is bidirectional: On the one hand, type 2 diabetes mellitus (T2DM) is a strong risk factor (alone or as part of metabolic syndrome) for nonalcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma. On the other hand, NAFLD in the absence of metabolic disorders is a risk factor for incidental DM as it has been demonstrated in lean subjects with NAFLD. In both cases genetics, [PNPLA3 rs738409 polymorphism (G allele), SREBF-2 rs133291 C/T polymorphism, TM6SF2 rs58542926 C>T and CETP rs12447924 and rs1259700 polymorfisms], as well as sedentary life style, diet and dysbiosis may also play an important role. HCV: Hepatitis C virus; IR: Insulin resistance; NAFLD: Nonalcoholic fatty liver disease; HD: Hepatogenous diabetes; FFA: Free fatty acids; LG: Lactoglobulin; T2DM: Type 2 diabetes mellitus; NASH: Non-alcoholic steatohepatitis; HCC: Hepatocellular carcinoma.

Figure 3

Algorithm for diagnosis and management of diabetes mellitus and nonalcoholic fatty liver disease based on the published evidences. As follows: (1) This treatment has been evaluated only in nonalcoholic fatty liver disease (NAFLD); (2) These drugs have been evaluated in NAFLD showing improvement of non-alcoholic steatohepatitis and fibrosis; (3) Direct-acting antiviral have demonstrated improvement of short and long term glycemic control after hepatitis C virus eradication; (4) Long term administration of metformin has demonstrated association to significant reduction of liver related complications, hepatocellular carcinoma and mortality; and (5) GLP-1 receptor agonists and sodium-glucose co-transporter-2 inhibitor drugs have demonstrated effectiveness for glycemic control and good tolerance in liver cirrhosis patients. NAFLD: Nonalcoholic fatty liver disease; DM: Diabetes mellitus; GLP-1Ras: GLP-1 receptor agonists; SGLT-2: Sodium-glucose co-transporter-2; HCV: Hepatitis C virus; FPG: Fasting plasma glucose; HbA1c: Glycated hemoglobin; HD: Hepatogenous diabetes; MS: Metabolic syndrome; OGTT: Oral glucose tolerance test; IGT: Impaired glucose tolerance.