The liver plays a key role in glucose metabolism as the major site of glycogen synthesis and gluconeogenesis. Hepatocellular functional impairment results in abnormal glycogen synthesis and decreased hepatic capacity for glycogen deposits[13]. IR in peripheral tissues (adipose and muscular tissues) and liver dysfunction play a central role in the glucose metabolism disturbance[19,20]. Reduced insulin clearance by the damaged liver and portosystemic shunts result in hyperinsulinemia which is potentiated by raised levels of contra-insulin hormones (glucagon, growth hormone, insulin-like growth factor) and free fatty acids and cytokines[20,21].

Hyperinsulinemia can be detected in the early stages of CLD, both in the fasting and postprandial state. A major precipitating factor of hyperinsulinemia is the reactive insulin hypersecretion by the pancreas for compensation of peripheral IR in muscle tissue and impaired hepatic glucose utilization.

Inadequate early increase in insulin secretion and decreased hepatic glucose production are often observed in LC even in the absence of DM. The progressive loss of insulin secretion culminates in a step-wise fashion in DM[22]. The trigger seems to be glucotoxicity from chronic hyperglycemia, which causes secretory impairment of pancreatic β-cells[23].

In a study comparing patients with HD to those with T2DM, the ratios of postprandial plasma glucose to FPG, fasting insulin and HOMA-IR index were significantly higher in patients with HD[50]. Consequently, the diagnosis of HD often requires an OGTT. It has been determined that around 50% to 70% of patients with compensated LC will require this test in order to diagnose IGT or DM[4,6,48]. In addition, research is being made to identify genetic and biochemical markers aimed to establish the differentiation among the two types of DM more precisely[50,51].

In 1997, the American Diabetes Association determined the cut-off value of FPG in 126 mg/dL for the diagnosis of DM because it corresponded to a 2 h value of 200 mg/dL in the OGTT[52]. A study in 60 LC patients based on the results of OGTT, however, showed that mean values of FPG levels corresponding to a 2 h value of 200 mg/dL were lower (107 mg/dL)[53]. Besides, nine of 42 patients (21%) with FPG levels < 110 mg/dL from this study, were diagnosed with DM using OGTT.

Therefore, lower FPG levels may be required in LC patients for predicting IGT or DM, so the use of lower cut-off values to diagnose HD should be considered in these patients.

HbA1c levels > 6.5%, are used to diagnose DM[54]. However, a previous study showed that LC patients with DM had lower HbA1c levels (mean 5.7%), and 40% of patients with compensated LC had levels below in the non-DM range[55]. The poor diagnostic performance of HbA1c in LC patients is due to the curvilinear relationship between HbA1c and erythrocyte turnover, which can occur in patients with advanced LC as a result of hemorrhage related to portal hypertension and coagulopathy, hemolysis caused by splenomegaly and impaired erythropoiesis due to bone marrow suppression[56]. HbA1c values can also be affected by blood transfusion, which are frequently prescribed to LC patients[57]. A study showed that in non-anemic CLD patients with DM with HbA1c < 7%, the decrease in liver functional reserve is associated with worsening of parameters of glycemic variability determined with continuous glucose monitoring. Mean blood glucose levels and the difference between highest and lowest blood glucose increased significantly with worsening of liver functional reserve[58].

Hepatic encephalopathy: Several studies have linked DM to an increased incidence of hepatic encephalopathy (HE) in patients with LC. Among patients with HCV-related LC, the severity of HE was higher in DM than in non-DM patients[59]. In a further study in LC patients, the association between DM and HE was independent of the model for end-stage liver disease (MELD) score[39]. In a large prospective study, LC patients with DM had more episodes of first-time overt HE compared to those without DM in one year. In addition, a greater proportion of first-time HE progressed beyond grade 2 in DM patients. Notably, the proportion of Child-Pugh class C LC was lower in the DM group, which suggested that DM conferred an additional risk of HE irrespective of liver disease severity[60].

In a recent study, the risk of both covert and overt HE was more pronounced among patients with poor glycaemic control[61]. Finally, DM increased significantly the risk of HE after a trans-jugular intrahepatic portosystemic shunt (TIPSS)[62].

Variceal haemorrhage: Hyperglycaemia may lead to splanchnic hyperaemia and increased portal pressure which may increase the risks of haemorrhage[59,63]. In a prospective study, DM was associated with increased hepatic venous pressure gradient, variceal haemorrhage (VH), and Child-Pugh's score. Postprandial hyper-glycaemia had a significant association with VH within 6 mo[64]. In another study, DM was a risk factor for rebleeding following endoscopic variceal ligation[65]. In a retrospective study, DM was also an independent predictor of in-hospital death in LC patients with acute gastro-intestinal bleeding[66]. Finally, in another study, LC patients with DM had a higher incidence of re-bleeding and hospitalizations, and a higher mortality rate than those without DM[67].

An impaired immunological response has been observed in patients with DM and LC[68]. DM was an independent predictor of bacterial infections in hospitalized patients with LC[40]. In hospitalized LC patients, the prevalence of bacterial infections was significantly higher in DM compared to non-DM subjects[68]. In a prospective study in LC patients with ascites, those with DM had an increased risk of developing spontaneous bacterial peritonitis (SBP) and the incidence of SBP was significantly higher when HbA1c values were ≥ 6.4%[69]. In a retrospective analysis of LC patients with DM, uncontrolled DM was associated with an increased overall risk of bacterial infection and a higher hospital mortality rate in the elderly[70].

The increased risk of HCC in diabetic patients was reported in two large meta-analyses[71,72]. DM was also found to increase the risk of mortality in HCC patients[71]. However, the published studies are somewhat inconsistent on this issue. In a retrospective study with LC patients, DM did not increas the risk of HCC in those with HCV infection compared to other causes of liver disease[73]. Another study in patients with chronic hepatitis B, reported a higher prevalence of DM among HCC patients without LC than in those with LC[74]. A large case control study found that DM was associated with an increased risk of HCC regardless of the prevalence of LC[75]. In another study, DM could not be confirmed as a major risk factor for HCC in general; however, DM did become an independent predictor when “traditional” risk factors such as LC, alcohol abuse, hepatitis B or C and smoking were excluded[76]. The inconsistent criteria for diagnosing DM may be an important cause of this discrepancy. Recently, it was observed that while high FPG levels were not associated with HCC, 2 h post-challenge hyperglycaemia remained as significant predictor for HCC development in HCV-RNA-positive patients[77].

Many studies have indicated that DM significantly reduced the survival rate in patients with CLD and LC[3,4,40,48,66,67,78,79]. Nevertheless, only some of them have been prospective. Bianchi et al[3] reported the adverse impact of DM on the 5-year cumulated survival in a study in patients with LC. Refractory ascites, DM, older age, and HCC, but not Child-Pugh score were independent predictors of poor survival[3]. Even subclinical abnormalities in glucose homeostasis have been found to adversely affect prognosis. In a recent prospective study of 100 compensated LC patients with normal FPG, those with abnormal OGTT had lower 5-year cumulated survival than those with a normal test[78]. In a similar prospective study, the cumulative 5-year survival rates of patients were 94.7%, 68.8% and 56.6%, in those with normal glucose tolerance, IGT and DM, respectively[48]. In another study, DM had an impact on survival only in patients with a baseline MELD score < 10. This implies that the severity of CLD may mask the deleterious effect of DM[40,80]. The results of these studies suggest that DM can be detected more clearly as reliable predictor of morbidity and mortality in the early stages of LC. In the advanced stages, its effect can be masked by other complications of LC. Therefore, further studies, based on the dynamic assessment of glycaemic parameters using OGTT, are needed to obtain a robust conclusion on this important issue (Table 3).

Pre-transplant DM is the major risk factor for DM after LT (7%-45%)[81-83]. Increased FPG levels were a risk factor for new-onset DM after LT[84]. Pre-operative β-cell function determined by an OGTT may be a useful predictive tool for the recurrence of DM after LT[85]. Post-LT DM is associated with increased risk of graft rejection, severe complications and mortality[81,86,87]. A study on adult LT recipients showed that post-LT DM incidence was 34.7%, 46.9%, and 56.2% at 1, 3, and 5 years, respectively, with overall survival rates of 90%, 80.9%, and 71.7%, respectively. The post-LT DM group had more rejection episodes and worse 5-year survival rates[86]. Persistent or new-onset DM after LT is also associated with cardiovascular disease, biliary complications, renal dysfunction, infections and graft rejection[81,87]. In patients with HCV-related LC, a pre-existing or new onset DM is associated with increased risk of HCV recurrence and hepatic fibrosis after LT[88]. Some studies have demonstrated improvement in glucose homeostasis after LT[49,89]. In a study where LT failed to cure overt DM in 33% of patients, a persistently reduced β-cell function was found[88]. However, normalized glucose production and insulin sensitivity after LT have the potential to reverse β-cell dysfunction and thus lead to remission in most cases of HD[90].

Diet and physical activity are a cornerstone of T2DM management. On the one hand, prevalence of obesity and NAFLD is increasing worldwide and > 10% of weight reduction has been shown to significantly reduce inflammation and fibrosis in patients with this disease[92]. On the other hand, malnutrition remains a common feature among LC individuals (20%-50%), mostly in those with decompensated liver disease[93]. Both obesity and malnutrition may be associated with sarcopenia, causing a major risk factor for frailty, conditions associated with a higher rate of severe complications[94].

A moderate caloric restriction is recommended for overweight/obese LC patients in order to achieve a weight reduction of > 5% to 10%, but paying a special attention to maintain an adequate protein intake to avoid loss of muscle mass (85%). A widely accepted approach is to supply at least 35 kcal/kg body weight/d, using the actual body weight, then subtracting a 5%, 10%, or 15% in case of mild, moderate, or severe ascites, respectively, plus an additional 5% in case of peripheral oedema[93].

Protein intake should be increased up to 1.2-1.5 g/kg body weight/d to avoid sarcopenia, unless moderate-to-severe renal insufficiency is present, but oral protein supplements, especially branched-chain amino acids[95], or short-term enteral or parenteral nutrition[93] may be necessary in some patients. The common deficits of vitamins should be corrected with supplementation[93].

Physical exercise is associated with increments of insulin sensitivity and is highly recommended in patients with NAFLD. However it may be limited in LC patients by the presence of asthenia, sarcopenia, and ascites[96,97]. A combination of aerobic and resistance training of moderate intensity is also recommended[93], as it may result in the concurrent improvement of muscle function and mass.

Despite the growing problem of management of DM in patients with CLD the existing literature data, especially on newer antidiabetic agents is very limited and furthermore, no guidelines exist. The recommended use of antidiabetic drugs and insulins is based mostly on available data on pharmacokinetics and safety drug studies taking into account the degree of liver dysfunction and the presence of comorbidities[98] (Tables 4 and 5).

The inhibitors of alpha-glucosidase such as the acarbose, inhibit α-glucosidases, which contribute to degradation of disaccharides in the intestine. It results in reduction in the absorption of carbohydrates and in the risk of postprandial hyperglycemia. Its safety has been evaluated in patients with DM and CLD[99,100]. Its use was associated with a significant reduction of fasting and postprandial hyperglycemia, HbA1c and C-peptide as well as improvement of mild HE in compensated cirrhosis[100].

The secretagogues sulfonylureas and glinides are extensively metabolized by the liver in a cytochrome P450-dependent manner and may accumulate in LC patients[99], thus increasing the risk of hypoglycemia[101]. Thus, it is recommended to avoid these agents in patients with moderate-to-severe liver failure.

The insulin-sensitizing agent metformin is not metabolized by the liver[102]. It has been associated with risk of lactic acidosis. However, this complication was reported only in anecdotal cases, particularly with concomitant alcohol intake[103]. Chronic use of metformin has been associated with a reduced risk of HCC[104-107], reduced liver-related complications[105,107], and increase survival in LC patients[105-107].

Probably, glycemic control of the patients contributed for obtaining these effects. Nevertheless, an independent anti oncogenetic mechanism has been recently described experimentally[108]. The other insulin-sensitizing agents, thiazolidinediones, are metabolized entirely by the liver, so they accumulate in patients with hepatic failure[101]. Therefore, their use is restricted to patients with Child-Pugh class A LC, also because of the fluid retention and decrease in bone mineral density caused by these drugs[109]. The significant reduction of liver fibrosis reported in NASH patients with and without T2DM supports the use of these drugs in early-stage LC due to this aetiology.

Despite the fact that all the inhibitors of dipeptidyl peptidase 4 (DPP-4) are metabolized by the liver, their use is generally allowed in patients with Child-Pugh class A or B LC with no dose adjustment[101,110]. A dose reduction of these drugs is however required in case of estimated glomerular filtration rate (eGFR) < 50 mL· min^-1· 1.73m^-2, except for linagliptin, which is not excreted by the kidney[111]. Notwithstanding, in a recently published population based cohort study with 2828 DPP-4 inhibitor user and nonuser patients with T2DM and LC, the incidence rate of decompensated cirrhosis during follow-up was significantly higher for DPP-4 inhibitor users. The adjusted hazard ratios (aHRs) (95%CI) of variceal bleeding and hepatic failure were 1.67 (1.11-2.52) and 1.35 (1.02-1.79), respectively, for DPP-4 inhibitor users over nonusers. The risk of all-cause mortality, HCC, and major cardiovascular events were not statistically different[112]. In another population-based, retrospective cohort study including patients with DM and LC treated with GLP-1 receptor agonists (GLP-1RAs), DPP-4 inhibitors, sulfonylureas or sodium-glucose co-transporter-2 (SGLT-2) inhibitors, GLP-1RAs use was associated to significantly reduced number of liver related complications compared to DPP-4 inhibitors and sulfonylureas. In contrast, complication rates were similar when GLP-1RAs and SGLT-2 inhibitors were directly compared[113]. The results of these studies suggest that patients using DPP-4 inhibitors should heave a tight monitoring.

The GLP-1RAs, are not metabolized by the liver and, hence, no dose adjustment is required[101,110]. As pharmacokinetic information in patients with end-stage liver disease are available only for liraglutide, dulaglutide, and semaglutide, so the use of these GLP-1RAs is allowed in Child-Pugh class A or B patients, whereas that of exenatide and lixisenatide should be restricted to Child-Pugh class A individuals[101,110]. The use of exenatide and lixisenatide should be avoided also if eGFR is < 30 mL· min^-1· 1.73 m^-2, as these agents are excreted by the kidney[111]. The reported beneficial impact of this class of drugs on NASH may support their use in patients with NASH-related LC. Conversely, these agents may not be suitable for malnourished sarcopenic individuals, due to their energy wasting effect[101].

The inhibitors of the SGLT-2 are all metabolized in the liver, but have significant accumulation only in severe liver failure[114]. Therefore, the use of SGLT2 inhibitors is allowed in Child-Pugh class A and B LC with no dose adjustment[101], unless impaired renal function is present[111]. Their diuretic properties might be useful for potentiating the effect of therapy with loop diuretics and mineralocorticoid receptor agonists[115], though they may cause dehydration that may further reduce effective plasma volume and precipitate renal dysfunction[101].

In general terms, the use of non-insulin agents (except secretagogues) is generally allowed in mild-to-moderate LC, whereas all of them should be avoided in severe LC, in which insulin represents the sole treatment option[101]. In HD, metformin alone may be sufficient. However, drugs potentially capable of preserving β-cell function (e.g., thiazolidinediones, incretin-based drugs, and SGLT2 inhibitors) may be also suggested[101].

As human insulin is metabolized by insulinase in the liver, it may be necessary to reduce dosage[116]. Conversely, as no significant changes in the kinetics of insulin analogues, either both short-acting[117], or long-acting insulins[101,116] have been reported, no dose adjustment is required for these agents.

For these reasons, use of insulin (with preference for insulin analogues) is allowed at all stages of cirrhosis (Table 5) and represents the first-choice treatment in LC patients with DM. Insulin requirements can be high in patients with compensated cirrhosis and low in decompensated patients. Few clinical studies have evaluated its long-term effects and safety. In a recently published retrospective cohort study, insulin use in people with T2DM and compensated LC was associated with higher risks of hypoglycemia, cardiovascular events, liver-related complications, and mortality than insulin nonusers. However, no information regarding important risk factors such as body weight, physical activity, alcohol consumption, and cigarette smoking was given and effective glycemic control or treatment adherence was not evaluated[118]. More studies are needed to confirm these findings. Anyway, insulin treatment should be started with close monitoring to avoid hypoglycemia. The insulin regimen may consist of basal insulin only or a combination of basal and prandial insulin (basal-plus or basal-bolus).

In the Figure 3 an algorithm for the diagnosis and management of DM in CLD and LC is depicted.

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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.

HD may be improved with LT, nevertheless it may persist in 30% of cases or DM may occur de novo after LT due to several factors with diabetogenic potential, such as immunosuppressant treatment, viral infections, and donor- and procedure-related factors[101].

The intra-operative and immediate post-LT periods are often characterized by severe hyperglycemia that may be transient and reverse with appropriate management[101]. Intravenous or subcutaneous intensive insulin therapy using validated algorithms is the standard of care, as a strict intra-operative glycemic control is recommended to reduce the associated increased risk of morbidity and mortality[119]. With reduction of steroid dose, insulin requirement rapidly decreases and insulin treatment may be interrupted in many instances[101].

Specific guidelines for the treatment of post-LT DM were released in 2014[83]. While lifestyle measures are identical to those for T2DM patients[91], there are insufficient data to recommend specific anti-hyperglycemic agents[101]. Indeed, all the available agents can be used to treat post-transplant DM[120], with limitations in case of renal dysfunction[121].