Diabetes and Cirrhosis: Clinical Implications and Management

By Digital Editor Dilgam H. Published April 6, 2017 Complications

Key points

In patients with cirrhosis, diabetes might be either a consequence of liver disease or an underlying type 2 diabetes
In patients with cirrhosis, fasting blood sugar may be normal despite diabetes. Oral glucose tolerance test allows detecting diabetes.
Diabetes is an element of poor survival and increases the risk of complications of cirrhosis. This suggests that active screening and management of diabetes could be beneficial in patients with cirrhosis.
Making use of metformin seems safe and might have an useful effect on patients’ outcome. Nevertheless, no treatment has actually been proven to improve the prognosis of patients with cirrhosis and concurrent diabetes.

Contents

Diabetes and Cirrhosis

Diabetes and Cirrhosis

The liver plays an essential function in glucose homeostasis. It stores glycogen in the fed state and produces glucose through glycogenolysis and gluconeogenesis in the fasting state. There are close relationships between liver illness and disorders of glucose metabolic process. On the one hand, the risk of death from chronic liver illness is increased in patients with type 2 diabetes mellitus. On the other hand, the presence of diabetes in patients with cirrhosis is an independent aspect for bad survival, and is related to the major complications of cirrhosis. The treatment of diabetes in patients with chronic liver illness is complex, because of impaired liver and/or renal functions, and of the potential hepatotoxicity of oral hypoglycaemic representatives. The objective of this review is to offer an upgrade on the relationships in between cirrhosis and diabetes. We will concentrate on recent advances in the pathophysiological mechanisms, medical diagnosis, clinical implications and restorative management of diabetes in patients with cirrhosis.

Effect of diabetes on progression of liver fibrosis and cirrhosis development

Epidemiological links in between type 2 diabetes and cirrhosis

Type 2 diabetes is a risk aspect for liver fibrosis advancement and development. There is a strong relationship in between the parts of the insulin resistance syndrome and the stage of liver fibrosis. A number of independent groups observed in big associates of patients that type 2 diabetes is connected with a 2 to 2.5-fold increased risk of cirrhosis advancement, and of death from chronic liver illness, generally attributable to non-alcoholic fatty liver diseases (NAFLD). Surprisingly, the impact of diabetes on fibrosis has actually been found to be independent from other parts of the metabolic syndrome. Moreover, current friend research studies in Taiwan revealed that diabetes mellitus is an independent predictor of cirrhosis in patients with chronic hepatitis B and chronic hepatitis C.

Pathophysiological mechanisms promoting liver fibrosis in patients with insulin resistance or type 2 diabetes

As a part of metabolic syndrome, type 2 diabetes can promote NAFLD. Patients with separated steatosis usually have an exceptional prognosis, while patients with non-alcoholic steatohepatitis (NASH) may establish fibrosis resulting in cirrhosis and its complications. Pathophysiological systems resulting in NASH and NASH-related fibrosis have been recently reviewed in detail in other places. Additionally, diabetes likely adds to fibrosis progression and cirrhosis independently from NAFLD by modulating numerous key procedures implicated in fibrogenesis.

Impact of cirrhosis on glucose homeostasis

In a normal person, the liver plays a key function in keeping glucose homeostasis. In patients with sophisticated cirrhosis, alterations in glucose metabolic process, the so-called hepatogenous diabetes, have been explained.

Medical diagnosis and clinical presentation of diabetes in patients with cirrhosis

In patients with cirrhosis, disorders of glucose metabolism range from mere glucose intolerance to obvious diabetes. It is estimated that only 30% of the patients have normal glucose tolerance, 30 — 50% have impaired glucose tolerance and approximately 30% have overt diabetes. This is much greater than in the basic population, where the occurrence of glucose intolerance is around 15% which of diabetes is 8%.

The diagnosis of diabetes in patients with cirrhosis might not be simple. First, at early stage, fasting serum glucose levels is normal in 23% of the patients with overt diabetes. Indeed, such patients have normal fasting blood sugar, whereas post-prandial blood sugar is > 200 mg/L. Thus, an oral glucose tolerance test is had to discover the problems of glucose metabolic process.

Moreover, discrimination in between type 2 diabetes and hepatogenous diabetes is regularly not possible. Still, hepatogenous diabetes may have various clinical characteristics from type 2 diabetes. Amongst 50 patients with hepatogenous diabetes, just 16% of patients had a family history of diabetes. Just 8% had retinopathy. After a mean follow-up of 5 years, no cardiovascular deaths was reported, whereas 52% of the patients had passed away, primarily from complications of cirrhosis. This may be either associated with the shorter period of diabetes in patients with hepatogenous diabetes than in patients with type 2 diabetes or to the fact that death is mainly associated to cirrhosis-related complications in these patients.

In patients with separated hepatogenous diabetes, liver hair transplant by itself can stabilize glucose tolerance and insulin sensitivity, supporting the idea that diabetes was connected to cirrhosis. Nevertheless, post-transplantation diabetes stays a very common condition, as it is estimated that about 30% of liver transplant receivers have diabetes. Interestingly, in patients getting a liver graft, pretransplantation diabetes, as well as advanced age, household history of diabetes, and maximum body mass index over 25 kg/m2 (which are risk factors for type 2 diabetes), is related to the development of post-transplantation diabetes. These information suggest that diabetes mellitus present at the time of liver transplantation was not just solely associated to advanced liver disease but also to pre-existing metabolic irregularities. The causes of liver disease also appear to be an important risk aspect for the advancement of diabetes in patients with cirrhosis. Certainly, diabetes is more regular in patients with liver disease C-related cirrhosis or alcohol-related cirrhosis than in patients with biliary cirrhosis. However, cirrhosis stays individually related to cirrhosis. Certainly, amongst patients with hepatitis C infection, diabetes is more often observed in patients with cirrhosis (24%) than in those without (6%).

Measurement of glycated haemoglobin (HbA1c) does not accurately reflect glycaemic status in patients with cirrhosis. In patients without liver illness, HbA1c is used for routine assessment and the management of patients with diabetes. HbA1c concentration reflects the previous 2 — 3 months of glycaemic status and is well correlated with the advancement of diabetes-related complications. Studies on small-sized series of patients suggest that HbA1c measurement is not precise in patients with cirrhosis. Indeed, 40% of the non-diabetic patients with cirrhosis had HbA1c worths below the normal variety in a non-diabetic referral population. Furthermore, patients with cirrhosis and concurrent diabetes also had HbA1c worths in the non-diabetic reference, specifically between 4 and 6%. Just a little proportion of patients with cirrhosis and diabetes had high HbA1c. Moreover, patients with cirrhosis revealed similar values of HbA1c compared to control patients, although fasting plasma glucose was greater in patients with cirrhosis. The reason why HbA1c measurement is not properly showing glycaemic control in patients with cirrhosis stays uncertain. Reduced erythrocyte life expectancy, which prevails in patients with cirrhosis and is known to cause low HbA1c worths, could play a role independent of glycaemia. Fructosamine measurement shows glycaemic status over a duration of 2 — 4 weeks. Fructosamine level seems a more precise tool than HbA1c for monitoring glycaemic control in patients with cirrhosis.

Management of diabetes in patients with cirrhosis.

In patients with type 1 and type 2 diabetes, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) research studies have actually shown that bad glycaemic control (based upon an HbA1c level above 7% for type 1 diabetes and 6.5% for type 2 diabetes) was straight associated with the development of diabetic micro- and macro-angiopathy. In patients with cirrhosis and diabetes, the risk of cirrhosis complications seems to be greater than the risk of diabetes complications. The effect of early diagnosis and treatment of diabetes on the scientific course of patients with cirrhosis and diabetes is unknown. Nevertheless, it is tempting to hypothesize that it could be advantageous. As detailed below, recent data suggesting that metformin reduces the risk of HCC in addition to the risk of hepatic encephalopathy are in favour of screening and dealing with diabetes in patients with cirrhosis.

Lifestyle interventions

The first-line therapy for type 2 diabetes consists of lifestyle changes, which includes hypocaloric diet and workout. The objective of physical exercise is to increase peripheral insulin sensitivity. Regrettably, in patients with cirrhosis, such treatments might be inappropriate or impractical. Indeed, as much as 50 percent of cirrhotic patients have malnutrition, a contraindication to hypocaloric diet. Moreover, ascites and edema hinder workout.

Pharmacologic therapies

Pharmacologic alternatives for the control of diabetes in patients with liver diseases are, for the a lot of part, similar to patients without liver disease. Just patients with severe impaired liver function have actually changed drug metabolism. Relating to the risk of hepatotoxicity, while patients with liver disease are not inclined to hepatotoxicity, the underlying liver disease might increase the seriousness of drug-induced liver injury.

Metformin

First-line therapy with metformin is theoretically proper in patients with cirrhosis due to the fact that it reduces insulin resistance. Metformin has actually long been thought about to be contraindicated in patients with advanced liver disease due to the fact that of a theoretical boost in the risk of lactic acidosis. Yet, regardless of the prevalent use of metformin, only rare patients with cirrhosis developed lactic acidosis, recommending that metformin is safe in patients with cirrhosis without kidney dysfunction.

A growing variety of observational studies suggest that metformin (relative to other glucose-lowering treatments) might be related to a minimized risk of cancer or cancer mortality, consisting of hepatocellular carcinoma. Furthermore, Zhang et al. recently reported that extension of metformin in patients with newly detected cirrhosis is associated with a longer survival. In a recent friend of 82 patients with cirrhosis and diabetes, the event of hepatic encephalopathy was significantly lower in patients getting metformin (5 vs. 41%). A sign bias may limit the interpretation of observational studies, as metformin is most normally recommended to patients with brief period of diabetes and without contraindicating elements (sophisticated age, liver or kidney disease) that likewise may affect the diagnosis. Nevertheless, these information recommend that metformin is the first-choice therapy for patients with cirrhosis and diabetes.

Thiazolidindiones

Thiazolidinediones are insulin-sensitizing peroxisome proliferator-activated receptor (PPAR) gamma agonists that do not increase insulin secretion directly or cause hypoglycaemia when used alone. Hence, thiazolidinediones may be particularly beneficial in patients with diabetes and chronic liver illness. However, troglitazone and rosiglitazone have been withdrawn from the marketplace since of their prospective hepatotoxic effect and the risk of congestive heart failure respectively. Pioglitazone is still presently offered. In patients with NASH, the effectiveness of thiazolidinediones is debated. A meta-analysis of 4 randomized controlled trials discovered that thiazolidinediones considerably improve steatosis and liver inflammation, however not fibrosis. Patients with cirrhosis were excluded from these trials.

Insulin secretagogues

Insulin secretagogues consist of sulphonylureas and glinides. They set off insulin release by the pancreatic beta cells. Hence, in patients with cirrhosis, they may not be the first-choice option, as they do not modify insulin level of sensitivity. Moreover, patients with cirrhosis, particularly those with alcohol-related cirrhosis, may have pancreatic beta-islets cell damage. Most notably, there is an increased risk of hypoglycaemia with these therapies. Therefore, secretagogues are not recommended in patients with high risk of hypoglycaemia.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors (acarbose) might be beneficial in patients with cirrhosis, because they reduce carbohydrate absorption in the bowel, which would decrease the risk of postprandial hyperglycaemia. Indeed, patients with cirrhosis and diabetes often have normal plasma fasting glucose and irregular oral glucose tolerance test. In a randomized, double-blind study including 100 patients with compensated cirrhosis and insulin-treated diabetes, the control of postprandial and fasting blood glucose levels enhanced substantially with the use of acarbose. In another crossover placebo-controlled research study involving patients with hepatic encephalopathy, there was a considerable improvement in postprandial blood glucose level in patients treated with acarbose.

Dipeptyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 is a gut-derived incretin hormone that promotes insulin and suppresses glucagon secretion, prevents gastric emptying and decreases appetite and food consumption. Therapeutic approaches for enhancing incretin action include DDP-4 inhibitors and GLP-1 analogues. These classes of therapeutic representatives for type 2 diabetes were established in the past 10 years and have shown to be reliable glucose decreasing agents. In addition, GLP-1 analogues promote (moderate) weight loss. So far, preclinical research studies have actually discovered that incretins can enhance hepatic steatosis. Although some effects might be because of an overall improvement in metabolic criteria, there are information to support enhancements independent from weight reduction, along with direct impact on the hepatocyte. Nevertheless, the safety and the usefulness of incretins in patients with cirrhosis require more investigations.

Insulin

Despite the possible interest of oral antidiabetic agents, insulin therapy is frequently prescribed in patients with cirrhosis, specifically in those with advanced cirrhosis. Among 348 patients with liver disease C-related cirrhosis, 62% were on insulin therapy.

Importantly, caution needs to be made regarding the dose of insulin therapy. Certainly, insulin requirements in patients with cirrhosis may differ depending upon the intensity of cirrhosis. In patients with compensated cirrhosis, insulin requirement might be very important since insulin resistance predominates. In patients with decompensated cirrhosis, the hepatic metabolism of insulin is lowered, which decreases the requirements for insulin. For that reason, hospitalization may be safe for the initiation of insulin therapy, by enabling close tracking of blood sugar levels, to minimize the risk of hypoglycaemia.

Non selective beta-blockers are extensively used in patients with cirrhosis for prophylaxis of variceal bleeding. With regard to diabetic patients under insulin treatment, beta-blockers might make hypoglycaemic episodes less symptomatic, causing more extensive change in mental state to establish without alerting symptoms. Moreover, hypoglycaemia can be precipitated by beta-adrenergic action since β2-adrenoceptors usually stimulate glycogenolysis and pancreatic release of glucagon. Nevertheless, a study comparing topics with diabetes getting or not beta-blockers discovered that beta-blockers did not increase the number or the seriousness of hypoglycaemic episodes. Hence, beta-blockers are not contraindicated in patients with cirrhosis treated with insulin.

Conclusion

Diabetes mellitus is observed in up to 30% of patients with cirrhosis. Diabetes can be either an underlying type 2 diabetes mellitus or the repercussion of modifications straight related to an impaired liver function. Diabetes mellitus is related to a poor prognosis in patients with cirrhosis, generally because of an increased risk of cirrhosis complications. Thus, evaluating for diabetes mellitus should be proposed to all patients with cirrhosis. Although it is appealing to hypothesize that controlling diabetes might have an useful effect, more controlled research studies are needed to examine the impact of diabetes control on the advancement of complications of cirrhosis.