Dr. Sanjay Kalra in this third part of his exclusive series for M3 India, details on an underestimated issue in diabetes management, the role and health status of the liver and its link to the disease.

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The liver is one of the largest organs of the body, and it plays a major role in diabetes. The liver can be an aetiology of dysglycaemia, a source of protection against hypoglycaemia, and a target of uncontrolled hyperglycaemia. An active contributor to insulin resistance, the liver also serves as a battleground for diabetes management. At times, the liver behaves as an innocent bystander, and at other times, like a spoilsport or a supportive element in diabetes care.

Because of these multifaceted associations, it is important to understand the role of the liver in diabetes aetiopathogenesis, clinical presentation, natural history, and management.

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Hepatic disease leading to diabetes

The term hepatogenous diabetes has been used to describe a syndrome of dysglycaemia that occurs due to hepatic dysfunction. In cirrhosis, for example, insulin resistance, coexistent pancreatic disease and hepatocyte dysfunction lead to altered glucose metabolism. Both, reduced inhibition of gluconeogenesis and reduced glucose uptake and storage in the hepatocytes, contribute to hyperglycaemia.

Impaired glucose intolerance often progresses to overt diabetes in persons with cirrhosis, but is often reversed after liver transplantation. Viral hepatitis, especially hepatitis C, is known to be a risk factor for the development of diabetes. Persons with HCV infection exhibit impaired first phase insulin release, and those who develop cirrhosis due to HCV experience a greater incidence of diabetes. This complication is most frequent in persons with HCV2a genotype, which in general has more extra-hepatic manifestations than other hepatic viruses. HCV may be linked to pancreatic beta-cell dysfunction, and to other autoimmune diseases. Hepatocellular carcinoma and fulminant hepatic failure are also diabetogenic states.

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Concomitant hepatic disease and diabetes

Bronze diabetes is a term used to describe hemochromatosis, an autosomal recessive disease which is characterised by excessive iron deposition in the liver as well as pancreas. This leads to cirrhosis and diabetes, with the main aetiopathologic factor being insulin deficiency, with or without insulin resistance.

Primary iron overload (PIO) is another syndrome that is associated with insulin resistance, dyglycaemia, and diabetes PIO is characterised by high serum and hepatic iron levels, relative to serum ferritin, and a normal transferees situation.

Autoimmune hepatitis (AIH) is a chronic autoimmune hepatic disease that can coexist with extra hepatic autoimmune disorders. While type 1 AIH which can occur at any age, is commonly associated with autoimmune thyroid disease, type 2 AIH onsets in adolescence or young adulthood, and can co-occur with type 1 diabetes.

Glycogen storage disease (GSD) is an inherited metabolic disorder in which glycogenolysis is impaired. This leads to a state of excessive glycogen storage in the liver, with paradoxical lack of glucose in times of hypoglycaemia. The commonest cause of GSD is glucose-6-phosphatase deficiency, which is inherited in an autosomal recessive manner.

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Diabetes leading to hepatic disease

Uncontrolled diabetes can lead to a varied spectrum of hepatic manifestations, including glycogen deposition, nonalcoholic steatohepatitis (NASH), cirrhosis, cholelithiasis and cholecystitis.

Non-alcoholic fatty liver disease (NAFLD), which is now being termed MAFLD (metabolic fatty liver disease) is a syndrome characterised by hepatic steatosis, or fat deposition in the liver, in the absence of heavy alcohol intake. NAFLD is staged according to the presence or absence of fat deposition, inflammation and hepatocyte destruction. Insulin resistance is widely accepted to be the primary aetiology of NAFLD, with some suggesting that a second hit, or second insult, is necessary to cause progression to NASH and cirrhosis. Some examples of second hit aetiologies include oxidative stress, antioxidant deficiency, iron overload, leptin resistance, adiponectin deficiency, intestinal microbial infection and obstructive sleep apnoea.

Mauriac syndrome is a rarely encountered complication of uncontrolled type 1 diabetes, characterised by hepatomegaly due to glycogen deposition.

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Clinical implication

An understanding of the various links between hepatic disease and diabetes allows the adoption of a rational clinical approach.

All persons with diabetes should be clinically screened for symptoms and signs suggestive of hepatic disease, including fatigue, malaise, right upper abdominal discomfort or fullness, loss of appelite and jaundice. Routine screening of serum aminotransferases may not detect all hepatic dysfunction, but abnormal results should not be ignored, and must be evaluated appropriately. Abnormal liver function tests warrant further investigation, including imaging and biopsy, if necessary, to pinpoint the aetiology and severity of the disease.

All persons with hepatic disease should be screened at regular intervals for dysglycaemia, including not only impaired glucose tolerance and diabetes, but hypoglycaemia as well. HbA1c may not be a good marker in some liver disease, and both fasting and post-load/ post-challenge glucose must be checked.

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Therapeutic implications

The management of diabetes in person with concomitant hepatic dysfunction is challenging. On one hand, many drugs that depend on the liver for metabolism and excretion may be contraindicated or may need to be used with caution, in lower doses. At the same time, certain glucose-lowering drugs have a beneficial effect on the liver, and can be used for their viscero-metabolic advantages. Another challenge is the need for frequent titration of insulin doses, due to varying levels of insulin sensitivity, and due to uncertain dietary intake in severely ill patients.

The Child-Pugh score, or Child-Turcolte-Pugh score, is a method used to calculate the severity of long term liver disease. Using values of serum bilirubin albumin, INR (international normalized ratio), and presence/absence of ascites and encephalopathy, it stratifies patients into class A,B and C. The MELD Score (Model for End-Stage Liver Disease) is used to stratify severity of end-stage liver disease, for transplant planning purposes.

This includes, as part of assessment, the need for dialysis, serum creatinine, serum bilirubin, serum bilirubin, INR and serum sodium.

1. In severe liver disease, or acute liver disease, insulin in the drug of choice. In mild or moderate liver disease, most oral drugs can be used, though with caution.
2. GLP1RA glucagon-like peptide 1 receptor agonists) such as liraglutide and dulaglutide, SGLT2i (sodium glucose cotransporter 2 inhibition)like canagliflozin, dapagliflozin and empagliflozin, and pioglitazone are shown to improve hepatic function.
3. The best intervention for NAFLD is weight loss. Vitamin E and ursodeoxycholic acid may be used in selected patients to improve liver enzyme levels. Statin therapy is safe, and vaccination against hepatitis A and B should be offered where necessary.

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Summary

The coming years should see greater emphasis on the role of the liver in diabetes, and the need to ensure comprehensive viscerometabolic optimisation. This can be achieved by universal screening for dysglycaemia in liver disease, institution of weight optimisation strategies, and use of glucose-lowering drugs which offer hepatotropic benefits. Though current use is of cardiovascular status as a tool for stratification, and a target for treatment, we hope that future guidance will include liver health as an integral part of target care.

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To read other articles in this series, click,

Difficult diabetes- The diagnosis is important

Hyperglycemia- Think beyond glucose

Disclaimer- The views and opinions expressed in the article and videos are those of the speakers and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sanjay Kalra is a leading Endocrinologist and the current President of the Endocrine Society of India.