Liver Disease and Diabetes Mellitus



Liver Disease and Diabetes Mellitus

• The liver plays a central role in the regulation of carbohydrate metabolism.

• Its normal functioning is essential for the maintenance of blood glucose levels and of a continued supply to organs that require a glucose energy source.

• This central role for the liver in glucose homeostasis offers a clue to the pathogenesis of glucose intolerance in liver diseases.

The Role of the Liver in Glucose Homeostasis

• The liver uses glucose as a fuel.

• Store it as glycogen promoted by insulin.

• Synthesize it from noncarbohydrate precursors (gluconeogenesis).

• Regulation of systemic blood glucose levels following a meal.

• Insulin is metabolized by insulinase in the liver, kidney, and placenta.

• About 50% of insulin secreted by the pancreas is removed by first-pass extraction in the liver.

• Insulin promotes glycogen synthesis (glycogenesis) in the liver and inhibits its breakdown (glycogenolysis).

• It promotes protein, cholesterol, and triglyceride synthesis and stimulates formation of very-low-density lipoprotein cholesterol.

• It also inhibits hepatic gluconeogenesis, stimulates glycolysis, and inhibits ketogenesis.

• The liver is the primary target organ for glucagon action, where it promotes glycogenolysis, gluconeogenesis, and ketogenesis.

Liver Disease and Diabetes Mellitus

Liver disease may cause or contribute to, be coincident with, or occur as a result of diabetes mellitus

1. Liver disease occurring as a consequence of diabetes mellitus

• Glycogen deposition

• Steatosis and nonalcoholic steatohepatitis (NASH)

• Fibrosis and cirrhosis

• Biliary disease, cholelithiasis, cholecystitis

• Complications of  therapy of  diabetes (cholestatic and necroinflammatory)

2 . Diabetes mellitus and abnormalities of glucose homeostasis occurring as a complication of liver disease

• Hepatitis

• Cirrhosis

• Hepatocellular carcinoma

• Fulminant hepatic failure

• Postorthotopic liver transplantation

3 . Liver disease occurring coincidentally with diabetes mellitus and abnormalities of glucose homeostasis

• Hemochromatosis

• Glycogen storage diseases

• Autoimmunebiliary disease

Liver Disease Occurring as a Consequence of Diabetes Mellitus

1. Glycogen Deposition

• Excess glycogen accumulation in the liver is seen in 80% of diabetic patients.

• Etiology ↑ activation of glycogen synthase in diabetes ( ↑glycogen synthesis in the liver.

o Long-standing insulin deficiency may facilitate synthase activity.

o Enhanced gluconeogenesis.

• Forms

o Cytoplasmic glycogen deposition (uncertain).

o Nuclear glycogen deposition.

▪ Glycogen is synthesized in the nucleus.

▪ 60–75% of diabetic patients.

▪ Seen also in sepsis, tuberculosis, some patients with hepatitis (particularly autoimmune chronic hepatitis), Wilson's disease, and cirrhosis.

• Glycogen nuclei in a patient with fatty liver ( confirmatory evidence that the fatty liver is secondary to diabetes even if the glucose tolerance test is normal.

• Diabetic patients showing excessive glycogen deposition

o Abdominal pain, nausea and vomiting.

o Hepatomegaly.

o Liver enzyme abnormalities.

o Improve with sustained glucose control.

2. Fatty Liver, Steatohepatitis

Fat accumulation

• Hepatic fat accumulation is a well-recognized complication of diabetes ( frequency of 40–70%.

• Associated obesity is a frequently occurring confounding variable.

• Type 1 diabetes is not associated with fat accumulation if glycemia is well controlled.

• Type 2 diabetes may have a 70% correlation regardless of blood glucose control.

• Fat is stored in the form of triglyceride and may be a manifestation of:

o Increased fat transport to the liver.

o Enhanced hepatic fat synthesis.

o Decreased oxidation or removal of fat from the liver.

• The steatosis may be microvesicular or macrovesicular and may progress to fibrosis and cirrhosis.

• The most common.

• Diagnosis

• Clinical presentation

o Hepatomegaly.

o Normal or mildly abnormal transaminases.

o Normal bilirubin.

• CT scan and ultrasound are claimed to be sensitive tests for detecting hepatic fat accumulation.

• Liver biopsy

o Best method for detecting hepatic fat accumulation.

o Assess the degree of fibrosis.

o Mallory bodies

• Excessive fat accumulation is seen in

|Alcoholic liver disease |Obesity |Ulcerative colitis |

|Prolonged parenteral nutrition |Protein malnutrition |Chronic pancreatitis |

|Jejunoileal bypass |Chronic illnesses complicated by impaired nutrition |

Steatohepatitis

• Higher prevalence in type 2 diabetic patients on insulin.

• Spectrum asymptomatic elevation of liver enzymes ( severe liver disease with fibrosis and nodular regeneration ( progressive liver disease and complications that may need liver transplantation.

• Obese and hyperlipidemia are particular risk factors.

• In type 2 diabetic patients with or without obesity

o 30% have fat with inflammation.

o 25% have associated fibrosis.

o 1–8% cirrhosis.

• Histopathological changes in diabetes ( periportal (situated in zone I.

• In type 1 diabetes, perisinusoidal fibrosis often parallels with diabetic microangiopathy.

• Control

• Gradual weight loss and good control of blood glucose levels.

• Rapid weight loss may worsen NASH.

• Weight loss >10% is necessary for normalization of liver enzymes in patients who are significantly overweight.

• Ursodeoxycholic acid

o Beneficial in reducing steatosis.

o Normalization of liver enzymes.

o Improvement in histology without impact on fibrosis.

3. Cirrhosis

• There is an increased incidence of cirrhosis in diabetic patients.

• 80% of patients with cirrhosis have glucose intolerance.

• Diabetes increases the risk of steatohepatitis, which can progress to cirrhosis.

• Obesity is a significant risk factor.

4. Cholelithiasis, Cholecystitis

• Two to threefold increased incidence of gallstones in diabetic patients.

• Pathogenesis:

o Gallbladder emptying abnormalities.

o Secretion of lithogenic bile by the liver (type 2 diabetes).

o Increased biliary cholesterol saturation.

• Obesity and hyperlipidemia are risk factors.

5. Complications of Diabetes Therapy

• Insulin therapy

o Increase patient’s risk of acquiring viral hepatitis because of the exposure to needles.

o Adhering to good infection-control practices should significantly reduce this risk.

• Oral hypoglycemics

• There is a rare association between the use of oral hypoglycemics and hepatic injury.

• The biguanide

o Metformin (Glucophage) ( no hepatic metabolism ( unchanged in urine.

▪ Associated with liver injury.

o Chronic liver disease may predispose patients taking metformin to developing lactic acidosis, probably due to a reduced ability of the liver to clear lactate

• Sulfonylureas

• Sulfonylureas can cause

o Chronic hepatitis with necroinflammatory changes.

o Granulomatous changes.

• Chlorpropamide (Diabinese) ( no hepatic metabolism ( unchanged in urine.

o Most hepatotoxic.

o Cholestatic hepatitis occurring in 0.5% of people on the drug.

o Jaundice develops over 2–5 weeks and resolves in virtually all patients when the drug is stopped.

• Glyburide (Glynase) is excreted in bile and urine in a 50/50 ratio.

• Glipizide (Glucotrol) is metabolized by the liver and hepatic disease may result in increased blood levels.

• Acetohexamide and glyburide can cause acute hepatocellular necrosis.

• Thiazolidinediones (decreasing insulin resistance)

• Troglitazone (Rezulin) ( severe idiosyncratic hepatocellular injury, usually reversible but possibly leading to death or liver transplantation.

• Serum transaminases should be checked at the start of therapy and periodically thereafter.

• If a patients ALT level is >3 times the upper limit of normal, therapy should not be started.

Diabetes and Abnormalities of Glucose Homeostasis Occurring as a Complication of Liver Disease

1. Viral Hepatitis

• There is an increased prevalence of viral hepatitis in diabetes possibly due to an increased exposure to needles for the injection of insulin or for blood testing.

• Diabetes is more prevalent in patients with hepatitis C.

o Causative role of hepatitis C in the pathogenesis of diabetes.

o Higher incidence of diabetes in liver transplant recipients with hepatitis C.

• Interferon therapy

o May induce hyperglycemia.

o Development of type 2 diabetes.

o Necessitate increased insulin requirements in patients with type 1 diabetes.

o Development of type 1 diabetes through the development of insulin autoantibodies.

o Severe hypertriglyceridemia in a diabetic patient.

1. Cirrhosis

• Individuals with cirrhosis have elevated insulin levels indicating:

o Insulin resistance.

o Reduced degradation of insulin by the cirrhotic liver.

• In the absence of peripheral insulin resistance, it is likely that patients with cirrhosis would become hypoglycemic.

• The proposed pathogenesis of the insulin resistance

o A receptor or postreceptor abnormality.

o Potassium depletion.

o Excess glucagon, growth hormone, cortisol.

o Increased fatty acid levels in blood.

o Reduced insulin receptors.

• Cirrhotic patients may develop fasting hypoglycemia by way of the "Insulin Autoimmune Syndrome" ( high levels of insulin autoantibodies in absence of HCC.

• Cirrhotic patients and patients with fulminant hepatic failure may have lower blood glucose concentrations but significant hypoglycemia may be prevented by:

o Decreased utilization of glucose.

o Increased utilization of nonglucose fuels such as fat.

• Precautions in the management of cirrhotic patients with diabetes

o Use insulin as it is anabolic hormone.

o Keep the patient on the hypoglycemic side.

2. Hepatocellular Carcinoma

• Hepatocellular carcinoma may be associated with hypoglycemia.

o Production of insulin-like growth factor-II (IGF-II) by HCC which functions as a partial insulin agonist.

• Diabetic patients who develop HCC may require progressively less insulin due to:

o Production of IGFs.

o Increased glucose utilization by insulin-sensitive tissue.

• Patients with diabetes are at increased risk for developing primary liver cancer.

3. Fulminant Hepatic Failure

• Fulminant hepatic failure may be complicated by hypoglycemia which may worse the prognosis and require:

o Close observation.

o Glucose supplementation.

• Aetiology:

o Destruction of hepatocytes.

o Hyperinsulinism.

o Inadequate storage of glucose in extrahepatic organs.

4. Liver Transplantation and Diabetes

• Effect of diabetes (pre or post) on the transplant recipient during the 1st year:

o No influence on graft survival.

o No influence on liver synthetic function.

o No influence on number of rejection episodes.

• Incidence of posttransplant diabetes 27% at 1 year, 9% at 2 years & 7% at 3 years.

• Patients with posttransplant diabetes had a significantly higher mortality in the second postoperative year.

• Fk506, tacrolimus (Prograf), a potent immunosuppressive agent used in liver transplantation to prevent allograft rejection ( diabetes mellitus.

• Stopping the drug may result in restoration of normal glucose tolerance.

Liver Disease Coincident With Diabetes and Abnormalities of Glucose Homeostasis

1. Hemochromatosis

• Hemochromatosis is an autosomal recessive inherited condition characterized by an abnormally high absorption of iron from the small intestine and excessive accumulation of iron in the liver and other tissues.

• The term bronze diabetes refers to the association of diabetes with hemochromatosis.

• Patients with hemochromatosis and diabetes (75%)

o Reduced survival.

o Impaired insulin secretion and increased insulin resistance.

• Diabetes in patients with hemochromatosis increases as the liver iron concentration increases.

• Patients with diabetes who have a family history of liver disease should probably be screened for hemochromatosis.

• Phlebotomy may recover pancreatic [pic]-cell but rarely will restore normal glucose tolerance.

2. Glycogen Storage Disease

• Absence of glucose-6-phosphatase or other enzymes necessary for glycogen degradation.

o The affected infant may require carbohydrate feedings every 2–3 hs to prevent possible brain damage.

o Glycogen content in the livers is excessive.

o The most common is type 1 glycogenesis, characterized by a deficiency of the enzyme glucose-6-phosphatase.

o It is inherited in an autosomal recessive fashion.

3. Autoimmune Biliary Disease

• Autoimmune polyglandular syndrome is a genetically determined autoimmune disease influenced by HLA genotype may manifest with:

o Type 1 diabetes

o Primary biliary cirrhosis (PBC).

o Ulcerative colitis.

o Sclerosing cholangitis.

• Primary sclerosing cholangitis (PSC) can also involve the pancreatic duct and result in chronic inflammatory pancreatic changes ( functional changes ( glucose intolerance.

• Glucose intolerance may be higher in patients with PSC than in patients with other liver disease.

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