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Liver Disease and Diabetes Mellitus
Gavin N. Levinthal, MD, and Anthony S. Tavill, MD, FRCP, FACP
This article addresses the role of the liver in normal glucose homeostasis and discusses a variety of liver conditions associated with abnormal glucose homeostasis. This association may explain the pathogenesis of the liver disease or of the abnormal glucose homeostasis, or may be purely coincidental (Table 1).
The prevalence of type 1 diabetes in the United States is ~0.26%. The prevalence of type 2 diabetes is far higher, ~12% in Caucasian Americans and up to 40% in Pima Indians. According to the Centers for Disease Control and Prevention, hepatitis C alone chronically infects more than 1.8% of the American population, or more than 4 million people. It would not be unusual for these two diseases to occur by chance in the same person, which explains in part the apparent association between liver disease and diabetes mellitus.
The liver plays a central and crucial 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 but little insight into the mechanisms of liver disease in diabetes mellitus. This review will draw on sources in the literature that address both pathogenetic directions.
The Role of the Liver in Glucose
Glucose absorbed from the intestinal tract is transported via the portal vein to the liver. Although the absolute fate of this glucose is still controversial, some authors suggest that most of the absorbed glucose is retained by the liver so that the rise in peripheral glucose concentration reflects only a minor component of postprandial absorbed glucose. Therefore, it is possible that the liver plays a more significant role than does peripheral tissue in the regulation of systemic blood glucose levels following a meal.3 Katz and associates,4 however, suggest that most absorbed glucose is not taken up by the liver but is rather metabolized via glycolysis in the peripheral tissues.
Many cells in the body, including fat, liver, and muscle cells, have specific cell membrane insulin receptors, and insulin facilitates the uptake and utilization of glucose by these cells. Glucose rapidly equilibrates between the liver cytosol and the extracellular fluid. Transport into certain cells, such as resting muscle, is tightly regulated by insulin, whereas uptake into the nervous system is not insulin-dependent.
Glucose can be used as a fuel or stored in a macromolecular form as polymers: starch in plants and glycogen in animals. Glycogen storage is promoted by insulin, but the capacity within tissues is physically limited because it is a bulky molecule.
Insulin is formed from a precursor molecule, preproinsulin, which is then cleaved to proinsulin. Further maturation results in the conversion of proinsulin into insulin and a smaller peptide called C-peptide.
A small amount of proinsulin enters the circulation. It has a half-life 34 times longer than that of insulin because it is not metabolized by the liver. However, proinsulin has <10% of the biological activity of insulin.
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.5,6
Glucose that is taken up by a cell may be oxidized to form energy (glycolysis). It is oxidized to pyruvate in the cytosol, and electrons generated from this process are transferred to the mitochondria. Pyruvate generated by this Emden-Meyerhof pathway is oxidized to acetyl CoA in the mitochondria, which in turn undergoes further oxidation by the Krebs tricarboxylic acid cycle. Nearly 36 moles of high energy phosphate are generated from each molecule of glucose by aerobic glycolysis.
Should oxygen not be available, pyruvate is converted to lactate by the action of lactate dehydrogenase. Lactate is a potential fuel, or it may be converted back to glucose. The formation of glucose from lactate and various noncarbohydrate precursors is known as gluconeogenesis and occurs mainly in the liver and kidneys.
The liver, kidney, intestine, and platelets contain the enzyme glucose-6-phosphatase, which produces glucose from glucose-6-phosphate and is the final step in the production of glucose via gluconeogenesis. This enzyme is absent in other tissues. Glucose that is metabolized peripherally may therefore be converted back to glucose or to hepatic glycogen via gluconeogenesis with lactate as the primary substrate.7 This is known as the Cori cycle.
In type 2 diabetes, excessive hepatic glucose output contributes to the fasting hyperglycemia. Increased gluconeogenesis is the predominant mechanism responsible for this increased glucose output, while glycogenolysis has not been shown to be increased in patients with type 2 diabetes.8 Hyperglucagonemia has been shown to augment increased rates of hepatic glucose output, probably through enhanced gluconeogenesis.
Liver Disease Occurring as a Consequence
of Diabetes Mellitus
The mechanism of cytoplasmic glycogen deposition is uncertain but is perhaps related to the large variations in glucose concentration and frequent insulin dosing. No correlation between hepatic glycogen content and fasting blood glucose levels has been demonstrated. There is also no demonstrable association between the type of diabetes or the fat content of the hepatocytes and the presence of glycogen.
The mechanism for nuclear glycogen deposition is also unclear, with the stored glycogen resembling muscle glycogen more than hepatocyte cytoplasmic glycogen.11-13 Nuclear glycogen deposition was first described by Ehrlich in 1883.14 It is postulated that glycogen is actually synthesized in the nucleus and has been found in 6075% of diabetic patients.15,16 Nuclear glycogen deposition is also seen in sepsis, tuberculosis, some patients with hepatitis (particularly autoimmune chronic hepatitis), Wilson's disease, and cirrhosis.
The finding of glycogen nuclei in a patient with fatty liver is useful confirmatory evidence that the fatty liver is secondary to diabetes even if the glucose tolerance test is normal. However, Creutzfeldt and associates have reported the combination also in obese patients.17-19
Patients showing solely excessive glycogen deposition may exhibit hepatomegaly and liver enzyme abnormalities and may have abdominal pain and even nausea and vomiting and rarely ascites. All these abnormalities may improve with sustained glucose control.20
Fatty Liver, Steatohepatitis
Fat is stored in the form of triglyceride and may be a manifestation of increased fat transport to the liver, enhanced hepatic fat synthesis, and decreased oxidation or removal of fat from the liver. The steatosis may be microvesicular or macrovesicular and may progress to fibrosis and cirrhosis. The degree of glycemic control does not correlate with the presence or absence of fat.21-26 The most common clinical presentation is hepatomegaly, and most patients have normal or only mildly abnormal transaminases and normal bilirubin.
CT scan and ultrasound are claimed to be sensitive tests for detecting hepatic fat accumulation. A negative ultrasound, however, does not exclude the presence of microscopic fatty infiltration.27 A liver biopsy is obviously the best method for detecting hepatic fat accumulation. It is unclear at this time whether a biopsy is always necessary in patients with suspected steatohepatitis. Biopsy probably should be performed when the diagnosis is unclear, although some authors suggest that it is necessary in all cases to confirm the diagnosis and assess the degree of fibrosis.28,29
Excessive fat accumulation is seen in alcoholic liver disease, obesity, prolonged parenteral nutrition, protein malnutrition, jejunoileal bypass, and chronic illnesses complicated by impaired nutrition, such as ulcerative colitis and chronic pancreatitis. It can also occur as a result of hepatotoxins, such as carbon tetrachloride, and can be seen in association with abetalipoproteinemia, Weber-Christian disease, the HIV virus, cholesterol ester storage disease, and Wilson's disease, in addition to diabetes mellitus. A number of drugs, such as amiodarone, perhexilene, glucocorticoids, estrogens, and tamoxifen, may cause macrovesicular steatosis. The amount of fat frequently diminishes with improvement of the underlying condition.
Nonalcoholic steatohepatitis (NASH) is a variant of fatty liver in which fat in the hepatocytes is accompanied by lobular inflammation and steatonecrosis. The diagnosis can only be made in the absence of alcohol abuse or other causes of liver disease, particularly hepatitis C. In patients with diabetes and steatohepatitis, Mallory bodies such as those seen in alcoholic liver disease may be seen. Nonalcoholic steatohepatitis has been associated most commonly with obese women with diabetes, but the disease is certainly not limited to patients with this clinical profile.30 There is certainly a higher prevalence in type 2 diabetic patients on insulin.31
The spectrum of clinical disease in fatty liver with steatohepatitis varies from the asymptomatic elevation of liver enzymes to severe liver disease with fibrosis and nodular regeneration. Patients with nonalcoholic steatohepatitis can develop progressive liver disease and complications to the point that they may need liver transplantation.32
Nonalcoholic steatohepatitis should be considered as a cause for chronically elevated liver enzymes in asymptomatic diabetic patients particularly if they are obese and have hyperlipidemia.33 In type 2 diabetic patients with or without obesity, up to 30% have fat with inflammation, 25% have associated fibrosis, and 18% have cirrhosis.34-36
The morphological pattern of diabetic steatohepatitis resembles that seen in alcoholic hepatitis. However, the histopathological changes in diabetes tend to be periportal (situated in zone I), while those in alcoholic hepatitis are predominantly pericentral (in zone III). It is not clear whether the diabetes is causally related to the steatohepatitis.37,38 In an animal model of type 1 diabetes, there is a high incidence of perisinusoidal hepatic fibrosis, while in humans perisinusoidal fibrosis often parallels with diabetic microangiopathy.39
Gradual weight loss and good control of blood glucose levels is recommended for patients with steatohepatitis, since rapid weight loss may actually worsen NASH.40,41 Weight loss >10% has been shown to be necessary for normalization of liver enzymes in patients who are significantly overweight.42 Ursodeoxycholic acid may be beneficial in reducing steatosis and may result in normalization of liver enzymes and improvement in histology without demonstrable impact on fibrosis.43-45
Biliary Disease, Cholelithiasis,
There is no indication in the literature that the natural history of gallstones is different in diabetic and nondiabetic individuals. The relative risk of mortality following acute cholecystitis is not significantly greater in diabetic patients than in the general population, and neither is the risk for serious complications. For that reason, prophylactic cholecystectomy cannot routinely be recommended for asymptomatic gallstones in patients with diabetes.55 Any increase in mortality may be attributed to underlying renal or vascular disease. Patients with diabetes have comparable survival outcomes from laparoscopic or open cholecystectomy.56
Complications of Diabetes Therapy
The biguanide metformin (Glucophage) does not undergo hepatic metabolism and, like chlorpropamide (Diabinese), is excreted unchanged in the urine.57 In contrast, the sulfonylurea glyburide (Micronase, Glynase, Diabeta) is excreted in bile and urine in a 50/50 ratio. The sulfonylurea glipizide (Glucotrol, Glucotrol XL) is metabolized mainly by the liver, and, in theory, hepatic disease may result in increased blood levels.
There is a rare association between the use of oral hypoglycemics and hepatic injury, but sulfonylureas can cause chronic hepatitis with necroinflammatory changes.58 Granulomatous changes can also be seen. They are described as having a well-circumscribed cellular infiltrate comprised of acidophilic histiocytes and eosinophils surrounding necrotic hepatocytes. The mechanism of liver injury is not known.
Chlorpropamide appears to be the most hepatotoxic of these drugs, with cholestatic hepatitis occurring in 0.5% of people on the drug. Jaundice develops over 25 weeks and resolves in virtually all patients when the drug is stopped. Hepatic disease is very rare with tolbutamide (Orinase and generics), and tolazamide (Tolinase and generics). Although very uncommon, acetohexamide and glyburide can cause acute hepatocellular necrosis, and fatalities have been reported. At least two cases of granulomatous hepatitis thought secondary to glyburide have been reported in the literature.59
The biguanides, such as metformin hydrochloride, have not been associated with liver injury. Lactic acidosis can be associated with the use of metformin to treat diabetes, but it is reported to occur occasionally and usually in patients with major contraindications to the drug. "Chronic liver disease" is one of the conditions that may predispose patients taking metformin to developing lactic acidosis, probably due to a reduced ability of the liver to clear lactate. It is therefore listed as a contraindication.60
Troglitazone (Rezulin) is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Its package insert carries a warning that severe idiosyncratic hepatocellular injury, usually reversible but possibly leading to death or liver transplantation, has been reported in patients using the medication, usually during the early months of therapy.
Serum transaminases should be checked at the start of therapy, monthly for the first 6 months of therapy, every 2 months for the remainder of the first year, and periodically thereafter. If a patientís ALT level is >3 times the upper limit of normal, therapy should not be started or should be discontinued in those already receiving the medication. In patients with levels >1.5 times the upper limit of normal, repeat evaluations at earlier intervals are necessary to ensure that more serious deterioration of liver enzymes is not developing. In addition, any symptoms suggesting hepatic dysfunction necessitate having liver tests performed.
Diabetes and Abnormalities of Glucose
Homeostasis Occurring as a Complication of Liver Disease
Diabetes is far more prevalent in patients with hepatitis C than in patients with other forms of viral hepatitis. In a study by Grimbert and associates, 152 patients with hepatitis C and the same number with either hepatitis B or alcohol-induced liver disease were compared over the same period. Twenty-four percent of the patients with hepatitis C had diabetes compared with only 9% of the controls. The authors suggested a causative role of hepatitis C in the pathogenesis of diabetes.63
Fraser and associates also found an association between chronic hepatitis C and the presence of impaired glucose control and reported that the prevalence of diabetes was much higher in hepatitis C than in the general population.64 One hundred adults with cirrhosis were evaluated in a retrospective study. Of the 34 patients with hepatitis C, 50% had diabetes mellitus, as opposed to 9% of the 66 patients with cirrhosis unrelated to hepatitis C. The association has been described also by others and was thought to be statistically significant.65-67
Simo and associates also suggested that the hepatitis C virus may have a direct causative role in the development of diabetes. Most of their diabetic patients with hepatitis C had abnormal liver tests.68
The association of diabetes with hepatitis C has also been investigated in posttransplantation patients, and there is a reported higher incidence of diabetes in liver transplant recipients with hepatitis C. This increased incidence appears to be significant, and the presence of the virus appears to be an independent risk factor.69
Interferon therapy used to treat hepatitis B and C may induce hyperglycemia, result in the development of type 2 diabetes, and necessitate increased insulin requirements in patients with type 1 diabetes.70-73 Interferon therapy has resulted in the development of type 1 diabetes likely through the development of insulin autoantibodies.74-76 Fattovich and associates retrospectively studied 11,241 patients with chronic viral hepatitis who had undergone interferon therapy. However, only 10 patients developed de novo diabetes mellitus.77 Interferon therapy also reportedly led to severe hypertriglyceridemia in a diabetic patient.78
The hepatitis B vaccine effectively induces protective antibodies in most patients with diabetes.79,80 One study in children with type 1 diabetes concluded that children may not respond as well to the vaccination. This suggested that children should perhaps be vaccinated with four injections instead of three.81
The pathogenesis of the proposed insulin resistance is not known, although a receptor or postreceptor abnormality is postulated.82 Impaired insulin secretion from the pancreatic -cells has been proposed as another cause for the hyperglycemia,83 and glucose intolerance in patients with decompensated cirrhosis has been found to be associated with low insulin secretion.84 Potassium depletion, excess glucagon, growth hormone, cortisol, and increased fatty acid levels in blood, and reduced insulin receptors may account for the insulin resistance, but these are all unproved hypotheses.
Cirrhotic patients may develop fasting hypoglycemia by way of the "Insulin Autoimmune Syndrome" associated with the development of high levels of insulin autoantibodies even in the absence of hepatocellular carcinoma.85 Cirrhotic patients and patients with fulminant hepatic failure may have lower blood glucose concentrations than matched subjects, but significant hypoglycemia may be prevented by decreased utilization of glucose and an increased utilization of nonglucose fuels such as fat.86-88
IGF-II is a protein that functions as a partial insulin agonist.89 Diabetic patients who develop HCC may require progressively less insulin, not only due to the production of IGFs, but also due to increased glucose utilization by insulin-sensitive tissue.90-93 A study by Adami and associates on a cohort of about 154,000 patients suggested that patients with diabetes are at increased risk for developing primary liver cancer.94 In a case-controlled study in Italy, it was again suggested that patients with diabetes may be at higher risk for hepatocellular carcinoma, although the reason why is unclear.95
Fulminant Hepatic Failure
Liver Transplantation and Diabetes
Trail and associates retrospectively investigated 497 patients who had received orthotopic liver transplants. Twenty-six patients (5.2%) had clinical evidence of diabetes 1 month after transplant. This did not influence graft survival, liver synthetic function, or number of rejection episodes during the first year. The investigators concluded that the presence of posttransplant diabetes did not significantly affect patient outcome in the first year.100
Navasa and associates evaluated 102 patients who survived longer than 1 year after orthotopic liver transplantation. Fourteen had diabetes before transplantation, and all but one were alive 3 years later. Their reported incidence of posttransplant diabetes was 27% at 1 year, 9% at 2 years, and 7% at 3 years. Patients with posttransplant diabetes had a significantly higher mortality in the second postoperative year than did patients without this complication. This may be related to an increased use of immunosuppressive agents in those patients with rejection and thus a greater predisposition to diabetes.101
Fk506, tacrolimus (Prograf), a potent immunosuppressive agent used in liver transplantation to prevent allograft rejection, may cause diabetes mellitus. Stopping the drug may result in restoration of normal glucose tolerance.102 Liver transplantation may be performed in patients with type 1 diabetes without any increased risk for graft or patient survival regardless of the underlying liver disease indication. Interestingly, in patients with renal transplants, both diabetes and hepatitis B were associated with less favorable outcomes.103
Liver Disease Coincident With Diabetes
and Abnormalities of Glucose Homeostasis
The term "bronze diabetes," coined by Hanot and Schachmann in 1886, refers to the association of diabetes with hemochromatosis.9 About 75% of patients with hemochromatosis and established cirrhosis have diabetes. Patients with hemochromatosis and diabetes have a significantly reduced survival compared to hemochromatosis patients without diabetes.105
Hemochromatosis is the most common single gene-inherited metabolic disease amongst Caucasians worldwide. The heterozygote frequency is about 10%; one in 250 people are homozygotes. Patients with hemochromatosis and diabetes have both impaired insulin secretion and increased insulin resistance.106 The likelihood of diabetes in patients with hemochromatosis increases as the liver iron concentration increases.107
Whether all diabetic patients should be screened for hemochromatosis has been considered. Turnbull and associates evaluated 727 patients in a diabetic clinic. Of those, 7.4% had elevated iron indices on initial screening, and in 3% these indices remained elevated on fasting blood specimens. However, only one had homozygous hereditary hemochromatosis, leading to their conclusion that routine screening for hemochromatosis in diabetic patients is probably not cost-effective.108 In contrast, patients with diabetes who have a family history of liver disease should probably be screened for hemochromatosis.
Excessive iron accumulation in conditions other than hemochromatosis, such as dyserythropoietic disorders, may also be associated with diabetes. The pancreatic -cell may recover to varying degrees when the excess iron is removed in conditions associated with iron overload,109,110 but rarely will phlebotomy therapy restore normal glucose tolerance.105
Glycogen Storage Disease
Autoimmune Biliary Disease
Primary sclerosing cholangitis (PSC), which involves to varying degrees the intrahepatic and extrahepatic biliary tree and which may progress to cirrhosis, can also involve the pancreatic duct and result in chronic inflammatory pancreatic changes. The pancreatic changes may be severe enough to cause functional changes and may result in glucose intolerance.113
It is also postulated that ulcerative colitis, sclerosing cholangitis, and diabetes may occur in the same patient as part of a generalized genetically determined autoimmune disease influenced by HLA genotype. Glucose intolerance may be higher in patients with PSC than in patients with other liver disease.114-116
The authors would like to extend their appreciation to Karen Desotell for her assistance in preparing this article.
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Gavin N. Levinthal, MD, is a staff gastroenterologist at the Maurice and Sadie Friedman Center for Digestive & Liver Disorders and an instructor at Case Western Reserve University School of Medicine, and Anthony S. Tavill, MD, FRCP, FACP, is the Mathile & Morton J. Stone Professor of Digestive & Liver Disorders at Mt. Sinai Medical Center and a professor of medicine and nutrition at Case Western Reserve University in Cleveland, OH.
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