The prevalence of type 1 diabetes in the United States is ~0.26%. The prevalence of type 2 diabetes is far higher, ~1–2% 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 Homeostasis
An appreciation of the role of the liver in the regulation of carbohydrate homeostasis is essential to understanding the many physical and biochemical alterations that occur in the liver in the presence of diabetes and to understanding how liver disease may affect glucose metabolism. The liver uses glucose as a fuel and also has the ability to store it as glycogen and synthesize it from noncarbohydrate precursors (gluconeogenesis). Mann and Magath demonstrated that a total hepatectomy in a dog results in death within a few hours from hypoglycemic shock,^1,2 underscoring the important role the liver plays in maintaining normoglycemia.

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 3–4 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
Glycogen Deposition
Excess glycogen accumulation in the liver is seen in 80% of diabetic patients.⁹ Glycogen synthesis in the liver is impaired in diabetes due to defective activation of glycogen synthase. However, studies attesting to this were usually performed on animals with recently induced diabetes. In patients with chronic diabetes, glycogen accumulation is seen, and it is postulated that long-standing insulin deficiency may actually facilitate synthase activity. This and enhanced gluconeogenesis may account for the net accumulation of glycogen in diabetes.¹⁰

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 60–75% 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
Hepatic fat accumulation is a well-recognized complication of diabetes with a reported frequency of 40–70%. Unfortunately, associated obesity is a frequently occurring confounding variable. Type 1 diabetes is not associated with fat accumulation if glycemia is well controlled, but 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 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 1–8% 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

Cirrhosis
There is an increased incidence of cirrhosis in diabetic patients, and, conversely, at least 80% of patients with cirrhosis have glucose intolerance.^46,47 The reported prevalence of cirrhosis in diabetes varies widely. Diabetes increases the risk of steatohepatitis, which can progress to cirrhosis. Obesity is a significant confounding variable in determining the prevalence of cirrhosis in diabetes. Even with normal glucose tolerance, obesity can cause steatohepatitis and cirrhosis. Likewise, the lack of a clear definition of diabetes in the past somewhat confounds these statistics.

Biliary Disease, Cholelithiasis, Cholecystitis
There is a reported increased incidence of cholelithiasis in diabetes mellitus, but obesity and hyperlipidemia may again be confounding variables. Several articles have reported a two- to threefold increased incidence of gallstones in diabetic patients, whereas others have failed to demonstrate a significant association.^17,48-52 Gallbladder emptying abnormalities found in diabetic patients may predispose patients to cholelithiasis.⁵³ Secretion of lithogenic bile by the liver in patients with type 2 diabetes probably predisposes them to forming gallstones, but this is likely a result of concomitant obesity rather than a result of the diabetes itself.⁵⁴ Increased biliary cholesterol saturation has not been demonstrated in insulin-dependent diabetic patients.

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
Insulin therapy may increase patientsí risk of acquiring viral hepatitis because of the exposure to needles. Adhering to good infection-control practices should significantly reduce this risk.

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 2–5 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
Viral Hepatitis
There is no evidence in the literature that viral hepatitis has a worse prognosis in patients with diabetes. 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. Possible contamination of the platform in spring-loaded lancet devices may increase the risk of acquiring hepatitis B or C from these instruments. In 1996, hepatitis B outbreaks were noted in an Ohio nursing home and a New York hospital. Transmission was thought to be related to the use of spring-loaded devices for fingerstick glucose testing.^61,62

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

Cirrhosis
Individuals with cirrhosis have elevated insulin levels, perhaps indicating insulin resistance or 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 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

Hepatocellular Carcinoma
Hepatocellular carcinoma may be associated with the development of hypoglycemia. A proposed mechanism for the development of this hypoglycemia is the production of insulin-like growth factor-II (IGF-II) by hepatocellular carcinoma cells (HCC). Numerous case reports have discussed the development of this phenomenon.

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
Fulminant hepatic failure may be complicated by hypoglycemia, and its development may portend a poor prognosis and increased mortality.^96,97 Such patients need to be closely observed, and most require glucose supplementation. Destruction of hepatocytes along with hyperinsulinism and inadequate storage of glucose in extrahepatic organs contributes to the hypoglycemia.⁹⁸

Liver Transplantation and Diabetes
The issue has been raised whether the presence of diabetes before or after liver transplantation influences the outcome. Carson and Hunt reported a 4–20% incidence of posttransplant diabetes following liver transplantation.⁹⁹

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
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. Most patients (>80%) with the hemochromatosis (HFE) gene have one of the two described gene mutations, namely, the Cys282Tyr mutation, situated on the short arm of chromosome six. Patients with untreated hemochromatosis develop progressive liver disease, cirrhosis, and diabetes and are at high risk for developing hepatocellular carcinoma.¹⁰⁴

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
Absence of glucose-6-phosphatase or other enzymes necessary for glycogen degradation, as occurs in a variety of glycogen storage diseases, would prevent the use of stored glycogen to maintain the blood glucose concentration in the fasting state. An infant so affected may require carbohydrate feedings every 2–3 hours to prevent possible brain damage. Glycogen content in the livers of most of these affected patients is excessive. The most common form is type 1 glycogenesis, characterized by a deficiency of the enzyme glucose-6-phosphatase. It is inherited in an autosomal recessive fashion.¹¹¹

Autoimmune Biliary Disease
Type 1 diabetes may be one of the manifestations of the autoimmune polyglandular syndrome. Primary biliary cirrhosis (PBC) has been reported in a patient with this syndrome, raising the possibility that PBC may be an associated autoimmune manifestation of this condition.¹¹²

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

Summary
The association between diabetes and liver disease has relevance to diabetologists, hepatologists, and primary care physicians. The finding of an excess prevalence of chronic liver disease in type 2 diabetic patients has stimulated interest in this association and on exploration of avenues of pathogenesis that promise to shed light on the relationship between hepatic metabolism and glucose homeostasis. This review attempted to summarize some of these associations. While it raises more questions than it answers, hopefully future research will fill in the gaps in our current understanding of this intriguing link between two major disease entities.

Acknowledgment

The authors would like to extend their appreciation to Karen Desotell for her assistance in preparing this article.

References

¹Mann FC, Magath TB: Studies on the physiology of the liver. II. The effect of the removal of the liver on the blood sugar level. Arch Intern Med 30:73-84, 1922.

²Mann FC, Magath TB: Studies on the physiology of the liver. IV. The effect of total removal of the liver after pancreatectomy on the blood sugar level. Arch Intern Med 31:797-806, 1923.

³Bjornstorp P, Sjostrom L: Carbohydrate storage in man: speculations and some quantitative considerations. Metabolism 27 (Suppl. 2):1853-65, 1978.

⁴Katz LD, Glickman MG, Rapaport S, Ferrannini E, De Fronzo RA: Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32:675-79, 1983.

⁵Karem JH, Forsham PH: Pancreatic hormones and diabetes mellitus. In Basic and Clinical Endocrinology. 4th edition. Greenspan FS, Baxter JD, Eds. Norwalk, Conn., Appleton and Lange, 1994, p. 571-634.

⁶McGilvery RW, Goldstein G: Biochemistry: a Functional Approach. 2nd edition. Philadelphia, Pa., W.B. Saunders, 1979.

⁷Scofield RF, Kosugi K, Schumann WC, Kumaran K, Landau BR: Quantitative estimation of the pathways followed in the conversion to glycogen of glucose administered to the fasted rat. J Biol Chem 260:8777-82, 1985.

⁸Consoli A, Nurjhan N, Capani F, Gerich J: Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38:550-57, 1989.

⁹Stone BE, VanThiel DH: Diabetes mellitus and the liver. Sem Liver Dis 5:8-28, 1985.

¹⁰Ferrannini E, Lanfranchi A, Rohner-Jeanrenaud F, Manfredini G, VandeWerve G: Influence of long-term diabetes on liver glycogen metabolism in the rat. Metabolism 39:1082-88, 1990.

¹¹Bogoch A, Casselman WGB, Kaplan A, Bockus HL: Studies of hepatic function in diabetes mellitus, portal cirrhosis and other liver diseases. Am J Med 18:354-84, 1955.

¹²Hildes JA, Sherlock S, Walshe V: Liver and muscle glycogen in normal subjects, in diabetes mellitus and in acute hepatitis. Clin Sci 7:289-95, 1949.

¹³Manderson WG, McKiddle MT, Manners DJ, Stark JR: Liver glycogen accumulation in unstable diabetes. Diabetes 17:13-16, 1968.

¹⁴Ehrlich P: ‹ber das Vorkommen von Glykogen im diabetischen und normalen Organismus. Z Klin Med 6:33-53, 1883.

¹⁵Kautzsch E: Leberbefunde bei diabetes mellitus. Med Mschr 17:229-34, 1963.

¹⁶Robbers H, Stohfeldt P, Kr¸ger C: Differential diagnose de diabetischen und alkoholischen fettleber: untersuchungen and 171 Diabetikern und 100 patienten mit alkoholabusus. Deutsch Med Wschr 93:112-13, 1968.

¹⁷Creutzfeldt W, Frerichs H, Sickinger K: Liver diseases and diabetes mellitus. Prog Liver Dis 13:371-407, 1970.

¹⁸Kalk H: ‹ber die beziehungen zwischen Fettleber und diabetes. Deutsch Med Wschr 84:1898-1901, 1959.

¹⁹Kalk H: Über die Fettleber. Munchen Med Wschr 107:1141-47, 1965.

²⁰Chatila R, West AB: Hepatomegaly and abnormal liver tests due to glycogenesis in adults with diabetes. Med Balt 75:327-33, 1996.

²¹Leevy CM, Ryan CM, Fineberg JC: Diabetes mellitus and liver dysfunction. Am J Med 8:290-99, 1950.

²²Silverman JF, O'Brien KF, Long S, Leggett N, Khazanie PG, Pories WJ, Norris JR, Caro JF: Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol 85:1349-55, 1990.

²³Jaques WE: The incidence of portal cirrhosis and fatty metamorphosis in patients dying with diabetes mellitus. N Engl J Med 249:442-45, 1953.

²⁴Bernuau D, Guillot R, Durand-Schneider A, Poussier P, Moreau P, Feldmann G: Liver perisinsoidal fibrosis in BB rats with or without overt diabetes. Am J Pathol 120:38-45, 1985.

²⁵Zimmerman HJ, MacMurray FG, Rappaport H, Alpert LK: Studies of the liver in diabetes mellitus, II. J Lab Clin Med 36:922-27, 1950.

²⁶Leevy CM: Fatty liver: a study of 270 patients with biopsy-proven fatty liver and a review of the literature. Med Balt 41:249-76, 1962.

²⁷O'Connor BJF, Katbamna B, Tavill AS: Nonalcoholic fatty liver (NASH syndrome). Gastroenterologist 5:316-29, 1997.

²⁸Schaffner F, Thaler H: Nonalcoholic fatty liver disease. Prog Liver Dis 8:283-98, 1986.

²⁹Scatarige JC, Scott WW, Donovan PJ, Siegelman SS, Sanders RC: Fatty infiltration of the liver: ultrasonographic and computerized tomographic correlation. J Ultrasound Med 3:9-14, 1984.

³⁰Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA: Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107:1103-09, 1994.

³¹Wanless JR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12:1106-10, 1990.

³²Kim WR, Poterucha JJ, Porayko MK, Dickson ER, Steers JL, Wiesner RH: Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 62:1802-1805, 1996.

³³Sheth SG, Gordon FD, Chopra S: Nonalcoholic steatohepatitis. Ann Intern Med 126:137-45, 1997.

³⁴Anderson T, Gluud C: Liver morphology in morbid obesity: a literature study. Int J Obesity 8:97-106, 1984.

³⁵Kern WH, Heger AH, Payne JH, DeWind LT: Fatty metamorphosis of the liver in morbid obesity. Arch Pathol 96:342-346, 1973.

³⁶Nasrallah SM, Wills CE, Glambos JT: Hepatic morphology in obesity. Digest Dis Sci 26:325-27, 1981.

³⁷Falchuk K, Fiske SC, Haggit RC, Federman M, Trey C: Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology 78:535-41, 1980.

³⁸Nagore N, Scheuer P: The pathology of diabetic hepatitis. J Pathol 156:155-60, 1988.

³⁹Bernuau D, Guillot R, Durand A, Raoux N, Gabreau T, Passa P, Feldmann G: Ultrastructural aspects of the liver perisinusoidal space in diabetic patients with and without microangiopathy. Diabetes 31:1061-67, 1982.

⁴⁰Ludwig J, McGill DB, Lindor KD: Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol 12:398-403, 1997.

⁴¹Braillon A, Capron JP, Herve MA, Degott C, Quenum C: Liver in obesity. Gut 26:133-39, 1985.

⁴²Palmer M, Schaffner F: The effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 99:1408-13, 1990.

⁴³Schlomerich J, Becher MS, Schmidt K, Schubert R, Kremer B, Feldhaus S, Gerok W: Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties: studies on isolated hepatocytes and lipid membrane vesicles. Hepatology 4:661-66, 1984.

⁴⁴Abdelmalek M, Ludwig J, Lindor KD: Two cases from the spectrum of nonalcoholic steatohepatitis. J Clin Gastroenterol 20:127-30, 1995.

⁴⁵Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, Rakala J, McGill DB: Ursodeoxycholic acid or clofibrate in the treatment of non-alcoholic-induced steatohepatitis: a pilot study. Hepatology 23:1464-67, 1996.

⁴⁶Zimmerman HJ, MacMurray FG, Rappaport H, Alpert LK: Studies of the liver in diabetes mellitus. J Lab Clin Med 36:912-21, 1950.

⁴⁷Hano T: Pathohistological study on the liver cirrhosis in diabetes mellitus. Kobe J Med Sci 14:87-106, 1968.

⁴⁸Warren S, LeCompte PM: The gall bladder. In The Pathology to Diabetes Mellitus. Warren S, LeCompte PM, Eds. Philadelphia, Lea & Febiger, 1952, 107-111.

⁴⁹Foster KJ, Griffith AH, Dewbury K, Price CP, Wright R: Liver disease in patients with diabetes mellitus. Postgrad Med J 56:767-72, 1980.

⁵⁰Yang O, Arem R, Chan L: Gastrointestinal tract complications of diabetes mellitus. Arch Intern Med 144:1251-56, 1984.

⁵¹Honore LH: The lack of a positive association between symptomatic cholesterol cholelithiasis and clinical diabetes mellitus: a retrospective study. J Chronic Dis 33:465-69, 1980.

⁵²Feldman M, Feldman M Jr: The incidence of cholelithiasis, cholesterosis, and liver disease in diabetes mellitus. Diabetes 3:305-307, 1954.

⁵³Bennion LJ, Grundy SM: Risk factors for the development of cholelithiasis. N Engl J Med 299:1161-67, 1978.

⁵⁴Cooper AD: Metabolic basis of cholesterol gallstone disease. Gastroenterol Clin North Am 20:21-46, 1991.

⁵⁵Ransohoff DF, Miller GL, Forsythe SB, Hermann RE: Outcome of acute cholecystitis in patients with diabetes mellitus. Ann Intern Med 106:829-32, 1987.

⁵⁶Onate-Ocana LF, Mondragon-Sanchez RJ, Ruiz-Molina JM, Aiello-Crocifoglio V: Laparoscopic cholecystectomy at an oncologic center: a comparative analysis (Abstract). Rev Gastroenterol Med 32:101-107, 1997.

⁵⁷Physicians Desk Reference, 51st edition. Montvale, NJ, Medical Economics, 1997.

⁵⁸Bloodworth JMB, Hamwi GJ: Histopathologic lesion associated with sulfonylurea administration. Diabetes 10:90-99, 1961.

⁵⁹Saw D, Pitman E, Maung M, Savasatit P, Wasserman D, Yeung CK: Granulomatous hepatitis associated with glyburide. Digest Dis Sci 41:322-25, 1996.

⁶⁰Sulkin TV, Bosman D, Krentz AJ: Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 20:925-28, 1997.

⁶¹Nosocomial hepatitis B virus infection associated with reusable fingerstick blood sampling devices - Ohio and New York City, 1996. Morb Mortal Wkly Rep 46:217-21, 1997.

⁶²Polish LB, Shapiro CN, Bauer F, Klotz P, Ginier P, Roberto PR, Margolis HS, Alter MJ: Nosocomial transmission of hepatitis B virus associated with the use of a spring-loaded finger-stick device. N Engl J Med 356:721-25, 1992.

⁶³Grimbert S, Valensi P, Levy-Marchal C, Perret G, Richardet JP, Raffoux C, Trinchet JC, Beaugrand M: High prevalence of diabetes mellitus in patients with chronic hepatitic C: a case-control study. Gastroenterol Clin Biol 20:544-48, 1996.

⁶⁴Fraser GM, Harman I, Meller N, Niv Y, Porath A: Diabetes mellitus is associated with chronic hepatitis C but not chronic hepatitis B infection. Isr J Med Sci 32:526-30, 1996.

⁶⁵Allison ME, Wreghitt T, Palmer CR, Alexander GJ: Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 21:1135-39, 1994.

⁶⁶Ozyilkan E, Arslan M: Increased prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. Am J Gastroenterol 91:1480-81, 1996.

⁶⁷Gray H, Wregitt T, Stratton IM, Alexander GJ, Turner RC, O'Rahilly S: High prevalence of hepatitis C infection in Afro-Caribbean patients with type 2 diabetes and abnormal liver function tests. Diabetic Med 12:244-49, 1995.

⁶⁸Simo R, Hernadez C, Genesca J, Jardi R, Mesa J: High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care 19:998-1000, 1996.

⁶⁹Knobler H, Stagnaro-Green A, Wallenstein S, Schwartz M, Roman SH: Higher incidence of diabetes in liver transplant recipients with hepatitis C. J Clin Gastroenterol 26:30-33, 1998.

⁷⁰Chedin P, Cahen-Varsauz J, Boyer N: Non-insulin-dependent diabetes mellitus developing during interferon-alpha therapy for chronic hepatitis C. Ann Intern Med 125:521, 1996.

⁷¹Campbell S, McLaren EH, Danesh BJ: Rapidly reversible increase in insulin requirement with interferon. Br Med J 313:92, 1996.

⁷²Shiba T, Morino Y, Tagawa K, Fujino H, Unuma T: Onset of diabetes with high titer anti-GAD antibody after IFN therapy for chronic hepatitis. Diabetes Res Clin Pract 30:237-41, 1995.

⁷³Lopes EP, Oliveira PM, Silva AE, Ferraz ML, Costa CH, Miranda W, Dib SA: Exacerbation of type 2 diabetes mellitus during interferon-alpha therapy for chronic hepatitis B. Lancet 343:244, 1994.

⁷⁴DiCesare E, Previti M, Russo F, Brancatelli S, Ingemi MC, Scoglio R, Mazzu N, Cucinotta D, Raimondo G: Interferon-alpha therapy may induce insulin autoantibody development in patients with chronic viral hepatitis. Digest Dis Sci 41:1672-77, 1996.

⁷⁵Waguri M, Hanafus T, Itoh N, Imagawa A, Miyagawa J, Kawata S, Kono N, Kuwajime M, Matsuzawa Y: Occurrence of IDDM during interferon therapy for chronic viral hepatitis. Diabetes Res Clin Pract 23:33-36, 1994.

⁷⁶Fabris P, Betterle C, Floreani A, Greggio NA, deLazzare F, Naccarato R, Chiaramonte M: Development of type 1 diabetes mellitus during interferon alpha therapy for chronic HCV hepatitis. Lancet 340:548, 1992.

⁷⁷Fattovich G, Giustine G, Favarato S, Ruol A: A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alpha interferon. J Hepatol 24:38-47, 1996.

⁷⁸Yamagishi S, Abe T, Sawada T: Human recombinant interferon alpha-2a (r INF alpha-2a) therapy suppresses hepatic triglyceride lipase, leading to severe hypertriglyceridemia in a diabetic patient. Am J Gastroenterol 89:2280, 1994.

⁷⁹Douvin C, Simon D, Charles MA, Deforges L, Bierling P, Lehner V, Buddowdka A, Dhumeaux D: Hepatitis B vaccination in diabeic patients: randomized trial comparing recombinant vaccines containing and not containing pre-S2 antigen. Diabetes Care 20:148-51, 1997.

⁸⁰Marseglia GL, Scaramuzza A, díAnnunzio G, Comolli G, Gatti G, Gatti M, Lorini R: Successful immune response to a recombinant hepatitis B vaccine in young patients with insulin-dependent diabetes mellitus. Diabetic Med 13:630-33, 1996.

⁸¹Ficicioglu C, Mikla S, Midilli K, Aydin A, Cam H, Ergin S: Reduced immune response to hepatitis B vaccine in children with insulin- dependent diabetes. Acta Paediatr Jpn 37:687-90, 1995.

⁸²Nolte W, Hartman H, Ramador G: Glucose metabolism and liver cirrhosis. Exp Clin Endocrinol Diabetes 103:63-74, 1995.

⁸³Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeter G: Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 19:616-27, 1994.

⁸⁴Sampelean D, Motocu M: Low insulin secretion in decompensated liver cirrhosis with diabetes mellitus. Rom J Intern Med 31:265-69, 1993.

⁸⁵Shah P, Mares D, Fineberg E, Pescovitz M, Filo R, Jindal R, Mahoney S, Lumeng L: Insulin autoimmune syndrome as a cause of spontaneous hypoglycemia in alcoholic cirrhosis. Gastroenerology 109:1673-76, 1995.

⁸⁶DeLissio M, Goodyear LJ, Fuller S, Krawitt EL, Devlin JT: Effects of treadmill exercise on fuel metabolism in hepatic cirrhosis. J Appl Physiol 70:210-15, 1991.

⁸⁷Romijn JA, Endert E, Sauerwein HP: Glucose and fat metabolism during short-term starvation in cirrhosis. Gastroenterology 100:731-37, 1991.

⁸⁸Schneeweiss B, Pammer J, Ratheiser K, Schneider B, Madl C, Kramer L, Kranz A, Ferenci P, Druml W, Grimm G, Lera K, Garg A: Energy metabolism in acute hepatic failure. Gastroenterology 105:1515-21, 1993.

⁸⁹Eastman RC, Carson RE, Orloff DG, Cochran CS, Perdue JF, Rechler MM, Lanau F, Roberts CT Jr, Shapiro J, Roth J, Roith D: Glucose utilization in a patient with hepatoma and hypoglycemia: assessment by a positron emission tomography. J Clin Invest 89:1958-63, 1992.

⁹⁰Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsudada N, Inada S, Inagaki Y, Miyamoto K, Suziki O, Okawa H, Kibyu Y: Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors. Liver 12:90-93, 1992.

⁹¹Barzilai N, Cohen P, Bar-Illan R, McIntyre N, Karnieli E: Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient: glucose metabolism in tumor hypoglycemia. Am J Med Sci 302:229-34, 1991.

⁹²Ishida S, Noda M, Kuzuya N, Kubo F, Yamada S, Yamanaka T, Isozaki O, Hizuka N, Kanazawa Y: Big insulin-like growth factor II-producing hepatocellular carcinoma associated with hypoglycemia. Intern Med 34:1201-1206, 1995.

⁹³Hunter SJ, Daughaday WH, Callender ME, McKnight JA, McIlrath EM, Teale JD, Atkinson AB: A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin. Clin Endocrinol Oxford 41:397-401, 1994.

⁹⁴Adami HO, Chow WH, Nyren O, Berne C, Linet MS, Ekbom A, Wolk A, McLaughlin JK, Fraumeni JF Jr: Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 88:1472-77, 1996.

⁹⁵La Vecchia C, Negri E, Decarli A, Fanceschi S: Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 73:204-207, 1997.

⁹⁶Fernandez OU, Canizares LL: Acute hepatotoxicity from ingestion of yellow phosphorus containing fireworks. J Clin Gastroenterol 21:139-42, 1995.

⁹⁷Kelly JH, Koussayer T, He DE, Chong MG, Shang TA, Whisennand HH, Sussman NL: An improved model of acetaminophen-induced fulminant hepatic failure in dogs. Hepatology 15:329-35, 1992.

⁹⁸Ilan Y, Shamir M, Eid A, Eidelman L, Tur-Kaspa R: Reversal of fulminant hepatitis associated hypoglycaemia at the anhepatic stage during liver transplantation. Neth J Med 48:185-87, 1996.

⁹⁹Carson KL, Hunt CM: Medical problems occurring after orthotopic liver transplantation. Digest Dis Sci 42:1666-74, 1997.

¹⁰⁰Trail KC, McCashland TM, Larsen JL, Jeffron TG, Stratta RJ, Langnas AN, Fox IJ, Zetterman RK, Donovan JP, Sorrell MF, Pillen TJ, Ruby EI, Shaw BW Jr: Morbidity in patients with posttransplant diabetes mellitus following orthotopic liver transplantation. Liver Transplant Surg 2:276-83, 1996.

¹⁰¹Navasa M, Bustamante J, Marroni C, Gonzalez E, Andreu H, Esmatjes E, Garcia-Valdecasas JC, Grane L, Cirera I, Rimola A, Rodes J: Diabetes mellitus after liver transplantation: prevalence and predictive factors. J Hepatol 25:64-71, 1996.

¹⁰²Kanzler S, Lohse AW, Schirmacher P, Hermann E, Oto G, Meyer-zum-Buschenfelde KH: Complete reversal of FK 506 induced diabetes in a liver transplant recipient by change of immunosuppression to cyclosporine. Am J Gastroenterol 34:128-31, 1996.

¹⁰³Jin DC, Yoon YS, Kim YS, Yoon SA, Ahn SJ, Kim SY, Chang YS, Bang BK, Koh YB: Factors on graft survival of living donor kidney transplantation in a single center. Clin Transplant 10(6 pt 1):471-77, 1996.

¹⁰⁴Bonkovsky HL, Ponka P, Bacon BR, Drysdale J, Grace ND, Tavill AS: An update on iron metabolism: summary of the fifth international conference on disorders of iron metabolism. Hepatology 24:718-29, 1996.

¹⁰⁵Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G: Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107-19, 1996.

¹⁰⁶Hramiak IM, Finegood DT, Adams PC: Factors affecting glucose tolerance in hereditary hemochromatosis. Clin Invest Med 20:110-18, 1997.

¹⁰⁷Adams PC, Deugnier Y, Moirand R, Brissot P: The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 25:162-66, 1997.

¹⁰⁸Turnbull AJ, Mitchinson HC, Peaston RT, Lai LC, Bennett MK, Taylor R, Bassendine MF: The prevalence of hereditary hemochromatosis in a diabetic population. Quart J Med 90:271-75, 1997.

¹⁰⁹Chim CS, Chan V, Todd D: Hemosiderosis with diabetes mellitus in untransfused Hemoglobin H disease. Am J Hematol 57:160-63, 1998.

¹¹⁰Inoue Y, Nakanishi K, Hiraga T, Okubo M, Murase T, Kosaka K, Miyakoshi S, Mutoh Y, Kobayashi T: Recovery of pancreatic beta-cell function in hemochromatosis: combined treatment with recombinant human erythropoietin and phlebotomy. Am J Med Sci 314:401-402, 1997.

¹¹¹Ghishan F: Inborn errors of metabolism that lead to permanent liver injury. In Hepatology: A Textbook of Liver Disease. vol. II, 3rd edition. Zakim D and Boyer TD, Eds. Philadelphia, Pa., W.B. Saunders, 1996, 1574-1630.

¹¹²Ko GT, Szeto CC, Yeung VT, Chow CC, Chan H, Cockram CS: Autoimmune polyglandular syndrome and primary biliary cirrhosis. Br J Clin Pract 50:344-46, 1996.

¹¹³Pohl R, Junge U: Primary sclerosing cholangitis with chronic pancreatitis. Dtsch Med Wochenschr 122:778-82, 1997.

¹¹⁴Kay M, Wyllie R, Michener W, Caulfield M, Steffen R: Associated ulcerative colitis, sclerosing cholangitis, and insulin-dependent diabetes mellitus. Cleve Clin J Med 60:473-78, 1993.

¹¹⁵Ivarsson SA, Eridsson S, Kockum I, Lernmark A, Lindgren S, Nilsson KO, Sundkvist G, Wassmuth R: HLA-DR3, DQ2 homozygosity in two patients with insulin-dependent diabetes mellitus superimposed with ulcerative colitis and primary sclerosing cholangitis. J Intern Med 233:281-86, 1993.

¹¹⁶Kawashima C, Nagamine T, Takezawa J, Kon Y, Yamada S, Higuchi T, Mori M, Ohshima K: Studies on the glucose tolerance and the endocrine function of the pancreas in primary sclerosing cholangitis. Nippon Shokakibyo Gakkai Zaasshi 89:1425-32, 1992.

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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