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Insulin autoimmune syndrome as a cause of spontaneous hypoglycemia in alcoholic cirrhosis
GASTROENTEROLOGY1995;109:1673-1676
CASE REPORTS Insulin Autoimmune Syndrome as a Cause of Spontaneous Hypoglycemia in Alcoholic Cirrhosis PRINCE S H A H , *
DAVID MARES,* S. EDWIN FINEBERG, ~ MARK PESCOVITZ, II RONALD FILO, II
RAHUL JINDAL, It STEPHEN MAHONEY, ~ and LAWRENCE L U M E N G * *Division of Gastroenterologyand Hepatology, Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis,Indiana; *Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis, Indiana; ~Divisionof Endocrinologyand Metabolism, Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis,Indiana; IIorgan Transplant Unit, Department of Surgery, Indiana UniversityMedical Center, Indianapolis, Indiana; and ~'Divisionof Gastroenterology,St. Francis Hospital, Beech Grove, Indiana
Hypoglycemia in fulminant hepatic failure and hyperinsulinemia in cirrhosis are well-described phenomena. A patient with alcoholic cirrhosis who developed fasting hypoglycemia with an extremely high immunoreactive insulin level and a mildly elevated C-peptide level is reported. An insulinoma was excluded by detailed radiological imaging of the pancreas and by endoscopic ultrasonography. Detection of very high levels of insulin autoantibodies with no prior exposure to exogenous insulin confirmed the diagnosis of insulin autoimmune syndrome. During his hospital course, the patient developed another rare syndrome, acquired inhibitors to factor V, which led to the fatal coagulopathy that resulted in his death. Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemia in Japan, where it has been associated with a variety of diseases and drugs. Outside of Japan, only approximately 20 cases have been reported and usually have been found in the context of an underlying autoimmune disorder or prior exposure to sulfhydryl drugs. It is believed that this is the first case reported outside Japan occurring in association with alcoholic liver d i s e a s e , and the first in the world with coexisting acquired inhibitots to factor V.
ow levels of autoantibodies to insulin have been found regularly at the onset of insulin-dependent diabetes mellitus in the young and in individuals who are at high risk for the development of insulin-dependent diabetes mellitus. They have also been reported to develop in nondiabetic individuals in unusual circumstances such as during penicillamine or methimazole therapy, in diffuse polyimmunity, and during viral infection. These antibodies, however, are often transient and are rarely of clinical significance) High levels of insulin autoantibodies in a patient with spontaneous hypoglycemia were first reported by Hirata in 1970. Insulin autoimmune syndrome (IAS) is characterized by the diagnos-
L
tic criteria of spontaneous hypoglycemia without evidence of exogenous insulin administration, high levels of total immunoreactive insulin, and the presence of a high titer of insulin autoantibodies. 2 Since 1970, 1AS has emerged as the third leading cause of spontaneous hypoglycemia in Japan. However, outside Japan, only about 20 cases have been reported. 3'4 This difference has been attributed to racial variations and a strong association with HLA-DR4, among other explanations. 2'4 The etiopathogenesis of IAS remains unexplained. It has been found to be very closely related to the presence of other autoimmune syndromes and treatment with sulfhydryl drugs. In Japan, it has also been reported in association with other disease states, such as hepatic dysfunction, and with the use of numerous drugs. 2'~ Hypoglycemia is not an uncommon finding in severe liver disease, particularly in fulminant hepatic failure. An unusual case of a cirrhotic patient with IAS as the cause of fasting hypoglycemia in the absence of any other autoimmune disease or sulfhydryl drugs is reported. Case Report A 55-year-old white man with end-stage liver disease secondary to alcoholic cirrhosis, listed for liver transplantation, was admitted after a road accident that occurred while riding a bicycle during the early hours of the morning. On close questioning, the patient was unable to explain his strange activity. His wife reported his sleep pattern as abnormal, with him waking at unusual hours of the night for no apparent reason. His past medical history included chronic alcohol abuse that led to severe liver disease by the age of 42 years. This was complicated by splenic vein thrombosis and recurrent variceal bleeding that required splenectomy and, later, a surgical endto-side portocaval shunt. His pretransptantation evaluation Abbreviations used in this paper:
IAS, insulinautoimmunesyn-
drome. © 1995 by the AmericanGastroenterologicalAssociation
0016-5085/95/$3.00
1674
SHAH ET AL.
ruled out other causes of chronic liver disease. There was no record of any thyroid disease or diabetes mellitus. His medications on admission included omeprazole, haloperidol, lactulose, zinc sulfate, thiamin, and multivitamins. Family history was noncontributory. On admission, physical examination showed the patient to be oriented to time, place, and person. His temperature was 99.5°F, pulse was 108 beats per minute, and blood pressure was 140/80 m m Hg. He had a large tender hematoma in his left leg with an intact distal neurovascular status and no evidence of a compartment syndrome. He was icteric; his liver span was 9 cm in the right midclavicular line and 5 cm in the midline. His abdomen was nontender with no ascites. Findings of the remainder of the physical examination (including examination of the thyroid and the nervous system) were normal. The patient's initial laboratory data were as follows: hemoglobin, 13.1 g/dL; white blood cells, 8800/btL; platelets, 100,000/~tL; blood urea nitrogen, 8 mg/dL; creatinine, 0.8 mg/dL; glucose, 78 mg/dL; bilirubin, 5.7 mg/dL; albumin, 2.6 g/dL; cholesterol, 106 mg/dL; creatine kinase, 331 IU/L; prothrombin time, 15.2 seconds; and partial thromboplastin time, 40.3 seconds. Results of serum electrolyte analysis and urinalysis were normal, and urine drug screening was negative for drugs of abuse. A roentgenogram of the patient's leg showed no fracture. The patient was admitted for observation. The nursing staff reported that he was asking for food multiple times each night. On several occasions, he raided the refrigerator in the kitchen when the nurses had not delivered his snacks. One evening, when food was unavailable, he developed a symptom complex of tachycardia, diaphoresis, and tremulousness leading to presyncope. He was evaluated and found to be profoundly hypoglycemic (blood glucose level, 42 mg/d£). His symptoms promptly responded to 50% dextrose intravenously, but not to glucagon. The patient's medication list was evaluated for causative agents, and administration of haloperidol, which rarely causes hypoglycemia, was stopped. The patient was moved to an intensive care unit for close observation and a controlled withholding of food. He became hypoglycemic and symptomatic within 3 - 4 hours. This sequence of events recurred consistently every time the patient fasted. Blood samples were drawn for glucose, insulin, and C-peptide levels. To prevent further episodes of hypoglycemia, the patient was subsequently maintained on continuous dextrose infusion. An extensive workup was performed, and results were as follows: adrenocorticotropic hormone stimulation test (baseline, 3.7 mg/dL; 30 minutes, 13.2 mg/dL; 60 minutes, 16.0 mg/dL), interpreted as normal; thyroid functions (T3, 31 ng/ dL; T4, 3.6 mg/mL; T3U, 56%; FTI, 5.7; TSH, 6.4 mIU/mL), suggestive of a failing thyroid gland with normal hormone levels; insulin-like growth factor 1, <24.8 ng/mL; 0~-fetoprotein, 2.7 ng/mL (normal, < 2 5 ng/mL); and carcinoembryonic antigen, 8.3 ng/mL (normal, <2.5 ng/mL). Blood samples drawn during several episodes of hypoglycemia revealed insulin
GASTROENTEROLOGY Vol. 109, No. 5
levels ranging from 374.4 to 4504.8 mU/mL (normal, 5 - 3 0 mU/mL) and C-peptide levels ranging from 8.83 to 17.81 ng/ mE (normal, 0.9-4.2 ng/mL). At this stage, an insulinoma was suspected, but because of the inordinately high insulin levels, it was thought to be unlikely. High-resolution abdominal computed tomography scanning with contrasts showed no pancreatic tumor and was unchanged from previous studies. Results of chest computed tomography scanning were normal. Endoscopic ultrasonography revealed no abnormalities of the pancreas. Results of visceral arteriography of the pancreas were negative, and selective venous samplings revealed similar elevations of insulin at multipie sites without localization. Insulin antibody-binding capacity was found to be elevated at 54 U/L. A meticulous search to rule out autoimmune disease revealed the following: antinuclear antibody titer, <1:20; rheumatoid factor, < 4 0 IU/mL; liver kidney microsomal antibody titer, < 1:40; antimitochondrial antibody, < 1:20; antismooth muscle antibody titer, < 1:20; and anti-microsomal antibody, 3.0 U/mL. Other autoantibodies were absent despite an extensive search. HLA typing results were as follows: A1, 24; B57, 7; Cw6, 7; W4, W6; DR4, DR7; DR53; DQ8, DQ9. The patient's clinical course was complicated by continuous oozing from intravenous catheter sites and a coagulopathy not correctable by infusion of fresh frozen plasma. Disseminated intravascular coagulation was ruled out. A critically low fibrinogen level ( < 5 0 mg/dL) was found, and the patient's coagulopathy improved with infusion of cryoprecipitate. His condition deteriorated as he developed pneumonia and severe refractory hepatic encephalopathy. Continuous oozing later developed again from a recently placed Hickman catheter site. Once more, blood products were administered as needed. The patient developed acute respiratory stridor during a fresh frozen plasma infusion, necessitating intubation and mechanical ventilation. His coagulopathy (prothrombin time, 47.7 seconds; partial thromboplastin time, 62.1 seconds) subsequently showed a lack of correction of coagulation test with a 1 : 1 mix with normal serum. This suggested the presence of a circulating inhibitor to a factor in the common pathway of the coagulation cascade. Factor V inhibitor was quantified at 30 Bethesda units of activity. Temporary success at homeostasis was obtained with platelet transfusions, which contain membrane-bound factor V. Over the next several days, the coagulopathy worsened and became unresponsive to platelet transfusions. The patient developed profound hypotension with intra-abdominal hemorrhage. Surgical consultants felt that, because of his severe coagulopathy and dire general condition, he was not a surgical candidate. He later developed shock liver and acute renal failure. In the light of multisystem organ failure, a mutual decision was made with the family to discontinue heroic measures. The patient died, presumably due to continuing intra-abdominal hemorrhage. The family elected not to allow an autopsy.
Discussion H y p o g l y c e m i a is a c o m m o n event in acute liver failure, and its occurrence is usually explained by de-
November 1995
pleted glycogen reserves and altered carbohydrate metabolism. It is a much rarer event in chronic liver diseases. This patient was involved in a bizarre road accident associated with an altered mental status, raising the possible involvement of alcohol and other drugs of abuse. However, these possibilities were shown to be absent. Primary and secondary hepatic malignancies were carefully ruled out. The patient did not show any evidence of counterregulatory hormone deficiencies. On admission, he showed no evidence of sepsis. Insulin is secreted directly into the portal venous system, and approximately 50% of this hormone is degraded in the first passage through the liver. Hyperinsulinemia in cirrhotics is believed to be caused by impairment of this first-pass uptake and degradation of insulin by the liver. The presence of a portocaval shunt may accentuate this metabolic abnormality, 5 but this hypothesis is controversial. 6 Altered carbohydrate metabolism and a prominent peripheral insulin resistance also contribute to the elevation of insulin levels. IAS is characterized by the triad of spontaneous hypoglycemia (without evidence of exogenous insulin administration), high levels of total immunoreactive insulin, and the presence of a high titer of insulin autoantibodies. 2 Hence, to establish the diagnosis, it is necessary to rule out an insulinoma and factitious causes. This patient consistently denied any prior exposure to insulin. His denial was confirmed by his family, and he had had no access to insulin or its accessories at home. Occurrence of hypoglycemia in the hospital raises the possibility of surreptitious administration of insulin. However, these episodes continued to happen despite the patient being isolated in an intensive care unit and under close observation. Also, exogenous insulin administration would lead to suppression of endogenous insulin secretion and would consequently result in very low C-peptide levels. As documented repeatedly, this patient had elevated levels of C-peptide, ruling out factitious hypoglycemia. Elevations of C-peptide and insulin levels in this syndrome are due in part to binding of proinsulin to insulin antibodies and cross-reactivity among the assays used. Fasting hypoglycemia associated with an elevation of serum insulin and C-peptide levels is characteristic of an insulinoma. The absence of such a lesion was demonstrated by careful radiological imaging of the pancreas and other structures and by endoscopic ultrasonography. Multiple venous samplings that showed similarly elevated insulin levels at multiple sites provided further confirmation. Graves' disease, rheumatoid arthritis, and systemic lupus erythematosus are the most common autoimmune diseases associated with IAS. 2'3 Liver dysfunction (includ-
INSULIN AUTOIMMUNE SYNDROME IN CIRRHOSIS 1675
ing alcoholic cirrhosis and alcoholic hepatitis, but not hepatocellular carcinoma or autoimmune hepatitis), cataracts, and hypertension are some of the other diseases associated with IAS, 2'3 (personal communication from Dr. Y. Uchigata, June 1994). Sulfhyldryl group-containing drugs such as methimazole, penicillamine, glutathione, gold thioglucose, and o~-mercaptopropionylglycine, and, to a lesser extent, captopril are reported to have a close association with IAS. 2'v'8 It has been postulated that the sulfhydryl group could interact with the disulfide bonds of insulin and thereby render it immunogenic by hapten formation or by cleavage of the disulfide bonds. Because relatively few drugs contain a sulfhydryl group, the association between IAS and prior use of such agents is striking. 9'1° IAS is often found in patients who have both an underlying disease and are undergoing therapy with an associated drug, for example, a patient with Graves' disease who is being treated with methimazole or a patient with rheumatoid arthritis being treated with pencillamine. 2'7'8 In this scenario, it is difficult to explain what led to the development of IAS. To confuse the issue further, a case has been reported by Burch et al. 4 in which during treatment with hydralazine, which often causes drug-induced lupus erythematosus, 1AS developed with no evidence of systemic lupus erythematosus. Uchigata et al. 1°'~* have studied the HLA class II genes of Japanese patients with Graves' disease undergoing treatment with methimazole. Those who developed IAS have a strong likelihood of possessing a specific allele combination: Bw62, Cw4, and DR4 carrying DRBI* 0406. Uchigata et al. have postulated that methimazole cleaves the disulfide bonds of insulin, and the latter is presented and recognized in association with the DRB 1" 0406 gene product on the antigen presenting cells and results in development of antibodies to insulin. There are reports of Japanese patients with liver disease who developed IAS while being treated with glutathione or 0~-mercaptopropionylglycine. In our patient, IAS developed in the absence of any such drugs, giving credibility to the postulation that severe hepatic disease has an independent association with IAS. In alcoholic liver disease, there is an altered immune state, which often leads to the development of various autoanribodies) 2 Nonsulfhydryl compounds reported in the literature to be associated with IAS include steroids, diltiazem, loxoprofen sodium, tolperisone hydrochloride, giclofenac sodium, tolbutamide and interferon alfa.2 The pathophysiology of hypoglycemia in IAS has not been established, and it is believed that insulin bound to antibodies is in equilibrium with free insulin in plasma. There is increased insulin secretion with a meal,
1676
SHAH ET AL.
but the buffering action of the antibodies impedes the development of free insulin, resulting in some glucose intolerance. Later, when free insulin levels decrease, bound insulin dissociates from the antibodies. Thus, a higher level of free insulin is present and results in hypoglycemia. This sequence of events explains why hypoglycemia is frequently reactive in IAS, 9 but not always so (as in this case in which the patient developed fasting hypoglycemia). The epidemiology of IAS in Japan has been summarized recently. 2 Usually IAS runs a benign course and affected patients often become asymptomatic in 1 year. The frequency of hypoglycemic episodes usually declines as the amount ofimmunoreactive insulin decreases. Small frequent meals with a low content of simple sugars can usually control the symptoms. Immunosuppressive agents such as steroids or azathioprine have on occasion been used successfully. In the early 1970s, partial pancreatectomy was successful in 6 patients, presumably by decreasing the amount of insulin secreted. 2 Factor V antibodies have been reported to be associated with aminoglycoside drugs, operative procedures, and transfusions. 13 This patient had undergone surgical placement of a Hickman catheter and was being treated with plasma transfusions and with gentamicin for pneumonia. Therefore, a number of possible reasons exist to explain why this patient developed factor V antibodies. Autoantibodies often develop in patients with alcoholic liver disease, and it may be speculated that the development of autoantibodies to factor V and insulin in this patient are manifestations of this phenomenon. In summary, a new case of IAS has been presented, the first reported outside of Japan in association with liver disease, and the first worldwide with coexisting acquired inhibitors to factor V (personal communication, Dr. Y. Uchigata, June 1994). Hypoglycemia and hyperinsulinemia are well-described events in liver disease, and IAS, albeit rare, makes their differential diagnosis even more fascinating. It is anticipated that with increased
GASTROENTEROLOGY Vol. 109, No. 5
testing for this syndrome in patients with liver disease, many more cases will be discovered.
References 1. Fineberg SE, Biegel AA, Durr KL, Huffered S, Fineberg NS, Anderson JH. Presence of insulin autoantibodies as regular feature of nondiabetic repertoire of immunity. Diabetes 1991;40:11871193. 2. Uchigata Y, Eguchi Y, Takauyama-Hasumi S, Omori Y. Insulin Autoimmune Syndrome (Hirata Disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract 1994;22:8994. 3. Hirata Y. Autoimmune insulin syndrome "up to date." In: Andreani D, Marks V, Lefebvre PJ (eds.). Hypoglycemia. New York: Raven, 1987:105-118. 4. Burch HB, Clement S, Sokol MS, Landry F. Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review. Am J Med 1992;92:681-685. 5. Shurberg JL, Resnick RH, Koff RS, Ros E, Baum RA, Pallotta JA. Serum lipid, insulin, and glucagon after portacaval shunt in cirrhosis. Gastroenterology 1977; 72:301-304. 6. Sirinek KR, O'Doriso TM, Levine BA. Glucose intolerance and hyperinsulinemia of cirrhosis are not results of spontaneous or surgical portosystemic shunting. Am J Surg 1991; 161:149-153. 7. Hirata Y. Methimazole and insulin autoimmune syndrome with hypoglycemia. Lancet 1983; 2:1037-1038. 8. Benson E, Healey LA, Barton EJ. Insulin autoimmunity in patients receiving pencillamine. Am J Med 1985; 78:857-860. 9. Taylor SI, Barbetti F, Accili D, Roth J. Gorden P. Syndrome of autoimmunity and hypoglycemia. Endocdnol Metab Clin North Am 1989; 18:123-143. 10. Uchigata Y, Kuwata S, Tsushima T, Tokunaga K, Miyamoto M, Tsuchikawa K, Hirata Y, Juji T, Omori Y. Patients with Graves disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-6Bw62/Cw4/DR4 carrying DRBI*0406. J Clin Endocrinol Metab 1993; 77:249-254. 11. Uchigata Y, Kuwata S, Tokunaga K, Eguchi Y, Takayama-Hasumi S, Miyamoto M, Omori Y, Juji T, Hirata Y. Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet 1992; 339:393-394. 12. Zetterman RK, Sorrell MF. Immunologic aspects of alcoholic liver disease. Gastroenterology 1981; 81:616-624. 13. Feinstein Dl. Acquired inhibitors of factor V. Thromb Haemost 1978;39:663-674. Received February 24, 1995. Accepted June 19, 1995. Address requests for reprints to: Lawrence Lumeng, M.D., Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Room 424, IB Building, 975 West Walnut Street, Indianapolis, Indiana 46202. Fax: (317) 274-3106.
CASE REPORTS Insulin Autoimmune Syndrome as a Cause of Spontaneous Hypoglycemia in Alcoholic Cirrhosis PRINCE S H A H , *
DAVID MARES,* S. EDWIN FINEBERG, ~ MARK PESCOVITZ, II RONALD FILO, II
RAHUL JINDAL, It STEPHEN MAHONEY, ~ and LAWRENCE L U M E N G * *Division of Gastroenterologyand Hepatology, Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis,Indiana; *Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis, Indiana; ~Divisionof Endocrinologyand Metabolism, Department of Internal Medicine, Indiana UniversityMedical Center, Indianapolis,Indiana; IIorgan Transplant Unit, Department of Surgery, Indiana UniversityMedical Center, Indianapolis, Indiana; and ~'Divisionof Gastroenterology,St. Francis Hospital, Beech Grove, Indiana
Hypoglycemia in fulminant hepatic failure and hyperinsulinemia in cirrhosis are well-described phenomena. A patient with alcoholic cirrhosis who developed fasting hypoglycemia with an extremely high immunoreactive insulin level and a mildly elevated C-peptide level is reported. An insulinoma was excluded by detailed radiological imaging of the pancreas and by endoscopic ultrasonography. Detection of very high levels of insulin autoantibodies with no prior exposure to exogenous insulin confirmed the diagnosis of insulin autoimmune syndrome. During his hospital course, the patient developed another rare syndrome, acquired inhibitors to factor V, which led to the fatal coagulopathy that resulted in his death. Insulin autoimmune syndrome is the third leading cause of spontaneous hypoglycemia in Japan, where it has been associated with a variety of diseases and drugs. Outside of Japan, only approximately 20 cases have been reported and usually have been found in the context of an underlying autoimmune disorder or prior exposure to sulfhydryl drugs. It is believed that this is the first case reported outside Japan occurring in association with alcoholic liver d i s e a s e , and the first in the world with coexisting acquired inhibitots to factor V.
ow levels of autoantibodies to insulin have been found regularly at the onset of insulin-dependent diabetes mellitus in the young and in individuals who are at high risk for the development of insulin-dependent diabetes mellitus. They have also been reported to develop in nondiabetic individuals in unusual circumstances such as during penicillamine or methimazole therapy, in diffuse polyimmunity, and during viral infection. These antibodies, however, are often transient and are rarely of clinical significance) High levels of insulin autoantibodies in a patient with spontaneous hypoglycemia were first reported by Hirata in 1970. Insulin autoimmune syndrome (IAS) is characterized by the diagnos-
L
tic criteria of spontaneous hypoglycemia without evidence of exogenous insulin administration, high levels of total immunoreactive insulin, and the presence of a high titer of insulin autoantibodies. 2 Since 1970, 1AS has emerged as the third leading cause of spontaneous hypoglycemia in Japan. However, outside Japan, only about 20 cases have been reported. 3'4 This difference has been attributed to racial variations and a strong association with HLA-DR4, among other explanations. 2'4 The etiopathogenesis of IAS remains unexplained. It has been found to be very closely related to the presence of other autoimmune syndromes and treatment with sulfhydryl drugs. In Japan, it has also been reported in association with other disease states, such as hepatic dysfunction, and with the use of numerous drugs. 2'~ Hypoglycemia is not an uncommon finding in severe liver disease, particularly in fulminant hepatic failure. An unusual case of a cirrhotic patient with IAS as the cause of fasting hypoglycemia in the absence of any other autoimmune disease or sulfhydryl drugs is reported. Case Report A 55-year-old white man with end-stage liver disease secondary to alcoholic cirrhosis, listed for liver transplantation, was admitted after a road accident that occurred while riding a bicycle during the early hours of the morning. On close questioning, the patient was unable to explain his strange activity. His wife reported his sleep pattern as abnormal, with him waking at unusual hours of the night for no apparent reason. His past medical history included chronic alcohol abuse that led to severe liver disease by the age of 42 years. This was complicated by splenic vein thrombosis and recurrent variceal bleeding that required splenectomy and, later, a surgical endto-side portocaval shunt. His pretransptantation evaluation Abbreviations used in this paper:
IAS, insulinautoimmunesyn-
drome. © 1995 by the AmericanGastroenterologicalAssociation
0016-5085/95/$3.00
1674
SHAH ET AL.
ruled out other causes of chronic liver disease. There was no record of any thyroid disease or diabetes mellitus. His medications on admission included omeprazole, haloperidol, lactulose, zinc sulfate, thiamin, and multivitamins. Family history was noncontributory. On admission, physical examination showed the patient to be oriented to time, place, and person. His temperature was 99.5°F, pulse was 108 beats per minute, and blood pressure was 140/80 m m Hg. He had a large tender hematoma in his left leg with an intact distal neurovascular status and no evidence of a compartment syndrome. He was icteric; his liver span was 9 cm in the right midclavicular line and 5 cm in the midline. His abdomen was nontender with no ascites. Findings of the remainder of the physical examination (including examination of the thyroid and the nervous system) were normal. The patient's initial laboratory data were as follows: hemoglobin, 13.1 g/dL; white blood cells, 8800/btL; platelets, 100,000/~tL; blood urea nitrogen, 8 mg/dL; creatinine, 0.8 mg/dL; glucose, 78 mg/dL; bilirubin, 5.7 mg/dL; albumin, 2.6 g/dL; cholesterol, 106 mg/dL; creatine kinase, 331 IU/L; prothrombin time, 15.2 seconds; and partial thromboplastin time, 40.3 seconds. Results of serum electrolyte analysis and urinalysis were normal, and urine drug screening was negative for drugs of abuse. A roentgenogram of the patient's leg showed no fracture. The patient was admitted for observation. The nursing staff reported that he was asking for food multiple times each night. On several occasions, he raided the refrigerator in the kitchen when the nurses had not delivered his snacks. One evening, when food was unavailable, he developed a symptom complex of tachycardia, diaphoresis, and tremulousness leading to presyncope. He was evaluated and found to be profoundly hypoglycemic (blood glucose level, 42 mg/d£). His symptoms promptly responded to 50% dextrose intravenously, but not to glucagon. The patient's medication list was evaluated for causative agents, and administration of haloperidol, which rarely causes hypoglycemia, was stopped. The patient was moved to an intensive care unit for close observation and a controlled withholding of food. He became hypoglycemic and symptomatic within 3 - 4 hours. This sequence of events recurred consistently every time the patient fasted. Blood samples were drawn for glucose, insulin, and C-peptide levels. To prevent further episodes of hypoglycemia, the patient was subsequently maintained on continuous dextrose infusion. An extensive workup was performed, and results were as follows: adrenocorticotropic hormone stimulation test (baseline, 3.7 mg/dL; 30 minutes, 13.2 mg/dL; 60 minutes, 16.0 mg/dL), interpreted as normal; thyroid functions (T3, 31 ng/ dL; T4, 3.6 mg/mL; T3U, 56%; FTI, 5.7; TSH, 6.4 mIU/mL), suggestive of a failing thyroid gland with normal hormone levels; insulin-like growth factor 1, <24.8 ng/mL; 0~-fetoprotein, 2.7 ng/mL (normal, < 2 5 ng/mL); and carcinoembryonic antigen, 8.3 ng/mL (normal, <2.5 ng/mL). Blood samples drawn during several episodes of hypoglycemia revealed insulin
GASTROENTEROLOGY Vol. 109, No. 5
levels ranging from 374.4 to 4504.8 mU/mL (normal, 5 - 3 0 mU/mL) and C-peptide levels ranging from 8.83 to 17.81 ng/ mE (normal, 0.9-4.2 ng/mL). At this stage, an insulinoma was suspected, but because of the inordinately high insulin levels, it was thought to be unlikely. High-resolution abdominal computed tomography scanning with contrasts showed no pancreatic tumor and was unchanged from previous studies. Results of chest computed tomography scanning were normal. Endoscopic ultrasonography revealed no abnormalities of the pancreas. Results of visceral arteriography of the pancreas were negative, and selective venous samplings revealed similar elevations of insulin at multipie sites without localization. Insulin antibody-binding capacity was found to be elevated at 54 U/L. A meticulous search to rule out autoimmune disease revealed the following: antinuclear antibody titer, <1:20; rheumatoid factor, < 4 0 IU/mL; liver kidney microsomal antibody titer, < 1:40; antimitochondrial antibody, < 1:20; antismooth muscle antibody titer, < 1:20; and anti-microsomal antibody, 3.0 U/mL. Other autoantibodies were absent despite an extensive search. HLA typing results were as follows: A1, 24; B57, 7; Cw6, 7; W4, W6; DR4, DR7; DR53; DQ8, DQ9. The patient's clinical course was complicated by continuous oozing from intravenous catheter sites and a coagulopathy not correctable by infusion of fresh frozen plasma. Disseminated intravascular coagulation was ruled out. A critically low fibrinogen level ( < 5 0 mg/dL) was found, and the patient's coagulopathy improved with infusion of cryoprecipitate. His condition deteriorated as he developed pneumonia and severe refractory hepatic encephalopathy. Continuous oozing later developed again from a recently placed Hickman catheter site. Once more, blood products were administered as needed. The patient developed acute respiratory stridor during a fresh frozen plasma infusion, necessitating intubation and mechanical ventilation. His coagulopathy (prothrombin time, 47.7 seconds; partial thromboplastin time, 62.1 seconds) subsequently showed a lack of correction of coagulation test with a 1 : 1 mix with normal serum. This suggested the presence of a circulating inhibitor to a factor in the common pathway of the coagulation cascade. Factor V inhibitor was quantified at 30 Bethesda units of activity. Temporary success at homeostasis was obtained with platelet transfusions, which contain membrane-bound factor V. Over the next several days, the coagulopathy worsened and became unresponsive to platelet transfusions. The patient developed profound hypotension with intra-abdominal hemorrhage. Surgical consultants felt that, because of his severe coagulopathy and dire general condition, he was not a surgical candidate. He later developed shock liver and acute renal failure. In the light of multisystem organ failure, a mutual decision was made with the family to discontinue heroic measures. The patient died, presumably due to continuing intra-abdominal hemorrhage. The family elected not to allow an autopsy.
Discussion H y p o g l y c e m i a is a c o m m o n event in acute liver failure, and its occurrence is usually explained by de-
November 1995
pleted glycogen reserves and altered carbohydrate metabolism. It is a much rarer event in chronic liver diseases. This patient was involved in a bizarre road accident associated with an altered mental status, raising the possible involvement of alcohol and other drugs of abuse. However, these possibilities were shown to be absent. Primary and secondary hepatic malignancies were carefully ruled out. The patient did not show any evidence of counterregulatory hormone deficiencies. On admission, he showed no evidence of sepsis. Insulin is secreted directly into the portal venous system, and approximately 50% of this hormone is degraded in the first passage through the liver. Hyperinsulinemia in cirrhotics is believed to be caused by impairment of this first-pass uptake and degradation of insulin by the liver. The presence of a portocaval shunt may accentuate this metabolic abnormality, 5 but this hypothesis is controversial. 6 Altered carbohydrate metabolism and a prominent peripheral insulin resistance also contribute to the elevation of insulin levels. IAS is characterized by the triad of spontaneous hypoglycemia (without evidence of exogenous insulin administration), high levels of total immunoreactive insulin, and the presence of a high titer of insulin autoantibodies. 2 Hence, to establish the diagnosis, it is necessary to rule out an insulinoma and factitious causes. This patient consistently denied any prior exposure to insulin. His denial was confirmed by his family, and he had had no access to insulin or its accessories at home. Occurrence of hypoglycemia in the hospital raises the possibility of surreptitious administration of insulin. However, these episodes continued to happen despite the patient being isolated in an intensive care unit and under close observation. Also, exogenous insulin administration would lead to suppression of endogenous insulin secretion and would consequently result in very low C-peptide levels. As documented repeatedly, this patient had elevated levels of C-peptide, ruling out factitious hypoglycemia. Elevations of C-peptide and insulin levels in this syndrome are due in part to binding of proinsulin to insulin antibodies and cross-reactivity among the assays used. Fasting hypoglycemia associated with an elevation of serum insulin and C-peptide levels is characteristic of an insulinoma. The absence of such a lesion was demonstrated by careful radiological imaging of the pancreas and other structures and by endoscopic ultrasonography. Multiple venous samplings that showed similarly elevated insulin levels at multiple sites provided further confirmation. Graves' disease, rheumatoid arthritis, and systemic lupus erythematosus are the most common autoimmune diseases associated with IAS. 2'3 Liver dysfunction (includ-
INSULIN AUTOIMMUNE SYNDROME IN CIRRHOSIS 1675
ing alcoholic cirrhosis and alcoholic hepatitis, but not hepatocellular carcinoma or autoimmune hepatitis), cataracts, and hypertension are some of the other diseases associated with IAS, 2'3 (personal communication from Dr. Y. Uchigata, June 1994). Sulfhyldryl group-containing drugs such as methimazole, penicillamine, glutathione, gold thioglucose, and o~-mercaptopropionylglycine, and, to a lesser extent, captopril are reported to have a close association with IAS. 2'v'8 It has been postulated that the sulfhydryl group could interact with the disulfide bonds of insulin and thereby render it immunogenic by hapten formation or by cleavage of the disulfide bonds. Because relatively few drugs contain a sulfhydryl group, the association between IAS and prior use of such agents is striking. 9'1° IAS is often found in patients who have both an underlying disease and are undergoing therapy with an associated drug, for example, a patient with Graves' disease who is being treated with methimazole or a patient with rheumatoid arthritis being treated with pencillamine. 2'7'8 In this scenario, it is difficult to explain what led to the development of IAS. To confuse the issue further, a case has been reported by Burch et al. 4 in which during treatment with hydralazine, which often causes drug-induced lupus erythematosus, 1AS developed with no evidence of systemic lupus erythematosus. Uchigata et al. 1°'~* have studied the HLA class II genes of Japanese patients with Graves' disease undergoing treatment with methimazole. Those who developed IAS have a strong likelihood of possessing a specific allele combination: Bw62, Cw4, and DR4 carrying DRBI* 0406. Uchigata et al. have postulated that methimazole cleaves the disulfide bonds of insulin, and the latter is presented and recognized in association with the DRB 1" 0406 gene product on the antigen presenting cells and results in development of antibodies to insulin. There are reports of Japanese patients with liver disease who developed IAS while being treated with glutathione or 0~-mercaptopropionylglycine. In our patient, IAS developed in the absence of any such drugs, giving credibility to the postulation that severe hepatic disease has an independent association with IAS. In alcoholic liver disease, there is an altered immune state, which often leads to the development of various autoanribodies) 2 Nonsulfhydryl compounds reported in the literature to be associated with IAS include steroids, diltiazem, loxoprofen sodium, tolperisone hydrochloride, giclofenac sodium, tolbutamide and interferon alfa.2 The pathophysiology of hypoglycemia in IAS has not been established, and it is believed that insulin bound to antibodies is in equilibrium with free insulin in plasma. There is increased insulin secretion with a meal,
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but the buffering action of the antibodies impedes the development of free insulin, resulting in some glucose intolerance. Later, when free insulin levels decrease, bound insulin dissociates from the antibodies. Thus, a higher level of free insulin is present and results in hypoglycemia. This sequence of events explains why hypoglycemia is frequently reactive in IAS, 9 but not always so (as in this case in which the patient developed fasting hypoglycemia). The epidemiology of IAS in Japan has been summarized recently. 2 Usually IAS runs a benign course and affected patients often become asymptomatic in 1 year. The frequency of hypoglycemic episodes usually declines as the amount ofimmunoreactive insulin decreases. Small frequent meals with a low content of simple sugars can usually control the symptoms. Immunosuppressive agents such as steroids or azathioprine have on occasion been used successfully. In the early 1970s, partial pancreatectomy was successful in 6 patients, presumably by decreasing the amount of insulin secreted. 2 Factor V antibodies have been reported to be associated with aminoglycoside drugs, operative procedures, and transfusions. 13 This patient had undergone surgical placement of a Hickman catheter and was being treated with plasma transfusions and with gentamicin for pneumonia. Therefore, a number of possible reasons exist to explain why this patient developed factor V antibodies. Autoantibodies often develop in patients with alcoholic liver disease, and it may be speculated that the development of autoantibodies to factor V and insulin in this patient are manifestations of this phenomenon. In summary, a new case of IAS has been presented, the first reported outside of Japan in association with liver disease, and the first worldwide with coexisting acquired inhibitors to factor V (personal communication, Dr. Y. Uchigata, June 1994). Hypoglycemia and hyperinsulinemia are well-described events in liver disease, and IAS, albeit rare, makes their differential diagnosis even more fascinating. It is anticipated that with increased
GASTROENTEROLOGY Vol. 109, No. 5
testing for this syndrome in patients with liver disease, many more cases will be discovered.
References 1. Fineberg SE, Biegel AA, Durr KL, Huffered S, Fineberg NS, Anderson JH. Presence of insulin autoantibodies as regular feature of nondiabetic repertoire of immunity. Diabetes 1991;40:11871193. 2. Uchigata Y, Eguchi Y, Takauyama-Hasumi S, Omori Y. Insulin Autoimmune Syndrome (Hirata Disease): clinical features and epidemiology in Japan. Diabetes Res Clin Pract 1994;22:8994. 3. Hirata Y. Autoimmune insulin syndrome "up to date." In: Andreani D, Marks V, Lefebvre PJ (eds.). Hypoglycemia. New York: Raven, 1987:105-118. 4. Burch HB, Clement S, Sokol MS, Landry F. Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review. Am J Med 1992;92:681-685. 5. Shurberg JL, Resnick RH, Koff RS, Ros E, Baum RA, Pallotta JA. Serum lipid, insulin, and glucagon after portacaval shunt in cirrhosis. Gastroenterology 1977; 72:301-304. 6. Sirinek KR, O'Doriso TM, Levine BA. Glucose intolerance and hyperinsulinemia of cirrhosis are not results of spontaneous or surgical portosystemic shunting. Am J Surg 1991; 161:149-153. 7. Hirata Y. Methimazole and insulin autoimmune syndrome with hypoglycemia. Lancet 1983; 2:1037-1038. 8. Benson E, Healey LA, Barton EJ. Insulin autoimmunity in patients receiving pencillamine. Am J Med 1985; 78:857-860. 9. Taylor SI, Barbetti F, Accili D, Roth J. Gorden P. Syndrome of autoimmunity and hypoglycemia. Endocdnol Metab Clin North Am 1989; 18:123-143. 10. Uchigata Y, Kuwata S, Tsushima T, Tokunaga K, Miyamoto M, Tsuchikawa K, Hirata Y, Juji T, Omori Y. Patients with Graves disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-6Bw62/Cw4/DR4 carrying DRBI*0406. J Clin Endocrinol Metab 1993; 77:249-254. 11. Uchigata Y, Kuwata S, Tokunaga K, Eguchi Y, Takayama-Hasumi S, Miyamoto M, Omori Y, Juji T, Hirata Y. Strong association of insulin autoimmune syndrome with HLA-DR4. Lancet 1992; 339:393-394. 12. Zetterman RK, Sorrell MF. Immunologic aspects of alcoholic liver disease. Gastroenterology 1981; 81:616-624. 13. Feinstein Dl. Acquired inhibitors of factor V. Thromb Haemost 1978;39:663-674. Received February 24, 1995. Accepted June 19, 1995. Address requests for reprints to: Lawrence Lumeng, M.D., Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Room 424, IB Building, 975 West Walnut Street, Indianapolis, Indiana 46202. Fax: (317) 274-3106.