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Home , Glucose test, Hypoalbuminemia, Hypoglycemia

Brief Report

Profound Ambulatory : A Rare Entity Suresh J. Antony, MD; David E. Graham; and George P. Sartiano, MD Greenville, North Carolina

A 49 -year-old man with a history of hepatocellular car­ Key words. Hypoglycemia; adaptation, physiological; cinoma, alcohol abuse, and -dependent carcinoma, hepatocellular; diabetes meilitus, insulin- meilitus was noted to be completely dependent. despite a plasma level of 4 mg/dL. The possible pathophysiology of this unusual occurrence of “hypo­ glycemia unawareness” is discussed. ( / Fam Pract 1993; 36:654-656)

The manifestations of hypoglyce­ which had resulted in chronic and IDDM. mia vary in presentation and range of severin' from The patient lived with his family, who were responsible altered mental status to . In addition, a small for his care and administration of his medications. On a proportion of patients with insulin-dependent diabetes routine visit to the ambulatory clinic, his family reported meilitus (IDDM) have decreased or absent hypoglycemic that he had been confused and weak for the past 3 days. awareness. Conditions that may induce hypoglycemia Physical examination at the time o f admission re­ include administration of exogenous insulin, excessive vealed a thin, emaciated, malnourished, icteric man who endogenous insulin production (as in ), was alert and oriented to time, place, and person. He , hepatic and renal diseases, , and malnutri­ followed commands well and answered questions appro­ tion. 1 priately. His speech was clear. Physical examination find­ The case described below serves as an important ings were within normal limits except for and reminder that hypoglycemia may be asymptomatic and can be missed if not considered. We report what we pitting of the lower extremities. believe is the first case in the literature of such profound Laboratory studies revealed a leukocyte count of hypoglycemia (4 mg/dL) in an asymptomatic ambulatory 10.3 x 109/L with a mild left shift. His hemoglobin level patient. was 8.5 g/dL. The PT and PTT were prolonged. Results of his function tests were as follows: total 6.9 g/dL; albumin 1.8 g/dL; total 3.0 mg/dL; 148 U/L; LDH 302 U/L; and AST Case Report 99 U/L. These results had not changed significantly from A 4 9 -year-old man was admitted to the with a those obtained during his previous admission a few history of hepatocellular carcinoma, chronic pancreatitis, weeks before. and were negative for ke­ IDDM, and alcohol abuse. At the time of admission, he tones. A routine determination of glu­ was receiving 25 units of NPH human insulin daily, as cose level was reported by the nurse to be zero. Because well as oxycodone, hydroxyzine, and . of the low results, a plasma blood was done. The patient had a history of chronic alcohol abuse, To our astonishment the patient’s glucose level was re­ ported as 4 mg/dL. The test was immediately repeated and the previous results were confirmed. Plasma insulin, Submitted, revised, February 11, 1993. C-peptide, and levels were not determined, as it From the Department of Medicine, East Carolina University School of Medicine, was believed that the profound level of the patient’s Greenville, North Carolina. Requests for reprints should be addressed to Suresh J. Antony, M D, Section of Internal Medicine, East Carolina University School of Med­ hypoglycemia was a result of the insulin that had been icine, Greenville, N C 2 7 8 5 8 -4 3 5 4 . administered by a family member a few hours before

© 1993 Appleton & Lange ISSN 0094-3509 654 The Journal of Family Practice, Vol. 36, No. 6, 1993 Ambulatory Hypoglycemia Antony, Graham, and Sartiano

Table 1. Causes o f Hypoglycemia Table 2. Adrenergic and Neuroglycopenic Symptoms of Hypoglycemia Conditions Associated with Conditions Associated with Overutilization of Glucose Underproduction of Glucose Autonomic Nervous System Central Nervous System Dysfunction Dysfunction Hvperinsulinism deficiencies Sweating Sulfonyl urea, exogenous insulin Shakiness Blurred vision Autoimmune disease insufficiency Drugs (eg, quinine, ) Glucagon deficiency Abnormal behavior Endotoxin Enzyme defects Unconsiousness Appropriate insulin level Glucose-6-phosphatase Seizures Cachexia with fat depletion From Service F J. Hypoglycemic disorders. In : W yngaarden JB , Smith H L , Bennett JC , Fructose 1,6-diphosphatase Extrapancreatic tumors eds. Cecil’s textbook o f medicine. Philadelphia: W B Saunders, 1992:1313. Reprinted Carnitine deficiency with permission by W B Saunders. Substrate deficiency Malnutriton Late pregnancy and confusion before being seen by us were probably a result of fluctuations in his plasma glucose levels resulting from unscheduled meals and irregular insulin administra­ Drugs tion. The absence of clinical symptoms when examined Alcohol probably reflected a variation in his plasma glucose level. Clinical manifestations of hypoglycemia range from Salicylate subtle impairment of mentation to and . Adapted from Foster and Rubenstein.3 Between these extremes, a variety of different expressions occur, including visual symptoms, confusion, lethargy, admission. Results of blood and urine cultures and find­ behavioral changes, impairment of performance of rou­ ings on chest radiographs taken at the time of admission tine tasks, vertigo, , and focal neurological were normal. signs and seizures.7 At least 23% of patients with 1DDM, The patient was immediately given 50 mL of 50% however, have partial or complete hypoglycemic un­ dextrose water intravenously, and within 2 hours, his awareness.7 This reduced level of awareness is thought to blood glucose level rose to 45 mg/dL. The hypoglycemia be associated with a reduced plasma re­ resolved without any discernible change in his mental sponse,8 which may be an important determinant for the status. wide variability^ of symptoms among patients with similar The patient was discharged a few days later with blood glucose levels and mechanisms of hypoglycemia.1 instructions not to take insulin. Blood glucose levels In addition, associated with long­ before discharge were consistently over 150 mg/dL. The standing diabetes and impaired glucagon secretion could patient died at home a few weeks later of unknown lead to central nervous system adaptation by reducing causes. No autopsy was performed. both the symptoms of and defenses against developing hypoglvcemia leading to recurrent severe hypoglycemia, thus creating a vicious cycle.9 Discussion In their study of 125 patients with hypoglycemia, Hypoglycemia is defined as the occurrence of a wide Malouf ct al1 found no correlation between blood glu­ variety of symptoms in association with plasma glucose cose levels and symptoms. The average blood glucose levels of 40 mg/dL or less.2 Diabetes mellitus, alcohol­ level was between 12 and 40 mg/dL, with a large pro­ ism, and sepsis, alone or in combination, account for portion of these patients brought to the emergency de­ 90% of hospital admissions.1-3 In fact, type II diabetics partment in a coma or near-comatose state. In patients treated with insulin have a 40% incidence of hypoglyce­ with , blood glucose levels as low as 2 mg/dL have- mic episodes.4 A list of the many causes of hypoglycemia been reported, with the patients in a coma.1 The hypo­ is given in Table 1. glvcemia that occurs in cancer patients is thought to he­ The diagnosis of hypoglycemia should be consid­ rniated to impaired , decreased glucose ered in patients presenting with adrenergic or neurogly- output by the liver, and excessive glucose utilization by copenic symptoms and signs (Table 2).5-6 Although the the .10 In addition, this patient was clinically clinical features are helpful in making the diagnosis, a malnourished, and this also probably contributed to the significant proportion of these patients either are asymp­ hypoglycemia. A combination of reduced tomatic or have only altered mental status when exam­ intake and are clinical predictors of ined. The patient’s initial symptoms of strange behavior hypoglycemia in diabetic patients.11

The loumal of Family Practice, Vol. 36, No. 6, 1993 655 Ambulatory Hypoglycemia Antony, Graham, and Sartiano

Alcohol in itself does not appear to cause a higher University School o f Medicine, Greenville, North Carolina, for thn- incidence of hypoglycemia when compared with a pop­ help in reviewing this manuscript. We would also like to thank Mrs ulation without elevated levels as reported by Nancy Hamm for her excellent secretarial assistance in the prepara­ tion of the manuscript. Spore et al.12 When consumed by a patient with malnu­ trition and hepatocellular cancer, however, alcohol could induce hypoglycemia. All these mechanisms probably were operational in the patient discussed in this report. References In the majority of reported studies, coma occurred at 1. Malouf R, Brust JCM. Hypoglycemia: causes, neurological man levels of 2 to 28 mg/dL, while stupor occurred in the ifestations and outcomes. Ann Neurol 1985; 17:421-30. range of 8 to 59 mg/dL and at 9 to 60 2. Gjedde A, Crone A. Blood brain glucose transfer: repression in mg/dL. Neither duration of hypoglycemia nor accompa­ chronic . Science 1981; 214:456-7. 3. Foster D, Rubenstein A. Hypoglycemia, insulinemia and other nying illness explained the overlapping of these ranges in hormone-secreting tumors of the . In: Witson JD, ed. the studies.13 Harrison’s principles of internal medicine. 11th ed. New York Alcohol induces hypoglycemia by inhibiting gluco- McGraw-Hill, 1991:1802 (table 329-3). ncogencsis14'15 as it depletes hepatic nicotinamide ade­ 4. Heller SR, Herbert M, MacDonald LA, et al. Influence of sympa­ thetic nervous system on hvpogivcemic warning symptoms Lancet nine dinucleotide (NAD), a cofactor that is necessary for 1987; 2:359-63. the entry of most precursors into the gluconeogenic 5. Hoeldtke RD, Boden G, Shuman CR, et al. Reduced epinephrine pathway. It does not inhibit . Ethanol also secretion and hypoglycemia unawareness in diabetic autonomic inhibits and responses to hy­ neuropathy. Ann Intern Med 1981; 96:456-62. 6 . Service FJ. Hypoglycemic disorders. In: Wyngaarden JB, Smith poglycemia.15-17 In addition, epinephrine responses are HL, Bennett jc , eds. Cecil’s textbook of medicine. Philadelphia: delayed as well.18 Glucagon release appears to be normal, WB Saunders, 1992:1313. although delayed responses have been reported.18 There­ 7. Cryer PE, Binder C, Bolli GB, et al. Hypoglycemia in insulin- dependent diabetes mellitus. Diabetes 1989; 38:1193-9. fore, in diabetics with prolonged hypoglycemia in which 8. Silbert CK, Rossinni AA, Ghazvinian S, et al. Tumor hypoglyce­ gluconeogenesis is the dominant source of hepatic glu­ mia: deficient splanchnic glucose output and deficient glucagon cose production, ethanol can contribute to the progres­ secretion. Diabetes 1976; 25:202-6. sion and severity of hypoglycemia. 9. Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia associated autonomic failure in IDDM. A vicious cycle. Diabetes The case reported herein demonstrates that a pro­ 1992; 41:255-60. foundly hypoglycemic patient can nonetheless be awake 10. Frier BM, Hepburn DA, Eadington DW, et al. How common is and oriented, and able to respond, speak, and communi­ hypoglycemic awareness in insulin-dependent diabetics and what is cate, despite blood glucose levels that are near the lower its relationship to autonomic neuropathy [abstract]? Diabetes Res Clin Pract 1988; 5:5622. limit of detection. In their study of the eifects of mild 11. Kresenic DM, Slavin SM. Incidence of hypoglycemia and nutri­ hypoglycemia on cognitive functioning in diabetic chil­ tional intake in patients on a general medical unit. Nurs Connec­ dren, Ryan et al19 found that there is a high degree of tions 1989; 2(4):33—40. subject variability and that, in addition to plasma glucose 12. Spore KA, Ernst AA, Conte R, Nick TG. The incidence of ethanol induced hypoglycemia. Am J Med 1992; 10:403-5. values, unknown physiological variables are also respon­ 13. Georgopoulos A, Margolis S. Hypoglycemia. In: Harvev AM. sible for triggering cognitive impairment in these pa­ John RJ, McKusick VA, et al. The principles and practice of tients. It is also likely that the hypoglycemia warning medicine. 22nd ed. East Norwalk, Conn: Appleton 8t Lange. symptoms arc unrelated to the type of insulin (ie, human 1988:968-75. 14. Siperstein MD. Diabetic microangiopathy and the control of or animal).20 blood glucose. N Engl J Med 1983; 309:1577-9. We speculate that this patient’s profound hypogly­ 15. Taylor SI, Grunberger G, Marcus-Samuel B, et al. Hypoglycemia cemia was present for an extended period owing to his associated with to the insulin receptor. N Engl J Med 1982; 307:1422-6. underlying disease, and the lack of altered sensorium was 16. Teutsch SM, Herman WH, Dwyer DM, Lane JM. Mortality the result of a remarkable physiological adaptation of the among diabetic patients using continuous subcutaneous insulin brain to hypoglycemia. infusion pumps. N Engl J Med 1986; 310:361-8. Despite extensive literature reviews, we did not find 17. Turnbridge WM. Factors contributing to o f diabetics under fifty years of age. Lancet 1981; 2:569-71. any other report ot such an unusual clinical presentation 18. Unger RH. Nocturnal hvpoglycemia in aggressively controlled of hypoglycemia with altered sensorium. diabetes. N Engl J Med 1982; 306:1294. 19. Ryan CM, Ateison J, Puczynski S, Puczvnski M. Mild hypoglyce­ mia associated with deterioration of mental efficiency' in children with insulin dependent diabetes mellitus. J Pediatr 1990; 117 Acknowledgment 32-8. 20. Muhlhauser I, Heinemann L, Fritsche E, Von Lennep K, Berger We would like to thank l’eter R. Lichstein, MD, FACP, Section Head, M. Hypoglycemic symptoms and frequency of severe hypoglyce­ General Internal Medicine, and Eugene D. Furth, MD, FACp ’ mia in patients treated with human and animal insulin preparation. Professor o f Medicine, Section of , East Carolina Diabetes Care 1991; 14:745-9.

656 The Journal of Family Practice, Vol. 36, No. 6, 1993