Case Report: Factitious Hypoglycemia in Diabetic Patients THOMAS W. SHEEHY, MD
ABSTRACT: Factitious hypoglycemia (FH) in a diabetic patient represents a difficult diagnostic and costly management problem. An adolescent diabetic with FH is reported. A literature search revealed 10 adolescent and 45 adult diabetic patients with FH. Tests currently available for diagnosis are evaluated. The role of psychiatric therapy in relation to overall management and prognosis is stressed. KEY INDEXING TERMS: Factitious hypoglycemia; Diabetes mellitus. [Am J Med Sci 1992;304(5):298-302.]
F
actitious hypoglycemia (FH) implies a covert attempt to lower the blood glucose concentration with insulin or a sulfonylurea agent. The few reports dealing with FH in diabetes mellitus probably belie its true incidence. 1- s Jordan believed it occurs with a frequency similar to that of insulinoma, ie, about 0.4/ 100,000.1 On the other hand, Schade emphasized the need to consider FH in all patients with "brittle" diabetes mellitus. 2 The recurrent episodes of hypoglycemia and ketoacidosis encountered in diabetes patients with FH pose a threat to the individual and constitute an unwarranted waste of medical expertise and funding. Both may be increased by the need to carry out exploratory surgery to eliminate the possibility of an insulinoma.3 This report: (1) emphasizes the difficulties encountered in establishing a diagnosis of FH in diabetes mellitus; (2) reviews the literature dealing with FH in diabetic adolescents and adults; and (3) discusses tests currently used to aid in identifying FH. Case Report A 12-year-old boy was referred to the Diabetes Hospital, VAB, in April 1989 for evaluation and treatment of "brittle" diabetes mellitus, which had existed since age 8. During the previous 2 years, he had been admitted to his local hospital 6 times for diabetic ketoacidosis or profound hypoglycemia.
From the Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294. Correspondence: Tlwmas W. Sheehy, MD, Deportment of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL35294.
298
Prior to transfer, he had been hospitalized for 6 months. During that time, he had five episodes of hypoglycemia and one episode of ketoacidosis. Each required vigorous and prolonged treatment. Surreptitious insulin usage was suspected, but repeated attempts to prove this failed, including 24-hour periods of restraint. Diagnostic studies included ultrasonography, head and abdominal computed tomography scans, and transhepatic aortography. All results were normal. He had: (1) insulin antibodies with titers ranging from 1:64 to 1:512; (2) species-specific antibodies for beef, pork, and human insulin; (3) total immunoreactive insulin levels ranging from 300-1500 /lU/ml and free insulin levels of 31-35 /lU/ml during hypoglycemia (normal levels = 16 years old) have been reported. Thirty two had insulin-induced and five had sulfonylurea-induced FH (Table 1).6-19 If Schade's eight diabetic patients with FH, classified as malingerers, are included, the total rises to 45 patients. 2o All but 4 of the 32 diabetic patients with FH were women (Table 1). Most were allied with the health profession. The average age for women when FH was discovered was 30.7 years (range 16-65). The four men were 22, 44, 44, and 49 years old. Only two patients were over 50 years old. In contrast, most patients with insulinomas are over 50 years 0Id. 21 .22 Table 2 lists 11 adolescent diabetic patients with FH-eight girls and three boys.23.24 Their average age at discovery was 13.6 years. In eight of these patients, a decreased requirement for insulin was noted before the diagnosis of FH was confirmed. A similar obserTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
vation has been made in adults with FH. The 8-yearold child listed in Table 2 had FH secondary to parenteral abuse. 2 Younger patients with parenterally induced hypoglycemia have been reported but are not included in this review. 14.25 FH and Insulinoma. There are many causes of hypoglycemia. But islet-cell adenomas and non islet-cell tumors represent the major illnesses to be considered in the differential diagnosis of self-induced hyperinsulinism. Patients with insulinomas tend to become hypoglycemic early in the morning or late in the afternoon or after a long fast. In contrast, factitious hypoglycemia is unpredictable, erratic, and often refractory to treatment. Islet-cell tumors induce hypoglycemia through excess insulin production. However, tumors of epithelial, mesenchymal, or hematologic origin induce hypoglycemia by other mechanisms. 3 Insulinomas are a rare complication of type II diabetes mellitus. However, they have not been observed in insulin-dependent diabetics. 3.26 Despite this, 9 of the 32 adult diabetic patients with FH had exploratory pancreatic surgery (Table 1), as did 16 of the 37 nondiabetic patients reported with FH,19,27 as well as our adolescent. Surgery and FH. Avoiding unnecessary surgery is only one of the reasons why a diagnosis ofFH is important. Others include: (1) the considerable risk for morbidity and mortality associated with pancreatic exploration; (2) the possibility that recurrent hypoglycemia may prove fatal or lead to disabling neurologic sequelae;2 (3) the enormous medical costs ($30,000 to $80,000 per year) associated with FH patients28 (our patient was in the hospital for almost 2 years before diagnosis); and (4) that diagnosis sometimes provides patients with insight and leads them to accept psychiatric care and guidance. 29,30 Diagnostic Tests. The diagnosis of FH in diabetic and nondiabetic patients is difficult. Fortunately, since the days of search and confrontation, an array of diagnostic procedures has become available,4,7 including the following. 1. Addition of a radioisotope to the patient's exogenous insulin source with subsequent identification of the radioisotope at injection sites or in the patient's plasma or urine. 4.7 2. Insulin antibodies. 31 ,32 These begin to appear in the plasma 3-4 weeks after exogenous insulin therapy is initiated. In a nondiabetic patient, their presence almost always indicates exogenous insulin usage. The exception is the rare patient with "autoimmune hypoglycemia.,,33-34 Unlike surreptitious insulin abusers, these patients lack speciesspecific antibodies against the C-peptide moiety of pro-insulin. 35 3. Total and free-immunoreactive insulin levels. The new tests use polyethylene glycol to precipitate insulin antibodies. They provide fairly accurate levels of free insulin and C_peptide.36,37 Fasting
299
Factitious HypoglycE;tmla in Diabetic Patients
Table 1. Insulin-Induced Factitious Hypoglycemia in Diabetes Mellitus
Ref.
Sex
Age
Occupational
4
F F F M F F M F F F M F F F F F F F F F F F F M F F F F F F F F
28 32 16 22 28 23 44 18 34 21 49 27 16 32 31 21 24 30 28 21 19 33 65 44 53 24 28 41 28 48 23 32
HR HR
5 6 7 9
10 11
12 13 14 15 2
16 17 18
Negative Pancreatic Exploration y
N
N N Y
HR HR
y
M M M
y
M M M
y
y
y
y
y
y y
HR N HR HR HR HR
N N Y
N N N N N
N N N N N N N Y
y
Confirmation
y y y y y
HR
HR HR HR HR HR
Agent Found After Search
y y
CP M-CP CP CP CP N
dilution y y N N N Y
CP CP CP N
observed y y y
CP CP CP
PL CP CP CP
PL-CP
Confession y y y y
y
y y y y
y N Y Y N Y Y N N Y
HR = health related. M = typhoid vaccine or radioisotope added to sequestered insulin vial. CP = low C-peptide concentration. PL = Plasma insulin.
concentrations of free insulin range from 0-25 JLU/ml. 4. free C-peptide assay. C-peptide is cleaved from pro-insulin during insulin synthesis and is stored in beta-cell granules.37,38 C-peptide levels are elevated in patients with insulinomas but not those with FH.14 Normal fasting C-peptide levels range from 1.0-2.5 ng/ml. 5. C-peptide suppression test. Normally, the intravenous administration of insulin (0.1 U/kg body weight, over a 1 hour period) suppresses the Cpeptide level to 1.2 ng/ml or less when the serum glucose falls to 40 mg % or below.39 With an insulinoma, this test leads to a rise in the C-peptide level to 3 ng/ml or more. Service et al found this test was positive in 19 of 20 patients with an insulinoma.39 6. A 72 hour fast. Patients with insulinomas tolerate fasting poorly. Among 90 such patients, 88 developed hypoglycemia within 72 hours. 3
300
7. Pancreatic aortography was diagnostic in 9 of 10 patients with insulinoma.3 8. Hepatomegaly. Transient liver enlargement may occur with FH because of hepatic glycogen and lipid deposition after the use of insulin. 25-40 9. Sulfonylurea assay. This assay is diagnostic in nondiabetic patients with FH.19 Our patient had insulin antibodies to beef, pork, and human insulin. His hypoglycemic episodes were accompanied by low C-peptide and elevated immunoreactive insulin levels compatible with FH. Both levels tend to be elevated during hypoglycemic episodes induced by an insulin-secreting tumor. His diagnostic studies were compatible with FH. Unfortunately, none of the diagnostic tests are 100% specific for an insulinoma or for FH. As a result, exploratory surgery has been employed frequently to diagnose an insulinoma and to treat it. Psychiatric Aspects. Psychiatric problems are common among diabetic patients with FH.18,24 Denial is November 1992 Volume 304 Number 5
Sheehy
Table 2. Adolescent Diabetics with FH
Ref.
Sex
Age
Negative Pancreatic Exploration
8 2 24
F F F M F F M F M F M
14 8 15 15 14 15 12 15 11 13 12
N N N N N N N N N N Y
23 Present case
Decreased Insulin Requirement N N Y Y Y Y Y Y Y Y N
Suicidal Behavior
Psychiatric Problem
N
N
N Y Y Y N N N N Y
Y Y Y Y Y Y N Y Y
*
* Parental abuse.
the rule among young and old; many prefer surgery to confession. Disease manipulation, too, is frequent, as noted by Schade in 16 of 30 brittle diabetic patients. 2,20 Some took insufficient insulin to ensure good metabolic control. Others intentionally omitted their insulin, inducing diabetic ketoacidosis. This type of noncompliance has been associated with a psychosocial pattern of poor self-reliability, dependence, and a high frequency of disturbed family relationships.24 Depression and suicidal tendencies also are prevalent (Table 2). Orr believes surreptitious insulin usage represents a suicidal gesture. 24 Adult diabetic female patients with FH may suffer from a specific psychiatric syndrome, characterized by hysterical features, inappropriate affect, lying, psychosexual difficulties, and occasionally suicide. 18,29 Emotional deprivation during childhood has been blamed for their dependency.3 Once the diagnosis of FH is confirmed, intensive psychotherapy is considered essential. The prognosis usually is poor and suicide is not uncommon. 18,24 Physicians today must maintain a high degree of suspicion for FH, particularly when they are dealing with brittle diabetes mellitus in young patients. Fortunately, they have a number of useful tests to aid in diagnosis. However, clinical judgment and common sense remain vital in the diagnosis of FH. References 1. Jordan RM, Kammer H, Riddle MR: Sulfonylurea-induced factitious hypoglycemia. Arch Intern Med 137:390-393, 1977. 2. Schade DS, Drumm DA, Eaton RP, Sterling WA: Factitious brittle diabetes mellitus. Am J Med 78:777-784,1985. 3. Service FJ, Moore GL: Factitial and Autoimmune Hypoglycemia in Hypoglycemic Disorders: Pathogenesis, Diagnosis and Treatment, Service FJ (ed). Boston, GK Hall Medical Publishers, 1983 pp. 129-142. 4. Rynearson EH: Hyperinsulinism among malingerers. Med Clin North Am 31:477-480,1947. 5. Dunim JJ: Factitious Disease: Clinical staff conference at the National Institutes of Health. Ann Intern Med 48:1328-1341, 1958. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
6. Marble A: Hyperinsulinism and Chronic Hypoglycemia in the Treatment of Diabetes Mellitus, Joslin EP (ed). Philadelphia, Lea and Febiger, pp. 328-347,1959. 7. Whelton MJ, Samols E, Williams HS, Hirson C, Marks V: Factitious hypoglycemia in the diabetic. Metabolic studies and diagnosis with radioactive isotopes. Metabolism 17:923-927, 1968. 8. Creutzfeldt W, Frerichs H: Hypoglycemia factitia: eine differential diagnostisch wichtige Form des Hyperinsulinismus. Dtsch Med Wochenschr 94:813-818, 1969. 9. Berkowitz S, Parrish JE, Field JB: Factitious hypoglycemia: Why not diagnose before laparotomy? Am J Med 51:669-674, 1971. 10. Burman KD, Cunningham EJ, Klachko DM, Bazzoui WE, Burns TW: Factitious hypoglycemia Am J Med Sci 266:23-30, 1973. 11. Maddoux GL, Townsend JL, Males JL: Metabolic malingering: Factitious Hyperinsulinism. Arch Intern Med 132:252-255, 1973. 12. Service FJ, Rubenstein AH, Horwitz DL: C-peptide analysis in diagnosis of factitial hypoglycemia in an insulin dependent diabetic. Mayo Clin Proc 50:697-701,1975. 13. Couropmitree C, Freinkel N, Nagel TC, Horwitz DL, Rubenstein AH, Metzger B, Rubenstein AH, Hahnel R: Plasma C-peptide and diagnosis of factitious hyperinsulinism. Study of an insulindependent diabetic patient with "spontaneous" hypoglycemia. Ann Intern Med 81:201-204, 1975. 14. Scarlett JA, Mako ME, Rubenstein AH, Blix PM, Goldman J, Horwitz DL, Tager H, Jaspan JB, Stjernholm MR, Olefsky JM: Factitious hypoglycemia. Diagnosis by measurement of serum C-peptide immunoreactivity and insulin-binding antibodies. N Engl J Med 297:1029-1032,1977. 15. Dimitriadis G, Raptis S, Zoupas C, Schizas M: Factitious hypoglycemia. Acta Diabetol Lat 17:67-71, 1980. 16. O'Brien lA, Lewin IG, Frier BM, Rodman H, Genuth S, Corrall RJ: Factitious diabetic instability. Diabetic Med 2:392-394, 1985. 17. Ensberg M, Gossain VV, Rovner DR: Factitious hypoglycemia: Clues to identifying an elusive disorder. Postgrad Med 79:7988,1986. 18. Grunberger G, Weiner JL, Silverman R, Taylor S, Gorden P: Factitious hypoglycemia due to surreptitious administration of insulin: Diagnosis, treatment, and long-term follow-up. Ann Intern Med 108:252-257, 1988. 19. Horwitz DL: Factitious and artifactual hypoglycemia. Endocrinol Metab CUn North Am 18:203-210, 1989. 20. Schade DS, Drumm DA, Duckworth WC, Eaton RP: The etiology of incapacitating brittle diabetes. Diabetes Care 8:12-20, 1985. 21. Service FJ, Dale AJ, Elveback LR, Jiang NS: Insulinoma: Clinical and diagnostic features in 60 consecutive cases. Mayo Clin Proc 51:417-429,1976. 22. Gittler RD, Zucker G, Eisinger R, Stoller N: Amelioration of diabetes mellitus by an insulinoma. N Engl J Med 258:932-935, 1958.
301
Factitious Hypoglycemia in Diabetic Patients
23. Brouhard BH: Surreptitious insulin administration. Am J Dis Child 141:28-29, 1987. 24. Orr DP, Eccles T, Lawlor R, Golden M: Surreptitious insulin administration in adolescents with insulin dependent diabetes mellitus. JAMA 256:3221-3230. 1986. 25. Dershewitz R, Vestal B, Maclaren NK, Cornblath M: Transient hepatomegaly & hypoglycemia: A consequence of malicious insulin administration. Am J Dis Child 130:998-999, 1976. 26. Sandler R, Horwitz DL, Rubenstein AH, Kuzuya H: Hypoglycemia and endogenous hyperinsulinism complicating diabetes mellitus. Application of C-peptide assay to diagnosis and therapy. Am J Med 59:730-736,1975. 27. Bhatnagar D: Diagnosis of factitious hypoglycemia. Br J Med 40:140-142,1988. 28. Zook CJ, Moore FD: High cost users of medical care. N Engl J Med 302:996-1002,1980. 29. Moore GL, McBurney PL, Service FJ: Self-induced hypoglycemia: A review of psychiatric aspects and report of three cases. Psychiatr Med 4:301-311, 1973. 30. Schade DS, Eaton RP, Drumm DA, Duckworth WC: A clinical algorithm to determine the etiology of brittle diabetes. Diabetes Care 8:5-11, 1985. 31. Palumbo PJ, Molnar GD, Taylor WF, Moxness KE, Tauxe WN: Insulin antibody binding in diabetic mellitus and factitious hypoglycemia. Mayo Clin Proc 44:725-737,1969.
302
32. Service FJ, Palumbo PJ: Factitial hypoglycemia: Three cases diagnosed on the basis of insulin antibodies. Arch Intern Med 134-340, 1974.33. Hirata Y, Ishizu H: Elevated insulin-binding capacity of serum proteins in a case with spontaneous hypoglycemia and mild diabetes not treated with insulin. Tohoku J Exp Med 107:277286,1972. 34. Hirata Y, Tominaga M, Ito JI, Noguchi A: Spontaneous hypoglycemia with insulin autoimmunity in Graves' disease. Ann Intern Med 81:214-218, 1974. 35. Reeves WG, Douglas CA: C-peptide antibodies induced by bovine insulin therapy. Clin Exp ImmunoI50:171-177, 1982. 36. Nakagawa S, Nadayama H, Sasaki T, Yoshino K, Yu YY: A simple method for the determination of serum for insulin levels in insulin treated patients. Diabetes 22:590-600, 1973. 37. Kuzuya H, Plix PM, Howitz DL, Steiner DF, Rubenstein AH: Determination of free and total insulin and C-peptide in insulintreated diabetics. Diabetes 26:22-29, 1977. 38. Block MR, Rosenfield RL, Mako ME, Steiner DF, Rubenstein AH: Sequential changes in insulin treated diabetic patients assessed by C-peptide immuno assay. N Engl J Med 288:11441148,1973. 39. Service FJ, Horwitz DL, Rubenstein AH: C-peptide suppression test for insulinoma. J Lab CUn Med 90:180-186,1977. 40. Gorman CA, Wahner HW, Tauxe WN: Metabolic malingerers: Patients who deliberately induce or perpetrate a hypermetabolic or hypometabolic state. Am J Med 48:708-714, 1970.
November 1992 Volume 304 Number 5
ABSTRACT: Factitious hypoglycemia (FH) in a diabetic patient represents a difficult diagnostic and costly management problem. An adolescent diabetic with FH is reported. A literature search revealed 10 adolescent and 45 adult diabetic patients with FH. Tests currently available for diagnosis are evaluated. The role of psychiatric therapy in relation to overall management and prognosis is stressed. KEY INDEXING TERMS: Factitious hypoglycemia; Diabetes mellitus. [Am J Med Sci 1992;304(5):298-302.]
F
actitious hypoglycemia (FH) implies a covert attempt to lower the blood glucose concentration with insulin or a sulfonylurea agent. The few reports dealing with FH in diabetes mellitus probably belie its true incidence. 1- s Jordan believed it occurs with a frequency similar to that of insulinoma, ie, about 0.4/ 100,000.1 On the other hand, Schade emphasized the need to consider FH in all patients with "brittle" diabetes mellitus. 2 The recurrent episodes of hypoglycemia and ketoacidosis encountered in diabetes patients with FH pose a threat to the individual and constitute an unwarranted waste of medical expertise and funding. Both may be increased by the need to carry out exploratory surgery to eliminate the possibility of an insulinoma.3 This report: (1) emphasizes the difficulties encountered in establishing a diagnosis of FH in diabetes mellitus; (2) reviews the literature dealing with FH in diabetic adolescents and adults; and (3) discusses tests currently used to aid in identifying FH. Case Report A 12-year-old boy was referred to the Diabetes Hospital, VAB, in April 1989 for evaluation and treatment of "brittle" diabetes mellitus, which had existed since age 8. During the previous 2 years, he had been admitted to his local hospital 6 times for diabetic ketoacidosis or profound hypoglycemia.
From the Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, Alabama 35294. Correspondence: Tlwmas W. Sheehy, MD, Deportment of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL35294.
298
Prior to transfer, he had been hospitalized for 6 months. During that time, he had five episodes of hypoglycemia and one episode of ketoacidosis. Each required vigorous and prolonged treatment. Surreptitious insulin usage was suspected, but repeated attempts to prove this failed, including 24-hour periods of restraint. Diagnostic studies included ultrasonography, head and abdominal computed tomography scans, and transhepatic aortography. All results were normal. He had: (1) insulin antibodies with titers ranging from 1:64 to 1:512; (2) species-specific antibodies for beef, pork, and human insulin; (3) total immunoreactive insulin levels ranging from 300-1500 /lU/ml and free insulin levels of 31-35 /lU/ml during hypoglycemia (normal levels = 16 years old) have been reported. Thirty two had insulin-induced and five had sulfonylurea-induced FH (Table 1).6-19 If Schade's eight diabetic patients with FH, classified as malingerers, are included, the total rises to 45 patients. 2o All but 4 of the 32 diabetic patients with FH were women (Table 1). Most were allied with the health profession. The average age for women when FH was discovered was 30.7 years (range 16-65). The four men were 22, 44, 44, and 49 years old. Only two patients were over 50 years old. In contrast, most patients with insulinomas are over 50 years 0Id. 21 .22 Table 2 lists 11 adolescent diabetic patients with FH-eight girls and three boys.23.24 Their average age at discovery was 13.6 years. In eight of these patients, a decreased requirement for insulin was noted before the diagnosis of FH was confirmed. A similar obserTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
vation has been made in adults with FH. The 8-yearold child listed in Table 2 had FH secondary to parenteral abuse. 2 Younger patients with parenterally induced hypoglycemia have been reported but are not included in this review. 14.25 FH and Insulinoma. There are many causes of hypoglycemia. But islet-cell adenomas and non islet-cell tumors represent the major illnesses to be considered in the differential diagnosis of self-induced hyperinsulinism. Patients with insulinomas tend to become hypoglycemic early in the morning or late in the afternoon or after a long fast. In contrast, factitious hypoglycemia is unpredictable, erratic, and often refractory to treatment. Islet-cell tumors induce hypoglycemia through excess insulin production. However, tumors of epithelial, mesenchymal, or hematologic origin induce hypoglycemia by other mechanisms. 3 Insulinomas are a rare complication of type II diabetes mellitus. However, they have not been observed in insulin-dependent diabetics. 3.26 Despite this, 9 of the 32 adult diabetic patients with FH had exploratory pancreatic surgery (Table 1), as did 16 of the 37 nondiabetic patients reported with FH,19,27 as well as our adolescent. Surgery and FH. Avoiding unnecessary surgery is only one of the reasons why a diagnosis ofFH is important. Others include: (1) the considerable risk for morbidity and mortality associated with pancreatic exploration; (2) the possibility that recurrent hypoglycemia may prove fatal or lead to disabling neurologic sequelae;2 (3) the enormous medical costs ($30,000 to $80,000 per year) associated with FH patients28 (our patient was in the hospital for almost 2 years before diagnosis); and (4) that diagnosis sometimes provides patients with insight and leads them to accept psychiatric care and guidance. 29,30 Diagnostic Tests. The diagnosis of FH in diabetic and nondiabetic patients is difficult. Fortunately, since the days of search and confrontation, an array of diagnostic procedures has become available,4,7 including the following. 1. Addition of a radioisotope to the patient's exogenous insulin source with subsequent identification of the radioisotope at injection sites or in the patient's plasma or urine. 4.7 2. Insulin antibodies. 31 ,32 These begin to appear in the plasma 3-4 weeks after exogenous insulin therapy is initiated. In a nondiabetic patient, their presence almost always indicates exogenous insulin usage. The exception is the rare patient with "autoimmune hypoglycemia.,,33-34 Unlike surreptitious insulin abusers, these patients lack speciesspecific antibodies against the C-peptide moiety of pro-insulin. 35 3. Total and free-immunoreactive insulin levels. The new tests use polyethylene glycol to precipitate insulin antibodies. They provide fairly accurate levels of free insulin and C_peptide.36,37 Fasting
299
Factitious HypoglycE;tmla in Diabetic Patients
Table 1. Insulin-Induced Factitious Hypoglycemia in Diabetes Mellitus
Ref.
Sex
Age
Occupational
4
F F F M F F M F F F M F F F F F F F F F F F F M F F F F F F F F
28 32 16 22 28 23 44 18 34 21 49 27 16 32 31 21 24 30 28 21 19 33 65 44 53 24 28 41 28 48 23 32
HR HR
5 6 7 9
10 11
12 13 14 15 2
16 17 18
Negative Pancreatic Exploration y
N
N N Y
HR HR
y
M M M
y
M M M
y
y
y
y
y
y y
HR N HR HR HR HR
N N Y
N N N N N
N N N N N N N Y
y
Confirmation
y y y y y
HR
HR HR HR HR HR
Agent Found After Search
y y
CP M-CP CP CP CP N
dilution y y N N N Y
CP CP CP N
observed y y y
CP CP CP
PL CP CP CP
PL-CP
Confession y y y y
y
y y y y
y N Y Y N Y Y N N Y
HR = health related. M = typhoid vaccine or radioisotope added to sequestered insulin vial. CP = low C-peptide concentration. PL = Plasma insulin.
concentrations of free insulin range from 0-25 JLU/ml. 4. free C-peptide assay. C-peptide is cleaved from pro-insulin during insulin synthesis and is stored in beta-cell granules.37,38 C-peptide levels are elevated in patients with insulinomas but not those with FH.14 Normal fasting C-peptide levels range from 1.0-2.5 ng/ml. 5. C-peptide suppression test. Normally, the intravenous administration of insulin (0.1 U/kg body weight, over a 1 hour period) suppresses the Cpeptide level to 1.2 ng/ml or less when the serum glucose falls to 40 mg % or below.39 With an insulinoma, this test leads to a rise in the C-peptide level to 3 ng/ml or more. Service et al found this test was positive in 19 of 20 patients with an insulinoma.39 6. A 72 hour fast. Patients with insulinomas tolerate fasting poorly. Among 90 such patients, 88 developed hypoglycemia within 72 hours. 3
300
7. Pancreatic aortography was diagnostic in 9 of 10 patients with insulinoma.3 8. Hepatomegaly. Transient liver enlargement may occur with FH because of hepatic glycogen and lipid deposition after the use of insulin. 25-40 9. Sulfonylurea assay. This assay is diagnostic in nondiabetic patients with FH.19 Our patient had insulin antibodies to beef, pork, and human insulin. His hypoglycemic episodes were accompanied by low C-peptide and elevated immunoreactive insulin levels compatible with FH. Both levels tend to be elevated during hypoglycemic episodes induced by an insulin-secreting tumor. His diagnostic studies were compatible with FH. Unfortunately, none of the diagnostic tests are 100% specific for an insulinoma or for FH. As a result, exploratory surgery has been employed frequently to diagnose an insulinoma and to treat it. Psychiatric Aspects. Psychiatric problems are common among diabetic patients with FH.18,24 Denial is November 1992 Volume 304 Number 5
Sheehy
Table 2. Adolescent Diabetics with FH
Ref.
Sex
Age
Negative Pancreatic Exploration
8 2 24
F F F M F F M F M F M
14 8 15 15 14 15 12 15 11 13 12
N N N N N N N N N N Y
23 Present case
Decreased Insulin Requirement N N Y Y Y Y Y Y Y Y N
Suicidal Behavior
Psychiatric Problem
N
N
N Y Y Y N N N N Y
Y Y Y Y Y Y N Y Y
*
* Parental abuse.
the rule among young and old; many prefer surgery to confession. Disease manipulation, too, is frequent, as noted by Schade in 16 of 30 brittle diabetic patients. 2,20 Some took insufficient insulin to ensure good metabolic control. Others intentionally omitted their insulin, inducing diabetic ketoacidosis. This type of noncompliance has been associated with a psychosocial pattern of poor self-reliability, dependence, and a high frequency of disturbed family relationships.24 Depression and suicidal tendencies also are prevalent (Table 2). Orr believes surreptitious insulin usage represents a suicidal gesture. 24 Adult diabetic female patients with FH may suffer from a specific psychiatric syndrome, characterized by hysterical features, inappropriate affect, lying, psychosexual difficulties, and occasionally suicide. 18,29 Emotional deprivation during childhood has been blamed for their dependency.3 Once the diagnosis of FH is confirmed, intensive psychotherapy is considered essential. The prognosis usually is poor and suicide is not uncommon. 18,24 Physicians today must maintain a high degree of suspicion for FH, particularly when they are dealing with brittle diabetes mellitus in young patients. Fortunately, they have a number of useful tests to aid in diagnosis. However, clinical judgment and common sense remain vital in the diagnosis of FH. References 1. Jordan RM, Kammer H, Riddle MR: Sulfonylurea-induced factitious hypoglycemia. Arch Intern Med 137:390-393, 1977. 2. Schade DS, Drumm DA, Eaton RP, Sterling WA: Factitious brittle diabetes mellitus. Am J Med 78:777-784,1985. 3. Service FJ, Moore GL: Factitial and Autoimmune Hypoglycemia in Hypoglycemic Disorders: Pathogenesis, Diagnosis and Treatment, Service FJ (ed). Boston, GK Hall Medical Publishers, 1983 pp. 129-142. 4. Rynearson EH: Hyperinsulinism among malingerers. Med Clin North Am 31:477-480,1947. 5. Dunim JJ: Factitious Disease: Clinical staff conference at the National Institutes of Health. Ann Intern Med 48:1328-1341, 1958. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
6. Marble A: Hyperinsulinism and Chronic Hypoglycemia in the Treatment of Diabetes Mellitus, Joslin EP (ed). Philadelphia, Lea and Febiger, pp. 328-347,1959. 7. Whelton MJ, Samols E, Williams HS, Hirson C, Marks V: Factitious hypoglycemia in the diabetic. Metabolic studies and diagnosis with radioactive isotopes. Metabolism 17:923-927, 1968. 8. Creutzfeldt W, Frerichs H: Hypoglycemia factitia: eine differential diagnostisch wichtige Form des Hyperinsulinismus. Dtsch Med Wochenschr 94:813-818, 1969. 9. Berkowitz S, Parrish JE, Field JB: Factitious hypoglycemia: Why not diagnose before laparotomy? Am J Med 51:669-674, 1971. 10. Burman KD, Cunningham EJ, Klachko DM, Bazzoui WE, Burns TW: Factitious hypoglycemia Am J Med Sci 266:23-30, 1973. 11. Maddoux GL, Townsend JL, Males JL: Metabolic malingering: Factitious Hyperinsulinism. Arch Intern Med 132:252-255, 1973. 12. Service FJ, Rubenstein AH, Horwitz DL: C-peptide analysis in diagnosis of factitial hypoglycemia in an insulin dependent diabetic. Mayo Clin Proc 50:697-701,1975. 13. Couropmitree C, Freinkel N, Nagel TC, Horwitz DL, Rubenstein AH, Metzger B, Rubenstein AH, Hahnel R: Plasma C-peptide and diagnosis of factitious hyperinsulinism. Study of an insulindependent diabetic patient with "spontaneous" hypoglycemia. Ann Intern Med 81:201-204, 1975. 14. Scarlett JA, Mako ME, Rubenstein AH, Blix PM, Goldman J, Horwitz DL, Tager H, Jaspan JB, Stjernholm MR, Olefsky JM: Factitious hypoglycemia. Diagnosis by measurement of serum C-peptide immunoreactivity and insulin-binding antibodies. N Engl J Med 297:1029-1032,1977. 15. Dimitriadis G, Raptis S, Zoupas C, Schizas M: Factitious hypoglycemia. Acta Diabetol Lat 17:67-71, 1980. 16. O'Brien lA, Lewin IG, Frier BM, Rodman H, Genuth S, Corrall RJ: Factitious diabetic instability. Diabetic Med 2:392-394, 1985. 17. Ensberg M, Gossain VV, Rovner DR: Factitious hypoglycemia: Clues to identifying an elusive disorder. Postgrad Med 79:7988,1986. 18. Grunberger G, Weiner JL, Silverman R, Taylor S, Gorden P: Factitious hypoglycemia due to surreptitious administration of insulin: Diagnosis, treatment, and long-term follow-up. Ann Intern Med 108:252-257, 1988. 19. Horwitz DL: Factitious and artifactual hypoglycemia. Endocrinol Metab CUn North Am 18:203-210, 1989. 20. Schade DS, Drumm DA, Duckworth WC, Eaton RP: The etiology of incapacitating brittle diabetes. Diabetes Care 8:12-20, 1985. 21. Service FJ, Dale AJ, Elveback LR, Jiang NS: Insulinoma: Clinical and diagnostic features in 60 consecutive cases. Mayo Clin Proc 51:417-429,1976. 22. Gittler RD, Zucker G, Eisinger R, Stoller N: Amelioration of diabetes mellitus by an insulinoma. N Engl J Med 258:932-935, 1958.
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Factitious Hypoglycemia in Diabetic Patients
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November 1992 Volume 304 Number 5
