67-Year-Old Woman With Recurrent Hypoglycemia

Abstract

A 67-year-old woman was referred to the Mayo Clinic in Rochester, Minn, for investigation and treatment of recurrent hypoglycemia. She had been well until 4 months before admission, when she felt vaguely ill at work and was unable to see her computer screen. She had not eaten lunch that day. The patient went home to rest, where her husband found her on the floor, unresponsive and having seizures. She was rushed to the local emergency department, where her blood glucose level was found to be 30 mg/dL. Intravenous dextrose was administered, and her symptoms resolved. She was hospitalized for several days to undergo tests, including a 72-hour fast that failed to reveal a diagnosis. She was discharged from the hospital with advice to eat 6 regular meals a day. The patient had an episode of “feeling weird” shortly after discharge and went to the emergency department, where she was given a glass of orange juice and discharged. She remained asymptomatic until 2 days before admission to our hospital, when a similar episode occurred and she was admitted to her local hospital. She was transferred to a Mayo Clinic-affiliated hospital in Rochester, Minn, for further investigation. The patient had a history of hypothyroidism, myocardial infarction, and hypertension. Her medications were metoprolol, 25 mg twice a day; aspirin, 325 mg/d; and levothyroxine sodium, 0.075 mg/d. Her family history was notable for a brother with type 2 diabetes mellitus. Physical examination revealed normal findings. The aforementioned information was all that was available when the patient arrived at our hospital. It was unclear what tests had been performed at her local hospital during her initial admission for a hypoglycemia-induced seizure. 1.Which one of the following is the most appropriate next step in the evaluation of this patient? a.A repeated 72-hour fastb.Computed tomography of the pancreasc.Endoscopic ultrasonography of the pancreasd.Magnetic resonance imaging of the pancreas and retroperitoneume.Somatostatin receptor scintigraphy (Octreoscan) of the pancreas The 72-hour fast is a well-established test for diagnosing hypoglycemia.1Service FJ Natt N The prolonged fast.J Clin Endocrinol Metab. 2000; 85: 3973-3974Crossref PubMed Scopus (81) Google Scholar All patients with a history of neuroglycopenic symptoms (eg, spells of blurred vision, confusion, or abnormal behavior) or confirmed low plasma glucose levels should be further evaluated with a 72hour fast unless an obvious cause is indicated on the history, physical examination, or laboratory tests. Our patient had documented hypoglycemia, with a serum glucose level of 30 mg/dL, and was symptomatic. Her history and findings on physical examination showed no obvious cause for the hypoglycemia; thus, a 72-hour fast is the most reasonable test. The 72-hour fast attempts to document Whipple triad (hypoglycemia, neuroglycopenic symptoms concurrent with the hypoglycemia, and resolution of symptoms with normalization of the blood glucose level) under controlled conditions. Because details of the patient's conduct and results of the 72-hour fast at her local hospital were unavailable, this fast should be repeated. The 72-hour fast is a sensitive diagnostic test for an insulinoma, and a patient with an insulinoma rarely completes a 72-hour fast unequivocally; in fact, most patients become hypoglycemic within 48 hours.2Hirshberg B Livi A Bartlett DL et al.Forty-eight-hour fast: the diagnostic test for insulinoma.J Clin Endocrinol Metab. 2000; 85: 3222-3226Crossref PubMed Google Scholar In a Mayo Clinic series, only 2 of 170 consecutive patients with insulinomas successfully completed a 72-hour fast.1Service FJ Natt N The prolonged fast.J Clin Endocrinol Metab. 2000; 85: 3973-3974Crossref PubMed Scopus (81) Google Scholar The 72-hour fast is difficult to perform correctly. Criteria for discontinuing the fast are strict: blood glucose level must be lower than 45 mg/dL, and the patient must be symptomatic. All nonessential medications must be discontinued, and only water, black decaffeinated coffee, and diet sugar-free sodas can be consumed. Computed tomography of the pancreas, transabdominal ultrasonography, and endoscopic ultrasonography3Ardengh JC Rosenbaum P Ganc AJ et al.Role of EUS in the preoperative localization of insulinomas compared with spiral CT.Gastrointest Endosc. 2000; 51: 552-555Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar are useful modalities for localizing a biochemically proven insulinoma, but they have no role in diagnosing an insulinoma. An insulinoma, a tumor of the insulin-producing pancreatic islet cells, is a possible cause of hypoglycemia in a patient with no obvious cause on the history or physical examination. However, sound biochemical evidence of the existence of an insulinoma should be obtained before the aforementioned tests are ordered. The 72-hour fast may provide this evidence. Magnetic resonance imaging of the pancreas and retroperitoneum and somatostatin receptor scintigraphy have no role in the diagnosis of a suspected insulinoma or in the localization of a biochemically proven insulinoma, and these tests would be inappropriate. While we arranged for a 72-hour fast, more information was obtained from the patient's local hospital regarding tests performed on blood drawn at the time of her initial presentation with hypoglycemia. 2.Which one of the following tests is the least important to perform on our patient's serum that was drawn at the time of her hypoglycemia? a.Glucoseb.Insulinc.β-Hydroxybutyrated.C peptidee.Cortisol The best setting for confirming the presence of and accurately diagnosing the type of hypoglycemic disorder is at the time of a spontaneous spell. Performing the correct blood tests at this time may eliminate the need for further testing. It may seem obvious that a serum glucose level should be measured in our patient. However, glucose levels measured by a reflectance meter are often inaccurate in the hypoglycemic range. Therefore, a low glucose measurement with a reflectance meter should be confirmed with a serum glucose measurement. Also, other blood tests that may lead to a diagnosis can be interpreted accurately only when the serum glucose level is known at the time the blood was drawn. β-Hydroxybutyrate is a surrogate marker of insulin secretion. Because insulin is antiketogenic, it suppresses β-hydroxybutyrate production; thus, low levels would be expected in a patient with hyperinsulinemia. β-Hydroxybutyrate is primarily useful in patients in whom insulin and C peptide levels are borderline, but the test result is difficult to interpret. Levels should be measured in all patients with spontaneous hypoglycemia. The utility of insulin and C peptide levels in our patient will be discussed subsequently. Taken together with the serum glucose level and interpreted correctly, they can provide substantial information about the cause of our patient's hypoglycemia. Cortisol, along with epinephrine, glucagon, and growth hormone, is one of the counterregulatory hormones that oppose insulin action, and serum levels increase in response to hypoglycemia. However, an isolated deficiency of one of these hormones rarely results in hypoglycemia except in children, and if the other counterregulatory systems are intact, hypoglycemia is probably not a concern. Our patient was healthy between attacks, and findings on physical examination were normal; therefore, measurement of her cortisol level would not be important. Test results were eventually forwarded from her local hospital and were as follows: insulin, 22 μIU/mL (high); C peptide, 4000 pmol/L (high); glucose, 30 mg/dL; urine sulfonylurea screen, negative; and insulin autoantibodies, negative. 3.Based on the aforementioned test results, which one of the following is the most likely cause of hypoglycemia in our patient? a.Alcohol-induced hypoglycemiab.Autoimmune hypoglycemiac.Exogenous insulin administrationd.Endogenous insulin excesse.Pseudohypoglycemia Alcohol can cause hypoglycemia by inhibiting gluconeogenesis; some emergency departments have reported alcohol as the cause in up to 18% of patients presenting with hypoglycemia.4Hart SP Frier BM Causes, management and morbidity of acute hypoglycaemia in adults requiring hospital admission.QJM. 1998; 91: 505-510Crossref PubMed Scopus (73) Google Scholar The hypoglycemia associated with alcohol abuse is not mediated by hyperinsulinism; thus, this cause has been effectively excluded by the aforementioned test results that demonstrated an elevated insulin level in the face of hypoglycemia. Autoimmune hypoglycemia is rare, with about 200 published cases, the vast majority of which occurred in Japan. Elevated insulin and C peptide levels are found in patients with hypoglycemia due to this condition.5Cho BY Lee HK Koh CS Min HK Spontaneous hypoglycemia and insulin autoantibodies in a patient with Grave's disease.Diabetes Res Clin Pract. 1987; 3: 119-124Abstract Full Text PDF PubMed Scopus (17) Google Scholar However, insulin autoantibodies are also found, and the negative insulin autoantibody screen excludes it as a cause of our patient's hypoglycemia. Our patient has documented hyperinsulinemic hypoglycemia, ie, an inappropriately high insulin level in the face of hypoglycemia. The normal response to hypoglycemia is suppression of insulin secretion. This picture of a high insulin level and a low blood glucose level could be caused by exogenous insulin administration. However, the elevated C peptide level excludes this as a cause of hypoglycemia in our patient. Insulin is manufactured in the pancreas as the peptide proinsulin, and this peptide is cleaved to form the active component, insulin, and the shorter C peptide, both of which are secreted from the pancreas simultaneously. If exogenous insulin is being administered in quantities sufficient to cause hypoglycemia, islet cell secretion of endogenous insulin will be suppressed, and C peptide secretion will be suppressed as a result. If endogenous insulin is being oversecreted, both insulin and C peptide levels will be inappropriately high in the face of a low blood glucose level, as in our patient. Therefore, endogenous insulin excess is the most likely cause of hypoglycemia in our patient. Pseudohypoglycemia can be suspected when a low blood glucose level is discovered in an asymptomatic patient, particularly a patient with leukocytosis or leukemia. A low blood glucose level is an artifact caused by metabolism of glucose in vitro by leukocytes. Our patient was obviously symptomatic during her episodes of hypoglycemia; thus, the diagnosis of pseudohypoglycemia is ruled out. Records obtained at this time from the patient's local hospital documented that she had no symptoms of hypoglycemia and her serum blood glucose level remained higher than 70 mg/dL throughout the 72-hour fast. A repeated 72hour fast at our institution also showed normal findings; at 72 hours, the patient's serum glucose level was 77 mg/dL. Our patient had documented hyperinsulinemic hypoglycemia, as previously discussed, normal results on two 72hour fasts, no insulin autoantibodies, and a negative urinary sulfonylurea screen. 4.Which one of the following should be done at this point in our patient's evaluation to determine the cause of hypoglycemia? a.Discharge her with advice to eat regular mealsb.Perform a 96-hour fastc.Perform a selective arterial calcium stimulation testd.Obtain serum from the time of her hypoglycemic episode for sulfonylurea screeninge.Perform an exploratory laparotomy Further diagnostic possibilities must be considered before the patient can be discharged because hypoglycemia is a potentially life-threatening condition; thus, discharging her is inappropriate at this time. Extending a 72-hour fast to 96 hours has not proved useful.1Service FJ Natt N The prolonged fast.J Clin Endocrinol Metab. 2000; 85: 3973-3974Crossref PubMed Scopus (81) Google Scholar The calcium stimulation test provides a means to regionalize insulinomas; selective catheterization of the arteries supplying the pancreas is performed, and hepatic vein insulin levels are measured after infusion of calcium, an insulin secretagogue. When used to regionalize an insulinoma, this test should be performed only when there is sound biochemical evidence of an insulinoma based on abnormal findings on a 72-hour fast and other causes of hypoglycemia have been excluded; therefore, this test has no role in the evaluation of our patient. Sulfonylurea ingestion gives the same biochemical picture as an insulinoma, causing endogenous hyperinsulinemia by releasing insulin from the pancreas. Sulfonylurea ingestion as a cause of our patient's hypoglycemia had not yet been excluded effectively by our tests. A urinary sulfonylurea screen performed at the patient's local hospital was negative; however, urinary sulfonylurea is an obsolete screening test for the agents most commonly used today because only the first-generation sulfonylureas are detectable in urine. Therefore, to rule out sulfonylurea ingestion as a cause of hypoglycemia in our patient, we needed to obtain serum from the time of her hypoglycemic episode for sulfonylurea screening. Exploratory laparotomy to search for an insulinoma should not be considered without a serum sulfonylurea screen being performed first. The patient's local hospital was contacted. Stored serum from her initial presentation was sent to our facility for analysis of first-, second-, and third-generation sulfonylureas. The sulfonylurea screen of the stored sample showed 332 ng/mL of glyburide. This result proved that sulfonylurea ingestion was the cause of our patient's hypoglycemia. However, our patient did not have diabetes and had not reported sulfonylurea ingestion. 5.Which one of the following is the most appropriate next step in the management of this patient? a.Confront the patient about surreptitious self-medicationb.Obtain a psychiatric consultationc.Arrange to have the patient's home searched for glyburide tabletsd.Examine the patient's medicationse.Contact the police because someone may be trying to poison the patient Surreptitious self-medication is certainly a possibility and is a common cause of hypoglycemia. However, suggesting this prematurely would jeopardize the patient-physician relationship. Obtaining a psychiatric consultation because of suspected deliberate self-harm by sulfonylurea ingestion is inappropriate without sufficient proof. Searching the patient's home for hidden stores of oral diabetic agents is unnecessary and also illegal without permission from the patient. Examining the patient's medications is the most appropriate action. Inspecting the pills, not just looking at the labels on the containers, may disclose an unexpected pharmacy error. Suspecting that someone is trying to poison the patient and contacting the police is obviously inappropriate at this time. Our patient reported to us that she was taking metoprolol, levothyroxine, and aspirin. We asked her to bring the medications in their original containers. Identification in our pharmacy department revealed that the pink tablets in a container marked “Lopressor” were indeed glyburide. Our patient's recurrent episodes of hypoglycemia were caused by inadvertent ingestion of sulfonylureas. The diagnosis of sulfonylurea-induced hypoglycemia was confirmed by performing appropriate blood tests on serum obtained at the time of hypoglycemia. A thorough inspection of the pills enabled us to establish that the patient's ingestion of sulfonylureas was inadvertent and due to pharmacy dispensation error (glyburide dispensed in error for metoprolol). In an ill-appearing patient with liver failure, sepsis, or malaria or a diabetic patient who is receiving treatment, the cause of hypoglycemia may be obvious. However, a well-appearing patient with spontaneous symptomatic hypoglycemia represents a diagnostic challenge. The search for a diagnosis should not automatically become a search for an insulinoma, as is often the case; patient deaths during intraoperative exploration for nonexistent insulinomas are uncommon but have been reported. Likewise patients have undergone pancreatectomy before discovery of inadvertent or surreptitious ingestion of hypoglycemic medication.6Harrop JS Golding PR Goodall P Leveau VM Steele GA Ingle AR C-peptide suppression test and sulphonylurea-induced factitious hypoglycaemia.Br Med J (Clin Res Ed). 1982; 284: 940-941Crossref PubMed Scopus (13) Google Scholar Sulfonylurea ingestion causing hypoglycemia in a nondiabetic has been well described. A case report and literature review in 19957Klonoff DC Barrett BJ Nolte MS Cohen RM Wyderski R Hypoglycemia following inadvertent and factitious sulfonylurea overdosages.Diabetes Care. 1995; 18: 563-567Crossref PubMed Scopus (41) Google Scholar found 43 cases of inadvertent sulfonylurea overdose and 23 cases of factitiously self-administered overdose resulting in hypoglycemia. Cases of factitious self-administration seem to have several common clinical features, the presence of which should alert the investigating physician to this possibility: (1) the patient is usually female, (2) is in a health-related profession or has a spouse in a health-related profession, (3) has a close relative or spouse with sulfonylurea-treated diabetes, (4) has an unusual affect or psychiatric history, (5) has an abrupt onset of severe symptoms without previous milder symptoms, and (6) has an absent hypoglycemic response to provocative testing, ie, negative results on a 72-hour fast. Our patient had a normal affect and normal psychiatric history, and she was not in a health-related profession; however, she fulfilled the other criteria, including having a brother with type 2 diabetes mellitus. Furthermore, she had had her prescription for metoprolol filled at 2 pharmacies, resulting in different colored tablets. Hypoglycemia occurred only with use of the pink tablets, not the blue tablets. Inadvertent administration of sulfonylureas appears to be most commonly due to pharmacy dispensation error. Published cases most commonly involve dispensation errors of drugs with similar-sounding names, eg, acetohexamide for acetazolamide, Diabinese for Diamox or Dialume, chlorpropamide for chlorpromazine, and Tolinase for Tolectin.8Ahlquist DA Nelson RL Callaway CW Pseudoinsulinoma syndrome from inadvertent tolazamide ingestion.Ann Intern Med. 1980; 93: 281-282Crossref PubMed Scopus (23) Google Scholar Dispensation errors with similar-appearing medications can also occur.9Huminer D Dux S Rosenfeld JB Pitlik SD Inadvertent sulfonylurea-induced hypoglycemia: a dangerous, but preventable condition.Arch Intern Med. 1989; 149: 1890-1892Crossref PubMed Google Scholar However, as in our patient, the explanation for the dispensation error is not always obvious, and a case of fatal hypoglycemia was reported when chlorpropamide was substituted for acetaminophen-codeine in a pharmacy error.10Scala-Barnett DM Donoghue ER Dispensing error causing fatal chlorpropamide intoxication in a nondiabetic.J Forensic Sci. 1986; 31: 293-295PubMed Google Scholar In a patient with hypoglycemia of unknown etiology who denies sulfonylurea ingestion, a thorough medication history is important, including over-the-counter medications taken sporadically. Our patient had 2 prescriptions for her metoprolol, of 2 different colors. She trusted her pharmacy and did not suspect the new, different-colored tablets as the cause of her symptoms. However, clinicians must be more skeptical and thoroughly examine a patient's pills.