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Description of case

A 47-year-old woman was admitted comatose in the overnightfasted state. She had no significant past medical history of noteand was taking no regular medication. She was a trained phys-iotherapist and married to a local consultant psychiatrist. Boththe patient and her husband denied any access to hypoglycaemicmedication. Clinical examination revealed her to be confusedand disorientated but was otherwise unremarkable.

The plasma glucose concentration was 1.7 mmol/ l. Simul-taneous samples were drawn for plasma insulin and C-peptideanalysis. A sample was sent for sulphonylurea screening.Treatment was commenced with intravenous 10% dextrose,and her neurologic state improved. Prolonged intravenousdextrose resuscitation was required to maintain stable bloodglucose concentrations. The patient remained in hospital for5 days without any further episodes of hypoglycaemia, andwas discharged awaiting the results of investigations.

She was readmitted, again in the overnight fasted state, in ahypoglycaemic coma 4 days later and again required pro-longed intravenous dextrose to normalize her blood glucoseconcentrations. The results from the initial admission indicatedendogenous hyperinsulinism as the cause of hypoglycaemia

(see chronology of events, Table 1). The original sulphonylureascreen was reported as negative and drug-induced hypoglycaemiawas felt to have been excluded. Tests of growth hormone andcortisol production were normal. Spiral CT scan of the pancreaswas normal. An insulinoma was suspected as the most likelydiagnosis and, as hypoglycaemia had been documented ontwo separate occasions, a formal fast was deemed unnecessary.In an attempt to localize the insulinoma to a particular arterialregion of the pancreas, a calcium stimulation test was performed.This was undertaken 2 days after the second admission, at atime when intravenous dextrose was still required to maintainnormal blood glucose levels. The results were atypical, inthat a positive response (a doubling of hepatic venous insulinconcentration in response to calcium) was detected in all arte-rial territories (Fig. 1). The greatest response was from thesplenic artery territory. Following consultation with anotherendocrine unit, pancreatic exploratory surgery was recom-mended. Due to the generalized pattern of response withcalcium stimulation, and the fact that the patient had sufferedtwo life-threatening episodes of neuroglycopaenia requiringprolonged resuscitation to correct, a decision was made pre-operatively to undertake a distal pancreatectomy if no insuli-noma was identified (in the expectation that histologicalexamination would reveal a single or multiple insulinomas inthe tail and/or body of the pancreas). Both the patient and herhusband were informed and agreed to the proposed surgery.

Correspondence to

: Dr Patrick J Manning, Department of Endocrinology, Dunedin Hospital, Dunedin, New Zealand. E-mail: PatrickManning@healthotago.co.nz

Abstract

Endogenous hyperinsulinism as a cause for hypoglycaemia can be attributed toa number of different causes including insulinoma, sulphonylurea drugs andthe newly described disorder non-insulinoma pancreatogenous hypoglycaemia(NIPH). The calcium stimulation test is increasingly used as a method for notonly localizing insulinoma but also for distinguishing the above entities. Wedescribe a case in which felonious sulphonylurea administration was used tomimic either an insulinoma or NIPH. Importantly, this case demonstrates that,contrary to previous reports, the insulin response to calcium stimulation insuch cases may be uniformly positive and should alert the physician to possiblesurreptitious sulphonylurea ingestion.

Diabet. Med. 20, 772–776 (2003)

Keywords

calcium stimulation test, homicide, hypoglycaemia, sulphonylurea drugs

Blackwell Publishing Ltd.Oxford, UKDMEDiabetic Medicine0742-3071Blackwell Science Ltd, 200320Case ReportCase reportFelonious hypoglycaemia

P. J. Manning et al.

An unusual cause of hyperinsulinaemic hypoglycaemia syndrome

P. J. Manning*, E. A. Espiner†, K. Yoon‡, P. L. Drury§, I. M. Holdaway¶ and A. Bowers**

Departments of *Endocrinology, ‡Pathology and **Medicine, Dunedin Hospital, Dunedin, †Department of Endocrinology, Christchurch Hospital, Christchurch, and Departments of ¶Endocrinology and §Diabetes, Auckland Hospital, Auckland, New Zealand

Accepted 3 April 2003

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At surgery, despite an attempt to localize an insulinoma byintra-operative ultrasound, no insulinoma was detected, and atwo-thirds distal pancreatectomy was performed. In addition,a small ileal nodule was identified and resected.

The patient remained normoglycaemic post operatively.However, on the 9th post-operative day a capillary bloodglucose concentration of 2.1 mmol/ l was recorded. Despitepatient reluctance, a formal supervised fast was commencedbut was discontinued at 36 h because of co-morbidity associated

with recent abdominal surgery. The patient remained normo-glycaemic throughout the 36 h. She was discharged after beingeducated on blood glucose monitoring and management ofhypoglycaemia. Instructions were given to the patient andher husband to return to hospital if hypoglycaemia shouldrecur.

Histological examination of the resected pancreas revealedno evidence of insulinoma or beta cell hyperplasia, however,the ileal nodule had the appearances of a small endocrine

Table 1 Chronology of events

Day Event False prescriptionsa Comment

1 Glibenclamide 225 mg5 First admission—hypoglycemic coma Plasma venous glucose 1.9 mmol/l

Plasma insulin 105 pmol/ lb

Plasma C-peptide 1060 pmol/ lb

Plasma sulphonylurea screen negative 10 Discharged to care of spouse12 Glibenclamide 450 mg14 Second admission—hypoglycaemic coma16 Calcium stimulation test (see Fig. 1) Insulinoma suspected28 Subtotal pancreatectomy Normal histology (no insulinoma)35 Glibenclamide 600 mg36 Capillary BSL 2.1 mmol/ l37 36-h supervised fast Euglycaemic throughout39 Discharged to care of spouse43 Glibenclamide 400 mg45 Glibenclamide 600 mg46 Glibenclamide 600 mg48 Glibenclamide 600 mg

Metformin 102 g49 Glipizide 600 mg50 Glibenclamide 100 mg

Humalog 1000 unitsPlasma venous glucose 1.9 mmol/ l Glibenclamide and Glipizide present in same sample

51 Patient found dead 06.15 h Autopsy toxicology positive for Glibenclamide, Glipizide and Metformin

aOnly hypoglycaemic drugs are listed. Numerous other false scripts were written (commencing day −48) for a variety of sedatives, e.g. clonazepam, throughout the illness.bPlasma insulin > 36 pmol/ l and C-Peptide > 200 pmol/ l in the presence of hypoglycaemia (plasma glucose < 2.5 mmol/ l) is indicative of endogenous hyperinsulinemia [12].

Figure 1 Selective arterial calcium stimulation test. Positive result indicated by doubling of plasma insulin in the hepatic vein following calcium injection.

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tumour. Specimens were sent to a different institution forimmunocytochemical analysis and electron microscopy.

Ten days after discharge the husband reported symptomsthat were consistent with his wife having had a brief hypogly-caemic event, but had recovered. Advice was given to himthat she would require a plasma glucose level checked andmedical attention be sought if similar symptoms were to recur.The following day a venous blood sample was obtained byher husband that revealed a plasma glucose concentration of1.9 mmol/ l, however, no medical attention was sought. Thepatient died during the night 12 days after discharge. Atpost-mortem no insulinoma was identified in the remainingone-third of pancreas or extra-pancreatic tissues.

A chance remark by a colleague of the patient’s husbandprompted notification of the death to the coroner. Six monthslater, toxicology results from blood samples obtained atpost-mortem examination became available and revealed thepresence of Metformin, Glibenclamide and Glipizide. In addi-tion, the presence of Clonazepam and Citalopram was alsoidentified. Post-mortem stomach contents revealed the presenceof Glibenclamide, Glipizide and Citalopram. Further analysisof the blood sample obtained 1 day prior to her death alsocontained ‘therapeutic’ levels of Glibenclamide and Glipizide.

More detailed histological examination of both the surgicaland post-mortem pancreas was carried out by cutting a 5-

µ

msection from every 1-mm-thick section of archival tissue. Atotal of 450 pancreatic tissue sections were analysed and showedhistologic and immunohistochemical appearances of alpha-cellhyperplasia, consistent with sulphonylurea-induced changesas reported by Bloodworth [1], but none of the classicalfeatures of nesidioblastosis [2], NIPH [3] or insulinoma [4].Immunohistochemical analysis of the ileal nodule confirmed itto be a carcinoid lesion, which stained negatively for insulin.

On further investigation, it transpired that the originalsample for sulphonylurea screening was drawn 17 h after thefirst admission, albeit at a time when there was evidence ofon-going hypoglycaemia. In addition, further testing revealedthat the screening test undertaken by the reference toxicologylaboratory was insufficiently sensitive (detection limit > 175

µ

g / lfor Glibenclamide) to detect any but the highest serum levels ofsulphonylureas and has since been withdrawn from clinicalservice.

Detailed police investigation subsequently identified thatnumerous false prescriptions (amounting to more than3500 mg Glibenclamide) had been written by the patient’shusband in the name of various of his psychiatric patients(who were not diabetic and who did not pick up any of themedication). Dispensing of these prescriptions commencedjust before her first admission (see Table 1). The day prior toher death, the spouse had also written a false prescription for1000 units of Humalog insulin. Later, forensic studies identifiedGlibenclamide in washings taken from the domestic (kitchen)waste-disposal unit and from the kitchen mortar and pestle.

The spouse was subsequently indicted for murder and, basedon the above information and overwhelming circumstantial

evidence, was found guilty of his wife’s death by poisoningand sentenced to life imprisonment.

Discussion

This tragic case is exceptional for several reasons. Firstly, toour knowledge it is the first scientific report of the surreptitioususe of oral hypoglycaemic drugs employed (successfully) withmurderous intent. Secondly, the insulin responses to directpancreatic arterial injections of calcium were uniformlypositive, mimicking those reported in some cases of islet cellhypertrophy [3,5]. However only subtle changes such as alphacell hyperplasia, consistent with sulphonylurea administration— were found on exhaustive histological examination of thepancreas.

Surreptitious use of sulphonylureas and related drugs bythe individual is not rare. Indeed, as a cause of hypoglycaemicsyndromes associated with inappropriately raised levels of insulinand C-peptide, it may be half as common as insulinoma itself[6]. As noted by others [7], features suggestive of surreptitiousdrug use—including the abrupt onset of symptoms, failure toreproduce hypoglycaemia during a formal fast, and a closecontact working in the health care industry—were all evidentin the present case.

While increasingly important, separation of surreptitiousdrug usage from other syndromes of hyperinsulinaemichypoglycaemia has become more complex—particularly sincethe advent of a variety of potent sulphonylurea compoundsand other non-sulphonylurea drugs such as repaglinide [8].Further, the increasing reliance on the selective intra-arterialcalcium stimulation test to discriminate between the varioushypoglycaemic syndromes [9], including the recently describeddisorder of NIPH [3,10], calls for better knowledge and under-standing of how drugs such as sulphonylurea may affect theinsulin response to this test.

Sensitive assays of sulphonylurea or related drugs by alaboratory equipped to measure the very low concentrationsof all drugs potentially involved in hypoglycaemia [9] isessential for accurate diagnosis. Nonetheless, because drugtiming and dose are rarely known it is unlikely that all cases aredetected. Clearly, blood samples should be taken as early aspossible once hypoglycaemia is recognized, preferably inseveral of the same plasma samples exhibiting low glucoseand inappropriately raised levels of insulin and C-peptide.However because continued hypoglycaemia can occur evenafter the disappearance of sulphonylurea from the blood, somepatients will inevitably be classified as ‘drug negative’ evenusing the most sophisticated assay systems, and therefore mayproceed to further investigations such as the intra-arterialcalcium stimulation test.

The current report shows that, contrary to publishedaccounts, prior use of sulphonylurea (in this case Glibenclamide)can sensitize the beta cell response to injected calcium. Hirsh-berg [11] also reported a positive response (doubling of theinsulin concentration in the hepatic vein) after calcium

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injection into a single pancreatic arterial vessel (gastro-duodenal artery) in a patient later found to be taking an insulinsecretagogue (repaglinide). While details of dose and timingwere unknown in the case reported by Hirshberg, it is interest-ing to note that one blood sample was subsequently foundto be positive for the drug just prior to the start of specialistinvestigations undertaken at the National Institute of Health.While not a sulphonylurea drug, repaglinide is closely relatedto meglitinide, the non-sulphonylurea moiety of Glibencla-mide. Like the latter drug, it increases the sensitivity of the betacell to glucose by closing ATP-sensitive potassium channelsand allowing increased calcium influx into the beta cell.Although Hirshberg reported the insulin response from only asingle pancreatic arterial injection, these authors imply in thediscussion that generalized (as opposed to local) response tocalcium injection would be expected ‘as all islets are influenced’.To our knowledge, there is no controlled study of the effect ofcalcium on insulin secretion in normal subjects receivingsulphonylurea drugs. However Gero [12], in a study of 14subjects with Type 2 diabetes (11 controlled by diet alone),showed that an intravenous bolus of calcium significantlypotentiated the insulin response to acute Glibenclamideadministration. Increase in peripheral venous calcium in thisstudy (mean 14 mg%) was similar or lower than that expectedin samples obtained at the level of the islets during a directintra-arterial bolus injection of calcium as described by Dopp-man [13]. Taken together, the data strongly favours the viewthat sulphonylurea drugs have the potential to positively affectthe insulin response to selective pancreatic arterial calciuminjection. Previous reports on the action of sulphonylurea onthe intra-arterial calcium stimulation test are few [14] andhave suggested that a negative (flat) response occurs. Assum-ing that normal human beta cells do not respond to a bolus ofcalcium [15] (i.e. there is less than a doubling of insulinrelease), a negative (normal) response might be expected ifsubjects had not taken an insulin secretagogue for several ormore days prior to testing. For obvious reasons, such crucialinformation relating to dose and timing is rarely available insurreptitious drug usage. In the report from O’Shea [14]—outlining the history of a patient with Type 2 diabetes previouslytreated for 1 year with Glibenclamide—the drug was detectedduring a prolonged fast at a subsequent admission

after

anegative intra-arterial calcium stimulation test. Thus, there isno information on the use of the drug immediately prior to hercalcium stimulation test. In the present case, the patient hadbeen admitted in hypoglycaemic coma just 2 days before thecalcium injection test, and following a series of falsified scriptsfor Glibenclamide written by her spouse. The hyper-sensitizedstate of the beta cells was shown in all three arterial beds (Fig. 1)—in contrast to the more usual ‘patchy’ response reported inNIPH [10], or the focal response characteristic of insulinoma[13–15]. Although more data are needed, our experience sug-gests that such a global pancreatic insulin response shouldalert the physician to the possibility of recent (occult) use ofsulphonylurea in difficult cases.

Detailed histological examination of the pancreas provedlargely unhelpful in our case— except in excluding an insuli-noma, the initial clinical diagnosis. The previously reportedchanges in the pancreatic islets observed in NIPHS [3,10]were not seen either in the surgical or post-mortem material.Whether distinctive histological changes occur in normalhumans exposed to sulphonylurea drugs is largely unknown.Rayman [16] described profound hyperplasia (includingnesidioblastosis) in a subject taking chlorpropamide, but thesignificance of these findings has been questioned in the lightof a report showing nesidioblastosis in routine autopsy studiesof pancreatic tissue [17]. In early studies on dogs, Bloodworth[1] noted islet-cell hyperplasia at 2–3 weeks after startingadministration of sulphonylurea drugs, with a selective increasein alpha cells. Studies in subjects with Type 2 diabetes havebeen inconclusive. When a detailed re-examination of thepancreas was made in our case, significant increases in thenumber of islets (but not in size or variation in islet celldiameter) were found, when compared with those reported inthe normal pancreas. Furthermore, when selective islets wereexamined, the percentage of alpha cells was increased—unlikethe observations reported in NIPH [3,10]. While these findingsmust be regarded as anecdotal, they are similar to the observa-tions made by Bloodworth and are consistent with the periodicand recent exposure to sulphonylurea drugs as outlined.

Exactly how the drugs were administered was neverestablished in the present case. Glibenclamide is tasteless andodourless and readily miscible in beverages and foods. In viewof the massive quantities of drug available [Table 1], and thefindings of detectable amounts of Glibenclamide in washingstaken from domestic appliances, it is likely that sufficientquantities of this highly potent hypoglycemic drug were con-cealed in food and/or drinks prepared by the husband for hiswife’s ingestion.

Surreptitious use of sulphonylurea drugs has often occurredin the clinical setting of an unusual affect or personal historyof disturbed behaviour or psychiatric disorder. A bizarre twistof the current case is that these features, while not present inthe patient and victim, were all too obvious in her spouse—ensuring a fatal outcome.

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