Approach to a Case of Hypoglycaemia

Transcription

1 POSTGRADUATE CLINIC JIACM 2007; 8(1): Approach to a Case of Hypoglycaemia AK Agarwal*, Sumeet Singla**, Nitin Agarwal***, Ashok Kumar****, Arun Jain***** Case 1 Mrs. K, a 45-year-old housewife, presented to the emergency room with history of brief episodes of loss of consciousness since last one year. (She was having one such episode at presentation). She was apparently well a year ago, when she started having brief episodes of loss of consciousness, from which she would recover after being given sweet drinks. Upon regaining consciousness, she was fully oriented, had normal behaviour, no weakness or loss of memory. She had no history of abdominal pain, jaundice, obstipation, diarrhoea, abdominal lumps, breathlessness, flushing, swelling in the neck, weight loss, bowel or bladder complaints, or fever. There was no history of any major medical, surgical, or psychiatric illnesses in the past. She was being treated for her symptoms with fluoxetine and haloperidol. There were no major medical or psychiatric illnesses in the family. Examination revealed an average built, well-nourished woman; she was drowsy, but responsive to verbal commands. A complete general physical examination and thorough systemic examination did not reveal any abnormal findings. The only abnormal result among the emergency investigations (which included a CT scan of the brain) was a blood sugar of 19 mg/dl. She was infused 50% dextrose, which resulted in immediate and complete recovery. A provisional diagnosis of recurrent hypoglycaemia was entertained and she was subjected to a fasting test. After fasting for 24 hours, she had a capillary blood glucose value of 44 mg/dl and was drowsy. At that time her plasma beta-cell polypeptide profile was as follows: Insulin (RIA) 41.8 µu/ml, C-peptide (ICMA) 1,200 pmol/l. This profile was highly suggestive of endogenous hyperinsulinaemia Fig. 1: MRI of abdomen showing multiple SOLs in liver. caused by an islet-cell tumour, i.e., an insulinoma. Radiological investigations (USG abdomen/cect abdomen/cemr abdomen) were suggestive of multiple SOLs in the liver, most likely secondaries, but the pancreas and other intra-abdominal and retroperitoneal structures were normal (Fig. 1). An USG-guided biopsy from one of the SOLs revealed liver tissue infiltrated by sheets of small, round, monomorphic cells with a high nucleo-cytoplasmic ratio. Immunohistochemical staining of the tumour cells was positive for synaptophysin (Figs. 2, 3). This was confirmatory evidence of the presence of an insulinoma. Investigations to localise the primary tumour (endoscopic ultrasound, somatostatin receptor scintigraphy, measurement of hormonal gradients after intra-arterial calcium injection, angiography) could not be performed. The final diagnosis was endogenous hyperinsulinaemia caused by a malignant metastatic insulinoma, possibly compounded by drugs (haloperidol and fluoxetine). * Consultant, Professor and Head, **** Senior Physician and Associate Professor, ***** Senior Physician and Professor, Department of Medicine, Dr. Ram Manohar Lohia Hospital, New Delhi ** Senior Resident, Department of Medicine, LN Hospital and Maulana Azad Medical College (MAMC), New Delhi , (Ex-Senior Resident in Medicine, Dr. Ram Manohar Lohia Hospital, New Delhi ). *** Senior Resident, Department of Surgery, All India Institute of Medical Sciences (AIIMS), Ansari Nagar, New Delhi

2 However, the patient died within 1 week of the operation. Case 2 Fig. 2: H and E staining of tissue from liver SOL showing sheets of small, round, monomorphic cells. Mrs SK, a known case of type 2 diabetes since the last 15 years (on oral hypoglycaemic agents), presented with recurrent symptoms of hypoglycaemia. The dose of her OHAs was adjusted downwards, but she continued to have these episodes, and her daily requirement of OHAs progressively decreased. She was investigated for the cause of hypoglycaemia. At the end of a fasting test, her plasma beta-cell polypeptide profile was as follows: Insulin (RIA) 17.8 µu/ml, C-peptide (ICMA) 500 pmol/l. Plasma sulphonylurea levels were not estimated. Plasma IGF-I levels were 63 ng/ml (normal 64 to 188 ng/ml). Plasma IGF- Fig. 3: Tumour tissue showing positive immunohistochemical staining with synaptophysin (brown areas). During the hospital stay she was administered dextrose infusion round-the-clock alongwith frequent oral glucose intake and a corn meal at bedtime. She did not have another episode of unconsciousness while in the hospital. In view of the metastatic insulinoma without an obvious primary tumour (which precludes surgical resection) and lack of affordability of any diagnostic or therapeutic modality, she was prescribed phenytoin 100 mg TDS. Despite our best efforts, diazoxide was found to be unavailable. The patient remained stable with the above treatment for approximately one year. Thereafter she deteriorated and was admitted at AIIMS, Department of Surgery. Evaluation at AIIMS revealed the presence of a primary tumour (size 5 cm x 6 cm) in the distal pancreas. Distal pancreatectomy was performed with the aim that the secondaries would regress after the resection. Fig. 4: CT scan of abdomen (transverse view) showing renal tumour. Fig. 5: CT scan of abdomen (sagittal view) showing renal tumour arising from the upper pole of the kidney. Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March,

3 II levels were not estimated. This profile was highly suggestive of endogenous hyperinsulinaemia. Radiological investigations (USG abdomen/cect abdomen) revealed a hypernephroma of the right kidney (Figs. 4, 5). She underwent right-sided radical nephrectomy; histopathology confirmed the presence of renal cell carcinoma. After the nephrectomy, she has not suffered any further episodes of hypoglycaemia and remains well. Q. 1. How will you confirm hypoglycaemia as the cause of the patient s symptoms? Hypoglycaemia is suspected because of a history of suggestive symptoms. But the symptoms are nonspecific, and a normal plasma glucose concentration measured when the patient is free of those symptoms does not exclude the possibility of hypoglycaemia. The symptoms and signs of hypoglycaemia are nonspecific, vary among individuals, and may change from time to time in the same individual. They are also typically episodic. The diagnosis of hypoglycaemia should not be made solely on the basis of plasma glucose measurements unless they are unequivocally subnormal. There are many pitfalls in diagnosing hypoglycaemia on the basis of a plasma glucose concentration alone: It is not possible to define a plasma glucose concentration below which neuroglycopenia invariably occurs, and above which it never occurs; symptoms can occur at higher plasma glucose levels in poorly controlled diabetics and only at lower levels in wellcontrolled diabetics (re-setting of the glucosensor in the ventromedial hypothalamus) 2. Young, lean, healthy women (sometimes young, healthy men also) may have plasma glucose levels of 40 mg/dl or even lower after overnight fasting without producing recognisable symptoms 2. Some patients with endogenous hyperinsulinism or intensively treated diabetes can tolerate glucose levels that are very low. These patients can have hypoglycaemic symptoms at other times (when their plasma glucose levels are even lower), and a diagnosis of hypoglycaemia should not be ruled out just because they were asymptomatic during the period of the very low plasma glucose levels. Pseudohypoglycaemia: erroneously low plasma glucose concentrations can result from glycolysis in vitro, particularly in the presence of leukocytosis or polycythaemia, or both, or if separation of plasma from the formed elements of the blood is delayed. A normal plasma glucose level reliably obtained* during the occurrence of spontaneous symptoms eliminates the possibility of a hypoglycaemic disorder; no further evaluation is necessary. Normoglycaemia during symptoms cannot be ascribed to spontaneous recovery from hypoglycaemia. Rather, the symptoms ease before euglycaemia is achieved. The Whipple s triad provides confirmatory evidence of hypoglycaemia: symptoms consistent with hypoglycaemia, a low plasma glucose concentration at the time that symptoms occur, and relief of those symptoms when the plasma glucose concentration is raised 3. This can be accomplished by measuring plasma glucose concentration and then administering glucose if the patient is seen while symptomatic. Often the measurement of plasma glucose level is not feasible when spontaneous symptoms occur during activities of ordinary life. Under these circumstances, the physician must decide to proceed with further evaluation, depending on the history. A history of neuroglycopenic symptoms or a confirmed low (< 50 mg/dl) plasma glucose level warrants further testing, i.e., the prolonged (72-hour) fast. * Performed by someone other than the patient, if using the reflectance glucometer; by drawing venous blood from forearm (prior to administration of glucose), if performed during hospitalisation. Q. 2. How is the prolonged (72-hour) fast performed? The prolonged (72-hour) fast is the classic diagnostic test for hypoglycaemia. It may be conducted for different purposes, i.e., to establish that hypoglycaemia is the basis for the patient s symptoms, or to establish the mechanism for the hypoglycaemia 1. The patient should be admitted to the hospital prior to conducting this test. When it is performed to establish hypoglycaemia, the Whipple s triad must be demonstrated. In this situation the fast should be terminated. 14 Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March, 2007

4 Prior to 72 hours, when a patient has both symptoms of hypoglycaemia and a plasma glucose level in the hypoglycaemic range (< 50 mg/dl) - test is positive (in general, plasma venous glucose concentrations greater than 70 mg/dl after an overnight fast are normal, those between 50 and 70 mg/dl are suggestive of hypoglycaemia and those less than 50 mg/dl indicate post-absorptive/ fasting hypoglycaemia). At 72 hours, when a patient has both symptoms of hypoglycaemia and a plasma glucose level less than 50 mg/dl test is positive. At 72 hours, if the patient has neither symptoms nor signs of hypoglycaemia test is negative. At 72 hours, if the plasma glucose concentration does not fall below 50 mg/dl test is negative The test was terminated within 12 hours in 35% of patients with insulinoma, within 24 hours in 75%, and within 48 hours in 92%. No patient with a negative result at 72 hours had a change to a positive result by extending the fast to 96 hours 1. When Whipple s triad has previously been documented (during previous investigations), the fast is performed to establish the mechanism for the hypoglycaemia. In this case the beta-cell polypeptides (insulin, pro-insulin, C-peptide), and plasma sulphonylureas are measured at the end of the fast. The fast should be terminated when the plasma glucose is 55 mg/dl or less, because beta-cell polypeptides can be expected to be suppressed at this plasma glucose level and sulphonylureas absent from the plasma (unless that drug is the cause of hypoglycaemia). Both the above goals can be achieved in one test, sequentially. First, establish the presence of low plasma glucose concentrations alongwith symptoms of hypoglycaemia at the end of the test; at the same instance draw blood to measure the beta-cell polypeptides and sulphonylureas; and finally administer glucose to confirm recovery from the symptoms of hypoglycaemia, thus completing Whipple s triad. There is absolutely no need to perform the test twice (once to establish hypoglycaemia, and the second time to establish the mechanism of hypoglycaemia), except when Whipple s triad was demonstrated during previous investigations. A suggested protocol is given in Table I 1. Table I: Protocol for prolonged supervised fast Date the onset of the fast as of the last ingestion of calories. Discontinue all non-essential medications. 2. Allow the patient to drink calorie-free and caffeinefree beverages. 3. Ensure that the patient is active during waking hours. 4. Measure plasma glucose, insulin, C-peptide, and, if an assay is available, pro-insulin in the same specimen. Repeat measurements every 6 hours until the plasma glucose is < 60 mg/dl, when the interval should be reduced to every 1 to 2 hours. 5. End the fast when the plasma glucose is < 45 mg/dl and the patient has symptoms, signs, or both of hypoglycaemia. 6. At the end of the fast, measure plasma glucose, insulin, C-peptide, pro-insulin, β-hydroxybutyrate, and sulphonylurea in the same specimen, then inject 1 mg of glucagon intravenously and measure plasma glucose after 10, 20, and 30 minutes. Feed the patient. 7. When a deficiency is suspected, measure plasma cortisol, growth hormone, or glucagon at the beginning and end of the fast. At the end of the fast, two insulin surrogates are to be measured. The first is plasma beta-hydroxybutyrate level, and the second is response of plasma glucose to intravenous injection of 1 mg glucagon. The clinical relevance and interpretation of their measurements are discussed below. A few caveats to be kept in mind while interpreting this test are 1 : Careful examination and testing for subtle signs or symptoms of hypoglycaemia should be conducted repeatedly when the patient s plasma glucose level is near or in the hypoglycaemic range. It is imperative that both a plasma glucose concentration in the hypoglycaemic range and symptoms or signs of hypoglycaemia should be demonstrated to label the test as positive. The test should not be considered positive solely on the basis of low plasma glucose concentrations if the symptoms or signs of hypoglycaemia are absent (either because Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March,

5 the symptoms or signs were not looked for or not looked for carefully enough). This is because normal persons with low plasma glucose concentrations may have no apparent symptoms or signs, while patients with hypoglycaemic disorders will have some subtle symptoms or signs of hypoglycaemia that are likely to be missed if not looked for carefully. Hence, many normal people would be inappropriately labelled as patients of hypoglycaemic disorders and subjected to unnecessary investigations. It is equally imperative that the test should not be considered negative on the basis that there are no signs or symptoms of hypoglycaemia at the time of low plasma glucose concentrations. It is essential to monitor patients closely during the fast and be vigilant for subtle signs of neuroglycopenia. Also, earlier detection of subtle signs or symptoms of hypoglycaemia will allow for early termination of the fast and save the patient from any further inconvenience. Q. 3. How does the prolonged (72-hour) fast help in elucidating the underlying mechanism for hypoglycaemia? The mechanism for the hypoglycaemia in a particular patient can be deduced by an interpretation of the concentrations of the beta-cell polypeptides, sulphonylureas, and the insulin surrogates. The plasma insulin, pro-insulin, C-peptide, sulphonylurea, and insulin surrogate patterns in the various hypoglycaemic disorders are shown in Table II 1. The test is based on the logic that in normal persons there is a direct correlation between the plasma levels of glucose and the beta-cell polypeptides (insulin, pro-insulin, C- peptide). Under conditions of fasting, as the plasma glucose levels drop, the secretion of insulin from the pancreas also drops and the level of plasma insulin decreases; i.e., it is suppressed. The critical pathophysiologic feature of endogenous hyperinsulinism is failure of suppression of insulin secretion: assessed by plasma insulin, pro-insulin, and C-peptide levels to fall very low during hypoglycaemia. Insulin, pro-insulin, and C-peptide levels need not be high in the absolute (i.e., relative to euglycaemic, post-absorptive norms), but only inappropriately high during post-absorptive hypoglycaemia. This diagnostic concept of relative hyperinsulinaemia is fundamentally important. i. Plasma insulin: When a radioimmunoassay (RIA) for insulin with a sensitivity of 5 µu/ml is used, insulinmediated hypoglycaemic disorders (hyperinsulinaemic hypoglycaemia) are characterised by plasma insulin concentrations of 6 µu/ml or higher during fasting. Persons with non-insulin-mediated hypoglycaemic disorders (hypoinsulinaemic hypoglycaemia) and normal persons have insulin concentrations of 5 µu/ml or less during fasting. If an immuno-chemiluminometric (ICMA) assay is used to measure plasma insulin, the criterion for hyperinsulinaemia is a level of 3 µu/ml or higher. Patients with insulinoma have insulin concentrations on RIA that rarely exceed 100 µu/ml. Values of 1,000 µu/ml or greater suggest recent insulin administration (exogenous Table II: Diagnostic interpretation of the results of a 72-hour fast 1. Diagnostic interpretation Symptoms Glucose Insulin C-peptide Pro-insulin β-hydroxybutyrate Change in Sulphonylurea orsigns (mg/dl) (µu/ml) (pmol/l) (pmol/l) (mmol/l) glucose(mg/dl) in plasma Normal No 40 < 6 <0.2 > 5 >2.7 < 25 No Insulinoma Yes No Factitioushypoglycaemia frominsulin Yes 45 6 <0.2 > No Sulphonylurea-induced hypoglycaemia Yes Yes Hypoglycaemiamediatedby insulin-likegrowthfactor Yes 45 6 <0.2 < No Non-insulin-mediated hypoglycaemia Yes 45 < 6 <0.2 <5 >2.7 < 25 No Inadvertentfeeding duringthefast No 45 < 6 <0.2 < No Non-hypoglycaemicdisorder Yes 40 < 6 <0.2 < 5 >2.7 < 25 No 16 Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March, 2007

6 hyperinsulinism) or the presence of insulin antibodies. Some authors advocate the use of glucose-to-insulin ratios to help in identifying relative hyperinsulinaemia when the plasma insulin level after an overnight fast are in the normal range. However, a diagnosis based on absolute values is far more accurate. i. Plasma pro-insulin: For many years, a pro-insulin assay was not available. Now, with the availability of the ICMA assay for pro-insulin, it s concentration can be reliably measured in any patient undergoing evaluation for hypoglycaemia. Invariably, it s concentration mirrors that of other beta-cell polypeptides, especially C-peptide. A level higher than 5 pmol/l (ICMA) or greater is diagnostic of hyperinsulinism. Plasma pro-insulin levels are disproportionately high in patients with insulinoma and sulphonylurea-induced hypoglycaemia, while they are low in exogenous hyperinsulinism. i. Plasma C-peptide: Plasma C-peptide levels are low in exogenous hyperinsulinism, whether it is therapeutic, (insulin induced), surreptitious, or malicious. C-peptide levels are high in insulinoma and sulphonylureainduced hypoglycaemia. A level higher than 200 pmol/ l (ICMA) or greater is diagnostic of hyperinsulinism. iv. Plasma sulphonylureas: Sulphonylureas produce glucose, insulin, and C-peptide patterns indistinguishable from those produced by insulinoma; but in this case sulphonylureas can be measured in the plasma. v. Plasma beta-hydroxybutyrate: This is an insulin surrogate measured at the end of the fast. Patients with hyperinsulinaemic hypoglycaemia have plasma concentrations less than 2.7 mmol/l, whereas normal individuals and those with hypoinsulinaemic hypoglycaemia have higher levels. This is because insulin is antiketogenic, and the plasma levels of insulin and beta-hydroxybutyrate are inversely proportional. vi. Plasma glucose response to glucagon 2 : This is also an insulin surrogate. At the end of the fast, 1 mg of glucagon is injected intravenously, and the plasma glucose response is measured serially at 10, 20, and 30 minutes. Patients with hyperinsulinaemic hypoglycaemia have an increment of 25 mg/dl or greater above the terminal fasting glucose, whereas normal individuals and those with hypoinsulinaemic hypoglycaemia have lower increments. The rationale behind this test is that insulin is glycogenic and antiglycogenolytic, and glucagon has the opposite actions, i.e., it is glycogenolytic and antiglycogenic. Hence, when glucagon is administered to patients with hyperinsulinaemic hypoglycaemia (in whom glucogenesis is suppressed by insulin) glucogenesis is stimulated and the plasma glucose levels rise. On the other hand, in patients with hypoinsulinaemic hypoglycaemia, there is no suppression of glucogenesis and hence administration of glucagon does not produce a significant rise in plasma glucose levels. Q. 4. What are the causes of hypoglycaemia? Once the diagnosis of hypoglycaemia has been confirmed as above, it is pertinent to think of the causes of hypoglycaemia to guide further investigations and arrive at the cause of hypoglycaemia in a particular patient. A practical approach to the classification of hypoglycaemia, based on clinical characteristics, is shown in Table III 1. Table III: Clinical classification of hypoglycaemia 1. Patient appears healthy No co-existent disease Drugs Ethanol Salicylates Quinine Haloperidol Insulinoma Islet hyperplasia/nesidioblastosis Persistent hyperinsulinaemic hypoglycaemia of infancy Non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) # Factitial hypoglycaemia from insulin or sulphonylureas Severe exercise Ketotic hypoglycaemia Compensated co-existent disease Drugs Dispensing error Disopyramide Beta-adrenergic blocking agent Sulphhydryl or thiol-containing drugs with Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March,

7 Patient appears ill autoimmune insulin syndrome Unripe ackee (Blighia sapida) fruit (N. B.: This African fruit is poisonous when unripe); and under nutrition Drugs Pentamidine and Pneumocystis carinii pneumonia Sulphamethoxazole and trimethoprim and renal failure Propoxyphene and renal failure Quinine and cerebral malaria Topical salicylates and renal failure Predisposing illness Small for gestational age infant Beckwith-Wiedemann syndrome Erythroblastosis foetalis Infant of diabetic mother Glycogen storage disease Defects in amino acid and fatty acid metabolism Reye s syndrome Cyanotic congenital heart disease Hypopituitarism Isolated growth hormone deficiency Isolated adrenocorticotrophic hormone (ACTH) deficiency Addison s disease Galactosaemia # Hereditary fructose intolerance # Carnitine deficiency Defective type 1 glucose transporter in brain Acquired severe liver disease Large non-beta cell tumour Sepsis Renal failure Congestive heart failure Lactic acidosis Starvation Anorexia nervosa Postoperative removal of phaeochromocytoma Insulin receptor antibody hypoglycaemia Hospitalised patient Diseases predisposing to hypoglycaemia Total parenteral nutrition and insulin therapy Shock Questran (cholestyramine) interference with glucocorticoid absorption # These disease states cause post-prandial hypoglycaemia. Q. 5. What is tumour-induced hypoglycaemia, and what are it s clinical correlates? Patients with certain types of tumours may suffer from hypoglycaemia. Among the causes of hypoglycaemia in cancer patients are secretion of insulin/insulin-like substances by the tumour cells, excessive glucose utilisation by tumour cells, failure of counter-regulatory hormone production, and marked anorexia 4. Tumours causing hypoglycaemia are broadly divided into two categories: i. Islet cell (beta-cell) tumours: Insulinomas are tumours of the beta-cells of the pancreas, hence they secrete insulin independent of plasma glucose levels, i.e., the secretion of insulin is not suppressed by low plasma glucose levels. Insulinomas arise within the substance of the pancreas in > 99% of cases and are usually small (1 to 2 cm). i. Non-islet cell (non-beta-cell) tumours: Non-islet cell tumours associated with hypoglycaemia are given in Table IV 5. Ectopic production of IGF-II (specifically an incompletely processed form [ big IGF-II ] that does not complex normally with circulating binding proteins and thus readily gains access to the target tissues) by these tumours is responsible for hypoglycaemia in most patients 8. IGF-II, acting on the insulin or IGF-I receptors, inhibits gluconeogenesis and glycogenolysis in the liver, suppresses lipolysis and increases peripheral utilisation of glucose, thereby causing hypoglycaemia. The commonest cause of hypoglycaemia is undoubtedly the overproduction of an aberrant form of IGF-II. There are, however, other rare causes such as production of insulin by the tumour, autoantibodies to the insulin receptor, overwhelming metastatic destruction of the liver and the production of tumour necrosis factor (TNF) and other hypoglycaemic cytokines 7. The tumour may come to light because of the hypoglycaemic spells, rather than the mass effects. The tumour itself may be diagnosed by appropriate radiological and histopathological investigations. That the tumour is the cause of the hypoglycaemia is suggested by low plasma insulin, pro-insulin and C- 18 Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March, 2007

8 peptide levels at the end of the prolonged fasting test. Further evidence for tumour-induced hypoglycaemia is found in raised plasma IGF-II levels and an elevated plasma IGF-II to IGF-I ratio. Table IV: Non-islet cell tumours associated with hypoglycaemia. Mesenchymal Mesothelioma Fibrosarcoma Rhabdomyosarcoma Leiomyosarcoma Haemangiopericytoma Epithelial Hepatic: hepatoma, biliary carcinoma Adrenocortical carcinoma Genitourinary: hypernephroma, Wilms tumour, prostate malignancy Reproductive: cervical or breast carcinoma Neurologic/neuroendocrine Phaeochromocytoma Carcinoid Neurofibroma Haematologic Leukaemia Lymphoma Myeloma Q. 6. What is the diagnostic approach for a case of hypoglycaemia? The diagnosis of a hypoglycaemic disorder requires a high level of suspicion, careful assessment of the patient for the presence of mediating drugs or predisposing illness, and, when indicated, methodic evaluation on the basis of welldefined diagnostic criteria. A step-wise approach is given below: 1. Before undertaking a series of investigations, the possibility of pseudohypoglycaemia must be excluded. 2. It is important to distinguish post-absorptive (fasting) hypoglycaemia from post-prandial (reactive, stimulative) hypoglycaemia 1, because hypoglycaemia in the post-absorptive state usually implies the presence of serious underlying disease and requires diagnostic work-up and therapy. In contrast, post-prandial hypoglycaemia usually does not imply a serious underlying disorder. A history of neuroglycopenic symptoms occurring exclusively after meals (typically within 4 hours), a history of prior gastric surgery and documentation of neuroglycopenic symptoms temporally related to a low plasma glucose concentration after a mixed meal and the relief of those symptoms as the plasma glucose concentration is raised are strongly suggestive of post-prandial hypoglycaemia. 3. Drugs are the most common cause of hypoglycaemia. The drugs implicated include those used to treat diabetes mellitus and others (Table V). Knowledge of the other drugs known to cause hypoglycaemia and a thorough history of the drugs the patient is/was consuming is the next important step in the evaluation of a patient. The possibilities of accidental use, malicious administration, prescription error, dispensing error, and wrong self-administration of drugs by the patient should be explored thoroughly. A history of a family member who is a diabetic, raises the possibility of factitious hypoglycaemia in the patient. Table V: Drugs associated with hypoglycaemia. A. Established hypoglycaemia-causing drugs Aspirin Quinine Insulin Quinidine Metformin Sulphonamides Pentamidine Sulphonylureas and other insulin secretagogues B. Putative hypoglycaemia-causing drugs ACE inhibitors Indomethacin Acetazolamide Isoniazid Benzodiazepines Imipramine Colchicine Lithium Chlorpromazine Lidocaine Chloroquine Mefloquine Chloramphenicol Metoprolol Ciprofloxacin Para-aminosalicylic acid Dicoumarol Paracetamol Ethionamide Propranolol Fluoxetine Ranitidine Furosemide Warfarin Haloperidol Halothane 4. The diagnostic approach for a healthy-appearing patient with episodes of neuroglycopenia is different from that for an ill-appearing patient. The healthy- Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March,

9 appearing adult patient usually has a hyperinsulinaemic hypoglycaemic disorder. The differential diagnoses in such a patient (after excluding drugs as the cause) include insulinoma, NIPHS, and insulin autoimmune hypoglycaemia. The relative frequency of these conditions is not known with any degree of accuracy. Of the 225 cases of hyperinsulinaemic hypoglycaemia seen at the Mayo Clinic over a 25-year period, 216 had insulinoma, 7 had NIPHS, and 2 had insulin autoimmune syndrome. A suggested diagnostic algorithm is shown in Fig In ill-appearing patients, it is sufficient to recognise the underlying disease and it s association with hypoglycaemia, and then to take action to minimise the recurrences of hypoglycaemia. Relevant critical illness, features suggestive of growth hormone or cortisol deficiency, inherited enzyme deficiencies, or features of a non-beta-cell tumour should be sought. 6. Hospitalised patients are often severely ill with multisystem disease. They are at risk for iatrogenic hypoglycaemia as well as for any hypoglycaemia that may be produced by the underlying disease. In determining the cause of hypoglycaemia in a hospitalised patient, a diligent examination of the medical record may be more fruitful than examination of the patient! Suspected hypoglycaemia Drug-treated diabetes mellitus Adjust regimen Document improvement Clinical clues to a hypoglycaemic disorder Document fasting hypoglycaemia (Whipple s triad) with low insulin No diabetes mellitus (or diabetes not drug-treated) Clinically healthy Fasting plasma glucose < 50 mg/dl mg/dl > 70 mg/dl Identify and treat the specific hypoglycaemic disorder Fast upto 72 hours Strong history Weak history Insulin, C-peptide Symptoms, glucose, insulin, C-peptide, Sulphonylurea (insulin antibody) < 50 mg/dl > 50 mg/dl Fasting hypoglycaemia excluded Sulphonylurea negative, insulin antibody negative Insulin, C-peptide Insulin, Sulphonylurea positive Insulin antibody positive C-peptide (± Exclude insulin receptor antibody, -cell antibody) Whipple s triad Gl surgery, strong history Mixed meal No Whipple s triad No Gl surgery, weak history Insulinoma Sulphonylurea ingestion Autoimmune hypoglycaemia Exogenous insulin Reactive hypoglycaemia Hypoglycaemia excluded Fig. 6: Diagnostic algorithm for a hypoglycaemic disorder. 20 Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March, 2007

10 Discussion Case 1 This lady was diagnosed following the approach outlined above, as a case of endogenous hyperinsulinaemia caused by a malignant insulinoma. The absence of an obvious primary in the pancreas was more a result of incomplete investigations at the outset than due to a truly extrapancreatic insulinoma (< 1% of insulinomas are extrapancreatic). In this respect, as in the relative infrequency of their malignancy (only 5 to 10% of insulinomas are malignant), insulinomas differ from other hormoneproducing tumours of the gastrointestinal tract. Almost every localisation technique has been advocated as a pre-operative aid to surgical removal of insulinomas, but none withstands critical survey. CT scan and MRI can localise only about 25 to 30% of the insulinomas in the pancreas. Somatostatin receptor scintigraphy, though very good for localising gastrinomas (86% positive), is no better than any other for localising insulinomas pre-operatively (positive in 12 to 50%). It is quite clear that no pre-operative localising technique including endoscopic ultrasonography, (positive in 77 to 93% of insulinomas) and measuring venous insulin gradients after intra-arterial infusion of calcium gluconate (positive in 80 to 100% of insulinomas) currently available is sufficiently reliable to make a diagnosis of insulinoma if the biochemical findings are negative, nor to justify delay in operating if they fail to localise a tumour, proven biochemically to be present. In contrast to pre-operative localisation, intra-operative ultrasonography has proved to be extremely useful by enabling even experienced surgeons to localise tumours that their unaided fingers have missed. Clinically significant insulinomas are generally between 10 and 20 mm in diameter at the time of diagnosis, although tumours as large as 150 mm or as small as 5 mm in diameter have been found during surgery. Occasionally, very small tumours are overlooked at operation, and are found only after very thorough histopathological examination of the resected pancreas, or not at all. In fewer than 5% of cases of true hyperinsulinaemic hypoglycaemia can no tumour be found. Whilst some of these may be due to a small tumour being overlooked either at operation or at autopsy, others are due to a functional abnormality of the beta-cells which manifests histologically as islet-cell hyperplasia (nesidioblastosis). The inability to provide a specific treatment for this patient s malignant insulinoma (due to financial and logistic constraints) was partially offset by two facts. First, provided hypoglycaemia can be prevented, good quality of life with survival (for 10 years or more) can occur, since these tumours though malignant are often very slow growing and do not produce the typical features of metastatic disease such as anorexia, nausea, and loss of body weight until late in the course of the disease. Second, palliative antihypoglycaemic therapy was provided by the use of phenytoin (diazoxide is the drug of choice, but is currently not available in India). Other drugs used to palliate hypoglycaemia include verapamil, diltiazem, octreotide, propranolol, glucocorticoids, and glucagon. Case 2 This case illustrates the importance of a stepwise approach in the diagnosis of the aetiology of hypoglycaemia. A diabetic having hypoglycaemic spells should be managed by adjusting the drug regimen. In this case, this action did not relieve her hypoglycaemic symptoms. A fasting test revealed a profile suggestive of endogenous hyperinsulinaemia. A plasma sulphonylurea level is a must in such a case, because an identical plasma beta-cell polypeptide profile can be produced by insulinoma and sulphonylurea-induced hypoglycaemia; the only discriminating feature being the presence of sulphonylureas in plasma in the latter condition. The second important aspect to consider in this case was the right-sided hypernephroma. Extrapancreatic tumours can produce hypoglycaemia (non-islet-cell or non-beta-cell tumour hypoglycaemia). The mechanisms and diagnosis of non-islet-cell tumour hypoglycaemia (NICTH) is explained above. A raised plasma IGF-II to IGF-I ratio would have helped to comment on whether the hypernephroma was the cause of hypoglycaemia. NICTH is almost always produced by tumours elaborating IGF-II. Very rarely, NICTH may be caused by tumours elaborating insulin (which would produce the plasma beta-cell polypeptide pattern, as in this case). However, it must be demonstrated unequivocally that: (i) the tumour cells contain insulin (by detection of pro-insulin messenger-rna in the tumour by in fluorescent in-situ hybridisation and positive staining of tumour cells with antiinsulin serum); (ii) the pancreas does not harbour an insulinoma (by highly sensitive diagnostic techniques); and Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March,

11 (iii) the plasma insulin decreases to normal levels after removal of the tumour. In the absence of many important clues in this case, it may be difficult to pinpoint the underlying cause of hypoglycaemia. The most likely diagnosis is a sulphonylureainduced hypoglycaemia, possibly compounded by the hypoglycaemic effects of the hypernephroma (as indirectly evidenced by the return of euglycaemia after tumour removal and consequently increased OHA and insulin requirement). Learning points 1. Hypoglycaemia is most commonly seen in the setting of a diabetic patient. 2. The most common cause of hypoglycaemia is drugs. Hence, a thorough history, especially a detailed drug history, and family history of diabetes should be elicited. 3. Insulin and particularly sulphonylureas are possible causative agents even when there is no history of diabetes, because these may be consumed surreptitiously, administered with criminal intent, or taken as the result of prescription/pharmacist error. 4. Laboratory errors in the measurement of plasma glucose (pseudohypoglycaemia) and pseudohyperglycaemia (artefactually raised plasma glucose levels, if blood is drawn from a vein into which a glucose containing fluid is being infused) should always be considered. 5. Most healthy adults with post-absorptive hypoglycaemia have endogenous hyperinsulinism. corrected. 9. Sulphonylurea-induced hypoglycaemia may recur after hours or days (owing to the long half-life of these drugs). Hence, careful monitoring and glucose replenishment must be continued along with complete cessation of drug intake. 10. Insulinomas may present as part of the multiple endocrine neoplasia (MEN) syndrome type 1. A careful search for other components of the MEN-1 syndrome should be undertaken in all patients of insulinoma. References 1. Service FJ. Hypoglycaemic disorders. In: Service FJ (ed). Endocrinol Metab Clin N Amer. Philadelphia, Saunders. 28 (3); Sep Cryer PE. Hypoglycaemic disorders. In: Larsen PR, Kronenberg HM, Shlomo M et al (eds). Williams Textbook of Endocrinology. Philadelphia, Saunders. 2003; pp Cryer PE. Hypoglycaemia. In: Braunwald E et al (eds). Harrison s Principles of Internal Medicine, New York, McGraw Hill. 2001; pp Dyer PH, Chowdhury TA, Milles J. Recurrent hypoglycaemia. Postgrad Med J 1998; 74 (871): Teale JD. Non-islet cell tumour hypoglycaemia. Clin Endocrinol 1999; 51: Teale JD, Marks V. Tumours producing hypoglycaemia. Endocr Rel Cancer 1998; 5: Seckl MJ, Mulholland PJ, Bishop AE et al. Hypoglycaemia due to an insulin-secreting carcinoma of the cervix. New Engl J Med 1999; 341 (10): Roith DL. Tumour-induced hypoglycaemia. New Engl J Med 1999; 341 (10): Hypoglycaemia in ill-appearing/hospitalised patients is due to the underlying disease or the drugs being used to treat the disease. 7. Apart from the other causes of hypoglycaemia (which are easily treatable), 90 to 95% of insulinomas are benign when detected, and resectable. Hence, aggressive attempts at diagnosis and localisation should be made in all cases of endogenous hyperinsulinism caused by an insulinoma. 8. A patient may have more than one cause of hypoglycaemia; all of these must be sought and ACKNOWLEDGEMENT Dr. Ajay Kumar has contributed a sum of Rs. 25,000/- to JIACM, out of the savings of the Annual Conference of IACM held at Patna in The Editorial Board of the Journal is extremely grateful to him for this kind gesture. Editors 22 Journal, Indian Academy of Clinical Medicine Vol. 8, No. 1 January-March, 2007