Case Discussion <Case Presentation> A 29-year-old pharmacist experienced severe diaphoresis, hand tremor, chest pain, dizziness, and shortness of breath in the early morning about 4 days prior to his admission. He could not even recognize his elder brother at that time and was taken to hospital where hypoglycemia was noted (blood glucose 20 mg/dl). The symptoms relieved after intravenous dextrose water administration. Another episode occurred 2 days later. He was then admitted to our hospital for further evaluation of the recurrent hypoglycemia. He denied obvious weight change in recent 1 year, and no any other systemic diseases has been noticed before this admission. He smoked 1/3 pack per day of cigarettes and drank 50-100 ml of wine nearly everyday for 7-8 years. Besides, he took estazolam and lorazepam for his insomnia occasionally. Physically, he was conscious and alert. His height was 170 cm and weight 55 kg and he was healthy-looking. The other physical findings were unremarkable. Complete blood counts and basic biochemical screening tests were all within normal limits. The results of laboratory exams are shown in Table 1-3. Table 1. Hematologic laboratory values on admission WBC K/μL RBC M/μL Hb g/dL Hct % MCV fL PLT K/μL Seg  % Eos % Lym  % Mono % Baso % 4.75 4.72 14.7 43.3 91.7 238 62 3 28 6 1 Table 2. Blood chemical values on admission Alb g/dL LDH U/L BUN mg/dL Cre mg/dL Na M K M TG mg/dL T-Cho mg/dL LDL-C mg/dL HDL-C mg/dL   4.2 304 20 1.0 142 4.0 80 160 105 37 Table 3. Endocrinology laboratory tests HGH ng/ml T4 μg/dL Free T4 ng/dl T3 ng/dl TSH μIU/ml Testosterone ng/ml 0.06 6.8 0.9 80.9 0.9 11.9   Cortisol  μg/dL ACTH  pg/ml 0800hr 9.5  28 1600hr 3.1  10 He underwent a prolonged fasting test and the plasma glucose was 110, 94, 104, 83 and 43 mg/dl, the c-peptide was 3.2, 0.9, 1.2, 0.9, and <0.3 ng/ml, and the insulin was 10.5, 9.2, 3.6, 2.9, 73.5 mIU/ml at 0, 6, 12, 18 and 23 hrs, respectively. The cortisol level 30 min after hypoglycemia was 23.2μg/dL. Insulin antibody was negative. Endoscopic ultrasound and abdominal computed tomography revealed no evidence of pancreatic tumor. Factitious hypoglycemia was highly suggested according to his occupational background, clinical course and laboratory results. <病案分析> 低血糖臨床上最常見的原因是由於治療糖尿病的藥物如胰島素或促胰島素分泌劑所引起。一般而言，這樣的病人常會自己知道是藥物所引起的低血糖，而有所警覺。低血糖的症狀可以區分為兩種類型：neuroglycepenic及neurogenic responses。Neuroglycopenic response是由於中樞神經系統缺乏葡萄糖所直接引起的症狀，包括行為改變、意識混亂、疲倦、抽痙、失去意識等等，甚至如果低血糖持續太久未被適時發現，也可能會引起死亡。Neurogenic response或所謂的autonomic response則包括adrenergic response及cholinergic response，前者如心悸、手抖、不安等等，後者則如冒冷汗、飢餓感及異樣感等等，本病例的種種表現症狀即為十分典型的低血糖症狀，但其背後的原因則需要進一步去探討。 由於病人體型較瘦 (BMI約為19)且最近無明顯之體重變化，比較不像是胰島素瘤所引起之低血糖。在低血糖發作時留下血液檢體作檢查變的十分重要。當血漿葡萄糖濃度低於45 mg/dl，胰島素濃度卻超過 6 mIU/ml時，就可以診斷是胰島素所引起的低血糖。這時若加測C-peptide濃度就可以知道是內生性或是外加之胰島素所引起的低血糖，當C-peptide濃度高起來，可以確定是內生型的胰島素，此時必須去詢問病人是否有服用sulfonylurea之類會引起內生型胰島素增加之藥物，或是加測病人的血中及尿液的藥物濃度。若C-peptide濃度在胰島素上升時反而低下去，則要強烈懷疑是外加的胰島素所致。若病人非糖尿病患者，但其職業或生活環境有接觸到胰島素的使用的可能性就必須懷疑是人為施打的原因所造成。通常這類患者有其心理或精神上的背景，觀察其行為語言與常會找到一些蛛絲馬跡。精神科的照會與諮詢通常是必要的。 繼續教育考題 1. (C) Which of the following is not the so-called “Whipple's triad”? A Symptoms consistent with hypoglycemia, B A low plasma glucose concentration, C A high insulin level, D  Relief of symptoms after the plasma glucose level is raised, E All of the above are right. 2. (E) Which of the following drugs will not cause hypoglycemia? A Ethanol, B Pentamidine, C Quinine, D Salicylate, E All of the above will cause hypoglycemia. 3. (D) A 42-year-old alcoholic man has eaten poorly for the last 10 days but has continued to drink. His family brings him to the emergency room. On neurological exam he is confused but otherwise normal. Blood glucose is 50 mg/dl. Intravenous infusion of 50% glucose solution fails to improve his condition and his consciousness worsens. He also develops horizontal Nystagmus, ataxia and tachycardia. IF you are the physician, what is the next you should do for him? A Administration of another bolus of 50% glucose solution, B Order immediate CT scan of the head, C Perform a lumbar puncture, D Administration of intramuscular thiamine, 50 mg, E Administration of intravenous folic acid, 5 mg. 4. (D) The patient in the above question may have which of the following syndrome? A Wernicke's syndrome, B Korsakoff's syndrome, C Beriberi heart disease, D  All of the above, E  None of the above. 5. (B) A 56-year-old male patient with type 2 diabetes is sent to ER because of behavioral change and confusion. His family claims that she has administered some cookies to the patient when she found the patient to have queer behavior but in vain. Which of the following medication do you think the patient may have taken and cause this scenario before this episode? A Repaglinide, B Acarbose, C Troglitazone, D Metformin, E Glibenclamide. 6. (E) When the cause of hypoglycemia is obscure, which of the following should be tested to determine the cause, except glucose and insulin concentration? A C-peptide, B Sulfonylurea levels, C Cortisol, D  Insulin autoantibodies, E All of the above. 7. (A) An 81-year-old man is found by his family to be disoriented and confused; In the ER he is diagnosed to have hypoglycemia. A bolus of intravenous glucose is administered and he recovers soon. His glucose level after the treatment is 120 mg/dl. Reviewing his medicinal history he has type 2 diabetes and for which he takes a sulfonylurea. He also has a history of renal insufficiency in recent 2-3 years. Which of the following is the most appropriate management for the patient? A He should be hospitalized. B The sulfonylurea should be discontinued and replaced with Metformin, a medication that does not cause hypoglycemia. C The sulfonylurea should be resumed on a reduced dose and the patient may be discharged from the ER. D The patient should undergo a workup for a possible insulinoma. E  The patient can be discharged without further intervention since the episode is likely accidental in patients with type 2 diabetes. 8. (B) Which of the following medication is known to cause hypoglycemia? A Acetaminophen. B Propranolol. C Epinephrine. D Verapamil. E Thiazides. 9. (A) Which of the following statement about insulinoma is not true? A 30% of insulinoma are malignant. B Women are more frequent than men to have insulinoma. C Insulinoma arise most frequently from the pancreas and are usually small. D Intraoperative ultrasound has high sensitivity and may localize tumor not identified by palpation. E Diazoxide can be used to treat hypoglycemia in patients with unresectable insulinomas. 10. (C) Fasting hypoglycemia in non-islet cell tumor occurs in some patients with large mesenchymal or other tumors, e.g., hepatoma, adrenocortical tumors, carcinoid. In patients with non-beta-cell tumor hypoglycemia, which of the following is the cause of the hypoglycemia? A  Insulin. B  Insulin-like growth factor I (IGF-I). C IGF-II. D Proinsulin. E All of the above may be attributed to the hypoglycemia. 答案解說 (C) A high insulin level is not included in the “Whipple's triad”. (E) Ethanol blocks gluconeogenesis but not glycogenolysis, thus alcohol-induced hypoglycemia typically occurs after several days of ethanol abuse with little food intake. Pentamidine is used to treat Pneumocystis carinii and is toxic to beta cells. It causes hypoglycemia because of initial insulin release and will cause hyperglycemia later due to insulin deprivation. Quinine can increase insulin secretion too. Salicylates and sulfonamides rarely can cause hypoglycemia, so do propranolol, a nonselective beta-adrenergic blocking agent. (D ) The presentation of thiamine deficiency in alcoholic patients can be abruptly prominent after the administration of glucose. Nystagmus, ataxia and confusion often accompanied by ophthalmoplegia strongly suggest Wernicke's encephalopathy; tachycardia due to peripheral vasodilatation also will be presented. Thiamine should be administered promptly before glucose is given to any person in whom subclinical thiamine deficiency is suspected. (D) Wernicke's syndrome is a condition frequently encountered in chronic alcoholics, largely due to thiamin deficiency and characterized by disturbances in ocular motility, pupillary alterations, nystagmus, and ataxia with tremors; an organic-toxic psychosis is often an associated finding, and Korsakoff's syndrome often coexists; Korsakoff's syndrome is a memory disorder which is caused by a deficiency of vitamin B1, also called thiamine, are characteristic cellular pathology found in several areas of the brain. Beriberi heart disease is a form of beriberi caused by a deficiency of thiamine characterized by cardiac failure and edema, but without extensive nervous system involvement. (B ) Treatment with an alpha-glucosidase inhibitor such as acarbose alters the management of hypoglycemia; pure glucose should be used rather than ingestion of complex carbohydrates. (E ) Adrenal insufficiency and autoimmune insulin hypoglycemia are the rare causes of obscure hypoglycemia, if the insulin and glucose levels can not explain the patient's hypoglycemia, these test should be performed to determine the cause. (A) Sulfonylureas have long half-lives and the patient may become hypoglycemic again hours later. He therefore should be hospitalized with careful monitoring of blood glucose and mental status until the drug effects have resolved. Metformin is contraindicated in patients with renal insufficiency since lactic acidosis may ensue. Sulfonylureas are the most likely cause of the patient's hypoglycemia, and a workup for insulinoma is unlikely to be revealing. (B) Hypoglycemia has been reported to be attributed to non-selective beta-blockers, e.g., Propranolol. Nonselective beta-blockers also may attenuate the recognition of hypoglycemia and they impair glycongenolysis. A relatively selective beta-blocker such as metoprolol or atenolol is preferred when a beta-blocker is indicated in patients with diabetes mellitus. (A) Only 5-10% of insulinomas are malignant, as evidenced by metastasis. 90% are benign tumors. (C)Although IGF-II levels are not consistently elevated in patients with non-islet cell tumor hypoglycemia, circulating free IGF-II levels are high. Hypoglycemia may result from IGF-II actions through the insulin or IGF-I receptors. Because of negative-feedback suppression of growth hormone secretion and insulin, the IGF-I and insulin levels tend to be low in these patients.