Case Discussion      A 38-year-old man was admitted because of postprandial vomiting for 2 weeks. He had been diagnosed as having type 2 diabetes mellitus and hypertension since 6 years earlier before this admission for which he had been taking nateglinide and losartan daily, respectively. The latest serum creatinine was 0.9 mg/dl and glycosylated hemoglobin (HbA1c) was 7.8% one month prior this admission. He had been in a habit of alcohol consumption, betel nut chewing and smoking for more than 5 years. He had been otherwise well until one month earlier when he noted poor appetite, nausea and a weight loss of 2 kg in one month. The symptom was accompanied by abdominal distention and slight abdominal pain. Two weeks prior to this admission, he developed vomiting after meals, and the vomitus was formed, undigested food and did not contain blood or bile. One week later, he developed general malaise and daily urine amount decreased, followed by constipation 3 days before this admission.      On arrival at this hospital, he was ill-looking and appeared in respiratory distress. The conjunctivae was relatively pale. The blood pressure measured at the Emergent Department was 116/67 mmHg which was lower than what he usually recorded. The pulse rate 88 beats per minute, respirations 26 breaths per minute. The conjunctiva was pale and sclera not icteric. Pupils were isocoric with prompt light reflex. No lymph nodes were palpable. His breath sounds were clear. There were no audible cardiac murmurs. The abdomen was soft and flat without tenderness. The liver and spleen were not palpable, and no shifting dullness was noted. Her bowel sounds were normoactive. No flank percussion tenderness was noted. The extremities were warm without cyanosis. There were no skin rashes or discoloration.      Serum creatinine was 6.9 mg/dL and pyuria and urine turbidity were noted. Serum calcium was 4.05 mmol/dL and a test of arterial blood gas while he was breathing ambient air revealed pH 7.47, PCO2 43.7 mmHg, PO2 64.6 mmHg, and HCO3- 31.7 mEq/L with a base excess of 7.4 mEq/L. Chest radiography was negative and abdominal radiography while he was in supine position revealed intestines containing much fecal material. Aminotransferse, amylase, and lipase levels were normal. Under the impression of hypercalcemia with acute renal failure, he was admitted to this hospital.      After admission, hydration and diuretics were continued and betal nut-related milk-alkali syndrome was highly suspected because of acute renal failure, hypercalcemia and metabolic alkalosis. Serum intact parathyroid hormone (iPTH) level was <3.00 pg/mL (reference range, 12-72 pg/mL). immunofixation electrophoresis [IFE] showed no monoclonal gammopathy. After hydration was administered, his serial laboratory data showed improving renal function and resolution of hypercalcemia one day later. Insulin was replaced by nateglinide daily after renal function improved. After the hypercalcemia and acute renal failure resolved, he was discharged and follow-up at OPD. After discharge, he quitted betel nut chewing and cigarette smoking. < Laboratory data > 1. Hemogram on arrival at this hospital WBC /μl RBC M/μl Hb g/dl Hct % MCV fL MCHC g/dl PLT K/μl 12.27 4.01 10.1 38.1 95.0 34.4 255 Meta % Band % Seg % Eos % Baso % Mono % Lym % 0 0 75.5 2.3 0.2 8.1 13.9 2. Biochemistries and serum electrolytes on arrival at this hospital Test BUN mg/dl Cre mg/dl Na mmole/L K mmole/L Ca mmole/L P mg/dl Mg mmole/l Reference value 4.5-24 0.6-1.3 135-148 3.5-5.3 2.02-2.60 2.7-4.5 0.7-1.03 Result 48.3 6.9 131 4.1 4.05 4.3 0.33 Test Glucose Mg/dL GOT U/L GPT U/L T-Bilirubin mg/dl       Reference value 70-110　 ♂<37,<31♀ ♂<41,<31♀ 0.2-1.2       Result 123 28 18 1.03       3. Urinalysis on arrival at this hospital Variables Sp Gr. PH Protein mg/dl Glucose g/dl Ketone  OB Urobil EU/dl Result 1.01 7.5 20 - - - 0.1 Variables Bil RBC /HPF WBC /HPF Epi /HPF Cast /LPF Crystal Bacteria Result  - - 20 - - - -  < Discussion >      Hypercalcemia in an adult who is asymptomatic is usually due to primary hyperparathyroidism. In malignancy-associated hypercalcemia the disease is usually not occult; in such patients the interval between detection of hypercalcemia and death is often <6 months. Accordingly, if an asymptomatic individual has had hypercalcemia or some manifestations of hypercalcemia, such as kidney stones, for >1 or 2 years, it is unlikely that malignancy is the cause. Nevertheless, differentiating primary hyperparathyroidism from occult malignancy can occasionally be difficult, and careful evaluation is required, particularly when the duration of the hypercalcemia is unknown. Hypercalcemia that is not related to hyperparathyroidism or malignancy can result from excessive vitamin D action, high bone turnover from any of several causes, or from renal failure. Dietary history and a history of ingestion of vitamins or drugs are often helpful in the diagnosis of some of the less frequent causes. PTH immunoassays based on double-antibody methods serve as the principal laboratory test in differential diagnosis.      A detailed history may provide important clues regarding the etiology of the hypercalcemia. Chronic hypercalcemia is most commonly caused by primary hyperparathyroidism, as opposed to the second most common etiology of hypercalcemia, an underlying malignancy. The history should include medications, previous neck surgery, and systemic symptoms suggestive of sarcoidosis or lymphoma.       Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a two-site assay for the intact hormone. Increases of PTH levels are often accompanied by hypophosphatemia. In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay. If the PTH level is increased (or "inappropriately normal") in the setting of an elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism. Since individuals with familial hypocalciuric hypercalcemia (FHH) may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition. A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when there is a family history of mild, asymptomatic hypercalcemia. Ectopic PTH secretion is extremely rare.      A suppressed PTH level in the face of hypercalcemia is consistent with non-parathyroid-mediated hypercalcemia, most often due to a underlying malignancy. Although a tumor that causes hypercalcemia is generally overt, a PTHrP level may be needed to establish the diagnosis of hypercalcemia related to malignancy. Serum 1,25(OH)2 D levels are increased in granulomatous disorders, and clinical evaluation in combination with laboratory testing will generally provide a confirmatory diagnosis. Milk-alkali syndrome      Intensive treatment with calcium-containing antacids and milk was first used in the early 20th century for the treatment of peptic ulcer disease and sometimes was associated with toxicity, eventually known as the milk alkali syndrome. Despite the introduction of H2 blockers and proton pump inhibitors for the treatment of peptic ulcer disease, the milk alkali syndrome continues to occur but is seen more frequently in older women who are receiving treatment for osteoporosis. The milk alkali syndrome provides a unique opportunity to discuss calcium homeostasis in a setting in which the primary calcium regulatory hormones, parathyroid hormone (PTH) and calcitriol, are not overtly abnormal. Betel nut      Betel nut is a common masticatory drug used in Far East Asia, India, and the South Pacific. It is used daily by 600 million people worldwide, yet is unknown to most Western physicians. As the world becomes more culturally and ethnically interconnected, physicians of emergency service will encounter the complications related to use of betel nut. Significant illness can be associated with its use, including exacerbation of asthma, cholinergic crisis, cardiac arrhythmias, acute psychosis, milk-alkali syndrome, and oropharyngeal tumors. Betel nut use refers to a combination of three ingredients: the nut of the betel palm (Areca catechu), part of the Piper betel vine, and lime. Anecdotal reports have indicated that small doses generally lead to euphoria and increased flow of energy while large doses often result in sedation. Although all three ingredients may contribute to these effects, most experts attribute the psychoactive effects to the alkaloids found in betel nuts < References > Nelson BS, Heischober B. Betel nut: a common drug used by naturalized citizens from India, Far East Asia, and the South Pacific Islands. Ann Emerg Med 1999;34:238-43. 2. Wu KD, Chuang RB, Wu FL, Hsu WA, Jan IS, Tsai KS. The milk-alkali syndrome caused by betelnuts in oyster shell paste. J Toxicol Clin Toxico. 1996;34:741-5. 3. Lin SH, Lin YF, Cheema-Dhadli S, Davids MR, Halperin ML. Hypercalcaemia and metabolic alkalosis with betel nut chewing: emphasis on its integrative pathophysiology. Nephrol Dial Transplant 2002;17:708-14. 繼續教育考題 1. (E) Which of the following descriptions of MAS is correct？ A Assay of intact PTH allows for a precise determination of the PTH level even in the presence of substantial renal failure. B Complications of MAS, including reversible cardiac conduction abnormalities, pancreatitis, and metastatic calcification. . C The central point in diagnosing MAS is the history of excess calcium carbonate intake, which can be easily overlooked without a high index of suspicion D Currently, calcium in the form of calcium carbonate rather than milk products is the primary causative factor in the development of MAS. E All of the above 2. (B) Which of the following descriptions of the relationship between metabolic alkalosis and hypercalcemia is wrong？ A Alkalosis inhibits calcium excretion. B Calcium increases H+ excretion. C Hypercalcemic suppression of PTH further contributes to the increased serum bicarbonate.  D Metabolic alkalosis further propagates hypoparathroidism. 3. (C) Which of the following clinical characteristics of MAS is wrong？ A Hypercalcemia B Metabolic alkalosis C Hyperparathyroidism D Renal insufficiency 4. (E) Which of the following side effects related to use of betel nut is wrong？ A Cardiac palpitations B Metabolic syndrome C Oral tumors D Cholinergic toxicity E None of above 5. (D) Which of the following characteristics of MAS is wrong？ A Milk-alkali syndrome almost never results in death. B A significant number of patients may be left with permanent renal impairment. C The cause of milk-alkali syndrome is ingestion of an inappropriately high amount of calcium carbonate. D Serum phosphorus concentration can be decreased in milk-alkali syndrome. 6. (B) Which of the following characteristics of MAS is wrong？ A Milk-alkali syndrome is caused by the ingestion of large amounts of calcium and absorbable alkali with resulting hypercalcemia. B Hypercalcemia produces a renal concentrating defect that can be considered a form of central diabetes insipidus. C Resultant dehydration and volume depletion may worsen the hypercalcemia. D Chronic milk-alkali syndrome can result in metastatic calcification due to high serum calcium levels and relatively high phosphate levels. 答案解說 1. Significant illness can be associated with betel nut use, including exacerbation of asthma, cholinergic crisis, cardiac arrhythmias, acute psychosis, milk-alkali syndrome, and oropharyngeal tumors. Betel nut use refers to a combination of three ingredients: the nut of the betel palm (Areca catechu), part of the Piper betel vine, and lime. 3. Measurement of the serum 1,25-hydroxy-vitamin D levels may help differentiate milk-alkali syndrome, in which both 1,25-hydroxy-vitamin D and PTH levels will be low, from primary hyperparathyroidism, in which both measurements are usually elevated. 5 & 6 Serum phosphorus concentration can be elevated in milk-alkali syndrome due to a low PTH level, although this finding is less prevalent in the present era than when ingestion of milk and bicarbonate caused the syndrome.