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CPC Clinical Discussion Douglas W. Ball, M.D. Division of Endocrinology and Metabolism January 29, 2008 Clinical history History of Present Illness The patient is a 55-year old Caucasian man who presented to an outside hospital with a chief complaint of abdominal pain and was admitted with acute pancreatitis. Abdominal ultrasound on admission only showed gallbladder sludge with no evidence of cholelithiasis. Serum triglycerides were 268. Clinical history History of Present Illness The patient is a 55-year old Caucasian man who presented to an outside hospital with a chief complaint of abdominal pain and was admitted with acute pancreatitis. Abdominal ultrasound on admission only showed gallbladder sludge with no evidence of cholelithiasis. Serum triglycerides were 268. Clinical history Three days later he was transferred to The Johns Hopkins Hospital for management of severe pancreatitis complicated by systemic inflammatory response syndrome, respiratory failure, and acute renal failure. Clinical history His past medical history is significant for the diagnosis of primary hyperparathyroidism, and he is status post single-gland parathyroidectomy for parathyroid adenoma. He also has a history of hypertension, hypertriglyceridemia and depression. The patient denies alcohol use. Clinical history Family History The patient's family history is unremarkable. Clinical history Medications Wellbutrin, 100 mg q8h Clinical history Medications Wellbutrin, 100 mg q8h No AIDS drugs, diuretics, metronidazole, valproic acid, sulindac….. others Clinical history Physical Exam Weight: 143 lbs. Height: 69 inches. T: 102.2 BP: 110/60 P: 100 General: Caucasian male, intubated HEENT: Sclera anicteric. Extraocular movements intact. CV: Regular rate and rhythm with no murmurs appreciated. Lungs: Clear to auscultation bilaterally. No wheezes, rales or rhonchi. Abdomen: Diffuse tenderness to palpation. Hypoactive bowel sounds Lymph Node Exam: No lymphadenopathy appreciated. Extremities: No cyanosis, clubbing, or edema. Clinical history Physical Exam Weight: 143 lbs. Height: 69 inches. T: 102.2 BP: 110/60 P: 100 General: Caucasian male, intubated HEENT: Sclera anicteric. Extraocular movements intact. CV: Regular rate and rhythm with no murmurs appreciated. Lungs: Clear to auscultation bilaterally. No wheezes, rales or rhonchi. Abdomen: Diffuse tenderness to palpation. Hypoactive bowel sounds Lymph Node Exam: No lymphadenopathy appreciated. Extremities: No cyanosis, clubbing, or edema. Clinical history Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Clinical history Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Clinical history Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Clinical history Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Add 0.8 mg/dl for every 1 g/dl below 4 Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Corrected calcium = 7.28 Add 0.8 mg/dl for every 1 g/dl below 4 Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Corrected calcium = 7.28 Add 0.8 mg/dl for every 1 g/dl below 4 Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Why relatively normal compared to corrected total calcium? Corrected calcium = 7.28 Add 0.8 mg/dl for every 1 g/dl below 4 Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Metabolic acidosis Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Why relatively normal compared to corrected total calcium? Corrected calcium = 7.28 Add 0.8 mg/dl for every 1 g/dl below 4 Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Metabolic acidosis Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Why relatively normal compared to corrected total calcium? Laboratory Values Na 145; K 3.8 ; Cl 119 ; BUN 87 ; Glucose 167; Cre 5.7; Ca 6.6; Tot protein 4.0; Albumin 2.4; TBili 0.6; ALT 78; AST 102; Alk Phos 45; CO2 16; WBC 13740;Hct 34.4 Plt 128,000; PT 10.4 Ionized calcium 1.09 Lipase 250; Amylase 867 pH, arterial 7.29; pCO2, arterial 37; pO2, arterial 103 Radiologic Studies Initial CT studies noted bilateral pleural effusions with associated compressive atelectasis and/or infiltrates. Marked edema and stranding were seen in the pancreatic bed, compatible with fulminant pancreatitis. Several indeterminate adrenal nodules were present bilaterally, and a stable, nonobstructing 1.5 cm stone was identified in the left kidney. Radiologic Studies Initial CT studies noted bilateral pleural effusions with associated compressive atelectasis and/or infiltrates. Marked edema and stranding were seen in the pancreatic bed, compatible with fulminant pancreatitis. Several indeterminate adrenal nodules were present bilaterally, and a stable, nonobstructing 1.5 cm stone was identified in the left kidney. Clinical Course The patient was in respiratory failure and acute renal failure when he arrived and was admitted to the MICU. Imaging and laboratory tests were consistent with acute pancreatitis. He demonstrated a period of initial improvement and was eventually extubated, but two weeks after admission developed a high fever and acute respiratory decompensation. Repeat CT imaging revealed a pulmonary embolus in his main right pulmonary artery and pancreatic necrosis. Cultures of peripancreatic fluid grew Candida albicans, and the patient underwent three operations for pancreatic debridement. A cholecystectomy, gastojejunostomy tube placement, and inferior vena cava filter placement were also performed. Additional complications during his admission included Pseudomonas aeruginosa-positive sputum cultures and critical illness neuropathy/myopathy. …an endocrine consultation was obtained for hypercalcemia. Review of calcium levels revealed hypocalcemia in 6.6- 6.8 mg/dL range on presentation to JHH. However, as patient’s condition improved, calcium elevation in 10.7-12.1 mg/dL was noted persistently. Serum albumin during that time ranged between 1.8 and 2.5 g/dl. An initial biochemical evaluation included PTH of 255 pg/mL concurrently with calcium of 10.2 mg/dL, PTHrp of <2.5 pmol/L, Phosphorus 2.7 mg/dL, 1,25 OHVitamin D 27 pg/mL, 25 OH-Vitamin D 10 ng/mL, TSH 3.62. …an endocrine consultation was obtained for hypercalcemia. Review of calcium levels revealed hypocalcemia in 6.6- 6.8 mg/dL range on presentation to JHH. However, as patient’s condition improved, calcium elevation in 10.7-12.1 mg/dL was noted persistently. Serum albumin during that time ranged between 1.8 and 2.5 g/dl. An initial biochemical evaluation included PTH of 255 pg/mL concurrently with calcium of 10.2 mg/dL, PTHrp of <2.5 pmol/L, Phosphorus 2.7 mg/dL, 1,25 OHVitamin D 27 pg/mL, 25 OH-Vitamin D 10 ng/mL, TSH 3.62. Corrected calcium = 11.9-13.3 …an endocrine consultation was obtained for hypercalcemia. Review of calcium levels revealed hypocalcemia in 6.6- 6.8 mg/dL range on presentation to JHH. However, as patient’s condition improved, calcium elevation in 10.7-12.1 mg/dL was noted persistently. Serum albumin during that time ranged between 1.8 and 2.5 g/dl. An initial biochemical evaluation included PTH of 255 pg/mL concurrently with calcium of 10.2 mg/dL, PTHrp of <2.5 pmol/L, Phosphorus 2.7 mg/dL, 1,25 OHVitamin D 27 pg/mL, 25 OH-Vitamin D 10 ng/mL, TSH 3.62. Corrected calcium = 11.9-13.3 …an endocrine consultation was obtained for hypercalcemia. Review of calcium levels revealed hypocalcemia in 6.6- 6.8 mg/dL range on presentation to JHH. However, as patient’s condition improved, calcium elevation in 10.7-12.1 mg/dL was noted persistently. Serum albumin during that time ranged between 1.8 and 2.5 g/dl. An initial biochemical evaluation included PTH of 255 pg/mL concurrently with calcium of 10.2 mg/dL, PTHrp of <2.5 pmol/L, Phosphorus 2.7 mg/dL, 1,25 OHVitamin D 27 pg/mL, 25 OH-Vitamin D 10 ng/mL, TSH 3.62. Corrected calcium = 11.9-13.3 …an endocrine consultation was obtained for hypercalcemia. Review of calcium levels revealed hypocalcemia in 6.6- 6.8 mg/dL range on presentation to JHH. However, as patient’s condition improved, calcium elevation in 10.7-12.1 mg/dL was noted persistently. Serum albumin during that time ranged between 1.8 and 2.5 g/dl. An initial biochemical evaluation included PTH of 255 pg/mL concurrently with calcium of 10.2 mg/dL, PTHrp of <2.5 pmol/L, Phosphorus 2.7 mg/dL, 1,25 OHVitamin D 27 pg/mL, 25 OH-Vitamin D 10 ng/mL, TSH 3.62. While in rehabilitation, he experienced a gastrointestinal bleed, and was admitted to an outside hospital. Endoscopy revealed ulceration in the duodenum and at the gastroesophageal junction …He was re-admitted to The Johns Hopkins Hospital for further management. At admission he was hemodynamically stable and afebrile, but presented with elevated white blood cell count, liver enzymes, alkaline phosphatase and amylase. He was treated with antibiotics and with discussion of further surgical intervention. Three days after admission, the patient was found in cardiopulmonary arrest and resuscitation attempts were unsuccessful. Discussion Questions 1) Could hypercalcemia explain his acute pancreatitis? Discussion Questions 1) Could hypercalcemia explain his acute pancreatitis? Yes Etiologies of Acute Pancreatitis Mechanical: Toxic: Metabolic: Drugs: Trauma: Vascular: Genetic: Gallstones, biliary sludge (?), pancreatic cancer, others Ethanol, others Hyperlipidemia, hypercalcemia AIDS drugs, salicylates, metronidazole, diuretics, calcium, others Injury, surgery, ERCP Ischemia, embolic, vasculitis CFTR, others Etiologies of Acute Pancreatitis Mechanical: Toxic: Metabolic: Drugs: Trauma: Vascular: Genetic: Gallstones, biliary sludge (?), pancreatic cancer, others Ethanol, others Hyperlipidemia, hypercalcemia AIDS drugs, salicylates, metronidazole, diuretics, calcium, others Injury, surgery, ERCP Ischemia, embolic, vasculitis CFTR, others Did the patient have hypercalcemia prior to developing acute pancreatitis? Did the patient have hypercalcemia prior to developing acute pancreatitis? Probably Did the patient have hypercalcemia prior to developing acute pancreatitis? Probably 1) Prior history of hyperpara 2) Nephrolithiasis 3) Hypocalcemia during acute pancreatitis with rebound hypercalcemia Do patients without underlying hyperparathyroidism have rebound hypercalcemia and PTH in recovery phase? Do patients without underlying hyperparathyroidism have rebound hypercalcemia and PTH in recovery phase? No, apparently not •Low ionized calcium common during acute pancreatitis •PTH responses variable, but seldom above normal •No evidence for “rebound hypercalcemia” in 41 patients followed prospectively McKay Br J Surg 1994 Hypercalcemia and acute pancreatitis •Hypercalcemia: a rare cause of pancreatitis •Hyperparathyroidism: accounts for fewer than 1% of cases of pancreatitis •Mechanism: Calcium deposition in pancreatic ducts Calcium activation of trypsinogen •Animal Models: Hypercalcemia -> amylase elevations Discussion Questions 2) What is the most likely cause of his initial hypocalcemia? Discussion Questions 2) What is the most likely cause of his initial hypocalcemia? Acute pancreatitis causes Ca FFA soaps Discussion Questions 2) What is the most likely cause of his initial hypocalcemia? Acute pancreatitis causes Ca FFA soaps Acute renal failure inhibits PTH secretion and action Discussion Questions 2) What is the most likely cause of his initial hypocalcemia? Acute pancreatitis causes Ca FFA soaps Acute renal failure inhibits PTH secretion and action –low magnesium –elevated phosphate impairs renal 1 alpha hydroxylase, associated with low 1,25 vitamin D Discussion Questions 3) What is the most likely cause of his hyperparathyroidism and what additional studies would help determine the most likely cause? DDx of Hypercalcemia Hyperparathyroidism Hypercalcemia of malignancy Drugs: Thiazide diuretics, lithium others Vitamin D intoxication Lymphoma Adrenal insufficency, pheochromocytoma DDx of Hyperparathyroidism Primary Hyperparathyroidism-sporadic Secondary Hyperparathyroidism vitamin D deficiency renal or GI calcium losses parathyroid hormone resistance Tertiary – Chronic End stage renal disease FHH- Familial Hypocalciuric hypocalcemia Men1 Men2A FHPT-JT –Familial hyperparathyroidism jaw tumor syndrome DDx of Hyperparathyroidism Primary Hyperparathyroidism-sporadic Secondary Hyperparathyroidism vitamin D deficiency renal or GI calcium losses parathyroid hormone resistance Tertiary – Chronic End stage renal disease FHH- Familial Hypocalciuric hypocalcemia Men1 Men2A FHPT-JT –Familial hyperparathyroidism jaw tumor syndrome DDx of Hyperparathyroidism Primary Hyperparathyroidism-sporadic Secondary Hyperparathyroidism vitamin D deficiency renal or GI calcium losses parathyroid hormone resistance Tertiary – Chronic End stage renal disease FHH- Familial Hypocalciuric hypercalcemia Men1 Men2A FHPT-JT –Familial hyperparathyroidism jaw tumor syndrome DDx of Hyperparathyroidism Primary Hyperparathyroidism-sporadic Secondary Hyperparathyroidism vitamin D deficiency renal or GI calcium losses parathyroid hormone resistance Tertiary – Chronic End stage renal disease FHH- Familial Hypocalciuric hypercalcemia Men1 Men2A FHPT-JT –Familial hyperparathyroidism jaw tumor syndrome DDx of Hyperparathyroidism Primary Hyperparathyroidism-sporadic Secondary Hyperparathyroidism vitamin D deficiency renal or GI calcium losses parathyroid hormone resistance Tertiary – Chronic End stage renal disease FHH- Familial Hypocalciuric hypercalcemia Men1 Men2A FHPT-JT –Familial hyperparathyroidism jaw tumor syndrome Focused DDx in this case Primary Hyperparathyroidism-sporadic Men1 Men2A Sporadic Hyperparathyroidism •Most common cause of hypercalcemia •Can be mild (adenoma) or severe (carcinoma) • Recurrent/persistent hyperpara in 5-10% (Fewer currently) •77% of surgical failures due to missed single gland Jaskowiak Ann Surg 1996 Known complications of hyperparathyroidism Peptic ulcer disease Neuropsychiatric symptoms Pancreatitis Bone disease Nephrolithiasis Known complications of hyperparathyroidism Peptic ulcer disease ◄ Neuropsychiatric symptoms ◄ Pancreatitis ◄ Bone disease Nephrolithiasis ◄ MEN1 Clinical Manifestations 3 P’s: Parathyroid, pancreas, pituitary Cardinal lesion: parathyroid adenomas >90% have hyperpara by age 50 Frequently multiple and recurrent GI tumors (50%) gastrinoma (40%)associated with severe peptic ulcers carcinoid (10%), insulinoma (10%), glucagon , VIP, somatostatin, “non-secretory” Pituitary tumors (30%) prolactinoma (20%), non-secretory, GH (5%), ACTH (2%) MEN1 Clinical Manifestations 3 P’s: Parathyroid, pancreas, pituitary Cardinal lesion: parathyroid adenomas ◄ >90% have hyperpara by age 50 Frequently multiple and recurrent ◄ GI tumors (50%) gastrinoma (40%)associated with severe peptic ulcers ◄? carcinoid (10%), insulinoma (10%), glucagon , VIP, somatostatin, “non-secretory” Pituitary tumors (30%) prolactinoma (20%), non-secretory, GH (5%), ACTH (2%) MEN1 Clinical Manifestations 3 P’s: Parathyroid, pancreas, pituitary Cardinal lesion: parathyroid adenomas ◄ >90% have hyperpara by age 50 Account for ~10% of cases recurrent HPT (non-renal) Frequently multiple and recurrent ◄ ofJaskowiak Ann Surg 1996 GI tumors (50%) gastrinoma (40%)associated with severe peptic ulcers ◄? carcinoid (10%), insulinoma (10%), glucagon , VIP, somatostatin, “non-secretory” Pituitary tumors (30%) prolactinoma (20%), non-secretory, GH (5%), ACTH (2%) MEN1: Additional tumors Adrenocortical adenomas (25%) ◄ Thyroid follicular adenomas (15%) Lipomas (30%) Angiofibromas Thymic carcinoids (2%) Bronchial carcinoid (2%) MEN2A: Clinical manifestations Medullary thyroid cancer (>80%) Pheochromocytoma (50%) Hyperparathyroidism (15%) Less likely to be recurrent than in MEN1 Sporadic HPTH Pros Common Can account for pancreatitis, kidney stones Cons Can’t account for adrenal adenomas Men 1 Pros Can account for recurrent hyperpara, kidney stones, pancreatitis, peptic ulcer dz, adrenal adenomas Cons Rare Negative family history Men 2A Pros Can account for hyperpara, kidney stones, pancreatitis Could the adrenal adenomas be misdiagnosed bilateral pheochromocytomas? Patient had pre-existing hypertension and died sudden cardiac death Cons No history to suggest thyroid tumor No mention of in-patient hypertension Negative family history Men 2A Pros Can account for hyperpara, kidney stones, pancreatitis Could the adrenal adenomas be misdiagnosed bilateral pheochromocytomas? Patient had pre-existing hypertension and died sudden cardiac death Cons No history to suggest thyroid tumor No mention of in-patient hypertension Negative family history Discussion Questions 4) What additional endocrine evaluation? Discussion Questions 4) What additional endocrine evaluation? To rule in MEN 1: Careful family history Gastrin Prolactin Insulin 24h U cortisol, ACTH possible: Menin gene testing Discussion Questions 4) What additional endocrine evaluation? To rule in MEN 2A: Careful family history Calcitonin Plasma or 24h urine metanephrines Ret gene testing