Hypercalcemia. Brian Rose, M.D. Bozeman Health June 6, 2018

Transcription

1 Hypercalcemia Brian Rose, M.D. Bozeman Health June 6, 2018

2 Hypercalcemia Diagnosis PTH Mediated Primary Hyperparathyroidism Lithium Familial Hypocalciuric Hypercalcemia Non PTH mediated Malignancy Humoral Direct bone mets Calcitriol Induced Milk Alkali Syndrome Hyperthyroidism Vitamin D toxicity Vitamin A toxicity Adrenal Insufficiency

3 EVALUATION Stepwise Calcium, albumin, creatinine, PTH, PTHrP, phosphorus, 25-hydroxyvitamin D and 1, 25 dihydroxyvitamin D.

4 Actions of PTH Activates 1-alpha-hydroxylase enzyme Coverts 25-hydroxyvitamin D to 1,25- dihydroxyvitamin D Stimulates calcium reabsorption in the distal nephron Stimulates renal phosphorus excretion PTH leads to calcium mobilization from the bone with help from 1,25 dihydroxyvitamin D

5 Actions PTHrp Nearly all human tissues Functions within microcirculation to regulate smooth muscle tone and transepithelial calcium transport Leads to osteoclast generation and activation Does not augment 1,25 dihydroxyvitamin D production.

6 Actions 1,25 dihydroxycholecalciferol Activated from 25-hydroxyvitamin D in the kidneys via 1-alpha-hydroxylase (which is activated by PTH) Increases absorption of calcium and phosphate from GI tract Decreases renal excretion of calcium and phosphate With PTH increases calcium release from bone

7 Etiology of Hypercalcemia PTH PTHrP PO4 25 D 1,25 D Primary Hyperparathyroidism - to Humoral Hypercalcemia Malignancy N to - Direct Bone Invasion N to - Calcitriol Induced Not N to

8 Hypercalcemia Case #1 62 year old woman. No history of kidney stones. No prior fractures. Noted to have high calcium on recent labs. History of hypothyroidism. Meds: levothyroxine, Vitamin D IU per day. Exam 119/74 64 W: 154 pounds 5 7 Neck exam normal

9 Hypercalcemia Case 1 Creatinine: 0.79 egfr: 75 ml/min Calcium: 10.5 mg/dl ( mg/dl) Albumin: 4.0 mg/dl PTH: 68 pg/ml (18-80 pg/ml) Phosphorous: 2.4 ( mg/dl) Ionized caclium 1.41 ( mmol/l)

10 Case 1 Is this PTH mediated or non PTH mediated Hypercalcemia? PTH: 68 (18-90 pg/ml) Calcium: 10.5 mg/dl

11 PTH MEDIATED

12 Case 1 Hypercalcemia 24 hour urine: Calcium: mg/24 hr Urine creatinine: 1247 mg/24 hr FE caclium: (0.79)/10.5 (1247) =

13 Case 1 Hypercalcemia 24 hour urine: Calcium: mg/24 hr Urine creatinine: 1247 mg/24 hr FE caclium: (0.79)/10.5 (1247) = PRIMARY HYPERPARATHYROIDISM

14 Case 1 Bone Density FN: T-score -2.7 TH: T-score L1-4: T score -1.6 (arthritis noted) Distal 1/3 radius: T-score -2.5

15 Case 1 Bone Density FN: T-score -2.7 TH: T-score L1-4: T score -1.6 (arthritis noted) Distal 1/3 radius: T-score -2.5 SEND FOR SURGERY CONSULT

16 Primary Hyperparathyroidism 0.86% US general population Most sporadic, 80% single gland disease Age often > 50 years 3-4 times as many women as men Consider hereditary etiologies individuals with multigland disease or onset < 35 years age. Parathyroid carcinoma < 1% pts with PHPT

17 Diagnosis Primary Hyperparathyroidism Elevated corrected total calcium or ionized calcium and simultaneous inappropriately normal to elevated PTH Calcium to creatinine clearence ratio FHH unlikely if CaCrCR > % with FHH CaCrCR < % FHH CaCrCR Low CaCrCR can occur renal insufficiency or vitamin D deficiency

18 Fractional Excretion of Calcium [Urine calcium x Serum creatinine ] [Serum calcium x Urine creatinine ]

19 Familial Hypocalciruric Hypercalcemia Rare autosomal dominant Mild hypercalcemia PTH normal to mildly elevated Loss of function mutations in calcium sensing rceptor 1:78000 Heterozygotes typically no sequalae FE calcium < 0.01 about 80% Endocrine Practice 2013: July(4):

20 Imaging and Primary HPT Used to assist in surgical planning Imaging is not used for the diagnosis Don t order imaging unless using to guide surgical planning and use imaging surgeon finds helpful.

21 Ultrasound of a Parathyroid Adenoma

22 Recommendations for the Evaluation of Patients with Asymptomatic PHPT Calcium, PO4, alk phosp, BUN, creatinine, PTH BMD per DXA: L spine, hip, distal 1/3 radius Vertebral spine assessment X-ray of VFA per DXA 24 hour urine calcium, creatinine +/- stone risk Abdominal imaging: X-ray, US or CT scan JCEM 2014: 99(10):

23 Primary HPT: who should have surgery? JCEM 2014:99: Symptomatic Age < 50 years Serum calcium > 1 mg/dl upper limit of normal BMD T-score < -2.5 L-spine, FN, total hip or 1/3 radius for postmenopausal women or men > 50 years or fragility fractures. GFR < 60 ml/minute. Eval. for asymptomatic stones. If urinary calcium > 400 mg/d perform complete urinary stone risk.

24 Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consenses Parathyroidectomy is the only curative approach to the disease. It is indicated in those with symptomatic PHPT and advised for those who meet surgical criteria. It is also reasonable option among those who request surgery, even if they do not meet surgical guidelines and have no contraindications. Osteoporosis Int 2017:28:1-19

25 What About Medical Therapy?

26 Cinacalcet Calcimimetic Activates Calcium sensing receptor 1) Parathyroid Carcinoma 2) Severe PHPT unable to have surgery 3) Parathyroidectomy indicated based on serum calcium but parathyroidectomy not clinically appropriate. 4) Secondary HPT with ESRD on dialysis Eur J Endocrinology 2015:172:527-35

27 Eur J Endocrinology 2015;172:527-35

28 JCEM 2010: 95(4):

29 Summary Primary HPT High calcium nonsuppressed PTH, calcium fractional excretion > 0.02 Replenish low 25 OH Vitamin D Evaluate for complications Consider role for surgery in all patients Consider availabilty of an experienced surgeon Imaging is used to aide surgery not to diagnose the disease

30 Hypercalcemia Case 67 yo woman referred for hypercalcemia Hypercalcemia noted late June 2010 when hospitalized with calcium 17 mg/dl and creatinine 3.0 mg/dl. She was given IVF/calcitonin/Zoledronic acid Early June 2010 before MRI with gadolinium calcium normal, creatinine Fatigue, nausea, anorexia, arthralgias, weight loss No h/o cancer Calcium intake <500 mg daily Routine calcium/d supplements stopped

31 Hypercalcemia Case 2 PE Somewhat ill-appearing, no evidence of nephrogenic fibrosing dermopathy Labs Calcium 12.1 mg/dl PTH <3 pg/ml (15-65) Phos 3.2 mg/dl Creatinine 1.3 SPEP, UPEP, TSH, 25D, cortisol, CXR normal

32 What diagnostic test would you do next? a. Parathyroid scan with sestimibi b. PTHrP and 1,25(OH)2D c. CT scan of chest, abdomen, and pelvis d. ACE level

33 What diagnostic test would you do next? a. Parathyroid scan with sestimibi b. PTHrP and 1,25(OH)2D c. CT scan of chest, abdomen, and pelvis d. ACE level

34 PTH-Independent Hypercalcemia Malignancy Calcitriol mediated (granulomatous, inflammatory) Hyperthyroidism Milk-alkali syndrome or calcium-alkali syndrome Immobilization Adrenal insufficiency Rare causes

35 Hypercalcemia case Additional studies PTHrP 0.4 pmol/l (<2) 1,25 (OH)2 D 275 pg/ml

36 Hypercalcemia Case Additional studies PTHrP 0.4 pmol/l (<2) 1,25 (OH)2 D 275 pg/ml CT gastric mass Bx large B cell lymphoma

37 Calcitriol-Mediated Hypercalcemia Sarcoid Lymphoma Tuberculosis Fungal disease Wegener s granulomatosis Crohn s Nephrogenic systemic fibrosis after gadolinium Mineral oil injection (oleogranulomatous mastitits paraffinoma) Silicone-induced granuloma Lipoid pneumonia Seminoma Leprosy Cat-scratch fever Acute granulomatous pneumonia BCG therapy Subcutaneous fat necrosis of the newborn Hepatic granulomatosis Talc-induced granuloma Inflammatory arthritis

38 Hypercalcemia of Malignancy 2.7% of cancer patients 50% survival of 30 days regardless of treatment Tumor-induced bone resorption mediated by an increase in osteoclasts Systemic secretion of PTHrP Local osteolytic bone resorption J Clin Endocrinol Metab 2014: 99(9):

39 Etiology of Hypercalcemia of Malignancy

40 Etiology of Hypercalcemia of Malignancy Squamous Cell Cancers Urinary Tract Cancers Breast Cancer NonHogkin s lymphoma Ovarian Cancer

41 Etiology of Hypercalcemia of Malignancy Breast Cancer Multiple Myeloma

42 Etiology of Hypercalcemia of Malignancy Lymphomas Ovarian germ cell tumors

43 Etiology of Hypercalcemia of Malignancy Parathyroid Carcinoma Small Cell Lung Cancer

44 Hypercalcemia Treatment Mild: calcium < 12 mg/dl Moderate: calcium mg/dl Severe: calcium > 14 mg/dl

45 Treatment Isotonic crystalloid ml/min Furosemide if fluid overload occurs Calcitonin 4-8 units/kg q 6-12 hours Onset within 4 hours Max drop about 2 mg/dl Bisphosphonates: Zoledronic acid 4 mg over minutes Onset 2-4 days, duration about 30 days Denosumab

46 Denosumab for Treatment of Hypercalcemia of Malignancy JCEM 2014, 99(9): By day 10, 36% CR Median time for response 9 days Median duration of response 100 days

47 Hypercalcemia Case 3

48 Hypercalcemia Case 3 66 year old woman with history of GERD Longterm H2 blockers and proton pump inhibitor. She stopped lansoprazole 10/16. Historically would use 6 Tums Ultra per day. No past kidney stones, No fractures, no history of cancer, no weight loss, mild lower back pain. Past total calcium was normal 2011

49 Hypercalcemia Case 3 11/8/16 routine labs: creatinine 0.80, calcium 10.7, albumin 4.1 Became lightheaded, nausea/vomiting Family members thought her odd on the phone and brought her to the ER dated 11/22 and calcium increased to 17.2 mg/dl CT abdomen/chest/pelvis was normal

50 Hypercalcemia Case 3 Past History: CVA, esophagitis, HTN, hyperlipidemia. Meds: simvastatin, losartan, amlodipine, MVI, zolpidem, ASA, ferrous sulfate Former smoker quit decades ago

51 Hypercalcemia case 3 11/8/16 11/22/16 calcium Creatinine CO2 (21-32) Albumin Phosphorus PTH intact 17 PTH rp 25 OH D (30-100) 34 1,25 OH D (18-79 pg/ml) 14 TSH 0.80 SPEP normal, CT scan chest/abdomen/pelvis negative Treated with Calcitonin and IV hydration

52 What is the cause of her severe hypercalcemia? A) Primary hyperparathyroidism as her PTH intact was not suppressed. B) Direct bone metastases from some unclear metastatic bone disease C) Past mild hypercalcemia from unclear etiology excerbated by milk alkali syndrome D) Probable granulomatous disease as PTH and PTHrP are not increased E) Familial Hypocalciuric hypercalcemia

53 Hypercalcemia Case 3 Additional history requested. After stopping the proton pump inhibitor the patient increased her consumption of TUMS ultra (1000 mg calcium carbonate) to 20 or more tablets per day.

54 What is the cause of her severe hypercalcemia? A) Primary hyperparathyroidism as her PTH intact was not suppressed. B) Direct bone metastases from some unclear metastatic bone disease C) Past mild hypercalcemia from unclear etiology exacerbated by milk alkali syndrome D) Probable granulomatous disease as PTH and PTHrP are not increased E) Familial Hypocalciuric hypercalcemia

55 Hypercalcemia case 3 11/8/16 11/22/16 1/27/17 2/6/17 calcium Creatinine CO2 (21-32) Albumin Phosphorus PTH intact PTH rp 25 OH D (30-100) 34 1,25 OH D (18-79 pg/ml) 14 TSH hour urine calcium 160 mg/d Creat=680 mg

56 Hypercalcemia Case 3 1) Severe calcium PTH independent but PTH not as low as expected for calcium of 17. 2) Not Humoral PTHrP from a cancer 3) No evidence of granulmatous disease as 1,25 not high normal to high with suppressed PTH and negative PTHrP 4) Persistent high calcium with nonsuppressed PTH supports primary hyperparathyroidism. Documentation of past normal calcium rules out FHH 5) Negative imaging less likely bone mets 6) She had high calcium, excessive calcium cabonate, alkalosis, and acute renal insufficiency: Milk Alkali Syndrome

57 Milk Alkali Syndrome 3 rd most common inpatient hypercalcemia 9-12% of hospitalized patients with Calc Most common cause for calcium >14 mg/dl Typically at least 4-5 grams of calcium carbonate per day Renal insufficiency Alkalosis 1,25 D low, PTH low (although variable levels reported), low-normal PO4 Treat with hydration. Mayo Clin Proc 2009;84(3):

58 Hypercalcemia Summary 1) Determine if PTH dependent or independent. 2) Consider cancer Humoral via PTHrP or bone mets 3) If not PTH dependent and not PTHrP. Review 1,25 Vit D and consider if inappropriately high normal to increased, ensure not 25 OH Vid D toxic 4) Consider other causes such as Milk Alkali, hyperthyroidism, AI