Grand Rounds Zebra or Duck Kathryn Dao MD

Grand Rounds: Zebra or Duck Kathryn Dao, MD Arthritis Center Presbyterian Hospital June 29, 2005

Common Dx Uncommon Dx Common S/Sx Common Dx Uncommon S/Sx Uncommon Dx Uncommon S/Sx

Case: Unknown CC: Joint pain, +ANA HPI: MS is a 44 y. o. WF with hyperlipidemia who developed ankle pain and swelling suddenly after she finished a ballet recital. She went to her PCP for evaluation and over the next month she was given in series ibuprofen, naproxen, and Vioxx. The symptoms persisted; she returned to her PCP who drew labs and found an abnormal ANA.

HPI (cont’d): She was given a Medrol dose pack and a referral to rheumatology. The steroids gave her partial relief. She stated the pain progressed to her hands, knees, and ankles. Pain scale 4 out 10. AM stiffness 15 min- 2 h. Activity and heat improve her symptoms. She denied sick contacts, recent travel, weight loss, fever, apthous ulcers, GI/GU complaints, and photosensitivity. Associated symptoms: ? ? Raynaud’s phenomenon, memory difficulties, fatigue, headache, insomnia, “bone pain”, myalgias, depressive symptoms, weight gain 5# since on steroids

PMH: Hyperlipidemia, Acne, Allergic Rhinitis Meds: Allegra, Lipitor, Minocin, Vioxx, Sudafed Allergies: None SX: Patient is married with 2 children; she is a full time homemaker whose hobbies include the ballet and interior design; no tobacco/Et. OH/IVDU, STD risks. FX: Mother with arthritis, Brother with UC

PE: T 98. 6 BP 110/72 HR 78 RR 16 weight 126 lb G: WD female NAD HEENT: No scalp lesions, eyes/ears normal, OP clear Skin: no malar rash, psoriatic plaques, discoid lesions Neck: No LAD/TM. Supple with FROM Pulmonary, CV, Abd: normal Sk. M: +synovitis LPIP 2, 3, right wrist, bilateral ankles L>R. Elbows, shoulders, hips, knees normal. 2+ pedal edema ROM good in all joints. 6 out 18 tender points present. No nodules or deformity.

Labs: from PCP (6/29/04)5. 6 14. 1 261 _ 40. 9 138 108 12 4. 1 24 0. 8 102 Ca 10. 6 TP 7. 4 Alb 4. 0 AST 18 ALT 20 ALP 100 Total chol: 190 TG 194 TSH 1. 4 ANA 1: 1280, RF neg, CRP 1. 2 mg/d. L, CK 35

From Rheum visit (7/13/04) 8. 5 14. 9 246 137 109 13 _ 40. 9 4. 1 24 0. 8 88 Ca 9. 8 TP 7. 2 Alb 3. 8 AST 16 ALT 50 ALP 102 ANA 1: 640, Sm/RNP neg, ds. DNA Ab neg, C 3, C 4 nl RF neg, CCP Ab neg, HLA-B 27 neg, ACE normal Parvo-B 19 Ig. M neg, HBs. Ag neg, HCV Ab neg ESR 1, CRP < 0. 1 Hand/feet x-rays : normal Bone scan: neg

• Possible reactive arthritis other DDx being entertained: RA, palindromic rheumatism, SLE, sarcoidosis, seronegative spondyloarthropathy with peripheral arthritis, drug-induced lupus, metabolic disorder, infectious/neoplastic not likely • Elevated LFTs—possible from NSAID use. Patient advised to minimize use of NSAIDs and to stop Minocin. Repeated LFTs normal. • Patient given prednisone 10 mg/d with followup in 4 weeks.

Patient returned with complete resolution of joint symptoms with the prednisone. Over the following month, she was able to wean herself off steroids completely. Headaches, myalgias, fatigue, memory difficulties, insomnia, depression still persistent. 6 months later, joint symptoms returned—pain and stiffness in feet, ankles, knees, and hands. Now has right thumb numbness. Recent URI illness which resolved with antibiotics. AM stiffness 60 min. Exam: No rash; +synovitis in LPIP 2 -4, RPIP 2, left wrist, and right ankle

From Rheum visit (9/13/04) 5. 8 12. 9 310 137 109 13 _ 37. 9 4. 1 24 0. 8 88 Ca 10. 4 TP 7. 2 Alb 3. 9 AST 18 ALT 22 ALP 102 ESR 4, CRP 0. 4

Review pertinent data/abnormalities • Acute onset inflammatory oligoarticular process with pitting edema progressed to polyarticular process; fatigue, memory problems, myalgias, headaches, bone pain • +ANA • Ca 10. 6 TP 7. 4 Alb 4. 0 AST 18 ALT 20 ALP 100 • Ca 9. 8 TP 7. 2 Alb 3. 8 AST 16 ALT 50 ALP 102 • Ca 10. 4 TP 7. 2 Alb 3. 9 AST 18 ALT 22 ALP 102 PTH 98

24 hour urine calcium elevated DEXA: Wards triangle -2. 7, Hip -2. 4, L-spine -2. 0 24 -0 H vitamin D normal. Sestimibi scan:

Primary Hyperparathyroidism Role of PTH: regulate serum calcium and bone metabolism n Function: 1. Stimulate renal tubular Ca reabsoption 2. Bone resorption 3. Convert calcidiol to calcitriol which stimulates intestinal calcium absorption n NEJM 2000; 343(25): 1863 -75.

Primary Hyperparathyroidism Incidence: more prevalent in persons > 50 y. o. 1/1000 males 2 -3/1000 females n Underlying cause in 85% of patients is a single adenoma (less than 15% due to multiple adenomas or glandular hypertrophy of all 4 glands; <0. 5% from malignancy, MEN syndromes, FHH) n

Primary Hyperparathyroidism NIH consensus panel classify patients as symptomatic vs. asymptomatic n Symptomatic: (15 -20%)- from hypercalcemia n Bones, stones, groans, moans, fatigue overtones (osteitis fibrosa cystica, kidney stones, DI, GI/CV/neuromuscular dysfunction) n Asymptomatic (75 -80%) (HTN, fatigue, PUD, normocytic anemia, weakness, depression, anxiety, cognitive dysfunction) NIH Consens Statement 1990 Oct 29 -31; 8(7): 1 -18.

Primary Hyperparathyroidism Rheumatologic manifestations of PHPTH 1983 Retrospective study of 34 patients with rheumatic symptoms: n myalgias (41%) n arthralgia/arthritis affecting large joints (32%) n erosive synovitis mimicking RA (5%) n radiologic abnormalities (24%) 1978 Prospective controlled study of PHPTH: n 8 out of 26 had chondrocalcinosis, 2 without chondrocalcinosis had documented pseudogout Postgrad Med J 1983; 59(690): 236 -40 J Rheumatol 1978 Winter; 5(4): 460 -8

Primary Hyperparathyroidism n Differential Diagnoses: Elevated Calcium with elevated PTH DDx: HCTZ Lithium FHH (Uca: cr <0. 01) 3 o Hyperparathyroidism (ESRD) Normal Calcium with elevated PTH DDx: Vitamin D deficiency (2 o Hyper. PTH)

Primary Hyperparathyroidism Elevated serum calcium Recheck labs with albumin and correct or check ionized calcium Evaluate for secondary causes (medications) Check intact PTH low Malignancy Granulomatous Dz Adrenal Insufficiency Vitamin A/D Toxicity Hyperthyroid Milk Alkali Syndrome Immobilization high low FHH CRI Check 24 U Cr. Cl, calcium, 25 -OH vitamin D high Primary Hyper. PTH

Primary Hyperparathyroidism n Once Primary Hyper. PTH established, check: Bone Mineral Density at all 3 sites: distal radius, L-spine, hip n Surgery vs. conservative management n Note: Sestimibi parathyroid scan (optional)— sensitivity 83%, PPV 93%

Primary Hyperparathyroidism Conservative Management: 1985 Longitudinal cohort study of 47 patients with PHPTH followed X 5 years; 34% experienced complication from PHPTH —PUD (8), RI (5), renal stone (1), hypercalcemic crisis (1), ventricular conduction defect (1) 1991 Cohort study of 176 patients with sustained hypercalcemia followed 15 years. Survival significantly lower from CV complications 2001 Longitudinal study with matched controls in 172 patients with PHPTH X 25 years, increased mortality in patients <70 y. o (p=0. 015) with CV disease representing deaths; HZ 1. 72 (95%CI, 1. 24 -2. 37); trend over time of normocalcemia in patients (NS) Surgery 1985; 98(6): 1064 -71. J Bone Miner Res 1991; (Suppl 2): S 111 -6. Surgery 2001; 130(6): 978 -85.

Primary Hyperparathyroidism Surgical resection: 2000 Prospective surgical cohort X 10 years- surgical cure obtained in 97. 7% after initial cervical exploration; 54% recovered fully from hypercalcemic syndrome in the 1 st month, 84% patients within first 2 years. No recurrence found 2004 Prospective randomized controlled study 53 patients: 25 SGY, 28 Med Rx followed for 2 years–BMD improved at all sites with SGY, but only in L-spine and radius with Med Rx; in SF-36 of Med Rx decline in social functioning, physical problem, emotional problem, energy, and health perception 2004 Controlled cohort study 3213 HPTH followed 20 years – 60% had surgery, 40% Med Rx; SGY risk for fx (HZ 0. 69), PUD (HZ 0. 59), death (HZ 0. 65), increased episodes of renal stones (HZ 1. 87). Survival in both cohorts decreased relative to general pop. by 2. 1 -2. 7 years; SGY not change CV event rate, psychoses, myalgias. Metab. 2004; 89(11): 5415 -22. J Intern Med. 2004; 255(1): 108 -14 World J Surg 2000; 24(5): 564 -9. J Clin End

Primary Hyperparathyroidism Old and New Criteria for Surgery of ASx Patients Variable 1990 NIH 2002 NIDDK s. Ca concentration 24 h Urine calcium Reduction in Cr. Cl BMD Age 1. 0 -1. 6 mg/d. L above nl >400 mg 30% Z score <-2. 0 in forearm <50 y. o 1. 0 mg/d. L above nl >400 mg 30% T score <-2. 5 any site <50 y. o. NIH Consens Statement 1990 Oct 29 -31; 8(7): 1 -18. J Bone and Mineral Res 2002; 17 (Suppl 2): N 2 -N 11.

Primary Hyperparathyroidism Old and New Guidelines for Medical Management Variable 1990 NIH 2002 NIDDK s. Ca monitoring 24 h Urine calcium Serum creatinine Cr. Cl BMD Abdominal radiograph Dietary guidelines every 6 months every year every year hydration every 6 month not recommended every year all 3 sites not recommended intake of 1000 -1200 mg Ca with 400 -600 IU vit D NIH Consens Statement 1990 Oct 29 -31; 8(7): 1 -18. J Bone and Mineral Res 2002; 17 (Suppl 2): N 2 N 11.

Primary Hyperparathyroidism Medical therapy: Bisphonates n Estrogens/raloxifene n Calcimimetic Drugs n

Primary Hyperparathyroidism n Etidronate: 2002 Japanese study 22 patients (1 yr f/u) Outcome LS-BMD Fracture rate n Etidronate (9) +10% (p<0. 03) Unchanged Surgery (13)____ +20% (p<0. 01) Unchanged Alendronate vs. Placebo: 2001: Italian Study of 26 pts. : alendronate 10 mg/d after 2 years, increase BMD of LS (+8. 6%), Hip (+4. 8%), T-BMD (+1. 2%) 2003: Chinese Study of 40 postmenopausal patients followed 48 weeks; alendronate increase BMD femoral neck +4. 17%, LS +3. 79% 2004 Canadian Study 44 patients (2 yr f/u, placebo crossover at 1 year): BMD of LS (+6. 85%, 4. 1%), hip (+4. 01%, 1. 7%), distal radius (NS) Gerontology. 2002; 48(2): 103 -8 J Bone Min Res 2001; 16(1): 113 -9 J Clin Endoc Metab 2003; 88(2): 581 -7 J Clin Endoc Metab 2004; 89(7): 3319 -25

Primary Hyperparathyroidism n Estrogen: 1996 Australian study: 15 patients (5 ERT, 10 SGY); ERT BMD LS (+5. 3%), femoral neck (+5. 5%), no sig change between ERT and SGY; SGY patients normalized serum calcium level 2000 New Zealand study: 23 patients (4 yr f/u)- RDBPCT with 0. 625 mg conj estrogen with medroxy. PG; HRT increase BMD LS (+7. 5%), femoral neck (+7. 4%), forearm (+7. 0%), total body (+4. 6%) n Raloxifene 2003 NY study: 18 patients drug vs placebo X 8 weeks with 4 week washout; calcium level decreased (10. 8 to 10. 4 mg/d. L) as well as markers of bone resorption and formation (osteocalcin 11. 4 to 9. 9 nm/L; s. NTX 21. 2 to 17. 3 nm/L). No change to PTH, 1, 25 -OH D 3 or urinary Ca Osteoporosis Int 1996; 6(4): 329 -33. Arch Int Med 2000; 160(14)2161 -6 J Clin Endo Met 2003; 88(3): 1174

Primary Hyperparathyroidism n Cinacalcet (calcimimetic) 2003 UCSF RDBPCT: 22 patients, 2 week of drug followed by 1 week observation. Cinacalcet (30, 40 or 50 mg bid) v. placebo. Serum calcium normalized on second dose of day 1 of all treated with drug and remained within normal range. PTH decreased by 50% with active treatment. 2004 Indiana Univ RDBPCT: 78 patients; 12 weeks therapy with 28 week followup. Cinacalcet 73% reduction in s. Ca vs placebo 5%; reduction in PTH with treatment (by 7. 6%) vs. rise in PTH in placebo (by 7. 7%). No change in BMD, increase in bone resorption and formation markers 2005 Arizona RDBPCT Cinacalcet in 2 o HPTH: 14 patients with ESRD, 26 week therapy. PTH decreased, BMD increased femur J Clin End Met 2003; 88(12): 5644 -9 Nephrol Dial Transpl 2005; 20(6): 1232 -7 (p<0. 05), no effect on L-spine J Clin End Metab 2005; 90(1): 135 -41

MS underwent surgical exploration or her neck; a parathyroid adenoma was resected from the left inferior aspect. Biochemical confirmation was made by a 67% drop in the intact PTH within 5 minutes consistent with the removal of autonomously functioning parathyroid tissue. Will her polyarticular synovitis resolve…. . . or does she have an underlying CTD? ? ?