Hypoparathyroidism and Difficult to Control Hypocalcemia

Question

: I am taking care of a 47 woman with PMH of RA and Hep B s/p thyroid lobectomy in 1994 for thyroid nodules with completion thyroidectomy in 2008 because of dysphagia in the Philippines. She reports that she did not have a history of cancer but her medical records are not available. She has had post-operative hypoparathyroidism. She is post-menopausal as of May 2011 and has osteopenia.

Her previous physicians had her on 1950mg of elemental Calcium TID for a total daily dose of 5850mg. She was also taking vitamin D3 600 IU daily and one-alpha (alfacalcidiol) 0.5mcg-1mcg daily . However, she was having significant diarrhea, and her calculated her fractional excretion of calcium = (6.11mmol/d x 0.107mmol/L)/(2.05mmol/L x 9.6mmol/d)=3.3% and so I slowly reduced her dose to 650mg QID, increased Vit D3 to 2000 IU daily and changed her one-alpha to Rocaltrol 1mcg BID. I also added a thiazide diurectic (HCTZ) at 12.5mg daily at a low dose considering her BP of 110/66 to reduce calciuria. I made these changes in February 2012.

She continues to be biochemically hypocalcemic with symptoms of parasthesias. an you please advise how to correct her hypocalcemia. Her labs are as below (reference ranges are in brackets).

Recent labs:

May 26 2012

Mg 0.69 (ref 0.65-1.05)

Cr 111 (ref 60-115)

Ca 1.76 mmol/L (ref 2.15-2.6)

Phos 1.88 (ref 0.8-152)

Feb 23 2012

Hgb 129

CK 337 (ref 29-165)

Ca 2.05 mmol/L

Albumin 45

TSH 6.66

FT3 3.3 (REF 3.5-6.5)

FT4 17 (REF 9-23)

iCA 1.06 (REF 1.15-1.35)

25OH VIT D 75

1,25 VIT D 51 (REF 30-120)

Dec 22 2011

Hgb 117

Cr 105

AST 24

ALT 19

CK 265

Ca 1.83 (ref 2.15-2.6)

iCa 0.91 (ref 1.15-1.35)

Phos 2.38 (ref 0.80-1.45)

Mg 0.77 (ref 0.7-1.0)

PTH < 0.3

FT3 4.3 (REF 3.5-6.5)

FT4 26 (REF 9-23)

TSH 0.05

25OH vit D 77

TTG Ab 6 (ref <20)

ACR 6.6

Dec 1 2011

Ca 1.64 (REF 2.15-2.60)

PHOS 2.6 (REF 0.8-1.45)

FT3 3.9 (REF 3.5-6.5)

FT4 22 (REF 9-23)

Cr 105

GFR 49

OCT 31 2011

PTH < 0.03

CA 1.68 (REF 2.15-2.60)

PHOSPHATE 2.28 (REF 0.8-1.45)

ALBUMIN 43

FT3 4.8 (REF 3.5-6.5)

FT4 34 (REF 9-23)

TSH < 0.05

ionizeD ca 0.82 (ref 1.15-1.35)

HGB 121

CR 98

AST 25

ALT 18

ALK PHOS 52

25 OH VIT D 80

OCT 6 2011

L FEMORAL NECK T -0.9, Z -0.5

L TOTAL FEMUR -1.1, Z -0.9

L SPINE T 0.6 T 0.9

Tharsan Sivakumar, MD, MPH, FRCPC
Toronto

Response

From the above it is not clear what Ca salt she was taking at the time she manifested diarrhea. My guess would be that the Ca was not giving her diarrhea but that she was malabsorbing the Ca due to diarrhea and rapid GI transit. Therefore if she still has significant diarrhea, I would recommend an evaluation for it. If it is due to a parasitic process or celiac disease for example, it can be addressed. Diarrhea and malabsorption are very important issues in the treatment of hypoparathyroidism. Important electrolytes can be lost as well as important nutritional factors (protein, fat, etc). These include K+ and Mg2+ as well as the Ca2+ supplements she is taking. I would recommend a gastroenterologist evaluate the patient if there is ongoing diarrhea.

Regarding her current supplements:

(1) vitamin D3: I think the amount of vitamin D3 at the current dose is sufficient (2000 IU/day). I would not recommend changes there. Serum levels are 75 and 80 with no units mentioned and no normal range. If the units are “nM”, then her levels are more than sufficient. If they are “ng/ml”, then you have her at the top of the desired “normal” range. With an undetectable PTH and high serum phosphate, it is doubtful she will be doing significant conversion of 25 OH vitamin D to 1,25 (OH)2 vitamin D.

(2) Rocaltrol: She is now taking a substantial dose of this medication. If she is malabsorbing in general, she should still be able to absorb most of this least of the polar vitamin D metabolites. I have seen patients taking more than 2 micrograms per day to treat hypoparathyroidism, but I have never been convinced that doses above this level were needed to restore gi absorption of Ca. The dose can be increased and spread out from bid to tidn(e.g., 1 ug tid), but I doubt that that alone will bring the serum Ca to the desired low normal range 8.0-9.0 mg/dL. You have a 1,25 D level showing she is in the middle of the normal range. Those levels are hard to interpret in this context.

(3) Ca supplements: With possible diarrhea and RA in the picture, one must think of a possible underlying process such as atrophic gastritis. I would check CBC, mcv, vitamin B12 level. I tend to favor the use of calcium citrate instead of carbonate in my patients with hypoparathyroidism. Citrate does not require gastric acid for absorption and does not need to be taken in conjunction with a meal for ideal absorption. So the type of supplement is not specified and I would convert the main Ca supplement to citrate to see if that allows for better control of the serum Ca. Clearly the doses of elemental Ca for this patient have gone as high as nearly 6 grams per day. With the undetectable PTH this is not surprising, since those with low to no residual PTH secretion are the most difficult patients to control. If you are switching her from her current Ca dosing to citrate, I would start with 1 Gm elemental Ca (as Ca citrate) tid and rocaltrol 1 ug tid and follow closely. Incrementally, she can be up-titrated with Ca 1.25 Gm tid, 1.5 Gm tid, 1.75 Gm tid, 2 Gm tid etc. Option #7 might be a consideration at these higher levels.

(4) Mg supplements: I see 2 borderline low normal serum Mg levels. In my experience, patients with hypoparathyroidism often need Mg supplements especially in light of the prior or ongoing problems with diarrhea. I would check a 24 hour urinary Mg and creatinine level to see if there is detectable Mg being excreted. If there was I would probably still try a gentle amount of supplementation, I say gentle because of the possible baseline diarrhea and the diarrhea that can come from oral Mg supplements. If the urinary level of Mg is very low or undetectable, then for sure, your patient is Mg depleted. This can happen even with a “normal” serum Mg level. I would supplement more vigorously in that case. Since Mg is an intracellular ion, serum levels do not reflect the degree of total body Mg depletion.

(5) I don’t see basic chemistries here, with ongoing diarrhea, K depletion is a concern and must be supplemented. Hypocalcemia, hypomagnesemia/Mg depletion, and hypokalemia all can present with tetany and muscle symptomatology. I would monitor the serum electrolytes periodically.

(6)Thiazide diuretics: Unfortunately at the dose the patient is taking, there may be little urinary Ca lowering effects ongoing. I would try to increase to at least 25 mg/day. If that is not tolerated, you could try giving an additional dose of 12.5 mg before going to bed as she might tolerate it then. I would follow the 24 hour urinary Ca level with creatinine. I am aiming to achieve a level less than 300 or 350 mg/24 hours (with an adequate urinary creatinine assuring a good collection). I am not familiar with the clinical application of the excretion assessment the doctor is using and just monitor the 24 hour urinary Ca and creatinine totals.

(7) Replacement with PTH: At present in the US, human recombinant PTH (1-34) is available for the treatment of patients with osteoporosis. I would consider it in this patient, as an off-label use if I up-titrated to 1-2 micrograms rocaltrol, added Mg supplements, added additional thiazide, and got the Ca supplements to 1.5-2 Gm tid without reaching at least a serum Ca of 8.0 mg/dl and controlled symptoms. Conversion to SI units would be about 2.00 mM Ca and relative control of symptoms. I have used PTH (1-34) 20 mcg once daily and even twice daily. It is reported sometimes that patients may be titrated down once they have improved. Outside the US, both recombinant PTH 1-34 and PTH 1-84 (the full-length authentic secreted form of the hormone) are available and could be considered in the context of an off-label use. There are several papers that report on the use of PTH 1-34 and PTH 1-84 in the treatment of hypoparathyroidism. They are listed below, but at least in the US, this is still an off-label use of the hormone and PTH 1-84 is not available in the US.

(8)Diet: No mention is made of this but I would encourage the patient to consume a diet with at least 1000 mg of absorbable Ca in it.

Dr Dolores Shoback

References on PTH 1-34 or PTH 1-84 for treatment of hypoparathyroidism.

Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism. J Clin Endocrinol Metab. 2012 Feb;97(2):391-9. Epub 2011 Nov 16.

Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K, Cutler GB Jr. Long-term treatment of 12 children with chronic hypoparathyroidism: arandomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010 Jun;95(6):2680-8. Epub 2010 Apr 14.

Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with poparathyroidism. J Clin Endocrinol Metab. 2008 Sep;93(9):3389-95. Epub 2008 May 20.

Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, Gerber LH, McGarvey C, Cutler GB Jr. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003 Sep;88(9):4214-20.

Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab. 1998 Oct;83(10):3480-6.

Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA. 1996 Aug 28;276(8):631-6.

Rubin MR, Dempster DW, Sliney J Jr, Zhou H, Nickolas TL, Stein EM, Dworakowski E, Dellabadia M, Ives R, McMahon DJ, Zhang C, Silverberg SJ, Shane E, Cremers S, Bilezikian JP. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res. 2011 Nov;26(11):2727-36.

Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP. Therapy of hypoparathyroidism with intact parathyroid hormone. Osteoporos Int. 2010 Nov;21(11):1927-34. Epub 2010 Jan 22.

Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L; Hypoparathyroid Study Group. The effect of adding PTH(1-84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res. 2011 Oct;26(10):2358-70.

Thank you Drs. Shoback for this detailed and informative response. I will try some of these suggestions to see if it helps with her hypocalcemia. Tharsan Sivakumar, MD, MPH, FRCPC