Hall
Centre for Diabetes and Metabolism, Southern General Hospital, 1345 Govan Road, Glasgow, G51 4TF
Correspondence to: lesleyhall@doctors.org.uk
SMJ 2006 51(2): 54
Abstract
A 28 year old man with primary hypoparathyroidism failed to respond to
treatment with calcium and vitamin D analogues. Despite extensive investigation no reason for this was found
and he is now successfully treated with teriparatide (synthetic human PTH)
Case
Report
A 28 year old former American footballer with no past medical history of
note, presented to our hospital, in July 1996 with a two-year history of
progressively marked paraesthesiae, carpo-pedal spasm and headache.
Serum calcium adjusted for albumin was 1.45mmol/l and parathyroid
hormone (PTH) (measured by an intact two site sandwich immunoassay with
chemiluminescence –Bayer ACS: 180 analyser) was undetectable, in keeping with
a diagnosis of primary hypoparathyroidism.
There was no evidence of a polyglandular autoimmune syndrome as skin and
dentition were normal, as were adrenal and thyroid function.
Other baseline investigations showed:
Serum phosphate:
2.05mmol/l (0.7-1.4mmol/l)
Serum magnesium: 0.90mmol/l (0.7-1.0mmol/l)
Alkaline phosphatase:
130U/l (80-250U/l)
25 hydroxyvitamin D:
41nmol/l (15-100nmol/l)
1,25 dihydroxyvitamin D:
40pmol/l (20-120pmol/l)
24 hour urinary calcium: 0.6mmol (2.50-7.50mmol)
Subsequent imaging of the brain was also normal with no evidence of
intracerebral calcification.
He was commenced on treatment with calcium carbonate (Calcichew) and
alfacalcidol (1 alpha-hydroxycholecalciferol) at initial doses of 2.5 grams
daily and 1 microgram daily respectively, but responses, both clinically and
biochemically were suboptimal. The
doses of both preparations were increased eventually to 6 grams of calcium
carbonate and 8 micrograms of alfacalcidol daily, but despite this serum calcium
(adjusted for albumin) remained below 1.70mmol/l.
To exclude a malabsorptive problem anti-endomysial antibody was measured and was negative, small bowel biopsy was normal and radiocalcium absorption was normal at 68% (normal range 47-69%). Serum calcium remained static between 1.55 and 1.70mmol/l.
The possibility that alfacalcidol was not being metabolised to 1,25
dihydroxyvitmin D was considered. Alfacalcidol was therefore changed to
calcitriol and the dose increased up to 12 micrograms daily. A peak serum
calcium of 1.86mmol/l was obtained but not sustained and he became progressively
more symptomatic with worsening weakness and evidence of a glove and stocking
distribution neuropathy. At this
stage he was admitted for further investigation and treatment.
During his 7 day long admission he was given a single infusion of
120mmol of calcium gluconate over 24 hours.
This resulted in a dramatic symptomatic improvement associated with a
peak in serum calcium of 2.59mmol/l. Unfortunately,
as expected, this effect was extremely short-lived and his symptoms returned 4
days later, when serum calcium dropped below 1.9mmol/l.
His drug compliance was carefully observed throughout his admission and
this seemed to be complete. Serum
calcium on discharge from hospital was 1.80mmol/l.
Measured vitamin D metabolites remained low normal, indicating scope to
increase the dose of calcitriol. Bendroflumethiazide
was also commenced for its anticalciuretic effect.
Despite these measures vitamin D metabolites and serum calcium remained
low and the patient was having major problems tolerating the high prescribed
doses of oral calcium carbonate. He
was admitted to hospital once again to investigate the effect of parenteral
(intravenous) alfacalcidol, which was given on only one occasion.
This resulted in a predictable increase in vitamin D metabolites (maximum
1,25 dihydroxyvitamin D; 80 pmol/l). Serum
calcium also rose but only to a plateau of 1.80mmol/l, and this effect lasted
for only 3 days.
By September 1998 he was using large doses of both benzodiazepines and
amitriptyline for neuropathic pain and having to wear wrist splints.
He had lost 16 kilograms in weight, which was mostly muscle bulk
secondary to poor mobility and investigations for other causes of weight loss
were negative. Early in 1999 he had
a generalised seizure. CT of the brain was normal and he was commenced on
carbamazepine. He continued to have
seizures approximately once a month despite persistently therapeutic
carbamazepine levels and serum calcium remained below 1.80mmol/l.
Further investigation showed a small benefit of subcutaneous calcitriol
over the oral preparation, in that it sustained normocalcaemia for longer
following an infusion of intravenous calcium gluconate, so he was changed on to
this at a dose of 1 microgram twice daily and remained on it for 3 years in
total. (Subcutaneous
cholecalciferol was not used, both to avoid potential problems in the metabolism
of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, and also because of erratic
and unpredictable absorption of this substance into the systemic circulation).
In view of frustration about the lack of benefit with the oral treatment
and the difficulty in continuing with such large doses of calcium carbonate, the
patient had largely abandoned this and he continued to attend hospital
approximately monthly for 24-hour infusions of intravenous calcium gluconate
(120mmol/ 24 hours). He lost a further 20 kilograms in weight.
In March 2004 synthetic human PTH (teriparatide) was licensed for use in
osteoporosis and this man was commenced on it at a dose of 20 micrograms daily,
the recommended treatment dose for osteoporosis.
Prior to treatment with teriparatide serum calcium was 1.28mmol/l.
A month after starting treatment he was symptomatically better, serum
calcium was 1.76 mmol/l, serum phosphate was 1.53mmol/l, alkaline phosphatase
was higher than before at 201U/l, however 24 hour urinary calcium remained low
at 0.3mmol. Two months later he was
seizure free, no longer wearing wrist splints and serum calcium was 1.84 mmol/l.
A plateau in serum calcium was reached at 1.85mmol/l so the dose of
teriparatide was increased to 20 micrograms twice daily.
A week later, serum calcium was 2.26, within the normal range and our
patient was asymptomatic. This effect was, unfortunately not sustained.
His serum calcium drifted down to around 1.85mmol/l and although he was
symptomatically much better, he was still suffering from carpo-pedal spasm on
exertion. The dose of teriparatide
has recently been increased to 20 micrograms three times a day, and serum
calcium is once again within the normal range at 2.28mmol/l (24 hour urinary
calcium 0.7mmol)
Figure 1 illustrates the
various interventions that were tried, and the serum calcium response to each
treatment.
Discussion
Hypoparathyroidism is one of the few hormone deficiency states for which
treatment with hormone replacement is not available.
Conventional therapy with calcium and vitamin D analogues increases
intestinal calcium absorption and usually results in normocalcaemia but this is
often at the expense of hypercalciuria, as the deficiency in renal calcium
absorption is not corrected. This
can, with time result in nephrocalcinosis, nephrolithiasis and eventual renal
impairment. PTH would therefore be
a more logical treatment.
Studies dating back over the last 25 years have shown that human
parathyroid hormone (PTH 1-34) can be used for diagnostic purposes in
differentiating PTH-responsive hypoparathyroidism from syndromes associated with
PTH resistance (pseudohypoparathyroidism).1,2 More
recently several studies have been done looking at PTH 1-34 as a treatment for
hypoparathyroidism. Studies by
Winer et al3,4, have compared teriparatide (PTH 1-34) with
conventional treatment for hypoparathyroidism, most recently in an open label
randomised controlled trial over a 3 year period.
The study showed that while serum calcium, magnesium and phosphate were
similar in both treatment arms, urine calcium excretion remained within the
normal range in the PTH treated group, but was significantly elevated in the
conventional treatment group3.
Our patient’s case is unusual in that despite apparently acceptable
compliance with calcium carbonate, alfacalcidol and eventually calcitriol, there
was a grossly suboptimal biochemical and clinical response.
Compliance with teriparatide is difficult to asses as the conventional
PTH assay does not pick up the PTH 1-34 fragment, which is, in any case short
lived in plasma. The mechanism for
his lack of response to treatment remains unclear and there is no significant
literature describing similar cases.
This case, however, also illustrates the fact that teriparatide can be an effective treatment for hypoparathyroidism when conventional therapy fails.
References
1.
Neer RM, Tregear GW, Potts JT Jr. Renal
effects of native parathyroid hormone and synthetic biologically active fragment
in pseudohypoparathyroidism and hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism.
44(2):420-3,1977 Feb
2.
McElduff A, Lissner D, Wilkinson M, Cornish C, Posen S.
A 6-hour human parathyroid hormone infusion protocol: studies in normal
and hypoparathyroid subjects. Calcified
Tissue International 41 (5) 267-73. 1987 Nov
3.
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. [Clinical Trial. Journal Article. Randomized Controlled Trial] Journal
of Clinical Endocrinology & Metabolism. 88(9):4214-20, 2003 Sep.
4.
Winer KK, Yanovski JA, Cutler GB Jr.
Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the
treatment of hypoparathyroidism. JAMA.
276(8):631-6. 1996 Aug