Clinical Chemistry 57:6
811–815 (2011)
Hypocalcemia following Treatment for Hyperthyroidism
Claire L. Meek,1* Felicity Kaplan,2 R. Scott Pereira,3 and Adie Viljoen1
CASE
A 17-year-old female was referred to the endocrinology
clinic after blood test results suggestive of hyperthy-
roidism. She had mild symptoms of thyrotoxicosis, in-
cluding menstrual disturbance with intermittent palpi-
tations and tremor. On examination, the patient was
normotensive, tachycardic (100 beats/min), and of
slim build with poor dentition. She had a small diffuse
goiter without retrosternal extension or bruit. There
was conjunctival injection but no evidence of lid lag or
proptosis. Auscultation of the precordium revealed
murmurs in systole and diastole consistent with mixed
aortic valve disease.
The only child of healthy nonconsanguineous par-
ents, the patient had previously been well. Her medical
history included mild learning difficulties, a bicuspid
aortic valve, recurrent urinary tract infections, and se-
vere constipation as a child that required a colostomy,
which was later reversed. Apart from an osmotic laxa-
tive, she received no other regular medication. A recent
echocardiogram had demonstrated a bicuspid aortic
valve with good flow and minor regurgitation.
Biochemically, the patient had an undetectable se-
rum concentration of thyroid-stimulating hormone
(TSH)4 (⬍0.03 mIU/L; reference interval, 0.3–5.6
mIU/L) and an increased concentration of free thyroid
hormone (fT4) [43 pmol/L (3.3 ng/dL); reference inter-
val, 7.5–21.1 pmol/L]. Her baseline serum concentrations
of total calcium [2.27 mmol/L (9.08 mg/dL)] and phos-
phate [1.26 mmol/L (3.9 mg/dL)] were both within their
reference intervals (2.20 –2.60 mmol/L and 0.75–1.36
mmol/L, respectively). The serum albumin concentration
was 41 g/L (reference interval, 35–50 g/L), and the mag-
nesium concentration was 0.71 mmol/L (reference inter-
val, 0.74 –1.00 mmol/L). The results of her other bio-
chemical tests were unremarkable. An immunologic
1
Departments of Chemical Pathology, 2 Endocrinology, and 3 Immunology, Lister
Hospital, Stevenage, UK.
* Address correspondence to this author at: Department of Chemical Pathology,
Lister Hospital, Corey’s Mill Lane, Stevenage SG1 4AB, UK. E-mail
claire.meek@nhs.net.
This case was presented in abstract form as a poster at the AACC conference,
2009.
Received May 25, 2010; accepted September 2, 2010.
DOI: 10.1373/clinchem.2010.150375
4
Nonstandard abbreviations: TSH, thyroid-stimulating hormone; fT4, free thyrox-
ine; PTH, parathyroid hormone.
Clinical Case Study
QUESTIONS TO CONSIDER
1. What effect does thyrotoxicosis have on serum calcium?
2. What other endocrine disorders affect serum calcium?
3. What genetic diseases can affect serum calcium?
analysis demonstrated increased thyroid peroxidase anti-
bodies (582 IU/L; reference interval, 0 – 60 IU/L) and in-
creased TSH receptor antibodies (6.9 U/L; reference in-
terval, 0 –1.5 U/L), confirming Graves disease. Thyroid
imaging revealed a diffusely enlarged thyroid gland, with
no visible parathyroid tissue apparent on ultrasound and
MRI evaluations.
After daily treatment with 30 mg carbimazole and
25 mg atenolol, the fT4 concentration in the patient
decreased as expected (fT4, 19.2 pmol/L; TSH, 0.03
mIU/L). Concomitantly, the patient developed asymp-
tomatic hypocalcemia [calcium, 1.72 mmol/L (6.88
mg/dL)]. The total 25-hydroxyvitamin D concentra-
tion was 38 nmol/L (reference interval, 15–100 nmol/
L), and her serum magnesium concentration was 0.87
mmol/L (reference interval, 0.74 –1.00 mmol/L). Both
were within their respective reference intervals. The se-
rum phosphate concentration was 1.28 mmol/L (refer-
ence interval, 0.9 –1.35 mmol/L), and the albumin con-
centration was 48 g/L (reference interval, 35–50 g/L).
The parathyroid hormone (PTH) concentration was
also within the reference interval [4.8 pmol/L (4.8 ng/
L); reference interval, 1.6 –9.3 pmol/L] and thus inap-
propriately normal given the degree of hypocalcemia.
A diagnosis of hypoparathyroidism was made, and the
patient was treated with 0.5 ␮g alfacalcidol daily. The
calcium concentration briefly normalized (Table 1).
After this improvement, the patient stopped com-
plying with her carbimazole and alfacalcidol treatment
regimen, and the results of thyroid function tests re-
turned to near pretreatment concentrations [fT4, 58.4
pmol/L (4.5 ng/dL); TSH, ⬍0.03 mIU/L; calcium, 2.34
mmol/L (9.36 ng/dL); Table 1]. With improved patient
compliance, the fT4 results improved, approaching eu-
thyroidism. The patient eventually achieved a normo-
calcemic state [fT4, 13.5 pmol/L (1.0 ng/dL); calcium,
2.35 mmol/L (9.4 mg/dL)]. More recently, compliance
has been a concern with recurrent increased fT4 con-
centrations (Table 1).
811
Clinical Case Study
Table 1. Chronological changes in the serum concentrations of total calcium and fT4 as treatment progressed.a
Reference
Analyte interval
TSH, mIU/L 0.3–5.6
fT4, pmol/L 10–21
Total calcium, mmol/L (mg/dL) 2.2–2.6 (8.8–10.4)
Phosphate, mmol/L 0.9–1.35
Albumin, g/L 35–50
a
At presentation of thyrotoxicosis, treatment with carbimazole caused fT4 to improve, with a significant reduction in calcium. Concomitant treatment with
alfacalcidol caused calcium concentrations to normalize. Treatment noncompliance 12 months after presentation caused a thyrotoxicosis relapse, which was
treated to achieve euthyroidism and normocalcemia. The most recent results demonstrate recurrent thyrotoxicosis, which may also be related to noncompliance.
Values in boldface are outside the reference interval. NA, data not available.
The patient gave full written consent for the use of
her clinical information and laboratory tests for the
purposes of submission of a case report to the medical
literature. She has very mild learning difficulties but
was able to understand, process, and retain the infor-
mation given.
DISCUSSION
The underlying cause of the hypoparathyroidism was
elucidated after several further laboratory investiga-
tions were undertaken for the patient. A fluorescence
in situ hybridization analysis revealed a deletion at
22q11 consistent with DiGeorge syndrome. An echo-
cardiography examination revealed a bicuspid aortic
valve, but no other cardiac abnormality. A lymphocyte
analysis showed typical lymphocyte subsets.
This report illustrates that a dual pathology may ob-
scure a diagnosis. In this case of previously undiagnosed
DiGeorge syndrome, the hypercalcemic effect of uncon-
trolled thyrotoxicosis masked the underlying diagnosis of
hypoparathyroidism. Treatment of the thyrotoxicosis al-
lowed the underlying hypoparathyroidism to be identi-
fied and led to the investigation for DiGeorge syndrome.
Biochemical testing was fundamental in elucidating the
multiple diagnoses in this case.
Calcium metabolism is under strict homeostatic
control through the coordinated actions of PTH and
activated vitamin D. Hypoparathyroidism is an un-
common condition characterized by inadequate PTH
secretion, which leads to hypocalcemia. The fact that
patients may experience few symptoms even at re-
markably low calcium concentrations can hinder diag-
nosis. In this case of the rare combination of hypopara-
thyroidism and thyrotoxicosis, hypocalcemia became
evident only upon treatment of the thyrotoxicosis. In-
terestingly, this patient had had slightly low and low-
normal calcium results in childhood. These findings
812 Clinical Chemistry 57:6 (2011)
Months after presentation
0 5 6 12 22 36
<0.03 0.03 0.03 <0.03 <0.03 <0.03
43.0 19.2 11.8 58.4 13.5 54.1
2.27 (9.08) 1.72 (6.88) 2.21 (8.84) 2.34 (9.36) 2.35 (9.40) 2.44 (9.76)
1.26 1.28 1.20 NA 1.25 0.83
41 48 53 NA NA 43
had been attributed to her stoma and appeared to nor-
malize after oral calcium administration.
Thyrotoxicosis has been known for many years to
cause a syndrome of hypercalcemia (1 ). The mecha-
nism for hypercalcemia in thyrotoxicosis has yet to be
fully elucidated, but one possibility is that it may be due
to increased bone resorption (2 ) causing calcium re-
lease into the circulation and increased urinary excre-
tion of calcium, phosphate, and hydroxyproline. The
association between long-standing thyrotoxicosis and
osteoporosis adds weight to the likelihood of this po-
tential mechanism. Another possibility is that thyro-
toxicosis may have some direct or indirect effect on the
parathyroid glands. Although there is evidence that the
hypercalcemia of thyrotoxicosis occurs independently
of the parathyroid axis (3 ), increased PTH concentra-
tions that normalize with successful treatment have
been described for patients with thyrotoxicosis (4 ).
The degree of hypercalcemia in thyrotoxicosis pa-
tients is extremely variable. A majority of patients have
minor fluctuations in the calcium or phosphate con-
centration, but some patients have markedly symp-
tomatic disease. Occasionally, the hypercalcemia can
be a presenting feature of the disease. In a recent series,
2 patients were found to have hyperthyroidism after an
investigation for hypercalcemia (5 ). The hypercalce-
mic effect of thyrotoxicosis in the present patient with
hypoparathyroidism produced a serum calcium con-
centration within the reference interval.
The dual pathology of idiopathic hypoparathy-
roidism and thyrotoxicosis has been described previ-
ously in the literature, beginning in 1962. The first 3
cases (6 – 8 ) were of female patients with idiopathic
hypoparathyroidism presenting with biochemical and
clinical evidence of hypocalcemia and concomitant hy-
perthyroidism. In 1 case, the patient presented in preg-
nancy. In the other 2 cases, the hypoparathyroidism

likely predated the thyrotoxicosis. None of these pa-
tients were tested for 22q11 deletions.
A more recent report described a case series of 4 chil-
dren who presented early in life with speech disturbance,
symptomatic hypoparathyroidism, thyrotoxicosis, and
appreciable congenital heart disease due to underlying
22q11.2 deletion (9 ). A subsequent report described a pa-
tient with DiGeorge syndrome with 22q11 deletion (10 )
who presented at age 18 years with symptoms of hypocal-
cemia and thyrotoxicosis. The authors referred to this case
as “partial” DiGeorge syndrome because the parathyroid
and thymic abnormalities were not as severe as those doc-
umented in other cases.
The present case is the first description in the lit-
erature of a patient with 22q11 deletion who presented
with concomitant symptomatic thyrotoxicosis and
asymptomatic hypoparathyroidism and who had a se-
rum calcium concentration that was paradoxically
within the reference interval. Treatment of the thyro-
toxicosis permitted the identification of the underlying
hypoparathyroidism and prompted investigation for
DiGeorge syndrome.
DiGeorge syndrome, which occurs at a frequency
of about 1 in 4000 live births, is caused by a deletion on
chromosome 22. The deletion is usually due to sponta-
neous mutation, but autosomal dominant inheritance
patterns have also been described. The disease has a
highly variable expression. DiGeorge syndrome and
the related conditions velocardiofacial syndrome and
conotruncal anomaly face syndrome are characterized
by the “CATCH-22” features: cardiac defects, abnor-
mal facies, thymic dysfunction, cleft palate, and hy-
pocalcemia caused by a deletion on chromosome 22.
Thymic dysfunction causes an abnormal maturation of
T cells and an increased susceptibility to infection.
Many affected children die in the perinatal period from
congenital cardiac disease or severe infections, whereas
other affected patients survive into adolescence with
few symptoms. The current case is of a patient with an
atypical presentation of features at the milder end of
the DiGeorge spectrum. Diagnosis requires cytogenetic
testing, which is prompted by the clinical features.
The mechanism for the development of thyrotox-
icosis in DiGeorge syndrome is unclear, but several re-
ports have demonstrated the presence of thyroid anti-
bodies, findings that indicate a likely autoimmune
etiology (9, 10 ). Paradoxically, these patients with a re-
duced immune function thus appear to develop likely
autoimmune-mediated thyrotoxicosis. T-regulatory
cell dysfunction due to a lack of thymus may lead to the
production of autoimmune phenomena, with autoan-
tibody production. The reason the thyroid is the usual
target endocrine organ in this condition may be that
the third and fourth pharyngeal pouches, which are the
embryologic source of all of the thymus and the 4 para-
Clinical Case Study
POINTS TO REMEMBER
• Thyrotoxicosis can cause hypercalcemia: The mecha-
nism for this feature is incompletely understood.
• A genetic cause of hypocalcemia should be considered
in patients with multiple abnormalities or in those who
present in an unusual manner.
• DiGeorge syndrome (22q11.2 deletion) is diagnosed
with the aid of fluorescence in situ hybridization.
• DiGeorge syndrome is characterized by the “CATCH-22”
conditions: cardiac abnormalities, abnormal facies, thy-
mic dysfunction, cleft palate, and hypocalcemia due to
a deletion on chromosome 22. Thyrotoxicosis is a rare
additional feature.
thyroids, are also involved in part of thyroid organ de-
velopment.
CONCLUSIONS
We describe the 10th case of DiGeorge (22q11 dele-
tion) syndrome with hypoparathyroidism and thyro-
toxicosis to be published. Unusually, in this case, the
dual endocrine pathology presented with a calcium
concentration that was paradoxically within the refer-
ence interval. Treatment of the thyrotoxicosis permit-
ted identification of the underlying hypoparathyroid-
ism and led to further investigation that confirmed
DiGeorge syndrome. The dual pathology was demon-
strated several times during periods of the patient’s
noncompliance with treatment.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: Upon man-
uscript submission, all authors completed the Disclosures of Potential
Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: C.L. Meek, Pfizer.
Research Funding: None declared.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
Acknowledgments: We are very grateful to Janine Burbridge and
Mamta Purbhoosing from North West Thames Genetics Service for
Clinical Chemistry 57:6 (2011) 813
Clinical Case Study
their analysis and interpretation of the fluorescence in situ hybrid-
ization results.
References
1. Baxter JD, Bondy PK. Hypercalcemia of thyrotoxicosis. Ann Intern Med
1966;65:429 – 42.
2. Mundy GR, Shapiro JL, Bandelin JG, Canalis EM, Raisz LG. Direct stimulation
of bone resorption by thyroid hormones. J Clin Invest 1976;58:529 –34.
3. Burman KD, Monchik JM, Earll JM, Wartofsky L. Ionized and total serum
calcium and parathyroidism in hyperthyroidism. Ann Intern Med 1976;84:
668 –71.
4. Barsotti MM, Targovnik JH, Verso TA. Thyrotoxicosis, hypercalcemia, and
secondary hyperparathyroidism. Arch Intern Med 1979;139:661–3.
Commentary
Donald Zimmerman*
This case describes an important metabolic effect of
increased thyroid hormone concentrations on calcium
and bone as well as subtle T-cell defects known to occur
in the setting of DiGeorge syndrome (also known as
DiGeorge sequence). DiGeorge sequence is caused by
chromosomal deletions at 22q11.2, which can be trans-
mitted with an autosomal dominant pattern of inheri-
tance; new mutations constitute 90% of cases.
Calcium metabolism is regulated by parathyroid
hormone and by vitamin D. Physiological concentra-
tions of thyroid hormone do not direct calcium ho-
meostasis, but high concentrations often produce im-
portant perturbations.
In 1891, von Recklinghausen described bone ab-
normalities in hyperthyroidism. In the 1920s, investi-
gators at Massachusetts General Hospital observed in-
creased calcium excretion in hyperthyroidism and that
it occurred independently of parathyroid hormone.
Hypercalcemia was observed in thyrotoxic pa-
tients in the 1930s and 1940s. Twenty-seven percent of
hyperthyroid patients have an increased total calcium
concentration, and 47% have increased ionized cal-
cium (1 ). Parathyroid hormone is suppressed in these
patients.
We described a patient who had hypoparathyroid-
ism, conotruncal cardiac abnormalities, and develop-
mental delay suggestive of DiGeorge sequence and who
became hypercalcemic with Graves disease (2 ).
Children’s Memorial Hospital, Chicago, IL.
* Address correspondence to the author at: Children’s Memorial Hospital, Box 54,
2300 Children’s Plaza, Chicago, IL 60614-3393. E-mail dzimmerman@
childrensmemorial.org.
Received December 12, 2010; accepted January 10, 2011.
DOI: 10.1373/clinchem.2010.159095
814 Clinical Chemistry 57:6 (2011)
5. Iqbal AA, Burgess EH, Gallina DL, Nanes MS, Cook CB. Hypercalcemia in
hyperthyroidism: patterns of serum calcium, parathyroid hormone and 1–25-
dihydroxyvitamin D3 levels during management of thyrotoxicosis. Endocr
Pract 2003;9:517–21.
6. Dahl JR, McFadden SD, Eisenberg E. Idiopathic hypoparathyroidism associ-
ated with hyperthyroidism. Ann Intern Med 1962;57:635– 8.
7. De Ycaza MM, Stinebaugh BJ. Idiopathic hypoparathyroidism with hyperthy-
roidism. South Med J 1972;65:246 – 8.
8. Farup PG. Idiopathic hypoparathyroidism and hyperthyroidism. Acta Med
Scand 1977;202:261–3.
9. Kawame H, Adachi M, Tachibana K, Kurosawa K, Ito F, Gleason MM, et
al. Graves’ disease in patients with 22q11.2 deletion. J Pediatr 2001;
139:892–5.
10. Kawamura T, Nimura I. DiGeorge syndrome with Graves’ disease: a case
report. Endocr J 2000;47:91–5.
DiGeorge sequence includes congenital conotrun-
cal cardiac defects, palate abnormalities, hypoplastic
thymus, T-cell immune defects, hypoparathyroidism,
and learning and psychiatric problems. Bicuspid aortic
valve, which is described in the report of Meek et al.,
has been described in only a single patient with this
condition.
T-cell deficiency is occasionally severe in DiGeorge
sequence. Less severe immune defects are more com-
mon and include autoimmune diseases, which occur in
30% of patients (3 ). Autoimmune thyroid diseases oc-
curring in DiGeorge sequence prominently include
Graves disease.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
References
1. Burman KD, Monchik JM, Earll JM, Wartofsky L. Ionized and total serum
calcium and parathyroid hormone in hyperthyroidism. Ann Intern Med 1976;
84:668 –71.
2. Segni M, Zimmerman D. Autoimmune hyperthyroidism in two adolescents
with DiGeorge/velocardiofacial syndrome (22q11 deletion). Eur J Pediatr
2002;161:233– 4.
3. Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody
deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child
2002;86:422–5.