PERSISTENT HYPOCALCEMIA 9/14/17
QUESTION--I have a patient who is a 59-year-old male with persistent hypocalcemia and I have been unable to determine the etiology. I suspect the patient has some sort of parathyroid hormone receptor defect but I really do not know. Calcium has been stable/acceptable on calcium, Vitamin D supplements. Other than Hashimoto’s disease, the patient has no other medical problems. Recent labs and calcium chart are below. His 24 hour urine calcium was 98 mg/day.
levothyroxine 88 mcg Tablet Oral 1 pill in the morning
Calcium-Vitamin D (calcium carbonate-vit D3-min) 600 mg calcium- 400 unit Tablet Oral 2 pills at Lunch
Vitamin D3 (cholecalciferol (vitamin D3)) 2,000 unit tablet Oral 1 pill once a day
multivitamin 1 pill Oral 1 pill once a day
Medicine reconciliation done with the patient today.
6/6/2017 3:31 PM
Magnesium H 2.5 (normal: 1.8-2.4) mg/dL
Vit D25 OH
Vitamin D 25 OH 45 (normal: 30-100) nGm/ml Vitamin D3 2,000 unit 1 pill once a day
blood urea nitrogen H 22 (normal: 7-18) mg/dL
creatinine 1.050 (normal: 0.550-1.300) mg/dL
Sodium 141 (normal: 136-145) mmol/L
Potassium 4.3 (normal: 3.6-5.2) mmol/L
Chloride 105 (normal: 98-107) mmol/L
CO2 27 (normal: 21-32) mmol/L
Anion Gap 9 (normal: 3-11)
Albumin 3.9 (normal: 3.5-5.0) Gm/dL
Calcium L 7.9 (normal: 8.5-10.1) mg/dL
glucose Random 88 (normal: 65-110) mg/dL
Phosphorus H 5.0 (normal: 2.4-4.9) mg/dL
Hep Func Panel
ALT 28 (normal: 6-78) Units/L
Alkaline Phosphatase 84 (normal: 45-117) Units/L
AST 24 (normal: 6-40) Units/L
Bilirubin Direct 0.1 (normal: 0.0-0.3) mg/dL
Bilirubin Total 0.4 (normal: 0.2-1.0) mg/dL
Total Protein 7.1 (normal: 6.0-8.0) Gm/dL
PTH 24.8 (normal: 14.0-72.0) pGm/ml
TSH, 3rd gen 2.220 (normal: 0.358-3.740) mclU/ml levothyroxine 88 mcg 1 pill in the morning
DATE calcium VitD-25OH Ca2+ Mg TSH PTH phos Cr VitD-1,25 Ur Ca
06/06/17 L7.8 45 H2.5 2.220 24.8 H5.0 1.080 Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning
04/29/16 L7.5 55 1.110 levothyroxine 88 mcg 1 pill in the morning, Vitamin D3 2,000 unit 1 pill once a day
03/12/15 L7.9 61 L1.03 1.9 2.800 25.3 Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning
10/14/14 L8.3 56 2.110 18.9 4.2 1.10 61 Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning
02/27/14 L8.0 68 L0.99 1.390 Vitamin D3 2,000 unit 1 pill once a day, levothyroxine 88 mcg 1 pill in the morning
07/02/13 L7.5 76 L1.01 43 vit d 2000 u daily
12/06/12 L7.9 H111.8 1.000 Ergocalciferol
09/13/11 L7.5 Ergocalciferol
02/01/11 8.6 61 L1.02 2.3 2.100 23.7 1.3 Ergocalciferol , Levoxyl 88 mcg in the morning
08/06/10 H3.820 Levoxyl 75 mcg in the morning
07/06/10 L8.3 2.2 2.360 20 4.8 Ergocalciferol , Levoxyl 75 mcg in the morning
04/23/10 L7.7 1.43 0.4 1.0 Levoxyl 75 mcg in the morning
11/09/09 L8.1 75 L1.10 2.3 22 4.4 1.20 51 Ergocalciferol (Vitamin D2) 50,000 unit two pills every Monday
07/14/09 L7.5 79 1.19 1.2
04/22/09 L7.6 46 19 4.7 Ergocalciferol (Vitamin D2) 50,000 unit one pill every week
01/06/09 L7.6 L28 L0.98 45 4.5
11/10/08 L8.0 53 L1.03 17 3.9 ergocalciferol 50,000 units one pill every week
10/20/08 L7.4 L0.96 2.0 2.83 21 ergocalciferol, Levoxyl 75 mcg in the morning
09/11/08 L7.6 L23 L0.93
RESPONSE--My overall assessment of this case is that this patient has a form of hypoparathyroidism and not PTH resistance (pseudohypoparathyroidism) or a problem in vitamin D metabolism or action (vitamin D deficiency or vitamin D resistance). These are the most common etiologies for chronic hypocalcemia. I say this because every time he has a low total serum Ca++ and/or low ionized Ca++, which is nearly every measurement, he has an inappropriately normal PTH level. His PTH level is never high. It should be elevated with the Ca levels above, if he has intact parathyroid function and healthy parathyroid glands.
I assume he has not had surgery on his neck for thyroid, parathyroid or laryngeal disease of tumors or neck irradiation and he does not have hemochromatosis (iron overload), thalassemia (with transfusional iron overload), or copper overload (Wilson’s disease).
He is taking thyroid hormone and the reason for that is not clear. Does he have hypothyroidism (for example due to Hashimoto’s thyroiditis) or was there a surgical procedure on his thyroid prior to 2007 that could have affected his parathyroid glands by inadvertent removal or damage to all 4 glands?
In the adult population, hypoparathyroidism is due to surgery-induced damage (75% of cases) and genetic, autoimmune, toxic or idiopathic etiologies (25% of cases). If he has autoimmune hypothyroidism + autoimmune hypoparathyroidism, this could be a case of “autoimmune polyendocrine syndrome” or APS. Classically, APS1 which is the syndrome that includes hypoparathyroidism, patients also have adrenal insufficiency and mucocutaneous candidiasis and due to mutations in the AIRE gene. These are nearly essential features, but not always, and there can be other autoimmune phenomena. Also, this is a pediatric syndrome typically, with the onset of the 3 cardinal syndrome manifestations before the age of 20. This does not fit the presentation of this case at age 49 or earlier, but what we are learning is that APS1 has a wider spectrum of presentations than previously thought and may be less penetrant than was concluded by the younger ages of the patients in the original series, when this disorder was identified.
Another option in terms of diagnosis for this patient is a genetic condition of isolated hypoparathyroidism. The pathway most favored would be that of the extracellular Ca++ sensing receptor (CaSR) which has two established disorders in it: (1) constitutively active CaSRs due to activating mutations in the CaSR and (2) constitutively active G alpha 11. The former seems to be much more common than the latter. Genetic testing is available in commercial labs for CaSR mutations. Several mutations in the PTH gene have also been described as causes for isolated hypoparathyroidism; they are super-rare and usually present very early in life with severe hypoparathyroidism (very low intact PTH levels) that are symptomatic.
Mutations in transcription factors (e.g., GATA3 and GCM2) can be the cause of hypoparathyroidism as well. GATA3 mutations can also cause renal disease (CKD and renal anomalies) and deafness. Sometimes the penetrance for the latter 2 tissues is less than for the parathyroid so these 2 transcription factors are worth considering as mutations in them do not always cause syndromes. Sometimes the hearing deficit is only evident with audiology testing in GATA3 mutations. You do not describe features or mention features of a syndrome in this 59-year old man, but they can be subtle. It would be very unusual for the DiGeorge Syndrome to present at this age, but sometimes its manifestations are not recognized, and the main feature that comes to medical attention is mild hypoparathyroidism and mild hypocalcemia. Overall, however, I favor a CaSR mutation as the etiology for the hypocalcemia and hypoparathyroidism/parathyroid insufficiency in this case and I would go over the patient carefully for any autoimmune, renal, skeletal, hearing, cardiac, and immunologic issues. His PTH levels are just in the range that has been described with CaSR mutations (detectable but not responsive to low, very low or even normal serum Ca++). Hence there is a disorder of parathyroid Ca++ sensing. Dolores Shoback, MD UCSF