HYPERCALCEMIA

Josh Gorang is a 69 year old retired businessman. He and his wife had
been looking forward to spending more time with their children and grandchildren.
Unfortunately, 3 years ago. Mr. Gorang was diagnosed with lung cancer. Despite
surgery, radiation therapy, and chemotherapy, his cancer returned. Mr. Gorang told
his physicians that he did not want further treatment and preferred to spend his
remaining time at home with his family, as pain free as possible. In the past week,
Mr.Gorang became very lethargic and had both polyuria (increased urine
production) and polydipsia (increased water drinking). He was admitted to the
hospital, where laboratory tests were performed.

Mr. Gorangs Laboratory Values

Serum Ca2+ 15. 5 mg/dL (normal, 10 mg/dL)
Serum Phosphate 1.8 mg/dl (normal, 3.5 mg/dl)
Serum Albumin 4.1 g/dl (normal, 3.5 5.5 g/dl)
Serum PTH 4 pg/ml (normal, 10 65 pg/ml)
Serum alkaline phosphatise Very elevated
PTH, parathyroid hormone

During a test involving 4 hours of water deprivation, Mr. Gorangs serum

osmolarity was 305 mOsm/L (normal, 290 mOsm/L) and his urine osmolarity was 90
mOsm/L.
The physicians concluded that Mr. Gorang had humoral hypercalcemia of
malignancy because his lung cancer was secreting parathyroid hormone (PTH)
related peptide (PTH rp). He was treated with a saline infusion and furosemide (a
loop diuretic), which caused his serum Ca 2+ to decrease to 10.8 mg/dl. He returned
home with a prescription for editronate, an inhibitor of bone resorption that was
expected to keep his serum Ca2+ in the normal range.

QUESTIONS:
1. PTH rp, secreted by certain malignant tumors, is chemically
homologous with PTH that is secreted by the parathyroid glands. PTH rp
has all of the biologic actions of PTH on bone and kidney. Given this
information, why was Mr. Gorang hypercalcemic (increased serum Ca 2+)
and hypophosphatemic (decreased serum phosphate)? Why was his
alkaline phosphatise level elevated?
The parathyroid hormone is directly proportional to calcium levels of the body
because the parathyroid hormone regulates intestinal absorption, renal reasorption
and bone resorption of calcium. Once PTH is released, calcium levels is increased.
Since malignant tumors secretes PTH rp, which is chemically homologous with PTH
secreted by parathyroid gland, it will cause bone resorption, intestinal absorption
and kidney reabsorption of calcium. The tumor is an abnormal cell so when the body
has reached its maximum of Calcium the normal mechanism should be inhibition of
PTH to be secreted so instead the tumor continues to secrete PTH rp causing also
the increasing levels of serum calcium. There is a decreased level of phosphate
because calcium and phosphate always have an inverse relationship to maintain
balance in the body. The alkaline phosphatase level is elevated because it is
associated with increased osteoblastic activity in states of high bone turnover.
2. What was the significance of Mr. Gorangs normal serum albumin level?
The significance of Mr. Gorangs serum albumin level being normal means
that the increased of serum calcium levels in due to protein bound calcium but
rather by increased in serum ionized or free calcium.

3. Why was Mr. Gorang serum PTH level decreased?

Parathyroid hormone is secreted due to decreased serum calcium levels.
Since the PTH rp is secret by malignant tumors it causes a high production of
calcium through bone resorption, kidney reabsorption and intestinal absorption. Due
to increased calcium levels, PTH levels will then decrease as a means of feedback
inhibition.

4. After the 4 hour water deprivation test, Mr. Gorangs serum osmolarity
was 305 mOsm/L (normal, 290 mOsm/L) his urine was 90 mOsm/L.
Administration of an ADH analogue (dDAVP) by nasal spray did not alter
his serum or urine osmolarity. The physician concluded that Mr. Gorang
had nephrogenic diabetes insipidus. Why? What might be the cause of this
condition?
After a water deprivation test, Mr. Gorangs serum osmolarity increased to
305 mOsm/L with his urine osmolarity of 90 mOsm/L. The abnormal pattern suggest
that Mr. Gorang had diabetes insipidus caused by ADH deficiency or by ADH
resistance to the collecting ducts (nephrogenic diabetes insipidus).

The ADH analogue (dDAVP) by nAsal spray confirmed that he had

nephrogenic diabetes insipidus because even exogenous ADH couldnt cause his
urine to become concentrated. His resistance for ADH was caused by
hypercalcemia. In this condition there would be Calcium deposition in the inner
medulla of the kidney which inhibits ADH dependent adenylyl cyclase and
prevention of ADH action in increasing water permeability of the collecting ducts.
Therefore, in the presence of exogenous ADH, urine cannot be concentrated.

5. Why did Mr. Gorang have polyuria and polydipsia?

Polyuria and polydipsia are classical signs for patients with diabetes insipidus.
Polyuria occurred becaused his collecting ducts were ADH resistant; thus, being
impermeable to water. Water that was not reabsorbed by the collecting ducts is
then excreted in the urine. Polydipsia occurred because increased urinary water
excretion made his body fluids more concentrated. And, increase serum osmolarity
is a potent stimulation for thirst and drinking behavior through osmoreceptors in the
thalamus.

6. How did treatment with saline and furosemide decrease his serum Ca 2+
concentration?
Furosemide treatment decreases his serum calcium concentration through
inhibition of the Na+ - K+ - 2Cl- contransporter in the thick ascending limb and
thereby inhibiting Na+ reabsorption. The Na+ - K+ - 2Cl- cotransporter normally
generates a lumen positive potential difference in the thick ascending limb that
drives calcium reabsorption from the lumen to the blood through a paracellular
route. By inhibition of this cotransporte, furosemide then eliminates the lumen
positive potential thereby inhibiting paracellular Calcium reabsorption. Saline on the
other hand was administered with furosemide to prevent paracellular volume
contraction.

7. How was etridonate expected to keep Mr. Gorangs serum Ca 2+ in the

normal range?
Etridonate is a biphosphonate that inhibits bone mineralization or osteoblast
activity. If bone mineralization or osteoblast activity occurs bone resoprtion will not
happen thus lowering or maintaining Mr. Gorangs serum calcium in normal levels.

SOURCES:
Koeppen, B. Stanton, B. Berne and Levy Physiology. 6 th edition. Page 696
701 copyright 2010
Helms, R. et al. Textbook of Therapeutics Drug and Disease Management, 8 th
Edition, page 1029 copyright 2006
Constanzo, Linda. Physiology Cases and Problems, 4 th edition. Page 318 319
copy 2012