Page 156 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

146 ELECTROLYTE DISORDERS

Humoral Hypercalcemia of Malignancy and transforming growth factor (TGF)-a and -ß or
HHM is a syndrome associated with many tumors calcitriol may have synergistic or cooperative actions with
in people and animals. 480 Characteristic clinical findings PTHrP (see Fig. 6-14). Before PTHrP was identified, it
in patients with HHM include hypercalcemia, was recognized that tumors associated with HHM
hypophosphatemia, hypercalciuria (often with decreased induced a syndrome that mimicked primary hyperpara-
fractional calcium excretion), increased fractional excre- thyroidism with secretion of a PTH-like factor that was
tion of phosphorus, increased nephrogenous cyclic aden- antigenically unrelated to PTH. 396,606 PTHrP binds to
osine monophosphate (cAMP), and increased osteoclastic the N-terminal PTH-PTHrP receptor in bone and the
bone resorption. Hypercalcemia is induced by humoral kidneys but does not cross-react immunologically with
effects on bone, kidneys, and possibly the intestine native PTH (Fig. 6-15). PTHrP stimulates adenylyl
(Fig. 6-14). 481 Increased osteoclastic bone resorption is cyclase and increases intracellular calcium in bone and
a consistent finding in HHM and increases calcium release
from bone. Thekidneysplayacriticalroleinthe pathogen-
esis of hypercalcemia because PTHrP stimulates calcium
Humoral factors
reabsorption, which binds and activates renal PTH- Ca ++
(ILs, TNFs, TGFs, etc.)
PTHrP receptors. The level of renal function in the patient
may also contribute to the development of hypercalcemia. Synergy or
Animals with dehydration or impaired renal function are additivity
Ca ++
more susceptibletodevelopinghypercalcemia ormayhave
more severe hypercalcemia because of decreased renal Tumor
excretion of calcium. In some forms of HHM, increased
serum 1,25-dihydroxyvitamin D concentrations may
489
increase calcium absorption from the intestine.
Malignancies that are commonly associated with HHM
in dogs include T-cell lymphoma and adenocarcinomas PTHrP Ca ++
derived from the apocrine glands of the anal
sac. 22,36,479,607,615 In a retrospective study of 109 dogs Figure 6-14 Humoral factors such as parathyroid hormone-
with hypercalcemia, 58% had hypercalcemia due to under- related protein (PTHrP), interleukin-1 (IL-1), tumor necrosis factors
lying neoplasia. Lymphosarcoma was present in 78% of (TNFs), or transforming growth factors (TGFs) produced by tumors
these patients, with 11% diagnosed with carcinoma and induce humoral hypercalcemia of malignancy (HHM) by acting as
6%diagnosedwithanalsacadenocarcinoma. 375 Dogswith systemic hormones and stimulating osteoclastic bone resorption or
cancer and HHM are expected to have shorter survival. increasing tubular reabsorption of calcium.
In addition, sporadic cases of HHM occur in dogs with
thymoma, myeloma, melanoma, or carcinomas
originating in the lungs, pancreas, thyroid gland, skin, PTH PTHrP PTH PTHrP
mammary gland, nasal cavity, and adrenal
medulla. 61,458,479-481 Tumors associated with hypercalce-
mia in cats include lymphosarcoma, multiple myeloma,
squamous cell carcinoma, bronchogenic carcinoma/ade-
AC
nocarcinoma, osteosarcoma, fibrosarcoma, undifferenti- PLC
PIP 2
ated sarcoma, undifferentiated renal carcinoma, anaplastic
carcinomas of the lungs and diaphragm, and thyroid carci- ATP cAMP
noma.* Lymphosarcoma and squamous cell carcinoma are IP + DAG
the two most common causes of hypercalcemia in cats. 511 PTH/PTHrP Receptor 3
Of 11 hypercalcemic cats with lymphosarcoma, two each
had renal, generalized, gastrointestinal, or mediastinal N-Terminus of PTH or PTHrP
involvement, and one each had laryngeal, nasal, or cutane-
ous disease. 61,119,161,167,511 Squamous cell carcinoma has Figure 6-15 Parathyroid hormone-related protein (PTHrP)
been found in mandibular, maxillary, pulmonary, and ear induces many of the effects of parathyroid hormone (PTH) by
interacting with the PTH receptor in bone and kidneys and activating
canal locations. 61,270,299,511 adenylyl cyclase (AC) to form cyclic AMP (cAMP) and phospholipase
Excessive secretion of biologically active PTHrP plays C (PLC) to form inositol triphosphate (IP 3 ) and diacylglycerol
a central role in the pathogenesis of hypercalcemia in (DAG) from phosphatidylinositol (PIP 2 ). Stimulation of the PTH
most forms of HHM, but cytokines such as IL-1, TNF-a, receptor results in increased osteoclastic bone resorption and renal
tubular reabsorption of calcium, inhibition of renal tubular
reabsorption of phosphorus, and stimulation of renal production of
*References 12, 47, 61, 119, 161, 167, 245, 270, 299, 511, 529. 1,25-dihydroxyvitamin D 3 (calcitriol).