Vice Principal (Learning and Student Experience), Professor of Small Animal Studies, The Royal Veterinary College, University of London, London, UK
Hypercalcemia results in impaired neurological, neuromuscular and muscular function, impaired collecting tubule sensitivity to ADH, vasoconstriction of the afferent glomerular arteriole and thus reduced GFR as well as a diminished membrane stability generally. As a result, the spectrum of clinical signs which result can be broad, affecting numerous body systems and variably prominent depending upon the magnitude of the hypercalcemia and the time it has taken to develop. What is imperative to remember is that when hypercalcemia is identified on routine biochemical analysis, it should always be followed up - remember quite significant increases in ionised calcium may only be associated with small increases in total calcium. Additionally, whenever an abnormality in serum calcium is observed, it is important to look at not only the albumin level but always look at the serum phosphate concentration. Finally remember hypercalcemia is not a diagnosis in itself, but a sign of another disorder that needs to be identified.
As hypercalcemia is brought about by a range of different diseases, the clinicopathological abnormalities encountered in a patient with hypercalcemia will depend on the underlying cause or causes. However, the presence of hypercalcemia itself will frequently produce some abnormalities in other clinicopathological findings, especially those related to the patient's renal function.
Hypercalcemia and Renal Function
As hypercalcemia interferes with the kidney's ability to concentrate urine, patients will have diminished ability to concentrate their urine. Consequently, if they become dehydrated and develop renal underperfusion and thus azotemia because of their dehydration (a so-called "prerenal azotemia"), they will still have urine that is inappropriately dilute (i.e., a urine SG < 1.030 in a dehydrated or azotemic patient). This tendency is exacerbated by the fact that hypercalcemia also results in vasoconstriction of the afferent glomerular arteriole, resulting in a decrease in GFR and thus a tendency towards azotemia. Thus any patient with hypercalcemia may be azotemic with inappropriately dilute urine simply as a result of the hypercalcemia alone. In other words, hypercalcemia, by and of itself, results in impaired renal function through mechanisms that do not affect renal structure.
Additionally, particularly if the hypercalcemia is accompanied by hyperphosphatemia, the resultant calciuria and phosphaturia increase calcium phosphate precipitation in the nephrons. Thus persistent hypercalcemia accompanied by hyperphosphatemia results in impairment of renal function not only via the "extrarenal" factors described above but also through an additional mechanism - structural renal disease caused by the deposition of calcium phosphate in the renal parenchyma.
Disorders Resulting in Hypercalcemia
It can often be difficult determining the cause of mild or transient hypercalcemia regardless of whether the parameter measured is total or ionised calcium. Interestingly, in one recent study, approximately 30% of dogs with ionised mild hypercalcemia had no confirmed diagnosis. However, because so many of the causes of hypercalcemia have serious prognostic implications, any animal with hypercalcemia needs to be investigated as thoroughly as possible.
Causes of hypercalcemia can be split into three broad categories: non-pathological, transient or inconsequential in terms of the effects on the patient and finally those that are truly "pathological".
Young, growing animals - especially large-breed dogs
Spurious or artefact, for example lipaemia
Transient and 'Inconsequential'
Hyperproteinaemia or more specifically hyperalbuminemia
These disorders can be broken up into two broad categories: disorders characterised by increased "parathyroid hormone-like activity" and those where the hypercalcemia is not mediated through increased parathyroid activity.
Hypercalcemia Due to Increased PTH or PTH-like Activity
In disorders where the hypercalcemia is dependent upon increased "parathyroid hormone-like activity," this increased activity is caused by autonomous or uncontrolled production of either PTH itself or peptides "related to parathyroid hormone" generally elaborated by malignant neoplasms. Because the hypercalcemia is brought about by excessive PTH activity, these patients will generally be characterised not only by elevated total and ionised serum calcium but also a serum phosphate concentration that is either subnormal or in the low-normal reference range.
Patients in this category will have one of two disorders: either a malignancy of non-parathyroid origin or a primary functional neoplasm of the parathyroid gland which is almost always small, benign and mediates its clinical significance through the generalised effects of the hypercalcemia. Many non-parathyroid neoplasms can elaborate PTH or PTH-related peptides and, as a result, create the so-called "humoral hypercalcemia of malignancy" (HHM), although generally lymphoid malignancies, anal sac adenocarcinomas and multiple myelomas have been more commonly associated with this sort of problem in dogs, while in cats lymphoid malignancies and carcinomas of various origins - particularly squamous cell carcinomas - are the more common culprits.
Primary hyperparathyroidism is markedly overrepresented in Keeshonds where it has an autosomal-dominant inheritance with age-dependent penetrance. In all breeds, it is invariably due to a parathyroid adenoma affecting one of the parathyroid glands. Generally the nodule is non-palpable but readily ultrasonographically demonstrable.
Primary hyperparathyroidism is likely to be the most common cause of hypercalcemia in an otherwise well dog or a dog "perceived to be normal" by the owner. Also remember because dogs with primary hyperparathyroidism will be phosphaturic (see above) and have no other concurrent problems, they tend to present with not only elevated calcium levels but also low or low-normal serum phosphate concentrations.
Hypercalcemia Unrelated to Increased PTH or PTH-like Activity
While most studies suggest that, at least in the dog, the most common causes of hypercalcemia are those associated with increased PTH or PTH-like activity, there is certainly an important range of other disorders that can produce hypercalcemia through non-PTH-mediated mechanisms.
A significant proportion of dogs and cats with hypoadrenocorticism are likely to have a total hypercalcemia accompanied by a normal phosphate concentration. While the mechanisms for this phenomenon remain obscure, it is always worth considering checking adrenal function in any patient, dog or cat, with an otherwise unexplained hypercalcemia.
Patients subjected to increased vitamin D activity will have increased calcium and phosphate retention and progressively develop diffuse soft-tissue calcification and hypercalcemia and hyperphosphatemia. The excessive exposure to analogues of vitamin D can occur through ingestion of vitamin D through inadequately formulated or controlled commercial pet foods, the ingestion of products rich in calcitriol analogues and any disorder that results in an active granulomatous inflammatory response. The hallmark of the hypercalcemia associated with vitamin D intoxication is that it will be generally accompanied by hyperphosphatemia.
In cats with hypercalcemia, it is now generally accepted the most common "reason" for this is the syndrome described as "idiopathic feline hypercalcemia" (IFH). Around half the cats with IFH show no clinical signs - with the remainder having signs not inconsistent with the usual systemic and gastrointestinal abnormalities produced by hypercalcemia: depression, inappetence and weight loss, vomiting, diarrhea and occasionally constipation. Uroliths, frequently calcium oxalate, have been reported in roughly 15% of cases. Both total and ionised serum calcium are increased, phosphate is usually normal or increased, PTH is diminished or normal, with normal PTH-rP and 25-D3 and variable but usually decreased 1,25-D3.
Another important reason for hypercalcemia unrelated to increased PTH activity is chronic kidney disease. Although the vast majority of dogs and most cats with azotemic chronic kidney disease (ACKD) have total serum calcium levels in the reference range, some patients will have an elevated total or ionised serum calcium. The overwhelming distinguishing feature between these patients and those with primary hyperparathyroidism is patients with ACKD and hypercalcemia tend to also have elevated or high-normal plasma phosphate concentrations.
There is no single treatment protocol that will be consistently effective for managing hypercalcemia, as first and foremost identification and removal of the underlying cause need to be paramount. However, as this might not always be possible, immediately supportive therapy might need to be considered for variable periods, and for those cases with idiopathic hypercalcemia, supportive therapy will be the only real option.
This is best achieved by first administering parenteral fluids and furosemide and then following up with a bisphosphonate. If the animal requires aggressive correction of the hypercalcemia, the parenteral bisphosphonate of choice is pamidronate given intravenously over 2–3 hours at a dose of 1.3–2.0 mg/kg in ~ 150 ml of 0.9% NaCl. This can be repeated weekly for a number of doses as long as renal function remains stable.
Where the situation is less critical and in cats with idiopathic hypercalcemia, the bisphosphonate of choice is alendronate administered orally. The starting dose is 10 mg once weekly in cats and 10–20 mg once weekly in dogs with dose adjustments after review approximately 2–3 weeks later. This class of drug has been linked with esophagitis and stricture in people, and its bioavailability can be compromised if given with food.
The principal long-term adverse effect of prolonged hypercalcemia is renal failure secondary to soft tissue mineralisation. This is much more likely if the phosphorus level is also elevated. A calcium phosphorus product of 4.8 to 6.5 or above (using SI units; 60–80 or above using mg/dl) suggests a high risk of soft tissue mineralisation.