Primary hyperparathyroidism and hypercalcaemia

Hyperparathyroidism is an endocrine disorder characterised by an excessive synthesis and secretion of parathyroid hormone (PTH) by the chief cells of the parathyroid glands. The disease can be primary or secondary.

In primary hyperparathyroidism (PHPTH), the hypersecretion of PTH is caused by an adenoma or, more rarely, by a carcinoma of the parathyroid chief cells. In the primary form, the disease is virtually always associated with hypercalcaemia.

In secondary hyperparathyroidism, excessive hormonal secretion occurs as an adaptive response of the body to an imbalance in the homeostasis of calcium and phosphorus. Several conditions can be the cause of a hypersecretion of PTH, but in the dog and cat the only two situations in which an excess of hormones can create significant clinical manifestations are: chronic renal failure and calcium deficiency during the active growth phase. These two diseases indirectly involve the parathyroid glands, thereby causing a diffuse hyperplasia. Unlike the primary form, in secondary parathyroid disorders the plasma calcium concentration may be normal, as well as increased or decreased.

AETIOPATHOGENESIS

Primary hyperparathyroidism is a rare disease in the dog, and even rarer in the cat; it is generally caused by an autonomous hypersecretion of PTH by a small solitary adenoma or, in some cases, by several hyperplastic glandular nodules. In most cases (90% approximately) the disease affects only one gland, but in both the dog and the cat adenomas and forms of adenomatous hyperplasia involving more than one gland have been identified. The differentiation between nodules in an adenoma and those in forms of glandular hyperplasia may be difficult, since both have the same functional characteristics, to the point of suggesting that multinodular hyperplasia may be a multiple form of solitary adenoma. Rarely, the disease may be caused by a parathyroid carcinoma.

PATHOPHYSIOLOGY

PTH, together with other body systems, has a role in the control of serum calcium homeostasis by having a hypercalcaemic effect. In animals, a linear correlation exists between the concentration of ionised calcium (the biologically active form) and the levels of PTH, allowing to maintain this parameter within a specified range (1.12 to 1.42 nmol/L in the dog and 1.1 to 1.4 nmol/L in the cat). As the concentration of ionised calcium decreases, the secretion of PTH is stimulated; on the contrary, high concentrations of ionised calcium suppress PTH secretion. In primary hyperparathyroidism,the production and secretion of PTH occur autonomously and independently of calcaemia; the outcome of this hormonal imbalance is an excess in the plasma concentration of calcium (both total and ionised).

SIGNALMENT

Primary hyperparathyroidism is usually found in older dogs, over 6 years of age (mean age 11 years) and affects both males and females, with no gender predisposition. In the dog, 20% of the cases reported in literature were Keeshond; in this breed, a genetic basis of inheritance of the disorder has been proven.

In the cat, primary hyperparathyroidism affects subjects of the same age range as that of dogs; in terms of breeds, Siamese queens seem to be more susceptible to the onset of this endocrine disorder.

CLINICAL SIGNS

In patients with PHPTH, the clinical signs caused by hypercalcaemia alone are usually mild and mostly go unnoticed by the owners. Hypercalcaemia is often found as a random finding during routine blood tests. Unlike subjects in whom hypercalcaemia is secondary to other diseases, the majority of dogs and cats with PHPTH, like in humans, show no significant signs of disease and the physical examination does not usually find anything worth signalling. In mildly symptomatic subjects, hypercalcaemia occurs predominantly with symptoms referable to the urinary tract: polyuria/polydipsia as a consequence of the interference of calcium on ADH renal receptor sites (nephrogenic diabetes insipidus), sometimes associated with urinary incontinence secondary to polyuria (in the dog) and urinary tract infections (pollakiuria , haematuria, strangury) caused by the presence of urolithiasis (present in 25% of subjects with PHPTH). The frequent presence of uroliths is caused by the intense calciuria promoted by PTH excess.

On rare occasions the disease may be present with a more severe symptomatology, with the presence not only of renal sigs but also with neuromuscular and gastrointestinal symptoms. In such cases, polyuria/polydipsia are associated with generalised muscle weakness, lethargy, loss of appetite, vomiting and weight loss.

In the cat, anorexia and a mild malaise may be the only non-specific signs.

DIFFERENTIAL DIAGNOSES

The main diagnostic problem in patients with primary hyperparathyroidism is the distinction between this disease and other conditions (more frequent) that cause hypercalcaemia, and particularly those associated with malignant hypercalcaemia  (Tab. 1). In the other cases, instead, the diagnostic doubt is marginal, since the diseases that cause an increase in calcium concentrations are usually characterised by the presence of specific signs associated with the primary pathology itself (e.g., renal failure,  primary hypoadrenocorticism, hypervitaminosis D). In an animal with a confirmed state of hypercalcaemia, the diagnostic approach is therefore based on ruling out - by a thorough physical examination and with the aid of laboratory tests, diagnostic imaging tests and possibly biopsies – hypercalcaemia of a different origin before proceeding to diagnose primary hyperparathyroidism.

Feline idiopathic hypercalcaemia
In a high percentage of cats, the cause of hypercalcaemia is often unknown; such cases are defined as "idiopathic" as it is not possible to identify a trigger. Young, adult and elderly subjects are affected; long-haired cats seem to be predisposed as well as subjects fed with acidifying diets. The concentrations of calcium (ionised and total) are moderately increased, while concentrations of PTH are low or undetectable.

IThe presence of nephrocalcinosis or  urolithiasis (mainly oxalate) is frequently detected; some individuals experience symptoms including anorexia, weight loss and weakness. A partial improvement of the condition can be obtained by changing the diet and/or recurring to a therapy with corticosteroids (prednisone 5-10 mg/cat/day).

Table 1. Differential diagnosis of hypercalcaemia. (From: Feldman and Nelson, Canine and Feline Endocrinology and Reproduction. Saunders, 2004)

LABORATORY TESTS

The complete blood count does not present particular alterations. The most significant findings of the biochemical profile are hypercalcaemia and hypophosphatemia. The mean concentration of total serum calcium, measured in dogs with PHPTH, is of about 14.5 mg/dl, with a range from 12.1 to 23.4 mg/dl, and those of ionised calcium of 1.71 mmol/L, with a range from 1.22 to 2.41 mmol/L. The average concentration of phosphorus is 2.8 mg/dl, with a range from 1.3 to 6.1 mg/dl. In the cat, unlike in the dog, increased values of creatinine and urea are often found in the course of PHPTH.

Urinalys is typically reveals the presence of isosthenuria (or hyposthenuria). Upon the examination of urinary sediment a frequent finding is haematuria, bacteriuria, pyuria, and crystalluria; in these patients, such findings typically reflect the presence of urolithiasis.

DIAGNOSTIC IMAGING

In patients with known hypercalcaemia, ultrasound and radiographic examinations are crucial to the diagnosis, as they may reveal hidden tumours, or tumours not seen during the physical examination. These tumours may be a potential cause of the hypercalcaemia (e.g., especially mediastinal lymphoma). Should any alteration be identified, biopsies must be taken from the suspect structure. No significant alterations are usually present in subjects with PTHPTH; the only characteristic finding concerns the identification of uroliths in the urinary tract.

DIAGNOSIS

The definitive diagnosis of primary hyperparathyroidism is made by measurement of PTH. The two-site immunoradiometric analysis (IRMA) system, used in humans, and also validated for the canine species, is currently considered the most reliable analytical system for measuring PTH. Most laboratories have a reference range for PTH from 2 to 13 pmol/L (in the dog). As PTH is a molecule susceptible to proteolysis, the measurement should preferably be done on a sample of EDTA serum that contains apoprotein (a protease-inhibiting substance). Should it not be possible to analyse the sample on the day of collection, the sample must be frozen during storage and transportation.

The results obtained should always be interpreted in relation to the existing calcaemia (preferably ionised calcium); in hypercalcaemic subjects, the finding of normal or increased values of PTH, in the absence of a chronic renal disease, confirms the diagnostic suspicion. In about 70% of cases of PHPTH the concentrations of PTH are within the reference range; however, under conditions of hypercalcaemia such concentrations are altered. In view of this, even the finding of normal concentrations of PTH in these animals confirms the diagnosis.

Localisation of the parathyroid tissue causing PHPTH
Cervical ultrasound
Parathyroid glands are routinely viewable at the ultrasound examination of the dog; in healthy subjects, the larger diameter of the gland is of about 3 mm.  In the dog with PHPTH, almost all adenomas can be identified by ultrasound examination; the masses usually have a rounded shape, well-defined margins and the larger diameter greater than 4-9 mm (range from 3 to 23 mm). Compared to the surrounding thyroid parenchyma, the echogenicity is inferior (hypoechoic or anechoic). In 90% of cases the tumour affects only one gland, whereas in the other cases a maximum of two parathyroid glands are involved. Before surgery, the ultrasound examination is extremely useful for identifying the neoformation since, in some cases, these cannot be identified during the surgery.

Cervical palpation of the parathyroid glands
In cats with primary hyperparathyroidism, about half of the parathyroid adenomas can be palpated using the same technique used for palpation of the thyroid (see hyperthyroidism). In any case, if there is a cervical mass, manual palpation alone will not enable the clinician to distinguish whether the pathological tissue is attributable to the thyroid or the parathyroid gland. Therefore, it is necessary to confirm the suspicion with hormonal evaluations. On the contrary, in the dog, the small size of the lesion makes identification by palpation difficult or impossible.

TREATMENT

Surgical removal of pathological parathyroid tissue has long been considered the therapy of choice for primary hyperparathyroidism; however, to date, other possible treatment options are still available: ultrasound-guided radiofrequency thermal ablation and ultrasound-guided percutaneous ethanol ablation (the latter technique is no longer recommended). The technique to be used is chosen on the basis of several factors, among which: the experience of the veterinarian using the technique in question, the size of the adenoma, the number of glands involved and the presence of any uroliths that would in any case require a surgical approach.

During the first week after treatment hypercalcaemia should be monitored (preferably ionised calcium) twice daily and the animal should be kept in a quiet environment (hospitalisation is recommended) to reduce the risk of a tetanic crisis. Generally, the risk of developing transient hypocalcaemia is higher for subjects who - before surgery - presented serum calcium values  ≥ 15 mg/dl or if two glands were involved; in these cases a preventive therapy with vitamin D (calcitriol 2-4 ng/kg every 12 hours) immediately before treatment is advisable, possibly in combination with calcium gluconate (50 mg/kg every 24 hours per os) in order to maintain hypercalcaemia within the normal range (or at the lower limit). Once the hypercalcaemia has stabilised, the treatments can be suspended gradually (usually over a period of 2-3 months).

PROGNOSIS

The prognosis for dogs with primary hyperparathyroidism is excellent; the only complications are related to the onset of a transient hypocalcaemia after treatment, which nevertheless can be prevented or treated appropriately. In cases of treatment with vitamin D (calcitriol) during the post-operative phase, extra vigilance is required in order to prevent the occurrence of an iatrogenic hypercalcaemia that could cause kidney damage.

Suggested readings

1. Feldman E.C. : Disorders of the Parathyroid Glands. In: Ettinger S.J., Feldman E.C.: Textbook of Veterinary Internal Medicine, VII edizione Elsevier Saunders, pg. 1722-1751, 2010.
2. Feldman E.C., Nelson R.W. : Canine Hypercalcemia and Primary Hyperparathyroidism. In: Bonagura J.D., Twedt D.C. : Kirk’s Current Veterinary Therapy XIV, Sounders Elsevier, pg. 247-251, 2009.
3. Feldman E.C., Nelson R.W.:Hypercalcemia and Primary Hyperparatyhroidism. In: Canine and Feline Endocrinology and Reproduction,  III edizione Saunders, pg 670-715, 2004.
4. Gear R.N. et al. : Primary Hyperparathyroidism in 29 dogs: diagnosis, treatment, outcome and associated renal failure. In: J Small Anim Pract, n 46, 2005.
5. Tryfonidou M.A., Hazewinkel H.A.W. : Calciotropic Hormones. In: Kooistra H. S.: Clinical Endocrinolgy of Dogs and Cats, II edizione Schlutesche, pg. 253-295, 2010.