THE CHALLENGES.

The physiologic response to a hypocalcemic challenge can be characterized by several distinct categories of adjustment in mineral metabolism (Fig. 17-1). The classic challenges include (1) a minor, transient challenge, (2) a moderate challenge, and (3) a severe, prolonged challenge. Hypocalcemia elicits corrective homeostatic responses that are mediated by PTH and vitamin D. Acute effects occur in seconds to minutes, subacute or moderate effects occur over several hours and may last a few days, and chronic effects occur over days to weeks and longer (Rosol and Capen, 1997; Rosol et al, 2000).

FIGURE 17-1 A, Regulation of extracellular fluid (ECF) calcium concentration by the effects of parathyroid hormone (PTH) and calcitriol (1,25-dihydroxyvitamin D₃) on gut, kidney, bone, and parathyroid gland. The principal effect of PTH is to increase the ECF calcium concentration by mobilizing calcium from bone, increasing tubular calcium reabsorption, and, indirectly on the gut, by increasing calcitriol synthesis. The principal effect of calcitriol is to increase intestinal absorption of calcium, but it also exerts negative regulatory control of PTH synthesis and further calcitriol synthesis. B, Normal calcium balance showing the major organs that supply or remove calcium from extracellular fluid: bone, gut, and kidney. Total calcium input into extracellular fluid equals total calcium leaving the extracellular space.

(From Rosol et al, 2000.)

MINOR, TRANSIENT CHALLENGE.

A 12- to 15-hour fast (or consumption of a diet completely deficient in calcium) in a normal mammal requires only subtle hormonal adjustments. The total quantity of calcium lost in the urine over this period is small. Negligible decreases in serum calcium concentration occur, causing a slight increase in PTH secretion. The dip in serum calcium concentration is corrected by this PTH-mediated increase in calcium reclamation efficiency from distal renal tubules and by rapid calcium resorptive responses from bone. Acute secretion of preformed PTH can maintain PTH concentrations for 1 to 1.5 hours during hypocalcemia. Hypocalcemia also decreases the proportion of PTH that is degraded in the parathyroid chief cells, making more hormone available for secretion. This effect typically occurs within 40 minutes. With increases in PTH secretion, renal calcium reabsorption and phosphorus excretion are enhanced within minutes, whereas bone mobilization of calcium and phosphate occurs over a period of 1 to 2 hours (Rosol et al, 2000). By 12 hours, only minor increases in 1,25(OH)₂ vitamin D synthesis have occurred.

MODERATE CHALLENGE.

An abrupt but significant reduction in dietary calcium intake (or other causes of hypocalcemia) initiates a series of adjustments in calcium metabolism, resulting in a new steady state of PTH secretion and vitamin D secretion. Several hours of persistent hypocalcemia increases PTH secretion, which in turn stimulates the synthesis and secretion of vitamin D (calcitriol). Calcitriol then increases intestinal transport of calcium and phosphorus into the vascular space, providing an external source of calcium that complements the internally mobilized calcium derived from bone. Hypocalcemia increases transcription of both the PTH gene and PTH mRNA, enhancing the ability of chief cells to produce PTH, a process that takes place within hours (Rosol et al, 2000).

Moderate increases in the secretion rate of PTH result in (1) increased calcium reabsorption from distal renal tubules, (2) increased mobilization of calcium and phosphorus from bone, and (3) increased synthesis of 1,25(OH)₂ vitamin D (calcitriol), which participates with PTH in bone resorption and increases the efficiency of calcium and phosphorus absorption from the intestine (see Fig. 17-1). The increased concentrations of circulating PTH enhance renal excretion of phosphorus, thereby compensating for the increased amounts of phosphorus mobilized from bone and absorbed from the intestine. In this new steady state, the serum calcium concentration returns to normal, the serum phosphorus concentration is unchanged or slightly reduced, and a state of mild secondary hyperparathyroidism and enhanced intestinal mineral absorption efficiency exists. The initial requirement for calcium mobilization from the skeleton is largely replaced by the enhanced absorption of calcium from the intestine.

SEVERE, PROLONGED CHALLENGE.

Significant lactation and chronic renal failure represent two examples of severe hypocalcemia-related challenges to calcium homeostasis that cannot be corrected by the processes that are stimulated to occur within minutes or hours. Assuming that the four parathyroid glands are intact and functional, the previously described sequence of events resulting from “minor transient” and “moderate” challenges caused by hypocalcemia ensue. However, continuing losses of calcium into milk associated with lactation (for example) prevents complete compensation by the usual calcium–PTH–vitamin D absorption axis. Physiologic compensation in this setting includes (1) a maximal PTH secretion rate of approximately five times normal, (2) a maximal rate of 1,25(OH)₂ vitamin D synthesis, and (3) initiation of maximal “rapid” and “late” phases of bone resorption in response to the combined effects of PTH and 1,25(OH)₂ vitamin D.

Over days, weeks, or even longer periods of hypocalcemia, increases in PTH secretion, beyond those already described, are achieved largely via hypertrophy and hyperplasia of parathyroid gland chief cells (Roth and Capen, 1974; Rosol et al, 2000). Hypocalcemia directly stimulates the growth of parathyroid cells. This effect occurs regardless of vitamin D metabolite concentrations (Li et al, 1998; Malloy et al, 1999, Marx, 2000). With hyperplasia of parathyroid chief cells, PTH secretion rates approach 10 to 50 times normal. These circulating concentrations of PTH result in recruitment of an increasing osteoclast population and the incorporation of substantial bone surfaces into the resorption process. In the final steady state, serum calcium concentrations are maintained at the expense of the skeleton, and significant bone losses ensue. Thus the integrity of skeletal mineral homeostasis is sacrificed in an attempt to compensate for systemic mineral deficits (Broadus, 1981).

PERIPHERAL NEUROMUSCULAR DISORDERS.

As discussed in Chapter 16, calcium ions are integral to the function of virtually all cells. However, although all cells in the body are affected by deficiencies in ionized calcium, clinical signs are most often associated with cells of the neuromuscular system simply because alteration in the function of these cells result in obvious visible abnormalities. Ionized calcium is involved in the release of acetylcholine during neuromuscular transmission. In addition, calcium is essential for muscle contractions and it stabilizes nerve cell membranes by decreasing their permeability to sodium. The role of calcium as a membrane stabilizer is most obvious during severe hypocalcemia, when insufficient stabilization exists.

When the extracellular fluid concentration of calcium ions declines below normal, the nervous system becomes progressively more excitable as a result of increases in neuronal membrane permeability. This increased excitability occurs both in the central nervous system (CNS) and in peripheral nerves, although the most obvious clinical signs are manifested peripherally. Nerve fibers may become so excitable that they begin to discharge spontaneously, initiating nerve impulses that pass to the peripheral skeletal muscles, where they elicit tetanic contraction (“cramps”). Consequently, hypocalcemia causes tetany, a random stiffening or tightening of various muscle groups. Nerve fibers seem particularly sensitive to decreases in calcium, in part because the signs are so acute, dramatic, and obvious. In fact, acute hypocalcemia usually results in death before effects in other major organ systems develop. Dogs with tetany that had previously undergone spinal cord transection at the thoracolumbar junction had classic signs of tetany above but not below the transection site (i.e., the rear legs were flaccid during the episodes of tetany). Thus tetany is initiated in the CNS, not peripherally (Arnaud, 1994).

Hypocalcemia is a relatively “common” laboratory abnormality, being observed on more than 13% of serum biochemical profiles in dogs in one report (Chew and Meuten, 1982). On the basis of total serum calcium concentration, hypocalcemia is usually defined as a concentration below 9.5 mg/dl in dogs and below 9 mg/dl in cats (Rosol et al, 2000). When serum ionized calcium concentration is used, hypocalcemia is generally defined as a concentration below 1.1 mmol/L in dogs and less than 1.0 mmol/L in cats. Clinical tetany, however, usually requires much lower serum calcium concentrations. For example, tetany can be assumed to exist whenever the serum total calcium concentration declines to or below 6 mg/dl or the serum ionized concentration to less than 0.7 mmol/L. These are values that are only 40% below normal. Total serum calcium concentrations below 4 mg/dl are frequently fatal.

Although dogs with untreated hypoparathyroidism consistently have abnormally decreased total serum calcium concentrations, the onset of clinical tetany is not entirely predictable. In studies on dogs undergoing total thyroparathyroidectomy, only approximately half developed tetany during a 96-hour period following the surgery. In each dog, however, the total serum calcium concentration decreased rapidly during the initial 24-hour postsurgical period. Why clinical tetany was not obvious in all the dogs was not understood. In our experience with dogs with primary hyper parathyroidism that have undergone surgical or alternative resolution of the condition, resulting in acute hypo parathyroidism, “clinical” signs of hypocalcemia have not always correlated with some absolute arbitrary serum calcium concentration. We tend to associate clinical signs with total calcium concentrations below 6 to 7 mg/dl and ionized serum calcium concentrations below 0.7 to 0.8 mmol/L. However, some dogs have had clinical signs with serum concentrations above these values, and others below our critical levels have had no signs. Without doubt, physical activity plays a role in development of clinical tetany. A quiet dog is much less likely than an active dog to exhibit signs at any low serum concentration of calcium. Individual variation, however, is the only consistent feature of this condition.

Calcium concentrations within cerebrospinal fluid (CSF) do not decrease as rapidly as serum concentrations in parathyroidectomized dogs. Although the serum total calcium concentration decreases as much as 27% (ionized calcium, 28%) within 24 hours of surgery, decreases in CSF total calcium concentration are less than 5% (ionized calcium, less than 10%). Rapid equilibrium does not occur between plasma and CSF ionic values. Thus the concentration of calcium ions in the CSF is relatively constant despite large fluctuations in plasma concentrations. However, relatively small changes in CSF calcium concentration may also result in dramatic changes in clinical appearance.

When serum calcium concentrations decline to abnormal levels, but not low enough to cause obvious clinical tetany, a physical state of “latent tetany” may exist. This condition is described as one in which an individual can progress from appearing clinically normal to becoming “tetanic” with minimal stimulation. Such a condition can be demonstrated to be present in people by weakly stimulating a nerve and observing an abnormal response (see Physical Examination, page 723). If a human with latent tetany hyperventilates, the resulting alkalinization of the body fluids can increase nerve irritability, causing overt signs of tetany. It is assumed that a similar situations develop in hypocalcemic dogs or cats.

In hypocalcemic pet dogs, latent tetany occurs, but the problem is less well documented. Owners mention that sudden excitement, activity, or petting may unpredictably cause muscle cramping, lameness, facial rubbing, pain, irritability, or aggressive behavior. These signs usually disappear quickly, only to recur sporadically. In addition, the nontetanic severely hypocalcemic pet is usually described by the owner as having a change in personality. These dogs are often observed to have poor appetites and to be irritable, nonplayful, and slow-moving. Frequently, owners report that the dogs “seem to be in pain.” Such signs are vague, but after hypocalcemia is diagnosed, the clinical signs are consistent with those of an animal in latent tetany. The various disturbances are completely and quickly reversible with therapy.

THE HEART.

In experimental animals, severe decreases in serum calcium concentration can result in marked dilatation of the heart, changes in cellular enzyme activities, and in increased membrane permeability in cells outside the nervous system. Calcium has both positive inotropic and chronotropic cardiac effects (Milnor, 1980). Hypocalcemia prolongs action potential duration in cardiac cells. This may result in decreased force of myocardial contraction (negative inotropic effect) and, in severe cases, bradycardia (negative chronotropic effect). An associated increase is seen electrocardiographically in the duration of the S-T and Q-T segments. The duration of the T wave itself is not altered with hypocalcemia. Although these disturbances in physical findings and the electrocardiogram (ECG) can be pronounced in humans, they are much less obvious in the hypocalcemic dog (Kornegay et al, 1980; Sherding et al, 1980). Rarely, hypocalcemia can cause a 2:1 heart block or heart failure requiring digitalis and diuretics in humans (Arnaud and Kolb, 1983).

DURATION OF ILLNESS.

The clinical course in the 37 dogs of our series consisted of an abrupt onset of intermittent neurologic or neuromuscular disturbances (see Table 17-1). In at least 20 dogs, owners noted that signs were initiated or worsened by excitement or exercise. The signs associated with hypocalcemia had been observed for periods of 1 day in some dogs to as long as 12 months in others. Only 8 of the 37 dogs had signs for longer than 14 days before the diagnosis was made and therapy initiated. The 8 dogs with prolonged illness had been symptomatic for 1 to 12 months and had been diagnosed and treated for nonspecific seizure disorders without the benefit of pretreatment laboratory testing. The dogs with signs for more than several days invariably had neuromuscular disturbances that became progressively more frequent and violent despite administration of anticonvulsant medication.

EARLY SIGNS.

Most owners reported that one of their first observations (retrospectively) was that their pet appeared abnormally “tense,” “nervous,” or “anxious.” Also retrospectively, owners noted that their dogs would intensely use their paws to rub their faces or the dog would use the ground for rubbing their faces (discussed below). Some owners noted their dogs intensely licking or chewing their paws. Although these signs were common, they were either not mentioned by owners until specifically questioned or were noted as having disappeared after treatment had been instituted.

The signs observed by owners that resulted in their seeking veterinary care were varied. The most common cause for seeking veterinary care was apparent grand mal convulsions (discussed in the next section). Owners also sought veterinary care after seeing apparent muscle cramping, tonic spasm of leg muscles, or pain in the legs. Focal muscle twitching, generalized tremors, fasciculations, or trembling was frequently observed. A stiff, stilted, hunched, or rigid gait was noted by most owners. Owners also commonly described their pets as having poor appetites or as being “slow,” “less playful,” or “not as friendly.”

Nervousness is probably an expression of tetany exaggerated by adrenergic secretions. Aggressive behavior is assumed to be caused by the pain associated with muscle cramping. The muscle cramping could be elicited by petting, thus explaining why dogs that previously suffered acute pain from such a mild stimulus are reluctant to be handled. This accounts for the observations of dogs appearing to be less friendly or for their change in behavior or personality.

SEIZURES.

Grand mal convulsions were observed by the owners in 32 of our 37 dogs with naturally occurring primary hypoparathyroidism. As previously reported, most of these dogs had typical grand mal convulsions. However, some seizures were atypical, in that the dogs either did not appear to lose consciousness or were not incontinent during the episode (Peterson, 1986). Of interest was the incidence of seizure activity seen by veterinarians. Of the 37 dogs, 32 were observed by a veterinarian to have seizures (often being suspected of having idiopathic epilepsy) or to be “in tetany.” This represents a much higher incidence of veterinarian-witnessed neuromuscular disorders than expected with idiopathic epilepsy. The neuromuscular problems became so severe that several dogs, although not having active obvious seizure activity, were not able to stand or walk. Also, as noted by other investigators (Sherding et al, 1980), the muscle tremors during some episodes began in one limb and gradually became generalized and progressively more violent, finally culminating in a generalized seizure. In some dogs, seizure episodes were as brief as 30 to 90 seconds; in others, they lasted for more than 30 minutes. Most, but not all, of the generalized seizures spontaneously abated.

MISCELLANEOUS SIGNS.

As can be seen in Table 17-1, many owners observed overlapping neurologic and neuromuscular signs. It can be safely stated, retrospectively, that each dog suffered bouts of significant hypocalcemic tetany as a part of their initial signs. Some vague signs included panting, ataxia, episodic weakness, complete anorexia, vomiting, diarrhea, and weight loss. Veterinarians noted fever, a problem not observed by owners. Previously described signs of circling and/or disorientation (Sherding et al, 1980) were not observed in our group of 37 hypocalcemic dogs. All of our owners observed some clinical signs; failure to see any sign, reported by others, was not noted. Although hypocalcemia was almost always considered a serendipitous finding on laboratory testing, it remains an abnormality that “made sense” after being demonstrated. Death remains a potential sequela of untreated hypocalcemia but is quite uncommon.

FACIAL RUBBING.

Of the 37 dogs in our series, 23 were observed to paw or rub violently at their muzzles, eyes, and ears and to rub their muzzles on the ground. Alternatively, owners noted their dogs intensely licking or chewing at their paws. These signs are thought to result from the pain associated with masseter and temporal muscle cramping caused by the hypocalcemia or as a result of the “tingling” sensation around the mouth or at the distal extremities. Classic signs of hypocalcemia in humans include “paresthesias,” defined as numbness and tingling that often occur around the mouth, in the tips of fingers, and sometimes in the feet (Arnaud, 1994). Dogs, assuredly, suffer these same sensations, which may account for facial rubbing as well as biting of their feet (see Table 17-1).

HYPERVENTILATION.

Because of the acute anxiety or pain associated with tetany, hypoparathyroid humans (and presumably dogs) may episodically hyperventilate and secrete increased amounts of epinephrine. Hyperventilation causes hypocapnia and alkalosis, which worsen hypocalcemia by causing increased binding of ionic calcium to plasma proteins. Prolonged hyperventilation in normal human subjects can cause a decrease in the serum ionic calcium concentration. It is almost impossible, however, for tetany to be caused solely by hyperventilation (Arnaud and Kolb, 1983).

EPISODIC NATURE OF THE ILLNESS.

All neurologic and neuromuscular signs in our hypocalcemic dogs were episodic in nature. Episodes of apparent or confirmed hypocalcemic tetany were followed by asymptomatic periods. The periods of clinical well-being lasted minutes to days. Tetany was rather unpredictable, although retrospectively, these signs were much more frequent or inducible with exercise (even slow or short “leash” walks), excitement, petting (“latent tetany”?), or stress (being taken to the veterinarian).

All the dogs were persistently hypocalcemic but displayed tetany only episodically. This illustrates some adaptation in each dog to hypocalcemia and suggests that relatively minor alterations in these calcium concentrations would result in profound clinical signs. One dog in our series had been diagnosed as having primary hypoparathyroidism but remained untreated for almost a year because of owner reluctance to treat. This dog was persistently hypocalcemic but had only one or two clinically obvious hypocalcemic episodes monthly. In spite of this tragic history, the dog was relatively well, suffering primarily from a poor appetite and weight loss.

GENERAL OBSERVATIONS.

Other than signs related to hypocalcemia, dogs with primary hypoparathyroidism do not have other abnormalities on physical examination. Findings on physical examination performed on the 37 hypoparathyroid dogs varied (Table 17-3). Numerous dogs were in tetany on presentation. Most of the time this was an observation made after serum biochemical results were reviewed. Alternatively, 33 of the 37 dogs were referred for evaluation of hypocalcemia and the veterinarian who examined the dog initially (usually one of us) was “primed” to observe tetany. These observations (almost all of which are noted in Table 17-3), although impressive to the uninitiated, may not have been made had the history not alerted us to the underlying condition.

TABLE 17-3 INITIAL PHYSICAL EXAMINATION FINDINGS IN 37 DOGS WITH NATURALLY OCCURRING PRIMARY HYPOPARATHYROIDISM

Five of the dogs appeared healthy, despite their previous history of neurologic or neuromuscular disorders. A few dogs were thin, and several growled when examined. Retrospectively, the growling dogs were in pain or were anticipating that handling would cause them pain, because after resolution of hypocalcemia, each became friendly. Cardiac abnormalities were apparent in 16 dogs on the initial examination. These abnormalities consisted of paroxysmal tachyarrhythmias suspected in 13 dogs and muffled heart sounds with weak pulses noted in 3 dogs.

SPONTANEOUS NEUROLOGIC AND NEUROMUSCULAR SIGNS.

On initial examination, 32 of the 37 dogs with primary hypoparathyroidism had at least one abnormality that could be attributed to hypocalcemia. Most of these dogs (18) had convulsions. Others growled, were extremely tense or “rigid,” or had “splinted” abdomens, stiff gaits, and/or muscle fasciculations. Virtually every time that a dog growled, the owner would comment that this was a “new behavior,” one they had noticed at home as well. Retrospectively, these dogs were either in pain or they were anticipating pain from contact. Fever was noted in 26 of the 37 dogs.

Thirty-two of the 37 dogs had at least one convulsion during the initial 48 to 96 hours of hospitalization. Complete neurologic examinations were attempted on 30 dogs. These 30 examinations revealed a variety of problems. By far the most commonly reported disorder was that “the dog was too tense and nervous to complete a thorough evaluation.” Retrospectively, these dogs were recognized to have been in tetany. Other findings included brisk reflexes, absent reflexes, clonus, and/or pain. Because these dogs were in latent or active tetany, their neurologic examinations were difficult to interpret until hypocalcemia was identified on laboratory testing.

INDUCED NEUROLOGIC OR NEUROMUSCULAR SIGNS.

Two physical tests are used in humans as aids in diagnosing latent tetany (hypocalcemia). Chvostek’s sign is elicited by tapping the facial nerve just anterior to the ear lobe. A positive sign is one of extensive facial muscle twitching or muscle contraction. Trousseau’s sign is induced with a blood pressure cuff inflated above systolic blood pressure for at least 2 minutes. A positive response consists of carpal spasm, at least 5 to 10 seconds in duration, after release of the cuff or while the cuff is inflated (Arnaud, 1994; Meininger and Kendler, 2000). Although not well described in the dog, episodes of intense muscle spasm have been stimulated when testing reflexes in hypocalcemic dogs.

CATARACTS.

Posterior lenticular cataract formation is the most common sequela of hypoparathyroidism in humans (Arnaud, 1994). Cataracts seen in hypoparathyroid human patients must be present and developing for 5 to 10 years before visual impairment occurs. Fully mature cataracts are confluent and produce total lens opacity. Successful treatment of hypocalcemia generally halts the progression of cataracts (Arnaud, 1994).

Cataracts were seen in 12 of the 37 dogs in our series and were first reported in 2 hypoparathyroid dogs in 1980 (Kornegay et al, 1980). Similar cataracts have been reported in several cats and were noted in 2 of the 5 cats with primary hypoparathyroidism in our series. These cataracts have been small punctate to linear white opacities in the anterior and posterior cortical subcapsular region. The opacities are randomly distributed along the lens fibers and are separated from the capsule by an intervening zone of normal thin cortex (Fig. 17-4). There has been no loss of vision. Other ocular signs not yet reported in dogs include papilledema, optic neuritis, conjunctivitis, keratitis, blepharospasm, loss of lashes, strabismus, nystagmus, and anisocoria.

FIGURE 17-4 Lenticular cataract in the lens of a hypoparathyroid dog.