Hypercalcemia in cats--emphasis on idiopathic hypercalcemia (Proceedings)

Question

How common is hypercalcemia in cats?

Answer

Hypercalcemia is most often defined in primary care practice initially by the finding of increased serum total calcium on routine serum biochemistry. The overall frequency of hypercalcemia is less common in cats than that encountered in dogs but the frequency of finding hypercalcemia in cats has dramatically increased in many regions of the world over the past 20 years mostly due to the diagnosis of idiopathic hypercalcemia (IHC). Mild hypercalcemia based on serum total calcium is often overlooked (often thought to be due to hemoconcentration from mild dehydration) during analysis of serum biochemical profiles so it is likely to be more common than generally appreciated. When screening cats for calcium status using ionized calcium instead of total serum calcium, hypercalcemia was found with greater frequency (Schenck Can Vet 2010).

Question

I just discovered a 12.8 mg/dl total calcium (10.2 mg/dl is upper limit of reference range for my laboratory) on blood test results taken during a wellness exam from what I thought was a reasonably healthy middle-aged cat.  All of the other biochemical tests were normal as was the CBC. How concerned should I be that this cat has malignancy- associated hypercalcemia (MAH)?

Answer

We are always concerned about the possibility for malignancy as the cause of hypercalcemia in both dogs and cats, but MAH is much less common in the cat compared to the dog (it is the number one cause of pathological hypercalcemia in the dog).  Based on serum total calcium, MAH is 3rd in frequency behind IHC and CKD. Patients with MAH are usually “sick” as it takes a reasonably large tumor burden to synthesize the compounds (especially PTHrP) that result in hypercalcemia. So it seems unlikely for this cat to have MAH especially if the hypercalcemia persists for a longer period of time without the cat showing more clinical signs. The less sick the cat is in the face of persistent hypercalcemia, the more the likelihood for the diagnosis to be that of IHC or primary hyperparathryodism. Remember, ionized calcium should always be performed first to confirm the diagnosis of clinically-relevant hypercalcemia.

Question

How do I know if this cat really has IHC?

Answer

The diagnosis of IHC is one of exclusion after initially confirming that the ionized calcium is increased. All the known causes of hypercalcemia should ideally be eliminated – but this kind of workup can be exhaustive and expensive. The ionized calcium must be increased, by definiton. Step one in patients with ionized hypercalcemia is to measure PTH to determine if the process is PTH-dependent (high PTH from abnormal parathyroid glands) or PTH-independent (PTH is suppressed from response of normal parathyroid glands).  Compared to dogs, cats have higher frequency of PTH-independent hypercalcemia.

In those with parathyroid-independent hypercaclemia, the next step in the diagnostic evaluation is to rule out MAH which requires imaging of the thorax and abdomen.  Abdominal imaging is also helpful. The typical pattern for calcium regulatory hormones in IHC would be for PTH concentration to be within the reference range (often lower end), PTHrP undetectable, and normal serum iMg. 25-hydroxyvitamin D and calcitriol concentrations are usually in the reference range. 

Question

What clinical signs should a cat with IHC display ?

Answer

About 50% of cats with IHC have no obvious clinical signs that are noted from owners and their veterinarians during submission of samples to endocrinology laboratories. In many instances, hypercalcemia based on total serum calcium evaluation is fortuitously discovered following submission of samples from wellness examinations or pre-anestheic evaluation of seemingly healthy individuals.

Hypercalcemia is also sometimes discovered following submission of samples from cats with seemingly trivial clinical complaints like intermittent vomiting.  History can include mild weight loss, a diagnosis of inflammatory bowel disease, chronic constipation, vomiting, and anorexia. GI signs may be attributed to the aderse effects of ionized calcemia on gut motility. Uroliths have been reported in about 15% of cats with IHC; calcium oxalate stones were specifically noted in 2/3 of these cats.

Question

Do I really need to treat IHC?  This cat doesn't seem to know it has IHC.  What bad things could happen if I don't treat the IHC ? 

Answer

Though many cats with IHC do not have obvious clinical signs at first look, a more careful review of the history and physical examination often discloses some abnormality that could be explained by persistence of chronic ionized hypercaclemia.  This includes low-grade weight loss, loss of muscle mass,  and lethargy.  Intermittent vomiting and constipation are also possible. Chronic ionized hypercalcemia is a risk factor for the genesis of calcium oxalate urolithiasis and for the development of chronic renal injury resulting in CKD – this may take months to years to develop.

Question

I believe I have a cat with IHC.  The owner's were willing to analyze PTH and ionized calcium but are reluctant to go further with my recommendations of more blood work, radiographs, and ultrasound to make an air tight  diagnosis of IHC.  What is the least amount of diagnostic workup I can do and still feel secure about the diagnosis and starting treatment ?

Answer

Yes it is true that full imaging with thoracic and abdominal radiographs along with abdominal ultrasound is the gold standard in the diagnosis of IHC, many clients will not pay for the gold standard diagnostic evalution. Lack of clinical signs in conjunction with low PTH and ionized hypercalcemia significantly increases suspicion of IHC. In this case, it may be appropriate to presumptively diagnose IHC.

Question

What is the best treatment for stable IHC in cats ?

Answer

The ideal treatment would be to remove the underlying cause for the hypercalcemia, but this is not possible because the pathogenesis for IHC remains unknown. Some combination of dietary change, oral prednisolone, or oral bisphosphonate (alendronate) is usually recommended. In our practice, oral alendronate is the treatment of choice for IHC that is most likely to result in long term restoration of normocalcemia (see other questions below).

Question

I have heard that a dietary change to a higher fiber diet works to restore normocalcemia in cats with IHC- do you agree, and which diet would you recommend if so ? 

Answer

The feeding of increased dietary fiber decreases serum calcium in some cats (McClain 1999) but not in others (Midkiff 2000). Higher fiber diets may decrease intestinal absorption of calcium due to decreased transit time, but the effects of fiber are considered complex since fiber also tends to decrease colonic pH leading to ionization of calcium, thus increasing its absorption. Types and amounts of fiber present may also affect calcium control.

These “high fiber diets” are supplemented with higher concentrations of calcium compared to maintenance diets. Therefore, calcium content is not the reason for the decrease in circulating calcium sometimes achieved on these diets. We suspect that some of the beneficial effect from these diets may be due to lower dietary intake of vitamin D; the actual amount of vitamin D in commercial diets is difficult to know for certain as  this is not a required lable disclosure. Some cats that show an initial decrease in serum calcium concentration following any type of dietary change will have a return to hypercalcemia over time.

Question

Are alkalinizing diets (or at least less acidifying diets, like renal diets) effective in the treatment of IHC ?

Answer:

The feeding of veterinary renal diets may result in normocalcemia in some cats with IHC though this is less studied than changes to a higher fiber diet. However, in one study, 2 of 15 cats with CKD developed ionized hypercalcemia after being fed low phosphorus and protein diet. Ionized calcium normalized after discontinuing dietary phosphorus and protein restriction. (Barber 1999)

Renal diets are generally low in calcium and phosphorus and are considered alkalinizing or at least less acidifying than maintenance diets. Chronic dietary acidification increases the availability of the ionized form of calcium in the intestinal lumen facilitating absorption. They also can increase bone resportion as a buffering response to chronic acidosis which contributes to an increase in circulating ionized calcium in normal cats (Ching 1989) and so could potentially contribute to hypercalcemia in disease.

Question

I have read that glucocorticoids work in IHC - do you think I should go ahead and give them? I am frightened of the side effects that could happen after I start them. 

Answer

Cats are more resistant to the side-effects of glucocorticosteroid administration than are dogs and require higher doses to become immunosuppressed. This treatment historically has been the second choice after dietary change failed to restore normocalcemia but we now consider this AFTER bisphosphonate treatment has been given.  If an insufficient response to bisphosphonates is seen, glucocorticosteroids are prescribed in addition to the bisphosphonate.

Glucocorticosteroids decrease serum calcium by decreasing intestinal absorption of calcium, decreasing renal tubular calcium reabsorption, and decreasing skeletal mobilization of calcium.  There may be a salutary effect from this treatment that changes intestinal calcium absoprtion in cats with underlying IBD be reducing inflammatory infiltrates. We recommend starting prednisolone at a dose of 5-10mg/cat/day, rechecking in 4 weeks, and dose escalating by 5mg every month as needed up to 20mg/cat/day.

It is important to not prescribe glucocorticosteriods before the diagnosis of the hypercalcemia has been established with some certainty, otherwise cytolytic effects in LSA and myeloproliferative disorders will make definitive diagnosis difficult or impossible. A mild calcium-lowering effect can be exerted by use of glucocortocosteroids in other forms of MAH and in those with primary hyperparathyroidism. It is also preferred to have biopsy-proven IBD before the start of glucocorticosteroids. Glucocorticosteroids can be very effective in restoring normocalcemia in many cats with IHC, though higher doses may be needed and some cats escape the initial beneficial effects with a return to hypercalcemia.

Question

Is it OK for me to prescribe prednisone to cats with IHC, or should I consider prednisolone ?

Answer

Oral prednisolone is superior to oral prednisone in cats. This may be due to less GI absorption of prednisone or decreased hepatic conversion of prednisone to prednisolone in cats (Graham-Mize 2005).

Question

I hear that oral bisophosphonates can be dangerous in people at times.  What kind of side-effects COULD occur in cats and what have you actually encountered ? 

Answer

Hypocalcemia is the most commonly reported serum biochemical abnormality following bisphosphonate therapy in humans, though hypophosphatemia and hypomagnesemia also can occur. Mild hypocalcemia is sometimes encountered during oral alendronate treatment of IHC in cats (Hardy 2008), but overt clinical signs are not usually encountered. One cat with IHC that was treated with IV pamidronate developed moderate and then severe ionized hypocalcemia 5 and 6 days respectively after treatment; this cat also developed severe hypophosphatemia (Whitney 2011).

Answer

Drug-induced esophageal damage (esophagitis and esophageal stricture) and gastritis are of concern in humans taking oral bisphosphonates. Studies in dogs suggest a direct adverse effect of alendronate on the esophageal mucosa rather than a simple mechanical effect from the pill. The presence of alendronate in the esophagus of dogs for 1 hour only caused minor mucosal damage.

However, esophagitis is exacerbated if gastric juice containing alendronate is refluxed into the esophagus. It is thought that alendronate sodium is converted to free acid in the presence of gastric juice (Peter 2002). No esophageal lesions and trivial gastric lesions (deemed not clinically significant by the pathologist) were reported from necropsy in cats undergoing relatively high doses (9 mg/kg twice a week in tuna juice) of oral alendronate for 49 weeks (Mohn 2009).

Question

Is there a role for oral bisphosphonates in the treatment  of IHC ?  

Answer

IV treatment with bisphosphonates is almost never needed in IHC since the hypercalcemia is chronic and the cats are usually not in an acute crisis. Traditionally, oral bisphosphonates have been recommended when dietary modification and treatment with prednisolone have been unsuccessful. In our practice, once weekly oral alendronate has become our first choice in the treatment of idiopathic hypercalcemia. However, long term information regarding the safety and efficacy of oral alendronate therapy has not been reported in cats. A pilot study at The Ohio State University was conducted on the safety and efficacy of oral alendronate treatment for 6 months in 12 cats with IHC (Hardy 2008).

In this study, alendronate was effective in lowering ionized calcium in all the cats and no side effects were noted.  There were no side effects noted in a single cat treated with oral alendronate for 18 months which successfully maintained normocalcemia at an average dose of 10 mg per week (Whitney 2011).

Question

What would be your typical treatment protocol when prescribing oral alendronate to treat IHC in cats ? 

 Answer

We typically start at 10 mg once a week. Given the risk of eosphagitis and stricture associated with oral bisphosphonate treatment in humans, extra caution is advised to prevent esophageal tissue damage following oral alendonate administration. We recommend “buttering” the cat's lips/nose as this has been shown to increase salivation and swallowing which contributes to decreased transit time and less time for mucosal contact from the pill (Griffin 2003). Five to 6 ml of tap water is administered via syringe to provide an additional measure to prevent the pills from getting caught in the esophagus (Westfall 2001). Using these preventative measures, we have not observed any signs of esophagitis in cats treated with alendronate thus far. Any food in the stomach can drastically reduce the absorpiton of alendronate to near zero – bisphosphonates are poorly absorbed at best. 

The oral bioavailability of alendronate administered in water to cats was recently reported to be about 3.0%.  This figure reduced in approximately ten-fold when alendronate was formulated in tuna juice (Mohn 2009). To maximize intestinal absorption of alendronate, we recommend an overnight fast for 12 hours prior to the adminstration of medication, give the pills in nothing else besides tap water, and then feed the cat two hours later. Ideally, 18-hour fast prior and 4-hour fast post-pill is recommended to achive oral bioavailability of 3%(Mohn 2009). We do not recommend any kind of alendronate that has been formulated by compounding pharmacies in flavored solution or suspension due to the severe decreases in intestinal absorption.

Question

How do you adjust the dose of oral alendronate ?

Answer

We reevaluate the cat's ionized calcium level 2-3 weeks after starting the 10 mg weekly dose of alendronate. If the ionized calcium has declined substantially but is not yet in the normal range, we recommend waiting another 3 to 4 weeks to see if a further reduction in circulating ionized calcium will occur. Some cats return to normocalcemia on 10 mg oral alendronate per week, whereas other require more to do so. If the ionized calcium remains above the reference range at this next visit, increase the dose to 20 mg once each week. 

If the ionized calcium is increased only slightly above the reference range, alternate giving 10 mg one week followed by 20 mg the next (average of 15 mg per week).  We do not advise splitting the 10 mg alendronate tablet as this may increase the chances for toxic injury to the esophagus. Once the ionized calcium enters the reference range, we recommend reevaluation in 1, 3, and 4 to 6 months if the ionized calcium is stable and within the reference range.

Selected references

Hardy B. Alendronate treatment of idiopathic hypercalcemia in cats (unpublished observations): The Ohio State University, 2008.

Midkiff AM, Chew DJ, Randolph JF, Center SA, DiBartola SP. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14:619-26.

McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.

Mohn KL, Jacks TM, Schleim KD, et al. Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study. J Vet Dent 2009;26:74-81.

Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets: possible mechanisms. Dig Dis Sci 1998; 43:1998-2002.

Savary KC, Price GS, Vaden SL. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-9.

Westfall DS, Twedt DC, Steyn PF, Oberhauser EB, VanCleave JW. Evaluation of esophageal transit of tablets and capsules in 30 cats. J Vet Intern Med 2001;15:467-70.

Whitney JL, Barrs VR, Wilkinson MR, Briscoe KA, Beatty JA. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. Journal of feline medicine and surgery 2011;13:129-34.