When To Start Thyroid Hormone Replacement in Cats Treated with Radioiodine (I-131)

I have a question about thyroid hormone supplementation for iatrogenic hypothyroidism, especially in cats treated with radioiodine (I-131). More specifically, how long after radioactive iodine therapy do you wait before recommending supplementing hypothyroid cats with thyroxine?

I work as a small animal internist at a referral hospital where we treat hyperthyroid cats with radioiodine. After treatment, we routinely run serum T4 and free T4 concentrations and full blood work 30 and 90 days after the cat is discharged. I have found that about 20% of these cats are biochemically hypothyroid (low total or free T4 values) at the 30-day recheck, but many of these cats will revert to normal by the 90-day recheck. The other internist at my practice supplements these cats with L-thyroxine at the first recheck if the serum T4 and free T4 values are low. She does this even if they are not azotemic, with the rationale being that the studies show that hypothyroid cats develop worsening azotemia, which can affect their survival (1).

I am not sure if this is the best approach since I have heard that the residual thyroid follicles may take a few months to regain full function after being suppressed by the over-active thyroid tissue for so long. However, I just want to do what's best (don't we all!)

Thank you so much. I enjoy reading your website and attending your lectures at conferences.

My Response:

First of all, I don't find that free T4 determinations are all that helpful in the diagnosis of feline hypothyroidism (2-4). Many cats treated with radioiodine with maintain low-normal values for both total and free T4 but develop high serum TSH concentrations, a situation commonly referred to as subclinical hypothyroidism in human patients. The problem with our cats, however, is that although most of these cats do remain nonclinical for hypothyroidism, many will develop azotemia that will progressively worsen without treatment with thyroid hormone replacement.

So what I do is as follows: at 30-days post-treatment, I monitor serum concentrations of T4, free T4, and TSH, along with a serum chemistry panel to follow kidney values. If T4 or free T4 values fall into the lower third of the reference range (below 1.5-2.0 µg/dl; reference interval ≈1-4 µg/dl) and TSH rises (above 0.5-0.6 ng/dl; reference range, 0.03-0.03 ng/ml), then the cat is mildly hypothyroid. Some of these cats will recover enough thyroid function to end up as euthyroid, but most remain mildly hypothyroid at both 3 and 6 months, at least based on the finding of high TSH concentrations.

In these cats with mild or subclinical hypothyroidism, I don't like to treat with levothyroxine (LT4) at this time unless evidence of chronic kidney disease (CKD) has developed, with serum creatinine values rising from normal to greater than 2.0 mg/dl. However, this definitely indicates the need for LT4 replacement in order to help maintain renal perfusion and stabilize the serum creatinine concentrations (3-5).

If we decide not to treat (which is generally the case unless new azotemia has developed), then we monitor again with the same thyroid and renal profiles at 3- and 6 months. Again, if T4 falls into the low-normal range (less than 1.5-2.0 µg/dl) and TSH is clearly high (above 0.5-0.6 ng/dl), I would definitely supplement if new or worsening azotemia is detected. If no azotemia is present, I generally continue to monitor and don't supplement with LT4 unless azotemia does develop.

Now, if the serum T4 is below normal and the TSH is clearly high at 3 or 6 months (or later), then the cat has overt hypothyroidism (no longer subclinical) and I would definitely supplement with L-T4 (2-4). Many of these cats are still not very symptomatic, but that may simply be a matter of time. If left untreated for 1 to 2 years, most of those cats will develop classical signs of hypothyroidism (eg, lethargy, hair loss, etc).

So in your case, I would add-in serum TSH to your monitoring protocol. If your owners find that too expensive, then I would replace the free T4 measurement with TSH determination, which is more more helpful in monitoring for cats treated with radioiodine.

References:

1. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4.  
3. Peterson ME. Diagnosis and management of iatrogenic hypothyroidism In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
4. Peterson ME, Guterl JN.Subclinical iatrogenic hypothyroidism in the cat: Clinical, laboratory, and thyroid scintigraphic findings in 35 cases. J Vet Intern Med 2015;29:448-449.
5. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255.

Blood Glucose Curves and the Fractious Diabetic Cat

My problem patient is a 12-year old, DSH, female spayed cat with a 2-year history of insulin-dependent diabetes mellitus. She has been treated with glargine insulin at a variable dose, but typically between 1-3 units, BID. This cat will not eat canned food so we are feeding higher protein, lower carb dry foods (Hill's MD and Purina DM).

Six months ago, the cat was diagnosed with immune-mediated hemolytic anemia (IMHA) and was treated successfully with prednisolone and cyclosporine (Atopica). This led to development of insulin resistance and loss of diabetic control, but the cat did relatively well after raising the insulin dose to 6 units while on prednisolone. After a long and slow taper, the cat is now off all glucocorticoids for the last month, and the insulin dose is back down to 2 U, twice daily. The cat remains on Atopica, probably for life.

We have periodically done in-house blood glucose curves to adjust her insulin dose, but she becomes extremely fractious when hospitalized, and we can't really handle her (she bites, scratches, cries, and screams louder than any other cat I've ever had!). The owner does not care to check blood glucose at home, and given the cat's nature, I doubt if they could even do it. Since weaning her off the prednisolone, we have seen a couple of hypoglycemic readings on spot blood glucose checks so we are now worried that the current insulin dose may be too high.

Therefore a week ago, we performed a serial glucose curve on 2 units glargine, BID. The results were as follows:

• 6 am = Insulin given
• 8 am = 317 mg/dl
• 10 am = 376 mg/dl
• 12 noon = 352 mg/dl
• 2 pm = 299 mg/dl
• 4 pm = 229 mg/dl

We were a bit surprised by the high glucose concentrations during the day on this curve, but we increased glargine from 2 to 3 units BID based on the severe and persistent hyperglycemia. However, when I checked a spot afternoon blood glucose value yesterday, it was low-normal at 69 mg/dl. I rechecked another blood glucose reading 30 minutes later, and it was even lower at 57 mg/dl. Right or wrong, I put her back down to 2 units glargine BID and pm spot check in 1 week.

My main question is this: could this cat's in-hospital curve be leading us astray because she is so fractious? I am aware that spot checks aren't ideal. However, this cat is relatively easy to handle during a quick exam and single spot check, but she become so angry when hospitalized throughout the day.

What would you do? How do I adjust the insulin dosage in this cat? We've been trying to get the cat into remission but it's not looking good!

My Response:

Well, first the bad news: I can almost guarantee that this cat's diabetes will not go into remission, given the fact that she has been diabetic for 2 years. A number of studies have reported that diabetic remission, when it does occur, will generally happen within the first 6 months of diagnosis (1,2). In addition, the fact that she has concurrent disease and has been treated with glucocorticoids certainly hasn't increased her chances for remission.

The good news is that once we decide that diabetic remission is no longer our goal, then we can be more lax with our glucose regulation. Our goal for diabetic cats should then be 3-fold:

1. Control clinical signs of diabetes (e.g., weight loss, polyuria, polydispsia)
2. Prevent diabetic ketoacidosis
3. Avoid hypoglycemia

To do this, it's not really necessary to do the tight glucose regulation and frequent blood glucose monitoring that we would ideally do if we are trying to increase the odds for diabetic remission (3-5).

In fractious diabetic cats, I would never recommend doing serial blood glucoses to determine the best insulin dose. The release of catecholamines during this excitable state can absolutely increase the glucose readings during the curve (commonly referred to as stress hyperglycemia) (6). Overall, this means that all of the serial blood glucose curves you have done in this cat are most likely next to meaningless and that such testing should be stopped.

Spot glucose checks can't hurt, but as you say, they can be hard to interpret and may be misleading. If the blood glucose reading is low, you might want to decrease the insulin dose, but if the blood glucose is in the ideal range or high, you could still be overdosing the insulin.

In cats like this, I'd recommend that you adjust the insulin dose based on the presence or absence of clinical signs, including body weight and water intake (7).  If the owners can measure water intake at home, that can be a very sensitive way to help determine if more insulin is needed. If there are no clinical signs of diabetes and the weight is stable, the cat is probably adequately controlled. Monitoring an occasional serum fructosamine level can also help (8,9), as well as home measurement of urine glucose, if the owner can do it (7,19,11). A weekly check for urinary ketones can also be used to monitor for pending ketoacidosis, and become extremely important if anorexia, vomiting, or any other signs of illness develop.

Bottom Line:
In fractious cats, I would not recommend in-hospital blood glucose curves for monitoring. Stress hyperglycemia will give you results that are meaningless, and one could easily be misled into giving higher doses of insulin than are actually needed. This is especially true in cats with long-term diabetes that are unlikely to ever develop remission.

In cats like this case, I use a combination of clinical signs and blood/urine values, looking at the overall trend in results rather than the specific or individual values. For example, I don't use serum fructosamine concentration as the sole means of judging control, but I still think it is helpful as one piece of the puzzle. If it is high, that suggests that the insulin dosage may have to be increased; if the fructosamine value is low to low-normal, this may indicate overdosage and hypoglycemia.

Believe me, both your hospital staff and the fractious diabetic cat will all be better off with this approach!

References:

1. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clinics North America 2013: 43: 245-249
2. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321.
3. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
4. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
5. Nack R, DeClue AE. In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Vet Q 2014; 34:132-136.
6. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002;16:123-132. 
7. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
8. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 1996;10:360-364. 
9. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64-68. 
10. Bennett N. Monitoring techniques for diabetes mellitus in the dog and the cat. Clin Tech Small Anim Pract 2002;17:65-69. 
11. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 

Unmasking Kidney Disease In Hyperthyroid Cats after Treatment

I have two hyperthyroid cats that both had "completely normal" kidney function until we started treating with methimazole. On treatment, the serum T4 concentrations in both cats have come down nicely to 1.2 and 2.0 µg/dl, respectively (reference interval, 1.0-4.0 µg/dl), so these values are within the low-normal range, which is what I aim for after treatment.

In the first cat, the serum creatinine has increased from 1.2 mg/dl up to 2.0 mg/dl, whereas the serum creatinine value in the second cat rose from 1.5 mg/dl up to 2.5 mg/dl. Based on the IRIS staging system, both cats could be classified as having stage 2 chronic kidney disease (CKD).

How do I manage such hyperthyroid cats that develop "new" CKD after treatment? Should I lower the methimazole or stop it all together in order to help improve the kidney function?

My Response:

Hyperthyroidism and CKD are both very common problems of the older cat and may occur concurrently in the same patient (1,2). Because hyperthyroidism increases the glomerular filtration rate (GFR) and renal blood flow (RBF), the kidney disease may be masked and only revealed once the cat is rendered euthyroid (3-5). As you know, that's what happened in these two feline patients.

However, it is very important to understand that treatment of hyperthyroidism doesn't cause new kidney problems; the CKD was already present in your cats before the methimazole treatment, but the serum creatinine values were normal, in part due to the high GFR associated with hyperthyroidism. Now that you have the hyperthyroidism under control, the lowering of circulating thyroid hormone concentrations has also resulted in a drop in GFR, unmasking the underlying CKD that was already there.

Management of hyperthyroid cats that develop kidney disease after treatment
So what do we do with hyperthyroid cats like your two patients here— cats that develop mild CKD after treatment of hyperthyroidism with methimazole?

It was once thought that if azotemia developed following medical treatment, then it would be best to stop the methimazole and leave the hyperthyroidism untreated (or at least under-treat it) to maximize renal function. This recommendation has now been widely abandoned, with the realization that hyperthyroidism could actually be causing renal injury in these cats through the process of glomerular hyperfiltration (1,2,6). This increase in glomerular pressure has been associated with proteinuria and evidence of tubular damage, which could result in progressive renal injury. In other words, hyperthyroidism has the potential to exacerbate these processes and worsen, rather than help, renal function.

On the other hand, it's also important not to over control hyperthyroidism. In other words, we don't want the post-treatment T4 concentrations to go too low because iatrogenic hypothyroidism will make the azotemia worse (7). Even mild degrees of hypothyroidism can worsen the azotemia in susceptible cats. This means that the serum T4 value does not have to be below reference range — even a serum T4 in the lower third of the reference range may be too low, especially if the serum TSH is high, diagnostic for mild hypothyroidism (8).

Because of this association between development of iatrogenic hypothyroidism and worsening of azotemia, my "goal" in treating cats with hyperthyroidism is to reduce the total T4 concentration into the middle of the reference range (e.g., 2.0-3.0 µg/dl with your lab). So in your first cat, you may want to lower the methimazole dose and allow the serum T4 to come up into the mid-normal range. This may help increase GFR and improve kidney function in that cat. One recent study found that restoration of euthyroidism in cats with iatrogenic hypothyroidism resulted in a significant reduction in serum creatinine concentration, with azotemia resolving in half of the cats (9).

Finally, if you unmask kidney disease after treatment of a hyperthyroid cat, this also means that you should take steps to attempt to slow the progression of CKD, just as you would in a geriatric cat with CKD alone. These steps may include one or more of the following, depending on secondary factors and stage of the CKD (10,11):

• Antibiotics, if urinary tract infection
• Antihypertensives, if hypertensive
• Low-phosphate diet
• Phosphorus binders
• Calcitriol or ACE-inhibitors, if necessary
• Subcutaneous fluids

Survival times of hyperthyroid cats that develop mild CKD after treatment
In most cats that develop newly-diagnosed azotemia after treatment for hyperthyroidism, the CKD is mild (usually IRIS stage 2) and associated with few clinical signs other than mild polyuria and polydipsia. Owners of cats that have developed azotemia still report that treatment of the hyperthyroidism has improved the clinical condition of their cat, as shown by weight gain and resolution of other clinical signs of hyperthyroidism.

The survival time of cats that develop azotemia following treatment of hyperthyroidism does not differ from those that do not develop any azotemia (7). This fact may be surprising to many practicing veterinarians who naturally assume that the development of CKD is associated with a worse prognosis. However, CKD progresses relatively slowly in cats, and only about half of all cats diagnosed with mild CKD will ultimately succumb to the disease (12). Many CKD cats die because of unrelated causes.

Survival times of hyperthyroid cats that are azotemic prior to treatment
The situation is completely different in cats that are already clearly azotemic (serum creatinine >2 mg/dl), even before any treatment for hyperthyroidism has been given. In general the survival of this group of cats with azotemic CKD prior to treatment is poor. In one study, the median survival time for azotemic cats was only 178 days; however, survival times in that study was very variable,  ranged from 0 days up to 1,505 days (4.1 years) (13).

Bottom Line:

Hyperthyroid cats that develop "new" CKD after treatment are common, but the azotemia is generally mild and we should not withhold methimazole treatment in those cats. However, we don't want to induce iatrogenic hypothyroidism, and steps should be taken to address the underlying CKD. Unless prior azotemia was present, the prognosis of most treated cats with mild CKD is good to excellent.

References:

1. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clin Tech Small Anim Pract 2006;21:17-21.  
2. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.  
3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.  
4. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec 2007;161:711-715.  
5. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domest Anim Endocrinol 2009;36:45-56.  
6. Syme H. Are methimazole trials really necessary? In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
7. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.  
8. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compendium 2013;35:E4. 
9. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
10. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
11. Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011;41:15-30. 
12. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41:235-242.
13. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 

Confirming the Diagnosis of Addison's Disease in Dogs on Corticosteroids

Is it possible to confirm diagnosis of Addison's disease with an ACTH stimulation test after treatment has been initiated? My patient is a 6-year-old, male West Highland White Terrier seen on an emergency basis for severe lethargy, vomiting, diarrhea, and anorexia that all began shortly after he was at the groomers. There was no history of dietary indiscretion in this dog.

A serum chemistry profile revealed hypoglycemia (glucose, 61 mg/dl), hyperphosphatemia (phosphorus, 9.1 mg/dl), hyponatremia (130 mEq/L), and hyperkalemia (6.1 mg/dl). The dog was also moderately azotemic, with a serum urea nitrogen of 52 mg/dl and serum creatinine of 2.2 mg/dl.

The dog was treated at the emergency clinic overnight with IV dexamethasone and IV fluids (normal saline). The following morning, he was given an injection of IM Percorten-V (25 mg) and started on oral prednisone (2.5 mg once daily).

He has now been home a week and has shown a marked response to replacement therapy. The dog is scheduled to recheck with me in a few days to recheck his serum chemistry panel and electrolytes. Although this case certainly seems to fit a diagnosis of primary hypoadrenocorticism (Addison's disease), I'd be happier if we could confirm the diagnosis with an ACTH stimulation test.

Is that possible, now that the dog has been treated with dexamethasone, prednisone, and Percorten-V?

My Response:

Yes, you certainly can (and should) do an ACTH stimulation test to confirm the preliminary diagnosis of Addison's disease, even after treatment has been instituted.

Confirming the diagnosis by documenting low serum cortisol secretion before and after ACTH stimulation is always a very good idea, since many other diseases can mimic the clinical features seen with this disease. In addition, even having the classical electrolyte changes associated with Addison's disease (hyponatremia, hypocholemia, and hyperkalemia) are not totally diagnostic, inasmuch as other diseases (e.g., whipworms, renal failure, pancreatitis) can also produce the same electrolyte abnormalities in some dogs.

Diagnostic workup for dogs with suspected Addison's disease on treatment with glucocorticoids and mineralocorticoids
On your recheck in a week, this is what I'd recommend. First of all, if the dog is doing well, have the owners stop the prednisone for at least 24 hours before the recheck exam and ACTH stimulation test is scheduled (48 hours is even better). The Percorten-V has minimal to no glucocorticoid activity so that drug isn't going to interfere with the results of the ACTH stimulation test.

If the dog is normal or is suffering from nonadrenal illness (but does not have Addison's disease), the glucocorticoid treatment (both the IV dexamethasone and oral prednisone) might result in adrenocortical suppression, but not nearly to the degree that we see in dogs with Addison's disease.

• Dogs with primary Addison's disease generally have very low basal and post-ACTH cortisol concentrations (both cortisol values less than 1.0 μg/dl in almost all dogs and always less than 2.0 μg/dl). 
• In dogs treated with glucocorticoids that develop suppression of the hypothalamic-pituitary-adrenal axis, the basal cortisol value may be low and the cortisol response to ACTH stimulation may be abnormal and "blunted."
• However, the serum cortisol values in dogs that do not have Addison's disease will rise to above 2-3 μg/dl after ACTH stimulation in these dogs, and many dogs will show a completely normal cortisol response. In these dogs, a search for other causes of hyperkalemia should be undertaken.

References:

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.
4. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184.

Dog on Long-Term Thyroid Hormone Supplementation: Hypothyroid, Hyperthyroid, or Cushing's Syndrome?

My patient is an 11-year old, spayed female Spaniel-Mix, named Molly. She weighs 31 pounds (14.1 kg) and is slightly overweight, with a body condition score of 7/9. About 5 years ago, she was initially diagnosed as having hypothyroidism based upon clinical signs of hair loss, together with low serum concentrations of total thyroxine (T4) and free T4. Molly responded well to thyroid hormone replacement with brand-name levothyroxine (L-T4) at the dose of 0.2 mg, twice daily.

Over the following 3 years, the dog did well (complete hair regrowth), but the daily L-T4 dose was increased (to 0.3 mg, twice daily) based on post-pill serum T4 testing, done about 5 hours after administration of the morning dose.

About 2 years ago, Molly was seen for new hair loss, increased appetite, and polyuria and polydipsia (PU/PD). Results of a CBC and serum chemistry panel were considered to be normal, and a post-pill serum T4 concentration was low-normal at 1.5 µg/dl (40 nmol/L). A complete urinalysis was unremarkable, other than a urine specific gravity of 1.013. Based on Molly's relapse of her hair loss and low-normal post-pill T4, the L-T4 dose was increased to 0.4 mg, BID.

Follow-up thyroid testing 6 months later revealed a post-pill serum T4 value in the high-normal range (3.9 µg/dL; 50 nmol/L) so the L-T4 was maintained at 0.4 mg BID. At that time, the PU/PD had lessened, and the increased appetite had normalized so no further workup was recommended.

On followup 1 year later (now 5 months ago), Molly again presented with increased appetite and more severe PU/PD. Her post-pill total T4 concentration was quite high at was 10.1 µg/dl (130 nmol/L), so the dosage of LT4 was decreased to 0.2 mg, BID. Repeat testing 2 months later revealed that the serum T4 value remained high (5.5 µg/dL; 70 nmol/L) so administration of L-T4 was discontinued. Other than truncal hair thinning, Molly's physical examination at that time was normal, with a normal heart rate (85 bpm); no thyroid masses could be palpated.

Now 3 months later, the owner reports progressive truncal hair loss, PU/PD, increased appetite, panting, and weight gain. Molly's physical exam was again unremarkable. Results of routine testing revealed a normal CBC (no stress leukogram), with severe hypercholesterolemia (660 mg/dL; 17.0 mmol/L). The serum alkaline phosphatase activity was also moderately high at 311 U/L (reference interval less than 100 U/L).

We next ran a complete thyroid profile, with the following results:

• Total T4: 16 nmol/L (reference interval, 11-60 nmol)
• Total T3: 0.4 nmol/L (reference interval, 0.8-2.1 nmol)
• Free T4 by dialylsis: 12 pmol/L (reference interval, 10-50 pmol/L)
• TSH: 1.0 ng/ml (reference interval, 0-0.6 ng/ml)
• Thyroglobulin autoantibodies: 10% (reference interval, 0-35%)

I'm at a loss. I thought that the dog's signs might indicate hyperthyroidism but these results appear to be most consistent with hypothyroidism. Should L-T4 be restarted? We have only used a single brand-name L-T4 preparation in this dog — should we switch to another product?

Should I be testing Molly's pituitary-adrenal axis to rule out Cushing's syndrome?

My Response:

This dog is indeed a rather complicated case. Looking back at the history, Molly has displayed clinical signs of hair loss, PU/PD, and increased appetite for the past 2 years. All of these signs have waxed and waned in severity over this time, which explains her long duration of illness.

During that entire time, she was being treated with adequate replacement doses of thyroid hormone and never had post-pill T4 values that were low. In fact, many of her serum T4 concentrations checked during monitoring were too high— clearly in the hyperthyroid range (1). Overall, this strongly suggests that hypothyroidism alone cannot explain all the dog's problems, a conclusion that also is consistent with the fact that neither PU/PD nor increased appetite are signs of thyroid hormone deficiency (2,3).

Hypothyroid or hyperthyroid?
Given the fact that 2 of the post-pill serum T4 values were high, could this dog have iatrogenic hyperthyroidism secondary to an overdosage of L-T4? That certainly is possible, and thyrotoxicosis could account for the increased appetite and PU/PD (4-6). In fact, almost all hyperthyroid dogs will develop moderate to marked PU/PD, which is a much more prominent sign in dogs than in most cats with hyperthyroidism (7).

However, these signs persisted for 3 months after we stopped all thyroid hormone supplementation. In addition, the last thyroid hormone panel showed low to low-normal serum concentrations of total T4, T3, and free T4, in conjunction with high serum concentration of TSH; this combination of results is most consistent with primary hypothyroidism (the original diagnosis) (2,3). Overall, these findings completely rule out either natural hyperthyroidism associated with a hyperfunctional thyroid tumor or iatrogenic thyrotoxicosis from overdosage of L-T4 (5-7).

Hypothyroid or Cushing's syndrome?
Since Molly's clinical signs are also classical for hyperadrenocorticism, we should consider testing for that common canine disorder. While the high cholesterol concentration could be due to hypothyroidism or Cushing's syndrome, the finding of a high serum alkaline phosphatase activity certainly is consistent with chronic cortisol excess (8,9).

Before embarking on a workup for spontaneous Cushing's syndrome, remember to first make sure that Molly is not on any exogenous steroids, including a topical preparation for her eyes, ears, or skin, which can result in iatrogenic hyperadrenocorticism. You determine that not only by reviewing the record to see what your hospital has dispensed, but also by asking the owner what they're using to treat their dog, as they may have bags of steroid medications at home that weren't dispensed by you.

If Molly is suffering from Cushing's syndrome, it is possible that chronic cortisol excess is contributing to the low serum thyroid hormone concentrations.  Canine Cushing's syndrome can actually produce a secondary form of hypothyroidism, one that is reversible upon correction of the hyperadrenocorticism (10,11). However, it is very unlikely that Molly has had undiagnosed Cushing's disease for the past 5 years, given that she appears to be doing so well clinically. In addition, chronic cortisol excess suppresses serum TSH values (9,11), so Molly's high TSH value goes along more with primary hypothyroidism than a secondary form of hypothyroidism resulting from Cushing's syndrome.

As you continue to work up this dog, I would restart your thyroid hormone supplementation at a low dose (0.2-0.3 mg per day, divided). The dog certainly appears to be hypothyroid, based on the last serum thyroid profile, as well as worsened hair loss.

Causes of marked variation in L-T4 absorption
The marked variation in serum post-pill T4 concentrations are both interesting, as well as somewhat perplexing.

I'd start by questioning the owners about the timing of L-T4 administration, since the absorption of the medication is known to be increased when given on an empty stomach, as compared to when administered with meals (12,13). Could some of the marked variation in her past serum post-pill T4 levels have been due to administration of the drug with meals on some occasions and on an empty stomach on others? 

Other drugs and medications can also have an effect on L-T4 absorption (14). In this dog, we must carefully record all dietary changes as well as any administered drugs or supplements, all of which could potentially alter the absorption of the L-T4 preparation. 

References:

1. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
2. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
3. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114. 
4. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
5. Peterson ME. Hyperthyroidism and thyroid tumors in dogs In: Melian C, Perez Alenza MD, Peterson ME, et al., eds. Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Spain: Multimedica, 2008;113-125.
6. Mooney CT. Canine hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;86-91.
7. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
8. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;167-189.
9. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
10. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyperadrenocorticism on serum thyroid hormone concentrations in the dog. Am J Vet Res 1984;45:2034-2038. 
11. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism. Am J Vet Res 1992;53:1636-1640. 
12. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876.
13. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101.
14. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.

Treatment and Monitoring of Hypothyroid Dogs with Thyroid Hormone Autoantibodies

I'm a veterinarian from Finland, and I'd like your opinion and advice on a 2-year old, male neutered Doberman Pincher (body weight, 42 kg). This dog had been diagnosed with hypothyroidism together with serum T3 antibodies by another veterinarian.

Clinically, the dog has shown a partial response to treatment with L-thyroxine (L-T4), but serum T4 concentrations remain very low and serum TSH remains high on post-pill testing. These are results of my thyroid testing (always at 4 hours post-pill), together with the L-T4 dose and physical examination:

Initial exam:

• Dose: Levothyroxine 400 µg BID
• Exam findings: Clinically quite normal but slightly overweight
• Total T4:  <9.0 nmol/L (reference interval =  13 - 52 nmol/L)
• Free T4 (CLIA): >77 pmol/L (reference interval =  8 - 48 pmol/L )
• TSH: 3.24 ng/ml (reference interval = less than 0.5 ng/ml)

4-week recheck:

• Dose: Levothyroxine 500 µg BID
• Exam findings: Clinically normal; but still overweight
• Total T4: < 9.0 nmol/L  
• TSH: 3.59 ng/ml  

8-week recheck:

• Dose: Levothyroxine 600 µg BID
• Exam findings: Mild weight loss, heart rate 82/bpm, very active and perky
• Total T4: <9.0 nmol/L  
• Free T4 (CLIA): 62 pmol/L
• TSH: 2.2 ng/ml  

I reviewed the L-T4 supplementation with the owner and made sure the dog is ingesting the pills and made certain that they administered the thyroid medication the morning of each recheck—  no problem there. I next recommended repeat testing, again looking at the autoantibody levels and free T4 measured by equilibrium dialysis (ED).

11-week recheck:

• Dose: Levothyroxine 800 µg BID
• Exam findings: Normal
• Total T4: < 9.0 nmol/L 
• Free T4 (ED): 8 pmol/L (reference interval = 6-40 pmol/L) 
• TSH: 1.5 ng/ml  
• T4 antibodies: 13% (1-20%)
• T3 antibodies: 43% (1-10%)
• Thyroglobulin autoantibodies: positive

Overall, I'm confused about this dog's thyroid status. Biochemically, this dog appears to have persistent hypothyroidism (low T4, high TSH) but may also have iatrogenic hyperthyroidism (high free T4 values). How do I know?

I also need advice about how to determine the correct L-T4 replacement dose for this dog. Do I just keep on increasing the medication until the serum T4 concentration normalizes?

My Response:

Obviously, your testing confirms that this dog has thyroiditis, with positive thyroglobulin autoantibodies and high levels of T3 autoantibodies (1-4). Based on the low serum concentrations of free T4 by dialysis and high TSH levels, the dog certainly is hypothyroid (5), but it does not appear that the dog is responding well to the L-T4 supplementation.

Method for T4 assay
What method is being used to measure total T4 concentrations? These days, most commercial veterinary labs don't use radioimmunoassay (RIA) to measure serum T4, even though that method is still considered the gold standard (5,6). Most laboratories use either a chemiluminescent immunoassay method (CLIA; Immulite) or an automated enzyme immunoassay (EIA) method (7,8).

For some reason not well understood, the EIA method will fail to accurately detect circulating post-pill T4 values, at least in some T4-treated dogs. In other words, the serum T4 values remain falsely low, even when the actual T4 values are within the mid- to high-normal range and the dogs are clinically improved. This issue needs more research and has not been published, but there is no doubt that the problem exists. If suspected, one can verify the problem very easily, simply by repeating the post-pill serum T4 concentration by either RIA or chemiluminescence.

Method for Free T4 assay
In this dog, the finding of a high free T4, measured by CLIA (Immulite) can not be easily explained. The fact that the serum TSH is persistently high in your dog suggests persistent hypothyroidism, not hyperthyroidism (5,9).  The low-normal value for the free T4 concentration, when remeasured by equilibrium dialysis (ED), also points to hypothyroidism. Thyroid autoantibodies can not interfere with the free T4 value when determined by the dialysis method, since all protein molecules (including the thyroid autoantibodies) are removed (dialyzed) prior to assay.

Given that we know your dog has thyroid hormone autoantibodies, it's tempting to postulate that the high free T4 value measured by CLIA are falsely high due to the autoantibodies. The bottom line is that we just don't know. However, what is clear is that these free T4 values are not helping us to determine the best treatment for this dog — only confusing the situation.

Brand of L-thyroxine
What brand of LT4 is being administered? In any dog that is not responding well to thyroid hormone supplementation, a brand name product is always recommended.  In addition, sometimes it can help to switch to another size or brand, suggesting that the absorption rate may vary slightly between products. In some studies, use of a liquid L-T4 solution has been found to be be better absorbed, at least in select patients (10,11).

Timing of L-T4 and meals
Are the owners giving the LT4 with meals or on an empty stomach?  The standard of care for human patients requiring L-T4 is to administer the drug on an empty stomach, generally an hour before meals.

Simultaneous administration of L-T4 with food can markedly delay and inhibit the absorption of the drug in both humans and dogs (11-13). In one study of dogs, giving the L-T4 with food decreased its absorption by about 45% (11).

Follow-up Information:

The serum T4 is being measured by EIA. We are giving a brand-name L-T4 product (14). The owner is consistently giving the L-T4 at 12-hour intervals at the time of meals. No other medication is being given.

My Response:

Again, with the EIA method, the total T4 result may not be accurate when measuring a post-pill T4 concentration. We need to do the post-pill T4 by either chemiluminescence (CLIA; Immulite) or RIA on the next followup.

However, the fact that the free T4 concentration is low-normal and the TSH is still high means that the absorbed dose of L-T4 is not high enough. None of your problems appear to have anything to do with T4 or T3 autoantibodies.

I'd first change the timing between the L-T4 dose and feeding to ensure "empty stomach dosing." If that fails to adequately increase the total T4 concentration (RIA or CLIA) and normalize the high serum TSH concentrations, I'd next consider switching to a liquid L-T4 preparation to see if that helps. Finally, if all else fails, you may have to continue to increase the L-T4 dose, but at 0.8 mg twice daily, your dog is already on a more-than-adequate dose for most dogs (5).

References:

1. Refsal KR, Nachreiner RF. Thyroid hormone autoantibodies in the dog: their association with serum concentrations of iodothyronines and thyrotropin and distribution by age, sex, and breed of dog. Canine Practice 1997;22:16-17.
2. Young DW. Antibodies to thyroid hormone and thyroglobulin in canine autoimmune lymphocytic thyroiditis. Canine Practice 1997;22:14-15. 
3. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
4. Patzl M, Mostl E. Determination of autoantibodies to thyroglobulin, thyroxine and triiodothyronine in canine serum. J Vet Med A Physiol Pathol Clin Med 2003;50:72-78. 
5. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
6. Kemppainen RJ, Birchfield JR. Measurement of total thyroxine concentration in serum from dogs and cats by use of various methods. Am J Vet Res 2006;67:259-265.
7. Singh AK, Jiang Y, White T, et al. Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses. J Vet Diagn Invest 1997;9:261-268. 
8. Horney BS, MacKenzie AL, Burton SA, et al. Evaluation of an automated, homogeneous enzyme immunoassay for serum thyroxine measurement in dog and cat serum. Vet Clin Pathol 1999;28:20-28. 
9. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
10. Pirola I, Formenti AM, Gandossi E, et al. Oral liquid L-thyroxine (L-T4) may be better absorbed compared to L-T4 tablets following bariatric surgery. Obes Surg 2013;23:1493-1496. 
11. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther 2008;31:95-101. 
12. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.
13. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876. 
14. Forthyron LT4 product insert: http://www.forthyron.com/data/acms/docs/treatment/1_forthyron_pi_200_400_en.pdf

Diet Recommendations for Dogs with Metastatic Insulinoma

My patient is “Ben,” a 10-year old, male Lab weighing 35 kg that presented with a 2-month history of having strange episodes, which included signs of disorientation and ataxia lasting from 10 minutes to 2 hours. The episodes were initially intermittent, but became much more frequent (2-3 times per day), so that the owner (finally) brought him in for an evaluation.

On physical exam, the dog was clinically normal. On our routine chemistry profile, the serum glucose value was very low (28 mg/dl; 1.56 mmol/l). We collected another blood sample for paired serum insulin and glucose concentrations. These test results showed an extremely low serum glucose concentration (25 ng/dl; 1.39 mmol/l) with a high serum insulin value (439 pmol/l; reference interval, 36-287 pmol/l).

An abdominal ultrasound showed a solitary 7-9 mm hypoechoic nodule on the pancreatic body between the pyloris and the proximal duodenal flexure. Unfortunately, multiple, small, very discrete solitary hypoechoic masses or nodules were also found throughout the liver, suggesting metastatic disease.

Based upon the hypoglycemia, hyperinsulinemia, and ultrasound findings, my presumptive diagnosis is insulinoma with metastasis to the liver. His owners have declined surgical exploration or biopsy.

We started Ben on oral prednisone (5 mg three times daily), and the owners have been feeding him small frequent meals. His improvement has been dramatic— no further episodes of disorientation or ataxia have been noted. I'm planning on keeping Ben on long-term, daily prednisone, but have some questions about the best diet to feed.

My understanding is that these dogs do best when fed frequent meals with high complex carbohydrates and low simple carbohydrates. I’ve also read that puppy diets are best, whereas others have said that a diabetic diet is better. But I was also concerned that a lower carbohydrate diet may not keep the blood glucose high enough. Which diets do you recommend?

My Response:

Unfortunately, there are no published studies to help us decide which is the best nutritional approach for management of dogs with insulinoma. This is not a very common endocrine tumor (1,2), so it’s difficult to do randomized trials that would evaluate the glucose response to different diets in dogs with insulinoma.

In my experience, there is not a single type of diet that will work well in all dogs. This is likely related to what stimulates that dog’s insulinoma to secrete insulin. In most dogs, hypoglycemia occurs most often during periods of fasting or exercise, whereas other dogs appear to develop the most severe signs of hypoglycemia after feeding (1,2).

Low carbohydrate, high protein diets?
Dogs with insulinomas should be fed every 4 to 8 hours, with a diet containing moderate to high levels of protein and fat and low amounts of simple carbohydrates (3). By avoiding simple sugars, an appropriate diet can dramatically reduce the stimulus for tumor insulin release, thereby controlling the clinical signs of hypoglycemia. The only exception is when a dog is actively exhibiting signs of hypoglycemia. In those cases, a rapidly absorbed source of sugar (such as honey, corn syrup, or maple syrup) may be administered orally at home pending further veterinary consultation (1,2).

Some dogs do well on a low-carbohydrate, high-protein diet, similar to what is commonly recommended for the diabetic cat. Most “young dog diets" fit reasonably well into this category. Since these diets are higher in fat, however, they can lead to weight gain in some dogs. Again, such low-carb diets reduce the stimulus for insulin secretion since these diets lessen postprandial hyperglycemia. During the metabolism of protein to glucose, glucose is liberated slowly into the blood stream, thus avoiding excessive production of insulin but providing a source of glucose over a prolonged period of time (4,5).

High-fiber, complex carbohydrate diet?
If a higher carbohydrate diet is fed, one containing complex carbohydrate and/or high fiber is ideal, since the digestion and absorption of carbohydrates should be slower and the rise in blood glucose more sustained over time (2). However, as opposed to the lower carbohydrate, higher fat diets, these high fiber diets tend to be low in energy density; therefore, if the dog is underweight or starts to lose weight, this type of diet might not be the best choice.

Bottom line
A number of different types of diets can be used to help manage the signs of hypoglycemia in dogs with insulinoma. Some dogs will do best on low carb diets, whereas others may respond better to a higher fiber diet. Whatever type of diet is chosen, multiple small feedings a day are indicated.

But remember: diet therapy generally plays only a minor role in management of dogs with insulinoma. Surgical resection of gross pancreatic disease is the treatment of choice and should always be considered, even in dogs with known metastatic disease. If surgery is not possible or it fails to control hypoglycemia, glucocorticoids (prednisone) and diazoxide are two drugs commonly used in conjunction with diet for the long-term management of dogs with insulinoma (1,2,6,7).

Overall, the combination of surgical and medical therapy, together with proper dietary management, offers the greatest chance to control clinical signs and prolong survival time (8,9) in dogs with this malignant islet-cell pancreatic tumor.

References:

1. Kintzer PP. Insulinoma and other gastrointestinal tract tumours. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:148-155.
2. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163.
3. Bell SJ, Forse RA. Nutritional management of hypoglycemia. Diabetes Educ 1999;25:41-47.
4. Conn JW. The advantage of a high protein diet in the treatment of spontaneous hypoglycemia. Preliminary report J Clin Invest 1936;15:673-678.
5. Blumberg S. Should hypoglycemia patients be prescribed a high-protein diet? J Am Diet Assoc 2005;105:196-197.
6. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
7. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64.
8. Rychel J, Worley DR, Hardy CS, et al. Prolonged survival in an aged labrador retriever with a metastatic insulinoma. J Am Anim Hosp Assoc 2013;49:224-229.
9. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156.

Hypocalcemia after Surgical Removal of an Anal Sac Adenocarcinoma in a Dog

My patient is a 55 pound (25 kg), 11-year old, female English Springer who presented with polyuria,  polydipsia, and a decreased appetite.  Physical examination revealed a huge (apple-sized) anal sac mass and enlarged sublumbar lymph nodes on rectal palpation (presumably metastatic disease).

Routine blood work revealed severe hypercalcemia (16.5 mg/dl). Fortunately, the renal function still appeared to be adequate, as evidenced by the normal serum concentrations of both urea nitrogen and creatinine. However, the urine specific gravity was low at 1.007.

Hypercalcemia was confirmed by finding a very high serum ionized calcium concentration (2.1 mmol/L; reference interval, 1.25-1.45 mmol/L). A serum parathyroid hormone (PTH) concentration was suppressed (0.2 pmol/L; reference interval, 0.5 - 5.8 pmol/L), consistent with PTH-independent (e.g., malignant) hypercalcemia.

One week ago, I removed the anal sac tumor along with the enlarged sublumbar lymph nodes (lymphadenectomy). The dog did well in the immediate post-surgical period, but she started showing anxiety and facial itching 3 to 4 days ago. Yesterday, the owner finally brought her back for a recheck, and she was exhibiting severe signs of hypocalcemia, with muscle twitching, anxiety, and panting. We don't have the ability to measure ionized calcium in-house, but her total calcium value was low at 4.8 mg/dl.

I administered calcium gluconate slowly by intravenous injection "to effect," which resolved the sigs of hypocalcemia.  Over the next 2 hours, multiple IV doses were required to prevent return of her twitching and other signs of hypocalcemia. Therefore, we started her on a constant rate infusion (CRI) of calcium gluconate to maintain the serum calcium concentration in the low-normal range and prevent clinical signs.

We also started the dog on calcitriol (Rocaltrol) later that day as soon as she could swallow, using an initial dose of 0.5 µg, followed by a second dose of 0.25 µg 12 hours later. We also started oral calcium carbonate (Tums) at a dose of 3000 mg divided TID. This protocol worked well, bringing her serum calcium up to 8.4 mg/dl the following morning, with no return of clinical signs of hypocalcemia. She started eating within an hour of first infusion.

I weaned her off CRI throughout today. After 4 hours, the serum calcium concentration had fallen to 7.4 mg/dl, but she had no clinical signs and acted great. Now 18 hours later, she is still doing well clinically on twice daily oral calcium and calcitriol (0.25 µg).

So I assume I will be treating her with calcitriol for a few weeks at a tapering dose. I understand the standard maintenance is 5-15 µg/kg/day divided BID with food (1,2). Of course, that means that I'll have to have the drug compounded into that dosage by a compounding pharmacy, with its cost and delay. Is there an alternative dosing scheme that would work for her?

My Response:

Malignancies commonly associated with hypercalcemia in dogs include T cell lymphoma and adenocarcinomas derived from the apocrine glands of the anal sac (3,4). In a recent study, lymphoma accounted for ≈75% of the dogs with ionized hypercalcemia and cancer (5).

Tumors in the apocrine glands of the anal sac appear primarily in middle-aged dogs and commonly lead to hypercalcemia. Clinical signs are referable to hypercalcemia (polyuria, polydipsia, anorexia, and weakness), a mass in the perineum (tenesmus, ribbon-like stools, increased odor, and protruding mass), a mass in the sublumbar region, or more distant metastases (6-12).

In addition to anal sac carcinoma, humeral hypercalcemia of malignancy can also develop in dogs with thymoma, myeloma, melanoma, or carcinomas originating in the lungs, pancreas, thyroid gland, skin, mammary gland, nasal cavity or adrenal medulla (3.4).

Hypocalcemia after treatment of malignant hypercalcemia
It is very unusual to see post-operative hypocalcemia in a dog suffering from a malignant tumor that has resulted in hypercalcemia of malignancy, but it certainly is possible if you have removed most or all of the cancerous tissue (13). Severe hypercalcemia, no matter what the cause, will suppress normal parathyroid hormone secretion (1-4); so now that the underlying cause of the hypercalcemia has been removed (the anal sac tumor), the dog currently has iatrogenic hypoparathyroidism.

Why do we commonly see postoperative hypocalcemia after removal of a parathyroid tumor (primary hyperparathyroidism) but only rarely see postoperative hypocalcemia after removal of a tumor associated with hypercalcemia of malignancy? Most likely, the difference is due to the fact that it is usually difficult to remove enough of the malignant, metastatic tissue responsible for the dog's hypercalcemia, whereas it's relatively easy to remove a parathyroid tumor(s) — at least once it's identified— since most of these parathyroid nodules are benign.

Protocol for treating postoperative (iatrogenic) hypocalcemia
With severe postoperative hypocalcemia, as seen in this dog, it's generally best to just go straight to a constant rate infusion of 10% calcium gluconate after initial stabilization (1,2).  To that end, 10% calcium gluconate should initially be given 0.5–1.5 ml/kg, IV, slowly over 20–30 minutes until clinical signs have subsided. An ECG should be used to monitor cardiac effects and the infusion stopped if there is ST segment elevation, QT shortening, or if arrhythmias develop. Thereafter, a continuous rate infusion should be used at 10–15 mg/kg/h (10–15 ml/kg over 24 hours) until oral therapy allows better control.

If you use intermittent injections of calcium gluconate, these must be be given via the intravenous route. Calcium salts should never be used subcutaneously, as this can lead to sterile abscess formation and skin sloughing in dogs (2).

Longer-term treatment for postoperative hypocalcemia includes the use of oral calcium and vitamin D (calcitriol) supplementation.  Successful management of this condition is rather expensive and requires intense monitoring, with serum total or ionized calcium measured at least once weekly and dose adjustment made as needed (1,2).

Eventually, this dog can be tapered off of both the calcium and vitamin D supplementation, but how quickly this will occur is impossible to predict. It could be days to many months, but recovery will likely occur within the next 2 to 3 months.This could be a good sign, indicating that the parathyroid glands are functioning again. On the other hand, this may also be a bad prognostic indicator, since this could also mean that the cancer (and humeral hypercalcemia) is recurring.

So it's not likely that you will need to keep this dog on the standard maintenance dosage (5-15 ng/kg/day divided bid) of calcitriol for very long (perhaps a couple weeks to a month) before you can try weaning completely off the drug.  In most of these dogs, the sizes of the Rocaltrol oral capsules (0.25 µg and 0.5 µg) are too large for maintenance. In these cases, an oral solution of calcitriol (Rocaltrol Oral Solution; 1 µg/ml) is available (14), or the calcitriol can be reformulated to the required concentration by a compounding pharmacy to assure accurate dosing.

References:

1. Chew D, Nagode L. Treatment of hypoparathyroidism. In: Bonagura JD, ed. Kirk’s Current Veterinary Therapy: XIII: Small Animal Practice. Philadelphia: Saunders; 2000:340–345.
2. Skelly BJ. Hypoparathyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med  2012;27:156-158.
5. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). J Vet Intern Med 2009;23:514-519.
6. Hause WR, DVM, Stevenson S, DVM, MS, Meuten DJD, et al. Pseudohyperparathyroidism associated with adenocarcinomas of anal sac origin on four dogs. J Am Anim Hosp Assoc 1981;17:373-379.
7. Meuten DJ, Cooper BJ, Capen CC, et al. Hypercalcemia associated with an adenocarcinoma derived from the apocrine glands of the anal sac. Vet Pathol 1981;18:454-471. 
8. Goldschmidt MH, Zoltowski C. Anal sac gland adenocarcinoma in the dog: 14 cases. J Small Anim Pract 1981;22:119-128. 
9. Ross JT, Scavelli TD, Matthiesen DT, et al. Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases. J Am Anim Hosp Assoc 1991;27:349 - 355.
10. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response to therapy. J Vet Intern Med 2002;16:100-104. 
11. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.
12. Hobson HP, Brown MR, Rogers KS. Surgery of metastatic anal sac adenocarcinoma in five dogs. Vet Surg 2006;35:267-270.
13. Saba C, Ellis A, Cornell K. Hypocalcemia following surgical treatment of metastatic anal sac adenocarcinoma in a dog. J Am Anim Hosp Assoc 2011;47:e173-177. 
14. Rocaltrol (calcitrol) web site. Assessed April 30, 2014.

Diagnostic Work Up for Dogs with Hypercalcemia of Unknown Origin

My patient is an 8-year old spayed female mixed-Labrador that presented with marked polydipsia and polyuria. Otherwise, she appears to be feeling well; she has a normal appetite, with no weight loss, vomiting, diarrhea, or coughing.

Her initial work-up identified a high total serum calcium of 13.7 mg/dl (reference interval, 8.9-11.4 mg/dl), which was confirmed two days later (repeat calcium, 13.1 mg/dl). The rest of the serum biochemical analysis (including the serum sodium, potassium, urea nitrogen and creatinine) were normal. The results of a complete blood count were normal and a complete urinalysis was also unremarkable, except for a low urine specific gravity (1.010).

Chest and abdominal radiographs were normal.

A complete calcium panel was next performed (1), with the following results:

• Serum ionized calcium (iCa) = 1.63 mmol/L (reference interval, 1.25-1.45)
• Serum parathyroid hormone (PTH) = 1.0 pmol/L (0.5 - 5.8)
• Plasma parathyroid hormone-related polypeptide (PTHrp) = 0.3 pmol/L (<0.5)

How would you recommend that I proceed in the workup of this dog? I'm considering an abdominal ultrasound and bone marrow exam to look for occult lymphoma, and maybe a trial response to asparaginase?

My Response:

In adult dogs with repeatable hypercalcemia, the two most common causes include primary hyperparathyroidism and malignancy (2,3). Most dogs with primary hyperparathyroidism feel good (normal attitude and appetite), whereas those with hypercalcemia of malignancy tend to be clinically ill (4-7).  With the low-normal serum PTH value and measurable (but normal) PTHrp value, neither of those categories can be completely excluded (2,3,8).

With the current assay for PTH employed at DCPAH (1), it's been my observation that a serum PTH value higher than 1 pmol/L is generally consistent with primary hyperparathyroidism and a PTH value lower than 1 is consistent with PTH-independent hypercalcemia (usually neoplasia).  However, remember that PTH is a peptide and is subject to breakdown and degradation during shipping, especially if the plasma sample was not kept frozen or at least cool.  Therefore, sample handling issues (delay in transit or sample warming) can result in falsely-low serum PTH concentration. If there is any doubt about the sample integrity when it arrived in the lab, a new serum sample should be collected to recheck the PTH concentration. After the serum is collected, it should be immediately frozen and shipped by overnight delivery to the lab (with dry ice or freezer pack) to ensure valid results.

Hypercalcemia associated with Addison's disease is also relatively common in dogs and is possible in this case (9). However, the normal serum concentrations of sodium and potassium and the fact that your dog is not showing signs of serious illness make hypoadrenocorticism unlikely.  Most of these hypercalcemic dogs have overt Addison's disease, with moderate to marked hyperkalemia and hyponatremia.  That said, you could certainly run a resting cortisol concentration to help exclude hypoadrenocorticism — the finding of a serum cortisol value above 2.0 µg/dl basically rules out Addison's disease (10).

Rare causes of hypercalcemia also include hypervitaminosis D or A and granulomatous disease, so these must be considered (2,3,11,12). Most of the other differentials can be excluded with routine serum biochemical analysis and history (Table 1).

Table 1: Differential list for hypercalcemia in dogs

Workup for undefined hypercalcemia

There are a number of ways to handle this case. Here is a workup list for you to consider, starting with the easiest and least invasive:

1. Perform thorough rectal exam to rule out an anal sac adenocarcinoma (13-15).
2. Carefully check for lymph node enlargement and aspirate any lymph nodes that you can palpate.
3. Measure a resting cortisol concentration to help exclude hypoadrenocorticism. If the basal cortisol concentration is low, this should be followed up with an ACTH stimulation test to confirm Addison's disease (10).
4. Consider repeating the serum PTH concentration. Since lipemia can effect the results, the dog should be fasted overnight. After blood collection, allow serum to clot at room temperature for 30 to 60 min prior to separation. The serum sample should be immediately frozen and shipped by overnight delivery to the lab (with dry ice or freezer pack) for PTH analysis (1).
5. If the repeat PTH value is above 1.0 pmol/L (in other words, not suppressed) consider having an experienced radiologist perform a cervical ultrasound exam looking for a parathyroid nodule, which would more strongly suggest primary hyperparathyroidism (16).  
6. If the repeat PTH value is suppressed or if the cervical ultrasound fails to detect a parathyroid tumor, then consider a complete abdominal ultrasound examination to screen for possible occult cancer, especially lymphoma.
7. Collect multiple aspirates of the liver and spleen with ultrasound-guidance, even if those organs appear normal on your ultrasound exam. I've had cases in which the ultrasound exam appears normal but the cytology said otherwise.
8. Consider a bone marrow aspirate. However, given the normal hematology results, this is less likely to be diagnostic.
9. Finally, if all of the above fails to yield a definitive diagnosis, then consider monitoring the ionized calcium and PTH concentrations to make sure that the hypercalcemia does not rapidly progress and that the PTH value remains stable.  If the PTH value increases to the mid-normal to high range, that finding would be most consistent with primary hyperparathyroidism; on the other hand, if the value falls further, that would be consistent with PTH-independent hypercalcemia (e.g., malignancy) (2,3).

Bottom Line

If nothing is found on your complete workup, I've learned that close observation and monitoring is sometimes the best route to take.  This includes periodic exams (including lymph node palpation and rectal exams), as well as following the serum iCa concentrations. I've had a few dogs with persistent, but stable, idiopathic hypercalcemia in which a definitive cause for the hypercalcemia was never identified. But the dogs (and eventually the owners) didn't care all that much, since the degree of hypercalcemia remains fairly stable and was not very progressive.

By contrast, in those dogs that have progressive disease and develop severe, worsening hypercalcemia, the underlying cause will eventually be obvious, even if it isn't apparent during the initial workup.

References:

1. Michigan State University, Diagnostic Center for Population and Animal Health (DCPAH).
   4125 Beaumont Road, Lansing, MI 48910-8104. 
2. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:221-233.
3. Skelly BJ. Hyperparathyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:43-55.
4. Jores K, Kessler M. Primary hyperparathyroidism in the dog. Diagnosis, therapy and postoperative management in 19 dogs. Tierarztliche Praxis Ausgabe K, Kleintiere/Heimtiere 2011;39:389-396.
5. Schaefer C, Goldstein RE. Canine primary hyperparathyroidism. Compend Contin Educ Vet 2009;31:382-390.
6. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med 2012;27:156-158.
7. Vasilopulos RJ. Humoral hypercalcemia of malignancy: Diagnosis and treatment. Compend Contin Educ Vet 2003;25.
8. Rosol TJ, Nagode LA, Couto CG, et al. Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 1992;131:1157-1164.
9. Peterson ME, Feinman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. J Am Vet Med Assoc 1982;181:802-804.
10.  Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007;231:413-416.
11. Mellanby RJ, Mee AP, Berry JL, et al. Hypercalcaemia in two dogs caused by excessive dietary supplementation of vitamin D. J Small Anim Pract 2005;46:334-338.
12. Dow SW, Legendre AM, Stiff M, et al. Hypercalcemia associated with blastomycosis in dogs. J Am Vet Med Assoc 1986;188:706-709.
13. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.
14. Meuten DJ, Capen CC, Kociba GJ, et al. Hypercalcemia of malignancy: Hypercalcemia associated with an adenocarcinoma of the apocrine glands of the anal sac. Am J Pathol 1982;108:366-370.
15. Hause WR, DVM, Stevenson S, DVM, MS, Meuten DJD, et al. Pseudohyperparathyroidism associated with adenocarcinomas of anal sac origin on four dogs. J Am Anim Hosp Assoc 1981;17:373-379.
16. Wisner ER, Penninck D, Biller DS, et al. High-resolution parathyroid sonography. Vet Radiol Ultrasound 1997;38:462-466.

Escalating Costs of Insulin Glargine (Lantus): Can We Switch to Another Insulin?

My patient is a 14-year-old male Toy Poodle (weighing only 5 kg) that has been maintained on insulin glargine (Lantus; Sanofi-Aventis) for several years. Currently, the dog is receiving an insulin dose of 6 units twice daily and is doing well (i.e., no obvious polyuria, normal appetite with stable body weight). However, over the last few months, the price of Lantus has skyrocketed to over $250 for a 10-ml vial. The owner would like to switch to a more affordable insulin, if possible. At 12 units a day, she is going through a 10-ml vial of Lantus every 2.5 months or so.

My question is this: would another long-acting insulin —such as detemir (Levemir) or PZI (ProZinc)— be more cost-effective in this dog? Or would you suggest that I start over with an intermediate-acting insulin, such as NPH (Humulin N or Novolin N) or Vetsulin?

I did not start this dog on Lantus, but the owner claims that they had great difficulty in regulating him after his initial diagnosis. Therefore, I'm a bit hesitant to "rock the boat" when the Lantus seems to be doing the job. Do you have any ideas why the price has gone up so much over the last year or so?

My Response:

Long-acting insulins, such as glargine, are not commonly used in dogs with diabetes, although they can work fine to control clinical signs in some dogs (1-3). However, because these insulins have a less potent glucose-lowering effect than do more commonly used intermediate-acting insulins (NPH, Vetsulin), larger doses of the long-acting insulin preparation are often needed (1,2). Therefore, use of glargine or PZI (ProZinc) are generally cost-effective only in smaller dogs.

For example, notice that the daily glargine dose in this Toy Poodle is over 1 U/kg twice a day, which is in the expected dose range for a long-acting insulin in dogs (1-3). If this dog weighed 50 kg rather than only 5 kg, this would equate to a dose of 60 U twice a day, which means that we would go through a 10-ml vial of Lantus every two weeks or so! In contrast, most diabetic dogs on an intermediate-acting insulin can be well-regulated using doses of 0.5-0.7 U/kg per injection (4,5).

What's leading to the steady increase in the price for insulin glargine(Lantus)?
The drug maker Sanofi-Aventis has steadily raised its price of Lantus (insulin glargine) during the past 12 months, prompting angst among many pet owners and veterinarians alike. These concerns, of course, are inconsequential to Sanofi, since Lantus is FDA-approved for human diabetic patients (a huge market), and the insulin is not marketed for use in either dogs or cats.

Since I don't work for Sanofi-Aventis, I do not know what’s driving the escalating price increases that we have seen over the past few months. However, we do know that Sanofi's patent for Lantus expires in 2015, opening the market to competitors who can then release generic glargine insulins. Therefore, it is likely that Sanofi is trying to generate as much income as the company can from this branded insulin preparation before the patent expires and generic glargine preparations hit the market.

In support of that, it's known that Eli Lilly also has a generic equivalent in the works (6). Sanofi recently responded by suing Eli Lilly for alleged patent infringement (7). The lawsuit triggered a stay of approval by the FDA, delaying the release of Eli Lilly’s generic to mid-­2016.

However, Merck & Co. also recently announced that it's version of generic glargine is in the late stages of clinical trials (8). It's likely that Sanofi will also sue Merck in order to delay their release of a generic product too, but again, I don't know.

Do you understand why I sometimes hate using these human insulin analogs? We, as veterinarians, have absolutely no say or control in anything that is going to happen to price or availability, and it's certainly no use to complain. These companies don't market their products to us and really do not even want to know we use them in our patients.

Are other long-acting insulins less expensive than Lantus?
Unfortunately, when we look at the cost of other long-acting insulin preparations, the cost is not much cheaper than the current cost of Lantus, at least when we look at the cost per unit of insulin. The dose of ProZinc would likely be approximately the same as the glargine in this dog— at about $100 per 10-ml vial, the cost of ProZinc seems significantly less, at least at first glance. However, we must remember that each vial of ProZinc (a U-40 insulin) contains only 400 units of insulin, so this dog (on 6 units, twice a day) would need about one new vial per month. Since each 10-vial of Lantus contains 1,000 units, the cost per unit of insulin is about the same when these two insulin preparations are compared.

Insulin detemir (Levemir, Novo Nordisk) is another story. Although the cost of this U-100 insulin is equivalent to Lantus (about $250 per vial), this insulin is a very potent insulin when used in dogs (this is not true in cats). The average determir dose that most diabetic dogs require ranges from only 0.1-0.2 U/kg per injection — 5 to 10 times less that the average glargine dose needed for diabetic dogs (9,10).

That all said, I would hesitate to use detemir in this toy breed dog because of it's high potency. The calculated starting dose for a 5 kg dog would only be 0.5 U, and it's unlikely that more than 1 U per injection would ever be needed. As we all know, it's very difficult to measure 0.5 units of insulin accurately and overdosage might be expected. Because of its potent glucose-lowering effects, hypoglycemia is more common with detemir than the other longer-acting insulins.

Should a switch to an intermediate-acting insulin be considered?
Most diabetic dogs that we treat are not started on a long-acting insulin. In fact, use of an intermediate acting insulin, such as NPH or Vetsulin, are generally considered to be the insulins of choice when starting treatment for dogs with diabetes mellitus (4,5).

NPH is a much less expensive human U-100 insulin that is available at Walmart as their ReliOn brand of Novolin-N for only about $25 (11). Personally, I find that Vetsulin (Merke Animal Health) is a better choice than NPH in most dogs since it's a bit longer acting, and this insulin is also made by a veterinary company (Merck Animal Health) and licensed for use in dogs. As you know, the veterinarian cost for Vetsulin is around $30 per 10-vial, but, again, each insulin vial contains only 400 units rather than the 1000 units in each vial of NPH. Therefore, the cost is indeed a bit more for Vetsulin than NPH, at least when we look at the price of the Walmart ReliOn brand.

No matter what insulin we change to (ProZinc, Levemir, NPH, or Vetsulin), the dog will have to again be regulated. This may go very smoothly—but then again, this is a diabetic, it's always difficult to predict what is going to happen with certainty. I'd give the owner the pro's and con's of continuing the Lantus vs switching, but in the long-run, it may be best to stick with the Lantus and hope that the generic versions hit the market sooner than Sanofi would like!

References:

1. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
2. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. 
3. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
4. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50-55. 
5. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682. 
6. Eli Lilly Press Release, Dec. 20, 2013. Eli Lilly and Company and Boehringer Ingelheim announce new drug application filing in the U.S. for new insulin glargine product. 
7. Reuters,  Jan 30, 2014. Sanofi sues Eli Lilly over patents for top-selling insulin drug.
8. Merck Newsroom.com, February 10, 2014. Merck and Samsung Bioepis Enter Collaboration Agreement to Develop and Commercialize Insulin Glargine Candidate for Diabetes.
9. Mori A, Sako T, Lee P, et al. Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Vet Res Commun 2008;32:563-573. 
10. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2011;90:396-403. 
11. ReliOn Insulins. http://relion.com/diabetes/insulin

Humulin Versus Novolin NPH Insulin: Are They Bioequivalent?

Two available brands of NPH insulin, manufactured by Eli Lilly (Humulin N) and Novo Nordisk (Novolin N)

Recently, several of my diabetic dog owners have asked if they can switch their NPH brand to Walmart's Relion/Novolin insulin to replace the Humulin N insulin that they are now using. It turns out that the Walmart ReliOn brand of NPH is much cheaper (only $25 per vial).

Though the two insulins both seem to be NPH insulin, I have some concerns about this change. Any concerns with the ReliOn brand or in switching from Humulin N to Novolin N insulin?

My Response:

In theory, you'd think that Humulin N (Eli Lilly) and Novolin N (Novo Nordisk) would be bioequivalent (and therefore interchangeable), as they're just different brands of NPH insulin. However, that is not always the case.

Humulin N and Novolin N are made using different ingredients and manufacturing techniques, so they are not identical (1,2). Like you noted, Walmart sells NPH insulin as the Novolin/ReliOn brand for much less than most other pharmacies do, at only about $25 per vial (3).

A number of dogs have now been reported where they were stable and doing well on Humulin N. However, when switched to the same dose of Novolin N, their diabetic state was no longer regulated and the dogs developed signs of either hypo- or hyperglycemia, requiring significant dose adjustments (4).

Bottom Line:

Most dogs will respond well to the Novolin/ReliOn brand of insulin, which is indeed much less expensive than most other brands of NPH insulin. However, we cannot just assume that the two insulin preparations would be equivalent. I would not recommend switching from one insulin to the other without close monitoring (including blood glucose curves) so that the dose can be adjusted as needed.

References:

1. Humulin.com website. 
2. Humulin N Prescribing Information. 
3. Novolin N Prescribing Information.  
4. ReliOn Insulins. http://relion.com/diabetes/insulin
5. VIN News Service. Changing insulin brands may disrupt diabetics. February 5, 2013.