Thursday, April 14, 2011

Q & A: Atypical Addison's Disease In Dogs With Gastrointestinal Signs

I read your recent post regarding Addison's disease and I'm writing to see if you could clear up (or add to the debate) a discussion that we are having at our hospital. I am a second-year medicine resident and our medical staff is having a debate about what is considered a normal vs. an abnormal cortisol response to ACTH stimulation and what exactly is "atypical" Addison's disease.

For example, what about dogs that have chronic gastrointestinal (GI) signs that have not yet been been diagnosed but a flat cortisol response to ACTH stimulation is found? If we perform an ACTH stimulation test on these dogs, many will have a basal cortisol level well within reference range limits (e.g., 2 to 4 μg/dl) but the post-ACTH stimulated cortisol concentration will not rise to levels 3-5 times higher than the basal cortisol concentration. Some of these dogs will have ACTH-stimulated cortisol concentrations that are below the post-ACTH reference range (e.g., in the range of only 3-6 μg/dl). Is this atypical Addison's disease?

What do you do in these cases? Look for other causes of the GI signs? And if no other cause found supplement with steroids? Should we just repeat the ACTH stimulation test down the line?

Thank you for your time!


My Response:

First of all, you must remember that the blog post on Addison's disease you are referring to was written primarily for dog owners, not veterinarians. I was trying to be clear, which is difficult when we are discussing a topic that could include typical, atypical, or secondary adrenal insufficiency.

Almost all dogs with primary hypoadrenocorticism (typical Addison's disease) and near complete destruction of the adrenal cortex will have subnormal basal and ACTH-stimulated serum cortisol concentrations (<1 μg/dl).

Dogs with secondary hypoadrenocorticism (pituitary ACTH deficiency) have low to low-normal basal cortisol values that may rise very slightly to ACTH stimulation, but the cortisol response is very blunted (post-ACTH values generally < 3 μg/dl). This has all been published (1-3), and I don't think anyone would strongly disagree with those guidelines.

The problem with "atypical" Addison's disease is that, at least most of the time, the dogs have never been worked up properly to differentiate primary from secondary hypoadrenocorticism. Most would define "atypical" Addison's simply as glucocorticoid-deficient hypoadrenocorticism, but that is really being quite simplistic and does not help guide what replacement therapy may be needed or predict prognosis.

In other words, if that "atypical" dog has primary Addison's disease with normal electrolytes, it is very possible or even likely that mineralocorticoid replacement will be needed. On the other hand, it a dog has secondary hypoadrenocorticism, mineralocorticoid replacement will never be needed, but pituitary imaging (CT or MRI scan) might be indicated to exclude a pituitary mass.

The easiest way to differentiate primary from secondary hypoadrenocorticism, of course, would be to measure plasma ACTH concentration, but that must be done before any glucocorticoids have been administered (or after 1-2 weeks off all steroids).

If the plasma ACTH value is low (generally < 20 pg/ml) in a dog with a severely blunted serum cortisol response to ACTH stimulation, that would be diagnostic for secondary hypoadrenocorticism (1-4). As you know, ACTH deficiency is rare and is most commonly associated with a pituitary tumor (3). By far the most common cause is iatrogenic secondary hypoadrenocorticism resulting from glucocorticoid administration. So it's extremely important in dogs with "atypical" Addison's disease to go back in the history and make sure that they haven't received any steroid in the last few weeks to even months.

If the plasma ACTH value is high (generally >250 pg/ml) with a severely blunted serum cortisol response to ACTH stimulation, that would be diagnostic for primary hypoadrenocorticism (1-4). If the serum electrolytes are normal, that could be called "atypical" Addison's disease. Some of these dogs will certainly go on to develop serum electrolyte changes, whereas others never seem to do so. I suspect that these latter dogs do not actually have adrenal destruction, but may have an ACTH receptor defect where circulating ACTH values are high but the adrenal gland doesn't bind the ACTH so it cannot act to stimulate cortisol secretion. Again, the best way to distinguish secondary from primary hypoadrenocorticism in these dogs is to measure plasma ACTH before any glucocorticoids are administered (or off all glucocorticoids for at least 1-2 weeks).

But let me get back to your original question about the dogs that have chronic GI signs and whose ACTH stimulation test results reveal a normal (or low) basal cortisol with a post-ACTH cortisol values that is blunted, rising to only 3-6 μg/dl. This is certainly not a "normal" response, abut it's very difficult for me to explain why these dogs would have any signs when these circulating cortisol values are within or slightly above the normal basal range. If this was a dog on mitotane or trilotane, for example, we would be very pleased with those serum cortisol results and would not be worried about hypoadrenocorticism (5-7).

In my experience, most of these dogs have a history of being treated with glucocorticoids, which could lead to secondary (iatrogenic) hypoadrenocorticism. Again, if you would measure a plasma ACTH concentration in these dogs, the values should be low-normal if they do indeed have secondary ACTH deficiency. If there is now history of glucocorticoid use, I would certainly repeat basal or ACTH-stimulated cortisol values in 2-4 weeks, but most of these dogs do not end up having primary adrenal disease.

Now that's not to say that they don't need steroid supplementation, but not for "atypical" adrenal disease.

References:
  1. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc 1996;208:85-91.
  2. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Vet Clin North Am Small Anim Pract 1997;27:349-357.
  3. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction.Third Edition. Saunders, 2003.
  4. Peterson ME, Orth DN, Halmi NS, et al. Plasma immunoreactive proopiomelanocortin peptides and cortisol in normal dogs and dogs with Addison's disease and Cushing's syndrome: basal concentrations. Endocrinology 1986; 119: 720-730.
  5. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1991;5:182-190.
  6. Peterson ME, Kintzer PP. Medical treatment of pituitary-dependent hyperadrenocorticism. Mitotane. Vet Clin North Am Small Anim Pract 1997;27:255-272.
  7. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283.

18 comments:

LisaT said...

I have a somewhat related follow-up question, if I may.

I have a dog that is presenting with low resting cortisol (1.3 on his ACTH Stim Test, normal range 2-5), but stimmed in the high normal range (16.7, normal range 6-18). A full vial of Cortosyn was used, IV; this is an 80 pound German Shepherd.

His electrolytes are within normal ranges, with Na:K ratio 35:1.

Unfortunately, at the time of the stim test, the resting ACTH level was not run, so we don't have that value; steroids were started shortly after. The low resting cortisol was confirmed on a later test also.

He also presents with hypovolemia (He was brought in for severe exercise intolerance and panting). His xrays are said to look just like an Addison's dog (under-sized heart with corresponding vascular changes), and this was confirmed by the cardiologist, that he does not have heart disease, but the left-side of his heart is not being supplied with enough blood and has become smaller. He is hypotensive.

On ultrasounds, his adrenals could not be visualized, they are assumed small. His spleen is slightly enlarged, but within breed standards.

An MRI or CT scan is not financially possible.

It appears that he became less responsive to his thyroid medication (Soloxine, .7mg BID) once he was on prolonged ketoconazole therapy. He has been off this drug since December 2010.

I do not know if this is related, but this GSD typically has a lipase value in the 50's (normal range 100-750), and a normal amylase. Since the end of November 2010, over the last 4 blood panels, the lipase has been steadily increasing, while the amylase is decreasing.

His bloodwork that was run several days after the ACTH Stim Test also showed a low normal calcium value of 8.5 (normal 8.2-12.4), as compared to his normal of about 10.0.


While this dog is not an Addison's dog, does it make sense to assume that there is a problem in the ACTH feedback loop somewhere? Perhaps the pituitary?

My understanding about hypovolemia in Addison's patients, is that it is caused by fluid imbalance and that would show up in the electrolyte values. This does not appear to be the case here. Do you know of any other possible cause for the hypovolemia?

Do you have a recommendation on prednisolone dosing for a dog in this situation? He is currently on 5mg in the morning, and 2.5 mg later in the day/early evening. We would like to keep the dose as low as possible, without putting him into a crisis.

Would there be any advantage to using methylprednisolone over prednisolone in this case?

Would it be recommended to monitor this dog's resting cortisol to check for response to treatment? Any other recommendations?

Dr. Mark E. Peterson said...

Hi Lisa,

As you noted, the results of the ACTH stimulation test showed a low-normal basal cortisol value but the adrenal glands did respond normally when tested. This completely excludes Addison's disease (both atypical or typical).

The fact that the adrenal glands could not be seen on ultrasound is confusing, but that doesn't mean Addison's because the ACTH stimulation test revealed a normal adrenal cortex. Sometimes the adrenal glands can be difficult to visualize but ultrasound cannot be used as a diagnostic tests for hypoadrenocorticism.

I do not know why the dog is hypovolemic, but again, you have proven it's not related to the adrenal gland. The dog could have a pituitary gland problem but that is not very likely, and it is clearly is not related to ACTH deficiency.

At the moment, you have the dog of higher-than-maintenance doses of prednisone. The dose of prednisone for an average human patient is only 5 mg per day, so an 80 pound dog with Addison's should do well on 5 mg per day too.

But again, this dog shouldn't need ANY prednisone because you have already excluded Addison's disease. I would consider stopping the drug.

When we administer synthetic steroids such as prednisone, you cannot use cortisol measurements to monitor the circulating glucocorticoid values. In fact, these drugs may feedback to the pituitary gland to inhibit pituitary ACTH secretion and make the whole situation worse.

In summary, I don't know what is wrong with your patient — it could be a number of different disorders — but I do now that the dog does not have Addison's disease or any other form of under-active adrenal disease. I'd stop the prednisone and continue the workup if the problems persist to get to the definitive diagnosis.

Good Luck!

Stephanie Artusa said...

i have a 5 month old french mastiff that is having a really hard time eating. he went into either an addisons crisis or hypoglycemic. my vet sent a cortisol out and we got a reading of 2.0 and a retest the next day of 1.8, we are going to do the ACTH test but we are waiting for the drug, do you think that is low enough to even be considered addisonian? some vets i spoke to said no way and others said maybe.

Dr. Mark E. Peterson said...

It's certainly possible, but unlikely that your dog has Addison's disease.

The age of 5 months is younger than we generally see (most dogs are much older), and the French mastiff isn't a breed that is predisposed to developing Addison's disease.

Stephanie Artusa said...

So his ACTH was 2.7 pre ACTH and 8.5 after the injection..normal?

Dr. Mark E. Peterson said...

Both the resting cortisol value (2.7 μg/dl) and the ACTH-stimulated cortisol value(8.5 μg/dl) are completely normal. This completely excludes a diagnosis of hypoadrenocorticism (or Addison's disease - both typical or atypical).

So now that we have ruled out Addison's disease, you can continue the workup for other problems.

Good luck!

Randi Bolton said...

Could you expand on the causes of a dog with a low resting cortisol but a normal ACTH stim?

I ran routine bloodwork on a 7yr SF lab that came back with Na:K ratio of 21, high K+ 6.9(N=4-5.6), low normal Na 145(N=141-156) high Cl+ 117(N=105-115.

Other bloodwork was WNL, including T4=2(N=1=4).

We did an ACTH stim which revealed low baseline Cortisol 0.5(N=2-6) and a normal post ACTH 7.7(N=6-18).

This dog has multiple limb lameness (bilateral TPLO's as well as elbow and metacarpal arthritis) treated with monthly injections on Adequan 1.5ml SQ, Legend 1.0 ml IM (off label)and Rimadyl 75mg BID as needed. The dog, is very active (mountain hiking multiple times a week), has normal energy, good weight and appetite.

The only other abnornalities are occassional vomiting (Bile and grass approx 1x/week) and loose stool during and after heavy exercise which resolves the following day.

Having ruled out Addison's with the ACTH stim, I am wondering if the drugs this dog gets for arthritis pain could cause the low cortisol?

Thanks, Randi Bolton, DVM

Dr. Mark E. Peterson said...

To my knowledge, none of these drugs have an impact on serum cortisol concentrations by directly affecting the cortisol synthetic pathways in the adrenal gland or indirectly by suppressing ACTH levels.

Remember that serum cortisol is secreted episodically, with peaks and valleys throughout the day. So you might have sampled at a low point.

We also have to consider lab error, both with the pre- or post-ACTH cortisol values AND the serum electrolytes. That is especially true is the labs were done "in-house." If there is any doubt, don't hesitate to repeat some of this labwork in the future.

Unknown said...

Hi Dr,
My veterinarian has diagnosed my dog Leopold as an Atypical Addison. I am having trouble understanding this diagnosis, and do not want to keep him on the 2.5mg of daily prednisone if it is not needed (he is a 37 pound, 1 year old Standard Poodle. He has normal lytes, and normal sodium. His basal cortisol level before any prednisone treatment was <27.6, and after his ACTH test it went up to 115. From my understanding, an increase this large would mean it is not Addison's, even if he is exhibiting many of the symptoms (GI, weight loss, excessive urination). His lipase levels are low, and his monocytes are high. The vet says none of these are a concern. We have already spent $5,000 dollars trying to diagnos him, and I would love to know if you think his results mean he has Atypical Addison's or not. Thank you so much for your help. This dog is my best friend and my whole heart!

Dr. Mark E. Peterson said...

Obviously, your dog is a complicated case and I cannot confirm the diagnosis based on what you have told me here. However, the ACTH stimulation test is certainly consistent with adrenal insufficiency or hypoadrenocorticism. If the prednisone is helping, it cannot hurt anything and I would recommend you continue it.

Robin Hopwood-Courville said...

Dr Peterson -

To follow up on your original comments regarding the original diagnosis and need to perform an ACTH level, I have a question. I currently have a 16 year old Chihuahua that was referred to me as an "atypical" Addisonian. He has been treated for years (I believe at least 8-10)with an appropriate prednisone dose. He has done really well. Recently he has been presenting with intermittent elevations in his amylase and lipase. On ultrasound his pancreas has been prominent intermittently and a PLI submitted was in the questionable range (217 ug/L, <=200 normal). I have increased his prednisone dosing as clearly this could be considered stressful. He is still fluctuating with intermittent GI signs. I am constantly bothered by his electrolytes which concern me that he may be developing mineralocorticoid deficiency as well and could be contributing to some of his signs (last 3 visit - Na 145, K 5.4, ratio 27;Na 143, K 5.2, ratio 28; Na 134, K 3.7, ratio 36). Is there any other test which I could perform to confirm the mineralocorticoid deficiency? I am just worried that an ACTH level will not be beneficial due to the prednisone and taking him off is not an option.

Thanks you so much.

Robin
(Robin Hopwood, DVM, PhD, DACVIM (SAIM))

Dr. Mark E. Peterson said...

You could do another ACTH stimulation test and measure aldosterone to help rule out mineralocorticoid deficiency, However, I've never seen a dog have atypical Addison's for 6-8 years and only then develop mineralocorticoid deficiency. But, as you know, anything is possible!

Kristen said...

Hi Dr. Peterson,

I am not sure if this thread is still open, but I have a 1 year old GSD who has gastrointestinal problems and severe allergies. I am getting conflicting information from all the vets he see's. Some think he has atypical addison's and some say definitely not. His baseline cortisol results from Idexx were very low below 1.0. His ACTH stim test came back high at 11.7 (range was 1.0-5.0). Can an adrenal glad disease be ruled out? Thank you!

Dr. Mark E. Peterson said...

That ACTH stim test DEFINITELY, POSITIVELY rules out any form of Addison's disease. I would fire anyone that wanted to call this Addison's!

Sheena said...

Hi Dr. Peterson,

I was wondering if you could provide an opinion: I have a 2ish terrier mix with intermittent GI problems. Based on her vet's suspicion, she had a Cortsyn ACTH test done with a resting cortisol of 1.1 (range 1.0-5.0) and stimulated cortisol of 4.2 (range of 8.0-17.0). Would this be considered definitely Addison's? (She took no steroids or any other medication prior to the ACTH test. Her electrolyte bloodwork has only just been sent out.)

Dr. Mark E. Peterson said...

No, this rules out Addison's disease.

Sheena said...

Thanks for the quick response! I just wanted to follow up: Does this rule out all types of Addison's, even though her stimulated cortisol levels are so low? (Primary, atypical, and secondary) Do you have any recommendations for what other tests to run to diagnose the low cortisol levels and GI problems? She's never had an Addisonian crisis so is it possible she's pre-Addisonian? Thanks again!

Dr. Mark E. Peterson said...

This rules out all types of Addison's disease. Most of these dogs have received some type of steroids in the recent past, which has partially suppressed the cortisol response. A pre-Addison's dog would not have any GI signs.

If you are worried, you can always repeat the test in the future (3-6 months from now).