Atypical cushing candidate

[apw2607]

Hi everyone.

My first post ! Looking for some help and feedback.

My female mixed breed dog, 70lbs around 9.5 yrs/old and has a thyroid issue that she has being taking Soloxine for the last 5 years.

Due to the thyroid condition she has a annual blood test.

Over the last 2 years her ALK-P has being steadily going up. However she hasn't really being exhibiting any clinical signs of cushings.

The vet suspected she might be a cushion's candidate, so we did the simple cushing urine test and the ultrasound. Both came back negative. Actually I think she might have had two ultrasounds from two different specialist, just in case they missed something.

I then got referred to a internal medicine specialist, and the dog was put on Ursodiol as they believed it was a liver issue.

With the Ursodiol initially her ALK-P of 403 went down to 263 .. but its now gone back up a bit to 323 over a 3 month window.

Due to lack of clinical signs, and we just wanted to rule it out completely before we investigated the liver some more ... we ordered up the U of Tenn Adrenal panel ... and here are the results:

Cortisol = 4.0 (baseline) 17 (post ACTH)
Androstenedione = 0.19 (baseline) 0.42 (post ACTH)
Estradiol = 64.8 (baseline) 56.3 (post ACTH)
Progesterone <0.20 (baseline) 2.81 (post ACTH)
17 OH Progesterone =0.14 (baseline) 2.46 (post ACTH)
Testosterone <15.0 (baseline) <15.0 (post ACTH)

The results indicate presence of increased adrenal activity. Marginal - early HAC?

So the internal medicine vet says shes Atypical cushings and recommends putting her on Lysodren maintenance dose only. And then recheck levels in 6 weeks.

What are you're thoughts? As i said, she doesn't really exhibit any clinical signs, other than being rather lethargic and uninterested ... but of course I just put that down to the type of dog and she was getting older.

I want to be pro-active, but at the same time, I'm torn for all the reasons you've spoken about already on this forum, regarding the Lysodre.

Based on her results, I'm not really sure if the Melatonin + Lignan would help though?

So I could wait and I suspect the conditions will get worse, or be proactive.

Thanks !

[Squirt's Mom]

MODERATOR NOTE: Your post has been manually approved so that members can start responding to you. Please check your email, possibly your spam / junk folder, for a message from k9cushings. You will need to reply to that email so that your post go directly to the board and are not delayed waiting for approval. If you have already received and responded to the confirmatory email, please be patient. Your registration will be finalized shortly. Thanks and welcome!

[judymaggie]

Welcome to you and your pup! You have done a great job in being proactive for the continued health of your dog. The UTenn results should include treatment recommendations. Did you get a copy of the full results from your vet? If so, would you post what their recommendations are?

My first Cushing's pup was diagnosed with atypical Cushing's through a UTenn evaluation. As I recall, she had high elevations of several different hormones (other than cortisol). At the recommendation of UTenn, my vet inserted a melatonin implant and I gave her lignans. I would have to go back into her records to see what response she had. I do know that she did have Cushing's symptoms prior to the testing.

[apw2607]

Thanks for you're insights.

Here is the lab's comments:

Post ACTH progestin concentrations are the only values increased and elevations are moderate. Since Luca is asymptomatic, a consideration may be to retest in about 6 - 8 months if you continue to suspect hyperadrenocorticism. Alternatively, various treatment options are attached for your consideration.

They attached their standard list of treatments for increased adrenal activity.

[molly muffin]

Hello and welcome.
Since progestin is the only actually elevated hormone (ranges should be included on the test) and I know from my own testing that they like to see a couple hormones elevated before my specialist would consider it to be atypical.

What you could do and the most benign form of treatment would be to start melatonin and see how that works. You could also add in the lignans.

I got mine from www.lignans.net

I think that is what I would do first.

[apw2607]

Thankyou for your reply.

Yes, only the Progesterone was out of range, post ACTH.

Progesterone ng/ml <0.20 (baseline) Normal range <0.20-0.49 (baseline) 2.81 (post ACTH) Normal range <0.2-1.50 (post ACTH)
17 OH Progesterone ng/ml =0.14 (baseline) Normal range <0.08-0.77 (baseline) 2.46 (post ACTH) Normal range <0.4-1.62 (post ACTH)

I'm going to give the melatonin and lignans a try and I will report back. Thanks.

[lulusmom]

Hi and a belated welcome to you and Luca.

Can you please confirm that ALKP is the only lab abnormality on the blood chemistry. If not, can you please post all of the highs and lows and please include the normal reference ranges. You mentioned that there have been two ultrasounds and both were normal. Can you please reconfirm this for us? I ask because it appears that at least one of the ultrasounds showed some abnormalities in the gall bladder, such as sludge or possible mucoceles which required Ursodiol. Can you check the interpretation for both of those ultrasounds and tell us if there is any mention of abnormalities in the liver and adrenal glands? I apologize for all of the questions, but I have to believe we are missing a good deal of information as it doesn't make sense that an internal medicine specialist would order a UTK panel for an asymptomatic dog whose only lab abnormality is a mild elevation in ALKP. The profile of an atypical cushingoid dog is one who is displaying the same physical symptoms and lab abnormalities that are commonly associated with typical cushing's yet the ACTH stimulation test, LDDS and/or cortisol creatinine ratio are normal. According to the information you have shared thus far, there simply wouldn't be enough convincing evidence to test for atypical cushing's nor prescribe a maintenance dose of Lysodren in a dog who has no symptoms. Most vets won't test an asymptomatic dog if an elevated ALKP is the only abnormality so testing for atypical cushing's would be even more unusual. I've cut and pasted below an excerpt from a page on Dr. Mark Peterson's Insights into Veterinary Endocrinology Q & A for veterinarians in which he describes who should and shouldn't be tested for cushing's. This relates to typical cushing's but would apply to atypical as well.


Who should be tested for hyperadrenocorticism?


Testing for hyperadrenocorticism in a dog should be done because they have one or more clinical signs of the disease. Typically the disease is insidious and slowly-progressive, so most dogs have had clinical signs, such as abdominal enlargement, panting, muscle weakness, thin skin, lethargy, polyphagia, polyuria and polydipsia (PU/PD) for months to even years before the owners recognize a problem and seek veterinary help.

Who should NOT be tested for hyperadrenocorticism?

Testing for Cushing's syndrome is not recommended if the only abnormality is an increased serum alkaline phosphatase (SAP) activity on a serum chemistry panel, and the dog is otherwise apparently healthy. It is difficult enough to interpret endocrine tests in dogs with clinical signs of the disease; if they have no clinical signs, all of the endocrine tests may be difficult to interpret because of false-positive and false-negative results. The first step in workup in these dogs may include an abdominal ultrasound or bile acid testing.

One should not screen dogs for hyperadrenocorticism when the dog is sick with clinical signs that would not be related to Cushing's syndrome (e.g., vomiting, anorexia, weight loss). Many non-specific illnesses and other systemic diseases will produce false-positive results with the endocrine tests. Remember, hyperadrenocorticism is only slowly progressive, so hyperadrenocorticism is never an emergency diagnosis.

Before diagnostic testing is performed, it is therefore always good to ask oneself: if the test results would indicate hyperadrenocorticism, would I then feel confident to start treating with mitotane (Lysodren®) or trilostane (Vetoryl®) given the clinical picture of the patient? Would treatment help the dog's clinically signs? If either answer is "no," then it is probably best not to screen for hyperadrenocorticism in the first place.


You can read the rest of the page at http://www.endocrinevet.info/2011/02/diagnosing-hyperadrenocorticism.html

As far as treatment for atypical cushing's is concerned, the efficacy of melatonin and lignans is not great. Even if effective, results are not immediate but you should know within three to four months if it is going to be effective. Atypical cushingoid dogs are symptomatic and it is improvement in symptoms that will tell you whether or not treatment is effective so I must assume that your specialist is not treating symptoms but rather an elevation in ALKP. Is that correct? Low thyroid can also cause elevations in ALKP so I'm sure that the specialist checked Luca's T4 to make certain current supplementation is adequate, yes?

I've also included a link below to a white paper written by Michael Schaer, DVM, Diplomate ACVIM, ACVECC titled The Atypical Cushing Patient. It is my hope that once you review it, you will understand why I am asking so many questions. Hopefully your responses can help me and others understand your internal medicine specialist's rationale for confirming an atypical cushing's diagnosis in the absence of symptoms and a relatively mild elevation in ALKP in comparison to what we are used to seeing.

http://www.delawarevalleyacademyvm.org/pdfs/may10/atypical_cushing.pdf

Glynda

[apw2607]

Thanks Glynda for spending time providing a detailed response. I will try and answer your questions and hope it may help and provide more info and background.

For the last 2 years (since Jan 2015), Luca's ALKP has being steadily rising. No other abnormality was noted on her blood panel. At the same time it was noted however she had a fair size growth on the right side of the belly/stomach. A ultrasound was ordered and the growth turned out to be benign, but the liver was enlarged. Nothing out of the ordinary for Luca's age apparently.

Moving on too 3 months ago, Luca's ALKP had risen to 403, so this is what prompted looking at the Liver again and adrenal glands in a follow up ultrasound. The internal medicine doctor assured me that everything looked fine. So given Luca really didn't have any clinical signs of cushings she thought the Ursodiol could help with the liver and we will retest her ALKP in a month or so.

Now, as you all know its sometime very difficult to see Cushings signs developing in a dog as its so gradual, and sometimes people just think of it as old age. Luca certainly has slowed down, and sleeps a fair bit of time. She sometimes pants, but its nothing that last very long. Her water consumption is nothing out of the ordinary .. however she is a "hungry" dog .. but she has always being that way. Like I said, symptoms can be difficult to spot.

So after the Ursodiol, the ALKP reading was encourging. It had dropped to 263. Again no other blood anomaly. So we kept her on the Ursodoil for another 3 months, and retested the ALKP again. This time it had gone back up too 323.

So after discussing this with the internal medicine doctor, we just thought we would once and for all, rule out cushings or atypical cushings ... by doing the extended blood panel with the U of T. This was more about ruling something out so we could focus on something else - such as the liver.

However with the results back from the U of T, at least 2 of Luca's intermediaries are elevated.

She has her annual blood test to check her thyroid and T4 levels. I don't have the results to hand, but I'm sure that its fine, as someone would have flagged a issue when it was being evaluated.

Thanks for the links of the papers. I will read them over.

It would be nice to better understand though why her Progesterone is higher and is this whats driving the ALKP higher in the liver? Or is it something else? By reducing these levels, what do I hope to see? Maybe she would have more energy and be back to her younger self ? I just don't know.

Cortisol = 4.0 (baseline) Normal range <1.0-5.9 (baseline) 17 (post ACTH) Normal range 6.5-17.5 (post ACTH)
Androstenedione = 0.19 (baseline) Normal range 0.05-0.57 (baseline) 0.42 (post ACTH) Normal range 0.27-3.97 (post ACTH)
Estradiol = 64.8 (baseline) Normal range 30.8-69.9 (baseline) 56.3 (post ACTH) normal range 27.9-69.2 (post ACTH)
Progesterone ng/ml <0.20 (baseline) Normal range <0.20-0.49 (baseline) 2.81 (post ACTH) Normal range <0.2-1.50 (post ACTH)
17 OH Progesterone ng/ml =0.14 (baseline) Normal range <0.08-0.77 (baseline) 2.46 (post ACTH) Normal range <0.4-1.62 (post ACTH)

Thanks again.

[lulusmom]

Thank you for your response. It is true that some pet owners don't recognize early onset of symptoms associated with cushing's but having cared for four cushingoid dogs, all of whom were overtly symptomatic, I can tell you that there is no mistaking the most common symptoms, clinical polyuria (peeing), polydipsia (drinking) and polyphagia (extreme hunger). These dogs lose their ability to concentrate their urine so a once housebroken dog is peeing all over the place, often times right in front of you. They pee huge volumes so they must drink huge volumes to stay hydrated. The hunger of a cushingoid dog is also unmistakable. They whine and beg for food constantly. They forage for any missed tidbit, they get into trash and they will often eat non food items, including their own poop. I could actually handle the pee a lot better than the constant hunger. It makes you want to pull your hair out. :D

I left out a very important piece of information in my prior post and that is that more than a few credible, sanctioned studies have shown that dogs with elevated progesterone and 17 OH progesterone is not always caused by adrenal dysfunction. Dogs with non-adrenal illness can have the same elevated adrenal hormones. By the way, your pup's elevations are negligible compared to what we're used to seeing here. Therefore, even with your additional information, I am still not understanding why your specialist felt it necessary to incur the expense of a full adrenal panel from UTK based solely on a rather mild elevation in ALKP. To be perfectly honest with you, if this were my dog and based on the information you have shared with us, I would not even consider treating with Lysodren at this point. I would simply monitor the ALKP every three to six months unless overt symptoms become apparent, at which time I would opt to pursue a cushing's diagnosis.

I have cut and pasted an excerpt below from a white paper entitled Atypical Hyperadrenocortism by Dr. Daniel Gasso. This is a case study that was reviewed by Dr. Theresa Ortega, a recognized and well published expert endocrinologist and contributor to veterinary teaching textbooks so I consider this reference to be very credible and in keeping with my extensive research on atypical cushing's. I have underlined some of the text that validate the concerns I have with pursuing a typical or atypical diagnosis in an asymptomatic dog whose only lab abnormality is an increase in ALKP. You can find the entire case study at http://www.vmsg.com/wp-content/uploads/2015/03/case-atypical-hyperadrenocorticism.pdf


Hyperadrenocorticism (HAC) is a clinical syndrome associated with various clinical signs and chemical abnormalities that result from chronic exposure to glucocorticoids (most notably, cortisol). With atypical HAC, patients may have the same constellation
of clinical signs and laboratory abnormalities, however, they have a normal or subnormal cortisol response to the common adrenal
function tests with elevations in other adrenocortical hormones (sex hormones, aldosterone). Approximately 85% of cases of
naturally occurring HAC are caused by a pituitary tumor that produces excessive amounts of ACTH, stimulating the secretion of
adrenocortical hormones. The remaining cases are caused by an adrenocortical adenoma or carcinoma that functions
autonomously to secrete excessive amounts of adrenal steroids. Approximately 5% of dogs with Cushing’s have atypical HAC,
and these may be pituitary or adrenal-dependent. It has been suggested that dogs with atypical HAC could have several
derangements in the adrenal steroid production pathway with relative deficiencies in some enzymes that are necessary for the
production of cortisol. This may result in the accumulation of cortisol precursors that are shunted into other metabolic pathways,
such as androgen biosynthesis. Some progestins have intrinsic glucocorticoid activity and this has been proposed as a potential
cause of the clinical signs in dogs with atypical HAC. Another theory suggests that progestins may displace cortisol from
cortisol-binding protein resulting in an excess of free cortisol (which is metabolically active) even though the total serum cortisol
concentrations are normal or decreased.

Diagnosis of atypical HAC is similar in many respects to typical HAC. Diagnostic work-up includes a thorough history,
physical exam, routine laboratory diagnostics, imaging, and adrenal function tests. The history commonly includes polyuria and
polydipsia (85% of cases) and polyphagia (60-90% of cases) and these signs may precede others by weeks to months. Lethargy
and excessive panting are also common complaints. Physical exam may reveal: a pendulous abdomen (70-90% of cases),
bilaterally symmetrical alopecia with a dull hair coat, muscular weakness and atrophy, calcinosis cutis, keratin plugs, thin skin,
hyperpigmentation, anestrus/testicular atrophy, or CNS signs. A CBC may reveal a stress leukogram and a chemistry panel may
show elevated ALP (85-90% of cases), ALT, and hypercholesterolemia. Urinalysis results often reveal hyposthenuria or
isosthenuria and proteinuria. About 50% of dogs with HAC will have a urinary tract infection and a urine culture is usually
indicated. Abdominal radiographs may reveal mineralization of adrenal tumors (about 50% of cases) and/or hepatomegaly.
Abdominal ultrasound findings consistent with pituitary dependent HAC include bilaterally normal adrenals, bilaterally
symmetric/asymmetric adrenomegaly while unilateral adrenomegaly is expected in dogs with an adrenal tumor (unless they have
bilateral adrenal tumors, which is rare). A low-dose dexamethasone suppression test (LDDST) and ACTH stimulation test that
measure only cortisol are normal in a dog with atypical HAC. The test for diagnosing atypical HAC is an ACTH stimulation test
that measures multiple adrenal steroids (progestins, androgens, glucocorticoids, and aldosterone). Frequently, dogs will have an
elevation in progesterone and 17 OH progesterone, although elevations in these hormones have also been documented in dogs
will non-adrenal illness. Therefore, the diagnosis of atypical HAC should only be made in conjunction with the aforementioned
findings in the history, physical exam, routine laboratory test results and imaging studies.

[apw2607]

Just a quick update. Luca has now being on Milk Thistle, Meltatonin and HMR Lignans for about 6 weeks now. I thought this was the most conservative approach to at least see what might happen with her liver levels. She just had another standard blood panel done and her ALKP reading had dropped to 170. We will test again in 3 months or so.

Other than that, shes still fine, and not exhibiting any clinical signs of cushings.

[molly muffin]

That is very good. Great news even. Congratulations.

[tank&kat]

That is an excellent response and I am happy to hear no signs of Cushing's. I just wanted to add that denamarin is used a lot to help lower ALP. That may be something to look into if things are still running high in the future. I hope she stays on track.

~Kat