Atypical Hyperadrenocorticism: incidence, clinical features and
treatment
Steve Marsden
DVM ND MSOM Lac Dipl.CH CVA AHG
Atypical Hyperadrenocorticism (AHAC)
Hyperadrenocorticism (pituitary dependent hyperadrenocorticism, PDH, Cushing's disease) arises from
benign functional tumors of the pituitary gland that result in hypersecretion of cortisol from the adrenal
glands. The clinical presentation of PDH is highly similar between dogs and humans. Characteristic signs
for both include abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes.
The incidence of pituitary tumors in humans is rare, yet in dogs the rate of incidence is accepted as 1 or
2 cases per 1,000 dogs per year (de Bruin et al, 2009). By comparison, a rule of thumb estimate of the
overall rate of cancer incidence in dogs suggests it occurs at about the same rate as humans - 400 cases
per 100,000 people per year, or 4 cases per thousand per year. The incidence of Cushing’s disease in
dogs is thus potentially as high as half of all other cancer cases combined. Such a high rate of incidence
should prompt us to wonder if the disease is being over-diagnosed; but if so, what is the true diagnosis
of the dog with apparent PDH?
While Cushing’s is rare in humans, hypercortisolism is abundant.. Hypercortisolism is a state of cortisol
hypersecretion, hyper-responsiveness to cortisol, or both. The condition produces characteristic signs of
Cushing’s disease, to the point of being almost clinically indistinguishable, yet is not at all due to a
pituitary tumor. Recent research suggests many dogs diagnosed as having Cushing’s may in fact have
hypercortisolism, otherwise known as atypical hyperadrenocorticism (AHAC).
Diagnosis of AHAC
ACAH is diagnosed in a dog that appears to have Cushing’s disease, yet tests negative for the condition
using definitive laboratory testing such as ACTH stimulation and low dose dexamethasone suppression
tests. Some authors have speculated the clinical signs are stemming for an over-production of sex
steroids, which others have contested. Recent research suggests AHAC dogs do indeed over-produce
cortisol, and have bilaterally enlarged adrenal glands (Frank et al, 2015), making differentiation from
from Cushing’s disease a potential challenge.
Many AHAC cases eventually go on to finally being diagnosed as having Cushing’s disease, leading some
authors to suggest AHAC is a precursor state to eventual pituitary adenoma. It is also possible, however,
that chance fluctuations in cortisol levels in AHAC patients will simply cross the threshold at which a
diagnosis of PDH is rendered, for seldom is the presence of an actual pituitary tumor confirmed in PDH
dogs. While overall hourly cortisol and total cortisol secretion in dogs with confirmed pituitary
adenomas is higher than in AHAC dogs, there is considerable overlap, with AHAC dogs at times secreting
more cortisol than PDH dogs. There was also a trend for adrenal gland size in AHAC dogs to actually be
larger than in dogs with PDH (Frank et al, 2015). It is thus easily conceivable that an AHAC patient may
be diagnosed as having PDH.
Diagnosis of AHAC vs. PDH may one day be easier once more is known about the pharmacodynamics
and pharmacokinetics of cortisol in hypercortisolism/AHAC. Unfortunately, after a decade of research, it
is still apparently unclear how cortisol metabolism is altered in hypercortisolism. Research suggests
changes include any or all of (Björntorp and Rosmond, 2000; Pasquali and Vicennati, 2000):



Hyper-responsiveness of the hypothalamic-pituitary-adrenal axis
Heightened clearance of cortisol
Altered or more frequent patterns of secretion
This HPA hyper-responsiveness would theoretically allow AHAC patients to theoretically test false
positive for PDH in stimulation tests. In addition, increased abdominal fat reserves can increase serum
cortisol. They contain type 1 11beta-hydroxysteroid dehydrogenase, which converts cortisone to cortisol.
Previous publications have dismissed any notion of a diagnostic challenge in differentiating AHAC and
PDH. Definitive tests for Cushing’s are reported as normal in AHAC dogs (Behrend and Kennis, 2010). The
recently discovered similarities, even overlap, in cortisol secretion between PDH and AHAC suggest,
however, that this statement may be presumptive. The dexamethasone suppression test was recently
proven inadequate for distinguishing AHAC from Cushing’s in humans, despite the literature asserting
otherwise (Lindholm, 2014). As early as 1997, the dexamethasone suppression test in dogs was shown
to be only 70% specific for Cushing’s (Van Liew et al, 1997). False positives for the ACTH and
dexamethasone suppression tests do exist, and in the case of the suppression test are even
commonplace, making confirmation of a pituitary tumor through medical imaging ideal, although
impractical (Peterson, 2007).
AHAC and Insulin Resistance
While metabolism of cortisol in AHAC is as yet unclear, the cause appears to be more defined. Insulin
resistance appears to play an important role in the genesis of the condition. Both humans and dogs with
AHAC/hypercortisolism demonstrate insulin resistance, and the relationship has long been established
(Karnieli et al, 1985; Peterson et al, 1984). Earlier medical literature for both humans and dogs (Hess,
2010) speculated that hypercortisolism causes insulin resistance, rather than the other way around.
Hypercortisolism is common in overweight humans, a condition that was speculated to cause so much
physiological stress as to spike cortisol levels and drive insulin resistance.
Recent studies, however, have documented insulin resistance (IR) as playing a causal role in
hypercortisolism, with affected patients demonstrating positive feedback of serum cortisol on further
secretion. Patients who are merely obese but who do not have IR have normal negative feedback
inhibition of further cortisone secretion (Prpić-Križevac et al, 2012).
AHAC Treatment
Four Marvels Combination (Si Miao San)
All available evidence suggests insulin resistance should be targeted first in any treatment protocol for a
dog presumptively diagnosed as having PDH, and in patients with AHAC, so it is surprising that
unprocessed low glycemic index diets are never advocated in the literature for either condition. Instead,
veterinarians move immediately to the use of drugs that either impair adrenal activity, or destroy the
gland altogether. Insulin resistance is effectively permitted to endure and potentially lead to additional
pathology.
In this context, Chinese herbal medicine, together with diet change, provides a safe and effective means
of treating AHAC and presumptive PDH. Herbal treatments can be integrated with drug therapy, or used
in its place as long as symptom control is adequate.
Perhaps the most important Chinese herbal therapy for the treatment of AHAC and presumptive PDH is
Si Miao San (Four Marvels Combination).
Si Miao San improves insulin sensitivity by
protecting and enhancing insulin signalling
(Yang et al, 2014; Liu et al, 2010). Berberine,
a plant compound extracted from
Phellodendron in Si Miao Sanhas been
shown through a systematic review of clinical trials to improve multiple aspects of type II diabetes and
insulin resistance, including blood glucose markers such as HbA1c, hyperlipidemia, and hypertension
(Lan et al, 2015).
Four Marvels Powder (Si Miao San)
Cang Zhu
Atractylodes rhizome
Huai Niu Xi
Achryanthes root
Yi Yi Ren
Coix seed
Huang Bo
Phellodendron bark
Case Example
Sensei, a 12 year old female spayed Bichon-Shih-Tzu cross, presented with signs and symptoms
compatible with pituitary dependent hyperadrenocorticism and AHAC, including:




Thinning hair over the dorsum
Increased ALP (about five times normal)
Hyperlipidemia
Hypercholesterolemia
Sensei had been eating a heavily processed diet for years (z/d, Hills) in a vain attempt to control chronic
pruritis. An abdominal ultrasound showed normal-sized adrenal glands and homogenous hyperechoic
changes in the liver consistent with of steroid hepatopathy. An ACTH stimulation test showed normal
cortisol levels prior to testing and cortisol levels well above normal after stimulation. A diagnosis of
hyperadrenocorticism was rendered.
Four Marvels Combination (Natural Path Herb Company) was prescribed in granular extract form, at a
dose of 1 gram per 10 lbs (0.2 mg/kg) BID. Additionally, Sensei was prescribed a commercial raw diet
supplemented with cooked vegetables and the z/d was discontinued. No pharmaceutical treatment was
offered.
Within two months, the owner was reporting reduced thinning of Sensei’s haircoat and a 50% reduction
in itch. Laboratory testing at that time revealed ALP levels were only 50% above high normal. Treatment
with Four Marvels and a low glycemic index diet was continued.
In another three months, five months after treatment was initiated, a repeat ACTH stimulation test
revealed normal cortisol levels pre- and post-testing. ALP and cholesterol levels were well within normal
limits, with mild lipemia being noted in the blood sample.
Approximately one year later, a chemistry screen showed ALP to still be well within normal limits. Mild
lipemia of the sample was noted. Four Marvels has been continued to the present day, now 2 years
later, although another berberine-containing formula (Hoxsey-Like Combination, Natural Path Herb
Company) was added at a dose of 1 ml BID (0.1 ml per kg) to achieve better control of recurrent otitis
externa and vulvar irritation.
Case Discussion
Sensei represents a case of presumptive PDH, although no confirmation was made of the presence of a
pituitary adenoma. No effect of Four Marvels Combination or its components is reported in the
literature on the pituitary gland. A clear, comprehensive, and sustained response to Four Marvels
Combination, with its known insulin-sensitizing effects, suggests a diagnosis of AHAC is as likely as PDH.
Four Marvels Combination does have the ability to lower cortisol levels directly, however.
Phellodendron has been shown to reduce cortisol secretion during stress (Talbott et al, 2013), and stress
from obesity was conjectured in the early literature as being the cause of hypercortisolism (Lindholm,
2014). Furthermore Coix, also known as Adlay, has been shown to suppress cortisol release from the
adrenal gland itself (Chang et al, 2006).
Other herbal formulas also increase insulin sensitivity but do not influence the adrenal cortex or the
pituitary gland. A response of a case like Sensei to these formulas would thus provide more direct
evidence that:


AHAC is caused by insulin resistance
Cases diagnosed routinely diagnosed as PDH are likely AHAC patients
Wei Ling Tang (Harmonize the Stomach with Poria Five Herb Combination)
Wei Ling Tang contains two sub-formulas, Ping Wei San (Harmonize the Stomach Combination) and Wu
Ling San (Poria Five Herb Combination). Of the two, only Wu Ling San was traditionally indicated for
signs of diabetes including polyuria with unslakable thirst. Research confirms an anti-diabetic effect,
both by protecting beta islet cells and improving insulin signalling in insulin resistance (Jung et al, 2012;
Han et al, 2013). A shared ingredient with Si Miao San of Wei Ling Tang is Atractylodes, which has been
shown to improve several metrics in diabetic patients (Shi et al, 2006). No effect of either of the
constituent formulas has been reported on adrenal cortical or pituitary actitivty.
Wu Ling San (Poria Five Herb Combination)
Harmonize the Stomach (Ping Wei San)
Bai Zhu
White Atractylodes rhizome
Cang Zhu
Atractylodes rhizome
Fu Ling
Poria
Chen Pi
Citrus peel
Ze Xie
Alisma tuber
Hou Po
Magnolia bark
Zhu Ling
Polyporus
Da Zao
Jujube
Gui Zhi
Cinnamon twig
Gan Cao
Licorice root
Sheng Jiang
Ginger rhizome
Case Example
Emma, a 2 year old female spayed Pomeranian, presented in 2010 with a chief complaint of thinning
hair coat. She weighed approximately 5 lbs. through the course of treatment. Testing for
hyperthyroidism revealed low circulating T3 and an ACTH test response test indicated
hyperadrenocorticism. About a year after treatment was initiated, an ultrasound revealed bilateral
adrenal gland enlargement
One of the owner’s top goals was for the alopecia not to progress. Treatment with trilostane was thus
initiated at a dose of 1 mg/lb (suggested dose range for the drug is 1-3 mg/lb). Treatment with trilostane
continued until November of 2014, at doses varying between 0.5 – 1 mg/lb.
Additionally, for much of that period, and in particular the first and last eight months, Emma also
received Wei Ling Tang. Emma’s diet was a commercial raw food diet. Treatment results are shown in
the figure below:
1200
1000
800
600
400
200
Pre
1-Oct-14
1-Jul-14
1-Apr-14
1-Jan-14
1-Oct-13
1-Jul-13
1-Apr-13
1-Jan-13
1-Oct-12
1-Jul-12
1-Apr-12
1-Jan-12
1-Oct-11
1-Jul-11
1-Apr-11
1-Jan-11
1-Oct-10
1-Jul-10
1-Apr-10
1-Jan-10
0
Post
Figure 1. ACTH Stimulation test results for Emma
The most ACTH stimulation test results are not shown in the chart above, but were normal. At that time,
Emma had been off trilostane for two months. Hairloss did progress to bilateral truncal alopecia with
Emma, but then improved to involve primarily just the caudal aspect of the hind limbs. No other
significant laboratory abnormalities were noted over the course of treatment.
Case Discussion
The red horizontal line in the chart above indicates high normal for cortisol levels post-ACTH stimulation
testing, and the bottom line indicates high normal for pre-stimulation testing. Apart from at the start of
treatment, Emma remained within the normal range for both, including the last two to three months,
when the dog was no longer on trilostane.
Concomitant use of a low glycemic index raw diet and Wei Ling Tang appears to have allowed low to
sub-normal doses of trilostane to be used throughout treatment, and for the drug to be withdrawn with
impunity at the conclusion of treatment. Given that the main treatment effect of both herbs and diet
was through insulin-sensitization, the PDH diagnosed in Emma is perhaps more likely to be a form of
ACAH.
Conclusions
Hypercortisolism, or AHAC, appears to be occurring in dogs to an unappreciated degree. It is typically
suspected only when a dog with consistent clinical findings does not test positive for PDH in stimulation
tests. Given its association with insulin resistance, however, it should probably be suspected when a low
glycemic diet and insulin sensitizing herbs effect clinical improvements or resolution. There is also
nothing about what is known about AHAC to preclude affected animals testing positive on stimulation
tests, as with humans.
If many PDH dogs actually have AHAC, symptomatic treatment through reliance upon drugs toxic to the
adrenal glands is far less optimal a treatment option than insulin sensitization through diet change, with
or without herbal supplementation. Herbal medicines and unprocessed diets that improve insulin
sensitivity are more definitive and safe treatment approaches, and will prevent drug side effects,
progression to hypoadrenocorticism, and the progression of untreated insulin resistance.
Where pharmaceuticals are elected for use, they should ideally be supplemental to an insulin sensitizing
protocol. Concomitant herbal medicine can reduce the required dose to manage patients, helping limit
side effects and sequelae of drug use, and perhaps obviate the need for drug use long term.
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