SAM2.21 Part 1: Cushing's Dz in Dogs

AG outer cortex produces

steroid hormones

AG inner medullar produces

catecholamines

Zona glomerulosa produces

mineralocorticoids - aldosterone

Zona fasiculata produces

glucocorticoids - cortisol

Zona reticularis produce

some cortisol.

androgens - Testosterone, E2, and P4.

Cushing's syndrome is the umbrella term for the CS seen due to

excess exogenous and endogenous steroid hormones

Cushing's syndrome CS (5)

PU.

polyphagia.

Panting.

M. wasting.

hairloss.

Iatrogenic Cushing is the result of

admin of exogenous steroids.

ACTH-dependent includes (3)

pituitary dependent hypercortisolism.

ectopic ACTH secretion syndrome (rare).

sub-diagnostic Cushing's syndrome.

Sub-diagnostic Cushing's syndrome

signs but adrenal test negative or equivocal aka atypical hyperadrenocorticism.

ACTH-independent Cushings (3)

Adrenal-dependent hypercortisolism.

aberrant adrenal receptor expression (rare).

Sub-diagnostic Cushing's syndrome.

Common form of Cushing's syndrome in cats

Iatrogenic (both in dogs)

Iatrogenic Cushing's syndrome are typically caused by (2)

PO or long-acting injectables.

May see w/ topical and rarely inhalant.

Primary excess production of cortisol

adrenals produce too much cortisol - adrenal-dependent hypercortisolism (ADH)

Secondary excess production of cortisol

the pituitary produces too much ACTH - pituitary-dependent hypercortisolism (PDH)

Which form of Cushing's syndrome is more common

Secondary (pituitary)

Pathophys of cortisol release (4)

Hypothalamus releases CRH (corticotropin releasing hormone).

CRH stimulates to PG to produce ACTH.

ACTH stimulates the AG to produce cortisol.

Cortisol has negative feedback to hypothalamus and PG.

ACTH feedback

Negative feedback on itself via the pituitary

Ectopic ACTH secretion syndrome

ACTH produced in excess amounts from tumors outside the PG.

Ectopic ACTH secretion syndrome is seen most commonly w/

carcinoids of the lungs and pancreas

Presentation of Ectopic ACTH secretion syndrome (4)

CS of Cushing's syndrome.

normal cortisol testing.

high endogenous ACTH.

Resolution w/ tumor removal.

ACTH independent Hypercortisolism

A response to inappropriate placement of receptors in the AG - respond to gastrointestinal inhibitory peptide (GIP). When dog eats - GIP is produced, followed by excess cortisol and CS.

PDH occur as a result of

pituitary microadenoma (more common) - <0.7-1cm.

pituitary macroadenoma (less common) - >0.7-1cm.

Adenocarcinoma - rare.

Pituitary macroadenoma are more likely to cause

neuro signs due to size (+ other signs of HAC), but even small rumors can cause neuro signs (size does not equate w/ presence of absence of neurologic signs).

Chronic increases in ACTH - pathologic effect on AG

hyperplasia of the AG and subsequent increased cortisol production.

Bilateral hyperplasia w/ PDH is

nodular hyperplasia of the adrenal. Believe to be secondary to PDH (not tumors).

Adrenal nodules can be

incidental findings and non-functional.

ADH results from (2)

benign adenoma - smaller (<2cm), local, and encapsulated.

malignant adenocarcinoma - larger (>2cm), local invasion, and distant spread.

ADH - tumor affects

one (common) or both (rare) AG.

When there is a single AG affected by a tumor

normal AG becomes non-functional (due to negative feedback) and is often (not always) much smaller.

When there are bilateral AG tumors, one may

produce cortisol and the other may be non-function or produce another hormone.

ADH: tumors autonomously secrete excess amounts of (2)

cortisol independent of the influence of ACTH.

The excess cortisol causes decreases in CRH and ACTH release (through normal feedback mechanism).

Iatrogenic Cushing's signs: CS can occur

w/in hours of admin.

Suppression of the HPA axis which will suppress endogenous production of CRH, ACTH, and thus glucocorticoids, will occur w/

continued admin of glucocorticoids - usually about 2wks.

Subdiagnostic Cushing's syndrome is believed to occur as a result of

increased cortisol in the presence of normal adrenal fxn test OR the signs may be due to other steroid hormones.

Subdiagnostic Cushing's syndrome dogs have negative or equivocal ACTH stim AND LDDST for hypercortisolemia, but

CS (some but not all) of Cushing's syndrome - suspected to be minor excess of cortisol and particularly sensitive.

Tx of Subdiagnostic Cushing's syndrome

respond to trilostane or mitotaine despite unremarkable ACTH stim/LDDST

Typical signalment of Cushing's dogs (2 - second w/ 5)

Middle-old aged.

Mini schnauzers, poodles, doxie, terriers, and beagles.

Trend of Cushing's based on weight

<20kg = 75% PDH.

>20kgs = equal frequency.

When dx Cushing's dz regardless of form, you should start w/

historical, physical, and routine lab testing supportive of dz.

Proactive test

LDDST or ACTH Stim.

PDH Dx (2- 2nd w/ five ex)

positive proactive test.

One or more test indicating pituitary involvement - specific LDDST pattern, HDDS suppression, elevated eACTH, absence of Adrenal tumor, CT/MRI suggesting pituitary mass.

Ectopic ACTH Dx (3)

Negative proactive test.

Elevated eACTH.

presence of mass/carcinoid w/ resolution post-removal.

ACTH-dependent or independent subclinical Cushing's Dx (3)

Negative proactive test.

eACTH and imaging suggestive of pituitary or adrenal mass.

Follow-up positive proactive test in 2-3m (preferred - can also see response to trilostane which is not preferred)

ADH Dx ( 2- second w/ 3)

Positive proactive test.

a test indicating adrenal involvement - absence of HDDS, decreased eACTH, an adrenal tumor.

Aberrant adrenal receptor expression Dx (5)

negative proactive test.

suppressed eACTH.

increased UCCR after eating.

no adrenal/pituitary mass.

cortisol suppression w/ octreotide - suppresses GIP production.

Most common CS of Cushing's Syndrome (7)

Primary PU, secondary PD.

Polyphagia.

Abdominal distention.

panting.

m. wasting.

cutaneous lesions - truncal alopecia most common, thin skin, and bruising w/ venipuncture.

lethargy.

Additional CS findings of Cushing's Syndrome (5)

Lameness.

Hypertension.

Proteinuria.

Anestrus.

Testicular atrophy.

Dog's w/ macroadenomas neuro signs (8)

leth.

dullness.

confusion.

pacing.

ataxia.

circling.

blindness.

eventual seizures.

CBC findings for Cushing's dz - may see (3)

stress leukogram - mature neutrophilia and lymphopenia.

mild increase in RBCs.

Thrombocytosis.

Chem findings of Cushing's dz (6)

ALP (+ GGT) increase primarily.

secondary, less marked ALT increase (vacuolar hepatopathy).

Increased cholesterol.

Hypertriglyceridemia.

Decreased BUN (secondary to PU).

Hyperglycemia (insulin resistance).

Dog's supected of Cushing's that have hyperglycemia

Tx'ed for DM - establishment of insulin resistance and then tx for concurrent HAC.

UA findings w/ Cushing's dz (4)

variable concentration.

Glucosuria when concurrent DM.

Proteinuria (infection, SHT, glomerular dz).

+/- Bacteria and WBC - impaired WBC response.

Cortisol effect on the Thyroid

negative feedback on TSH - secondary reversible hypothyroidism.

Do not reco testing a dog w/ uncontrolled HAC.

ABG may be done on a Cushing's dog when

PTE is expected - hypoxemia, increased alveolar gradient, and hypocapnia (secondary to hyperventilation).

Thoracic Radiographic findings of HAC (2)

Typically normal.

Dystrophic mineralization - generalized interstitial pattern, bronchial, or tracheal (non-specific finding).

Abdominal rad findings of HAC (3)

Hepatomegaly.

Mineralization of adrenal tumor (unlikely to see adrenal tumor itself).

Calcium containing urinary calculi (rare).

Mineralization of adrenocortical tumors

can occur w/ both malignant or benign tumors (less likely w/ pheos).

Screening tests (Provoactive for HAC)

ACTH stim.

LDDST.

What test is not reliable for dx of HAC

A single basal cortisol measurement.

Premise of ACTH stim

A normal dog will stimulate after admin of ACTH (cortrosyn), but only to a certain amount

ACTH stim epidemiology

Higher specificity.

Lower sensitivity.

ACTH stim results for PDH

exaggerated response (b/c adrenals are hyperplastic)

ACTH stim results for ADH

exaggerated response, but often the AG does it on it's own, not as response to COrtrosyn.

ACTH as a differentiation test

Cannot be used (b/c both forms cause exaggerated response)

Which form of HAC is worse to screen w/ ACTH stim

Adrenal tumors

If HAC is expected in a dog w/ a normal response on an ACTH stim (you think it is a false negative), then perform

LDDST test

ACTH stim is the test used to ID

iatrogenic HAC

Iatrogenic HAC response on ACTH stim (2)

low basal cortisol.

fail to stimulate w/ Cortrosyn due to suppressive effect of exogenous glucocorticoids on ACTH secretion.

Premise of LDDST

when given exogenous cortisol (even a small amount), the hypothalamus/pituitary will be suppressed w/in 3h and up to 48h.

Normal measurements w/ LDDST

low measurement (usually below lower limit of RI) at 4 and 8h.

A LDDST with a measurement >1.4 (greater than lower limit of baseline) at 4 and/or 8h

considered abnormal - HAC dog do not suppress w/ small addition of cortisol b/c they already have a lot of cortisol.

8-hour cortisol measurement should be above 1.4 w/

both forms of HAC, so to dx HAC you compare 8hr to baseline.

How do you dx PDH v. ADH w/ LDDSR

4h cortisol

Measurement of cortisol w/ LDDST w/ HAC

suppression of endogenous cortisol for only 3-6h (which is why we measure at 4 and 8h)

PDH (60% of cases) LDDST results (2) - general concept

(pituitary and adrenals can be susceptible to exogenous dex for 3-6h then unresponsive by 8h.)

suppression at 4h.

Unresponsive/increased at 8h.

PDH (40%) and all ADH LDDST results

will not respond to dexamethasone suppression at 4 OR 8h. 8h should be above baseline.

LDDST in dogs w/ other dz OR chronic stressors

chronically elevated cortisol and does not suppress like a normal dog.

LDDST epidemiology

Higher sensitivity.

Poorer specific.

Urine Cortisol Creatinine Ratio (UCCR) sampling (2)

first morning urine collected at home.

Has to be 48 after any stressful events to avoid affects on cortisol levels.

UCCR results: Dog's w/ HAC

should have levels about the RI.

Increased UCCR results are seen w/

many pathologic and non-pathologic conditions could lead to an increased ratio b/c of effects on cortisol.

UCCR epidemiology

Poor screening test for HAC and not reco

Steroid hormones profiles were historically performed on dogs suspected of

subclinical Cushing's syndrome based on clinical findings that fail to test positive on an ACTH stim AND a LDDST.

Subclinical Cushing's dog - theory is that these dogs

may be more sensitive to excess cortisol and exhibit signs at lower concentration.

Steroid Hormone Profiles tests for what hormones (5)

17-OH progesterone.

E2.

Androstenedione.

P4.

Aldosterone.

Steroid Hormone Profile: The above 5 hormones are measures b/c

increases in these hormones may instead be responsible for clinical manifestations.

Results of Steroid Hormone Profile: Subclinical Cushing's

increases in one or more of the atypical steroid hormones.

Important note for Steroid Hormone Profile

Poor specificity - some of these steroid hormones are increased w/ many other dzs.

Tx for Subclinical Cushing's

Many dogs respond to tx for excess cortisol and other steroid hormones.

Differentiation of the types for HAC (4)

LDDST.

eACTH.

Abdominal U/S.

CT.

(Not HDDST - lower specificity compared to other tests).

Differentiation w/ LDDST (3)

PDH: suppression at 4h, but not at 8h.

PDH or ADH: If the dog fails to suppress at 4 and 8h - need further differentiating test.

Remember that animals w/ non-adrenal illness will not completely suppress.

HDDST is not used as a screening test b/c

it does not differentiate between normal dogs and PDH - can both suppress at 8h (ADH do not suppress at all).

Blood collection for eACTH (3)

EDTA tube spun down.

Plasma frozen immediately.

Hormone easily degrades.

ADH results for eACTH

low b/c large amounts of cortisol suppress ACTH release from the pituitary

PDH results for eACTH

increased since the pituitary tumor is responsible for excess ACTH production.

eACTH is non-diagnostic b/c

many ACH and a few of the PDH have ACTH levels w/ the RI.

Standard measurement on U/S for adrenals

DV measurement of the Ca. pole.

Normal: <7.4 diameter at Ca pole of L adrenal.

PDH U/S findings (2)

appropriate clinical findings + 2 normal or bilaterally enlarged adrenals.

Adrenal asymmetry.

ADH U/S findings

Unilateral adenomegaly w/ small or undetectable contralateral AG (may be normal, but unlikely).