Cushing’s Disease/Syndrome

Humans vs. Dogs

Dylan Djani

Cushing’s - Definition

Hyperadrenocorticism Endocrinopathy / Endocrine syndrome (Cohan)

Characterized by hypercortisolemia Clinical signs Improper cortisol regulation

Affects humans, dogs, and horses (very rarely cats) 1-2 cases/1000 dogs/year (de Bruin et. al.) ~1-2 cases/million people/year More common in females than males

Cushing’s: Disease vs. Syndrome

Cushing’s Syndrome General signs and symptoms due to hyperadrenocorticism Non-specific cause

Cushing’s Disease Specific cause: pituitary adenoma Resulting in hyperadrenocorticism and hypercortisolemia

Referring to the same pathophysiologic process (Pluta and Burke)

Hypothalamic-Pituitary-Adrenal Axis(HPA Axis)

Note* CRF = CRH

Corticosteroids from adrenal cortex: Glucocorticoids (cortisol) Mineralocorticoids (aldosterone)

Cortisol release is triggered by stress(Bronstein)

Systemic effects are metabolic

Multiple levels of regulation Feedback loops Negative feedback on H and AP “Feedback inhibition”(Kooistra and Galac)

Source: http://upload.wikimedia.org/wikipedia/commons/a/ad/ACTH_Negative_Feedback.jpg

Cushing’s – EtiologyDisruption of Feedback Loops in HPA

Axis Tumors

Pituitary tumor (80-85% cases) Cushing’s disease; pituitary/ACTH-dependent Cushing’s Excess ACTH – does not respond to feedback (Bronstein)

Adrenal tumor (15-20% cases) Adrenal-dependent, pituitary/ACTH-independent

Cushing’s Excess cortisol – unaffected by presence of ACTH or lack

thereof

Prolonged exogenous corticosteroid administration Iatrogenic Associated with corticosteroid therapy (i.e. Addison’s

patients)

Cortisol – Main Functions

Stimulatory effects on:

Gluconeogenesis

Lipolysis

Protein/collagen degradation

Sodium/water retention

PTH release

Osteoclast activity

Inhibitory effects on:

Gonadotropin releaseFSH and LH

TSH and GH release

Gonadal steroidogenesis

Vitamin D and calcium intestinal reabsorption

Immune and inflammatory responses

STRESS RESPONSE

METABOLIC EFFECTS

HypercortisolemiaPathophysiologic Effects in Humans and

Dogs

Hyperglycemia and hyperlipidemia Insulin release & resistance Increased plasma osmolarity ADH release

Altered fat deposition Central trunk weight gain and peripheral weight loss

Muscle wasting and thinning of the skin

Stunted growth, loss of libido, and hypogonadism

Immunosuppression immunocompromised

Hypercalcuria and hypertension

Polyuria and polydipsia (more prominent in dogs)

Cushing’s Disease - Clinical Presentation Examples

Source: http://jama.jamanetwork.com/article.aspx?articleid=1104780 Source: personal photographs

Canine Cushing’s Disease - Thinning of Skin (ventral abdomen)

Source: http://www.dog-health-guide.org/image-files/dog_cushings_disease.jpg

Cushing’s: Humans vs. Dogs

Main Clinical Signs (de Bruin et. al.) Dogs: polyuria/polydipsia/polyphagia Humans: obesity and skin changes

Overwhelming rates of companion animal obesity

Polyphagia from cortisol excess is unique to dogs

Differences at the level of the kidney Species-specific physiologic implications of glucocorticoid

interactions with the ADH receptor Changes in ADH receptor sensitivity

Polyuria and PolydipsiaCanine Cushing’s

Vasopressin Interference (Feldman and Nelson)

Increased osmotic diuresis – hence polyuria Cushing’s is more “diabetogenic” in dogs

Main water sources for lowering plasma osmolarity in dogs Intracellular fluid compartment & dietary intake Intracellular fluid compartment is eventually depleted

Exacerbated thirst signaling – hence polydipsia From increased plasma osmolarity Additionally from body tissue dehydration

Less prominent of a feature in human Cushing’s

In conclusion…

Endocrinopathies are extremely complicated

Hormone dysregulation and lack of feedback have many systemic pathophysiologic effects

Each clinical sign can be traced back to one of the hormone’s proper physiologic functions occurring in excess

Bibliography

Overview of Hyperadrenocorticism by Mindy Cohan, VMD

Cushing’s Syndrome – Pathophysiology, Diagnosis, and Treatment by Bronstein

Cushing’s Syndrome and Cushing’s disease JAMA by Pluta and Burke

Cushing’s Disease in Dogs and Humans by de Bruin, et. al.

Canine and Feline Endocrinology and Reproduction by Feldman and Nelson

Recent Advances in the Diagnostics of Cushing’s Syndrome in Dogs by Kooistra and Galac

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A few thoughts medical students studying for USMLE Step 1 on online forums…