Hyperadrenocorticism Flashcards
What factors stimulate or suppress the release of CRH from the hypothalamus?
Stimulation:
- Cytokines
- IL-1, IL-6, TNF-a
- Leptin
- Dopamine
- Vasopressin
- Angiotensin II
Inhibition:
- Corticosteroids
- Somatostatin
POMC is the precursor molecule for ACTH.
Other biologically active metabolites are also produced when POMC is cleaved. What are these substances and briefly note their effect
- beta-lipotropin
- mechanism of action is unknwon
- beta-endorphin
- Likely act as an endogenous opiate with a role in pain alleviation
- Melanocte stimulating hormone
- Involved in the secretion of melanin in the skin
- CLIP (corticotropin-like intermediate peptide)
- Insulin secretagogue
- Also increases exocrine pancreatic function
What are the three zones of the adrenal cortex?
What substances do each of the three regions secrete?
- Zona glomerulosa - outer most
- Mineralocorticoids
- Zona fasiculata - middle
- Zona reticularis - inner most
- Both the fasciulata and reticularis contain 17-a hydroxylase necessary for synthesis of cortisol and androgens
The pituitary theory is most supported as the mechanism of development of PDH
What is the pituitary theory and describe the support for the theory
- The pituitary theory is most likely accurate
- Somatic mutation of a corticotroph produces a tumour clone
- The majority of dogs with PDH have reduced CRH production
- Likely due to negative feedback from consistently elevated ACTH and cortisol levels
- Most pituitary adenomas are monnoclonal suggesting they arise from a single cell
- Most adenomas contain stem cells that drive growth and most are likely the result of a multi-stage process of tumourogenesis
Functional Adrenal Tumour have a variable response to ACTH.
With reference to the literature, discuss why and how adrenal tumours may respond to ACTH
- Functional adrenal tumours tend to secrete cortisol autonomously and excessively
- Circulating ACTH and CRH levels are suppressed
- The role of ACTH receptors in the function of functional adrenal tumours varies.
- Human studies suggest that steroidogenesis requires ACTH even in adrenal tumours
- With regards to the ACTH stimulation test:
- Some tumours do not respond at all to ACTH
- Some have a normal response
- Some tumours show an exaggerated response as may be expected with PDH
- Upregulation of ACTH receptors does not appear to involved in the pathogenesis, but down regulation may be involved in malignancy
- Malignant FAT’s may be less likely to respond to ACTH due to receptor down-regulation
What is the proposed mechanism of polyuria and polydipsia in dogs with hyperadrenocorticism?
- Corticosteroids potentiate sodium and chloride retention
- This leads to expansion of the effective circulating volume
- Increased blood pressure
- Increased glomeurlar filtration rate
- Cortisol appears to exert a negative feedback effect on ADH release, similarly to the negative effect on other hypothalamic / pituitary hormones
- Cortisol also antagonises the effect of ADH at the collecting duct, reducing free water resorption, causing primary polyuria
- Hypernatremia can also stimulate primary polydipsia
UTI is common in dogs with uncontrolled HAC - what is the reported incidence?
What mechanisms may lead to the development of UTI in dogs?
- The most often quoted incidence of UTI at the time of diagnosis comes from a 1990 paper that assessed 42 dogs with HAC, DM or both.
- This paper reported an incidence of 40-50% UTI
- A large cohort controlled study (1519 HAC dogs from 1984-2004) assess the presence of UTI at the time of death
- They reported a 6.6% incidence, significantly higher than dogs without HAC
- Poor urine concentration - reduced bactericidal properties
- Immunosuppressive effects of elevated cortisol levels
- Urine retention
- Due to increased urine production
- Decreased bladder tone / function
- Urine incontinence
What are the potential causes for excessive panting in dogs with hyperadrenocorticism
- Respiratory muscle weakness
- Reduced pulmonary compliance
- Secondary to pulmonary hypertension / vasocontriction
- Cortisole has a direct effects on the respiratory centre
- Stress and fear have been show to increase tidal volume in humans with activation of the thalamus and other central regions of the brain.
What are the common clinicopathological abnormalities commonly seen with newly diagnosed HAC in dogs?
Haematology:
- Lymphopenia - steroid lympholysis
- Eosinopenia - bone marrow sequestration
- Neutrophilia / monocytosis - steroid enhanced capilliary margination
- Thrombocytosis - marrow stimulation
- Erythrocytosis
Biochemistry:
- Elevated liver enzymes
- ALKP (85-95%) - primarily due to induction
- ALT mild increases likely secondary to vacuolar changes or blood flow changes
- Cholesterol and triglycerides - increased lipolysis
- Normal or mildly elevated glucose
- Gluconeogenesis and insulin resistance
- BUN - 30-50% low due to diuresis
- Phosphate - High or low
- Low due to renal excretion
- High with renal secondary hyperparathyroidism due to calciuresis
- Bile acids and cPLi may be increased - potentially not specifically due to hepatic dysfunction or overt pancreatitis
Discuss the reasons for a hypercoagulable state in dogs with uncontrolled hyperadrenocorticism
- Numerous small studies have assessed coagulability in dogs with newly diagnosed and controlled HAC
- Most studies indicate hypercoagulability in ~ 80-90% of dogs with newly diagnosed HAC and these persist despite adequate treatment
Documented abnormalities:
- Increased fibrinogen
- Increased thrombin-anti-thrombin complexes
- Decreased anti-thrombin (possibly due to urinary protein loss - or utilisation by thrombin binding)
- Increased platelet aggregation
- TEG - Increased angle and MA and reduced K
- Suggests more rapid and larger/stronger clot formation
- Some dogs show reduced fibrinolysis parameters
- Thrombocytosis may play a role
No specific coagulation abnormality is able to predict others
Discuss the relationship and relevance of urinary protein loss in hyperadrenocorticism
- ~ 70% of dogs have an elevated UPC (>0.5) at the time of diagnosis
- ~ 45% are increased above 1.0
- Note that the presence of urinary tract infection may spuriously increase these results, though the sediment is usually inactive
- The UP:C may be increased due to elevated GFR (~60% of dogs) - may be caused by the increased ECV and BP
- The GFR reduces with treatment, so UP:C should also reduce with treatment
Clinical relevance:
- To date, there are no studies that suggest a specific clinical relevance to the elevated UPC
- No specific treatment is recommended for the elevated UP:C
List the screening tests used to investigate for hyperadrenocorticism in dogs with a strong suspicion of disease
Indicate the sensitivity and specificity of each test
- Urinary cortisol:creatinine ratio
- Very high sensitivity - approaching 100%
- Low specificity of ~ 20-77%
- PPV of 90% when the UCCR is >100 (ref. < 10)
- ACTH stimulation test
- Sensitivity of ~85% for PDH and 60% for AT
- Specificity is 85-90% for both
- LDDST
- Sensitivity is ~ 90-95% for PDH and ~100% for AT
- Specificity is highly variable and dependent on the patient population
- With low prevalence, then specificity may be as low as 40-50%
- With a high prevalence, the specificity is much improved
- UCCR/LDDST combined
Discuss the interpretation of LDDST results.
What criteria are used to diagnose HAC?
What criteria can be used for distinguishing PDH from AT?
- Blood is collected for cortisol readings at baseline, 4 hours and 8 hours post IV dexamethasone administration
- Normal dog will have cortisol results < cut-off for 24-48 hours post ACTH
- 4 or 8 hour results above the laboratory cut off are supportive of HAC
PDH can be supported by any of the following: 60-65% of dogs with PDH will display one or more of the following.
- Suppression at 4 hours (below cut-off) with loss of suppression at 8 hours result > lab cut-off = HAC
- 4 hour cortisol < 50% of baseline
- 8 hour cortisol < 50% of baseline
List the available tests that can differentiate between PDH and a functional AT as cause for hyperadrenocorticism in dogs.
Describe the interpretation and utility of the tests
- HDDST
- ~ an additional 10% of dogs that do not suppress with the LDDST will suppress with HDDST.
- Lack of suppression does not exclude PDH or prove AT
- Endogenous ACTH
- Should be elevatated with PDH and undetectable with a functional AT
- ~ 20% will be non-diagnostic (between low and elevated)
- Sample handling can result in spuriously low results
- Imaging - abdominal US
- PDH - normal to hypertrophied, bilaterally symmetrical or not.
- Nodular hyperplasia maybe difficult to interpret
- AT - mass present, contralateral gland < 5 mm
- Advanced imaging
- ~ 50% of adrenal microadenomas are not detected on advanced imaging (3-4 mm tumour size)
- Most indicated when there is evidence of PDH and concurrent neurological signs
- Larger tumours can be detected by either modality, though MRI better estimates size and impact on surrounding structures
What is the mechanism of action of trilostane?
- Trilostane is a synthetic steroid analogue
- Acts as a competitive inhibitor of 3-beta-hydroxysteroid dehydrogenase
- Blocks conversion of pregnenelone to progesterone
- Blocks the conversion of 17-hydroxy pregnenolone to 17-hydroxy progesterone also
- Peak action occurs at ~ 2 hours with complete metabolism within 10-18 hours
- Hence twice daily dosing being preferred
- 11 beta hydroxylase may also be inhibited, reducing conversion of cortisone to cortisol