Hyperadrenocorticism Flashcards

1
Q

What factors stimulate or suppress the release of CRH from the hypothalamus?

A

Stimulation:

  • Cytokines
    • IL-1, IL-6, TNF-a
  • Leptin
  • Dopamine
  • Vasopressin
  • Angiotensin II

Inhibition:

  • Corticosteroids
  • Somatostatin
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2
Q

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

A
  1. beta-lipotropin
    • mechanism of action is unknwon
  2. beta-endorphin
    • Likely act as an endogenous opiate with a role in pain alleviation
  3. Melanocte stimulating hormone
    • Involved in the secretion of melanin in the skin
  4. CLIP (corticotropin-like intermediate peptide)
    • Insulin secretagogue
    • Also increases exocrine pancreatic function
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3
Q

What are the three zones of the adrenal cortex?

What substances do each of the three regions secrete?

A
  1. Zona glomerulosa - outer most
    • Mineralocorticoids
  2. Zona fasiculata - middle
  3. Zona reticularis - inner most
    • Both the fasciulata and reticularis contain 17-a hydroxylase necessary for synthesis of cortisol and androgens
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4
Q

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

A
  • 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
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5
Q

Functional Adrenal Tumour have a variable response to ACTH.

With reference to the literature, discuss why and how adrenal tumours may respond to ACTH

A
  • 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
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6
Q

What is the proposed mechanism of polyuria and polydipsia in dogs with hyperadrenocorticism?

A
  • 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
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7
Q

UTI is common in dogs with uncontrolled HAC - what is the reported incidence?

What mechanisms may lead to the development of UTI in dogs?

A
  • 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
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8
Q

What are the potential causes for excessive panting in dogs with hyperadrenocorticism

A
  • 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.
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9
Q

What are the common clinicopathological abnormalities commonly seen with newly diagnosed HAC in dogs?

A

​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
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10
Q

Discuss the reasons for a hypercoagulable state in dogs with uncontrolled hyperadrenocorticism

A
  • 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

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11
Q

Discuss the relationship and relevance of urinary protein loss in hyperadrenocorticism

A
  • ~ 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
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12
Q

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

A
  1. Urinary cortisol:creatinine ratio
    • Very high sensitivity - approaching 100%
    • Low specificity of ~ 20-77%
    • PPV of 90% when the UCCR is >100 (ref. < 10)
  2. ACTH stimulation test
    • Sensitivity of ~85% for PDH and 60% for AT
    • Specificity is 85-90% for both
  3. 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
  4. UCCR/LDDST combined
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13
Q

Discuss the interpretation of LDDST results.

What criteria are used to diagnose HAC?

What criteria can be used for distinguishing PDH from AT?

A
  • 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.

  1. Suppression at 4 hours (below cut-off) with loss of suppression at 8 hours result > lab cut-off = HAC
  2. 4 hour cortisol < 50% of baseline
  3. 8 hour cortisol < 50% of baseline
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14
Q

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

A
  1. 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
  2. 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
  3. Imaging - abdominal US
    • PDH - normal to hypertrophied, bilaterally symmetrical or not.
    • Nodular hyperplasia maybe difficult to interpret
    • AT - mass present, contralateral gland < 5 mm
  4. 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
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15
Q

What is the mechanism of action of trilostane?

A
  • 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
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16
Q

Discuss the indications for radiation therapy and the expected outcomes

A
  • Radiation therapy is generally reserved for dogs with a macroadenoma.
  • Tumour size > 8 mm has been suggested as an indicated for radiation treatment
  • While plasma endogenous ACTH is expected to reduce in all dogs, the clinical improvement in signs of HAC may only improve in ~ 50%
    • One study of 6 dogs revealed resolution of HAC signs in 3/6 dogs, but return of signs in 2 of those dogs.
    • While the tumours do consistently reduce in size, the functionality of a smaller tumour can persist
  • Radiation is most useful at preventing the signs associated with a pituitary mass
  • Requirement for medical management of the hyperadrenocorticism should be expected.
  • Radiation takes months to cause a reduced tumour size
17
Q

Contrast and compare the clinical signs of HAC in cats with those in dogs

A
  • The majority of cats diagnosed with HAC have concurrent diabetes mellitus (79%)
  • PU/PD/PP are the most common metabolic signs, similar to dog
    • However, these signs are most likely to be attributed to the poor control of diabetes
    • PU/PD does not appear to be a feature of the disease unless there is concurrent DM or CKD
    • Low USG is not common unless associated with DM or CKD
  • Pendulous abdomen and muscle loss are common, as for dogs
  • Skin fragility syndrome appears to be an extreme presentation dermal atrophy that is not seen in dogs
    • Calcinosis cutis has not been reported in cats
    • Alopecia is uncommon
18
Q

List the endocrine tests available to investigate hyperadrenocorticism in cats.

Note the utility, sensitivity and specificity of each

A
  1. Baseline cortisol - not useful
    • Normal values less established that for dogs
  2. ACTH stimulation test
    • Timing of peak varies, so post-ACTH samples should be collected at 60 and 90 minutes
    • Dose of 5 mcg/kg or 0.125 mcg/cat
    • Sensitivity from 56-80%
      • post-ACTH levels of 400-600 are “grey” but could be positive with other supportive clinical signs
  3. Dexamethasone suppression test
    • Normal canine dose 0.01 mg/kg fails to suppress 20% of normal cats (reduced specificity)
    • Higher dose of 0.1 mg/kg is recommended, but some cats with PDH remain suppressed at 8 hours (reduced sensitivity)
  4. UCCR
    • Expected to be a similar test as for dogs with excellent sensitivity and poor specificity
    • Assay variabilities may limit the usefulness