PBL 11- Cushings/Addisons Flashcards
What is the definition of Cushings syndrome?
The symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoid
What are some causes of Cushings syndrome?
Excess adrenal secretion ○ ACTH dependent § Pituitary § Non-pituitary § Increased CRH secretion ○ ACTH independent § Functioning adrenal tumours § Other rare syndromes
Iatrogenic
Steroids such as in asthma
What is the normal hypothalamic pituitary adrenal axis?
○ Various stressors, low levels of circulating cortisol and the body’s circadian rhythm stimulated the hypothalamus
○ Hypothalamus secretes corticotrophin releasing hormone (CRH) into the hypophyseal portal system ○ CRH is transported to the anteriorituitary where it stimulates the cleaving into Adrenocorticotropic Hormone (ACTH) ○ ACTH is released by the corticotroph cells of the anterior pituitary and acts as the pivotal regulator of cortisol synthesis in the adrenal gland
ACTH also has short term effects on the mineralocorticoid and adrenal androgen synthesis
What are the three steroid hormones produced by the adrenal cortex and where are they produced?
○ Mineralocorticoids = Zona Glomerulosa
○ Glucocorticoids = Zona Fasciculata
Androgens = Zona Reticularis
What is the basic action of ACTH?
○ ACTH stimulates secretion of steroid hormones in the adrenal cortex
○ It especially works in the Zona Fasciculata by binding to the cell surface ACTH receptors (G protein coupled) ○ Influences steroid hormone secretion by both rapid short-term mechanisms that take place within minutes and then slower long-term actions
What are the rapid short term actions of ACTH?
○ Stimulation of cholesterol delivery to the mitochondria cholesterol side chain cleavage enzyme (CYP11A1) is located
○ The enzyme catalyses the first step of steroidogenesis which is the cleavage of cholesterol to form pregnenolone ○ ACTH also stimulates lipoprotein uptake into the adrenal cortical cells increasing the bioavailability of cholesterol in these cells
What are the long term actions of ACTH?
○ Stimulation of the transcription of genes coding for the steroidogenic enzymes, especially CYP11B1 and their electron transfer proteins
○ This is observed over several hours ○ Also enhances transcription of mitochondrial genes that encode for subunits of mitochondrial oxidative phosphorylation systems ○ These are necessary for the supply of the increased energy needs of the adrenocortical cells stimulated by ACTH
Describe the ACTH receptor:
○ It is a seven membrane spanning G protein coupled receptor
○ Stimulate adenyl cyclase which leads to increase in intracellular cAMP
Activation of protein kinase A
What are the ACTH dependent causes of Cushings?
○ Cushings disease ( ACTH secreting pituitary adenoma)
○ Ectopic ACTH syndrome
○ CRH Hypersecretion
What is Cushings Disease?
○ 70% of non–iatrogenic cushings syndrome
○ Located in the anterior pituitary
○ M: F = 1:6
○ Age : 20-40
○ Basophilic corticotroph cell pituitary adenoma (usually less than 10mm)
○ Bilateral adrenocortical hyperplasia
○ Hyperplasia is usually micronodular
○ Slow progressive course over many years
What is Ectopic ACTH syndrome?
○ A non-pituitary tumour synthesizes and hyper secretes biologically active ACTH or a ACTH like peptide
○ Most commonly caused by small cell and non-small cell carcinomas of the lung
○ More common in men 3:1
○ 15% of non - iatrogenic Cushing’s syndrome
○ Age: 40-60
○ Bilateral adrenocortical hyperplasia
○ Course and prognosis is of the underlying neoplasm
What is CRH hypersecretion?
○ Very rare condition where patients have diffuse hyperplasia of the pituitary corticotroph cells which results in hypersecretion of ACTH
○ Due to either:
○ Hypersecretion of CRH by the hypothalamus
○ Non-hypothalamic tumours that secrete ectopic CRH (bronchial carcinoids, medullary carcinoma of the thyroid, prostate carcinoma)
○ Chronic CRH hypersecretion does not cause pituitary adenomas
What are ACTH Independent Causes of Cushings Syndrome?
○ Functioning adrenocortical tumours (the main causes)
○ ACTH independent macronodular hyperplasia
○ Primary pigmented nodular adrenal disease
○ McCune-Albright Syndrome
What are functioning adrenocortical tumours?
○ Adenomas and carcinomas that produce cortisol autonomously
○ More common in women
○ 40 years of age
○ Prognosis depends on the underlying neoplasm
Adrenal Adenomas
○ Responsible for about 8% of non iatrogenic cushings syndrome
○ 1-6 cm in diameter
○ Encapsulated and consist mainly of zona fasciculata cells
○ Relatively inefficient producers of cortisol
○ Clinical features are only mind and androgenic effects usually absent
○ Onset is gradual
○ Only elevated Cortisol
Adrenal Carcinomas
○ 7% of Cushings syndrome
○ Large
○ Often palpable as an abdominal mass by the time the syndrome manifests
○ Highly vascular with areas of necrosis, haemorrhage, cystic degeneration and calcification
○ Highly malignant tumours and invade the adrenal capsule, neighbouring organs and blood vessels
○ Metastasize to the liver and lungs
○ Rapid onset and progression
○ Marked elevations of glucocorticoids, Mineralocorticoids and androgens
What is ACTH independent macronodular hyperplasia?
○ Rare but notable cause of adrenal cortisol excess
○ Characterised by the ectopic expression of receptors not usually found in the adrenal gland
○ Examples of present receptors are: LH, ADH, Serotonin, IL-1 and GIP- the cause of food dependent cushings
○ Activation of these receptors results in upregulation of Protein Kinase A signalling which is the same as what happens in ACTH
○ Subsequently this results in increase in cortisol production
What is primary pigmented nodular adrenal disease?
○ Mutations in the regulatory subunit R1A of Protein Kinase A
○ This is part of Carneys complex- a multiple neoplasia condition associated with cardiac myxomas, hyperientiginosis, sertolis cell tumours and PPNAD
What is McCune-Albright Syndrome?
○ Very rare
○ Associated with polyostotic fibrous dysplasia
○ Unilateral cage-au-lait spots and precocious puberty
○ Activating mutations in GNAS-1
What are the Clinical manifestations of Cushings syndrome?
○ Glucose intolerance ○ Muscle Wasting ○ Obesity and redistrubution of body fat ○ Weight gain ○ Moon face ○ Supraclavicular fat pads ○ Truncal obesity ○ Buffalo hump ○ Sparing of the extremities ○ Skin Changes ○ Cutaneous atrophy ○ Easy brusing ○ Abdominal striae ○ Cigarette paper skin ○ Poor wound healing ○ Hirsutism and acne ○ Pigmentation ○ Osteopenia ○ Back pain and fractures ○ Nephrolithiasis ○ Gonadal dysfunction ○ Females have menstrual irregularity ○ Males have less testicular testosterone ○ Hypertension ○ Psychiatric disturbances ○ Ocular involvement ○ Glaucoma, cataracts, exophthalmos ○ Visual field defects (pituitary macroadenoma) ○ Impaired immune response ○ Growth Retardation
Why does Cushings cause Glucose intolerance?
○ Cortisol excess promotes the synthesis of glucose in the liver from amino acids liverated by protein catabolism
○ This increased gluconeogenesis occurs via stimulation of the enzyme Glucose 6 phosphatase and phosphoenolpyruvate carboxykinase ○ Cortisol also antagonises the actin of insulin in peripheral glucose utilisation possibly by inhibiting glucose phosphorylation
What are the characteristics of Diabetes in Cushings syndrome?
○ Overt diabetes occurs in 10-15% of patients with Cushings syndrome
○ They have insulin resistances, ketosis and hyperlipidaemia
○ Acidosis and microvascular complications are rare
What causes Muscle wasting in Cushings syndrome?
○ Result of excess protein catabolism
○ Decreased protein synthesis
○ Induction of insulin resistance in a muscle via a post insulin receptor defect
○ Proximal muscle weakness occurs in about 60% of cases
○ Usually manifested by difficulty in climbing stairs or rising from a chair or bed without arms
○ Fatigue when combing the hair is also seen.
Why is there increased weight gain in Cushings syndrome?
○ Result of excess protein catabolism
○ Decreased protein synthesis
○ Induction of insulin resistance in a muscle via a post insulin receptor defect
○ Proximal muscle weakness occurs in about 60% of cases
○ Usually manifested by difficulty in climbing stairs or rising from a chair or bed without arms
○ Fatigue when combing the hair is also seen.
Why is there increased weight gain in Cushings syndrome?
○ Plasma leptin levels are significantly elevated- probably as a result of the visceral obesity
○ Glucocorticoids may act on adipose tissue to increase leptin synthesis and secretion
○ Chronic hypercortisolism may also have an indirect effect via associated insulin resistance
○ Intra abdominal fat seems to have a higher density of glucocorticoid receptors
Why are there skin changes in Cushings Syndrome?
○ Glucocorticoid excess inhibits fibroblasts leading to loss of collagen and connective tissue
○ This leads to thinning of the skin, abdominal striae, easy bruising and poor wound healing
○ Atrophy leads to a translucent appearance of the skin
○ Cutaneous atrophy is best appreciated as a fine cigarette paper wrinkling on the hand or over the elbow
○ On the face corticosteroid excess causes perioral dermatitis
○ Small follicular papules on an erythematous base around the mouth and rosacea like eruption
○ Central facial erythema
○ Loss of subcutaneous tissue with hypercortisolism leads to facial telangiectases and plethora over the cheeks
○ Striae also caused from increased subcutanous fat deposition that stretches the thin skin and ruptures subdermal tissues- they are depressed below the skin surface because of the loss of subcutanous connective tissue
○ In ectopic ACTH syndrome- hyperpigmentation can occur because some of the elevated ACTH is converted to melanocyte stimulating hormone- rare in cushings.
Why do people get osteopenia in Cushings Syndrome?
○ Excessive glucocorticoids inhibits bone formation and accelerates bone resorption
○ Exert direct effects on the main cell types that regulate bone metabolism
○ Inhibit osteoblast differentiation
○ Induce osteoblast and osteocyte apoptosis whilst prolonging osteoclast survival
○ Leads to a state of hypogonadism which reduces the beneficial effects of sex hormones on bone strength
○ Decreases intestinal Ca absorption and increases urinary excretion by inhibiting the effects of vitamin D as well as decreased hydroxylation of vitamin D in the liver
○ Secondary increase in PTH secretion accelerating bone resorption
○ Combination of decreased bone formation and increased resorption leads to loss in bone mass (osteoporosis) and increased risk of fracture
Why do people get kidney stones in cushings syndrome?
○ Excess glucocorticoids leads to increased Ca resorption from bone and to its increased excretion in the urine.
○ Kidney stones occur in about 15% of patients causing such patients to present with renal colic
○ Also reduce the renal tubular reabsorption of phosphate leading to phosphaturia and reduced phosphorus concentrations
Why do people get Gonadal dysfunction in Cushings?
○ Females get menstrual irregularity due to inhibition of hypothalamic GnRH
○ due to increased adrenal androgens and cortisol
○ Males have decreased testicular testosterone leading to decreased libido and impotence as well as loss of body hair due only to increased cortisol
○ Due to inhibition of hypothalamic GnRH which then inhibits normal LH and FSH pulsatility
Why do people get hypertensive in Cushings syndrome?
○ Occurs in 80% of cushings
○ Increased alt and water retention from the mineralocorticoid effects of the excess glucocorticoid - in high concentrations they escape inactivation by the kidney
○ Increased secretion of angiotensinogen - due to direct stimulatory effect of glucocorticoids on the hepatic synthesis (Renin levels are normal or suppressed in cushings )
○ Increased Endothelin and a decrease in nitric oxide predisposing to vasoconstriction
○ Increase a-adrenergic receptor density
What are the psychiatric disturbances that people experience in Cushings disease and why?
○ Depression, irritability, emotional lability
○ Euphoria, hypomania
○ Psychosis
○ Impaired cognitive function
○ Sleep disorders
○ Mechanism not well understood
Possibly loss of synapses in the prefrontal lobe. Decrease in neurogenesis and increase in olgiodendrogenesis
Why do people get Ocular involvement in Cushings syndrome?
○ Mild to moderate elevations of intraocular pressure and glaucoma related to swelling of collagen strands in the trabecular meshwork
○ This interferes with aqueous humour drainage
○ Posterior sub capsular cataracts may develop
○ Pituitary adenomas may also put pressure on the optic chiasm
○ Microadenomas should not cause visual field defects.
Why do people with Cushings syndrome have an impaired immune response?
○ Glucocorticoid excess suppresses the normal inflammatory response
○ Patients are more susceptible to infections especially those with a cell mediated immune response such as TB, fungal or pneumocystis infections
Why do children with Cushings get Growth Retardation?
○ Direct inhibition of bone cells and a decrease in growth hormone and TSH secretion as well as decreased somatomedin generation
○ Glucocorticoids suppress growth by exerting direct effects on the growth plate
○ Inhibits mucopolysaccharide production resulting in reduced cartilaginous bone matrix and epiphyseal proliferation
What is the diagnostic process for cushings syndrome?
○ Do they have consistent clinical features that are multiple and progressive?
○ Exclude exogenous glucocorticoids
○ Perform the following tests
○ 24 hour urinary free cortisol (repeated 3 x)
○ Midnight salivary cortisol level (repeated 3 x)
○ Low dose dexamethasone suppression test
○ If both tests are negative = unlikely but can re test in 6 months if pre test probability is high
○ If one is abnormal- causes for the syndrome should be sought
○ If both abnormal the diagnosis is confirmed and further investigations should be undertaken to find the cause
○ High dose Dexamethasone suppression testing (8mg)
○ CRH test
○ Imaging
○ MRI for a pituitary adenoma
○ MRI/CT for ectopic ACTH syndrome
○ CT for Adrenal Tumour
What is a urinary free cortisol excretion test and how is it done?
○ Measures unbound cortisol - not effected by conditions and medications that alter cortisol binding globulin (such as oral oestrogen)
○ Requires an accurate 24 hour collection of urine- total volume and creatinine
○ False negatives occur once the eGFR is < 60mL/min
○ Interpretation of result depends on upper limit of normal for the particular assay being used
○ Due to variability it should be repeated 3 times
What’s the normal circadian rhythm of cortisol?
○ Level begins to rise at 3-4am and then reaches a peak at 7-9am
○ Falls for the rest of the day to very low levels when the person in unstressed and asleep at midnight
What are the circadian abnormalities of cortisol in cushings syndrome and how can they be used in tests?
○ There is a loss of rhythm with the absence of the late night cortisol low
○ This is the basis for the measurement of midnight salivary cortisol level
○ The morning cortisol peak is unable to be suppressed by supra-physiological doses of glucocorticoid
○ This forms the basis of the dexamethasone suppression test.
What is the salivary cortisol test?
How is it performed?
What is the normal value?
○ Biologically free cortisol in the blood is equal to that in the saliva
○ Salivary production does not appear to change the concentration
○ Normal subjects have a midnight level of < 4nmol/L
○ Values > 4 are consistent with Cushings syndrome
○ Easily performed and non invasive
○ Collected either by passive drooling into a tube or placing a cotton bud in the mouth and chewing for 1-2 minutes
○ Should be performed on 3 separate occasions
What is a Dexamethasone suppression test?
○ Two forms of low dose dexamethasone suppression test which give roughly the same results
○ Overnight 1mg test ○ Given at midnight ○ Blood drawn at 8-9am the next day ○ Normal response is < 50nmol/L because the early morning circadian peak is suppressed ○ 48 hour 2mg/day test ○ Oral administration of 0.5mg at 6 hourly intervals ○ Followed by drawing of blood for cortisol level, 6 hours after the last dose at 9am ○ Normal response is < 50 nmol/L due to early morning circadian peak suppression
How can a Dexamethasone suppression test be used to determine cause of problem?
○ Normal anterior pituitary coricotrophs , pituitary basophilic adenomas and non pituitary neoplasms can secrete ACTH
○ Cells in each of these tissues vary in their responsiveness to ciruclating cortisol
○ Normal pituitary cells are extremely sensitive and are suppressed by physiological amounts of Glucocorticoid ie 1mg
○ Pituitary adenomas are still composed of corticotrophs- but they are less sensitive. They can still be suppress by glucocorticoids however they need about 8mg
○ Non pituitary neoplasms that produce ACTH are not composed of corticotrophs and therefore are NOT suppressed by any mount of Glucocorticoid
How much of cortisol is bound to plasma proteins?
90%
Once Cushings syndrome has been confirmed what is the next investigation that should be performed?
How would the results be interpreted?
What would the results be in Cushings DISEASE?
What would the results be with autonomous adrenal tumours?
○ A 9am plasma ACTH level to determine if the cause is ACTH dependent or independent
○ An elevated or inappropriately normal ACTH level is consistent with ACTH dependent causes ○ Undetectable or low-normal ACTH level is consistent with an ACTH independent (usually adrenal) cause ○ In cushings disease, 50% of people have ACTH within the normal range, 50% is ELEVATED ○ In patients with autonomous adrenal tumours the plasma ACTH is undetectable
If 9am plasma ACTH is elevated what would the possible diagnosis be?
How would you distinguish them from each other?
○ ACTH secreting adenoma (cushings disease)
○ Ectopic ACTH syndrome
Can be distinguished by using
Dexamethasone suppression test
○ In cushings disease there is an element of negative feedback so high doses of dexamethasone suppresses ACTH and therefore cortisol ○ In 90% of cushings disease the second plasma level will be <50% of the baseline level ○ Unfortunately 10% of patients with ectopic ACTH syndrome will have the same result
Corticotrophin releasing hormone test
○ This test stimulates the pituitary secretion of ACTH and hence cortisol ○ In cushings disease this response is exaggerated ie a 100% increase in ACTH and a 50% increase in cortisol ○ In ectopic ACTH syndrome or adrenal neoplasms this dramatic response is ABSENT
What is inferior petrosal sinus sampling
When would you use it?
What do the results mean?
○ This is the most robust way of distinguishing Cushings disease from an ectopic ACTH syndrome
○ Most costly and technically demanding
○ Blood from each half of the pituitary drains into the ipsilateral inferior petrosal sinus
○ Catheterisation of both with sampling can distinguish the cause
○ In cushings disease the sinus ACTH is more than the peripheral and ipsilateral is usually more than contralateral
○ In ectopic ACTH the sinus ACTH is equal to the peripheral
Use:
More making the differential between ACTH dependent cushings syndrome AFTER high dose dex testing and peripheral CRH testing have not been conclusive.
What test results would point towards a pituitary ACTH secreting tumour?
What Imaging would you order?
○ If the plasma ACTH is normal or elevated
○ The high dose dexamethasone suppression test shows >50% suppression of the morning cortisol
○ The CRH test causes significant increase in the secretion of ACTH (100%) and cortisol (50)
○ MRI would be ordered
What test results would point towards a non pituitary ACTH secreting tumour?
What imaging would you order?
○ The plasma ACTH is elevated
○ The high dose dexamethasone test shows LESS than 50% suppression of the morning cortisol
○ The CRH test causes NO increase in the secretion of ACTH and cortisol
○ A MRI/CT can be ordered
○ 2/3 of the ectopic ACTH secreting tumours occur in the chest so this cavity should be imaged first
What test results would point towards a Primary Adrenal tumour?
What imaging would you order?
○ If plasma ACTH is low normal or undetectable
○ CT should be ordered rather than MRI
○ They are large and often associated with metastatic spread at presentation
What is the treatment for Cushings Disease?
○ Trans-sphenoidal surgery
○ Remission rate is 75%
○ Recurrence 25% within 10 years
○ Hydrocortisone 25 mg mane
○ In some patients they develop adrenocortical insufficiency following removal of the adenoma and the ACTH and cortisol levels become undetectable
Glucocorticoid replacement therapy is then required until the axis is recovered
○ Monthly measurement of 8am plasma cortisol after the hydrocortisone has been omitted for 24 hours
What is the treatment of ectopic ACTH syndrome?
○ Depends on the cause
○ Treatment of the primary tumour
○ Prognosis for small cell lung cancer associated with the syndrome is poor
○ If the source cannot be found then consider bilateral adrenalectomy.
What is the treatment of Adrenal Tumours?
○ Adrenalectomy even though metastasis may be present
○ 100% cure rate
○ May take many years for the suppressed adrenal to recover. In these casesglucocorticoid therapy is required
○ Monthly 8am plasma cortisol monitoring when it has been omitted for 24 hours
○ Poor prognosis - most people die within 2 years
What are some medical treatments that can be used regardless of the Cushign syndromes cause?
○ Metyrapone
○ Ketoconazole
○ Mitotane (in adrenocortical carcinoma)
○ Act by inhibiting steroid biosynthesis in the adrenal cortex
○ Can be used regardless of the cushings syndromes cause
○ Not curative
○ Lead to rapid improvement in the clinical features of Cushings by reducing the secretion of cortisol
○ This can be used whilst awaiting definitive treatment
○ Aim is to use the smallest dose that will normalise the 24 hour urinary free cortisol
What is the broad definition of Addisons Disease?
What hormones are involved?
- Adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex
- All three groups of hormones are affected- mineralocorticoids, glucocorticoids and androgens
What is the Zona Glomerulosa?
What Hormone does it produce?
- It is the layer of the adrenal gland that is most superficial and lies underneath the capsule
- Produces aldosterone through aldosterone synthase CYP11B2
- The activity of aldosterone synthase is controlled by circulating angiotensin II and to a lesser extend Potassium
- Does not make androgens or cortisol- lacks the enzymes needed.
What is the Zona Fasciculata?
What does it produce?
- The middle and widest later
- Makes up about 75% of the cortex
- Secretes Glucocorticoids - mainly CORTISOL
- Activity is regulated by the hypothalamic-pituitary adrenal axis via ACTH
What is the Zona Reticularis?
What does it secrete?
- The deepest layer of the adrenal cortex
* Secretes androgens as well as oestrogens in small amounts
What are primary and secondary causes of Hypoadrenocorticosteroidism?
Primary Adrenal Insufficiency:
• Dysfunction or destruction of the adrenal cortex itself= Addisons disease
Secondary Adrenal Insufficiency:
* Dysfunction within the hypothalamus with failure to produce enough CRH * Dysfunction within the anterior pituitary with failure to produce enough ACTH
What are some causes of secondary hypoadrenocorticosteroisism?
- Mass lesions- tumours
- Radiation
- Infiltrative lesions such as sarcoidosis or haemachromatosis
- Infection or abscess- TB
- Infarction- sheehans syndrome
- Genetic mutatinons
- Empty sella
- Trauma or stroke
How do primary and secondary causes of hypoadrenocorticosteroidism affect aldosterone and androstenedione?
- Primary insufficiency will result in the under secretion of these hormones
- Secondary causes should have little effect
What happens to cortisol and ACTH levels in Addisons disease?
How does this effect the skin?
- Decreased production of cortisol
- Less feedback inhibition of hypothalamus and pituitary
- Increase in levels of ACTH
- Increased pigmentation
