Adrenal gland diseases

Done by Mayar Alatrash

Anatomy

Pyramidal in shape. 3- 5 cm in height , 3 cm in width , less than 1 cm thick, Mass 3.5 - 5 g

The adrenal gland is divided into 2 areas, the cortex and medulla.

The cortex is divided into 3 areas: GFR

- the outer zone (glomerulosa): aldosterone synthesis

- the central zone (fasciculata): cortisol synthesis

- the inner zone (reticularis): androgen biosynthesis.

The adrenal medulla is an extension of the sympathetic nervous system that secretes catecholamines into capillaries rather than synapses.

Physiology Mineral corticosteroid (most important is aldosterone )

Its function can explain as part of RAAS

K+ &

proton

excretion

The principle stimulus

hypovolemia or renal

artery stenosis

Glucocorticoids , so most cortisol in the blood is bound to a special soluble hormones-lipid

carrier protein, called cortisol-binding globulin, and only about 5% is unbound or free (biologically active) , have to stay within the normal range, Using negative feedback .

, when peak in the morning. Cortisol levels circadian rhythmit’s part of the , drop in the eveningthe body knows we need to “get up and go” and then

when we’re preparing for sleep.

substrates plenty of energy , the body needs to have In times of stressaround, so cortisol increases gluconeogenesis , proteolysis and lipolysis.

helps to maintain the blood pressure by increasing the sensitivity of peripheral blood vessels to catecholamines , and this narrows the blood vessel lumen.

helps to dampen the inflammatory and immune response

cortisol receptors are present in the brain, might influence mood and memory.

Adrenal androgens ACTH

They are probably important in the initiation of puberty (adrenarche).

For males promote prostate growth and give masculine characteristic (hair growth and deep voice )

For females important in libido

Catecholamines SNS

Small proportion of NA from medulla, remaining from sympathetic nerve endings

Major source of Adrenaline

Conversion of NA to Adrenaline by Catechol-O-MethylTransferase (COMT), which is induced by glucocorticoids.

Cushing syndrome

named after the famous neurosurgeon, Harvey Cushing who first described it

Elevated cortisol levels in the blood , constantly higher than normal = loss of

circadian rhythm.

Clinical features

1) Increase breakdown of most types of tissues :

muscle wasting and thin extremities

skin thinning

Easy bruising

Abdominal striae(Thick purple striae, greater than 1cm in diameter)

Bone thinning (osteoporosis) increase risk of fractures

2)Fat redistribution :

Round ,full moon shaped face

Buffalo hump

Truncal obesity- central obesity

3) Hypertension

for two reasons. First, they amplify the effect of catecholamines on blood vessels. Second, cortisol starts cross-reacting with mineralocorticoid receptors.

4) Hyperglycemia DM

5) Suppress immune system increased risk for infection (fungal)

6) inhibit the secretion of GRH, which messes up normal ovarian and testicular function.

7) high levels of cortisol seem to impair normal brain function but the exact mechanism of that is unclear.

What are the causes ?

Causes of Cushing syndrome

Exogenous Endogenous

ACTH dependent

80%

Pituitary adenoma=

Cushing disease

Ectopic ACTH secretion (SC

lung carcinoma

ACTH independent

20%

Adrenal adenoma

Adrenal carcinoma

Variation in clinical features ! some common disorders can be confused with Cushing’s syndrome because they are associated with alterations in cortisol secretion, e.g. obesity and depression

Features that favor Cushing’s syndrome in an obese patient are bruising, myopathy and thin skin.

An 0800–0900-hr serum cortisol of < 100 nmol/L (3.6 μg/dL) in a patient with a normal sleep–wake pattern and Cushingoid appearance is consistent with exogenous synthetic glucocorticoid use (common) or cyclical secretion of cortisol from endogenous Cushing’s (uncommon).

Ectopic ACTH secretion not affected by negative feedback like Cushing disease , resulting in higher levels of both ACTH and cortisol marked pigmentation , hypokalemic alkalosis that aggravates myopathy and hyperglycemia (by inhibiting insulin secretion).

Malignant onset is usually rapid and may be associated with cachexia , the classical features of Cushing’s syndrome are less common in ectopic ACTH syndrome; if present, they suggest that a less aggressive tumor, such as a bronchial carcinoid

In Cushing’s disease, the pituitary tumor is usually a microadenoma (< 10 mm in diameter); hence other features of a pituitary macroadenoma (hypopituitarism, visual failure or disconnection hyperprolactinemia

Causes of Cushing syndrome

Exogenous Endogenous

ACTH dependent

80%

Pituitary adenoma=

Cushing disease

Ectopic ACTH secretion (SC

lung carcinoma

ACTH independent

20%

Adrenal adenoma

Adrenal carcinoma

First step

Second step

Some confirmations

To diagnose .. Start with HX

to exclude this

Third step

First step ( Is it Cushing syndrome ?!)

1) Late night salivary cortisol level

>2 ng/ml ..BUT not best first choice for whom ??

2) 24h urinary free cortisol level - normal 3.5-45 mcg/24 hours –

> 3X the upper limit of normal

For 1 & 2 we need 2 abnormal result to confirm Cushing’s

3) Low – dose or overnight dexamethasone suppression test

LDDST administration of 0.5 mg of dexamethasone( start at 9 am ) every 6 h for 48h (total 4 mg) then check serum cortisol level

ONDST administration of 1 mg dexamethasone at 11 pm

then checking cortisol serum level between 8 & 9 am

it’s Cushing when serum cortisol level in both >1.8mcg/dl

Keep in your mind any estrogens should be stopped 6 weeks prior

to investigation , to avoid false positive

response .

Second step ( Ok It’s Cushing , but what is the cause ?)

* Serum ACTH level :

> 15 ng/L ACTH dependent

<5 ng/L ACTH independent

Third step (ACTH dependent )

High dose dexamethasone suppression test

Measure serum cortisol at 8 am , then give 8 mg

Of dexamethasone at 11 pm , then measure

Serum cortisol at 8 am of the following morning.

Serum cortisol 50% lower than the previous day indicative of Cushing disease.

But , its recommended to confirm the DX

- CRH stimulation test

- Bilateral inferior petrosal sinus sampling

- Brain MRI or thorax abdomen and pelvis CT or MRI

The idea here that high doses of dexamethasone

are able to suppress pituitary ACTH secretion,

but not ectopic ACTH

CRH stimulation test

Administration of 100 mg hCRH IV , serum ACTH and cortisol samples obtained before and 45min after the injection.

>20% rise in cortisol or > 50% rise in ACTH indicative of Cushing disease.

BIPSS

Catheter is inserted in the LT & RT jugular or femoral veins , and advanced all the way up to LT&RT inf. Petrosal sinuses ( drain the blood from the pituitary ) , CRH injected , ACTH samples obtained from peripheral veins and petrosal sinus before and 10min after the injection

Inf. Petrosal sinus ACTH : peripheral veins ACTH > 2:1 before the injection or > 3:1 after the injection indicative of Cushing disease.

Brain MRI if Cushing disease is suspected or thorax abdomen and pelvis CT or MRI if ectopic ACTH is suspected

Third step (ACTH independent )

Adrenal adenoma or carcinoma

- Clinical signs

- abd.CT

Some clinical signs of an adrenal carcinoma include age below 10, or over 50, as well as signs of androgen excess in women - like acne, hirsutism, and deepening of the voice, which are not usually present with adenomas.

Also, on an abdominal CT, adrenal carcinomas usually have necrosis, hemorrhage, and calcifications, whereas adenomas typically don’t.

Management Cushing disease

the tumor can be removed through transsphenoidal resection

If the entire tumor can’t be removed, then radiation therapy may also be used to eliminate the tumor.

, months and three years for hypercortisolism to disappear6 between However, it may take anywhere and during this time, drugs that block the adrenal synthesis of cortisol, like metyrapone may be used to control the symptoms.

surgically remove both adrenal , a last resort is to medications aren’t sufficient to block cortisol effectsIf lifelong substitution therapy with glucocorticoid and mineralocorticoid . In that situation, glands

hormones is needed.

Ectopic ACTH secretion

treatment here depends on the kind of tumor it is, and its stage.

Adrenal adenoma

laparoscopic adrenalectomy of the affected adrenal gland.

Adrenal carcinoma

usually an open adrenalectomy, and nearby lymph nodes are often removed as well.

If the carcinoma is invasive, then surgical resection of nearby organs, like the kidney, liver, or spleen may be needed.

Exogenous tapering of glucocorticoids

** when surgery contraindicated or unsuccessful , or pt. is awaiting surgical treatment , medical therapy is appropriate (Adrenal enzyme inhibitors like ketoconazole)

Hyperaldosteronism

.aldosteronethe adrenal gland produces above normal levels of the hormone

Primary hyperaldosteronism independent of RAAS

- bilateral adrenal hyperplasia (idiopathic hyperaldosteronism)

- aldosterone-producing adenoma (APA; Conn’s syndrome)

- Glucocorticoid-suppressible hyperaldosteronism (rare)

Secondary hyperaldosteronism Renin induced

- Inadequate renal perfusion (diuretic therapy, cardiac failure, liver

- failure, nephrotic syndrome, renal artery stenosis)

- Renin-secreting renal tumor (very rare)

Decrease K & Proton

(hypokalemia , increase PH , metabolic alkalosis ?)

Increase Na &H2O

( hypernatremia , increase blood volume and pressure )

High aldosterone

Clinical features

- Usually asymptomatic

- Hypertension, but accelerated phase hypertension is rare.

- HTN related symptoms ( headache , fascial flushing , fatigue)

- Hypokalemia related symptoms ( weakness , polyuria (secondary

nephrogenic diabetesto renal tubular damage, which produces

(because of associated metabolic tetany) and occasionally insipidus alkalosis and low ionized calcium).

Diagnosis

1- primary or secondary ?

2- confirm primary

3- the cause of primary

primary or secondary ? (plasma aldosterone to renin ratio)

confirm primary ( saline infusion test or oral sodium loading )

the cause of primary

Management Mineralocorticoid receptor antagonists (spironolactone and eplerenone) are valuable in treating both hypokalemia and hypertension in all forms of mineralocorticoid excess.

Up to 20% of males develop gynecomastia on spironolactone. Amiloride

regulated by blocks the epithelial sodium channel mg/day), which 40 –10(aldosterone, is an alternative.

In patients with an APA, medical therapy is usually given for a few weeks to normalize whole-body electrolyte balance before unilateral adrenalectomy. Laparoscopic surgery cures the biochemical abnormality but, depending on the pre-operative duration, hypertension remains in as many as 70% of cases, probably because of irreversible damage to the systemic microcirculation.

Bilateral hyperplasia is treated with spironolactone.

Adrenal insufficiently

adrenal glands don't produce enough adrenal hormones - particularly cortisol, but sometimes aldosterone can be deficient as well.

Adrenal insufficiency

Primary

(Addison’s disease )

problem with the adrenal glands

themselves.

Both cortisol and aldosterone are

deficient

Secondary

insufficient pituitary ACTH production.

( Pituitary )

Only cortisol is deficient

Tertiary

insufficient CRH production

(Hypothalamus)

Only cortisol is deficient

Primary adrenal insufficiency causes 1) Autoimmune most common cause in industrialized countries . by its own or part of polyglandular autoimmune syndrome type 1 or 2

at least two rare immune endocrinopathies characterized by the coexistence of that are based on autoimmune mechanisms. endocrine gland insufficiencies

may occur. nonendocrine immune diseases Associations with Three subtypes , two of them have adrenal involvement

-Type 1 : usually appears in childhood at age 3–5 yr. or in early adolescence and, therefore, is also called juvenile autoimmune polyendocrinopathy , It is defined by a persistent fungal infection (chronic mucocutaneous candidiasis), the presence of acquired hypoparathyroidism, and adrenal failure (Addison’s disease) most individual have primary hypogonadism .

- Type 2 :more common and occurs in adulthood, mainly in the third or fourth decade, It is characterized by primary adrenal failure (Addison’s disease) with autoimmune thyroid disease (Schmidt’s syndrome) and/or type 1 diabetes (Carpenter’s syndrome). other disorders like immunogastritis , pernicious anemia, and alopecia areata.

2) Infectious most common cause worldswide TB / HIV / disseminated fungal infection 3) Adrenal metastases from lung, breast, stomach and colon cancer, or lymphoma. 4) Iatrogenic : Bilateral adrenalectomy 5) Adrenoleukodystrophy is an inherited disease that predominantly affects young males. In this

, and they very long chain fatty acids accumulate in various tissuesdisease, , causing affect the central nervous system and the adrenal cortexparticularly

learning disabilities, seizures, and the development of blindness and quadriparesis 6) Congenital adrenal hyperplasia. 7) Drugs: metyrapone, ketoconazole, etomidate

8) Intra-adrenal hemorrhage (Waterhouse–Friderichsen syndrome following meningococcal sepsis) 9) Amyloidosis 10) Haemochromatosis

Secondary adrenal insufficiency causes

patients on long tem steroid therapy (chronic CRH and ACTH inhibition )

Hypopituitarism

Tertiary adrenal insufficiency causes Hypothalamic causes

Most frequently, individuals have chronic symptoms which may or may not go unnoticed, and then some sort of stress ,like:

serious illness/ during febrile / after trauma / during surgery etc.

precipitates an Adrenal crisis.

Its presentation

circulatory shock with severe hypotension, hyponatremia, hyperkaliemia and, in some instances, hypoglycemia and hypercalcemia. Muscle cramps, nausea, vomiting, diarrhea, unexplained fever and mental status changes.

Patients with suspected acute adrenal crisis and with circulatory compromise treatment SHOULD NOT be delayed

random blood sample should be stored for subsequent measurement of serum cortisol and, if possible, plasma ACTH, then start your treatment!

if the patient’s clinical condition permits or present with features suggestive of chronic adrenal insufficiency , it may be appropriate to

before minutes performing a short ACTH stimulation test 30 spend administering hydrocortisone

Adrenal insufficiency?

Plasma cortisol level

Low

< 18 mcg/dl

Serum ACTH ,

Aldosterone , Renin

↑ ACTH ↓aldosterone ↑renin

Primary adrenal insufficiency

ACTH stimulation test (to confirm)

↓ACTH

Aldosterone and renin are normal

Central adrenal insufficiency

CRH stimulation test ( secondary or tertiary ?)

Normal

>18 mcg/dl

ACTH stimulation test

give 250 mcg of Cosyntropin, which is the synthetic analog of ACTH, and the serum cortisol is taken before ACTH is given, and 30 min later.

Serum cortisol levels > 18 mcg/dl before or after the ACTH injection rule out adrenal insufficiency.

On the other hand, if serum cortisol is < 18 stay the same , and cortisol levels mcg/dl

following Cosyntropin administration, that confirms primary adrenal insufficiency.

If they rise, that means the adrenals are responding properly to ACTH, so the issue is central, either with the pituitary or the hypothalamus.

CRH stimulation test

Give a CRH injection, and ACTH is measured four times - 5 minutes before the CRH injection, then again when the injection is given, and then 15 minutes later, and finally 30 minutes later.

No rise in serum ACTH compared to the basal value points towards a pituitary, or secondary adrenal insufficiency .

if serum ACTH increases, then the hypothalamus is to blame - so tertiary adrenal insufficiency.

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Head MRI for further identification of each one cause

OK , consider it is Addison's disease , what is the cause?

To know we will do the following work up

1) serum anti-adrenal antibodies, particularly anti-21-hydroxylase Autoimmune

2)Chest X-ray and a tuberculin skin test TB anti tuberculosis medications

3) Screening for an HIV infection with PCR or with antibody-antigen tests. If an HIV infection is the cause, antiretroviral therapy should be initiated.

enlarged adrenal glands that may have ) abdominal CT can identify 4, like with disseminated fungal infectionwhich is evidence of a -calcifications

Histoplasma capsulatum, which causes histoplasmosis, or Paracoccidioides brasiliensis, which causes paracoccidioidomycosis Treatment here is antifungal medication.

treatment depends on adrenal metastases identifyA CT scan can also identify the source of the primary tumor.

Management Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid therapy.

There is some evidence that adrenal androgen replacement may also be beneficial in women.

Other treatments depend on the underlying cause.

Glucocorticoid replacement Adrenal replacement therapy consists of oral hydrocortisone (cortisol) 15–20 mg daily in divided doses, typically 10 mg on waking and 5

physiological . These are hrs00 :15mg at around that should not cause replacement doses

Cushingoid side-effects.

The dose may need to be adjusted for the individual patient but this is subjective.

Excess weight gain usually indicates overreplacement.

while persistent lethargy or hyperpigmentation may be due to an inadequate dose or lack of absorption.

Measurement of serum cortisol levels is not usually helpful.

Mineralocorticoid replacement Fludrocortisone (9α-fluoro-hydrocortisone) is administered at the usual dose of 0.05–0.15 mg daily. Adequacy of replacement may be

measurement of blood assessed by and plasma electrolytes , pressure

.plasma renin It is indicated for virtually every patient with primary adrenal insufficiency but is not needed in secondary adrenal insufficiency.

Androgen replacement Androgen replacement with DHEAS (50 mg/day) is occasionally given to

primary adrenal women with who have symptoms of insufficiency

reduced libido and fatigue, but the evidence in support of this is not robust Treatment may be associated with side-effects such as acne and hirsutism.

Thank you