THE ADRENAL GLANDS.

1 THE ADRENAL GLANDS ...
Author: Scot Mason
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1 THE ADRENAL GLANDS

2 Anatomy -paired organs adjacent to the kidneys, containing: a cortexa medulla→epinephrine (E), norepinephrine (NE), small amounts of dopamine The adrenal cortex – 3 functional and morphological different zones: - glomerulosa secreting mineralocorticoids-Aldosterone, DOC(deoxycorticosterone) - fasciculata secreting glucocorticoids(cortisol) and androgens -reticularis secreting adrenal androgens ( dehydroepiandrostenedione (DHEA), DHEA sulfate and androstendione ) and cortisol

3 Regulation of the adrenal secretionGlucocorticoid and androgen production ( the zonae fasciculata and reticularis) are under the control of ACTH, which regulates both steroid synthesis and also adrenal growth; excess or deficiency of this hormone alters their structure and function → ↑ ACTH: hyperplasia and hypertrophy of these zones occur+ ↑production of cortisol and androgens → ↓ ACTH:both zones atrophy +↓production of cortisol and androgens !!! Only cortisol is responsible of the negative FB on the CRH and ACTH secretion CRH ACTH CORTISOL

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5 REGULATION OF THE ADRENAL SECRETIONThe adrenal androgens, DHEA, DHEA-sulfate, androstendione have minimal intrinsic androgenic activity, and they contribute to androgenity by their peripheral conversion to the more potent androgens testosterone(T) and DHT. The synthesis of aldosterone by the zona glomerulosa is primarily regulated by- the renin-angitensin system (RAS) - potassium - (lesser extent ACTH ) → in ACTH deficiency- aldosterone secretion remains normal except in a few cases.

6 ADRENOCORTICAL INSUFFICIENCY (ADDISON’S DISEASE)

7 ADRENOCORTICAL INSUFFICIENCY= deficient adrenal production of glucocorticoids or mineralocoricoids results in adrenocortical insufficiency (ACI) CLASSIFICATIONS According to the location of lesion Primary ACI← either the consequence of destruction or dysfunction of the cortex Central ACI ←secondary to deficient pituitary ACTH secretion ! Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency According to evolution Chronic ACI Acute ACI

8 ACI ETIOLOGY PRIMARY ADRENOCORTICAL DISEASE (ADDION’S DISEASE)TUBERCULOSIS ( prior to 1920, was the major cause ) AUTOIMMUNE Sporadic APS, type I: hypoparathyroidism, chronic mucocutaneous candidiasis, adrenal insufficiency, gondal failure, hypothyroidism, DM type 1, DI+ nonendocrine diseases: alopecia, pernicious anemia, chronic active hepatitis APS type II: adrenal insufficiency, autoimmune thyroid disease, gonadal failure, DM type1, DI+ celiac sprue, vitiligo, pernicious anemia, myastenia gravis (also known as Schmidt’s syndrome) RARE CAUSES Metastatic adrenal disease (lung cancer, non-Hodgkin’s and Hodgkin’s lymphoma) Other infections – fungi, CMV, HIV Infiltrations: amyloidosis, hemochromatosis Intra-adrenal hemorrhage ( when Addison’s disease is caused by meningococcus, the association with adrenal insufficiency is known as Waterhouse-Friderichsen syndrome) after menngococcal septicemia Bilateral adrenalectomy or drugs : ketoconazole, mitotane

9 ACI ETIOLOGY CENTRAL (SECONDARY) ADRENOCORTICAL INSUFFICIENCY ( see hypotalamus-pituitary section) ACUTE ADRENOCORTICL INSUFFICIENCY ( INFANTS CONGENITAL ADRENAL HYPOPLASIA CONGENITAL ADRENAL HYPERPLASIA (←defects in several enzymes implicated in the steroid biosynthetic pathways e.g 21 hydroxylase deficiency) ADRENAL HEMORRHAGE ADRENAL VEIN TROMBOSIS BILATERAL ADRENALECTOMY

10 CLINICAL FEATURES IN ADDISON’S DISEASEPRIMARY ADRENOCORTICAL INSUFFICIENCY 1.Hyperpigmentation (=the classic physical finding) of the skin and mucous membranes 2.weakness and fatigue 3.gastrontestinal disturbances: nausea, vomiting, diarrhea or constipation, abdominal pain, salt craving 4.anorexia, weight loss 5.hypotension, postural hypotension; + orthostatic symptoms: dizziness and ocasionally syncope 6.hypoglycemia (sweats, tremor, headache 7.irritability, emotional instability, depression 8.loss of axillary and pubic hair-in women (← ↓ secretion of adrenal androgens) 9.associated conditions: vitiligo, features of other autoimmune endocrinopathies

11 SECONDARY ADRENOCORTICAL INSUFFICIENCYhyperpigmentation is not present; the skin is pale! + /- complex clinical features (panhypopituitarism), features of underlying cause( e.g. headache, visual field defects if pituitary tumor)

12 GLUCOCORTICOID DEFICIENCYDIAGNOSIS OF ACI 1. ESTABLISHING THE DIAGNOSIS OF ACI GLUCOCORTICOID DEFICIENCY Cortisol (basal) 8a.m. <70 ng/ml; since basal levels of adrenocortical steroids in either urine or plasma may be normal in partial adrenal insufficiency ( low-normal), tests of adrenocortical reserve are necessary to establish the diagnosis. urine free cortisol ( measured in a 24-h urine collection)↓ Urinary 17-hydroxycorticosteroids ( the urinary metabolites of cortisol) (should no longer be used) < 3 mg/24h women si < 5 mg/24h in men Serum glucose ↓< 70mg/dl

13 mild acidosis, mild hypercalcemiaDIAGNOSIS OF ACI MiNERALOCORTICOID DEFICIENCY Plasma aldosterone↓or low-normal (in primary form!!!) Plasma renin activity↑(in primary form!!!) Hyponatremia and hyperkalemia are classic manifestations of glucocorticoid and mineralocorticoid deficiency and should suggest the diagnosis – K ↑ (acute adrenal crisis) ADRENAL ANDROGENS DEFICIT Plasma levels of DHEA, DHEA sulfate, androstendione ↓ Urinary 17-ketosteroids ( urinary androgen metabolites) ↓(should no longer be used) women < 7mg/24h, men <10 mg/24 h) Others ECG: low voltage, vertical QRS axis, nonspecific ST-T wave abnormalities secondary to abnormal electrolytes FBC - normocytic, normochromic anemia (← altered androgen metabolism) neutropenia, eosinophilia and a relative lymphocitosis azotemia with ↑concentration of blood urea nitrogen and serum creatinine (←volume depletion and dehydration) mild acidosis, mild hypercalcemia

14 DIAGNOSIS OF ACI 2. DIAGNOSIS OF PRIMARY AND SECONDARY FORMS OF ACIIf adrenal insufficiency is present, plasma ACTH levels are used to differentiate primary and secondary forms; ACTH plasmatic  – primary ACI ACTH plasmatic  / “low-normal”– central ACI The rapid ACTH stimulation test (250µg tetracosactide (synacthen)) / The ACTH (Synacthen) test (1 mg)

15 DIAGNOSIS OF ACI 3. TESTS FOR ETIOLOGY → TUBERCULOSISChest radiograph, tuberculin testing, and early morning urine samples cultured for Mycobacterium tuberculosis – abdominal radiograph: calcifictions of the adrenals - CT scan : may reveal enalrged or calcified glands ( this aspect is also suggestive for hemorrhagic or malignant diagnosis) → AUTOIMMUNE Test (radioimmunoassays) for autoantibodies such as those against the 21-hydroxylase antigen ( indirect information ← testing for thyroid autoantibodies) CT: small, atrophic adrenal glands → CENTRAL FORM CT/MRI of the hypotalamus –pituitary can identify the lesion

16 TREATMENT OF ADRENOCORTICAL INSUFFICIENCYreplacement treatment (life-long gluco- and mineralo-corticoid therapy) !the aim = to produce levels of glucocorticoids and mineralocorticoids equivalent to those achieved in an individual with normal HPA function under similar circumstances. MAINTENANCE THERAPY GLUCOCORTICOIDS CORTISOL ( HYDROCORTISON) is the glucocorticoid preparation of first choice mg/day in 2 doses (10-20mg/5-10mg) PREDNISONE 5-7,5(10 )mg/day  MINERALOCORTICOIDS 9--fluorocortisol (fludrocortisone) (ASTONIN H) 0.1 mg/tb ½-2 tb/day  ANDROGENS DECANOFORT 1 f/2 weeks i.m. or DHEA 50mg/day→ an improvement in well-being and sexual function in F LIFESTYLE ADVICE – ↑ in proteins, vitamine, adequate dietary sodium intake (!!!not restriction)

17 TREATMENT OF THE CHRONIC ADRENOCORTICAL INSUFFICIENCYGENERAL MEASURES –PREVENTION OF ADRENAL CRISIS The essential elements are patient education and increased glucocorticoid dosages during illness! The replacement therapy will not be interrupted for any cause!!! It is generally expected that the daily dose of hydrocortisone should be doubled (or 3*) during period of minor stress and the dose needs to be increased to as much as mg/day during periods of major stress, such as a surgical procedure; the usual maintenance dosage may be resumed in h if improvement occurs ETIOLOGIC TREATEMENT when it is possible

18 ACUTE ADRENAL CRISIS CLINIC: a state of acute ACI and occurs in patients with Addison’s disease who are exposed to stress of infection, trauma, surgery, or dehydration due to salt deprivation, vomiting or diarrhea. Abdominal pain, tenderness ( mimic an acute abdominal emergency) ( abdominal distention, rigidity and rebound tenderness are less frequent) nausea, vomiting, anorexia Fever (← infection or hypoadrenalism per se) Weakness, apathy, depressed mentation Hypoglycemia Hypotension and shock LABORATORY FINDINGS hipoNa,hiperK, hypoglycemia, urea, creatinin , hematocrit , metabolic acidosis TREATMENT Iv glucose and saline are administered to corect volume depletion, hypotenion and hypoglycemia HHC 100mg iv every 6 h for 24 h; when the patient is stable, reduce the dosage to 50 mg every 6 h; taper to maintenance therapy by day 4 or 5 and add mineralocorticoid as required

19 CUSHING’S SYNDROME

20 CUSHING’ SYNDROME = the constellation of symptoms and physical features caused by chronic glucocorticoid excess it is most commonly iatrogenic, resulting from chronic glucocorticoid therapy “spontaneous” Cushing’s syndrome is caused by abnormalities of the pituitary or adrenal or may occur as a consequence of ACTH or CRH secretion by nonpituitary tumors ( ectopic ACTH sdr, ectopic CRH sdr) ! Cushing’s disease is defined as the specific type of Cushing’ s syndrome due to excessive pituitary ACTH secretion from a pituitary tumor

21 Cushing’s syndrome: differential diagnosisACTH-DEPENDENT Cushing’s syndrome Pituitary adenoma (Cushing’s disease ) Nonpituitary neoplasm ( ectopic ACTH, CRH syndrome) Tumors causing the ectopic ACTH syndrome: small cell carcinoma of the lung (50% of cases), carcinoid tumors (lung, thymus, gut pancreas, ovary), pancreatic islet cell tumors, medullary carcinoma of the thyroid, pheocromocytoma Iatrogenic ( treatment with ACTH 1-24) ACTH-INDEPENDENT Cushing/s syndrome Adrenal adenoma and carcinoma Iatrogenic (e.g. pharmacologic doses of prednisolone, dexamethasone) Nodular adrenal hyperplasia

22 CUSHING’S SYNDROME CRH CRH ACTH ACTH   CORTISOL CORTISOL 

23 CUSHING’ SYNDROME ACTH-LIKE CRH  ACTH  CORTISOL  

24 CRH  CRH  ACTH  ACTH  CORTISOL   CORTISOL CUSHING’ SYNDROME CRH  CRH  ACTH  ACTH  CORTISOL   CORTISOL 

25 CUSHING’S SYNDROME –CLINICAL FEATURESOBESITY : weight and obesity are the commonest sign, →centripetal in nature; + patients develop fat depots over the thoracocervical spine (“buffalo hump”), in the supraclavicular region, and over the cheeks and temporal regions, giving rise to the rounded “moon-like” facies ( accompanied by facial plethora in most patients) SKIN : →thin and atrophic; easy bruisability following minimal trauma; red striae- abdominal, over the breast, hips, buttocks, thighs and axillae; acne and papular lesions. Opportunistic bacterial and fungal infections may occur; hyperpigmentation is rare in Cushing’s disease but common in the ectopic ACTH sdr (← overstimulation of melanocyte receptors by ACTH) MUSCLE : muscle weakness is more often proximal and is usually most prominent in the lower extremities (myopathy) BONE : significant osteopenia and osteoporosis → fractures, typically of the feet, ribs or vertebrae; in chilhood the commonest presentation is with poor linear growth and weight gain( !generalized obesity) CARDIOVASCULAR: hypertension is a classic feature of spontaneous Cushing’s syndrome( dBP>100mmHg ); this, togheter with the established metabolic consequences of the disease ( diabetes, hyperlipidemi..), is thought to explain the ↑ cardiovascular mortality in untreated cases; + thromboembolic events

26 CUSHING’S SYNDROME –CLINICAL FEATURESMetabolic: IGT and overt DM; ↑circulating cholesterol and triglycerides; renali calculi secondary to glucocorticoid induced hypercalciuria; CNS and psychologic disturbances: emotional lability, irritability, anxiety, depression, poor concentration, poor memory; euphoria Reproductive dysfunction In women: menstrual irregularities: oligomenorrhea, amenorrhea, hypertricosis on the face; signs of masculinization (virilization): hirsutism, alopecia, acne, amenorrhea (← usually signifies concomitent androgen excess as may occur secondary ACTH-mediated adrenal androgen secretion) In men: ↓libido, impotence+/- some degree of gynecomastia (← cortisol suppression of LH secretion →↓testosterone secretion by the testis)

27 LABORATORY FINDINGS CUSHING’s syndrom- DIAGNOSIShigh normal hemoglobin, hematocrit and red cell counts total white count –usually normal Lymphocites, eosinophils ↓ Serum electrolytes : hyper Na+, hypo K+ fasting hyperglycemia/ clinical diabetes/ abnormal glucose tolerance test metabolic alkalosis cholesterol and triglicerides=↑ Serum calcium= normal, hypercalciuria ECG← hypertensive, ischemic and electrolyte-induced changes Abdominal ultrasound : renal stones X-ray: vertebral compression fractures, rib fractures, cardiomegaly due to hypertensive or atherosclerotic heart disease

28 GLUCOCORTICOID EXCESSCUSHING’S SYNDROME GLUCOCORTICOID EXCESS a. Plasma cortisol 8 a.m. i (V.N.: 8 a.m ng/ml; nmol/l; 4-6 p.m.: nmol/l) Circadian rhytm: - is superimposed on episodic secretion; it is the result of CNS events that regulate both the number and magnitude of CRH and ACTH secretory episodes; the absence of diurnal rhytm has been considered a hallmark of the diagnosis of Cushing’ s syndrome; normally cortisol is secreted episodically with a diurnal rhytm paralleling the secretion of ACTH; levels are usually highest early in the morning and ↓ gradually throughout the day, reaching a nadir in the late evening. Disrupted (abnormal) circadian rhytm: is carachterized by failure to ↓ cortisol secretion during the evening

29 +/- ANDROGEN EXCESS b. Diurnal rhytm of cortisol (8ºº, 18ºº)SINDROMUL CUSHING b. Diurnal rhytm of cortisol (8ºº, 18ºº) c. Urinary 17-hydroxycorticosteroids ( the urinary metabolites of cortisol) (should no longer be used) ↑ d. Urinary free cortisol- the assay of unbound cortisol excreted in the urine is an excellent method for the diagnosis of Cushing’s sdr (24h urine collection)→ the method is particularly useful in differentiating simple obesity from Cushing’s sdr +/- ANDROGEN EXCESS Plasma levels of DHEA, DHEA sulfate, androstendione ↑ Urinary 17-ketosteroids ( urinary androgen metabolites) ↑(should no longer be used) women < 7mg/24h, men <10 mg/24 h)

30 DIAGNOSIS-DYNAMIC TESTS! The clinical suspicion of Cushing’s sdr must be confirmed with biochemical studies. A. Dexamethasone(DXM) suppression test(overnight DXM suppression test)(Bricaire test)= the best screening test B The 48-hour low-dose DXM test (Liddle test-2*2)

31 DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROMC. Plasma ACTH (vn :9-52 pg/ml) =the best way to distinguish between ACTH-dependent Cushung’s sdr (pituitary or nonpituitary ACTH-secreting neoplasm) and ACTH-independent hypercortisolism ACTH ↓ (<10 pg/ml) in ACTH- independent Cushing’s sdr ACTH normal or ↑ (> 10pg/ml and frequently >52pg/ml)= ACTH secreting neoplasm D. High-dose DXM suppression test (Liddle test -2*8) → distinguish pituitary causes from ectopic ACTH production E. Morphological investigations Pituitary MRI : when ACTH-dependent Cushing’s sdr is present, MRI of the pituitary gland with gadolinium enhancement should be performed. Adrenal localizing procedures: abdominal CT scan =the best (or MRI- adrenal carcinoma); abdominal ultrasonography CT of the chest → nonpituitary ACTH-secreting tumor ((! Majority of these lesions are in the thorax)); then CT of abdomen pelvis

32 ACTH-independent formsCUSHING’S SYNDROME ACTH-independent forms cortisol  + ACTH + test 2x2 (-) + test 2x8 (-) ACTH-dependent forms Pituitary form cortisol  + ACTH n/  + test 2x2 (-) + test 2x8 (+) Paraneoplstic form cortisol  + ACTH   + test 2x2 (-) + test 2x8 (-)

33 Iatrogenic: remove source if possible CUSHING’S DISEASE CUSHING’S SDR TREATMENT DEPENDS ON THE CAUSE Iatrogenic: remove source if possible CUSHING’S DISEASE Selective removal of a pituitary adenoma( transsfenoidal approach)/+/-pituitary radiotherapy (when no response to pituitary surgery or incomplete removal ) Bilateral adrenalectomy – when pituitary surgery has failed or when the condition has recurred (+ pituitary radiation at the time of bilateral adrenalectomy- to avoid subsequent development of Nelson’s sdr =postadrenalectomy hyperpigmentation with a locally aggressive pituitary tumor) + replacement therapy

34 CUSHING’ S SYNDROME TREATMENTECTOPIC ACTH SYNDROME Removal of the primary tumor ( when it is possible- ! ) Bilateral adrenalectomy if the primary tumor is not found (+ replacement therapy) ADRENAL CAUSES Adrenal adenomas unilateral (laparoscopic) adrenalectomy Adrenal carcinoma – try to remove the primary tumor - medical treatment: mitotane= the drug of choice (an adrenolytic drug) ketoconzole (blocks a variety steroidogenic enzymes and thus ↓ plasma cortisol levels)

35 POSTTERAPEUTHYC SPECIFIC COMPLICATIONS NELSON SYNDROME CUSHING’ SYNDROME POSTTERAPEUTHYC SPECIFIC COMPLICATIONS NELSON SYNDROME ADRENOCORTICAL INUFFICIENCY