Adrenocortical Hyperfunction (Hyperadrenalism)

Hypercortisolism (Cushing Syndrome) is caused by any condition that produces an elevation in glucocorticoid levels. The causes of this syndrome are 
A. Exogenous through administration of exogenous glucocorticoids; the most common causeB. Endogenous 
1. Hypothalamic-pituitary diseases causing hypersecretion of ACTH (Cushing disease)
2. Adrenocortical hyperplasia or neoplasia 
3. Ectopic ACTH secretion by nonendocrine neoplasms (paraneoplastic)

Pathological features 

- The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. 
- The most common change in the pituitary, results from high levels of endogenous or exogenous  glucocorticoids, is termed Crooke hyaline change. In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material. This is due to accumulation of intermediate keratin filaments in the cytoplasm. 
- There is one of four changes in the adrenal glands, which depends on the cause.
1. Cortical atrophy 
2. Diffuse hyperplasia
3. Nodular hyperplasia 
4. Adenoma, rarely a carcinoma 

1. In patients in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of the cortex by ACTH. In cases of endogenous hypercortisolism, in contrast, the adrenals either are hyperplastic or contain a cortical neoplasm. 
2. In Diffuse hyperplasia the adrenal cortex is diffusely thickened and yellow, as a result of an increase in the size and number of lipid-rich cells in the zonae fasciculata and reticularis. 
3. Nodular hyperplasia, which takes the form of bilateral, up to 2.0-cm, yellow nodules scattered throughout the cortex. 

4. Primary adrenocortical neoplasms causing Cushing syndrome may be benign or malignant. The  adrenocortical adenomas are yellow tumors surrounded by capsules, and most weigh < 30 gm .

Keratoses (Horny Growth)
1. Seborrheic keratosis is a common benign epidermal tumor composed of basaloid (basal cell-like) cells with increased pigmentation that produce a raised, pigmented, "stuck-on" appearance on the skin of middle-aged individuals.
 - they can easily be scraped from the skin's surface.
 - frequently enlarge of multiply following hormonal therapy.
 - sudden appearance of large numbers of Seborrheic keratosis is a possible indication of a malignancy of the gastrointestinal tract (Leser-Trelat sign).

 2. An actinic keratosis is a pre-malignant skin lesion induced by ultraviolet light damage.
 - sun exposed areas.
 - parakeratosis and atypia (dysplasia) of the keratinocytes.
 - solar damage to underlying elastic and collagen tissue (solar elastosis).
 - may progress to squamous carcinoma in situ (Bowen's disease) or invasive cancer.

 3. A keratoacanthoma is characterized by the rapid growth of a crateriform lesion in 3 to 6
weeks usually on the face or upper extremity.
 - it eventually regresses and involutes with scarring.
 - commonly confused with a well-differentiated squamous cell carcinoma. 

THE ADRENAL GLANDS 
ADRENAL CORTEX 
The adrenal cortex synthesizes three different types of steroids: 
1. Glucocorticoids (principally cortisol), which are synthesized primarily in the zona fasciculata 
2. Mineralocorticoids, the most important being aldosterone, which is generated in the zona glomerulosa; and 
3. Sex steroids (estrogens and androgens), which are produced largely in the zona reticularis.  

ADRENAL MEDULLA

The adrenal medulla is populated by cells derived from the neural crest (chromaffin cells) and their supporting (sustentacular) cells. 
They secrete catecholamines in response to signals from preganglionic nerve fibers inthe sympathetic nervous system.

Pathology gives explanations of a disease by studying the following four aspects of the disease.

1. Etiology,

2. Pathogenesis,

3. Morphologic changes and

4. Functional derangements and clinical significance.

1. Etiology Etiology of a disease means the cause of the disease. If the cause of a disease is known it is called primary etiology. If the cause of the disease is unknown it is called idiopathic. Knowledge or discovery of the primary cause remains the backbone on which a diagnosis can be made, a disease understood, & a treatment developed. There are two major classes of etiologic factors: genetic and acquired (infectious, nutritional, chemical, physical, etc).

2. Pathogenesis Pathogenesis means the mechanism through which the cause operates to produce the pathological and clinical manifestations. The pathogenetic mechanisms could take place in the latent or incubation period. Pathogenesis leads to morphologic changes.

3. Morphologic changes The morphologic changes refer to the structural alterations in cells or tissues that occur following the pathogenetic mechanisms. The structural changes in the organ can be seen with the naked eye or they may only be seen under the microscope. Those changes that can be seen with the naked eye are called gross morphologic changes & those that are seen under the microscope are called microscopic changes. the morphologic changes will lead to functional alteration & to the clinical signs & symptoms of the disease.

4. Functional derangements and clinical significance The morphologic changes in the organ influence the normal function of the organ. By doing so, they determine the clinical features (symptoms and signs), course, and prognosis of the disease.

Posterior Pituitary Syndromes 

The posterior pituitary, or neurohypophysis, is composed of modified glial cells (termed pituicytes) and axonal processes extending from nerve cell bodies in the hypothalamus. The hypothalamic neurons produce two peptides: antidiuretic hormone (ADH) and oxytocin that are stored in axon terminals in the neurohypophysis.

The clinically important posterior pituitary syndromes involve ADH production and include  
1. Diabetes insipidus and 
2. Inappropriate secretion of high levels of ADH.  

- ADH is released into the general circulation in response to increased plasma oncotic pressure & left atrial distention. 
- It acts on the renal collecting tubules to increase the resorption of free water. 
- ADH deficiency causes  diabetes insipidus, a condition characterized by polyuria. If the cause is related to ADH Diabetes insipidus from - - ADH deficiency is designated as central, to differentiate it from nephrogenic diabetes insipidus due to renal tubular unresponsiveness to circulating ADH. 
- The clinical manifestations of both diseases are similar and include the excretion of large volumes of dilute urine with low specific gravity. Serum sodium and osmolality are increased as a result of excessive renal loss of free water, resulting in thirst and polydipsia. 

- ADH excess causes resorption of excessive amounts of free water, with resultant hyponatremia. 
- The most common causes of the syndrome include the secretion of ectopic ADH by malignant neoplasms (particularly small-cell carcinomas of the lung), and local injury to the hypothalamus and/or neurohypophysis. 

- The clinical manifestations are dominated by hyponatremia, cerebral edema, and resultant neurologic dysfunction.

Autoimmune(acquired) Haemolytic anaemia

Auto antibodies are usually Ig g type (may be Ig M or Ig A). They may or may not bind complement and may be active in warm or cold temperature  They may be complete (agggIutinating) or incomplete. Haemolysis s may be intravascular  due to destruction of the antibody coated cells by RE system.

Causes:

a. Idiopathic
b. Secondary to
o    Drugs - Methyldopa, Mefanamic acid

o    Disease like
    -> Infections especially viral.
    -> Autoimmune disease especially SLE.
    -> Lymphomas and chronic  lymphatic leukaemia.
    -> Tumours.
    
Diagnosis : is based on

•    Evidences of haemolytic  anaemia.
•    Demonstration of antibodies

    - On red cell surface by direct Coomb’s test
    - In serum by indirect Coomb’s test.