ADRENAL INSUFFICIENCY

Adrenocortical hypofunction is either primary (adrenocrtical) or secondary (ACTH deficiency). Primary insufficiency is divided into acute & chronic. 
Acute Adrenocortical Insufficiency occurs most commonly in the following clinical settings
- massive adrenal hemorrhage including  Waterhouse-Friderichsen syndrome 
- Sudden withdrawal of long-term corticosteroid therapy
- Stress in those with chronic adrenal insufficiency 

Massive adrenal hemorrhage may destroy the adrenal cortex sufficiently to cause acute adrenocortical 
insufficiency. This condition may occur 
1. in patients maintained on anticoagulant therapy 
2. in postoperative patients who develop DIC
3. during pregnancy 
4. in patients suffering from overwhelming sepsis (Waterhouse-Friderichsen syndrome) 

Waterhouse-Friderichsen syndrome is a catastrophic syndrome classically associated with Neisseria meningitidis septicemia but can also be caused by other organisms, including Pseudomonas species, pneumococci & Haemophilus influenzae. The pathogenesis of the syndrome remains unclear, but probably involves endotoxin-induced vascular injury with associated DIC.

Chronic adrenocortical insufficiency (Addison disease) results from progressive destruction of the adrenal cortex. More than 90% of all cases are attributable to one of four disorders: 
1. autoimmune adrenalitis (the most common cause; 70% of cases) 
2. tuberculosis &fungal infections 
3. AIDS
4. Metastatic cancers   
In such primary diseases, there is hyperpigmentation of the skin oral mucosa due to high levels of MSH (associated with high levels of ACTH).

Autoimmune adrenalitis is due to autoimmune destruction of steroid-producing cells. It is either isolated associated other autoimmune diseases, such as Hashimoto disease, pernicious anemia, etc. 

Infections, particularly tuberculous and fungal

Tuberculous adrenalitis, which once was responsible for as many as 90% of cases of Addison disease, has become less common with the advent of antituberculous therapy. When present, tuberculous adrenalitis is usually associated with active infection elsewhere, particularly the lungs and genitourinary tract. Among fungi, disseminated infections caused by Histoplasma capsulatum is the main cause. 

AIDS patients are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium avium-intracellulare) and noninfectious (Kaposi sarcoma) complications.
 
Metastatic neoplasms: the adrenals are a fairly common site for metastases in persons with disseminated carcinomas. Although adrenal function is preserved in most such patients, the metastatic growths sometimes destroy sufficient adrenal cortex to produce a degree of adrenal insufficiency. Carcinomas of the lung and breast are the major primary sources. 

Secondary Adrenocortical Insufficiency

Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism having many similarities to Addison disease. In such secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low. 

Secondary adrenocortical insufficiency is characterized by low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administration. 

Pathological features of adrenocortical deficiency 

- The appearance of the adrenal glands varies with the cause of the insufficiency. 
- In secondary hypoadrenalism the adrenals are reduced to small, uniform, thin rim of atrophic yellow cortex that surrounds a central, intact medulla. Histologically, there is atrophy of cortical cells with loss of cytoplasmic lipid, particularly in the zonae fasciculata and reticularis. 
- In primary autoimmune adrenalitis there is also atrophy of the cortex associated with a variable lymphoid infiltrate that may extend into the subjacent medulla. The medulla is otherwise normal.  
- In tuberculosis or fungal diseases there is granulomatous inflammatory reaction. Demonstration of the responsible organism may require the use of special stains.  
- With metastatic carcinoma, the adrenals are enlarged and their normal architecture is obscured by the infiltrating neoplasm.  
 

Eosinophilia:
Causes

-Allergic disorders.
-Parasitic infection.
-Skin diseases.
-Pulmonary eosinophilia.
-Myeloproliferative lesions and Hodgkin's disease.

Smallpox (variola)
 - vesicles are well synchronized (same stage of development) and cover the skin and mucous membranes.
 - vesicles rupture and leave pock marks with permanent scarring.

Growth and spread of tumours

Growth in excess of normal is a feature of all tumours but extension to tissue away from the site of origin is a feature of malignant tumours.

Modes of spread of malignant tumours

- local, invasion. This is a feature of all malignant tumors and  takes place along tissue spaces and facial planes
    o    Lymphatic spread. Most often seen in carcinomas. This can be in the form of 
    o    Lymphatic permeation:  Where the cells extend along the lymphatics as a  solid core 
    o    Lymphatic embolisation: Where a group of tumour cells break off and get carried to the draining mode

-Vascular spread :  This is a common and early mode of spread for sarcomas but certain carcinomas like renal cell carcinoma and chorio carcinoma have a predilection to early vascular spread.

Vascular spread is most often due .to invasion of venous channels and can be by permeation or embolisation.

Lungs, liver, bones and brain are the common sites for vascular metastasis but
different tumours have different organ preference for metastasis, e.g. : Bronchogenic carcinoma often spreads to liver and adrenals.

-Body cavities and natural passages
    o    Gastrointestinal carcinomas spread to ovaries (Krukenberg’s tomour)
 

Hepatitis A virus.
- Hepatitis A (HAV) is a self-limited hepatitis caused by an RNA virus 

- Symptoms last 2 to 4 weeks.
- There is no risk of developing chronic hepatitis in the future.
- Incubation period is short, lasting 2 to 6 weeks.
- Infection is identified by HAV-specific antibodies (IgM if acute, IgG if past disease).
- The usual route of infection is fecal-oral transmission by contaminated food. There is no carrier state and no chronic disease
- Laboratory diagnosis: ELISA test for IgM antibody.
- Vaccine: killed virus.
- Prevention: serum immunoglobulins are available.

INFLAMMATION

Response of living tissue to injury, involving neural, vascular and cellular response.

ACUTE INFLAMMATION

It involves the formation of a protein .rich and cellullar exudate and the cardinal signs are calor, dolor, tumour, rubor and function loss

The basic components of the response are

Haemodynamic changes.

Permeability changes

Leucocyte events.

1. Haemodynamic Changes :

• Transient vasoconstriction followed by dilatation.
• Increased blood flow in arterioles.
• More open capillary bed.
• Venous engorgement and congestion.
• Packing of microvasculature by RBC (due to fluid out-pouring)
• Vascular stasis.
• Change in axial flow (resulting in margination of leucocytes)

.2. Permeability Changes:

Causes.

• Increased intravascular hydrostatic pressure.
• Breakdown of tissue proteins into small molecules resulting in
• increased tissue osmotic pressure.
• Increased permeability due to chemical mediators, causing an
• immediate transient response. .
• Sustained response due to direct damage to microcirculation.

3. White Cell Events:

.Margination - due to vascular stasis and change in axial flow.

Pavementing - due to endothelial cells swollen and more sticky.

Leucocytes more adhesive.

Binding by a plasma component

Emigration - of leucocytes by amoeboid movement between endhothe1ial cells and beyond the basement membrane. The passive movement of RBCs through the gaps created during emigration is called diapedesis

Chemotaxis - This is a directional movement, especially of polymorphs and monocytes towards a concentration gradient resulting in aggregation of these cells at the site of inflammation. .Chemotactic agents may be:

• Complement components. (C₃and C₅  fragments and C₅₆₇)
• Bacterial products.
• Immune complexes, especially for monocyte.
• Lymphocytic factor, especially for monocyte.

 Phagocytosis - This includes recognition, engulfment and intracellular degradation. It is aided by .Opsonins., Specific antibodies., Surface provided by fibrin meshwork.

Functions of the fluid and cellular exudate

1. Dilution of toxic agent.

2. Delivers serum factors like antibodies and complement components to site of inflammation.

3. Fibrin formed aids In :

• Limiting inflammation
• Surface phagocytosis
• Framework for repair.

4. Cells of the exudate:

Phagocytose and destroy the foreign agent.

Release lytic enzymes when destroyed, resulting in extracellular killing of organisms- and digestion of debris to enable healing to occur