EXOCRINE PANCREAS

Congenital anomalies
1. Ectopic pancreatic tissue most commonly occurs in the stomach, duodenum, jejunum, Meckel's diverticulum, and ileum. It may be either asymptomatic or cause obstruction, bleeding, intussusception. 

2.Annular pancreas is a ring of pancreatic tissue that encircle the duodenum and may cause duodenal obstruction. 

Cystic fibrosis

Cystic fibrosis is a systemic disorder of exocrine gland secretion presenting during infancy or childhood. 
Incidence is 1:2500 in Caucasians; it is less common in Black and extremely rare in Asians. 

Pathogenesis. Cystic fibrosis shows autosomal recessive transmission; heterozygotes are unaffected. It results in a defective chloride channel, which leads to secretion of very thick mucus. 

Characteristics

- Tissues other than exocrine glands are normal, and glands are structurally normal until damaged by cystic fibrosis.
- The only characteristic biochemical abnormalities are an  elevation of sodium and chloride levels in sweat, and a decrease in water and bicarbonate secretion from pancreatic cells, resulting in a viscous secretion. 

Clinical features

- Fifteen percent of cases present with meconium ileus.
- Most cases present during the first year with steatorrhea (with resultant deficiencies of vitamins A, D, E, and K), abdominal distention, and failure to thrive.

Complications are also related to pulmonary infections'and obstructive pulmonary disease as a result of viscous bronchial secretions. 

Pathology
- There is mucus plugging of the pancreatic ducts with cystic dilatation, fibrous proliferation, and atrophy. Similar pathology develops in salivary glands. 

- Lungs. Mucus impaction leads to bronchiolar dilatation an secondary infection. 
- The gastrointestinal tract shows obstruction caused mucus impaction in the intestines with areas of biliary cirrhosis, resulting from intrahepatic bile duct obstruction

Diagnosis depends on demonstrating a "sweat test" abnomality associated with at least one clinical feature In sweat test, high levels of chloride are demonstrated.

Prognosis. Mean survival is age 20; mortality is most often due to pulmonary infections. 

Degenerative changes

1. Iron pigmentation (e.g., from hemochromatosis) may be deposited within acinar and islet cells and may cause insulin deficiency. 

2. Atrophy 
a. Ischemic atrophy is due to atherosclerosis of pancreatic arteries and is usually asymptomatic. 
b. Obstruction of pancreatic ducts affects only the exocrine pancreas, which becomes small, fibrous, and nodular.

Acute hemorrhagic pancreatitis 

presents as a diffuse necrosis of the pancreas caused by the release of activated pancreatic
enzymes. Associated findings include fat necrosis and hemorrhage into the pancreas. 

Incidence. This disorder is most often associated with alcoholism and biliary tract disease.
It affects middle-aged individuals and often occurs after a large meal or excessive alcohol ingestion; approximately 50% of patients have gallstones. 

Pathogenesis. There are four theories.
- Obstruction of the pancreatic duct causes an elevated intraductal pressure, which results in leakage of enzymes from small ducts. 
- obstruction may be caused by a gallstone at the ampulla of Vater; chronic alcohol ingestion may cause duct obstruction by edema. 
- Hypercalcemia may cause activation of trypsinogen; its mechanism is unclear. Pancreatitis occurs in 20% of patients with hyperparathyroidism. 
- Direct damage to acinar cells may occur by trauma, ischemia, viruses, and drugs. 
- Hyperlipidemia may occur as a result of exogenous estrogen intake and alcohol ingestion. 

Clinical features are typically the sudden onset of acute, continuous, and intense abdominal pain, often radiating to the back and accompanied by nausea, vomiting, and fever. This syndrome frequently results in shock. 

Laboratory values reveal elevated amylase (lipase elevated after 3-4 days) and leukocytosis. Hypocalcemia is a poor prognostic sign. 

Chronic pancreatitis 

It refers to remitting and relapsing episodes of mild pancreatitis, causing progressive pancreatic damage. 

Incidence is similar to acute pancreatitis. It is also seen in patients with ductal anomalies. Almost half the cases occur without known risk factors. 

Pathogenesis is unclear; possibly, there is excess protein secretion by the pancreas, causing ductal obstruction. 

Clinical features include flareups precipitated by alcohol and overeating, and drugs. Attacks are characterized by upper abdominal pain, tenderness, fever, and jaundice. 

Laboratory values reveal elevated amylase and alkaline phosphatase, X-rays reveal calcifications in the pancreas. Chronic pancreatitis may result in pseudocyst formation, diabetes, and steatorrhea. 

Carcinoma of the pancreas 

Incidence: 
Carcinoma of the pancreas accounts for approximately 5% of all cancer deaths. Increased risk is associated with smoking. high-fat diet, and chemical exposure. There is a higher incidence in the elderly, Blacks, males, and diabetics. 

Clinical features
- The disease is usually asymptomatic until late in its course. 
- Manifestations include weight loss, abdominal pain frequently radiating to the back, weakness, malaise, anorexia, depression, and ascites.
- There is jaundice in half of the patients who have carcinoma of the head of the pancreas.
- Courvoisier's law holds that painless jaundice with a palpable gallbladder is suggestive of pancreatic cancer. 

Pathology
Carcinomas arise in ductal epithelium. Most are adenocarcinomas. 
- Carcinoma of the head of the pancreas accounts for 60% of all pancreatic cancers. 
- Carcinoma of the body (20%) and tail (5%) produce large indurated masses that spread widely to the liver and lymph nodes. 
- In 15% of patients, carcinoma involves the pancreas diffusely. 

Complications 
include Trousseau's syndrome, a migratory thrombophlebitis that occurs in 10% of patients. 

Prognosis is very poor. if resectable, the 5-year survival rate less than 5%. The usual course is rapid decline; on average death occurs 6 months after the onset of symptoms.

Hypoparathyroidism

Hypoparathyroidism is a condition of reduced or absent PTH secretion, resulting in hypocalcaemia and hyperphosphataemia. It is far less common than hyperparathyroidism.

The causes of hypoparathyroidism are:
- Removal or damage of the parathyroid glands during thyroidectomy—most common cause of hypoparathyroidism resulting from inadvertent damage or removal.
- Autoimmune parathyroid disease—usually occurs in patients who have another autoimmune endocrine disease, e.g. Addison’s disease (autoimmune endocrine syndrome type 1).
- Congenital deficiency (DiGeorge syndrome)— rare, congenital disorder caused by arrested development of the third and fourth branchial arches, resulting in an almost complete absence of the thymus and parathyroid gland.

The effects of hypoparathyroidism are:
- ↓ release of Ca²⁺ from bones. 
- ↓ Ca²⁺ reabsorption but ↑ PO ₄³⁻ re absorption by the kidneys
- ↓ 1-hydroxylation of 25-hydroxyvitamin D by kidney.

Most symptoms of hypoparathyroidism are those of hypocalcaemia:
- Tetany—muscular spasm provoked by lowered plasma Ca 2+ 
- Convulsions.
- Paraesthesiae.
- Psychiatric disturbances, e.g. depression, confusional state and even psychosis.
- Rarely—cataracts, parkinsonian-like movement disorders, alopecia, brittle nails.

Management is by treatment with large doses of oral vitamin D; the acute phase requires intravenous calcium and calcitriol (1,25-dihydroxycholecalciferol, i.e.  activated vitamin D).

 Staphylococcal aureus
 - cutaneous infections
    - furuncles (boils)
    - carbuncles (more complicated furuncle with multiple sinuses)
    - impetigo (often mixed with Streptococcus and has a more bullous appearance than crusted)
    - hidradenitis suppurative (abscess of apocrine glands→e.g., axilla)
    - nail bed (paronychial infection) 
    - postoperative wound or stitch abscess
    - postpartum breast abscesses 
 
toxin related skin rashes
 - infants and young children develop toxic epidermal necrolysis or Ritter's syndrome (scalded baby syndrome)→large, red areas of denuded skin and generalized bulla formation.
 - toxic shock syndrome (TSS) is due to a toxin producing strain of Staphylococcus aureus (bacteriophage induced) usually, but not exclusively in tampon wearing (hyperabsorbent type), menstruating women; 1-4 day prodrome of high fever, myalgias, arthralgias, mental confusion, diarrhea and on erythematous rash that occurs during or soon after menses; rash predominantly on hands and feet with eventual desquamation in 5-12 days. 

CHRONIC INFLAMMATlON

When the inflammatory reaction instead of subsiding after the acute phase (or without entering an acute phase), persists as a smouldering lesion, it is called chronic inflammation. .

Characteristics

• Predominantly mononuclear response.
• Inflamation.and..repair going on simultaneously.
• Usually results in more prominent-scarring.

Causes:

Chronicity may be due to :

- Defective defence mechanisms.

- Persistence of injurious agent.

(a) Certain organisms resist phagocytosis and destruction e.g tubercle bacillus, fungi

(b) insoluble particulate matter e.g., crystals. fibres suture materials.

(c) Constants supply of causative agent as in autoimmune disease where body reacts against its own tissues.

- Defective healing.

Granulomatous inflammation

It is a type of chronic inflammation characterised by localised collections of histiocytes.

These cells are usually accompanied by lymphocytes, fibroblasts and giant cells also.

Granulomas are characteristically seen in diseases like tuberculosis. syphilis, leprosy, sarcoidosis, fungal infections etc. In some of these, the lesion is morphologically distinct  enough to point to the type of underlying disease. These are sometimes called' specific' granulomas. Granulomas can also be elicited by particulate, insoluble foreign material e.g. granuloma, suture granuloma, cholesterol granuloma (organising haemorrhages).

THYROIDITIS 
The more common and clinically significant thyroidites are:  
1. Hashimoto thyroiditis 
2. Subacute granulomatous thyroiditis
3. Subacute lymphocytic thyroiditis 

Hashimoto thyroiditis 

Hashimoto thyroiditis (Chronic Lymphocytic Thyroiditis) is the most common cause of hypothyroidism. It results from gradual autoimmune destruction of the thyroid gland. There is striking female predominance (10: 1 to 20:1), and is most prevalent around a mean age of 50 years. 

Pathogenesis 
• The dominant feature is progressive destruction of thyroid follicular epithelial cells with gradual replacement by mononuclear cell infiltration and fibrosis. 
• Sensitization of CD4+ T-helper cells to thyroid antigens seems to be the initiating event.
• The reaction of CD4+ T cells with thyroid antigens produces interferon γ  which promote inflammation and activate macrophages. Injury to the thyroid results from the toxic products of these inflammatory cells. 
• CD8+ cytotoxic T cells also contribute to epithelial cells killing as are natural killer cells. 
• There is a significant genetic component to disease pathogenesis. This is supported by 
1.  The increased frequency of the disease in first-degree relatives, 
2.  Unaffected family members often have circulating thyroid autoantibodies.  

Gross features 
• The thyroid shows moderate, diffuse, and symmetric enlargement.
• The cut surface is pale, gray-tan, firm, nodular and somewhat friable. 
• Eventually there is thyroid atrophy 

Microscopic features

• There is widespread, diffuse infiltration of the parenchyma by small lymphocytes, plasma cells.  The lymphocytes are also form follicles some with well-developed germinal centers 
• The thyroid follicles are atrophic and lined by epithelial cells having abundant eosinophilic, granular cytoplasm (Hurthle cells). This is a metaplastic response to the ongoing injury; ultrastructurally the Hurthle cells are stuffed by numerous mitochondria. 
• Interstitial connective tissue is increased and may be abundant.

Hashimoto thyroiditis presents as painless symmetrical goiter, usually with some degree of hypothyroidism. In some cases there is an initial transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones ("hashitoxicosis"). As hypothyroidism supervenes T4 and T3 levels progressively fall & TSH levels are increased. Patients often have other autoimmune diseases and are at increased risk for the development of B-cell non-Hodgkin lymphomas. 

Subacute Granulomatous (de Quervain) Thyroiditis 

Subacute Granulomatous (de Quervain) Thyroiditis is much less common than Hashimoto disease.

- It is most common around the age of 40 years and occurs more frequently in women than in men.

- An upper respiratory infection just before the onset of thyroiditis. Thus, a viral infection is probably the cause.

- There is firm uni- or bilateral enlargement of the gland.

Microscopically, there is disruption of thyroid follicles, with extravasation of colloid. The extravasated colloid provokes a granulomatous reaction, with giant cells.
Thyroid function tests are those of thyrotoxicosis but with progression and gland destruction, a transient hypothyroid phase occurs. The condition is self-limited, with most patients returning to a euthyroid state within at most 2 months.

Subacute Lymphocytic Thyroiditis

Subacute Lymphocytic Thyroiditis may follow pregnancy (postpartum thyroiditis).

- It is most likely autoimmune in etiology, because circulating antithyroid antibodies are found in the majority of patients.

- It mostly affects middle-aged women and present as painless, mild, symmetric neck mass. Initially, there is thyrotoxicosis, followed by return to a euthyroid state within a few months. In a minority there is progression to hypothyroidism.

Microscopically, there is a lymphocytic infiltration and hyperplastic germinal center within the thyroid parenchyma; unlike Hashimoto thyroiditis, follicular atrophy or Hürthle cell metaplasia are not commonly seen.

Riedel thyroiditis 

Riedel thyroiditis is a rare disorder of unknown etiology, characterized by extensive fibrosis involving the thyroid and the surrounding neck structures. The presence of a hard and fixed thyroid mass may be confused clinically with thyroid cancer. It may be associated with idiopathic fibrosis in other sites, such as the retroperitoneum. The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology. 

HEALING

Definition. Replacement of damages tissue by healthy tissue. It is an attempt to restore the tissue to structural and functional normalcy.

Healing may be of 2 types

A. Regeneration.

B. Repair by granulation tissue.

A. Regeneration

Where the replacement is by proliferation of parenchymatous cells of type destroyed. This depends upon:

(1) Regenerative capacity of cells. Cells may be :

(a) Labile cells which are constantly proliferating to replace cells continuously shed off or destroyed

Epithelial cells of skin and lining surfaces.

Lymphoid and haemopoietic tissue.

(b) Stable cell. Cells mostly in resting-phase, but capable of dividing when necessary e.g.

• Liver and other parenchymatous and glandular cells.
• Connective tissue cells.
• Muscle cells have a limited capacity to divide.

(c) Permanent cell. These cells, once differentiated are not capable. of  dividing e.g.-nerve

(2) The extent of tissue loss. If  there is extensive destruction including disruption of the framework, complete.regeneration is not possible. even with labile an stable cell

B. Repair by granulation tissue

Granulation tissue is formed by proliferation of surrounding connective tissue elements. which migrate into the site to be repaired.

Granulation tissue formation  seen in :

• Wound healing.
• Organisation of exudates.
• Thrombi.
• Infarcts.
• Haematomas.

The process of repair can be best studied in clean incised wounds, where there is .no or minimal tjssue loss or the_edges or the  edges of the wound are approximated closely as in a surgical wound. This is called Primary union (healing by first intention).

1. The blood in the incised area clots and the fibrin binds the edges together.

2. During the first 24 hours, an acute  inflammation sets in to .bring protein and phagocyte rich exudates to the site.

3. The superficial part of the clot get dry and dehydrated{scab). The surface epithelium proliferates just beyond the cut edges and the cells migrate-deep to dry scab. Epithelialisation is usually complete by 24- 48 hours.

4 Granulation tissue, with actively growing fibroblasts and capillary buds invades the clot (stage of vascularisation). These fibroblasts 'posses contractile myofibrils & hence are termed as myofibroblasts'.

5. Simultaneously, demolition of the debris and clot components takes place.

6 The granulation tissue initially lays down a mucopolysacharide rich ground substance

7.Reticulin and later collagen fibrils are formed by the fibroblasts (with 5 days)

8 with progressive maturation of collagen, some of the capiliary buds develop into arterioles and venules and majority of them are obliterated (stage of devascularisation).

9. With time (weeks to months) the tensile strength of the scar increases and it shrinks.

Secondary union (excised wound-healing by secondary intention).

1. Coagulum forms and fills the gap.

2. Inflammatory reaction is seen as in primary union but is more intense, as a lot more debris has to be removed. .

3. Epithelial proliferation starts covering the surface from the periphery by proliferation beyond the edges and migration under scab.

4.Debridement starts and simultaneously granulation tissue grows into the coagulum from the sides and base of the wound. This is much more exuberant than in primary union. The surface now looks red and granular.

5. Wound contraction. This is early contraction (starts after 3 days and is complete in 2 weeks) and  must be differentiated from contraction after scar formation Wounds can contract by up to 80% of original size of that the gap to be filled is much reduced, resulting in faster healing with a smaller scar.

Wound contraction is probably caused by:

• Dehydration
• Collagen contraction.
• Granulation tissue contraction .(myofibroblasts).

The exact mechanism is not known.

6. Laying down of collagen.

7 Maturation to form a scar which later shrinks and devascularises.

Factors affecting wound healing

Wound healing is delayed by :

A. Local  factors

1. Poor blood supply.

2. Adhesion to bony surfaces (e.g. over the tibia).

3. Persistent injurious agents (infective or particulate) results in chronicity of  inflammation and ineffective healing. .

4. Constant movement (especially in fracture healing).

5. ionizing radiation (in contrast, ultraviolet rays hasten healing).

6. Neoplasia.

B. General factors

I. Nutritional deficiency, especially of.

(i) Protein

(ii) Ascorbic acid (Vitamin C).

(iii) Zinc

2. Corticoids adversely affect wound contraction and granulation tissue formation

(anabolic steroids have a favorable effect).

3. Low temperature.

4. Defects (qualitative or quantitative) in polymorphs and macrophages

.Complication of wound healing

1. Wound dehiscence

2.  Infection

3. Epidermal inclusion (implantation) cysts.

4. Keloid formation

5. Cicatrisation resulting in contract Ires and obstruction(in hollow viscera).

6. Calcification and ossification.

7. Weak scar which could be a site for incisional hernia

8. Painful scar if it involves a nerve twig.

9. Rarely neoplasia (especially in burn scars).