ESOPHAGUS Pathology

Congenital malformations 
1. A tracheoesophageal fistula (the most prevalent esophageal anomaly) occurs most commonly as an upper esophageal blind pouch with a fistula between the lower segment of the esophagus and the trachea. It is associated with hydramnios, congenital heart disease, and other gastrointestinal malformation. 

2. Esophageal atresia is associated with VATER syndrome (vertebra1 defects, anal atresia, tracheoesophageal fistula, and renal dysplasia)

3. Stenosis refers to a narrowed esophagus with a small lumen.  lt may be congenital or acquired, e.g., through trauma or inflammation. 

Inflammatory disorders 

Esophagitis 

most often involves the lower half of the esophagus.  Caused by the reflux of gastric contents (juices) into the lower esophagus. One of the most common GI disorders.

Clinical features. 

Patients experience substernal burning  associated with regurgitation, mild anemia, dysphagia,  hematemesis, and melena. Esophagitis may predispose to esophageal cancer. 

Etiology

- Reflux esophagitis is due to an incompetent lower esophageal sphincter that permits reflux of gastric juice into the lower esophagus. 
- Irritants such as citric acid, hot liquids, alcohol, smoking, corrosive chemicals, and certain drugs, such as tetracycline, may provoke inflammation. 
- Infectious etiologies include herpes, CMV, and C. albicans. The immunocompromised host is particularly susceptible to infectious esophagitis. 
Although chronic or severe reflux disease is uncommon, consequences of these conditions can lead to Barrett’s esophagus, development of a stricture, or hemorrhage.

Pathology

-Grossly, there is hyperemia, edema, inflammation, and superficial necrosis. 

Complications include ulceration, bleeding, stenosis, and squamous carcinoma. 

Treatment: diet control, antacids, and medications that decrease the production of gastric acid (e.g., H blockers).

Barrett's esophagus, 

gastric or intestinal columnar epithelium replaces normal squamous epithelium in response to  chronic reflux.- A complication of chronic gastroesophageal reflux disease.
- Histologic findings include the replacement of squamous epithelium with metaplastic columnar epithelium.
- Complications include increased incidence of esophageal adenocarcinoma, stricture formation, or hemorrhage (ulceration).

 Motor disorders. 

Normal motor function requires effective peristalsis and relaxation of the lower esophageal sphincter. 

Achalasia is a lack of relaxation of the lower esophageal sphincter (LES), which may be associated with aperistalsis of the esophagus and increased basal tone of the LES. 

Clinical features. Achalasia occurs most commonly between the ages of 30 and 50. Typical symptoms are dysphagia, regurgitation, aspiration, and chest pain. The lack of motility promotes stagnation and predisposes to carcinoma. 

Hiatal hernia is the herniation of the abdominal esophagus, the stomach, or both, through the esophageal hiatus in the  diaphragm.

Scleroderma is a collagen vascular disease, seen primarily in women, that causes subcutaneous fibrosis and widespread  degenerative changes. (A mild variant is known as CREST syndrome which stands for calcinosis. raynaud's phenomenon , esophageal dysfunction, sclerodactyly and telengectseia. esophagus is the most frequently involved region of the gastrointestinal tract.

Clinical features are mainly dysphagia and heartburn due to reflux oesophagitis caused by aperlistalsis and incompetent LES. 

Rings and webs 

1. Webs are mucosal folds in the upper esophagus above the aortic arch. 
2. Schatzki rings are mucosal rings at the squamocolumnarjunction below the aortic arch.
3. Plummer Vinson Syndrome consist of triad of dysphagia, atrophic glossitis, and anemia. Webs are found in the upper esophagus. The syndrome is associated specifically with iron deficiency anemia and sometimes hypochlorhydria. Patients are at increased risk for carcinoma of the pharynx or esophagus. 

Mallory-Weiss syndrome
Mallory-Weiss tears refers to small mucosal tears at the gastroesophageal junction secondary to recurrent forceful vomiting. The tears occur along the long axis an result in hematemesis (sometimes massive).

- Characterized by lacerations (tears) in the esophagus.
- Most commonly occurs from vomiting (alcoholics).
- A related condition, known as Boerhaave syndrome, occurs when the esophagus ruptures, causing massive upper GI hemorrhage.

Esophageal varices
- The formation of varices (collateral channels) occurs from portal hypertension.
Causes of portal hypertension include blockage of the portal vein or liver disease (cirrhosis).
- Rupture of esophageal varices results in massive hemorrhage into the esophagus and hematemesis.
- Common in patients with liver cirrhosis.

Diverticula 
are sac-like protrusions of one or more layers of  pharyngeal or esophageal wall. 

Tumors 
- Benign tumors are rare. 
- Carcinoma of the esophagus most commonly occurs after 50 and has a male:female ratio of 4.1. 

Etiology: alcohal ingestion, smoking, nitrosamines in food, achalasia , web ring, Barrettes esophagus, and deficiencies of vitamins A and C , riboflavin, and some trace minerals

Clinical features include dysphagia (first to solids), retrosternal pain, anorexia, weight loss, melena, and symptoms secondary to metastases. 

Pathology 

- 50% occur in the middle third of the esophagus, 30% in the lower third, and 20% in the upper third. Most esophageal cancers are squamous cell carcinomas. 
Adenocarcinomas arise mostly out of Barrett's esophagus.

Prognosis

is poor. Fewer than 10% of patients survive 5 years, usually because diagnosis is made at a late stage. The  most common sites of metastasis are the liver and lung. The combination of cigarette smoking and alcohol is particularly causative for esophageal cancer (over l00%  risk compared to nondrinkers/nonsmokers). 

TUBERCULOSIS

A chronic, recurrent infection, most commonly in the lungs

Etiology, Epidemiology, and Incidence

TB refers only to disease caused by Mycobacterium tuberculosis, M. bovis, or M. africanum. Other mycobacteria cause diseases similar to TB

Pathogenesis

The stages of TB are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB.

Primary TB may become active at any age, producing clinical TB in any organ, most often the apical area of the lung but also the kidney, long bones, vertebrae, lymph nodes, and other sites. Often, activation occurs within 1 to 2 yr of initial infection, but may be delayed years or decades and activate after onset of diabetes mellitus, during periods of stress, after treatment with corticosteroids or other immunosuppressants, in adolescence, or in later life (> 70 yr of age), but especially after HIV infection. The initial infection leaves nodular scars in the apices of one or both lungs, called Simon foci, which are the most common seeds for later active TB. The frequency of activation seems unaffected by calcified scars of primary infection (Ghon foci) or by residual calcified hilar lymph nodes. Subtotal gastrectomy and silicosis also predispose to development of active TB.

Pulmonary Tuberculosis

recrudescent disease occurs in nodular scars in the apex of one or both lungs (Simon foci) and may spread through the bronchi to other portions

Recrudescence may occur while a primary focus of TB is still healing but is more often delayed until some other disease facilitates reactivation of the infection.

In an immunocompetent person whose tuberculin test is positive (>= 10 mm), exposure to TB rarely results in a new infection, because T-lymphocyte immunity controls small, exogenous inocula promptly and completely.

Symptoms and Signs:

Cough is the most common symptom,

At first, it is minimally productive of yellow or green mucus, usually on rising in the morning, but becomes more productive as the disease progresses

Dyspnea may result from rupture of the lung or from a pleural effusion caused by a vigorous inflammatory reaction

Hilar lymphadenopathy is the most common finding in children. due to lymphatic drainage from a small lesion, usually located in the best ventilated portions of the lung (lower and middle lobes), where most of the inhaled organisms are carried.

swelling of the nodes is common

Untreated infection may progress to miliary TB or tuberculous meningitis and, if long neglected, rarely may lead to pulmonary cavitation.

TB in the elderly presents special problems. Long-dormant infection may reactivate, most commonly in the lung but sometimes in the brain or a kidney, long bone, vertebra, lymph node, or anywhere that bacilli were seeded during the primary infection earlier in life

TB may develop when infection in an old calcific lymph node reactivates and leaks caseous material into a lobar or segmental bronchus, causing a pneumonia that persists despite broad-spectrum antibiotic therapy.

With HIV infection, progression to clinical TB is much more common and rapid.

HIV also reduces both inflammatory reaction and cavitation of pulmonary lesions. As a result, a patient's chest x-ray may be normal, even though AFB are present in sufficient numbers to show on a sputum smear. Recrudescent TB is almost always indicated when such an infection develops while the CD4⁺ T-lymphocyte count is >= 200/µL. By contrast, the diagnosis is usually infection by M. avium-intracellulare if the CD4+ count is < 50. The latter is noninfectious for others.

Pleural TB develops when a small subpleural pulmonary lesion ruptures, extruding caseous material into the pleural space. The most common type, serous exudate, results from rupture of a pimple-sized lesion of primary TB and contains very few organisms.

Tuberculous empyema with or without bronchopleural fistula is caused by a more massive contamination of the pleural space resulting from rupture of a large tuberculous lesion. Such a rupture allows air to escape and collapse the lung. Either type requires prompt drainage of pus and initiation of multiple drug therapy

Extrapulmonary Tuberculosis

Remote tuberculous lesions can be considered as metastases from the primary site in the lung, comparable to metastases from a primary neoplasm. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints were once commonly caused by ingestion of milk infected with M. bovis.

GENITOURINARY TUBERCULOSIS

The kidney is one of the most common sites for extrapulmonary (metastatic) TB. Often after decades of dormancy, a small cortical focus may enlarge and destroy a large part of the renal parenchyma.

Salpingo-oophoritis can be a complication of primary TB after onset of menarche, when the fallopian tubes become vascular.

TUBERCULOUS MENINGITIS

Spread of TB to the subarachnoid space may occur as part of generalized dissemination through the bloodstream or from a superficial tubercle in the brain

Symptoms are fever (temperature rising to 38.3° C [101° F]), unremitting headache, nausea, and drowsiness, which may progress to stupor and coma. Stiff neck (Brudzinski's sign) and straight leg raising are inconstant but are helpful signs, if present. Stages of tuberculous meningitis are (1) clear sensorium with abnormal CSF, (2) drowsiness or stupor with focal neurologic signs, and (3) coma. Likelihood that CNS defects will become permanent increases with the stage. Symptoms may progress suddenly if the lesion causes thrombosis of a major cerebral vessel.

Diagnosis is made by examining CSF. The most helpful CSF findings include a glucose level < 1/2 that in the serum and an elevated protein level along with a pleocytosis, largely of lymphocytes. Examination of CSF by PCR is most helpful, rapid, and highly specific.

MILIARY TUBERCULOSIS

When a tuberculous lesion leaks into a blood vessel, massive dissemination of organisms may occur, causing millions of 1- to 3-mm metastatic lesions. Such spread, named miliary because the lesions resemble millet seeds, is most common in children < 4 yr and in the elderly.

TUBERCULOUS LYMPHADENITIS

In primary infection with M. tuberculosis, the infection spreads from the infected site in the lung to the hilar nodes. If the inoculum is not too large, other nodes generally are not involved. However, if the infection is not controlled, other nodes in the superior mediastinum may become involved. If organisms reach the thoracic duct, general dissemination may occur. From the supraclavicular area, nodes in the anterior cervical chain may be inoculated, thus sowing the seeds for tuberculous lymphadenitis at a later time. Most infected nodes heal, but the organisms may lie dormant and viable for years or decades and can again multiply and produce active disease.

HAEMORRHAGIC DISORDERS

Normal homeostasis depends on

 -Capillary integrity and tissue support.

- Platelets; number and function

(a) For integrity of capillary endothelium and platelet plug by adhesion and aggregation

(b) Vasoactive substances for vasoconstriction

(c) Platelet factor for coagulation.

(d) clot retraction.

- Fibrinolytic system(mainly Plasmin) : which keeps the coagulatian system in check.

Coagulation disorders

These may be factors :

Deficiency .of factors

• Genetic.
• Vitamin K deficiency.
• Liver disease.
• Secondary to disseminated intravascular coagulation.or defibrinatian

Overactive fibrinolytic system.

Inhibitors of  the factars (immune, acquired).

Anticoagulant therapy as in myocardial infarctian.

Haemophilia. Genetic disease transmitted as X linked recessive trait. Comman in Europe. Defect in fcatorVII  Haemophilia A .or in fact .or IX-Haemaphilia B (rarer).

Features:

• May manifest in infancy or later.
• Severity depends  on degree of deficiency.
• Persistant woundbleeding.
• Easy Bruising with Haemotoma formation

Nose bleed , arthrosis, abdominal pain with fever and leucocytosis

Prognosis is good with prevention of trauma and-transfusion of Fresh blood or fTesh plasma except for danger of developing immune inhibitors.

Von Willebrand's disease. Capillary fragility and decreased factor VIII (due to deficient stimulatory factor). It is transmitted in an autosomal dominant manner both. Sexes affected equally

Vitamin K  Deficiency. Vitamin K is needed for synthesis of factor II,VII,IX and X.

Deficiency maybe due to:

Obstructive jaundice.

Steatorrhoea.

Gut sterilisation by antibiotics.

Liver disease results in :

Deficient synthesis of factor I II, V, Vll, IX and X  Incseased fibrinolysis (as liver is the site of detoxification of activators ).

Defibrination syndrome. occurs when factors are depleted due to disseminated .intravascular coagulation (DIC). It is initiated by endothelial damage or tissue factor entering the circulation.

Causes

Obstetric accidents, especially amniotic fluid embolism. Septicaemia. .

Hypersensitivity reactions.

Disseminated malignancy.

Snake bite.

Vascular defects :

(Non thrombocytopenic purpura).

Acquired :

Simple purpura a seen in women. It is probably endocrinal

Senile parpura in old people due to reduced tissue support to vessels

Allergic or toxic damage to endothelium due to  Infections like Typhoid Septicemia

Col!agen diseases.

Scurvy

Uraemia damage to  endothelium (platelet defects).

Drugs like aspirin. tranquillisers, Streptomvcin pencillin etc.

Henoc schonlien purpura Widespeard vasculitis due to hypersensitivity to bacteria or foodstuff

It manifests as :

Pulrpurric rashes.

Arthralgia.

Abdominal pain.

Nephritis and haematuria.

Hereditary :

(a) Haemhoragic telangieclasia. Spider like tortous vessels which bleed easily. There are disseminated lesions in skin, mucosa and viscera.

(b) Hereditary capillary fragilily similar to the vascular component of von Willbrand’s disease

.(c) Ehler Danlos Syndrome which is a connective tissue defect with skin, vascular and joint manifestations.

Platelet defects

These may be :

(I) Qualitative thromboasthenia and thrombocytopathy.

(2) Thrombocytopenia :Reduction in number.

(a) Primary or idiopathic thrombocytopenic purpura.

(b) Secondary to :

(i) Drugs especially sedormid

(ii) Leukaemias

(iii) Aplastic-anaemia.

Idiopathic thrombocytopenic purpura (ITP). Commoner in young females.

Manifests as :

Acute self limiting type.

Chronic recurring type.

Features:

(i) Spontaneous bleeding and easy bruisability

(ii)Skin (petechiae), mucus membrane (epistaxis) lesions and sometimes visceral lesions involving any organ.

Thrombocytopenia with abnormal forms of platelets.

Marrow shows increased megakaryocytes with immature forms,

vacuolation, and lack of platelet budding.

Pathogenesis:

hypersensitivity to infective agent in acute type.

Plasma thrombocytopenic factor ( Antibody in nature) in chronic type

DIABETES MELLITUS 
a group of metabolic disorders sharing the common underlying characteristic of hyperglycemia.  
Diabetes is an important disease because
1. It is common (affects 7% of the population). 
2. It increases the risk of atherosclerotic coronary artery and cerebrovascular diseases.
3. It is a leading cause of 
   a. Chronic renal failure
   b. Adult-onset blindness
   c. Non traumatic lower extremity amputations (due to gangrene) 
     
Classification 
Diabetes is divided into two broad classes:
1. Type1 diabetes (10%): characterized by an absolute deficiency of insulin secretion caused by pancreatic βcell destruction, usually as a result of an autoimmune attack.

2. Type2 diabetes (80%): caused by a combination of peripheral resistance to insulin action and an inadequate secretion of insulin from the pancreatic β cells in response to elevated blood glucose levels. 

The long-term complications in kidneys, eyes, nerves, and blood vessels are the same in both types.

Pathogenesis
Type 1 diabetes is an autoimmune disease and as in all such diseases, genetic susceptibility and environmental influences play important roles in the pathogenesis. The islet destruction is caused primarily by T lymphocytes reacting against immunologic epitopes on the insulin hormone located within β-cell; this results in a reduction of β-cell mass. The reactive T cells include CD4+ T cells of the TH1 subset, which cause tissue injury by activating macrophages, and CD8+ cytotoxic T lymphocytes; these directly kill β cells and also secrete cytokines that activate further macrophages. The islets show cellular necrosis and lymphocytic infiltration (insulitis). Autoantibodies against a variety of β-cell antigens, including insulin are also detected in the blood and may also contribute to islet damage. 

Type 2 Diabetes Mellitus: the pathogenesis remains unsettled. Environmental influences, such as inactive life style and dietary habits that eventuates in obesity, clearly have a role. Nevertheless, genetic factors are even more important than in type 1 diabetes. Among first-degree relatives with type 2 diabetes the risk of developing the disease is 20% to 40%, as compared with 5% in the general population. 
The two metabolic defects that characterize type 2 diabetes are 1.  A decreased ability of peripheral tissues to respond to insulin (insulin resistance) and 2. β-cell dysfunction manifested as inadequate insulin secretion in the face of hyperglycemia. In most cases, insulin resistance is the primary event and is followed by increasing degrees of β-cell dysfunction.

Morphology of Diabetes and Its Late Complications

The important morphologic changes are related to the many late systemic complications of diabetes and thus are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), and nerves (neuropathy). These changes are seen in both type 1 and type 2 diabetes. 

The changes are divided into pancreatic & extrapancreatic 
A. Pancreatic changes are inconstant and are more commonly associated with type 1 than with type 2 diabetes.
One or more of the following alterations may be present.
1. Reduction in the number and size of islets
2. Leukocytic infiltration of the islets (insulitis) principally byT lymphocytes.  

3. Amyloid replacement of islets; which is seen in advanced stages

B. Extrapancreatic changes 

1. Diabetic macrovascular disease is reflected as accelerated atherosclerosis affecting the aorta and other large and medium-sized arteries including the coronaries. Myocardial infarction is the most common cause of death in diabetics. Gangrene of the lower limbs due to advanced vascular disease, is about 100 times more common in diabetics than in the general population. 
2. Hyaline arteriolosclerosis
 is the vascular lesion associated with hypertension. It is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension.
3. Diabetic microangiopathy
 is one of the most consistent morphologic features of diabetes, which reflected morphologically as diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the retina, renal glomeruli, and peripheral nerves. The thickened capillary basement membranes are associated with leakiness to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
4. Diabetic Nephropathy: renal failure is second only to myocardial infarction as a cause of death from diabetes.

Three lesions encountered are: 
1. Glomerular lesions
2. Renal vascular lesions, principally arteriolosclerosis; and
3. Pyelonephritis, including necrotizing papillitis.  

Glomerular lesions:  these include 
a. diffuse glomerular capillary basement membrane thickening
b. diffuse glomerular sclerosis : diffuse increase in mesangial matrix; always associated with the above.  
c. nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) refers to a rounded deposits of a laminated matrix situated in the periphery of the glomerulus 

Pyelonephritis: both acute and chronic pyelonephritis are more common & more severe 

Ocular Complications of Diabetes: Visual impairment up to total blindness may occur in long-standing diabetes. The ocular involvement may take the form of 
a. retinopathy 
b. cataract formation
c. glaucoma 

In both forms of long-standing diabetes, cardiovascular events such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality. Diabetic nephropathy is a leading cause of end-stage renal disease. By 20 years after diagnosis, more than 75% of type 1 diabetics and about 20% of type 2 diabetics with overt renal disease will develop end-stage renal disease, requiring dialysis or renal transplantation. 
Diabetics are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, 
pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of diabetics. 

Pyelonephritis

- A bacterial infection that affects the renal tubules, interstitium, and renal pelvis.
- One of the most common renal diseases. 
- Usually caused by gram-negative, rod-shaped bacteria that are part of the normal flora of the enteric tract. Most commonly caused by Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter.
- The infecting bacteria are usually from the patient’s own enteric flora an example of an endogenous infection.
- Usually associated with a urinary tract infection (acute pyelonephritis) or involved with another precipitating condition, such as obstruction (chronic pyelonephritis).

Peutz-Jeghers syndrome
1. Lesions appear as small, melanotic, and freckle-like. They can be found on the skin, oral mucosa, lips, feet, and hands. 
2. May also present with intestinal polyps, which may develop into a gastrointestinal carcinoma. 
3. Genetic transmission: autosomal dominant.