Nephritic syndrome

Characterized by inflammatory rupture of the glomerular capillaries, leaking blood into the urinary space.

Classic presentation: poststreptococcal glomerulonephritis. It occurs after a group A, β–hemolytic Streptococcus infection (e.g., strep throat.)

Caused by autoantibodies forming immune complexes in the glomerulus.

Clinical manifestations: 

oliguria, hematuria, hypertension, edema, and azotemia (increased concentrations of serum urea nitrogen
and creatine).

Autoimmune Diseases
These are a group of disease where antibodies  (or CMI) are produced against self antigens, causing disease process.

Normally one's immune competent cells do not react against one's own tissues. This is due to self tolerance acquired during embryogenesis. Any antigen encountered at that stage is recognized as self and the clone of cells capable of forming the corresponding antibody is suppressed.

Mechanism of autoimmunity

(1) Alteration of antigen

-Physicochemical denaturation by UV light, drugs etc. e.g. SLE.
- Native protein may turn antigenic  when a foreign hapten combines with it, e.g. Haemolytic anemia with Alpha methyl dopa.

(2) Cross reaction: Antibody produced against foreign antigen may cross react with native protein because of partial similarity e.g. Rheumatic fever.

(3) Exposure of sequestered antigens: Antigens not normally exposed to immune competent cells are not accepted as self as tolerance has not been developed to them. e.g. thyroglobulin, lens protein, sperms.

(4) Breakdown of tolerance : 
Emergence of forbidden clones (due to neoplasia of immune system as in lymphomas and lymphocytic leukaemia)
Loss of suppressor T cells as in old age and CMI defects

Autoimmunity may be
Organ specific.
Non organ specific (multisystemic)

I. Organ specific

(1) Hemolytic anaemia:

Warm or cold antibodies (active at 37° C or at colder temperature)
They may lyse the RBC by complement activation or coat them and make them vulnerable to phagocytosis

(2) Hashimoto's thyroiditis:
 
Antibodies to thyroglobulin and microsomal antigens.
Cell mediated immunity.
Leads to chronic. destructive thyroiditis.

(3) Pernicious anemia

Antibodies to gastric parietal cells and to intrinsic factor.

2. Non organ specific.

Lesions are seen in more than one system but principally affect blood vessels and
connective tissue (collagen diseases).

1. Systemic lupus erythematosus  (SLE). Antibodies to varied antigens are seen. Hence it is possible that there is abnormal reactivity of the immune system in self recognition.

Antibodies have been demonstrated against:

Nuclear material (antinuclear I antibodies) including DNA. nucleoprotein etc. Anti nuclear antibodies are demonstrated by LE cell test.
Cytoplasmic organelles- mitochondria, rib osomes, Iysosomes.
Blood constituents like RBC, WBC. platelets, coagulation factors.

Mechanism. Immune complexes of body proteins and auto antibodies deposit in various
organs and cause damage as in type III hypersensitivity

Organs involved
Skin- basal dissolution and collagen degeneration with fibrinoid vasculitis.
Heart- pancarditis.
Kidneys- glomerulonephritis of focal, diffuse or membranous type 
Joints- arthritis. 
Spleen- perisplenitis and vascular thickening (onion skin).
Lymph nodes- focal necrosis and follicular hyperplasia.
Vasculitis in other organs like liver, central or peripheral nervous system etc,

2. Polyarteritis nodosa. Remittant .disseminated necrotising vasculitis of small and medium sized arteries

Mechanism :- Not definitely known. Proposed immune reaction to exogenous or auto antigens 

Lesion : Focal panarteritis- a segment of vessel is involved. There is fibrinoid necrosis
with initially acute and later chronic inflammatory cells. This may result in haemorrhage
and aneurysm.

Organs involved. No organ or tissue is exempt but commonly involved organs are :
- Kidneys.
- Heart.
- Spleen.
- GIT

3. Rheumatoid arthritis. A disease primarily of females in young adult life. 

Antibodies
- Rheumatoid factor (An IgM antibody to self IgG)
- Antinuclear antibodies in 20% patients.

Lesions

- Arthritis which may progress on to a crippling deformity.
- Arteritis in various organs- heart, GIT, muscles.
- Pleuritis and fibrosing alveolitis.
- Amyloidosis is an important complication.

4. Sjogren's  Syndrome. This is constituted by 

- Kerato conjunctivitis sicca
-Xerostomia
-Rheumatoid arthritis. 

Antibodies

- Rheumatoid factor
- Antinuclear factors (70%).
- Other antibodies like antithyroid, complement fixing Ab etc
- Functional defects in lymphocytes. There is a higher incidence of lymphoma

5. Scleroderma (Progressive systemic sclerosis)
Inflammation and progressive sclerosis of connective tissue of skin and viscera.

Antibodies

- Antinuclear antibodies.
- Rheumatoid factor. .
- Defect is cell mediated.

lesions

Skin- depigmentation, sclerotic atrophy followed by cakinosis-claw fingers and mask face.
Joints-synovitis with fibrosis
Muscles- myositis.
GIT- diffuse fibrous replacement of muscularis resulting in hypomotility and malabsorption
Kidneys changes as in SLE and necrotising vasculitis.
Lungs – fibrosing alveolitis.
Vasculitis in any organ or tissue.

6.Wegener’s granulomatosis. A complex of:
Necrotising lesions in upper respiratory tract.
Disseminated necrotising vasculitis.
Focal or diffuse glomerulitis.

Mechanism. Not known. It is classed with  autoimmune diseases because of the vasculitis  resembling other immune based disorders.
 

ATROPHY
It is the acquired decrease in the size of an organ due to decrease in the size and/or number of its constituent cells.
Causes:
(1) Physiological

- Foetal involution.
    o    Branchial clefts.
    o    Ductus arterious.
- Involution of thymus and other lymphoid organs in childhood and adolescence.
- In adults:
    o    Post-partum uterus.
    o    Post-menopausal ovaries and uterus
    o    Post-lactational breast
    o    Thymus.
(2) Pathological:
- Generalised as in

    o    Ageing.
    o    Severe starvation and cachexia
- Localised :
    o    Disuse atropy of bone and muscle.
    o    Ischaemic atrophy as in arteriosclerotic kidney. .
    o    Pressure atrophy due  to tumours and of kidney in hydronephrosis.
    o    Lack of trophic stimulus to endocrines and gonads.
 

LARGE INTESTINE (COLON) 

Congenital anomalies 

1. Hirschsprung's disease produces a markedly distended colon, usually proximal to the rectum. Caused by a section of aganglionic colon, which failed to develop normally due to the absence of ganglion cells).
This results in bowel obstruction and distention of the bowel proximal to the affected area.

2. Imperforate anus is due to a failure of perforation of the membrane that separates the endodermal hindgut from the ectodermal anal dimple. 

Benign conditions

1. Diverticular disease refers to multiple outpouchings of the colon.
Incidence. Diverticular disease is present in 30%-50%  adult autopsies in the United States. There is a higher dence with increasing age. 
Pathogenesis. Herniation of mucosa and submucoq through weak areas of the gut wall where arterial vasa recta perforate the muscularis is a characteristic pathological finding of the disease. 

Clinical features

- Diverticulosis is often asymptomatic, but may present with pain and/or rectal bleeding.
- In contrast, diverticulitis presents with pain and fever.  It is distinguished from diverticulosis by the presence of inflammation, which may or may not cause symptom. 

When symptomatic, the patlent experiences colicky left lower abdominal pain, change in bowel habits, and melena, so-called " left-sided appendicitis." 

Pathology 
Grossly, diverticula are seen most frequently in the sigmoid colon. 

Inflammatory diseases 

1. Crohn's disease, or regional enteritis, causes a segmental, recurrent, granulomatous inflammatory disease of the bowel. It most commonly involves the terminal ileum and colon but may involve any part of the gastrointestinal tract. There is a familial disposition. 
Etiology.

There is probably a similar etiology for both Crohn's disease and ulcerative colitis, which together are called inflammatory bowel disease. The following possible etiologies have been considered: infectious; immunologic (both antibody-mediated and cell-mediated); deficiencies of suppressor cells; and nutritional, hormonal, vascular, and traumatic factors. 

Clinical features.

Crohn's disease usually begins in early adulthood and is common in Ashkenazic Jews. Patients present with colicky pain, diarrhea, weight loss, malaise, malabsorption, low-grade fever, and melena. There is typically a remitting and relapsing course. If the involved bowel is resected, lesions frequently develop in previously uninvolved regions of the bowel. 

Pathology. Crohn's disease has a very characteristic pathology. 
Grossly, there are segmental areas (skip lesions) of involvement, most commonly in the terminal ileum. 

3. Ulcerative colitis is a chronic relapsing disease characterized by ulcerations, predominantly of the rectum and left colon, but which may affect the entire colon and occasionally the terminal ileum.

Incidence is higher in Caucasians than in Blacks, and is also more frequent in women than in men. The typical age of onset ranges from 12-35 years of age. There is a definite familial predisposition. 

Etiology. Etiologic theories are similar to those for Crohn's disease. Some inflammatory bowel disease has microscopic  features of both ulcerative colitis and Crohn's disease. 

Clinical course is characterized by relapsing bloody mucus diarrhea, which may lead to dehydration and electrolyte  imbalances, lower abdominal pain, and cramps. There is an  increased incidence of carcinoma of the colon, up to 50% after 25 years with the disease. 

Pathology 

Grossly, the disease almost always involves the rectum. It may extend proximally to involve part of the colon or its entirety. There are superficial mucosal ulcers, shortening of the bowel, narrowing of the lumen, pseudopolyps, and backwash ileitis. 

In contrast to Crohn's disease, the inflammation is usually confined to the mucosa and submucosa. 

Pseudomembranous colitis is an inflammatory process characterized by a pseudomembranous exudate coating the colonic mucosa 

Pathogenesis. The syndrome is associated with antibiotic  use (especially clindamycin), allowing proliferation of Clostridium difficile, which produces an exotoxin.

Clinical features include diarrhea that is often bloody, fever, and leukocytosis.
Diagnosis is made by identification of C. difficile and toxin  in stool.
Treatment includes stopping the original antibiotic and starting oral vancomycin or metronidazole. This disease is often a terminal complication in immunosuppressed patients. 

Vascular lesions 
Hemorrhoids are variceal dilatations of the anal and perianal venous plexus. They are caused by elevated intra-abdominal venous pressure, often from constipation and pregnancy and are occasionally due to portal hypertension, where they are associated with esophageal varices. Hemorrhoids may under thrombosis, inflammation, and recanalization. External hemorrhoids are due to dilatation of the inferior hemorrhoidal
plexus, while internal hemorrhoids are due to dilatation of the superior hemorrhoidal plexus. 

Polyps are mucosal protrusions. 

1. Hyperplastic polyps comprise 90% of all polyps. They are no neoplastic and occur mostly in the rectosigmoid colon. 
Grossly, they form smooth, discrete, round elevations.

2. Adenomatous polyps are true neoplasms. There is a higher incidence of cancer in larger polyps and in those containing a greater proportion of villous growth.

a. Tubular adenomas (pedunculated polyps) make up 75% of adenomatous polyps. They may be sporadic or familial 

For sporadic polyps, the ratlo of men to women is 2:1. The average age of onset is 60. 
Grossly, most occur in the left colon. Cancerous transformation (i.e., invasion of the lamina propria or the stalk) occurs in approximately 4% of patients.

b. Villous adenomas are the largest, least common polyps, and are usually sessile. About one-third are cancerous. Most are within view of the colonoscope. 
(1) Grossly, they form "cauliflower-like" sessile growth 1-10 cm in diameter, which are broad-based and have no stalks. 

3. Familial polyposis is due to deletion of a gene located on chromosome 5q. 

Familial multiple polyposis (adenomatous polyposis coli) shows autosomal dominant inheritance and the appearance of polyps during adolescence; polyps start in the rectosigmoid area and spread to cover the entire colon. The polyps are indistinguishable from sporadic adenomatous polyps. Virtually all patients develop cancers. When diagnosed, total colectomy is recommended. 

Gardner's syndrome refers to colonic polyps associated with other neoplasms (e.g., in skin, subcutaneous tissue, bone) and desmoid tumors. The risk of colon cancer is nearly 100%. 

Peutz-Jeghers syndrome presents with polyps on the entire gastrointestinal tract (especially the small intestine) associ-
ated with melanin pigmentation of the buccal mucosa, lips, palms, and soles. The polyps are hamartomas and are not premalignant. Peutz-Jeghers syndrome shows autosomal dominant inheritance. 

Turcot's syndrome is characterized by colonic polyps associated with brain tumors (i.e., gliomas, medulloblastomas). 

Malignant tumors 

Adenocarcinoma is the histologic type of 98% of all colonic cancers. Both environmental and genetic factors have been
identified.

Incidence is very high in urban, Western societies. It is the  third most common tumor in both women and men. The peak incidence
is in the seventh decade of life. 

Pathogenesis is associated with villous adenomas, ulcerative colitis, Crohn's disease, familial polyposis, and Gardner's syndrome. lncidence is possibly related to high meat intake, low-fiber diet, and deficient vitamin intake. A number of chromosomal abnormalities hme been associated with the development of colon cancer. 

Clinical features include rectal bleeding, change in bow habits, weakness, malaise, and weight loss in high-stage disease. The tumor spread by direct metastasis to nodes, liver, lung, and bones. carcinoembryonic antigen (CEA) is a tumor marker that helps to monitor tumor recurrence after surgery or tumor progression in  some patients.

Pathology 
(1) Grossly, 75% of tumors occur in the rectum and sigmoid colon.
(2) Microscopically, these tumors are typical mucin-producing adenocarcinomas. 
2. Squamous cell carcinoma forms in the anal region. It is often associated with papilloma viruses and its incidence is rising in homosexual males with AIDS. 

DYSPLASIA
 It is disturbed growth or  cells in regard to their size, shape arrangement. In its mild degrees it represents a reversible reaction to chronic inflammation whereas the most severe degrees warrant a labelling of intraepithelial neoplasia. Hence it includes a wide spectrum of changes ranging from a reversible disorientation to 'carcinoma-in-situ'.

Histologically it is characterized by:

o    Basal cell hyperplasia.
o    Variation in size and shape of cells.
o    Disorderly maturation.
o    Increased mitotic activity.
o    Disorientation of arrangement of cells (loss of polarity)

Dysplasia is commonly seen in:

o    Squamous epithelium of cervix.
o    Bronchial epithelium in habitual smokers.
o    Gastric and colonic mucosa in long standing inflammation
o    Oral and vulval leucoplakia
 

Neutrophilia
Causes
    
-Pyogenic infections.
-Haemorrhage and trauma.
-Malignancies.
-Infarction.
-Myelo proliferative disorders.