NEET MDS Lessons
General Pathology
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.
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.
(I) 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
(ii) 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).
(I) 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.
German measles (rubella)
- sometimes called "three day measles".
- incubation 14-21 days; infectious 7 days before the rash and 14 days after the onset of the rash.
- in adults, rubella present with fever, headache, and painful postauricular Lymphadenopathy 1 to 2 days prior to the onset of rash, while in children, the rash is usually the first sign.
- rash (vasculitis) consists of tiny red to pink macules (not raised) that begins on the head and spreads downwards and disappears over the ensuing 1-3 days; rash tends to become confluent.
- 1/3rd of young women develop arthritis due to immune-complexes.
- splenomegaly (50%)
DIPHTHERIA
An acute, contagious disease caused by Corynebacterium diphtheriae, characterized by the formation of a fibrinous pseudomembrane, usually on the respiratory mucosa, and by myocardial and neural tissue damage secondary to an exotoxin.
Cutaneous diphtheria (infection of the skin) can occur when any disruption of the integument is colonized by C. diphtheriae. Lacerations, abrasions, ulcers, burns, and other wounds are potential reservoirs of the organism. Skin carriage of C. diphtheriae is also a silent reservoir of infection.
Pathology
C. diphtheriae may produce exotoxins lethal to the adjacent host cells. Occasionally, the primary site is the skin or mucosa elsewhere. The exotoxin, carried by the blood, also damages cells in distant organs, creating pathologic lesions in the respiratory passages, oropharynx, myocardium, nervous system, and kidneys.
The myocardium may show fatty degeneration or fibrosis. Degenerative changes in cranial or peripheral nerves occur chiefly in the motor fibers
In severe cases, anterior horn cells and anterior and posterior nerve roots may show damage proportional to the duration of infection before antitoxin is given. The kidneys may show a reversible interstitial nephritis with extensive cellular infiltration.
The diphtheria bacillus first destroys a layer of superficial epithelium, usually in patches, and the resulting exudate coagulates to form a grayish pseudomembrane containing bacteria, fibrin, leukocytes, and necrotic epithelial cells. However, the areas of bacterial multiplication and toxin absorption are wider and deeper than indicated by the size of the membrane formed in the wake of the spreading infection.
Jaundice, or icterus
a. Characterized by yellowness of tissues, including skin, eyes, and mucous membranes.
b. Caused by excess conjugated and/or unconjugated serum bilirubin. (increased levels of bilirubin in the blood)
lcterus is visible when the serum bilirubin exceeds 2 mg/dl. In unconjugated hyperbilirubinemia, bilirubin is not excreted into the urine because of tight protein binding in serum. In conjugated hyperbilirubinemia, small amounts of bilirubin are excreted in the urine because
it is less tightly protein bound.
NOTE: Concentration of bilirubin in blood plasma does not normally exceed 1 mg/dL (>17µmol/L). A concentration higher than 1.8 mg/dL (>30µmol/L) leads to jaundice.
The conjunctiva of the eye are one of the first tissues to change color as bilirubin levels rise in jaundice. This is sometimes referred to as scleral icterus.
c. Types and causes include:
(1) Hepatocellular jaundice—caused by liver diseases such as cirrhosis and hepatitis.
(2) Hemolytic jaundice—caused by hemolytic anemias.
(3) Obstructive jaundice—caused by blockage of the common bile duct either by gallstones (cholelithiasis) or carcinomas involving the head of
the pancreas.
Differential diagnosis
Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are:
Pre-hepatic → The pathology is occurring prior to the liver.
Hepatic → The pathology is located within the liver.
Post-Hepatic → The pathology is located after the conjugation of bilirubin in the liver.
Pre-hepatic
Pre-hepatic jaundice is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells).
Certain genetic diseases, such as sickle cell anemia, spherocytosis, thalassemia and glucose 6-phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic jaundice.
Commonly, diseases of the kidney, such as hemolytic uremic syndrome, can also lead to coloration. Defects in bilirubin metabolism also
present as jaundice, as in Gilbert's syndrome (a genetic disorder of bilirubin metabolism which can result in mild jaundice, which is found in about 5% of the population) and Crigler-Najjar syndrome.
In jaundice secondary to hemolysis, the increased production of bilirubin, leads to the increased production of urine-urobilinogen. Bilirubin is not usually found in the urine because unconjugated bilirubin is not water-soluble, so, the combination of increased urine-urobilinogen with no bilirubin (since, unconjugated) in urine is suggestive of hemolytic jaundice.
Laboratory findings include:
• Urine: no bilirubin present, urobilinogen > 2 units (i.e., hemolytic anemia causes increased heme metabolism; exception: infants where gut flora has not developed).
• Serum: increased unconjugated bilirubin.
• Kernicterus is associated with increased unconjugated bilirubin.
Hepatocellular
Hepatocellular (hepatic) jaundice can be caused by acute or chronic hepatitis, hepatotoxicity, cirrhosis, drug induced hepatitis and alcoholic liver disease. Cell necrosis reduces the liver's ability to metabolize and excrete bilirubin leading to a buildup of unconjugated bilirubin in the blood.
Laboratory findings depend on the cause of jaundice.
• Urine: Conjugated bilirubin present, urobilirubin > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.
• Plasma protein show characteristic changes.
• Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.
Bilirubin transport across the hepatocyte may be impaired at any point between the uptake of unconjugated bilirubin into the cell and transport of conjugated bilirubin into biliary canaliculi.
Post-hepatic
Post-hepatic jaundice, also called obstructive jaundice, is caused by an interruption to the drainage of bile in the biliary system. The most common causes are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas. Also, a group of parasites known as "liver flukes" can live in the common bile duct, causing obstructive jaundice. Other causes include strictures of the common bile duct, biliary atresia, cholangiocarcinoma, pancreatitis and pancreatic pseudocysts. A rare cause of obstructive jaundice is Mirizzi's syndrome.
Pathophysiology
When RBCs are damaged, their membranes become fragile and prone to rupture. As each RBC traverses through the reticuloendothelial system, its cell membrane ruptures when its membrane is fragile enough to allow this.
Hemoglobin, are released into the blood. The hemoglobin is phagocytosed by macrophages, and split into its heme and globin portions. The globin portion, a protein, is degraded into amino acids and plays no role in jaundice.
Two reactions then take place with the heme molecule.
The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron
and carbon monoxide.
The next step is the reduction of biliverdin to a yellow color tetrapyrol pigment called bilirubin by cytosolic enzyme biliverdin reductase.
This bilirubin is "unconjugated," "free" or "indirect" bilirubin. Approximately 4 mg of bilirubin per kg of blood is produced each day.[11] The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described.
However approximately 20 percent comes from other heme sources, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes.
Hepatic events
The unconjugated bilirubin then travels to the liver through the bloodstream. Because bilirubin is not soluble, however, it is transported through the blood bound to serum albumin.
In Liver, it is conjugated with glucuronic acid (to form bilirubin diglucuronide, or just "conjugated bilirubin") to become more water soluble.
The reaction is catalyzed by the enzyme UDP-glucuronyl transferase.
This conjugated bilirubin is excreted from the liver into the biliary and cystic ducts as part of bile. Intestinal bacteria convert the bilirubin into urobilinogen.
Urobilinogen can take two pathways. It can either be further converted into stercobilinogen, which is then oxidized to stercobilin and passed out in the feces, or it can be reabsorbed by the intestinal cells, transported in the blood to the kidneys, and passed out in the urine as the oxidised product urobilin.
Stercobilin and urobilin are the products responsible for the coloration of feces and urine, respectively.
Congenital heart defect
Congenital heart defects can be broadly categorised into two groups,
o acyanotic heart defects ('pink' babies) :
An acyanotic heart defect is any heart defect of a group of structural congenital heart defects, approximately 75% of all congenital heart defects.
It can be subdivided into two groups depending on whether there is shunting of the blood from the left vasculature to the right (left to right shunt) or no shunting at all.
Left to right shunting heart defects include
- ventricular septal defect or VSD (30% of all congenital heart defects),
- persistent ductus arteriosus or PDA,
- atrial septal defect or ASD,
- atrioventricular septal defect or AVSD.
Acyanotic heart defects without shunting include
- pulmonary stenosis, a narrowing of the pulmonary valve,
- aortic stenosis
- coarctation of the aorta.
cyanotic heart defects ('blue' babies).
obstructive heart defects
cyanotic heart defect is a group-type of congenital heart defect. These defects account for about 25% of all congenital heart defects. The patient appears blue, or cyanotic, due to deoxygenated blood in the systemic circulation. This occurs due to either a right to left or a bidirectional shunt, allowing significant proportions of the blood to bypass the pulmonary vascular bed; or lack of normal shunting, preventing oxygenated blood from exiting the cardiac-pulmonary system (as with transposition of the great arteries).
Defects in this group include
hypoplastic left heart syndrome,
tetralogy of Fallot,
transposition of the great arteries,
tricuspid atresia,
pulmonary atresia,
persistent truncus arteriosus.
POLYCYTHEMIA
It is an increase in number of RC per unit volume of blood (Hb more than 1.9.5 gms% and 18 gms% for women)
Causes :
True polycythemia.
- Idiopathic Polythemia vera.
- Secondary to :
o Hypoxia of high altitude , heart disease, chronic lung disease etc.
o Erythopoietin oversecretion as in renal diseases , tumours of liver, kidney and adrenal etc.
o Compensatory in haemogIobinopathies
- Relative polycythemia due to reduction in plasma volume as in dehydration or in redistribution off fluids
Polycythemia vera: It is a myeloprolifeative disorder, usually terminating in myelosclerosis.
Features: are due to hypervolaemic circulation and tendency to tbrombosis and haemorrhage
-Headaches, dizziness and cardiovascular accidents.
-Hypertension.
-Peripheral vascular thrombosis.
-GIT bleeding. retinal haemorrhage.
-Gout.
-Pruritus.
Blood Finding
-Increased Hb. PCV and RBC count.
-Leucocytosis with high alkaline phosphatase.
-Platelets increased.
Marrow picture Hypercellular with increase in precursors of all series
Course Chronic course ending in myelosclerosis or acute leukaemia.