NEET MDS Lessons
General Pathology
Thrombosis
Definition-The formation from constituents of the blood, of a mass within the venous or arterial vasculature of a living animal. Natural defense of the body to acute vascular injury.
Pathologic thrombosis includes deep venous thrombosis (DVT), pulmonary embolism (PE), coronary artery thrombosis leading to myocardial infarct and cerebrovascular thrombosis leading to stroke.
Coagulated blood- clots formed
Clot – formation of solid mass of blood components formed outside the vascular tree
Thrombosis with resulting embolic phenomena is important cause of morbidity and mortality.
Haemostatic system allows blood to remain in fluid form under normal conditions and causes the development of temporary thrombus at site of vascular injury.
Components of haemostatic system:
1. Platelets
2. Vascular endothelium
3. Procoagulant plasma protein clotting factors
4. Natural anticoagulants
5. Fibrinolytic proteins
6. Antifibrinolytic proteins
Normal haemostasis:
1. Primary haemostasis-platelet plug formation
2. Secondary haemostasis-stable plug or thrombus
3. Natural anticoagulants-confines thrombus site and size to maintain blood flow
4. Fibrinolysis-degrades fibrin , limits thrombus size and dissolves thrombus once vessel injury is repaired
Changes in any of these factors may result in pathologic thrombosis.
Pathophysiology of thrombosis:
Virchow’s Triad-Thrombosis results from a) decreased blood flow b) vascular endothelial injury and c) alterations in the components of blood.
Vessel wall:
EC (intima), smooth muscle cells (media) and the connective tissue (adventitia).Vascular endothelium is thromboresistant. EC injury leads to TF expression and thrombosis.
Vessel wall has antiplatelet, anticoagulant and fibrinolytic activities which make it thromboresistant.
Antiplatelet activities:
1. Prostacyclin synthesized by EC in response to thrombin. Inhibits platelet adhesion as well as causes vasodilation
2. NO regulates vascular tone as well as functioning as inhibitor of platelet adhesion. Constitutive expression as well as induced expression by EC in response to cytokines
3. Ectozymes which metabolize ADP and ATP to AMP and adenosine. Adenosine inhibits platelet function, ADP is platelet agonist
Anticoagulant activities:
1. Synthesis of heparin like GAG which inactivate activated clotting factors
2. Protein C and S and thrombomodulin-Thrombin generated binds to thrombomodulin which activates protein C which then binds to Protein S and this inhibits coagulation by its proteolytic effect on Factors Va and VIIIa
3. TFPI is synthesized by EC and regulates TF-VIIa activation of Factor X. Also inhibits vascular cell proliferation
Fibrinolytic activities:
1. Secretion and synthesis of plasminogen activators TPA in response to thrombin and vasoactive stimulants such as vasopressin and histamine
2. Synthesis of urokinase in response to inflammatory cytokines
3. FDP’s generated have antiplatelet and antithrombin activity
4. Secretion of PAI
Prothrombotic properties of vascular endothelium promote coagulation with appropriates stimuli.
EC exposure to stimuli such as trauma, cytokines, atherogenic stimuli, endotoxins and immune complexes result in increased TF expression, reduced Protein C activation and reduced fibrinolysis so converting an antithrombotic surface to a prothrombotic surface.
Inherited conditions which result in abnormalities of EC derived or regulated proteins will cause thrombosis.
Arterial thrombosis:
1. Abnormal vessel wall due to atherosclerotic plaque rupture, arterial outflow obstruction, vessel dissection EC injury promote platelet adhesion and activation
2. Release of contents of platelet granules cause recruitment and activation of additional platelets
3. Thromboxane synthesis induces platelet aggregation
4. Thrombin generation due to presence of PL
Platelets are pathogenetically more important in arterial thrombi thus antiplatelet agents are very important in arterial thrombosis management.
Venous thrombosis:
1. Vessel wall is usually normal except if there is direct vessel trauma, extrinsic venous compression or damage due to drugs like chemotherapy
2. Reduction in venous tone is important in pathophysiology
Venous thrombi can be of two types.
A. Phlebo thrombosis
This is thrombus formation in an uninflammed vein usually due to stasis or changes in coagulability of blood. This occurs mostly in deep calf veins and varicose veins in the legs originating near valve pockets. They may propagate to extend to popliteal ,femoral and iliac-veins. These are a common source of massive emboli ‘Phlegmasia alba dolens’ (painful white leg) is a condition seen in late pregnancy and puerperium. In this condition, in addition to iliofemoral thrombosis , there is arterial spasm
B Thrombophlebitis:
In this condition venous wall is inflamed and initiates thrombosis. This is more firmly attached to the vessel wall and also there is much less tendency for propagation Hence there is little chance or embolism.
Cardiac Thrombosis
Intra cardiac thrombus formation can be at 3 sites
• Valvular: as in endocarditis
• Atrial : as in atrial fibrilation ('ball valve thrombus") over MacCallum’s patch is Rheumatic Fever.
• Ventricular mural thrombus over site of MI
Fate of Thrombus
- Resolution : if small, the thrombus is rapidly covered by endothelial cells. Then it can Resolved by a combination of retraction, phgocytosis , platelet autolysis, and fibrinolysis
- Organisation: there is in growth of vascular granulation tissue. This can result in
a. recanalisation
b. collagenisation and-scarring
- Detachment resulting in thromboembolism
VIRAL DISEASES
RABIES (Hydrophobia)
An acute infectious disease of mammals, especially carnivores, characterized by CNS pathology leading to paralysis and death.
Etiology and Epidemiology
Rabies is caused by a neurotropic virus often present in the saliva of rabid animals
Pathology
The virus travels from the site of entry via peripheral nerves to the spinal cord and the brain, where it multiplies; it continues through efferent nerves to the salivary glands and into the saliva.
microscopic examination shows perivascular collections of lymphocytes but little destruction of nerve cells. Intracytoplasmic inclusion bodies (Negri bodies), usually in the cornu Ammonis, are pathognomonic of rabies, but these bodies are not always found.
Sign/Symptoms
In humans, the incubation period varies from 10 days to > 1 yr and averages 30 to 50 days.
Rabies commonly begins with a short period of depression, restlessness, malaise, and fever. Restlessness increases to uncontrollable excitement, with excessive salivation and excruciatingly painful spasms of the laryngeal and pharyngeal muscles. The spasms, which result from reflex irritability of the deglutition and respiration centers, are easily precipitated Hysteria due to fright
Prognosis and Treatment
Death from asphyxia, exhaustion, or general paralysis usually occurs within 3 to 10 days after onset of symptoms
NECROSIS
Definition: Necrosis is defined as the morphologic changes caused by the progressive degradative
action of enzymes on the lethally injured cell.
These changes are due to
I. Autolysis and
2. Heterolysis.
The cellular changes of necrosis i.e. death of circumscribed group of cells in continuity with living tissues are similar to changes in tissues following somatic death, except that in the former, there is leucocytic infiltration in reaction to the dead cells and the lytic
enzymes partly come from the inflammatory cell also. (Heterolysis). Cell death occurs in the normal situation of cell turnover also and this is called apoptosis-single cellular dropout.
Nuclear changes in necrosis
As cytoplasmic changes are a feature of degeneration ,similarly nuclear changes are the hallmark of necrosis. These changes are:
(i) Pyknosis –condensation of chromatin
(ii) Karyorrhexis - fragmentation
(iii) Karyolysis - dissolution
Types of necrosis
(1) Coagulative necrosis: Seen in infarcts. The architectural outlines are maintained though structural details are lost. E.g, myocardial infarct.
(2) Caseous necrosis: A variant of coagulative necrosis seen in tuberculosis. The architecture is destroyed, resulting in an eosinophilic amorphous debris.
(3) Colliquative (liquifactive). Necrosis seen in Cerebral infarcts and suppurative necrosis.
Gangrenous necrosis: It is the necrosis with superadded putrefaction
May be:
a. dry - coagulative product.
b. Wet - when there is bacterial liquifaction.
Fat necrosis
May be:
a. Traumatic (as in breast and subcutaneous tissue).
b Enzymatic (as in pancreatitis). It shows inflammation of fat with formation of lipophages and giant cells.
This is often followed by deposition of calcium as calcium soaps.
Hyaline necrosis: Seen in skeletal muscles in typhoid and in liver ceIs in some forms of hepatitis.
Fibrinoid necrosis: In hypertension and in immune based diseases.
Joint pathology
1. Rheumatoid arthritis
a. Cause is autoimmune in nature.
b. More common in women aged 20 to 50.
c. Characterized by inflammation of the synovial membrane. Granulation tissue, known as pannus, will form in the synovium and expand over the articular cartilage. This causes the destruction of the underlying cartilage and results in fibrotic changes and ankylosis.
Scarring, contracture, and deformity of the joints may occur.
d. Clinical symptoms include swollen joints. It can affect any joint in the body.
2. Osteoarthritis
a. Most common arthritis.
b. Cause is unknown.
c. Higher incidence in women, usually after age 50.
d. Characterized by degeneration of the articular cartilage and the formation of osteophytes (bony spurs) at the margins of affected areas.
Clinical signs and symptoms include:
(1) Stiff and painful joints affecting joints in the hand (phalangeal joints) and weight-bearing joints.
(2) Heberden’s nodes—nodules at the distal interphalangeal joint.
(3) Bocard’s nodes—nodules at the proximal interphalangeal joint.
Salivary gland pathology
Inflammation
a. Sialolithiasis produces a secondary inflammatory reaction to obstruction and the resultant enlargement of ducts by stones. It may be complicated by actual infection with mouth flora.
b. Sialadenitis is a primary inflammatory reaction, but it is not always infectious. It may be part of an autoimmune disease (e.g., Sjogren's syndrome), or the result of bacterial or virals (e.g., mumps) infection.
Sjögren’s syndrome
a. An autoimmune disease of the salivary and lacrimal glands.
b. Autonuclear antibodies (ANAs) against salivary ducts may be seen.
c. Triad of symptoms include:
(1) Xerostomia—from decreased saliva production.
(2) Keratoconjunctivitis sicca (dry eyes)—from decreased tear production.
(3) Rheumatoid arthritis.
(4) Enlargement of the salivary or lacrimal glands, known as Mikulicz syndrome, may also be observed.
d. Histologically, a dense infiltration of the gland by lymphocytes is observed.
Tumors
The parotid gland accounts for more than three-quarters of these tumors, most of which are benign. Of the remainder, more occur in the submandibular gland than in the sublingual, and most of these are malignant. Many are surgically, cured, but local recurrence is common.
a. Pleomorphic adenoma is generally benign and accounts for approximately three-quarters of all salivary gland tumors. If is composed of multiple epithelial and mesenchymal cell types. Complications may arise due to involvement of cranial nerve VII.
(a) The most common salivary gland tumor.
(b) Is benign.
(c) Prognosis is good after proper surgical excision.
b. Warthin's tumor (adenolymphoma) is also benign, occuring almost exclusively in the parotid gland. It is grossly cystic.
Microscopic examination reveals cell types suggestive of branchial cleft origin embedded in a lymphoid matrix.
c. Mucoepidermoid tumors also occur primarily in the parotid and have a high rate of malignant transformation.The malignant component is usually squamous cell. Prognosis of tumor depends on grade and stage of disease.
d. Cylindroma (adenoid cysticc. Mucoepidermoid tumors carcinoma) is more common in the minor salivary glands found in the oral mucosa, and metastases are more common than in other tumors of the salivary glands. Facial nerve complications are frequent.
(1) Grossly, the tumor forms multiple lobules surrounded by a capsule.
(2) Microscopically, small cells form glands containin mucoid material
Hyperparathyroidism
Hyperparathyroidism is defined as an elevated secretion of PTH, of which there are three main types:
1. Primary—hypersecretion of PTH by adenoma or hyperplasia of the gland.
2. Secondary—physiological increase in PTH secretions in response to hypocalcaemia of any cause.
3. Tertiary—supervention of an autonomous hypersecreting adenoma in long-standing secondary hyperparathyroidism.
Primary hyperparathyroidism
This is the most common of the parathyroid disorders, with a prevalence of about 1 per 800
It is an important cause of hypercalcaemia.
More than 90% of patients are over 50 years of age and the condition affects females more than males by nearly 3 : 1.
Aetiology
Adenoma 75% -> Orange−brown, well-encapsulated tumour of various size but seldom > 1 cm diameter Tumours are usually solitary, affecting only one of the parathyroids, the others often showing atrophy; they are deep seated and rarely palpable.
Primary hyperplasia 20% -> Diffuse enlargement of all the parathyroid glands
Parathyroid carcinoma 5% -> Usually resembles adenoma but is poorly encapsulated and invasive locally.
Effects of hyperparathyroidism
The clinical effects are the result of hypercalcaemia and bone resorption.
Effects of hypercalcaemia:
- Renal stones due to hypercalcuria.
- Excessive calcification of blood vessels.
- Corneal calcification.
- General muscle weakness and tiredness.
- Exacerbation of hypertension and potential shortening of the QT interval.
- Thirst and polyuria (may be dehydrated due to impaired concentrating ability of kidney).
- Anorexia and constipation
Effects of bone resorption:
- Osteitis fibrosa—increased bone resorption with fibrous replacement in the lacunae.
- ‘Brown tumours’—haemorrhagic and cystic tumour-like areas in the bone, containing large masses of giant osteoclastic cells.
- Osteitis fibrosa cystica (von Recklinghausen disease of bone)—multiple brown tumours combined with osteitis fibrosa.
- Changes may present clinically as bone pain, fracture or deformity.
about 50% of patients with biochemical evidence of primary hyperparathyroidism are asymptomatic.
Investigations are:
- Biochemical—increased PTH and Ca2+ , and decreased PO43- .
- Radiological—90% normal; 10% show evidence of bone resorption, particularly phalangeal erosions.
Management is by rehydration, medical reduction in plasma calcium using bisphosphonates and eventual surgical removal of abnormal parathyroid glands.
Secondary hyperparathyroidism
This is compensatory hyperplasia of the parathyroid glands, occurring in response to diseases of chronic low serum calcium or increased serum phosphate.
Its causes are:
- Chronic renal failure and some renal tubular disorders (most common cause).
- Steatorrhoea and other malabsorption syndromes.
- Osteomalacia and rickets.
- Pregnancy and lactation.
Morphological changes of the parathyroid glands are:
- Hyperplastic enlargement of all parathyroid glands, but to a lesser degree than in primary hyperplasia.
- Increase in ‘water clear’ cells and chief cells of the parathyroid glands, with loss of stromal fat cells.
Clinical manifestations—symptoms of bone resorption are dominant.
Renal osteodystrophy
Skeletal abnormalities, arising as a result of raised PTH secondary to chronic renal disease, are known as renal osteodystrophy.
Pathogenesis
renal Disease + ↓ vit. D activation , ↓ Ca 2+ reabsorption → ↓ serum Ca 2+ → ↑ PTH → ↓ bone absorption
Abnormalities vary widely according to the nature of the renal lesion, its duration and the age of the patient, but include:
- Osteitis fibrosa .
- Rickets or osteomalacia due to reduced activation of vitamin D.
- Osteosclerosis—increased radiodensity of certain bones, particularly the parts of vertebrae adjacent to the intervertebral discs.
The investigations are both biochemical (raised PTH and normal or lowered Ca 2+ ) and radiological (bone changes).
Management is by treatment of the underlying disease and oral calcium supplements to correct hypocalcaemia.
Tertiary hyperparathyroidism
This condition, resulting from chronic overstimulation of the parathyroid glands in renal failure, causes one or more of the glands to become an autonomous hypersecreting adenoma with resultant hypercalcaemia.
Tuberculosis
Causative organism
-Mycobacterium tuberculosis
-Strict aerobe
-Pathogenic strains
-hominis, bovis, avium, murine& cold blooded vertebrate strain
Koch’s bacillus
-small slender, rod like bacillus, 4umnon-motile, aerobic -high lipid content
-divides every 16 to 20 hours, an extremely slow rate
-stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolicacid content of its cell wall
-can withstand weak disinfectant and survive in a dry state for weeks.
Demonstrated by
-ZiehlNeelsenstaining
-Fluorescent dye method
-Culture in LJ media
-Guinea pig inoculation
Modes of transmission
Inhalation , Ingestion, Inoculation , Transplacental
Route Spread
Local , Lymphatic , Haematogenous , By natural passages,
Pathogenesis
- Anti‐mycobacterial CMI, confers resistance to bacteria → dev. of HS to tubercular Ag
- Bacilli enters macrophages
- Replicates in phagosomeby blocking fusion of phagosome& lysosome, continues for 3 weeks →bacteremiabut asymptomatic
- After 3 wks, T helper response is mounted by IL‐12 produced by macrophages
- T cells produce IFN, activates macrophages → bactericidal activity, structural changes
- Macrophages secrete TNF→ macrophage recruitment, granuloma& necrosis
Fate of granuloma
- Caseousmaterial undergo liquefaction---cold abscess
- Bones, joints, lymph nodes & epididymis---sinuses are formed & sinus tract lined by tuberculousgranulation tissue
- Dystrophic calcification
Types of TB
1. Primary Pulmonary TB
2. secondary TB (miliary, fibrocaseous, cavitary)
3. Extra-pulmonary TB (bone, joints, renal, adrenal, skin… )
Primary TB
Infection in an individual who has not been previously infected or immunised
Primary complex
Sites
-lungs, hilarlymph nodes
-tonsils, cervical lymph nodes
-small intestine, mesenteric lymph nodes
Primary TB
In the lung, Ghon’scomplex has 3 components:
1. Pulmonary component -Inhalation of airborne droplet ~ 3 microns.
-Bacilli locate in the subpleuralmid zone of lung
-Brief acute inflammation –neutrophils.
-5-6 days-invoke granulomaformation.
-2 to 8 weeks –healing –single round ;1-1.5 cm-Ghon focus.
2. Lymphatic vessel component
3. Lymph node component
Fate of primary tuberculosis
- Lesions heal by fibrosis, may undergo calcification, ossification
-a few viable bacilli may remain in these areas
-bacteria goes into a dormant state, as long as the person's immune system remains active
- Progressive primary tuberculosis: primary focus continues to grow & caseousmaterial disseminated to other parts of lung
- Primary miliarytuberculosis: bacilli may enter circulation through erosion of blood vessel
- Progressive secondary tuberculosis: healed lesions are reactivated, in children & in lower resistance
Secondary tuberculosis
-Post-primary/ reinfection/ chronic TB
-Occurs in immunized individuals.
-Infection acquired from
-endogenous source/ reactivation
-exogenous source/ reinfection
Reactivation
-when immune system is depressed
-Common in low prevalence areas.
-Occurs in 10-15% of patients
-Slowly progressive (several months)
Re-infection
-when large innoculum of bacteria occurs
-In areas with increased personal contact
Secondary TB
-Sites-Lungs 1-2 cm apical consolidation with caseation
-Other sites -tonsils, pharynx, larynx, small intestine & skin
Fate of secondary tuberculosis
•Heal with fibrous scarring & calcification
•Progressive secondary pulmonary tuberculosis:
-fibrocaseoustuberculosis
-tuberculouscaseouspneumonia
-miliarytuberculosis
Complications:
a) aneurysm of arteries–hemoptysis
b) bronchopleuralfistula
c) tuberculousempyema
MiliaryTB
• Millet like, yellowish, firm areas without caseation
• Extensive spread through lympho-hematogenousroute
• Low immunity
• Pulmonary involvement via pulmonary artery
• Systemic through pulmonary vein:
-LN: scrofula, most common
-kidney, spleen, adrenal, brain, bone marrow
Signs and Symptoms of Active TB
• Pulmonary-cough, hemoptysis, dyspnea
• Systemic:
• fever
• night sweats
• loss of appetite
• weight loss
• chest pain,fatigue
•If symptoms persist for at least 2 weeks, evaluate for possible TB infection
Diagnosis
•Sputum-Ziehl Neelsen stain –10,000 bacilli, 60% sensitivity
-release of acid-fast bacilli from cavities intermittent.
-3 negative smears : low infectivity
•Culture most sensitive and specific test.
-Conventional Lowenstein Jensen media-10 wks.
-Liquid culture: 2 weeks
•Automated techniques within days
should only be performed by experienced laboratories (10 bacilli)
•PPD for clinical activity / exposure sometime in life
•X-ray chest
•FNAC
PPD Tuberculin Testing
- Read after 72 hours.
- Indurationsize -5-10 mm
- Does not d/s b/w active and latent infection
- False +: atypical mycobacterium
- False -: malnutrition, HD, viral, overwhelming infection, immunosuppression
- BCG gives + result.
Tuberculosis Atypical mycobacteria
- Photochromogens---M.kansasii
- Scotochromogens---M.scrofulaceum
- Non-chromogens---M.avium-intracellulare
- Rapid growers---M.fortuitum, M.chelonei
5 patterns of disease
- Pulmonary—M.kansasii, M.avium-intracellulare
- Lymphadenitis----M.avium-intracellulare, M.scrofulaceum
- Ulcerated skin lesions----M.ulcerans, M.marinum
- Abscess----M.fortuitum, M.chelonei
- Bacteraemias----M.avium-intracellulare as in AIDS