NEET MDS Lessons
General Pathology
Rickets and Osteomalacia
Rickets in growing children and osteomalacia in adults are skeletal diseases with worldwide distribution. They may result from
1. Diets deficient in calcium and vitamin D
2. Limited exposure to sunlight (in heavily veiled women, and inhabitants of northern climates with scant sunlight)
3. Renal disorders causing decreased synthesis of 1,25 (OH)2-D or phosphate depletion
4. Malabsorption disorders.
Although rickets and osteomalacia rarely occur outside high-risk groups, milder forms of vitamin D deficiency (also called vitamin D insufficiency) leading to bone loss and hip fractures are quite common in the elderly.
Whatever the basis, a deficiency of vitamin D tends to cause hypocalcemia. When hypocalcemia occurs, PTH production is increased, that ultimately leads to restoration of the serum level of calcium to near normal levels (through mobilization of Ca from bone & decrease in its tubular reabsorption) with persistent hypophosphatemia (through increase renal exretion of phosphate); so mineralization of bone is impaired or there is high bone turnover.
The basic derangement in both rickets and osteomalacia is an excess of unmineralized matrix. This complicated in rickets by derangement of endochondral bone growth.
The following sequence ensues in rickets:
1. Overgrowth of epiphyseal cartilage with distorted, irregular masses of cartilage
2. Deposition of osteoid matrix on inadequately mineralized cartilage
3. Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction
4. Microfractures and stresses of the inadequately mineralized, weak, poorly formed bone
5. Deformation of the skeleton due to the loss of structural rigidity of the developing bones
Gross features
• The gross skeletal changes depend on the severity of the disease; its duration, & the stresses to which individual bones are subjected.
• During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. The softened occipital bones may become flattened. An excess of osteoid produces frontal bossing. Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the "rachitic rosary." The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum (pigeon breast deformity). The pelvis may become deformed.
• When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and long bones (e.g., tibia), causing, most notably, lumbar lordosis and bowing of the legs .
• In adults the lack of vitamin D deranges the normal bone remodeling that occurs throughout life. The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, thus producing the excess of persistent osteoid that is characteristic of osteomalacia. Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.
Microscopic features
• The unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae.
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.
Bronchiectasis
- Bronchiectasis is abnormal and irreversible dilatation of the bronchi and bronchioles (greater than 2 mm in diameter) secondary to inflammatory weakening of bronchial wall.
- Occur in childhood and early adult life
- Persistent cough with copious amount of foul smelling purulent sputum
Aetiopathogenesis
Bronchial wall destruction is due to:
- Endobronchial obstruction due to foreign body
- Infection due to local obstruction or impaired defence mechanism
Clinical conditions:
- Hereditary and congenital factors
- Obstruction
- Secondary complication
Hereditary and congenital factors:
- Congenital bronchiectasis due to developmental defects
- Cystic fibrosis causing defective secretion resulting in obstruction
- Hereditary immune defiency diseases
- Immotile cilia syndrome- immotile cilia of respiratory tract, sperms causing Kartagener’s syndrome (bronchiectasis, situs inversus and sinusitis) and male infertility
- Allergic bronchial asthma patients
Obstruction:
Localised variety in one part of bronchial system.
Obstruction can be due to
Foreign body
Endobronchial tumors
Hilar lymph nodes
Inflammatory scarring (TB)
Secondary complication:
Necrotizing pneumonia in Staph infection and TB
Morphologic changes
- Affects distal bronchi and bronchioles
- Lower lobes more frequently
- Lungs involved diffusely/segmentally
- Left lower lobe than right
- Pleura fibrotic & thickened adherent to chest wall
C/S lung: Honey-combed appearance
Microscopic examination:
Bronchiole-dilated
Bronchial epithelium-normal, ulcerated, squamous metaplasia
Bronchial wall-infiltration by ac & Ch inflammatory cells,
destruction of muscle, elastic tissue
Lung parenchyma-fibrosis, surrounding tissue pneumonia
Pleura-fibrotic and adherent
IMMUNO PATHOLOGY
Abnormalities of immune reactions are of 3 main groups
- Hypersensitivity,
- Immuno deficiency,
- Auto immunity.
Hypersensitivity (ALLERGY)
This is an exaggerated or altered immune response resulting in adverse effects
They are classified into 4 main types.
I. Type I-(reaginic, anaphylactic). This is mediated by cytophylic Ig E antibodies, which get bound to mast cells. On re-exposure, the Ag-Ab reaction occurs on the mast cell surface releasing histamine.
Clinical situations
I. Systemic anaphylaxis, presenting with bronchospasm oedema hypertension, and even death.
2. Local (atopic) allergy.
- Allergic rhinitis (hay fever)
- Asthma
- Urticaria.
- Food allergies.
2. Type II. (cytotoxic). Antibody combines with antigen present on-cell surface. The antigen may be naturally present on the surface or an extrinsic substance (e.g.drug) attached to cell surface.
The cell is then destroyed by complement mediated lysis (C89) or phagocytosis of the antibody coated cell.
Clinical situations
- Haemolytic anemia.
- Transfusion reaction
- Auto immune haemolytic anemia.
- Haemolysis due to some drugs like Alpha methyl dopa
2. Drug induced thrombocytopenia (especially sedormid).
3 Agranulocytosis due to sensitivity to some drugs.
4 Goodpasture’s syndrome-glomermerulonephritis due to anti basement membrane antibodies.
3. Type III. (Immune complex disease). Circulating immune complexes especially small soluble complexes tend to deposit in tissues especially kidney, joints, heart and arteries.
These then cause clumping of platelets with subsequent release of histamine. and serotonin resulting in increased permeability. Also, complement activation occurs which being chemotactic results in aggregation of polymorphs and necrotising vasculitis due to release of lysosmal enzymes
Clinical situations
- Serum sickness.
- Immune complex glomerulonephritis.
- Systemic lupus erythematosus.
- Allergic alveolitis.
- Immune based vasculitis like
o Drug induced vasculitis.
o Henoch – Schonlein purpura
4. Type IV. (Cell mediated). The sensitized lymphocytes may cause damage by cytotoxicity or by lymphokines and secondarily involving macrophages in the reaction.
Clinical situations
I. Caseation necrosis in tuberculosis.
2. Contact dermatitis to
- Metals.
- Rubber.
- Drugs (topical).
- Dinitrochlorbenzene (DNCB).
5. Type V. (stimulatory) This is classed by some workers separately and by other with cytotoxic type (Type II) with a stimulatory instead of toxic effect
Clinical Situations :
LATS (long acting thyroid stimulator) results in thyrotoxicosis (Grave’s disease)
Hepatitis C virus.
It is most often mild and anicteric but occasionally severe with fulminant hepatic failure. It is caused an RNA virus, which may be transmitted parenterally (a cause of post-transfusion hepatitis); the route of transmission undetermined in 40%-50% of cases
a. 90% of blood transfusion-related hepatitis is caused by hepatitis C.
b. 50% progress to chronic disease.
c. Increased risk for hepatocellular carcinoma.
d. Incubation period: ranges from 2 to 26 weeks, but averages 8 weeks.
- Antibody is detected by enzyme-linked immunosorbent,assay (ELISA). The incubation period is between 2 and weeks with peak onset of illness 6-8 weeks after infection
- Most patients progress to chronic liver disease, specifically chronic persistent hepatitis or chronic active hepatitis
- Cirrhosis is common in patients with chronic active hepatitis and occurs in 20%-25% of infected patients. HCV is also associated with hepatocellular carcinoma.
e. Treatment and prevention: α-interferon is used to treat chronic hepatitis C. There is currently no vaccine available.
Hepatitis B virus (“serum hepatitis”)
- Hepatitis B (HBV) may cause acute hepatitis, a carrier state, chronic active disease, chronic persistent disease, fulminant hepatitis, or hepatocellular carcinoma
- It is caused by a DNA virus, the virions are called Dane particles.
b. Incubation period: ranges from 4 to 26 weeks, but averages 6 to 8 weeks.
a. Symptoms last 2 to 4 weeks, but may be asymptomatic.
c. The hepatitis B viral structure has also been named the Dane particle.
Transmission is through contact with infected blood or other body fluids. It can be transmitted by sexual intercourse and is frequently transmitted to newborns of infected mothers by exposure to maternal blood during the birth process
- Associated antigens include core antigen (HBcAg) and surface antigen (HBsAg).
The latter is usually identified in the blood for diagnosis. HbsAg is the earliest marker of acute infection.
HBeAg is also associated with the core. Its presence indicates active acute infection; when anti-HBeAg appears, the patient is no longer infective
- HBV is associated with hepatocellular carcinoma; HBsAg patients have a 200-fold greater risk of hepatocellular carcinoma than subjects who have not been exposed.
Antibodies
- Antibodies to surface antigen (anti-HBs) are considered protective and usually appear after the disappearance of the virus.
-Antibodies to HBcAg are not protective. They are , detected just after the appearance of HBsAg and are used to confirm infection when both HBsAg and anti HBs are absent (window).
- Antibodies to HBeAg are associated with a low risk of infectivity.
d. Infection increases the risk for hepatocellular carcinoma.
e. Laboratory assay of hepatitis B antigens and antibodies:
(1) HBsAg—present only in acute infection or chronic carriers.
(2) HBsAb—detectable only after 6 months post-initial infection. HBsAb is present in chronic infections or vaccinated individuals. Note: HBsAb is also being produced during acute infections and in chronic carriers; however, it is not detectable via current laboratory methods.
(3) HBcAg—present in either acute or chronic infection.
(4) HBeAg—present when there is active viral replication. It signifies that the carrier is highly infectious.
(5) HBeAb—appears after HBeAg. It signifies that the individual is not as contagious.
f. Vaccine: contains HBsAg.
g. Prevention: immunoglobulins (HBsAb) are available.
Aneurysm
An aneurysm is a localized abnormal dilation of a blood vessel or the heart
Types:
1. True aneurysm - it involves all three layers of the arterial wall (intima, media, and adventitia) or the attenuated wall of the heart.
e.g. Atherosclerotic, syphilitic, and congenital aneurysms, and ventricular aneurysms that follow transmural myocardial infarctions.
2 False aneurysm
(also called pseudo-aneurysm) is a breach in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space ("pulsating hematoma").
E.g. ventricular ruptures after MI that are contained by a pericardial adhesion
E.g. a leak at the junction of a vascular graft with a natural artery.
Aneurysms are classified by macroscopic shape and size
Saccular aneurysms
spherical outpouchings (involving only a portion of the vessel wall, and often contain thrombi.
Fusiform aneurysms
diffuse, circumferential dilation of a long vascular segment;
they vary in diameter and length and can involve extensive portions of the aortic arch, abdominal aorta, or even the iliacs.
Aortic Aneurysm
The two most important causes are:
1- atherosclerosis : the most common cause
It causes thinning and weakening of the media. The intimal plaques compress the underlying media and also compromise nutrient and waste diffusion from the vascular lumen into the arterial wall. The media consequently undergoes degeneration and necrosis, thus allowing the dilation of the vessel
2- cystic medial degeneration of the arterial media. E.g. Marfan syndrome.
3- Other causes include: trauma, congenital defects (e.g., berry aneurysms), infections (mycotic aneurysms), systemic diseases, such as vasculitis.
Mycotic Aneurysm :
Infection of a major artery that weakens its wall is called a mycotic aneurysm
possible complications: thrombosis and rupture.
It can originate from:
(1) embolization of a septic thrombus, usually as a complication of infective endocarditis
(2) extension of an adjacent suppurative process;
(3) circulating organisms directly infecting the arterial wall
Mycotic AAAs are atherosclerotic lesions infected by lodging of circulating microorganisms in the wall
- e.g. bacteremia from a primary Salmonella gastroenteritis.
Abdominal Aortic Aneurysm
Atherosclerotic aneurysms occur most frequently in the abdominal aorta ,the common iliac arteries, the arch, and descending parts of the thoracic aorta can also be involved
Pathogenesis
AAA occurs more frequently in men and rarely develops before age 50.
Atherosclerosis is a major cause of AAA
hereditary defects in structural components of the aorta (e.g., defective fibrillin production in Marfan disease affects elastic tissue synthesis)
Morphology :
Usually positioned below the renal arteries and above the bifurcation of the aorta
AAA can be saccular or fusiform
as large as 15 cm in diameter, and as long as 25 cm.
Microscopically: atherosclerosis with destruction and thinning of the underlying aortic media
the aneurysm frequently contains a laminated mural thrombus
Syphilitic Aneurysm
Caused by The spirochetes T. pallidum
Tertiary stage of syphilis can cause obliterative endarteritis of the involve small vessels in any part of the body, including the vasa vasorum of the aorta
This results in ischemic medial injury, leading to aneurysmal dilation of the aorta and aortic annulus, and eventually valvular insufficiency.
valvular insufficiency and massive volume overload lead to hypertrophy of the left ventricle. The greatly enlarged hearts are sometimes called "cor bovinum" (cow's heart).
CLINICAL CONSEQUENCES
1. Rupture → massive potentially fatal hemorrhage
2. Obstruction of downstream vessel → tissue ischemic injury
3. Embolism → from atheroma or mural thrombus
4. Impingement and compression on an adjacent structure
5. Presentation as an abdominal mass