Necrosis

Necrosis

NECROSIS – Pathological cell or cells death in living body due to injury.

NECROBIOSIS – It is a physiological cell death e.g. desquamation of surface epithelium.

APOPTOSIS – It is a programmed cell death, it may be pathological or physiological. In this process the nucleus is condensed the cell is divided into small membrane bounded bodies called apoptotic bodies. Eventually the apoptotic bodies are engulfed by phagocytes.

Causes –

1. Hypoxia (lack of O₂ or ischaemia) – disturbed blood supply.

2. Physical agents – Excessive heat and cold etc.

3. Chemical agents – Strong acids and alkaloids etc.

4. Immunological reactions

General features –

1. The cytoplasm is homogeneous or granular and eosinophilic.

2. The cell cytoplasm may show vacuolation.

3. The nucleus shows three types of changes …

            a. Pyknosis – It is a initial change, in which nuclear material is condensed.

            b. Karyorrhexis – The nucleus is divided into small fragments.

            c. Karyolysis – Finally the nucleus is dissolved out and disappeared.

Types of necrosis –

1. Coagulation

2. Liquefaction or colliquative necrosis

3. Caseous necrosis

1. Coagulation necrosis – It is the most common type of necrosis. It is more often caused by ischaemia and less often caused by bacterial and chemical agents. It is commonly seen in heart, kidney and spleen.

GROSSLY – The affected part is pale, firm, swollen then become yellowish, softer and shrunken.

MICROSCOPICALLY – The necrosed cells are swollen and cytoplasm is eosinophilic with nuclear changes (Pyknosis, Karyorrhexis and Karyolysis) but detail is lost (due to proteolytic enzymes which release from lysosomes) but cell membrane remain intact for days or weeks giving “tomb stone” appearance, finally dead cells are phagocytose remain cell debris behind.

Contrasting features of necrosis and apoptosis

2. Liquefaction or colliquative necrosis – It is caused by ischaemia, bacterial and fungal infection. The affected part is soft then liquefied later a cyst is form containing necrotic cell debris and macrophages. This type of necrosis is commonly seen in brain. Abscess is also an example of liquefaction necrosis.

3. Caseous necrosis – In this type of necrosis the affected area is converted into yellowish and granular cheese like material. It is commonly seen in the central part of tubercle in tuberculosis.

            Caseous necrosis seen centrally which is surrounded by epithelial cells which are covered by giant cells and loose connective tissue and these all material are covered by connective tissue.

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Atrophy

Cell Injury

Etiology of disease

Functional  disease

Gangrene

Organic disease

Lesion

Endocarditis

Hypertrophy of the heart

Diabetes Mellitus

Acute Peptic Ulcers

Appendicitis

Dysentery

Enteric Fever

Food Poisoning

Pancreatic Heterotopia

Pseudomembranous Enterocolitis

Gangrene

Gangrene

Massive cell death of a part of living tissue superadded putrefaction due to saprophytic bacteria.

Classification 

1. Dry gangrene

2. Wet or moist gangrene

3. Gas gangrene

1. Dry Gangrene : This type of gangrene is seen in that part of the body there is lack of water quantity like - hands and feet.

Causes : 

1. Gradual vascular obstruction as seen in senile gangrene, diabetic gangrene.
2. Sudden vascular obstruction as seen in thrombosis, embolism and ligation.
3. Extreme cold (frost bite).
4. Strong acid, coagulate the fluid of the tissue so produce dry gangrene while strong alkalies liquefies the tissue so produce the moist gangrene.

Features of dry gangrene : 

1. This type of gangrene is seen in the body there is lack of water like hands and feet.
2. This type of gangrene generally starts in distal part (great toe) and spread toward the heart.
3. Growth rate of this type gangrene is slow.
4. The affected part is initially waxy then becomes dry and shrunken then it become yellowish blue then finally dark blackish due to pigmentary changes ( The stagnant blood RBCs are starts to breakdown and Hb release their iron which combines with hydrogen sulfide that produced by the bacteria and form iron sulfide, which stains the tissue black).
5. There is found a red line between healthy and dead tissues which is called 'line of demarcation' due to inflammatory reactions, noxious substances produce by necrotic cells.
6. There are necrotic features are also present.

• Senile Gangrene : This type of gangrene is seen in old age people due to arteriosclerosis but finally thrombosis is responsible for the occlusion of artery.
• Diabetic Gangrene : This type of gangrene is due to atheromatous plague in the artery. bacterial growth is favored due to high percent of sugar in red tissue.

Dry gangrene

2. Moist Gangrene : This type of gangrene is seen in the body where, there is present abundant quantity of water like oral cavity, intestine, vulva etc.

Causes : This type of gangrene is heavy develops due to -

1. Blockage of venous and arterial flow as seen in strangulated hernia, intussusception, volvulus etc.
2. Burn also produce moist gangrene.
3. Bed-sore is an example of pressure gangrene may cause occlusion of vessels followed by necrosis and gangrene. It is seen in old age, chronic illness and injury of spinal cord.

Features of moist gangrene : 

1. This type of gangrene is seen at the area of abundant water.
2. The affected part is cold and pulseless.
3. The color of affected part is bluish to green and black due iron sulfide.
4. There is absent line of demarcation.
5. The rate of spread is rapid.
6. Growth of bacteria also rapid due to excessive fluid concentration. Toxins of bacteria are absorbed and produce severe toxaemia and even death.

Moist or wet gangrene

3. Gas or Infective Gangrene : This type of gangrene is caused by the infection of anaerobic bacteria it is seen in wounds.

Causes : This type of gangrene is produced by following clostridia species -

A). Saccharolytics

• Clostridium welchii (80%)
• Clostridium septicum

B). Proteolytics

• Clostridium histolyticum
• Clostridium sporogenes

Contrasting features

Pathogenesis : 

1. The infection of anaerobic bacteria, laceration and crush injury is essential. The organism don't grow with healthy tissue.
2. Haemorrhage and blood clot help the infection specially by calcium supply.
3. Contaminated soil, supplies silica and calcium to the wounds is also help in infection.
4. Dirty splits and fragments causes laceration and contamination of wounds.
5. Circulatory obstruction caused by the occlusion or damage of the artery. pressure on vessels by tourniquet or tight bandage are contributory factors.
6. Inadequate drainage and exudate and favours the spread of infection.

Infection of damage tissue by Streptococci, E. Coli, Staphylococci etc. produce anaerobic atmosphere by loosing oxygen of the tissue that's by giving the chance when anaerobic bacteria to grow. 

        The saccharolytic group of organism breaks the glycogen into carbon dioxide, hydrogen and lactic acid. Excessive production of lactic acid  stop the growth of saccharolytic organism at the same time proteolytic group of organism is starts to growth and liberate proteinase and forms the amino acid in the tissue. This amino acid breakdown into ammonia which neutralized lactic acid. At the same way the cycle repeat again and again.

        The liberation of toxins in blood causing increase blood pressure. This toxins also damage the endocardium causing sudden heart failure. The gas gangrene producing bacteria produce enzymes hyaluronidase, proteinase and collagenase which helps in spread of lesion.

Morphological features - The affected part is swollen and crepitant on palpation due to accumulation of gas in the tissue. The color of skin is affected part is yellowish green or black. On microscopic examination  the causative organism are seen, the muscle fibers lose striation hyalinized and disintegrated.

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Atrophy

ATROPHY

Definition – Reduction of the number and size of parenchymal cells of a normal organ or its parts called atrophy.

HYPOPLASIA – Incomplete developments of a tissue or organ.

APLASIA – Defective development or congenital absence of a tissue or organ.

Causes – It may be physiological or pathological…

PHYSIOLOGICAL ATROPHY –

• Atrophy of lymphoid tissue with age.
• Atrophy of thymus in adult life.
• Atrophy of gonads after menopause.
• Atrophy of brain with ageing.
• Osteoporosis with reduction in size of bony trabeculae due to ageing.

PATHOLOGICAL ATROPHY –

1. Starvation atrophy – This type of atrophy is due to lack of food and using stored food. It is seen in cancer and severely ill patients.
2. Ischaemic atrophy – Gradual diminution of blood supply due to atherosclerosis may result in shrinkage of the affected organ e.g. small atrophic kidney and atrophy of the brain due to atherosclerosis.
3. Disuse atrophy – Prolonged diminished functional activity may cause atrophy e.g. wasting of muscles of limb immobilized in cast and atrophy of the pancreas in obstruction of pancreatic duct.
4. Neuropathic atrophy – Interruption in nerve supply leads to wasting of muscles e.g. poliomyelitis, motor neuron disease, nerve section.
5. Endocrine atrophy – Loss of endocrine regulatory mechanism results in related tissue atrophy e.g. hypopituitarism may lead to atrophy of thyroid, adrenal and gonads. Hypothyroidism may cause atrophy of skin and its adnexal structures.
6. Pressure atrophy – Prolonged pressure from benign tumours or cyst or aneurysm may cause compression and atrophy of the tissue e.g. erosion of the spine by tumour in nerve root, erosion of the skull by meningioma, erosion of the sternum by aneurysm of arch of aorta.
7. Idiopathic atrophy – Atrophy without known cause e.g. myopathies, testicular atrophy.

Adaptive disorders of growth

MORPHOLOGICAL FEATURES – Affected organ is small due cell size decrease, often shrunken due to reduction in cell organelles chiefly mitochondria, myofilaments and endoplasmic reticulum. There is increase number of autophagic vacuoles containing cell debris, these vacuoles may persists to form ‘residual bodies’ in the cell cytoplasm e.g. lipofuscin pigment granules in brown atrophy.

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Cell injury

Cell injury

Definition : Whenever cell adaptation exceed due to disturbance of cell function called cell injury.

Causes of cell injury : 

1. Hypoxia and ischaemia (common cause) - Deficiency of oxygen or lake blood supply or ischemia. 
2. Physical agents - Include excessive heat, excessive cold, trauma, electricity, radiations, sudden change in atmospheric pressure. These are the physical agents that caused cell injury.
3. Chemical agents - Include strong acid, strong alkalides, drugs, pollutants. These are the chemical agents that caused cell injury.
4. Microbial agents - Includes virus, bacteria, fungi and some protozoa. These are the microbial agents that caused cell injury.
5. Immunological reactions - Hypersensitivity reactions, anaphylactic reactions and autoimmune diseases.
6. Genetical effects
7. Aging 
8. Nutritional imbalance - Lake ( starvation, marasmus, kwashiorkor, anaemia) or exceed (obesity, atherosclerosis, heart disease and hypertension) of nutrition. 

PATHOGENESIS : Most common cause of cell injury is hypoxia and ischaemia, so we will discus about only hypoxic cell injury -

Pathogenic events of reversible and irreversible injury

   


 On the basis of severity, hypoxic cell injury are two types i.e. reversible and irreversible cell injury ...

1. Reversible cell injury : When hypoxia or ischaemia is of short duration, the effects may be reversible on restoration of oxygen supply the cell return to the normal state.

      The first effect of hypoxic cell injury is on mitochondria resulting in decreased oxidative phosphorylation consequently ATP formation is reduced, result in decreased sodium pumps and subsequently their is accumulation of sodium inside the cell and diffusion of potassium ion from the cell. Due to accumulation of sodium ion water is drawn inside the cell which result in swelling of cell.

       Decrease number of ATP and increased number of AMP stimulate enzyme phosphofructokinase resulting in increased anaerobic glycolysis. Increased glycolysis resulting in accumulation of lactic acid which is responsible for decreased pH of cell cytoplasm. After that detachment of ribosomes from rough endoplasmic reticulum resulting in reduced protein synthesis. 

        If hypoxia is no relieved. worsening mitochondrion functions results in more damage like loss of microvilli, formation of blebs ( prominent) on the cell surface and swelling of whole cell. All the above disturbance are reversible but if ischaemia persists irreversible, cell injury may occur.

Ultrastructural changes during cell injury

2. Irreversible cell injury : In this stage the matrix of mitochondria shows vacuoles and deposition of calcium. Plasma membrane is more damage and lysosomes are swollen their is continue loss of protein, co-enzymes and RNA and vital metabolites are leaked out from the cell.

Generation of free radicals by four electron step reduction of oxygen

       

      

          Injury to lysosomal membrane results in leakage of their enzymes in cytoplasm, more ever their is leakage of intracellular enzymes into extracellular space and influx of macromolecules from the interstitial space. The that cell may ultimately replaced by large whorled phospholipid bodies, these are called myelin figures. Phospholipid is either phagocytose or they convert with calcium ion into "calcium soap".

Cell death by hydroxyl radical

         Leakage of intracellular enzymes into peripheral circulation help in detecting cell death e.g, cardiac muscles contain an enzyme creatine kinase and troponins, liver cells contain alkaline phosphatase. Increased level of these enzymes help to detect death of these cells.

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Hypertrophy Of The Heart

HYPERTROPHY OF THE HEART

Definition - Hypertrophy of the heart is defined as an increase in size and weight of the myocardium. In which involve predominantly the left or the right or both sides of the heart. It generally results from increase pressure load while increased volume load results in hypertrophy with dilatation. It is a compensatory mechanism of the heart.

Common causes – (usually causes are unknown)

• Stretching of myocardial fibrosis.
• Anoxia (e.g. in coronary atherosclerosis).
• Certain hormones (e.g. Catecholamines and pituitary growth hormone).
• Left ventricular hypertrophy.

Causes of left ventricular hypertrophy –

• Systemic hypertension.
• Aortic stenosis and insufficiency / regurgitation.
• Mitral insufficiency / regurgitation.
• Coarctation of the aorta.
• Occlusive coronary artery disease.
• Congenital anomalies like septal defects and patent ductus arteriosus.
• Conditions with increased cardiac output e.g. thyrotoxicosis, anaemia, arteriovenous fistula.

Causes of right ventricular hypertrophy – 

• Pulmonary stenosis and regurgitation.
• Tricuspid regurgitation.
• Mitral stenosis and regurgitation.
• Chronic lung diseases (e.g. chronic emphysema, bronchiectasis, pneumoconiosis, pulmonary vascular disease).
• Hypertrophy and failure of left ventricle.

Causes of dilatation –

• Valvular regurgitation.
• Left to right shunt (e.g. in ventricular septal defect (VSD).
• Conditions with high cardiac output (e.g. thyrotoxicosis, arteriovenous shunt).
• Myocardial diseases (e.g. cardiomyopathies, Myocarditis).
• Systemic hypertension.

Morphological features - Hypertrophy of myocardium without dilatation called concentric and with dilatation called eccentric hypertrophy. The weight of the heart is increased above normal (500 gm). Excessive pericardial fat not indicate true hypertrophy. Thickness of the left ventricular wall (above 15 mm) is indicates hypertrophy.

Schematic diagram showing transverse section through the ventricles with left ventricular hypertrophy (concentric and eccentric)

GROSSLY -

• In concentric hypertrophy, the lumen of the chamber is smaller than normal, while in eccentric hypertrophy the lumen is dilated.
• Papillary muscles and trabeculae carneae are rounded and enlarged in concentric hypertrophy, while flattened in eccentric hypertrophy.

MICROSCOPICALLY - There is increase in size of myocardium. There may be multiple minute foci of degenerative changes and necrosis in affected myocardium resulting in develop hypoxia due to inadequate blood supply to increased muscle fibers, while ventricular hypertrophy is lead to ischaemia.

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COVID-19

COVID-19 (Coronavirus Disease 2019)

Definition - It is an acute highly infectious viral disease caused by SARS cov-2. It affects only respiratory system. Cases may be asymptomatic to severe and critical, 80% cases recover spontaneously and 15-20% cases are severe and critical and characterized by fever, non-productive cough, myalgia shortness of breath and  may show severe pneumonia even death.

Agent factors -

AGENT - novel coronavirus (SARS cov-2)

RESISTANCE - It resists at surface from few hours to several days depending upon the condition (e.g. temperature and humidity of the environment)

Novel coronavirus

SOURCE OF INFECTION - Case - clinical and subclinical (80 % of infections are mild or asymptomatic, 15 % are severe infection and 5 % are critical infection) (as per on that days data)

INFECTIVE MATERIAL - Oropharyngeal secretion, nasal secretion (research going on)

PERIOD OF COMMUNICABILITY - Starts before 24-48 hours appearance of symptoms till patient recover (research going on)

Host factors -

AGE - Older age and immunosuppressed persons are severely affects (but less affecting age is 0-19 years)... (research going on)

SEX - Equal effects on both sexes
ENVIRONMENTAL FACTORS - Environmental contamination, cold places and overcrowding area

IMMUNITY - No natural immunity (research going on)

MORTALITY RATE (MR) - 3-4 % till now

Mortality rate (MR) in different types of people
Types of patient	MR in %
Above 80 years of age	21.9
Males	4.7
Female	2.8
CVS diseased patients	13.2
Diabetic patients	9.2
Hypertension	8.4
Chronic respiratory disease	8.0
Cancer	7.6

SECONDARY ATTACK RATE - 3-10 % estimate (research going on)

Mode of Transmission - Direct contact, droplet nuclei, fomite borne

Incubation Period - 5-6 days ( range 1-14 days)

Clinical features - 
ASYMPTOMATIC CASES - Few cases are reported asymptomatic
MILD TO MODERATE DISEASE (80 %) - Include non-pneumonia and pneumonia.
SEVERE DISEASE (14 %) - Dyspnoea and hypoxia
CRITICAL CASES (6 %) - Respiratory failure, septic shock and multiple organ failure
COMMON SYMPTOMS - Fever, tiredness, dry cough, some patient may have ache and pain, nasal congestion, runny nose, sore throat or diarrhoea and in severe cases shows difficulty in breathing.

Clinical categorization

Prevention & control -

• Early detection
• Isolation
• Vaccination (vaccine are under investigation till now)
• Treatment - There is no specific treatment (only symptomatic treatment till now)
• Sanitation

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Diphtheria

Diphtheria

Definition - It is an acute infectious bacterial disease caused by corynebacterium diphtheriae found in clinical forms i.e. Anterior nasal, Pharyngotonsiller (faucial) and Laryngotracheal. The bacteria produces a powerful exotoxin locally and it is responsible for the formation of pseudo-membrane, local oedema and lymphadenopathy with sign of toxaemia.

Agent factors -

AGENT - Corynebacterium diphtheria. It is a gram +ve non-motile organism and it has no invasive power but produce a powerful exotoxin.

There are two types of strains – 

(a) Pathogenic strain – Gravis, mitis, belfanti and intermedius. 

(b) Non-pathogenic strain – They are capable to change into pathogenic strains due to ß-phase.

INFECTIVE MATERIAL – Nasopharyngeal secretion and contaminated wounds, fomite and dust.

SOURCE OF INFECTION - (a) Case (5%) – mild and frank clinical cases. (b) Carrier (95%) – Temporary and chronic carrier

PERIOD OF COMMUNICABILITY – 14-28 days from onset of disease or till two throat cultures are negative

Host factors -

AGE – Usually 1-5 years

SEX – Equal in both sexes.

IMMUNITY – Passive immunity formation up to few months of birth (70% herd (group) immunity up to age of 3 years and 90% up to 5 years.

ENVIRONMENTAL FACTORS – Winter season is favorable but cases can be seen throughout the year.

Incubation Period - 2-6 days

Mode of transmission – Direct droplets, droplet nuclei and freshly contaminated fomite

Clinical features -

PHARYNGO-TONSILLAR – Sore throat, mild to moderate fever (On examination – Erythema at pharynx and tonsils, formation of pseudo-membrane “greenish black or bluish white” initial can be wipe off easily but later it can’t be wipe off and attempt can cause bleeding), submandibular edema and localized lymphadenopathy (bull neck deformity)

LARYNGOTRACHEAL (It is always secondary) - Croupy cough and hoarseness of voice

NASAL - Formation of pseudo-membrane in nasal mucosa.

NON-RESPIRATORY DIPHTHERIA - Cutaneous diphtheria (infective material - come in contact with wound), conjunctival diphtheria and vulvar diphtheria.

Schick test -

Schick test	Diphtheria anti-toxin (test arm)	Inactivated diphtheria anti-toxin (control arm)
+ve	Test arm +ve	Control arm –ve (susceptible)
-ve	Test arm –ve	Control arm –ve (immune)
Pseudo-positive (false)	Test arm –ve	Control arm +ve (allergic)
Combined	Test arm +ve	Control arm +ve
0.2 ml toxin given on forearm and 5-10 mm erythema (red area) indicate +ve test.

Prevention and control –

1.      Early detection

2.      Isolation

3.      Treatment

4.      Vaccination – (dose of vaccine is 0.5 ml IM, 6,10, 14 weeks, 15-24 month and 5 year)

a.       Single vaccine

                                                              i.      Formal toxoid (FT)

                                                            ii.      Alum precipitated toxoid (APT)

                                                          iii.      Purified toxoid aluminium phosphate (PTAP)

                                                          iv.      Purified toxoid aluminium hydroxide (PTAH)

                                                            v.      Toxoid anti-toxin floccules (TAF)

b.      Combined or mixed vaccine

                                                              i.      Diphtheria pertussis tetanus vaccine (DPT)

                                                            ii.      Diphtheria tetanus toxoid (DT)

                                                          iii.      Diphtheria tetanus toxoid (dT – adult type)

c.       Antisera – Diphtheria antitoxin

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