Additional information

Table showing the differences between necrosis and apoptosis

Necrosis	Apoptosis
Always pathological	Physiological or pathological
Plasma membrane is disrupted	Plasma membrane is intact
Presence of inflammation	Absence of inflammation
Nucleus shows pyknosis, karyorrhexis and karyolysis	Nucleus is fragmented into nucleosome sized fragments
Swelling of cell	Shrinkage of cell
Shear pattern on agarose gel electrophoresis	DNA ladder pattern on agarose gel electrophoresis

Ischemia-reperfusion injury: This is seen in myocardial infarction and stroke after restoration of the blood supply. It refers to the paradoxical increase in cell death that occurs after reperfusion of ischemic tissue, including cells that would otherwise have survived once blood flow was restored. It is caused by increased free radical formation (for example, superoxide anions) from ischemic tissue and from locally infiltrating inflammatory cells, leading to free radical-mediated injury. Local activation of complement by IgM in the ischemic tissue may also contribute.

Dissolution of cells in necrosis leads to leakage of intracellular enzymes into the circulation. This can be detected by several biochemical assays. Some enzymes can also be used as markers for tissue regeneration or enzyme induction.

Enzyme	Relevance of assay	Comments
AST or SGOT	Raised in liver cell necrosis; may be low in advanced cirrhosis and loss of hepatocytes	Mitochondrial enzyme; more specific than ALT for alcoholic liver disease; released after membrane damage
ALT or SGPT	Raised in liver cell necrosis; may be low in advanced cirrhosis and loss of hepatocytes	Cytoplasmic enzyme; more specific for liver than AST; released after membrane damage
GGT or gamma glutamyl transferase	Increased in alcoholic liver disease, marker for atherosclerosis, heart failure, gestational diabetes, viral hepatitis, bile duct disorders and type 2 diabetes mellitus	Located in endoplasmic reticulum; induced by alcohol
Alkaline phosphatase	Raised in biliary duct obstruction; increased osteoblast activity in bone formation; Paget’s disease; hyperparathyroidism; Vit D deficiency; celiac disease; seminomas; decreased levels seen in many conditions such as OC pill use; AML; aplastic anemia; Mg deficiency; malnutrition; hypothyroidism.	Cell membrane enzyme, elevated levels indicate glutathione depletion
CK-MB	Increased in AMI, myocarditis, cardiac surgery or biopsy	Enzyme present in cardiac muscle and released on cell membrane damage
Troponin T*	Increased in AMI, renal failure, heart failure, subarachnoid hemorrhage, pulmonary embolism, cardiac trauma, strenuous exercise, cardioversion or defibrillation, sepsis	Component of actin myofibrils
Troponin I*	Increased in AMI, renal failure, heart failure, subarachnoid hemorrhage, pulmonary embolism, cardiac trauma, strenuous exercise, cardioversion or defibrillation, sepsis	Component of actin myofibrils
Amylase	Increased in acute pancreatitis (non-specific), Ca pancreas, cholecystitis, mumps, blockage of salivary ducts, gastroenteritis	Secreted by exocrine glands
Lipase	Increased in acute pancreatitis (more specific than amylase), obstruction of the pancreatic ducts, renal failure, IBD, renal failure, GI cancers, diabetic ketoacidosis, cholecystitis, peptic ulcers, IV heparin, sitagliptin, saxagliptin	Secreted by exocrine glands in the oral cavity, gastric glands, colon and pancreas

*cTnT and cTnI are cardiac specific troponins

Pyknosis: The nucleus becomes condensed and more basophilic.

Karyorrhexis: The pyknotic nucleus undergoes fragmentation.

Karyolysis: Breakdown of nuclear material by DNAse causes the chromatin to become much less basophilic.

Conditions where Psammoma bodies are seen: (See mnemonic below)

P - Papillary carcinoma of thyroid
S - Serous cystadenocarcinoma of the ovary
A - Adenocarcinoma of lung
M - Mesothelioma
M - Meningioma
O - Other benign conditions like cervical polyps, endometriosis, pregnancy etc.
MA - SchwannoMA

Wheal and flare response: Firm stroking of the skin causes the appearance of a red line followed by a red flush and swelling, known as the “triple response”.

The red line is due to local vasodilation.
The flare (flush) is due to dilation of adjoining arterioles.
The wheal (swelling) results from transudation of fluid from capillaries into the interstitium.

Transudate

Due to increased capillary hydrostatic pressure or reduced plasma oncotic pressure
Protein poor fluid accumulates, fluid protein <3g/dl
Specific gravity < 1.015
Fluid LDH/ Serum LDH < 0.6
LDH lesser than ⅔ rd of serum LDH level
Fluid LDH less than 200 U/litre
Lack of or scant cells
Seen in heart failure, cirrhosis, hypoalbuminemia, nephrotic syndrome, hypothyroidism

Exudate

Due to increased vascular permeability from inflammation of any cause, endothelial damage by toxins causing loss of protein rich plasma from the vasculature
Protein rich fluid accumulates, fluid protein >3g/dl
Specific gravity > 1.015
Fluid LDH/ Serum LDH > 0.6
LDH greater than ⅔ rd of serum LDH level
Fluid LDH more than 200 U/litre
Inflammatory cells present like neutrophils, lymphocytes
Pneumonia, pulmonary embolism, malignancies, sepsis, pleural effusions, empyema, tuberculosis, rheumatoid arthritis, pancreatitis, post cardiac surgery, drug induced.

Acute phase reactants: These are proteins released into the plasma in response to inflammation. They are synthesized in the liver and macrophages. They help regulate and limit the extent of inflammation. Common examples include alpha 1 antitrypsin, plasminogen activator inhibitor, factor VIII, von Willebrand factor, CRP or C reactive protein, haptoglobin, ceruloplasmin, serum amyloid A, heat shock proteins etc. Their levels are elevated during an inflammatory response.

Types of neutrophil granules**

Type of granule	Component
Primary or azurophilic granules	MPO, acid hydrolases, acid phosphatase, lysozyme, defensin, phospholipase, cathepsin, elastase, protease
Secondary or specific granules	Alkaline phosphatase, lactoferrin, gelatinase, collagenase, lysozyme, plasminogen activator
Tertiary granules or C particles	Gelatinase, acid hydrolase

Leukocyte adhesion deficiency (LAD): This is a group of autosomal recessive immunodeficiency syndromes in which leukocytes cannot adhere to endothelium and transmigrate into tissues in response to injury or infection. Laboratory workup shows leukocytosis. LAD I, II and III are the main syndromes in this group.

LAD I is caused by mutations in the ITGB2 gene, which codes for the beta 2 subunit of beta 2 integrins (CD 11a:CD 18). It presents with delayed wound healing, delayed separation of the umbilical cord, absence of pus formation, and recurrent bacterial and fungal infections (especially of the skin and mucosal surfaces). Periodontitis and gingivitis are also seen.

LAD type II, also called congenital disorder of glycosylation type IIc, is less severe than type I. It occurs due to a defect in neutrophil binding to endothelial selectins, which interferes with rolling. Mutations of the SLC35C1 gene are present. There is a deficiency in the expression of cell surface fucosylated glycan structures, including the H and Lewis blood group antigens and the Sialyl Lewis X epitope (CD 15). This results from a defect in the synthesis of GDP-fucose from GDP-mannose. Bombay blood type (hh) is seen in patients affected by LAD II. Patients present with recurrent bacterial infections (for example, otitis media, pneumonia, periodontitis, cellulitis), hypotonia, mental retardation, growth retardation, and short stature.

In LAD III, the genetic defect is a mutation in the gene for Kindlin 3 or, less commonly, CalDAGGEF1. These proteins are essential for activation of integrins. LAD III affects the ability of leukocytes and platelets to bind to the endothelium. Patients present with recurrent bacterial and fungal infections along with bleeding tendencies due to associated Glanzmann thrombasthenia. Other clinical features include purpura, post-surgical bleeding, epistaxis, and easy bruising.

Types of acute inflammation

Types of acute inflammation

Purulent: Pus formation; seen in infections with pus forming microbes e.g. abscess with S.aureus
Fibrinous: Leak of plasma with plasma proteins, protein rich exudate causing fibrin deposition in cavities e.g. fibrinous pericarditis
Serous: Thin, watery exudate e.g. burn blisters
Pseudomembranous: Characterised by pseudomembrane formation composed of necrotic tissue e.g. C.difficile colitis

Complications of wound healing

Infection
Deficient scar formation
Pigmentation, rust colored from hemosiderin
Epidermal implantation cyst from trapped epithelial cells in the wound
Wound dehiscence
Incisional hernia
Excessive wound contraction e.g. Dupuytren’s contracture, Peyronie’s contracture
Keloids and hypertrophic scars*
Neoplasia e.g. Marjolin’s ulcer** following burns

Both keloids and hypertrophic scars are due to excessive collagen formation by fibroblasts and can look similar histologically. However, a hypertrophic scar is confined to the wound margins, while a keloid outgrows the original wound. Both are abundant in type III collagen. Injury to the reticular dermis is required to cause keloids or hypertrophic scars. Broad, haphazardly arranged dense collagen bundles are seen in keloids, while dense collagen bundles oriented parallel to the epidermal surface are seen in hypertrophic scars.