Pathology Flashcards
Inflammatory Response - normal phases (6)
Vascular Exudative Resolution Supparation Organisation Chronic inflammation
What is the vascular phase of inflammation and how long does it last
Lasts 15 mins to several hours. Up to 10 fold increase in blood flow increases the hydrostatic pressure and causes a transudate (low protein). Plasma protein leaks into the tissues due to the decreased intravascular oncotic pressure.
What causes the increased vascular permeability of the vascular phase of inflammation?
Contraction of endothelial cells
What are the three phases of the exudative phase?
Margination
Adhesion
Emigration
Inflammation, exudative phase, what is margination
The loss of intravascular fluid due to a breach from injury causes increased plasma viscosity, so flow slows at the injury site allowing neutrophils to flow closer to the epithelium
Inflammation, exudative phase, what is adhesion and what impairs it
Neutrophils adhere to the endothelial surface by increased expression of leukocyte adhesion molecule and increased expression of epithelial surface adhesion molecule
Impaired by diabetes, corticosteriod use, acute alcohol intoxication, inherited adhesion deficiencies
Inflammation, exudative phase, what is emigration
Migration of neutrophils through the basement membrane by active amoeboid movement
Inflammation, what is resolution
Back to normal state with regeneration of damaged tissue
Inflammation, what is supparation
A persistent causative agent that leads to pus formation and becomes walled off by a pyogenic membrane that is inaccessible to the body’s defences.
Inflammation, what is fibrosis
Where a large area of tissue is destroyed or unable to regenerate. The scar tissue is mainly collagen, inflexible and may impair function
Inflammation, what is chronic inflammation
A persistent causative agent that lasts months to years. There is tissue destruction and cellular exudate changes. It is mainly dominated by macrophage, lymphocyte and plasma cells, and their toxins damage host tissue
In the later stage of inflammation, what is chemotaxis
Neutrophils are attracted towards complement, IL8, leukotriene B4 and bacterial products
What is opsonisation
This prepares a particle for phagocytosis by coating it in Ig or complement, thus marking it for destruction
How do bacteria activate the complement pathway?
Bacterial polysaccharides activate the alternative complement pathway and generate C3b.
Antibodies bind bacterial antigens and activate the classical complement pathway and generate C3b
What happens at the phagocytosis phase
Neutrophils send out pseudopodia around the opsonised particles which fuse, containing the particle in a phagosome bound by a cell membrane. Lysosomes bind with the phagosome forming a phagolysosome to begin intracellular killing
Explain oxygen dependent intracellular killing
Neutrophils produce hydrogen peroxidase which reacts with myeloperoxidase to produce microbicidal agents. Oxygen is reduced by NADPH oxidase to produce free radicals.
What does oxygen independent intracellular killing use?
Lysozymes, lactoferrin, acid hydrolase and defensins
What happens in chronic granulomatous disease?
NADPH is deficient causing recurrent bacterial infections
What happens in myeloperoxidase deficiency
Frequent candidal infections
Chemical mediators - histamine
From mast cells, basophils and platelets. Stimulated by C3a, C5a, IgE, lysosomal proteins and physical injury
Chemical mediators - serotonin
from platelets - causes vasodilation, increases vascular permeability and promotes chemotaxis
Chemical mediators - lysosomal compounds
from neutrophils - causes vasodilation, increases vascular permeability and promotes chemotaxis
Chemical mediators - Prostaglandins
From arachadonic acid
Thromboxane A2 - from platelets, causes vasoconstriction and platelet aggregation
Prostacyclin - from endothelium, inhibits platelet aggregation
Prostaglandin - causes pain
Chemical mediators - Cytokines
From arachadonic acid
IL1 +TNF - causes fever, increases adhesion molecules and activates neutrophils
IL8 - chemotactic
Complement C5a
Chemotactic
Complement C3b, C4b, C2a
Oponin
Complement C3a, C5a
Stimulates histamine release
Complement C5b-C9
Membrane attack complex
The Kinin cascade
Activated by factor XII and leads to formation of bradykinin which causes vasodilation, increased vascular permeability, bronchoconstriction and pain
Beneficial local effects of inflammation (6)
Permits entry of antibodies leading to the breakdown of microorganisms, increased delivery of nutrients and oxygen, dilution of toxins and stimulation of the immune system
Harmful local effects of inflammation (2)
Damage to normal tissue
Swelling (epiglottitis, compartment syndrome)
Systemic effects of inflammation (5)
Malaise, anorexia, nausea, pyrexia, raised ESR
Causes of leukocytosis - neutrophilia
Pyogenic infection
Causes of leukocytosis - eosinophilia
Allergy and parasites
Causes of leukocytosis - lymphocytosis
Chronic infection and viral
Causes of leukocytosis - monocytosis
mononucleosis, some bacterial (TB, Typhoid)
Causes of abnormal inflammation (9)
Genetic malformation, cancer, atherosclerosis, allergy, asthma, autoimmune, chronic inflammation, vasculitis, transplant rejection
What is CRP
An acute phase reactant hat rises dramatically with inflammation in response to increased Il6 released by macrophages. Rises more in bacterial infections than viral. It is synthesised and secreted by the liver. It binds phosphocholine opsonizing damaged or foreign cells for phagocytosis
What is Rheumatoid Factor
An autoantibody against the Fc portion of IgG. High levels indicate rheumatoid arthritis and Sjogren’s syndrome. The sigher the level the higher the risk of a more destructive arthropathy.
What is ANF
Antinuclear factor or antinuclear antibodies are autoantibodies against the cell nucleus, present in various disorders
Specific subtype of ANF found in SLE
All ANF
Specific subtype of ANF found in systemic sclerosis
All ANF, Scl-70
Specific subtype of ANF Limited scleroderma
All ANF, anti-centromere
Specific subtype of ANF Sjogren’s syndrome
All ANF, anti-RO, Anti-La
3 layers of the normal immune response
Physical, innate, adaptive
Physical immune barriers (5)
Coughing and sneezing Tears and urine to flush away Skin and mucus Commensal flora outcompete Gastric acid neutralises most bacteria
What is the innate immune response
Non-specific. Initiated when microbes are identified from components common to large groups of microbes and when injured cells signal
What are the four main functions of the immune system?
Recruit immune cells to the site
Activate the complement cascade
Identify and remove foreign substances
Activate the adaptive response by antigen presentation
First innate immune response is
Inflammation
Second innate immune response is
Cellular response - white cells (neutrophils, eosinophils, basophils and natural killer cells) identify and eliminate pathogens
Third innate immune response
Complement cascade
When is the adaptive immune response initiated?
When the innate response presents enough antigen
What is the function of the adaptive immune response
Recognises non-self
Generate specifically tailored immune responses to the particular pathogen
Develop a memory to remember the pathogen and allow easier elimination of subsequent infections
What are the main cellular components of the adaptive immune response
T and B lymphocytes
Explain the adaptive immune response: Antigens are presented to…
Naïve T lymphocytes which activate to become either cytotoxic CD4 cells or helper CD4 cells.
Cytotoxic T lymphocytes undergo rapid clonal expansion and travel in search of the antigen. Cells with the antigen are punctured and lysed by cytotoxins.
Activation of the T lymphocyte requires either
a strong signal or a prompt from a CD4 helper cell
What happens after the infection resolves
Some T cells remain to form immune memory, ready to be quickly activated if the same pathogen returns.
What do CD4 helper cells do?
Manage the immune response and activation leads to the release of assorted cytokines
What do B cells do?
Create antibodies - Y shaped proteins that identify and neutralise foreign material
What are the 5 types of antibodies
IgA, IgD, IgE, IgG, IgM
How are B cells activated
Antigen and signals from CD4 cells
What do activated B cells do next?
Multiply and mature into plasma cells, which last 2-3 days and produce antibodies which bind antigens, opsonise and activate the complement cascade. 10% of plasma cells survive to form antigen specific immune memory cells to fight off repeated further infection.
What is a type 1 hypersensitivity reaction
Allergic - includes atopy, anaphylaxis and asthma. Provoked by re-exposure to a specific antigen. IgE mediated - released from mast cells and basophils
What is type 2 hypersensitivity reaction
Cytotoxic, antibody dependent reaction where antibodies bind antigens on ‘self’ and mark for destruction.
IgG and IgM mediated of autoimmune thrombocytopenic purpura and haemolytic disease of the newborn
What is type 3 hypersensitivity reaction
Immune complex disease - small antibody-antigen immune complexes are not cleared by macrophages and are deposited in tissues causing disease. IgG or IgM mediated eg SLE, polyarteritis nodosum
What is type 4 hypersentivity reaction
Delayed hypersensitivity - eg Type 1 DM, MS.
T cells mediated. T cells targeting specific ‘self’ cells proliferate and destroy on contact.
What is Autoimmunity
Overactive immune response with a failure to distinguish self and non-self leading to immune attack of body tissues eg Autoimmune hepatitis, Goodpastures, MS, RA
What is immunodeficiency
One or more components of the immune system are deficient or malfunctioning. It may be inherited or acquired.
5 stages of wound healing
Haemostasis Inflammation Reconstruction Epithelialisation Maturation
Haemostasis stage of wound healing
Local vascular contraction, platelet plug formation and activation of the clotting cascade
Inflammation stage of wound healing
Removes bacteria, foreign material and devitalised tissue to prepare the wound for healing. Prolongation of this stage causes increased macrophage activity and poor wound healing.
Reconstruction stage of wound healing
Fibroblasts synthesise collagen and elastin and contract to bring the wound edges together. Macrophages release growth factor to stimulate new blood vessel formation
Epithelialisation stage of wound healing
In wounds that are closed epithelial coverage develops in 24-48 hours, impaired by surface debris, eschar or devitalised tissue
Maturation stage of wound healing
The amount of scar tissue formed depends upon the forces that act across a wound. Strength is gained as collagen matures and further modelling and maturation occurs over 2years.
Wound healing specific tissues - skin
may need delayed closure.
Wound healing specific tissues - tendon
Reconstruction lasts 6 weeks and full strength is never regained, It heals with fibrous scar tissue, Controlled movement while undergoing reconstruction aids healing
Wound healing specific tissues - Peripheral nerves - levels of injury (3)
Neuropraxia
Axonotmesis
Neurotmesis
What is neuropraxia
Mildest form of injury - block or reduction of conduction across a segment with conduction preserved above and below
What is Axonotmesis
Middle severity - neural tube intact but axons disrupted - likely to recover
What is Neurotmesis
Most severe - neural tube severed. Likely permanent without repair.
3 phases of bone repair
Reactive
Reparative
Remodelling
Reactive stage of bone repair
Incorporates haemostatic and inflammatory stages of normal wound healing
Reparative stage of bone repair
Incorporates reconstruction and epithelialisation. There is callous formation and lamellar bone deposition. Periosteal cells proximal to the fracture and fibroblasts in the granulation tissue develop into chondroblasts and form hyaline cartilage. Periosteal cells distal to the fracture develop into osteoblasts and form woven bone. These tissues grow and unite to forma fracture callus. Osteoblasts then replace the fracture callus with lamellar bone
Remodelling phase of bone healing
Lamellar bone is replaced with compact bone and is at 80% strength by 3 months. Full healing can take 18 months.
Wound healing specific tissues - Myocardial plus complications
Injury usually comes from infarction where coronary arteries are blocked causing cell death which is irreparable. Collagen scar formation can lead to arrhythmias or rupture
Wound healing specific tissues - brain
No reparative or regenerative function but sometimes other areas of the brain can take over function to compensate.
How is anaemia classified and what are the three types
By red blood cells size
Macrocytic - larger
Normocytic - normal
Microcytic - smaller
Causes of macrocytic anaemia (5)
Meagaloblastic anaemia - low B12 with or without concurrent low folate (either from poor intake or poor absorption)
Pernicious anaemia - poor absorption of B12 due to autoantibodies against intrinsic factor or the parietal cells that produce it
Gastric bypass surgery
Hypothyroidism
Methotrexate
Causes of microcytic anaemia
Issues with haem synthesis - iron deficiency
Issues with globin synthesis - thalassaemia
Lead poisoning
Causes of normocytic anaemia
Acute blood loss
Anaemia of chronic disease - cytokine action or iron metabolism
Aplastic anaemia
Haemolytic anaemia
Investigations for anaemia
FBC, ESR, Ferritin, Serum iron, Transferrin, Serum B12 and folate. Occasionally a bone marrow biopsy is needed.
What is leukaemia
Malignant disease or blood or bone marrow causing an increase in WBC. It presents as bruising, bleeding, petechial haemorrhage, frequent infections, anaemia, fever, chills, night sweats, splenomegaly, weight loss.
Classification of leukaemia
Acute or chronic and then by cell line affected - lymphoblastic (lymphocytes - usually B cells) or myeloid (marrow cells that form RBC, eosinophils, basophils, neutrophils and platelets)
What are acute leukaemias
Feature a rapid rise in immature cells. Crowding makes the bone marrow unable to produce healthy cells. Requires quick treatment to prevent malignant cells spilling into the blood stream. Most common form of childhood leukaemia
What are chronic leukaemias
Feature an excessive build up of mature abnormal WBC that takes years or months to progress. More common in the elderly, but can be affect any age.
Acute lymphoblastic leukaemia
Most common in young children but can affect adults over 65. Survival 85% in children, 50% in adults
Chronic lymphoblastic leukaemia
Most common in adults over 55, almost never occurs in children. Incurable but chemo can control symptoms
Acute myeloid leukaemia
More common in adults than children and men more than women. Survival 40% at 5 years
Chronic myeloid leukaemia
Mainly adults but some children. 90% survival at 5 years.
What is lymphoma
Lymphocyte cancers that present as a solid mass of lymphoid cells and are classified by cell type
Types of lymphoma
Mature B cells - Burkitt’s lymphoma, follicular, Hodgkin’s
Mature T cells and NK cells - Aggressive NK cell lymphoma, anaplastic large cell lymphoma
Signs and symptoms of lymphoma
Presents with night sweats, weight loss, lymph node enlargement and hepatosplenomegaly
Investigations for lymphoma
Investigate with FBC, U&E, LFT, LDH, CXR, Staging CT and biopsy
What is myeloma
An incurable cancer of plasma cells - the B cells which make antibodies. Signs and symptoms vary, depending on the proteins released by the malignant plasma cells
Signs and symptoms of myeloma (5)
Bone pain /fractures Infections Anaemia Renal failure Neurological symptoms
Explain bone pain in myeloma
Plasma cells produce RANKL which binds osteoclasts and induces bone resorption. Bone lesions are lytic and cause hypercalcaemic
Explain increased infection rate in myeloma
Decreased production and increased destruction of normal antibodies
Explain renal failure in myeloma
Damage caused by hypercalcaemia and the deposition of light chains produced by the malignant plasma cell
Explain neurological symptoms in myeloma
Weakness, confusion and fatigue due to hypercalcaemia. Spinal cord syndromes from pathological fractures
Investigations for myeloma
FBC, U&E, Ca, Seruma nd Urine electrophoresis for paraproteins like Bence-Jones. Skeletal survey, bone marrow biopsy, Ig levels and B2 - microglobulin
Treatment for myeloma
High dose chemo to induce remission. Younger patients may get a bone marrow transplant
Low platelet count disorder - What is throbocytopenia
Causes low platelet count, eg ITP - autoantibodies against platelets
Low platelet count disorder - What is Aplastic anaemia
Bon marrow failure secondary to autoimmune, toxins or infection. Causes pancytopenia as the bone marrow fails to make new cells
Low platelet count disorder - What is Gaucher’s disease
A lysosomal storage disease where lipids accumulate in cells and tissues including the bone marrow, resulting in pancytopenia.
High platelet count disorder - What is thrombocytosis (primary and reactive)
Primary thrombocytosis isa myeloproliferative disorder causing increased risk of thrombosis and may progress to AML or myelofibrosis.
Reactive thrombocytosis can be due to inflammation, hyposplenia or asplenia
Platelet dysfunction disorder - HELLP syndrome
A variant of pre-eclampsia
Haemolytic anaemia, Elevated Liver enzymes, Low Platelets.
Platelet dysfunction disorder - Haemolytic Uraemic Syndrome
Toxins from enterohaemorrhagic E Coli cause haemolytic anaemia, acute renal failure and thrombocytopenia, mostly in children
Platelet dysfunction disorder - Dengue
Viral haemorrhagic fever caused by flavivirus
Platelet adhesion disorder - Von Willebrand disease (4 types)
Type 1 - heterozygous - decreased levels of vwf
Type 2 - qualitative defect
Type 3 - homozygous, most severe
Type 4 - platelet type - defect in the VWF receptor on the platelet
Inherited coagulation disorders (2)
Von Willebrand Disease
Haemophilia - recessive X linked disorder affecting clotting factors
Haemophilia A
Factor VIII deficiency, most common
Haemophilia B
Factor IX Christmas disease
Treatment of haemophilia
Infusions of the missing factor, but some people develop antibodies tot he replacement an therefore need larger amounts or nonhuman factor
Causes of acquired coagulation disorders (4)
Toxins
Infections
Liver failure
DIC
Toxins or drugs that cause acquired coagulation disorder
Rattlesnake and viper venom
Warfarin
Actions of warfarin
Inhibits vitamin K dependent synthesis of clotting factors II, VII, IX, X, protein C, protein S and protein Z which regulate the clotting process
Infections that cause acquired clotting disorder
Viral haemorrhagic fever - multifactorial aetiology - hepatic damage, consumptive coagulopathy, primary marrow dysfunction
How does liver failure cause an acquired clotting disorder
decreased protein syntesis
Acquired clotting disorders - DIC
A consumptive coagulopathy leading to depletion of platelets and clotting factors. Micro-emboli form in the vascular system, threatening end organ function.
Causes of DIC
Cancer (lung, pancreas, stomach) Eclampsia Amniotic fluid embolus Massive trauma Burns Infection (Gram negative sepsis, strep pneumonia, malaria) Snake/scorpion venom
What is thrombophilia
An abnormality causing hypercoagulability - can be congenital or acquired
Congenital causes of thrombophilia - Factor V Leiden
Factor V is a cofactor of Factor X that leads to activation of thrombin and is broken down by Protein C to limit clotting. Factor V Leiden is a form of factor V that cannot be broken down by Protein C.
Congenital causes of thrombophilia - Protein C deficiency
Protein C is an anticoagulant that inhibits Factor V and Factor VIII
Congenital causes of thrombophilia - Protein S deficiency
Protein S is a vitamin K dependent anticoagulant that acts as a cofactor to protein C
Acquired causes of thrombophilia - antiphospholipid antibodies
Autoimmune issue. Has various forms that cause either up regulation of prothrombotic factors or inhibition of antithrombotic factors or a combination of the two.
Signs and symptoms of thrombophilia
DVT, PE, clots in unusual places - venous sinus thrombosis, portal vein thrombosis, hepatic vein thrombosis, mesenteric vein thrombosis, renal vein thrombosis, recurrent miscarriage
