Pathology and medicine PDF

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Pathology and medicine1.Disease = a presence of abnormality (structural or functional) in the body causes a loss of normal health. It occurs when an organism is unable to adapt to a challenge and shows itself through signs and symptoms.Nomenclature.Primary/secondary- causation: Primary- disease with...

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Pathology and medicine 1. Disease = a presence of abnormality (structural or functional) in the body causes a loss of normal health. It occurs when an organism is unable to adapt to a challenge and shows itself through signs and symptoms. Nomenclature. Primary/secondary- causation: Primary- disease without apparent cause Secondary- disease is a complication or manifestation of an underlying lesion Stages of a disease e.g. cancer: Primary- initial Secondary- subsequent stages Acute/chronic- dynamics. Acute: rapid onset sometimes followed by rapid resolution. Chronic- may follow an acute initial episode and have prolonged course lasting months/years. Benign/malignant- likely outcome of a disease. Benign- remain localised to the tissue of origin and are rarely fatal. Malignant- invade and spread from their origin and are commonly fatal.

Prefixes and their meanings: Ana- absence e.g. anaplasia Dys- disordered e.g. dysplasia Hyper- excess over normal e.g. hypertension Hypo- deficiency below normal e.g. hypotension Meta- change from one stage to another e.g. metaplasia Neo- new e.g. neoplasia

Suffixes and their meanings: Itis- inflammation e.g. appendicitis Oma- tumour e.g. carcinoma Osis- abnormal increase e.g. atherosclerosis Oid- resembling to e.g. rheumatoid disease Plasia- disorder of growth e.g. hyperplasia

Opathy- abnormal state lacking specific characteristics e.g. cardiomyopathy Eponymous names- a disease is named after a person or place associated with it e.g. Grave’s disease (primary thyrotoxicosis), Crohn’s disease (inflammation of the gut). Aim of classifying disease- to determine the best treatment, estimate the prognosis, ascertain the cause so the disease can be prevented in the future. Classifications are based on aetiology (cause) and pathogenesis (mechanisms causing the disease).

Genetic- due to abnormalities in the genome, most are inherited but 20% are due to new mutations. Acquired- caused by environmental factors e.g. pollution. Disease that are acquired includeinflammatory, haemodynamic, growth disorders, injury and disordered repair, disordered immunity, metabolic and degenerative disorders. In most diseases, environmental and genetic factors interact. Congenital- affects 5% of births in the UK and are initiated before or during birth but may not manifest until adult life. Genetic- inherited form parents or a genetic mutation before birth e.g. Down’s syndrome. Non genetic- normal embryonic and foetal development with external influence e.g. deafness, Zika.

2. Aetiology (cause): Initiator of illness.     

Genetic- inherited or acquired (during conception or embryogenesis). Environmental- infectious agents (bacteria, virus, fungi, parasites), chemicals, radiation, mechanical trauma. Multifactorial- genetic and environmental combinational cause e.g. diabetes. Unknown- classified as idiopathic, spontaneous, cryptogenic, primary, essential. Risk factor- aetiology is unknown but the disease is observed in people with certain habits e.g. smoking, age, some occupations.

Pathogenesis (mechanism where the aetiology works to produce the pathological and clinical manifestations):   

Inflammation- a response to many microorganisms and harmful agents that cause tissue injury. Degeneration- deterioration of cells/tissues in response to failing to adapt to agents. Carcinogenesis- cancer causing agents result in the development of tumours.

Manifestations. Symptoms- what the patient suffers e.g. commonly pain, fever, nausea, could be a rash, diarrhoea/constipation. Signs- what the doctor is looking for e.g. body temperature, blood pressure.

Syndrome- an aggregate of signs and symptoms or a combination of lesions which allow the disease to be recognised. E.g. Cushing’s syndrome is a combination of obesity, hypertension and many more symptoms, due to too much ACTH. Lesions- the structural or functional abnormality that is responsible for the ill health e.g. the patch of dead muscle from a myocardial infarction. Complications- the prolonged, secondary or distant effects of a disease e.g. a lung embolism due to a thrombosis in the leg vein. Prognosis- the anticipated outcome of a disease e.g. the survival prospects for lung cancer after 5 years 5%. It can give useful information to patients and allows them to plan appropriate treatment. Medical or surgical intervention can influence the prognosis. Epidemiology- pathology of the populations. Determination of causes, incidence, mortality, characteristic behaviour of disease outbreaks. Morbidity- the disease state of an individual or the incidence of illness in a population. The proportion of patients who develop a specific disease during a given year, per unit of population e.g. morbidity of influenza is 20% in children, 10% in adults. Mortality- the probability that the result of disease will result in death, expressed as a percentage of all the patients with the disease e.g. 50% in myocardial infarctions. Prevalence- the total number of cases of a disease in a population at a given time e.g. 6% prevalence of diabetes.

For example, lung cancer: Aetiology- smoking. Pathogenesis- genetic mutation. Disease- lung tumour. Complication- secondary tumours from metastases. Hypertension: Aetiology- unknown. Pathogenesis- increased renin production from kidneys. Disease- high blood pressure. Complicationcerebral haemorrhage.

3. Diagnosis- identifying a disease in an individual by looking at their clinical history, current symptoms, examining for clinical signs and performing investigations. Diagnostic lab test from a patient sample, to allocate the case into a diagnostic group. Quantitative measurement- interpreted in relationship to a ‘normal’ range of values. E.g. Serum insulin level test- can test if insulin is too high or too low, using ELISA to detect molecules through specific antibody binding to antigen. An enzyme reaction occurs and product of the reaction can be measured using the spectrophotometer. Subjective assessment- from the pathologist. E.g. Cervical epithelial cell slide- looking at the cytology- nucleus size etc. to detect early changes, like cancer.

Epidemiological approach- the study of disease in populations and the distribution of diseases in relation to place and time. It identifies all possible causes and modes of acquiring the disease. Data is recorded and analysed, studying disease in a group. It establishes an association between a risk factor and the occurrence of a disease but not the causal relationship. Aims: to provide aetiological clues towards the cause of disease, plans preventative measures, to provide adequate medical facilities, and screen the population for early diagnosis. Example- HDV hepatitis delta virus has highest prevalence in South America and Africa so preventive measures can be planned there, coronary heart disease is prevalent in older ages so medical checkups can be provided for that age category. Prospective studies- subjects followed over time, risk factors monitored, relative risk is determined% chance of disease, a ratio of prevalence from non exposed to exposed. This is the most reliable study as a group of healthy population is split into two, where one of the groups is exposed to the risk factor. This study takes a long time as the follow up study takes place later. Retrospective studies- looking back over a period of time and past exposure to suspected aetiological factors are examined and an odds ratio is determined. Relying on people’s memory can be unreliable. Cross sectional studies- the prevalence between different populations at a time, for public health planning. This is the least reliable and shows what part of a population is most likely to get a disease. Autopsies can be performed for medical or legal reasons and can be used for medical research, improving disease diagnosis and for education. 30% of autopsies show inaccurate diagnosis. 

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Medicolegal autopsies determine the cause of death so that evidence can be used to prosecute someone responsible for the death, and has to be performed by forensic/home office pathologists. Clinical autopsies are used when patients die in hospital with an unknown cause or unclear diagnosis, to determine the condition that killed them.

Cell injury and cell death: Normal cells adapt in response to challenges to meet new demands. Cell injury occurs if the challenge is too big or is prolonged and the cell fails to meet the demand and shows signs of injury- change/loss of function, change of morphology. Light/early injury is reversible but irreversible injury can lead to cell death by going through necrosis or apoptosis. Reversible- eR or mitochondria swells without leakage or shrinking (pinosis) and if the challenge is removed (can be put in a hypotonic solution), the cell can recover. Irreversible- lysosome rupture and releases enzymes that damage the membrane so that it leaks, the mitochondria bleb and leads to necrosis.

Causes of injury:  

Oxygen deprivation- hypoxia, ischemia (lack of blood supply). Physical agents- mechanical trauma, extreme temperature.

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Chemical agents- cyanide, CO, alcohol (inhibit enzyme function, remove binding of oxygen from haemoglobin). Infectious agents- viruses, bacteria, parasites, fungi. Immunological reactions- anaphylactic reaction. Nutritional imbalance- deficiencies (vitamin B12 deficiency can cause anaemia, vitamin D deficiency can cause improper growth) overnutrition (high fat can cause atherosclerosis). Genetic defects- sickle cell anaemia.

Mechanisms of injury: Is complex and unknown in many cases.   

Cell response to stimuli- depends on the type, severity and duration of injury. Consequence of injury- depends on the type and state of the cell (some are more resistant to challenge and ability to repair itself). Cell injury results from functional and biochemical abnormalities in one/more of the essential cell components e.g. mitochondria, nucleus, eR.

Injury by free radicals: Have a single unpaired electron in the outer shell, it can oxidise tissue and damage it. ROS is generated by:    

Absorption of radiant energy- UV light, x-rays Reduction-oxidation reactions Transition metals Nitric oxide

Effects:   

Liquid peroxidation of membranes- double unsaturated fatty acid bonds are broken in membrane lipids Oxidation of proteins through the amino acid side chains or the backbone, formation of protein-protein cross linkages, causes protein fragmentation DNA damage- affects thymine and causes single strand breaks

4. Responding to injury- is reversible, then becomes irreversible and results in cell death (necrosis). Reversible injury. Functional changes:    

Decreased ATP production by mitochondria- ionic balance is lost as the pump cannot be maintained Cell membrane is not intact- cannot protect against the environment Protein synthesis defects Cytoskeleton damage and DNA damage

Morphological changes:     

Cell swelling- can be seen under a light microscope Cell membrane blebs, microvilli are lost in epithelial cells Mitochondria swells Endoplasmic reticulum dilates Nuclear disaggregation

Irreversible injury- death- necrosis.       

Extensive damage to cell membrane, leakage Lysosomes swell, mitochondria vacuolization Extracellular calcium enters the cell Intracellular calcium is released from stores in eR and mitochondria Enzymes are activated (from calcium)- breaks down membranes, proteins, ATP and nucleic acid Loss of proteins, coenzymes and RNA from the membrane as it is hyperpermeable Nuclear changes- pyknosis (shrinking), karyorrhexis (fragmentation), karyolysis (disintegration)

Necrosis- cell death, irrespective of cause. 1. Coagulative necrosis- most common and is due to hypoxia in tissues (but not in the brain), cell shape is not lost and stains with pink eosin.

2. Liquefactive necrosis- due to focal bacterial infection and many WBCs are present, caused by hypoxia in the CNS (brain), dead cells are digested and form a liquid viscous mass or it can form pus from dead WBCs. 3. Caseous necrosis- typical of TB infection, has a cheesy yellow-white appearance, tissue structure is destroyed. 4. Fat necrosis- fat tissue is destroyed and fatty acid is released, due to lipases (from e.g. pancreatitis), fatty acid binding to calcium can form soap.

Apoptosis (programmed cell death).     

Individual cell death that occurs in disease and in growth control Activated or prevented by many stimuli Reduced apoptosis leads to cell accumulation e.g. neoplasia Increases apoptosis leads to cell loss e.g. atrophy Process is well organised and tightly controlled; a cell’s own enzymes are activated to degrade DNA and proteins. The enzymes are normally used to remove unwanted or harmful cells. In pathological conditions, genetically defected cells are removed.

Characteristics:     

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Cytoskeleton is degraded DNA is fragmented Mitochondrial function lost Nuclear changes- pyknosis and karyorrhexis- shrinkage and fragmentation Cell shrinks but the plasma membrane stays intact so damage cannot leak- does not cause inflammation Apoptotic bodies formed to be phagocytosed

5. Haemostasis (stopping bleeding) in the circulation through the clotting system to block the leakage. Blood circulation is regulated to maintain a fluid, clot free state so that tissues can be provided with the blood they need and oxygen. However, the blood also needs to be able to form clots to block wounds to prevent injury.

Haemostasis: Vascular wall- is contractile so leakage can be sealed up. This is only limited and does not work on larger cuts. Platelets- fragments can block blood leakage. Coagulation cascade- for large cuts. Enzymes/clotting factors are activated when a tissue is damaged and results in a fibrin mesh to block the blood vessel and trap blood cells. Thrombosis- pathological overactive formation of clotting- not just normal haemostasis. A solid mass forms inside the blood vessel and is weakly attached to the vessel wall and prone to fragmentation. Factors for thrombosis: 1. Endothelial injury- not intact. The ECM is exposed and activates platelets and clotting factor and tissue factor is released. 2. Change of blood flow- stasis (slow- clotting factors not washed away- occurs in veins) or turbulent (fast- can damage endothelial layer- occurs in arteries). 3. Blood hypercoagulability/thrombophilia- clotting factors have high activity. These can interact with each other- endothelial injury causes a rough surface and can change blood flow to be turbulent. And abnormal flow can damage the endothelial lining.

1. Normal laminar flow 2. Atheroma- atherosclerosis elevated plaque causes turbulence and damages endothelial layer 3. Ulceration- ECM and collagen are exposed

4. Platelet adherence- to site where endothelial layer is lost and become activated 5. Thrombosis- clotting factors join in and block the blood vessel Risks for thrombosis:       

Prolonged bed-rest or immobilization Myocardial infarction- exposed blood vessel can release tissue factor Atrial fibrillation- no atrial contraction so there is stasis Prosthetic cardiac valves- not natural so does not have an endothelial layer, need to take anti-clotting mechanisms Tissue injury, surgery, fracture, burn- damage causes tissue factors to be released Cancer- can cause tissue damage, clotting system is 5x overactive Increased age- less active so more stasis and tissues are more easily damaged

Arterial thrombosis Higher blood pressure causes turbulence or endothelial injury. It often occurs in combination with atherosclerosis where there is an elevated plaque, then the thrombus forms and detaches and blocks the vessel- causes hypoxia and necrosis (infarction). It is often occlusive and occurs in the coronary artery (leads to myocardial infarction), cerebral artery (in brain) and femoral arteries. Venous thrombosis Occurs in the deep/superficial veins in the leg as the blood flow is slower as it is further away from the heart- there is more stasis. Can be offset by collateral bypass channels so 50% of people don’t notice it and are asymptomatic. It can cause local pain and oedema. The thrombus can go into the lung, but not the heart. DVT is concentrated in the valves because they generate local turbulence. It often occurs on long haul flights and can be reduced by walking around, taking blood thinning medication, drinking water to dilute the clotting factor and wearing socks to promote blood flow. Fate of a thrombus    

Propagation- become bigger Embolization- dislodging and moving to another place Dissolved- from fibrinolysis Organization and recanalization- connective tissue is formed as a scar and re-opened in older thrombus’

Complications

Arterial- myocardial infarction, or tissue infarction distally. Venous- oedema, lung embolism.

6. Embolus is a mass of material in the vascular system, embolism is its ability to become lodged in a vessel and block the lumen. The most common pulmonary (lung) embolism is from deep vein thrombosis. Thromboembolismemboli dislodged from a thrombus. The outcome of the embolism depends on where the emboli originate and where they lodge. Sources of emboli:      

Thrombus pieces, mixed thrombus and blood clots (smaller) Infected lesions in the blood stream Gas bubbles e.g. diving in deep parts of the sea and coming back up too rapidly can form bubbles Fat, bone marrow in bone fractures Tumour cells Amniotic fluid

Pulmonary embolism Is the major form of embolism. Most emboli (60-80%) are silent and 95% are from deep vein thrombosis. It can cause sudden death, right heart failure and cardiovascular collapse. Blockage in a medium sized vessel can cause pulmonary haemorrhage- bleeding in the lung. Multiple emboli can cause pulmonary hypertension. Systemic arterial emboli Emboli come from arterial circulation- mostly the heart chamber, otherwise unknown regions, and can travel to a wide variety of sites. The size of the lodge depends on the source and amount of blood supply. It mainly causes tissue infarction. Formed from atheroma plaques in arteries that can come off as a thrombus. Valve vegetation- debris can come off as emboli. In atrial fibrillation there is no proper movement of blood and a thrombus forms from stasis and endothelial damage. Myocardial infarction can cause thrombus too. They can travel to major arteries- brain (stroke), kidney (renal infarct), intestine (ischaemic), lower limbs (tissue necrosis causes gangrene infection and blockage needs to be removed).

Infarction- an area of ischemic necrosis caused by occlusion of the arteries supplying the tissue or venous drainage. It is an important cause of clinical illness and death. Tissue can also die from toxins or trauma (necrosis) but this is not from infarction.

99% of infarcts are from thrombotic or embolic events and mostly from arterial occlusion. Other causes are:    

Vasospasm (blood vessel is constricted and blocks flow) Haemorrhage of atheromatous plaque (becomes enlarged and blocks the lumen) Vessel compression by tumour Traumatic rupture- blood vessel is broken so cannot supply blood

Infarcts have different shapes due to the shape of blood supply in its specific location:   

Lung- wedge shaped Kidney- triangular Spleen- scarred

Classification based on colour (extent of bleeding and infection):    

White- anaemic- in solid organs like the heart, spleen, kidney Red- haemorrhagic Septic- infected Bland- uninfected

Factors influencing infarct development: 

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The nature of the blood supply- e.g. in the heart only the coronary artery supplies blood so there is a severe consequence, however in other tissues there may be different br...