Prc Diseases

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Cell theory

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all living things are composed of cells

the cell is the most basic unit of life

all cells arise from pre-existing, living cells

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Pathology

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The study of how and why people fall ill in order to reveal the targets for their treatment; vital to diagnosis and clinical management of disease.

Define success or failure of progress and final outcome of treatment.

"Gateway" science to clinical care.

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Histopathology

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The study of diseased tissues for the diagnosis and guidance in the care of patients; major branch of clinical medicine.

Examination of surgical specien or biopsy.

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Disease

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an impairment of health or a condition of abnormal functioning

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Health

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state of complete physical, mental and social well-being and not merely the absence of disease

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Epidemiology

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study of how often diseases occur in different groups of people and why; used to plan and evaluate strategies to prevent illness.

recognises associations (likely to be causal if biologically plausible, disease associated with prior exposure, dose relationship, removal lessens risk)

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Incidence

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number of new cases in a specified population and time

conveys information about the risk of contracting the disease

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Prevalence

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the number of individuals affected in a given population at a specified point in time

estimate of how common a condition is within a population over a certain period of time; how widespread the disease is

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Mortality

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crude death rate; total number of deaths per year per 1000 people

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Prognosis

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likely outcome of an illness

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Pathogenesis

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mechanism by which a disease is caused, or the sequence of events in response to an aetiological agent; pathogenetic processes at work in most diseases

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Lung cancer epidemiology

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Most common cancer in the world today

3:1 males:females, median age range of 50-75

High mortality rate - 22% of all cancer deaths

Geographical variation; higher incidence in US and Europe than Africa and Southern Asia; per year, 53/100k Europe, 58/100k in US, 8/100k in Africa

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Lung cancer aetiology

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Tobacco smoking causes almost all lung cancers in UK

Radiation (uranium miners, radon) and asbestos

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Lung cancer symptoms

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Persistent cough, coughing up blood

Persistent breathlessness

Unexplained tiredness and weight loss

Ache or pain when breathing or coughing

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Lung cancer pathogenesis

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multiple pathways involving chromosomal changes, epigenetic effects (methylation) and changes in gene expression; different stages associated with different genetic alterations

p53 mutation by benzpyrene

changes to genes on chromosome 3p

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Lung cancer morphology

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Tumour appears soft and whitish; smokers lungs grey-black (impurities phagocytosed by macrophages)

Cells appear untidy, loss of order

Cancer categorised according to histology

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Lung cancer prognosis

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aggressive tumour

5 year survival rate of 6%

less than 1% for stage 4

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Acute disease

Chronic disease

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Rapid onset, short course, neutrophils

Slow progress, long duration, lymphocytes, fibroblasts, histiocytes

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Congenital non-genetic defects

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Injury to fetus during pregnany e.g.

maternal rubella (cardiac abnoramalities)

maternal diabetes

congenital toxoplasmosis (CNS effects, visual impairment etc.)

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Inflammatory disorders

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Physiological response of living tissue to injury, causative agent may be physical, chemical or infectious.

pneumonia (lung infection)

colitis (inflammation of large bowel)

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Disorders of immunity

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Defense mechanism against foreign/infectious agents.

autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis

hypersensitivity reactions: hayfever, penicillin or food allergy, bronchial asthma

immune deficiency syndromes: HIV - AIDS (can be congenital)

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Congenital errors of metabolism

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phenylketonuria (hydroxylase deficiency), ketone deficiency in brain

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Degenerative disorders

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Characterised by loss of the specialised structure and function of a tissue

osteoarthritis: loss of cartilage at joint causes bone to wear away, painful; only cure is joint replacement

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Benign tumours (oma; lipoma, fibroma) vs malignant (sarcoma or carcinoma; liposarcoma, fibrosarcoma)

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Slow vs fast growing

Capsulated vs non-capsulated

Non-invasive vs invasive

Do not metastasize vs metastasize

Well vs poorly differentiated

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Down's syndrome

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Numerical chromosomal defect

Caused by trisomy 21; extra copy of 21 caused by nondisjunction in female meiosis

Increased heart disease, infection disposition to childhood leukaemia, intellectual disability

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Cri-du-chat syndrome

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Structural chromomsal defect

Caused by deletion of short arm of chromosome 5

Intellectual disability, children have characteristic cry similar to meowing kitten

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Turner's syndrome

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Sex chromosomal defect (45,X0)

Sterile female, doesn’t menstruate, short, possible learning difficulties

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Klinefelter syndrome

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Sex chromosomal defect (47,XXY)

Sterile male with enlarged breasts, small testis, lack of facial hair

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Huntingdon's disease

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Achondroplasia

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Familia adenomatous polypoptosis

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Cystic fibrosis

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Sickle cell anaemia

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X-linked recessive disorders

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Affects only males; hemizygous for abnormal allele. Offspring of female carrier: 1/2 sons affected, 1/2 daughters carriers. Often traceable through many generations; can often ‘skip’ a generation if no boys born.

Haemophilia (F8 or F9 gene mutations, decreased plasma levels of FVIII or FIX, bleeding disorder)

Colour blindness

Duchenne muscular dystrophy (deletion in dystrophin gene leads to muscle weakening)

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Polygenic disorders

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Involve several genes and are often multifactorial (both environmental and genetic factors); iInclude common diseases, e.g. coronary heart disease:

Genetic factors: 1st degree relative heart attack, men

Environmental factors: high fat, low fibre diet, lack of exercise, smoking (atherosclerosis), stress

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Mosaicism

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Proportion of cells in the body carry the genetic defect e.g mosaic trisomy 21

Nondisjunction or a point mutation during development; phenotype depends on how early in development nondisjunction occurs, and the proportion of cells with the genetic defect.

Gonadal mosaicism: proportion of cells in gonads carry mutation, so disease is only passed onto some offspring

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Genetic vs environmetal disease

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Early onset, familial, uncommon

Genetic studies involve identical twins, patterns of inheritance and population genomic studies

Adult onset, not familial (but can appear so), common, area clustering

Classic epidemiology; study of risk factors (diet, smoking, work-related etc.), migrant studies

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Chemical

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H2SO4, NaOH

Chemical burn kills tissues (necrosis), generates scar tissue

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Metabolic

e.g. cyanide, carbon tetrachloride, alcohol

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Converted in the liver to acetaldehyde; causes cell damage

Excess alcohol leads to altered redox state; increased ratio of NADH:NAD+ impairs fatty acid oxidation, leading to fat accumulation Liver has potential to regenerate but long term damage causes scarring and loss of function; cirrhosis

Alcohol also affects stomach, heart, pancreas, and developing fetus (fetal alcohol syndrome)

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Allergic

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Nickel, latex

Proteins present cause dermatitis, type 1 hypersensitivity reaction; can lead to anaphylactic shock

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Teratogenic

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Thalidomide

Disturbs development of embryo or fetus; may cause birth defects

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Drugs

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Drug abuse e.g. heroin, cocaine destroys nasal septum

OD e.g. paracetamol fatal dose not much larger than therapeutic, kills liver

Side effects; may be unexpected (allergic response, drug interactions)

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Thermal

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Cold: hypothermia, frostbite. If serious, can lead to gangrene, autoamputationHeat: burns; coagulates proteins, causes tissue damage. As little as 20% burns can be fatal; skin main barrier to infection, leads to huge fluid loss.

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Coal miner’s pneumoconiosis

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(black lung disease)

Exposure to coal dust severely reduces lung capacity; simple cases cause breathlessness, complicated cases cause fibrosis

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Silicosis

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Exposure to dust from hard rocks has toxic effect on lung macrostructure; scarring

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Asbestos

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Asbestosis (fibrosis); fibres enter cells and interfere with DNA replication, causing DNA damage

Lung mesothelioma 100% exclusive to asbestos exposure; malignant lung mesothelium, constricts lung.

Also causes lung carcinoma.

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Organic dusts cause

Farmer’s lung

Bird fancier's lung,

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hypersensitivity pneumonitis (inflammation of alveoli)

caused by fungal spores in hay

caused by bird droppings; granuloma formation

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Ionising radiation

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Electromag (X, gamma), particle (alpha, beta, neutrons)

Radon makes up 50.1%, medical/diagnostic use 14.3%

Direct action affects macromolecules, but mainly indirect action via production of highly reactive free radicals (OH-) in burst causes DNA damage (strand breaks, base changes, cross-links)

Rapidly dividing tissues (bone marrow, gut) most affected, also gonads and developing fetus

Repair of DNA damage (cell cycle arrest) means cell survives; failure to repair damage leads to cell death or mutations (risk of cancer)

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Acute exposure to ionising radiation

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Low dose rad sickness, high dose death; SCs killed

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Chronic exposure to ionising radiation

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Vascular damage, sterility, lung damage , cancer (leukaemias followed by solid cancers), instant death

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Non ionising radiation

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UV light induces pyrimidine dimers in DNA. If damage not repaired, can cause skin cancer (very common in white migrant populations). Incidence increasing.

Non-melanoma: prolonged exposure, slow developing e.g. basal cell carcinoma (~75%), squamous cell carcinoma (~20%)

Melanoma (less than 5%): early acute sunlight exposure

Also induces production of protective melanin (tanning) and has a skin ageing effectNB: dark skin has more actin, not melanin

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Nutritional

Underdeveloped and developed countries

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Protein-energy malnutrition (lack of food)

Vitamin deficiencies

Trace element deficiencies (goiter, iodine)

Overeating causes obesity; one of the biggest causes of disease in developing countries

High fat and sugar, low fibre diet; increased risk of diabetes, cancer and heart disease

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Smoking

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Epidemiological studies; smoking habits in doctors revealed association

Tobacco use causes ~20% of all deaths in the UK every year, ~half of all regular cig smokers will eventually be killed by their habit

80% lung cancer deaths, 80% bronchitis and emphysema deaths, 17% heart disease deaths, 30% of all cancer deaths

Increased lung infections, asthma, emphysema and bronchitis, Atherosclerosis and thrombosis; MI or stroke

Gastric ulcers

Cancer: lung, throat and mouth, bladder, cervix

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Damaging components of smoke

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Carcinogens: tar, polycyclic aromatic HCs, nitrosamines

Cell irritants and toxins: ammonia, formaldehyde, nitrogen oxidesCO: binds irreversibly to Hb and reduces O2 delivery to tissues

Nicotine: addictive, raises bp and heart rate

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Knudson's 2 hit hypothesis (only applicable to cancer, not other genetic diseases)

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First applied to retinoblastoma; hypothesised that 2 genetic events (hits) needed for cancer to develop:

1st hit germline if genetic predisposition, somatic if sporadic, usually point mutation or small deletion

2nd hit somatic in all cases, often a large scale event

To develop a cancer, one or both copies of tumour suppressor genes must be lost or inactivated. Patients with genetic predisposition have one copy already mutated or deleted, so only need a single event to develop cancer.

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WAGR syndrome

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Wilms’ tumour (1 in 2 risk, childhood kidney cancer bilateral or multifocal)

Aniridia

Genitourinary abnormalities

Mental retardation

95% cases sporadic; not inherited. Constitutional deletions of one copy of chromosome 11, at band 11p13 (deletion in the short arm, P, of chromosome 11, at band 13); 11p13 contains Wilm's tumour suppressor gene, WT1.

Encodes tf essential for normal kidney development; loss of oe copy causes GU abnoralities, loss of second copy causes Wilm's tumour. Only mutated in 20% of sporadic Wilm's tumours.

Loss of PAX6, a tf, causes aniridia

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Type 1 DM

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(previously insulin-dependent DM)

characterised by autoimmune beta cell destruction (insulitis) usually leading to absolute insulin deficiency with juvenile onset

0.4% of population

Multifactorial; caused by interaction between environmental factors and inherited genetic predisposition; affects a genetically distinct subset

Mean age of onset of 12 y

Highest incidence of T1D in Northern Europe

Incidence increasing at a rate of 3% per year

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Maturity onset diabetes of the young (MODY)

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monogenic defect leading to defects of the beta cell

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Type 2 DM

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(previously non-insulin-dependent DM)

associated with obesity and tends to occur later in life; disorder manifests as a result of insulin resistance and relative insulin deficiency