BMS106 Pathobiology - Roehl Flashcards
What is a disease?
Any state in which the health of the organism is impaired
- a consequence of a failure of homeostasis
What is homeostasis?
Maintaining a physiological steady state, despite changes in internal or external processes
- usually desirable as allows constancy in function of organs, tissues, cells, organelles and proteins
What is pathobiology?
Study of biological mechanisms underlying disease processes
- identifies molecular and cellular interactions that create disease predispositions and enable exposures to produce pathological changes
- aims to understand disease mechanisms, produce diagnostic tools for disease prevention and to develop new treatments to cure disease
What is aetiology?
The primary cause of a specific disease
E.g. Mycobacterium tuberculosis causes tuberculosis, transmitted by air and infecting the lungs
What is pathogenesis?
The series of biological changes leading to clinically evident disease
What is pathology?
Diagnostic evidence of disease
What are disease risk factors?
Intrinsic biological disposition - a susceptibility or tendency to develop a disease - or extrinsic variable exposure which makes a disease more likely
What determines an organisms characteristics?
Interactions between intrinsic and extrinsic factors
- genes interact with factors located in the external environment to determine an organism’s physical characteristics (I.e. phenotypes)
What do some BRCA1 genetic variants cause?
Predispositions to breast and ovarian cancer
What can intrinsic risk factors be? Give examples of diseases
Metabolic - diabetes, gallstones
Cellular - autoimmune e.g. rheumatoid arthritis; degenerative and aging e.g. Alzheimer’s
Structural - spins bifida, a thermos, Osteoarthritis
Blood - sickle cel anaemia, thalassemia
How can exposure lead to pathogenesis?
Variable contact with an extrinsic harmful agent that makes a disease more likely
Give an example of an extrinsic harmful agent and how it can affect disease pathogenesis
Smoking increases the risk of developing lung cancer
What can extrinsic risk factors be?
Physical, chemical, biological, nutritional
Give agents and examples for physical extrinsic risk factors
Trauma - bone fracture
Radiation - Cancer
Give agents and examples for chemical extrinsic risk factors
Toxic substances - tobacco lung damage
Inflammatory agents - asthma
Give agents and examples for biological extrinsic risk factors
Bacterial - tuberculosis
Virus - AIDS
Protozoa - Malaria
Give agents and examples for nutritional extrinsic risk factors
Unbalanced diet - obesity, type 2 diabetes
How can the specific changes in biological structure and function that characterise each disease be recognised?
Macroscopic changes in organs
Light microscope level - cells/tissues
Electron microscope level - cells and organelles
Molecular level - e.g. DNA, RNA, proteins, hormones
What is epidemiology?
The study of the distribution and determinants of health and disease in populations
Aims to inform public health strategies to control disease
Can also help to understand the pathobiology of a disease
What can geography affect?
The prevalence and impacts of many diseases - markedly different in different countries
What are DALYs?
Disability Adjusted Life Years - sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability
What else can affect life expectancy?
Deprivation - can differ markedly between social groups within one society
Adults in the poorest fifth of the population are much more likely to be at risk of developing a mental illness than those on average incomes
How are epidemiology and pathobiology complementary?
Epidemiologist aims to reduce exposures, pathobiology aims to reduce disease burden through more effective diagnosis and treatment
What is Alkaptonuria?
A defect in the enzyme Homogentisate 1,2
Homogentisic acid accumulates in joints, causing cartilage damage and back pain and precipitates as kidney/prostate stones.
High levels are excreted blackening urine (which allows diagnosis)
Discovered by Archibald Garrod
What did Archibald garrod discover about alkaptonuria?
That it was a classical autosomal recessive Mendelian trait - this led to the identification of other inherited genetic disorders:
Cystinuria Phenylketonuria Albinism Glycogen storage disorders Galactosaemia
What does autosomal mean?
associated with one of the 22 non-sex chromosomes
What did William Bateson do?
Began to catalogue disease that exhibited Mendelian inheritance
- skin disorders, eye disorders, neurological disorders, inborn errors of metabolism, anatomical abnormalities
What is brachydactyly?
Short digits, small or missing phalanges
Name 2 autosomal recessive Mendelian diseases
Alkaptonuria
Cystic fibrosis
Name 2 autosomal dominant Mendelian diseases
Brachydactyly
Huntington’s disease
Name 2 x-linked Mendelian diseases
Duchess muscular dystrophy
X-linked mental retardation
Haemophilia
What is sickle-cell anaemia?
A painful, sometimes life threatening disorder of erythrocytes
Caused by a single-point mutation in the codon for amino acid 6 in the ß-gloving subunit (turns Glu codon into Val codon) - haemoglobin tetramers containing Hbs tend to form large insoluble polymers which distort erythrocyte shape
Autosomal co-dominant
Prevalence of sickle cell anaemia is ~2% in some sub-Saharan countries and the heterozygous carrier frequency is 10-40%.
Why is the frequency of the HBs allele so high?
Heterozygous carriers have sickle cell trait (mild suckling) but exhibit increased resistance to malaria - heterozygotes are fitter than both homozygotes.
How does karyotyping allow genes to be mapped to specific chromosomal locations?
Abnormalities in banding due to mutagenic rearrangements can be recognised and associated with specific phenotypes
What is aniridia?
An autosomal dominant phenotype caused by deletion or loss-of function point mutations in one copy of the gene
What is duchenne muscular dystrophy?
An x linked disease causing progressive muscle damage and wasting disease. Lethal in childhood or early adulthood
DMD gene located at chromosome position Xp21
How was the DMD gene identified?
A DNA sequence that was deleted in the X chromosome of the DMD patient BB and confirmed in other DMD patients
DNA marker for dystrophin protein
What is Huntington’s disease?
A progressive, late-onset, inherited neurodegenerative disorder (dementia and movement disorder)
Autosomal dominant
Whereabouts in the HD brain is massive neuronal loss exhibited?
Basal ganglia and dilation of lateral ventricles
How large is the HD gene?
1.7 X 10^5 base pairs
What do HD mutations do?
Expand a CAG repeat sequence in the first exon if the HD gene (CAGCAGCAGCAG…), increasing the size of a polyglutamine tract in the HD protein. The expanded polyQ tract makes the mutant Huntington protein toxic to neurones
What do some animal virus genomes contain?
Genes that cause cancer
- tumotigenicity of Rous Sarcoma Virus is due to the presence of DNA sequences captured from the chicken genome (the v-src oncogene) - encodes an abnormally hyperactive version of a tyrosine kinase
What is an oncogene?
A gene that has the potential to cause cancer
What are viral oncogenes?
Dominant, gain-of-function mutant alleles of cellular genes
How can loss-of-function mutations cause cancer?
Inactivation of tumour suppressor genes, e.g. retinoblastoma
What is retinoblastoma?
A rare retinal tumour that can be either hereditary or non-hereditary - tumours may be unilateral or bilateral
Non-hereditary retinoblastomas are typically unilateral
Hereditary blastimas are typically bilateral
Caused by mutations in a tumour supressor gene that normally prevents cells from becoming cancerous
What is Alfred Knudson’s two-hit hypothesis regarding retinoblastoma?
Caused by inactivation of both alleles of a tumour supressor gene
Hereditary retinoblastoma - inherited germline mutation present in all cells - only one somatic RB mutation required in retinal cell
Many chronic non-communicable human diseases are caused by multiple genes interacting both with each other and environmental factors…
This makes it impossible to identify “the gene” in such situations, since many genes are involved
Heart Disease Diabetes Obesity Cancer Hypertension Schizophrenia Autism Multiple sclerosis
What are SNPs?
Single Nucleotide Polymorphisms - total of 3 X 10^7 SNPs within the human genome - distributed randomly across the genome
How can SNPs be used to identify DNA sequences associated with common diseases?
SNPs present in each individual genome within a group of patients compared to SNPs present in the genomes of healthy individuals
Case vs control comparison
SNPs identified that are more frequently found in patients than in healthy individuals - may play potentially causative roles in the disease process.
These studies are called Genome Wide Association Studies (GWAS)
What are genomic imprints?
Structural modifications to specific regions of particular chromosomes that prevent the transcription of genes within such regions
What is an example of how genomic imprints can be made?
Methylation of DNA sequences
Where are different genomic imprints introduced?
Sperm vs eggs
Localised methylation of DNA occurs on a specific subset of genes during…
Oogenesis vs spermatogenesis
Distinct modified genes for each
The imprinted gene is the one that is…
Not expressed
When are maternal and paternal imprints created?
During gametogenesis
Imprints are erased in…
embryonic precursors of germ cells during embryonic development
What is Prader-Willi syndrome?
A disease caused by a mutation of the SNORD116 complex that leads to low muscle tone, short stature, cognitive disability, chronic hunger, morbid obesity
What is angelman syndrome?
A disease caused by a mutation of UBE3A that leads to cognitive disability, sleep disturbance, seizures, jerky movements, frequent smiling
What does epidemiology assume?
Disease does not occur randomly
Disease has identifiable causes
What is epidemiological research used to do?
- describe the health status of a population
- explain the aetiology of disease
- predict the disease occurrence
- control the disease distribution
What type of study is very useful in epidemiology?
Migrant studies - in order to determine importance of location and environment and lifestyle over genetics on different diseases
What proportion of cholera (Vibrio cholera) cases prove fatal in unprepared communities vs well organised and prepared countries?
50% vs <1%
How many deaths occur each day as a result of smoking in the UK?
Over 320
120,000 per year
1/5 of all deaths across all ages
7.5 Years average loss of LE
Smoking is highly addictive. What percentage of smokers who want to succeed giving up before age 65 (bearing in mind 70%+ want to)
50%
What percentage of smokers with a lung removed for lung cancer smoke up again?
50%
What are the factors behind cigarette addiction?
Pharmacology —> nicotine is a highly addictive drug
Learning mechanisms
Social and economic influences
What are some major health consequences of smoking?
Cancer (lung, mouth, larynx, throat, bladder, kidney etc)
Respiratory disease e.g. COPD
Vascular disease (CHD, stroke, peripheral vascular disease)
Pregnancy and birth complications
What is pulmonary emphysema (which can be caused by smoking)?
Enlargement of alveoli due to:
- loss of elastin surrounding alveoli
- destruction of cells in alveolar walls
Imbalance of more processes than anti-proteases. Inhaling toxins increases proteases (such as metalloprotease) which damage alveolar cells.
Protease balance can also be affected by genetics, for example decreased a-antitrypsin decreases anti-protease
What are attracted by IL-8 when it is released by macrophages due to smoking, and what do these do?
Neutrophils release the protease elastase
What are the consequences of pulmonary emphysema?
Decrease in the SA of the respiratory membrane leading to decreased gas exchange
Air becomes trapped in alveoli during exhalation as there is no elastic recoil
What are the critical factors that determine whether smoking exposure leads to disease?
Chemical and biological composition
Shape and size of particles
Dose (conc and duration)
Pre-existing health or genetic status
Concurrent exposure to other toxic agents
What are the 2 broad response types of the body to smoking?
Allergic responses (asthma, laryngitis, rhinitis, alveolitis) - histamine release by mast cells due to inhaled antigens (IgE)
Pneumoconiosis
Asbestos can cause many diseases including…
Asbestosis
