ILOs Flashcards
Describe the spirometric pattern that would be expected in obstructive versus restrictive respiratory disease
Obstructive (e.g. COPD/Asthma) - Reduced FEV1:FVC (<70%), Reversibility (>15% AND 400ml in Post-BD FEV1) in Asthma but NOT in COPD
Restrictive - Preserved FEV1:FVC (>70%) with Reduced % Predicted FVC
State the Alveolar Air Equation
PaO2 = FiO2 - (1.25 x PaCO2)
PaO2 - Alveolar Oxygen Partial Pressure, kPa
FiO2 - Inspired Oxygen Concentration, kPa
Describe the clinical application of the Alveolar Air Equation
Arterial pO2 can be directly measured by ABG analysis, whereas Alveolar pO2 must be calculated
The difference between Alveolar pO2 and Arterial pO2 is known as the Alveolar-Arterial Oxygen Gradient
Normally, this should be less than 2-4kPa
Higher than this suggests a V/Q mismatch
Using the Alveolar Air Equation comment on the following patient:
Man with COPD, on 28% Oxygen
pO2 - 7.6
pCO2 - 6.6
Alveolar pO2 = 28 - (1.25 x 6.6) = 19.75
Therefore, A-a = 19.75 - 7.6 = 12.15
Alveolar-Arterial Gradient is increased, suggesting V/Q mismatch
Describe an approach to the analysis of blood gases in clinical practice
Always look at pO2 first to assess if the patient is in respiratory failure or requires additional oxygen
Next look at the pCO2 to determine Type 1 vs Type 2 Resp. Failure
Then look at the acid-base balance to determine if:
Acute Resp. Acidosis (Elevated pCO2, Normal Bicarb, Acidosis)
Comp. Resp. Acidosis (Elevated pCO2, Elevated Bicarb, Not Acidotic)
Acute on Chronic Resp. Acidosis (Elevated pCO2, Elevated Bicarb. Acidosis)
Define COPD
‘a chronic disease characterised by progressive airflow limitation that is not fully reversible and characterised by chronic bronchitis and emphysema’
Describe the pathology of COPD
Increased number of mucus-secreting cells
CD8 lymphocyte driven inflammation of the airways, leading to scarring and thickening
Neutrophil infiltration
Loss of defined alveolar air spaces leading to loss of elasticity and air trapping
Causes airway collapse, and blockage of airways
State some clinically differentiating features of Asthma and COPD
Episodic SOB in Asthma
Nocturnal Symptoms and Diurnal Variation in Asthma
Productive Cough in COPD
Asthma is Not Progressive, Has Exacerbations and Variable Symptoms
COPD is Progressive, Has Exacerbations and Persistent Symptoms
Describe the effects of cigarette smoke on the airways and how this leads to pathology
Mucus Gland and Goblet Cell Hypertrophy –> Increased Mucus Production –> Cough and Sputum
Reduced Cilial Motility –> Decreased Mucus Clearance –> Increased Infection Risk
Anti-Protease Inhibition –> Increased Protease Activity –> Inflammation
Describe the typical features of a ‘Blue Bloater’
Usually in chronic bronchitis
Due to CO2 retention (becomes insensitive to it)
Low Resp. Drive and Type 2 Resp. Failure
(Low PaO2 and High PaCO2)
Cyanosis, Obesity, Crackles and Wheeze, Peripheral Oedema
Chronic Productive Cough, Purulent Sputum
Describe the typical features of a ‘Pink Puffer’
Due to Emphysema
CO2 responsive with compensatory hyperventilation
Desaturates on Exercise, Pursed Lip Breathing, Use of Accessory Muscles, Wheeze, Indrawing of Intercostals, Tachypnoea, Cachectic Appearance
High Resp. Drive, Type 2 Resp. Failure
Low PaO2 and PaCO2
Define Obstructive Sleep Apnoea Syndrome
Recurrent episodes of partial or complete upper airway (pharyngeal) obstruction during sleep, intermittent hypoxia and sleep fragmentation manifesting as excessive daytime sleepiness
State risk factors which predispose to development of Obstructive Sleep Apnoea Syndrome
Obesity
Male Sex
Post-Menopause (Women)
Large Neck Circumference (>40cm)
Maxillomandibular Anomalies (Narrowing, Retrognathia)
Increased Tonsil/Adenoid/Tongue Size
FHx
Describe the investigations used in the diagnosis of Obstructive Sleep Apnoea Syndrome
History (from Pt and Family)
Clinical Exam
Daytime Sleepiness Assessment (Epworth Score)
Limited Polysomnography (Home, 5 Channel; O2 Sats, HR, Flow, Thoracic and Abdominal Effort and Position)
Full Polysomnography (In-Hospital, Multi-Channel; EEG, Video, Audio, Thoracic/Abdominal Bands, Position, Flow, O2 Sats, Limb Leads, Snore)
Transcutaneous Oxygen Saturation and Carbon Dioxide Assessment
Describe the methods of management of Obstructive Sleep Apnoea Syndrome
Weight Loss
Avoidance of Triggers (e.g. Alcohol)
Treatment of Underlying Factors
Continuous Positive Airway Pressure (Splints airway open to stop snoring and sleep fragmentation to reduce daytime sleepiness and improve quality of life)
Mandibular Advancement Device
Sleep Position Training
Describe pathological features in the lung which lead to pneumothorax
Sub-Pleural Blebs (blister-like air pockets) at the apex of the lung
Diffuse, microscopic emphysema below the surface of the visceral pleura
Spontaneous rupture can lead to a tear in the visceral pleura
Outline the diagnostic features of spontaneous pneumothorax
Pleuritic Chest Pain
Dyspnoea
Respiratory Distress
Reduced Air Entry on Affected Side
Hyper-Resonance to Percussion
Reduced Vocal Resonance
Tracheal Deviation (If Tension)
Outline the initial management of spontaneous pneumothorax
Observation if small or not very symptomatic
Aspiration (urgently if tension) with syringe in 2nd intercostal space, midclavicular line
Intercostal drain with underwater seal
State pathological and clinical features that predispose to pulmonary embolism
Surgery <12 Weeks Previously
Immobilisation >3 Days in Previous 4 Weeks
Previous DVT/PTE
FHx of PTE/DVT
Lower Limb Fracture
Pregnancy or Post-Partum
Long Distance Travel
Oestrogen-Containing OCP Use
Antithrombin Deficiency
Protein S or C Deficiency
Factor V Leiden
Describe clinical features of pulmonary embolism
Tachypnoea
Crackles
Tachycardia
Fever
Signs of Peripheral DVT
Pleuritic Chest Pain
Dyspnoea
Cough
Haemoptysis
Syncope
Describe investigations for pulmonary embolism
Modified Geneve Score (Risk Assessment)
D-Dimer (Raised, >230mg/L)
ABGs (Resp. Alkalosis with Reduced PaCO2)
Troponin
ECG
Echocardiogram
Radiology (CXR, CT-Pulmonary Angiogram, V/Q Scan)
Describe the immediate management of pulmonary embolism
Massive:
(PE associated with SBP <90mmHg or a drop in SBP of >40mmHg in <15 Minutes)
Give Unfractionated Heparin IV
Fluid Resuscitation
Thrombolysis with Alteplase if Fails to Improve
Sub-Massive:
Initially LMWH
Then Oral Anti-Coagulant for 3 Months (Factor Xa Inhibitors or Warfarin)
Describe the features of Usual Interstitial Pneumonia
Heterogenous appearance with areas of normal lung punctuated by marked fibrosis and honeycombing (mainly in subpleural areas) and fibroblastic foci (dense proliferations of fibroblasts and myofibroblasts)
Describe the clinical diagnosis of Pulmonary Fibrosis
Clinical manifestation of UIP
Fibrotic lung disease, usually with no definitive cause
Progressive Breathlessness, Bibasilar Crackling, Hacking Dry Cough, Fatigue, Weakness, Finger Clubbing, Appetite and Weight Loss
Describe the pathological processes in Sarcoidosis
Chronic granulomatous disorder characterised by accumulation of lymphocytes and macrophages in organs (typically the lungs and intrathoracic lymph nodes)
Non-necrotising granulomas with multi-nucleated giant cells in the centre
Describe the clinical presentation of Sarcoidosis
May present with pulmonary, neurological, cardiac, dermatological or ocular findings
Systemic symptoms: Fever, Anorexia, Fatigue, Night Sweats, Weight Loss
Pulmonary symptoms: Cough, Haemoptysis, Dyspnoea on Exertion, Chest Pain
May be asymptomatic
Describe the pathology and presentation of Extrinsic Allergic Alveolitis
T-Cell mediated (immunological) inflammatory reaction in the alveoli and respiratory bronchioles
(N.B. EAA is NOT atopy)
May present with flu-like illness, cough, fever, chills, myalgia, malaise, dyspnoea
State the pathological classification of Lung Cancer
Small Cell
Non-Small Cell (Large Cell, Adenocarcinoma or Squamous Cell)
Describe the pathology of Small Cell Lung Cancers
Most aggressive form, often metastasising early and widely
Often a good initial response to chemotherapy, but most patients relapse
Appearance: Oval to Spindle Shaped Cells, Inconspicuous Nucleoli, Scant Cytoplasm, Nuclear Moulding
Describe the pathology of Squamous Non-Small Cell Lung Cancer
Tends to arise centrally from major bronchi
Slow growing and late to metastasise
Often within dysplastic epithelium following squamous metaplasia
Appearance: Malignant Epithelial Tumour showing Keratinisation and/or Intracellular Bridges
Describe the pathology of Adenocarcinoma Non-Small Cell Lung Cancer
Common tumour in females
Also seen in non-smokers
Two-thirds arise in the periphery
Appearance: Glandular, Solid, Papillary or Lepidic with Mucin Production
Describe the pathology of Large Cell (Non-Small Cell) Lung Cancer
Usually arises centrally
Undifferentiated malignant epithelial tumour that lacks the cytological features of SCLC and glandular or squamous differentiation
Describe the pathological consequences of local spread of lung cancer
Bronchial Obstruction
Lung Collapse or Consolidation (Retention Pneumonia)
Pleura - Haemorrhagic Effusion
Blood Vessels - Haemoptysis
Pericardium - Pericardial Effusion
Mediastinum - SVC Obstruction
Pancoast Tumour - Horner’s Syndrome, Brachial Plexus Compression
Describe the distant spread of lung cancer
Haematogenous - Liver, Bone, Brain, Adrenal
Lymphatic - Cervical Lymph Nodes
State cancers which most commonly metastasise to the lungs
Bowel, Breast, Prostate, Bladder, Kidney
Describe the classification of Beta-Lactam Antibiotics
Penicillins: Benzylpenicillin, Flucloxacillin, Amxocillin
Cephalosporins: Ceftriaxone
Carbapenems: Meropenem
Monobactams: Aztreonam
Co-Amoxiclav
Tazocin
Briefly describe normal skin anatomy
Describe the embryological process of skin development
Epidermis is derived from the ectoderm while the dermis is from the underlying mesenchyme
In the 5th week, the skin of the embryo is covered by simple cuboidal epithelium
In the 7th week there is a single squamous layer (periderm) and a basal layer
In the 4th month an intermediate layer containing several cell layers is interposed between the basal cells and the periderm
In the early foetal period, the epidermis is invaded by melanoblasts (cells of neural crest origin)
Describe the role of the immune system in the skin
Langerhans Cells (dendritic cells) reside in the basal layers of the skin
Acquire antigens in the periphery, transport them to regional lymph nodes to activate naive T-Cells and initiate an adaptive immune response
Activated T-Cells then initiate cytokine release cascade
Describe the effects of UV light on the skin
Direct effects include photoaging, DNA damage and carcinogenesis
p53 tumour suppressor genes are mutated by DNA damage (implicated in development of melanoma and non-melanoma skin cancers)
Chronic exposure can lead to loss of skin elasticity, fragility, abnormal pigmentation, haemorrhage of blood vessels, wrinkling and premature ageing
Describe the aetiology of Acne Vulgaris
- Sebaceous gland hyperplasia and excess sebum production, especially during puberty where androgens drive gland enlargement
- Abnormal follicular differentiation (keratinocytes are retained and accumulate)
- Propionibacterium Acnes colonisation, stimulate the production of pro-inflammatory mediators and lipases
- Inflammation and immune response leads to development of papules, pustules, nodules and cysts
Describe the management options for Acne Vulgaris
- Reduce Plugging:
- Topical Retinoid
- Topical Benzoyl Peroxide
- Reduce Bacteria
- Topical Antibiotics (Erythromycin, Clindamycin)
- Oral Antibiotics (Tetracycline, Erythromycin)
- Reduce Sebum Production
- Hormones - Anti-Androgens (Dianette/OCP)
Describe the role of Isotretinoin in the management of Acne Vulgaris
An oral retinoid (concentrated Vitamin A) for severe Acne Vulgaris
Reduces sebum production, plugging and bacterial colonisation
Standard course of 16 weeks at 1mg/kg
Causes remission in around 80% of teenagers
Trivial Side Effects - Dry Lips, Nose Bleeds, Dry Skin, Myalgia
Serious Side Effects - Deranged Liver Function, Raised Lipids, Mood Disturbance, Teratogenicity
(Must have regular pregnancy tests to prevent pregnancy while on therapy)
Describe how psoriasis may present in the skin
Extensive erythematous, circumscribed, scaly papules and plaques
Describe the immune mechanisms associated with psoriasis
Hyperproliferative disorder where cells migrate from the basal layer to the stratum corneum in just a few days
T-Cell mediated autoimmune response
Abnormal infiltration of T-Cells causes release of inflammatory cytokines including interferon, TNF and interleukins
Causes increased keratinocyte proliferation
Describe treatment options for psoriasis
- Topical Creams and Ointments
- Moisturisers help to reduce flaking and dryness
- Steroids reduce immune response
- Phototherapy Light Treatment
- Non-Specific Immunosuppressant Therapy
- Reduces T-Cell Proliferation
- Encourages VitD to reduce skin turnover
- Risk of burning and skin CA
- Acitretin
- Methotrexate and Ciclosporin
- Immunosuppressants
- Biologics
- Etanercept, Infliximab, Adalimumab
- (Anti-TNF)
Describe the different types of psoriasis
- Chronic Plaque
- Pink-red, well-demarcated plaques with a silver scale especially seen on extensor surfaces of the knees
- Guttate
- Raindrop like psoriasis most commonly seen in young adults and children characterised by an explosive eruption of very small circular or oval plaques over the trunk about 2 weeks after a streptococcal sore throat
- Erythrodermic and Pustular
- Can be life-threatening
- Sterile pustules filled with inflammatory cells
- Associated with malaise, pyrexia and circulatory disturbance
Describe the conditions associated with psoriasis, i.e. psoriatic arthritis and metabolic syndrome
Psoriatic Arthritis - Inflammatory disease often affecting the fingers and toes causing swelling
Metabolic Syndrome - Central Obesity, HTN, T2DM, Low HDL Levels and High Serum Triglycerides
Describe the different subtypes of eczema
- Atopic
- Itch inflammatory skin condition
- Associated with asthma, allergic rhinitis, conjunctivitys and hay fever
- High IgE levels
- 10-15% of infants affected, remission in 75% by 15 years
- Contact
- Precipitated by an exogenous agent
- Type IV Hypersensitivity (Delayed T-Cell Response)
- Common allergens include nickel, chromate, cobalt, fragrance
- Seborrhoeic
- Chronic,scaly inflammatory condition often on the scalp or face
- Overgrowth of Pityrosporum Ovale yeast
- Venous
- Associated with underlying venous disease
Describe the management of eczema
- Atopic
- Emollients
- Topical Steroids
- Bandages
- Antihistamines
- Antibiotics/Anti-Virals
- Avoidance of Exacerbating Factors
- Seborrhoeic
- Scalp - Mediated Anti-Yeast Shampoo
- Face - Anti-Microbial, Mild Sterooid and Simple Moisturiser
- Venous
- Emollient
- Mild/Moderate Topical Steroid
- Compression Bandages/Stocking
- Venous Surgical Intervention
Describe the association between eczema and diseases such as asthma, hay fever etc.
Atopic diseases
Associated with immune response and high IgE levels
Define Acute Compartment Syndrome
‘an orthopaedic emergency resulting from elevated interstitial pressure within a closed fascial compartment resulting in microvascular compromise, most commonly in the leg, forearm or thigh which could lead to loss of function, limb or life’
Describe the pathology of Acute Compartment Syndrome
Increased Internal Pressure (Bleeding, Swelling)
Increased External Compression (Casts, Bandages)
Pressure within the compartment exceeds the pressure within the capillaries
Muscles become ischaemic and develop oedema through increased endothelial permeability
Necrosis begins in the ischaemic muscles after four hours
Ischaemic nerves become neuropraxic (loss of motor and sensory function)
This may recover if relieved early, however permanent damage may result after only four hours
In the later stages, there is a compromise of the arterial supply
Describe the clinical features of Acute Compartment Syndrome
Pain (out of proportion to that expected from the injury and on passive stretching of the compartment)
Pallor
Paraesthesia
Paralysis
Pulselessness
Swelling
Shiny Skin
Autonomic Response - Sweating, Tachycardia
Reduced Consciousness Level
Describe the management of Acute Compartment Syndrome
Open any constricting dressings/bandages
Surgical Release:
Full length decompression of all compartments
Excise any dead muscles
Leave wounds open
Repeat debridement until pressure is down and all dead muscle has been excised
Later, close the wound and graft the skin if needed
Define Tendinopathy
‘chronic tendon injury of over use due to repetitive loading, characterised by degeneration and disorganisation of collagen fibres, increased cellularity and only little inflammation’
Describe the pathology of Tendinopathy
Tendinopathy is likely not an inflammatory process
Deranged collagen fibres and degeneration with a scarcity of inflammatory cells
Increased vascularity around the tendon
Failed healing response to micro-tears
Inflammatory mediators including IL-1, NO and Prostaglandins are released which cause apoptosis, pain and provoke degeneration through release of Matric Metalloproteinases
Describe the management of Tendinopathy
Pharmacological:
NSAIDs
GTN Patches
PRP Injection
Prolotherapy
Steroid Injection
Non-Pharmacological:
Activity Modification
Physiotherapy
Extracorporeal Shockwave Therapy
Radiofrequency Coblation
Operative Management:
Debridement
Excision of Diseased Tissue
Describe the features of autosomal dominant inheritance
e.g. Achondroplasia
Affects every generation
Males and Females equally affected
Vertical pattern of inheritance
50% chance of child being affected if a parent is heterozygous
Disease = Aa or AA, Healthy = aa
Describe the concept of ‘variable expression’ in Mendelian Inheritance
Variable Expression: Two people in the same family, who have inherited the same mutation in the same gene, may have different disease severities or age of onset
Describe the concept of ‘incomplete penetrance’ in Mendelian Inheritance
Complete/Incomplete Penetrance: One may inherit the mutation but this would not be enough to develop the disease (i.e. incomplete penetrance)
Describe the concept of ‘gonadal mosaicism’ in Atypical Mendelian Inheritance
Presence of more than one cell line in the gonads (but NOT in somatic cells) due to a mutation in a gamete precursor cell
Describe the concept of ‘modifier genes’
Genetic variants that can affect the manifestation of a disease by altering indirectly influencing expression of another gene
This may help explain the variable expressivity seen in some mutations, and may affect the age of onset, rate of disease progression and severity of symptoms
Describe the features of autosomal recessive inheritance
e.g. Sickle Cell, CF, PKU
Equal frequency and severity in males and females
Horizontal pedigree pattern
Disease expressed in homozygotes (two identical mutations) or compound heterozygotes (two different mutations in the same gene)
Low risk to offspring of affected individuals
Expressivity more constant in a family
May suggest consanguinity in the family
Describe X-Linked Recessive Inheritance
e.g. Duchenne’s Muscular Dystrophy
No male to male transmission
‘Knights Move’ pattern of inheritance
Male-Female transmission = All Daughters are Carriers
Female-Female Transmission - 50% of Daughters are Carriers
M>>>F
Describe X-Linked Dominant Inheritance
e.g. Vitamin D Resistant Rickets
No male to male transmission
Vertical pattern of inheritance
Male-Female Transmission = All Daughters Affected
Female-Female Transmission = 50% of Daughters Affected
F:M = 2:1
Describe the difference between Tumour Suppressor Genes, Proto-Oncogenes and Oncogenes
TSG: Normally inhibit progression through cell cycle and cell prilferation, promote apoptosis or act as stability genes
Mutation Results in Loss of Function
Requires 2 Mutated Copies to Become Tumourigenic
Proto-Oncogenes: Normally stimulate cell cycle or promote cell division/growth
Activation by mutation results in Oncogenes with Gain of Function in protein
Only needs one mutated copy for tumourigenic effect
Describe the ‘Two-Hit Hypothesis’
The Two-Hit Hypothesis states that two mutated alleles are required for progression to cancer
The first may be inherited, meaning a second sporadic mutation is required to initiate tumourigenesis
Describe Gain and Loss of Function mutations
LOF: Mutation causes a reduction in the activity or amount of the encoded protein
GOF: Mutation results in a greater level of activity, a greater amount of protein or rarely, acquisition of a new function (e.g. BCR-ABL)
LOF mutations are more common
Describe the role of BRCA1/2 mutations in the contribution to cancer
BRCA1/2 proteins are large nuclear proteins and with roles including DNA repair, transcriptional regulation of other genes and cell-cycle regulation
They promote double-stranded DNA repair by homologous recombination
Describe the molecular genetic basis and clinical aspects of Huntington’s Disease
Onset typically between 30-50 years
Characterised by progressive chorea (involuntary movements), dementia and psychiatric symptoms
Autosomal Dominant with Genetic Anticipation
Unstable length mutation in the HTT gene
Number of CAG repeats increased from 10-35 to 36-120
This repeat encodes a polyglutamine tract
Expansion of tract causes insoluble protein aggregates and neurotoxicity
Describe the concept of Genetic Anticipation
The phenomenon where symptoms of an inherited condition become more marked and become apparent at an earlier age in subsequent generations
Describe the clinical aspect and molecular genetic basis of Myotonic Dystrophy
Progressive muscle weakness in early childhood with myotonia and cataracts
Autosomal Dominant with Genetic Anticipation
Unstable length mutation of a CTG repeat
Affected if 50 or more repeats
Define ‘Cascade Screening’
Systematic identification and testing of members of the family of a proband with a particular disease of interest
(aka testing the family of a patient diagnosed with a disease such as CF)
Describe the clinical aspects and molecular genetic basis of Cystic Fibrosis
Characterised by recurrent lung infections and exocrine pancreatic insufficiency
CFTR mutation results in defective chloride ion channels and increased thickness of secretions
Most common mutation is F508del (in-frame deletion of one codon resulting in loss of phenylalanine ‘F’ at position 508 )
Prevents normal protein folding and insertion into the plasma membrane
Describe the clinical aspects and molecular genetic basis of Duchenne Muscular Dystrophy
Onset at 3yrs, Wheelchair by 12yrs
X-Linked Recessive Inheritance
Serum Creatine Kinase leaks from damaged muscle fibres into serum
Out-Of-Frame Deletion Mutations
Describe the clinical and genetic consequences of Fragile X Syndrome
Significant Learning Disability
X-Linked Recessive Inheritance
With Genetic Anticipation
If Full Mutations: Phenotypes in males can be severe, some carrier females also affected more mildly
Briefly describe the main autosomal trisomies
Down’s: Trisomy 21, Learning Difficulties, Heart Defects, Hypothyroidism
Edwards’s: Trisomy 18, Small Chin, Clenched Hands, Malformation of Organs, Profound Learning Difficulties if Survive Past 1 Year
Patau: Trisomy 13, Congenital Heart Disease, 50% SR at 1/12, 10% at 1Yr, Profound Learning Difficulties
State some important aspects of clinical history and examination that are especially helpful in clinical genetics
Hx: Age of Onset, Progression
FHx: Consanguinity, Miscarriages, Stillbirths
O/E: Dysmorphic Features (Head Shape/Size, Eyes, Ears, Nose, Philtrum), Unusual Features (Polydactyly)
Describe Pre-Implantation Diagnosis and state its advantages and disadvantages
One or Two cells are removed from an embryo to undergo PCR or FISH to check for a mutation and only unaffected embryos are transferred into the patient
Pros: Permits implantation of unaffected embryos
Cons: Possible long wait, Not available to all women, Difficulty with multiple visits and procedures, Take home baby rate usually <50% per cycle
State the genetic conditions tested for (and the tests used) during pregnancy
Down Syndrome: Combined Ultrasound (Nuchal Translucency Increases in DS) and Biochemical Screening (CUBS)
State the genetic conditions tested for (and the test method) during the neonatal period
Heel Spot on Guthrie Card
Phenylketonuria and Medium-Chain Acyl-CoA Dehydrogenase Deficiency (Mass Spectrometry)
Congenital Hypothyroidism and Cystic Fibrosis (Immuno-Assay)
Sickle Cell Disorder (High-Performance Liquid Chromatography)
State some of the genetic conditions screened for in specific adult populations
Tay Sachs Disease - Screened for in Jewish people, e.g. Pre-Pregnancy
Thalassaemia - Population Carrier Screening
Briefly describe Sanger DNA Sequencing
i.e. Fluorescent Dideoxynucleotide Sequencing
Used in detection of point mutations
Analyses a single gene at a time
State the application of Array Comparative Genomic Hybridisation in DNA Analysis
Detection of sub-microscopic duplications and deletions
Describe the basis of next generation DNA sequencing
i.e. Massively Parallel Sequencing
Of many or all genes
Used to find small mutations somewhere in the exome
Describe Type I Hypersensitivity, including Anaphylaxis
Immediate, Atopic, IgE Mediated Response
Responsible for most allergies, including asthma, eczema and hayfever
Response to the challenge occurs immediately, tends to increase in severity with repeated exposure
Predominantly mediated by IgE bound to mast cells
Antigen binds to IgE associated with mast cell, causing degranulation and release of histamine, cytokines, prostaglandins and leukotrienes
Anaphylaxis is a life-threatening severe, systemic Type I Hypersensitivity as a result of systemic exposure to an antigen and vascular permeability is the immediate danger (soft tissue swelling threatens airway and loss of circulatory volume causes shock)
Describe Type II Hypersensitivity
Cytotoxic, Antibody Dependent
IgM/IgG Bound to Cell /Matrix Antigen
Caused by binding of antibodies directed against human cells (usually IgG)
Associated with Drug Associated Haemolysis more than allergy
Common cause of autoimmune disease
e.g. Autoimmune Haemolytic Anaemia
Describe Type III Hypersensitivity
Immune Complex
IgM or IgG Bound to Soluble Antigen
Mediated by immune complexes bound to soluble antigen
Cause of autoimmune disease and drug allergy
Aggregates in small blood vessels causes direct occlusion, complement activation and perivascular inflammation
e.g. SLE or RA
Describe Type IV Hypersensitivity
T-Cell Mediated Response
Delayed-type hypersensitivity, presents several days after exposure
Mediated by action of lymphocytes infiltrating the area
e.g. Contact Dermatitis
Describe the features of reversible cell injury
Changes due to stress in the environment
Returns to normal once the stimulus is removed
Features include:
‘Cloudy Swelling’ - Osmotic disturbance due to loss of energy-dependent Na pump leads to Na influx and build up of intracellular metabolites
Cytoplasmic Blebs
Disrupted Microvilli
Swollen Mitochondria
‘Fatty Change’ - Accumulation of lipid vacuoles in cytoplasm caused by disruption of fatty acid metabolism, esp. in the liver
Describe the features of irreversible cell injury
Permanent
Cell death (usually necrosis) follows
Features include:
ATP Depletion
Calcium Influx
DNA Damage
Accumulation of Oxygen Free Radicals
Extensive Physical Damage
Define apoptosis
Genetically programmed (physiological) or activated cell death (pathological) requiring energy and distinct pathways
State some physiological and pathological aetiologies of apoptosis
- Physiological:
- Deletion of cell populations in embryogenesis
- Cell deletion in proliferating populations (e.g. epithelium)
- Deletion of inflammatory cells after an inflammatory response
- Deletion of self-reactive lymphocytes in thymus
- Pathological:
- Viral Infection: Cytotoxic T-Lymphocytes
- DNA Damage
- Hypoxia/Ischaemia
Describe the morphological features of apoptosis
Cell Shrinkage
Chromatin Condensation (Packaging up of nucleus, unlike in necrosis)
Membranes of Cell and Mitochondria Remain Intact
Cytoplasmic Blebs form and break off to form apoptotic bodies which are phagocytosed by macrophages
Define necrosis
Pathological, unprogrammed cell death following injury and which is uncontrolled and due to external stimuli
Describe the histological changes seen in necrosis
Cell swelling, vacuolation and disruption of membranes of cells and its organelles including mitochondria, lysosomes and ER
Release of cell contents (cell lysis) including enzymes causes adjacent damage and acute inflammation
DNA disruption and hydrolysis
Describe the types of necrosis
Coagulative: Firm, tissue outline retained (Haemorrhagic - due to blockage of venous drainage or Gangrenous - larger area especially lower leg)
Colliquitive: Tissue becomes liquid and its structure is lost (e.g. infective abscess or cerebral infarct)
Caseous: Combination of coagulative and colliquitive, appearing cheese-like (caseous), classical for granulomatous inflammation, especially TB
Fat: Due to action of lipases on fatty tissue
Describe the effects of necrosis
Functional - Depends on the tissue/organ
Inflammation - Release of cell contents activates inflammation and causes damage (either acute with removal of stimulus and then healing and repair or chronic with persistence of stimulus and chronic inflammation)
Outline the nature, causes and effects of amyloid accumulation
Organisation of amyloid soluble protein fibrils into specific abnormal, insoluble aggregates
Can be due to multiple myeloma or chronic inflammation (e.g. RA)
Effects depend on site of deposition from renal impairment/failure, heart failure or dementia
Outline the nature, causes and effects of pathological calcification
Deposition of calcium salts
May be dystrophic (deposition in abnormal tissue with normal serum calcium) or metastatic (deposition in normal tissue with raised serum calcium, often in the connective tissue of blood vessels resulting in compromised tissue function)
Causes include increased levels of PTH due to a parathyroid tumour or kidney disease
Describe inflammation
An acute or chronic physiological response to tissue injury with vascular and cellular components, terminating in resolution, repair or continuing inflammation
Describe the role of vascular changes in inflammation
- Vasodilation
- Transient vasoconstriction then vasodilation
- Starts in the arterioles
- Increased blood flow
- Due to histamine and NO on vascular smooth muscle
- Increased Vascular Permeability
- Permits escape of protein-rich fluid exudate into extravascular tissue
- Contraction of endothelial cells increases inter-endothelial spaces
- Mediated by histamine, bradykinin and substance P
- Endothelial injury in severe injuries
- Injury can be caused by neutrophils
- Increased transcytosis
- Vascular Congestion/Stasis
- Slower flow and increased concentration
- Endothelial Activation
- By mediators produced during inflammation
- Increased levels of adhesion molecules
Describe the cellular changes in the vasculature associated with inflammation
- Margination
- WBCs become more peripheral due to stasis
- Rolling
- WBCs stick and detach from wall
- Mediated by Selectins
- Up-regulated by IL-1 and TNF (from Macrophages/PMNs)
- Adhesion
- Mediated by Integrins
- Stimulated by IL-1 and TNF
- Chemokines also facilitate binding (directly released at site of injury)
- Reorganisation of cytoskeleton
- Migration (Diapedesis)
- Chemokines act on leucocytes to stimulate migration across endothelium
Describe the various types of exudate
Exudate - Extracellular fluid with a high protein and cellular content
Transudate - Extracellular fluid with a low protein and cellular content
Serous - Usually a transudate found in pleural, pericardial and peritoneal spaces
Fibrinous Exudate - Fluid rich in fibrin, and exudate due to high protein content often on serosal surfaces such as the meninges
Suppurative Exudate - Pus-forming, and exudate rich in neutrophil polymorphs (abscess)
Pseudomembranous - Surface exudate on mucosal/epithelial sites
Describe the main concepts of how infection may spread
- Localised Infection
- Remain at initial site
- Spread to local lymph nodes via draining lymphatics
- Five cardinal signs!
- Systemic Infection
- Haematogenous - i.e. spread through blood/lymph to cause SYSTEMIC INFLAMMATOrY RESPONSE
- Can track through tissue to form abscess/infection elsewhere, e.g. psoas abscess
Describe the role of neutrophil polymorphs in inflammation
Opsonise and phagocytose
Intra-cellular killing of micro-organisms (both oxygen dependent and independent)
Release lysosomal products, propagating the response
Describe the role of mast cells in inflammation
Reside in tissues
Contain histamine and heparin in preformed granules
Stimulated to release contents by injury, complement and IgE
Play an important role in allergy/anaphylaxis
Also make eicosanoids to propagate immune response
Describe the role of macrophages in inflammation
Macrophages - Tissue Resident, Monocyte - Circulating
Chemotaxis
Synthesise TNF, IL-1, IL-6
Phagocytosis
Antigen-presenting cells, link between innate and adaptive immune response
Describe the role of complement in inflammation
Activated by the classical pathway (Ag/Ab complexes), alternative pathway (bacterial products), products of dying cells in tissue necrosis, components of kinin, coagulation or fibrinolytic systems
C3a/C5a - Chemotactic for neutrophils, increases vascular permeability and releases histamine from mast cells
C5-C9 - Cytolytic Activity
C2a/C3b/C4b - Opsonisation of Bacteria
Describe how various chemical mediators affect the inflammatory response
Histamine - Vasodilation, Increased Vascular Permeability, Endothelial Activation
Serotonin - Vasodilation, Increased Vascular Permeability
Prostaglandins - Vasodilation, Pain, Fever
Leukotrienes - Increased Vascular Permeability, Chemotaxis, Leucocyte Adhesion
NO - Killing of Microbes, Vascular Smooth Muscle Relaxation
!L-1/TNF/IL-6 - Endothelial Activation, Fever, Pain, Shock
Chemokines - Chemotaxis, Leucocyte Activation
Describe the possible sequelae of acute inflammation
- Resolution (complete restoration of tissue to normal)
- If minimal tissue damage
- If occurs in tissue with regenerative capacity i.e. skin
- If cause is rapidly removed or destroyed
- If there is good vascular drainage
- Healing by fibrosis
- After substantial tissue damage
- Tissue incapable of regeneration
- Abundant fibrin exudate
- Progression to chronic inflammation
- Persistent stimulus
- Tissue destruction leading to ongoing inflammation
Define chronic inflammation and describe the circumstances in which it arises
‘a physiological response characterised by infiltrates of lymphocytes, plasma cells and macrophages that persists and lacks resolution when the inflamed tissue is unable to overcome the effects of the injurious agent’
Many factors are important, including site affected, type of wound, presence of infection and type of organism involved, presence of indigestible material, treatment given and background disease
Describe granulomatous inflammation
A distinctive pattern of chronic inflammation with predominantly activated macrophages (with a modified epithelioid appearance) and giant cells (formed from fused epithelioid macrophages)
Epithelioid macrophages are arranged in small nodules or clusters and have a mainly secretory role rather than phagocytic and multinucleated giant cells form where material is difficult to digest
Granuloma formation is a manifestation of T-Cell mediated immune reaction (Delayed Type Hypersensitivity)
Associated with TB, Hodgkin Lymphoma, Sarcoidosis, Crohn’s Disease, Leprosy, Toxoplasmosis
Describe the factors which may influence wound healing
Local - Type, size and location of wound, movement within wound, infection, presence of foreign/necrotic material, irradiation, poor blood supply
Systemic - Age, Nutrition (Vit C, Zinc), Systemic Disease (Renal Failure, Diabetes), Drugs (esp. Steroids), Smoking
Describe the various stages of cutaneous wound healing
- Haemostasis
- Aggregation of platelets, vasoconstriction and inflammatory factor release
- Inflammation
- Increased vascular permeability allows migration of inflammatory cells
- Tissue Proliferation
- Re-Epithelialisation by keratinocytes moving into the wound
- Neovascularisation by proliferation of collagen-producing fibroblasts to support new blood capillaries
- Tissue Remodelling
- Cross-linking of collagen into thick bundles
Describe the various stages of fracture healing
- Haematoma Formation
- Clotted blood forms around fracture site and area becomes inflamed as phagocytic cells remove debris
- Fibrocartilaginous Callus Formation
- Fibroblasts and chondroblasts from the periosteum arrive at the site to roughly lay down collagen and fibrocartilage (known as a fibrocartilaginous soft callus)
- Bony Callus Formation
- Pre-Osteoblasts differentiate to mature osteoblasts which lay down spongy bone
- Over time the fibrocartilage is replaced by spongy bone to form a bony (hard) callus
- Bone Remodelling
- Finally and remaining portions of dead bone are resorbed by osteoclasts
- The spongy bone around the periphery of the site is replaced with compact bone
Describe healing by primary and secondary intention
Primary - Wound edges are close together with minimal tissue loss so can be held together with sutures, heal quickly with minimal scar formation
Secondary - Wound edges are separated with greater tissue loss, so healing occurs slowly with more scar tissue formation
Describe the two types of Post-Mortem Examination
- Hospital ‘Consented’ PM
- Usually at the request of clinicians to answer question about the patient’s pathology or treatment
- Requires specific consent of the family
- Few cases per year (40-50 in Glasgow)
- Medico-Legal PM
- At the instruction of the Procurator Fiscal (Scotland) or Coroner (England and Wales)
- Does not require consent of the family
- Constitute the vast majority of PMs performed in the UK (110,000 per year in England and Wales, 6500 in Scotland)
Describe the process of a Post-Mortem Examination
- External Examination
- Identification of the deceased
- Height/Weight/BMI
- Skin/Hair/Eye Colour
- Iatrogenic - Scars, Drains and IV Lines
- Evidence of trauma
- Jaundice, cyanosis, finger clubbing, oedema, lymphadenopathy
- Evisceration
- Single incision from sternal notch to symphysis pubis to remove thoracic, abdominal and pelvic organs
- Second incision around posterior skull to reflect the scalp, remove the skull and remove the brain
- Organ Dissection
- Pathologist inspects each organ and carefully dissects (macroscopic assessment)
- They may retain a small of tissue for microscopic assessment
- Finally
- Organs returned to patient’s body cavity
- Death certificate issued
- Report prepared and sent to PF or clinician
- Body is reconstructed for viewing
- Body released for burial/cremation
Define congenital anomaly and developmental anomaly
Congenital anomalies are ones that exist at or before birth, regardless of the cause and may be either functional/metabolic or structural
Developmental anomaly is a deformity, absence or excess body parts/tissues which occur when normal growth is disturbed
Developmental Anomaly = Structural Congenital Anomaly
Describe Hamartoma
Malformation that may resemble a neoplasm that results from faulty growth in an organ
Composed of a mixture of mature tissue elements which would normally be found at that site which develop and grow at the same rate as the surrounding tissue
Chondroid Hamartoma - Benign lung lesion composed of epithelium, cartilage, fat and smooth muscle
Describe congenital ectopias
An abnormal location or position of an organ or tissue, most often occurring congenitally but also as a result of injury
Ectopia Cordis: Displacement of heart outside the body
Ectopic Thyroid Tissue: Nodules of mature thyroid tissue located elsewhere in the neck
Define hypertrophy, describe important physiological and pathological factors and describe stimuli responsible
‘increase in the size of cells and therefore an increase in the size of the organ/tissue’
Enlargement is due to an increased synthesis of structural proteins and organelles
Occurs when cells are incapable of dividing
Can be physiological (muscle hypertrophy) or pathological (LV hypertrophy)
Causes by increased functional demand and/or hormonal stimulation
Define hyperplasia, describe important physiological and pathological factors and describe stimuli responsible
‘increase in the number of cells in an organ or tissue’
Adaptive response in cells capable of replication
Critical response of connective tissue cells in wound healing
Physiological - Hormonal (Normal Proliferative Endometrium) or Compensatory (Occurs when a portion of tissue is removed or diseased)
Pathological - Caused by excessive hormonal or growth factors stimulation (androgens; BPH or oestrogen; atypical endometrial hyperplasia)
Define atrophy, describe important physiological and pathological factors and describe stimuli responsible
‘shrinkage in the size/number of the cells by the loss of cell substance resulting from decreased protein synthesis and increased protein degradation’
Causes include; Loss of Innervation, Diminished Blood Supply, Inadequate Nutrition, Decreased Workload, Loss of ENdocrine Stimulation, Aging (Senile Atrophy)
e.g. Post-Menopausal Uterus Atrophy, Cortical Atrophy in Dementia
Define metaplasia, describe important physiological and pathological factors and describe stimuli responsible
‘reversible change from one fully differentiated cell type into another’
Adaptation so cells sensitive to a particular stress are replaced by other cells better able to withstand the adverse environment
Cigarette Smokers - Normal ciliated columnar epithelial cells of the trachea and bronchi are replaced by stratified squamous epithelial cells
Chronic Gastric Reflux - Normal stratified squamous epithelium of the lower oesophagus may undergo metaplasia to gastric columnar epithelium
Describe the effects of the mechanical tissue injury, diverticula
Circumscribed pouch/sac caused by herniation of the lining mucosa of an organ through defect in muscular coat
- Diverticular Disease
- Effects include inflammation, bleeding, perforation and fistulation
- When there is chronic inflammation and healing, there will be fibrosis which in turn will cause hypertrophy of the muscle which can lead to stenosis and large bowel obstruction
- Meckel’s Diverticulum
- Congenital
- Two inches long, blind-ending duct that is a remnant of the yolk sac at the terminal ileum
- Contains all layers of the intestine and often has ectopic pancreatic/gastric tissue within
- Complications include inflammation, bleeding, perforation, obstruction, intussusception and pain
Describe the effects of the mechanical tissue injury, intussusception
‘a process by which a section of intestine invaginates into the adjoining intestinal lumen’
Can result in small bowel obstruction, peritonitis or bowel perforation
Define neoplasm
‘an abnormal tissue mass the growth of which is excessive (i.e. not an adaption to physiological demands) and uncoordinated compared to adjacent normal tissue that persists even after cessation of the stimuli that caused it’
i.e. Uncontrolled or Irreversible
Can be Benign or Malignant
Define dysplasia and describe its characteristic features
‘disordered growth in which cells fail to differentiate fully, but are contained by the basement membrane, i.e. non-invasive’
Cell nuclei become hyperchromic
Nuclear membranes become irregular
Nuclear to cytoplasmic ratio increases
Dysplasia may regress, persist or progress
Describe differences between benign and malignant neoplasms
- Benign Neoplasm
- A neoplasm that grows without invading adjacent tissue or spreading to distant sites
- Usually well-circumscribed due to lack of invasion of surrounding tissues
- Malignant Neoplasm
- A neoplasm that invades the surrounding normal tissue
- Can spread to distant sites (metastasise)
- Usually is not well circumscribed
Describe different routes of tumour growth and spread
- Local Invasion
- Lymphatic Spread
- Most common pathway for dissemination of carcinomas (although sarcomas can also use this route)
- The pattern of lymph node involvement follows the natural routes of drainage
- Haematogenous Spread
- Typical of sarcomas
- Arteries are more difficult for a tumour to penetrate than veins
- With venous invasion, the blood-borne cells follow the venous flow draining the site of the tumour
- Liver and lungs are frequently involved
- Seeding of Body Cavities (Transcoelomic Spread)
- Occurs when a malignant neoplasm penetrates into a natural ‘open field’ such as peritoneal cavity, pleural space, pericardial cavity, etc.
- Most common examples include ovarian carcinoma and gastric carcinoma
Describe the principles of tumour grading and staging and their clinical relevance
As tumours become more poorly differentiated, the higher the grade
Therefore, a poorly differentiated tumour is a high-grade malignancy and a well-differentiated tumour is a low-grade malignancy
Tumour stage is based on its size, extent of invasion into the surrounding tissue, spread to regional lymph nodes and presence or absence of lymph nodes
Grading and staging are of prognostic importance and can help determine treatment options
Describe methods to establish a neoplastic diagnosis
- History & Clinical Examination
- Imaging – X-Ray, US, CT, MRI
- Tumour Markers Laboratory Analysis – CEA, AFP, Ca125
- Cytology – Pap Smear, FNA, Flow Cytometry
- Biopsy – Histopathology, ICC
- Molecular – Gene Detection
- Bloods - As Appropriate
- Scopes - ENT, Bronchoscopy, Gastroscopy, Colonoscopy, Cystoscopy, Colposcopy
Describe Carcinoma in Situ
Full thickness epithelial dysplasia extending from the basement membrane to the surface of the epithelium
Applicable only to epithelial neoplasms, if the entire lesion is no more advanced than CIS then the risk of metastasis is zero
This is because there are no blood vessels or lymphatics within the epithelium above the basement membrane
Describe the importance of the bone marrow microenvironment in haemopoiesis
The bone marrow microenvironment (stroma) supports developing haematopoietic stem cells
It provides a rich environment for growth and development of stem cells
Stromal cells are supported by an extracellular matrix
Stromal cells include; Macrophages, Fibroblasts, Endothelial Cells, Fat Cells, Reticulum Cells
Describe the major myeloproliferative disorders
Clonal blood disorder characterised by over effective haemopoiesis
JAK2 mutation is highly prevalent
Too many platelets = Essential Thrombocytosis
Too many RBCs = Polycythaemia Rubra Vera
Too much fibrous tissue = Myelofibrosis
- ET & PRV
- Good outcome
- Risk of vascular events (managed with aspirin)
- Managed by cytoreduction (hydroxycarbamide, venesection or interferon)
- 5-10% risk of progression to AML
- 10% progress to myelofibrosis
- MF
- Splenomegaly + Systemic Symptoms
- Blood counts may be high or low
- Incurable other than with SCT
- New drug class - JAK2 inhibitors
Describe myelodysplastic syndrome
Clonal blood disorder characterised by failure of effective haemopoiesis (low blood count)
More common in the elderly
Dysplastic blood and marrow appearance
Approx. 25% rate of progression to AML
(Blast cell % cut off for MDS vs AML is 20%)
Symptoms characterised by consequences of marrow failure
Incurable other than with SCT for those <65yrs
Consider supportive care and drug therapy (e.g. azacitidine)
State the requirements for normal RBC production
Erythropoietin (Drive for Erythropoiesis)
Genes (Recipe for Erythropoiesis)
Iron, B12, Folate and Minerals (Ingredients for Erythropoiesis)
Functioning Bone Marrow
No Increased Loss or Destruction of RBCs
Describe the physiology of B12 metabolism
Essential for DNA synthesis and nuclear maturation
Required for all dividing cells
B12 (Cobalamin) necessary for methionine production and methylmalonyl-CoA isomerisation
Found in meats (esp. liver and kidney)
Require 1ug/day
Absorbed with Intrinsic Factor in the ileum
Stores in the body for 3-4 years
Describe the physiology of Folate metabolism
Essential for DNA synthesis and nuclear maturation
Required for all dividing cells
Found in green veg (but destroyed by cooking)
Absorbed in the small intestine (no carrier molecule required)
Only a few days store in the body but quickly used up if there is increased demand (i.e. increased cell turnover)
Describe the effects of B12/Folate deficiency
Affects all tissues with rapidly growing, DNA synthesising cells (bone marrow, epithelia etc.)
Blood (B12 and Folate) - Megaloblastic Anaemia
Neurological (B12) - Bilateral Peripheral Neuropathy, Demyelination of the Posterior and Pyramidal Tracts of the Spinal Cord
Growing Foetus (Folate) - Neural Tube Defects in first 12 Weeks
State causes of B12 and Folate deficiency
B12 - Dietary, Pernicious Anaemia, Gastrectomy, Achlorhydria, Crohn’s, Ileal Resection
Folate - Dietary, Coeliac, Severe Crohn’s, Haemolysis, Severe Skin Disorders, Pregnancy
Define haemoglobinopathies
‘a group of inherited conditions characterised by a relative lack of normal globin chains due to absent genes (thalassaemias) or abnormal globin chains (e.g. sickle cell disease)’
Describe Alpha-Thalassaemia
Relative lack of alpha globin chains
Alpha globin chains are duplicated on each chromosome for a total of 4 genes
Prevalent in Meditteranean countries, Africa, South East Asia and the Indian subcontinent
If missing 4 Genes - Incompatible with Life
If Missing 3 Genes - HbH Disease (significant anaemia and abnormally shaped RBCs)
If Missing 1/2 Genes - Alpha Thalassaemia Trait (mild anaemia, microcytosis, reduced MCV and MCH but increased RBC count)
Describe Beta-Thalassaemia
Deficiency in beta globin genes (should normally two)
Prevalent amongst Greek Cypriots, Turks, Asians and Africans
Beta Thalassaemia Major - Missing Both Genes - Autosomal Recessive - Severe anaemia due to ineffective erythropoiesis and haemolysis renders patient transfusion dependent from early life with iron overload being the major problem
Thalassaemia Intermedia
Beta Thalassaemia Trait - May be a mild microcytic anaemia, is often confused for IDA
Describe Sickle Cell Disease
Arises due to abnormal HbS which occurs following a single amino acid substitution in the beta-globin gene
RBCs undergo sickling
Results in reduced RBC survival due to haemolysis and vaso-occlusive crises leading to tissue hypoxia and infarction
Complications include Stroke, Moya Moya, Acute Chest Syndrome, Retinopathy, Osteonecrosis
Crisis Prevention - Hydration, Analgesia, Vaccination, Antibiotics and Folic Acid
Cris Management - Oxygen, Fluids, Analgesia, Antibiotics, Transfusion
Can be cured with Bone Marrow Transplantation
Describe the Direct and Indirect Coombs Test
The Coombs test detects autoantibodies against antigens on the RBC membrane
The direct test detects antibodies on the RBC surface and is positive in Haemolytic Disease of the Newborn and Acquired Immunohaemolytic Anaemia
The indirect test detects antibodies in the plasma and is used in prenatal screening of Rh antibodies
Describe an approach to the investigation of a patient with anaemia
- Is it new?
- Congenital or Acquired?
- History
- Blood Loss
- Diet
- Chronic Disease
- Family History
- Medication
- Examination
- Angular Stomatitis
- Splenomegaly
- Lymphadenopathy
- Abdominal Masses
- Haematology
- Size of RBCs
- Are WBCs/Platelets affected?
- Is marrow able to mount a reticulocyte response?
- What are the haematinic results?
- What does the blood film look like?
Define Lymphoma and describe a basic classification system
‘a group of malignancies of lymphoid tissue with accumulation of B/T-Lymphocytes’
Broadly divided into Hodgkin and Non-Hodgkin Lymphomas
Describe the pathology of Hodgkin Lymphoma
The malignant cells (Reed-Sternberg and Hodgkin’s cells) comprise a minority of the tumour, with the remainder comprised of lymphocytes, granulocytes, fibroblasts and plasma cells
Reed-Sternberg cells are bi/multi-nucleated giant cells of B-Lymphocyte origin
Up to 40% of HL cases are associated with EBV
Describe the clinical presentation of Hodgkin Lymphoma
Bimodal Age Incidence (20s-30s and >50s)
Painless Lymphadenopathy (Cervical or CXR Mass)
Spread from one nodal group to adjacent
Later there may be haematogenous spread to liver or lungs
May have B symptoms (fever, drenching night sweats or weight loss)
Managed by Chemo and Radiotherapy
Describe the clinical presentation of high-grade Non-Hodgkin’s Lymphomas such as Diffuse Large B-Cell Lymphomas
Most common subtype of NHL
Increasing incidence with age
Aggressive
Often presents with localised or generalised painless lymphadenopathy
40% present extra-nodally with abdominal pain, anaemia, CNS disease or on the skin
May also present with Pyrexia of Unknown Origin
Managed by R-CHOP Chemotherapy +/- Radiotherapy
Describe the pathology of low-grade/indolent Non-Hodgkin’s Lymphomas such as Follicular Lymphoma
B-Cell Lymphoma
90% of follicular lymphomas are characterised by the t(14;19) translocation where the BCL2 gene on chromosome 18 is moved to the immunoglobulin heavy chain
This leads to excessive expression of BCL2, an oncogene known to inhibit apoptosis
it is likely that further change (e.g. activation of a proto-oncogene or an antigenic stimulus) produces the clonal malignancy
Describe the clinical presentation of low-grade/indolent Non-Hodgkin’s Lymphomas such as Follicular Lymphoma
Increasing incidence with age
Median presentation between 60-65 years
Often presents with late-stage disease due to its indolent course
Local disease may be managed with radiotherapy but most cases require a rituximab-containing regime (e.g. R-CVP or R-CHOP)
Average survival of 15-20 years
Responsive to treatment but tendency to relapse or transform to DLBCL
Describe the staging of Lymphoma
Ann-Arbor Staging System
I - Single Lymph Node Group
II - More than one LN group on the SAME side of the diaphragm
III - LN groups on BOTH sides of the diaphragm
IV - Extranodal involvement (e.g. liver, bone marrow)
A or B is added to signify absence or presence of B symptoms (fever, night sweats, weight loss)
Early Stage = 1 or 2A
Advanced Stage = 2B or 3 or 4
Describe the diagnosis of Lymphoma
Excision or Core Biopsy of Lymph Node, Other Tissue or Bone Marrow
CT Neck, Chest, Abdomen and Pelvis
PET-CT
Define Multiple Myeloma
‘a clonal malignancy characterised by uncontrolled proliferation of plasma cells in the bone marrow and production of monoclonal immunoglobulin’
Describe the pathophysiology of Multiple Myeloma
MM is preceded by a clinical syndrome known as Monoclonal Gammopathy of Undetermined Significance
Plasma cells in the bone marrow secrete paraprotein (monoclonal immunoglobulin or immunoglobulin fragments)
Most produce IgG or IgA or light chains only
Occasionally myelomas may be non-secretory
Myeloma Triad = Increased Plasma Cells in the Bone Marrow + Clonal Immunoglobulin/Paraprotein + Lytic Bone Lesions
Describe the clinical presentation of Multiple Myeloma
Back Pain
Rib Pain
Pathological Fractures
Vertebral Collapse
Anaemia
Thrombocytopenia
Frequent Infection
Hypercalcaemia
Renal Failure
Describe the main differences between Hodgkin’s (HL) and Non-Hodgkin’s (NHL) Lymphoma
NHL is a monoclonal proliferation of B/T-Lymphocytes and HL is a lymph malignancy of proliferating germinal centres
EBV is associated with both
HL has a bimodal age distribution
HL is characterised by presence of Reed-Sternberg Cells
Both present with painless lymphadenopathy and possibly B symptoms and HL may also present with pruritis
Contiguous LN spread in HL, Non-Contiguous LN spread in NHL
Radiation and Chemotherapy for both
State techniques used to diagnose Lymphoma
Morphology
Immunohistochemistry
Flow Cytometry
Karyotyping
Fluorescence in situ Hybridisation
PCR Clonality Assays
Gene Sequencing/Array Based Technologies
Describe lymphocyte development
B-Cells are produced in bone marrow from a committed stem cell progenitor
Mature B-Cells circulate in peripheral blood and populate lymphoid and other organs
T-Cells originate in bone marrow from committed stem cell progenitor
Precursor T-Cells migrate to thymus where they develop into mature T-Cells
Mature T-Cells circulate in peripheral blood and populate lymphoid and other organs
Describe the physiological processes involved in the coagulation system
- Blood Vessel Damage
- Endothelial Disruption
- Exposure of Tissue Factor and Collagen
- Primary Haemostasis
- Recruitment of Platelets
- Secondary Haemostasis
- Activation of Coagulation Factors
- Cascade:
- Initiation - Extrinsic Pathway
- Propagation - Intrinsic Pathway
- Thrombin Generation
- Fibrin Production (The Clot)
- Each step in the cascade requires phospholipids from the platelet surface and calcium
State the laboratory tests used to assess the coagulation system
- Assessment of Primary Haemostasis
- In Vivo - Bleeding Time
- Ex Vivo - FBC, Platelet Count, Platelet Function
- Assessment of Secondary Haemostasis
- Prothrombin Time (PT)
- Activated Partial Thromboplastin Time (APTT)
- Thrombin Clotting Time (TCT)
- Individual Coagulation Factor Assays
Describe the use of Prothrombin Time (PT) to assess the coagulation system
Simulates activation via the extrinsic pathway
Add patient’s plasma and thromboplastin, warm to 37C, add calcium and time taken to form clot
Normal range is 10-13 seconds
Ratio is the patient’s PT/average of 20 normal PTs (normal ratio is 1 - 1.2)
PT depends on factors in the extrinsic and common pathways (Factors VII, X, V, II and Fibrinogen)
Describe the use of International Normalised Ratio (INR) to assess the coagulation system
The standardised form of prothrombin time
Used in the monitoring of oral coumarins such as Warfarin
A patient’s INR is identical in any laboratory
Patient’s PT/Average of 20 Normal PTs
Result factored by the International Sensitivity Index (ISI)
Every thromboplastin preparation has its own ISI
Describe the use of Activated Partial Thromboplastin Time (APTT) to assess the coagulation system
Stimulates activation via the intrinsic pathway
Add the patient’s plasma, contact factor and phospholipid
Warm to 37C and add calcium and time the taken to form a clot
Normal range is 26-38 seconds
Ratio of Patient/Average of 20 Normals
APTT depends on factors in the intrinsic and common pathways (Factors VIII, IX, XI, XII, X, V, II and Fibrinogen)
Describe the use of Thrombin Clotting Time (TCT) to assess the coagulation system
Measures conversion of fibrinogen to fibrin clot
At 37C, add the patient’s plasma and bovine thrombin
Less calcium or phospholipid-dependent
Measure the time taken to clot
Normal range is 10-16 seconds
Depends on how much fibrinogen is present in the plasma and how well it functions
Will also be prolonged by inhibitors of thrombin (heparin, dabigatran), FDPs or inhibitors of fibrin polymerisation (paraprotein)
State and briefly describe the three classes of anti-thrombotics
Anti-Coagulants (inhibit one or several components of the coagulation cascade)
Fibrinolytic Agents (enhance lysis of the fibrin clot)
Anti-Platelet (inhibit platelet activation or aggregation)
Describe some of the acquired disorders of the coagulation system
- Disseminated Intravascular Coagulation
- Acquired, consumptive process with activation of the coagulation cascade (resulting in microthrombi) and subsequent exhaustion of the coagulation cascade (resulting in bleeding)
- Caused by sepsis, malignancy, massive haemorrhage, severe trauma or complications in pregnancy
- Treat the underlying cause and give FFP +/- platelets if bleeding or at high risk
- Warfarin-Induced Bleeding
- If INR is too high, stop warfarin or reduce dose, give Vitamin K or give coagulation factors
- Coagulopathy in Liver Disease
- Poor coagulation factor synthesis due to liver damage
Describe some of the inherited disorders of the coagulation system
- Haemophilia A
- Classical Haemophilia
- Factor VIII Deficiency
- Prolonged APTT
- X-Linked Inheritance
- Replacement with Recombinant Produced Factor Concentrate
- Von Willebrand Disease
- VW Factor facilitates platelet adhesion and aggregation in primary haemostasis
- Binds Factor VIII and prolongs its half-life in the plasma
- Thrombophilia
- Deficiencies of natural anticoagulants such as antithrombin, Protein C or Protein S
- May be due to specific gene mutations such as Factor V Leiden (resistance to APC) or the prothrombin gene (which results in increased prothrombin)
Describe developmental abnormalities involving the breast
- Ectopic (Heterotopic) Breast Tissue
- Commonest congenital abnormality
- Most often on ‘milk line’ between axilla and groin
- Absent Nipple
- Nipple with Little Glandular Development
- Breast Hypoplasia
- Macromastia
- Stromal overgrowth leading to excessive breast size, occasionally begins at puberty (juvenile hypertrophy) or during pregnancy (gestational hypertrophy)
- Nipple Inversion
- Asymmetry
Describe periductal mastitis
Periductal Mastitis/Plasma Cell Mastitis/Duct Ectasia
A dilation of central lactiferous ducts, periductal chronic inflammation and scarring
Often asymptomatic but there may be discomfort, a mass, nipple retraction or inversion
Calcified luminal secretions may be seen on mammogram
It is commonest in middle age and is associated with smoking
Describe fat necrosis of the breast
The initial change is disruption of fat cells where vacuoles with the remnants of necrotic fat cells are formed
They then become surrounded by lipid-laden macrophages, multinucleated giant cells, and acute inflammatory cells
Fibrosis develops during the reparative phase peripherally enclosing an area of necrotic fat and cellular debris
Eventually, fibrosis may replace the area of degenerated fat with a scar, or loculated and degenerated fat may persist for years within a fibrotic scar
May follow trauma
Benign, but biopsy may be required to exclude cancer
Describe intraduct papilloma of the breast
A benign tumour of the epithelium lining of the mammary ducts
Solitary central papillomas are thought to be innocuous if there is no epithelial atypia
Multiple papillomas (papillomatosis) are thought to be slightly more likely to be associated with malignancy elsewhere in the same or the contralateral breast
Describe fibroadenoma of the breast
About 25% of asymptomatic women have at least one fibroadenoma in which there is characteristic overgrowth of epithelium and stroma
Symptomatic fibroadenomas are commonest in young women
Usually regarded as a benign neoplasm, hormone-sensitive and regress after the menopause
Usually firm, non-tender, mobile, usually <25-30mm
Rare fibroadenomas in adolescent girls may become very large
Describe the ranges of fibrocystic change in the breast
Very common and frequent benign breast condition
Tends to be multifocal and bilateral and may cause breast tenderness and nodularity
Ranges from small/large cysts, increased amounts of glandular tissue (adenosis), increased fibrous stroma, epithelial hyperplasia (of usual or occasionally atypical type)
State factors modifying breast cancer risk
Early Menarche
Late Menopause
Being Older at First Pregnancy
Oral Contraceptive Use
HRT
Obesity
Alcohol
Family History (BRCA1/BRCA2)
Protective factors include Exercise and Breast Feeding
Describe signs and symptoms of breast cancer
- New lump or thickening in breast or axilla
- Altered shape, size or feel of the breast
- Pain
- Skin changes:
- Puckering
- Dimpling
- Skin oedema (orange peel)
- Rash
- Redness
- Nipple changes:
- Tethering/inversion
- Discharge
- Eczema-like change
- Widespread inflammation
- Redness
Describe the diagnosis of breast cancer
- Clinical Examination
- Imagine
- USS
- X-Ray Mammography
- MRI
- Fine Needle Aspiration Cytology
- Core Biopsy
- Excisional Biopsy
- May be diagnostic, therapeutic or both
- Women between 47 and 73 are invited for triennial 2-view mammography breast screening and may self-refer after 73
Describe the importance of steroid hormone receptors in breast cancer
About 80% of breast cancers overexpress oestrogen receptors (ER) and progesterone receptor (PR)
ER/PR positive carcinomas are likely to respond to endocrine treatment (e.g. with Tamoxifen which in breast is predominantly an ER antagonist)
In endometrium and bone, Tamoxifen has a significant agonistic effect and there is elevation of endometrial cancer risk in women treated with Tamoxifen
Describe the importance of Her2 status in breast cancer
As a group, cancers which overexpress Her2 have a worse prognosis than other breast cancers
But treatment with the monoclonal antibody Trastuzumab (Herceptin) and other Her2 targeted therapies has improved outcomes
Adjuvant Herceptin reduces the risk of relapse in women with Her2 +ve breast cancer and prolongs survival in women with metastatic breast cancer
Describe the grading of breast cancers
Based on Nuclear Pleomorphism, Number of Mitoses per mm2 and Degree of Gland Formation by the Cancer Cells
Grade 1 - Well-Differentiated and Slow Growing
Grade 2 - In Between
Grade 3 - Poorly Differentiated and Fast Growing
Describe the Nottingham Prognostic Index
Prognostic index for breast cancer, following surgery
(Tumour Size x 0.2) + Grade + LN Involvement
0 Nodes = 1
1-3 Nodes = 2
4+ Nodes = 3
Higher the NPI, the lower the 5 Yr SR
Describe the molecular classification of breast cancer
The main distinction is still between ER -ve and ER +ve cancers
Luminal A ER+ cancers tend to be low grade, less proliferative and have a better prognosis
Luminal B ER+ cancers tend to be high grade, more proliferative and potentially do less well
In the ER- cancer group, there are three subtypes; normal breast-like, Her2 or basal-like
Describe the management options for breast cancer
Surgery (wide local excision plus radiotherapy or mastectomy for larger cancers)
Endocrine targeted treatment can help prevent relapse at distant sites
in triple negative cancers especially, adjuvant chemotherapy is important
1 in 3 potential episodes of metastatic relapse can be prevented by adjuvant chemotherapy
Describe cervical intraepithelial neoplasia (CIN)
Replacement of normal squamous epithelium by neoplastic squamous cells
Basement membrane remains intact
The neoplastic cells have the usual morphological features, abnormally intense staining (hyperchromasia), greater variability (pleomorphism) and fail to mature properly (and go on proliferating with mitotic cells visible) as they migrate from the base of the epithelium to its surface
Immature and dividing cells are confined to the basal 1/3 of the epithelium in CIN 1, the basal 2/3 in CIN 2 and persist into the surface 1/3 in CIN 3
Invasive squamous carcinoma of the cervix almost always develops from pre-existing CIN, but not all CIN will become squamous cancer
CIN 2 and CIN 3 are more likely to progress than CIN 1
Describe squamous metaplasia of the cervical transformation zone
Prior to puberty, the ectocervix is covered by non-keratinising stratified squamous epithelium and the endocervix is lined by columnar (glandular) epithelium
With growth of the cervix after puberty, the squamo-columnar junction is everted into the vagina and the squamous epithelium adapts to the vaginal environment by squamous metaplasia in the ‘transformation zone’
These changes are reversed at the menopause
This zone of unstable differentiation is where most cervical neoplasia develop
Describe the effect of HPV on the cervix
More than 99% of cervical carcinomas are associated with HPV infection
Even in the absence of CIN, HPV infection does visibly affect the cells of the cervical squamous epithelium
Even in the absence of productive infection, viral DNA can persist extra-chromosomally or integrated into the host’s cells
High risk HPV types 16 and 18 are strongly associated with CIN 2, CIN 3 and cervical cancer
State the outcomes of cervical smear reporting
- Negative
- Repeat Routinely in 3 Years
- Borderline Nuclear Abnormality
- Repeat 6 Months
- (If 3 x BNAs - Refer to Colposcopy)
- Mild, Moderate or Severe Dyskaryosis
- Refer to Colposcopy
- Features SUggestive of Invasion
- Urgent Referral to Colposcopy
Describe the features and effects of Salpingitis
Part of the spectrum of pelvic inflammatory disease
Most commonly infective (mainly bacterial - chlamydia trachomatis, mycoplasma, coliforms, streptococci, staphylococci, Neisseria gonorrhoea)
Usually considered to be an ascending infection
Symptoms include fever, lower abdominal/pelvic pain and pelvic mass (if tubes distended with exudate or secretions)
Complications: Adherence of tube to ovary (tubo-ovarian abscess); Adhesions involving tubal plicae increase risk of ectopic pregnancy; Damage or obstruction of tube lumen may produce infertility which may be difficult to treat
Describe the features and effects of non-neoplastic cysts of the ovaries
Non-neoplastic cysts include inclusion, follicular and luteal cysts
Symptoms include oligomenorrhoea, hirsutism, infertility, over-production of androgens by cystic follicles, high LH and low FSH
Effects include enlarged ovaries, multiple subcortical cysts (5-15mm), thickened and fibrotic outer surface, absence of corpus lutea and corpus albicans (as ovulation is not occurring) and insulin resistance (which may lead to T2DM)
Describe the processes, features and effects of ovarian surface epithelial tumours
Thought to arise from coelomic mesothelium on the surface of the ovary
Benign lesions usually cystic (cystadenoma) with or without a solid stromal component (cystadenofibroma)
Malignant epithelial tumours (carcinomas) may be cystic (cystadenocarcinoma) or solid (adenocarcinoma)
Carcinomas may be high grade serous (HGSC), endometroid, clear-cell, low grade serous (LGSC) or mucinous
HGSC is closely associated with p53 and BRCA1 mutations
Most women with ovarian cancer present late and in many the prognosis is poor
(Surface epithelial tumours also have an intermediate, borderline category called tumours of low malignant potential which have limited invasive potential and a much better prognosis)
Describe ovarian sex cord/stromal tumours
These include granulosa and theca cell tumours which often secrete oestrogen and (uncommonly) Sertoli-Leydig cell tumours which may secrete androgens
Granulosa cell tumours usually occur in post-menopausal women and are not rare (oestrogen overproduction may lead to endometrial hyperplasia or endometrial carcinoma)
Ovarian fibromas and thecomas are usually benign and not rare
Describe the features of ovarian germ cell tumours
95% of ovarian germ cell tumours are mature cystic teratomas (dermoid cysts)
Totipotent germ cells differentiate into mature tissues of all 3 germ cell layers
Mostly found in young women as ovarian masses or found incidentally on abdominal scans
May contain foci of calcification associated with bone or teeth
Approx. 10% are bilateral
Grossly they appear smooth, filled with sebaceous secretions and matted hair
Sometimes foci of bone and cartilage, nests of bronchial or GI epithelium, teeth and other recognisable lines of development may be present
About 5% of ovarian teratomas in adult are immature cystic teratomas, associated with more aggressive behaviour
Describe the basic physics underlying an ECG
ECG records the electrical activity of the heart from the skin
This is usually done by a 12-Lead ECG, where a lead is an electrical vector
Unipolar Leads measure the potential variation at a single point (Limb Leads aVR, aVL and aVF and Chest Leads V1-V6)
Bipolar Leads measure the potential difference between two points (Leads I, II and III)
Describe features of a normal ECG
Sinus Rhythym (each P wave is followed by a QRS complex)
Normal HR
PR interval <1 large square (<200ms)
QR interval <3 small squares (<120ms)
QT interval <11 small squares (<440ms)
Positive QRS complex in leads I and II
P wave upright in inferior leads
ST segment flat
T wave has same polarity as QRS complex
Describe and diagnose this ECG
Regular Rhythym
No Relation Between P and QRS
HR <60bpm
Complete Heart Block
Describe and diagnose this ECG
Regular, Sinus Rhythm
Rate = 56bpm
P:QRS is 1:1
Sinus Bradycardia
Describe and diagnose this ECG
Regular, Sinus Rhythm
150bpm
P Waves followed by QRS Complex (1:1)
Narrow QRS
= Sinus Tachycardia
Describe and diagnose this ECG
Irregular Rhythym
Narrow QRS
No discernible P waves
= Atrial Fibrillation
Describe and diagnose this ECG
Irregular Rhythm
Saw Tooth Pattern
No discernible P waves
= Atrial Flutter
Describe and diagnose this ECG
Regular Rhythym
Rate - 83bpm
ST elevation in V1-4
Reciprocal ST depression in III
Hyperacute peaked T waves in V2-4
= (Anterior) STEMI
State which lead in a standard 12 lead ECG represents each position in the heart (i.e. Anterior, Lateral, Inferior, Septal)
Describe the radiological signs of heart failure
Pleural Effusions
Cardiomegaly
Kerley B Lines (horizontal lines of the periphery of the lower posterior lung fields)
Upper Lobe Pulmonary Venous Congestion
Interstitial Oedema
Describe the mechanism of action of drugs used to manage heart failure
- ACE Inhibitors or Angiotensin II Receptor Blocks
- e.g. Enalapril or Valsartan
- Reduce activity of AngII to reduce afterload and fluid retention to slow progression of LV dysfunction
- Beta Blockers
- e.g. Carvedilol
- Reduces afterload and HR to reduce work on the heart
- Mineralocorticoid Receptor Antagonist
- e.g. Spironolactone
- Inhibits sodium resorption to reduce retention of sodium and water
- Ivabradine
- Acts on the ‘funny channel’ to reduce HR
- Digoxin
- Increases force of contraction while reducing rate of conduction through the AV node
Describe the diagnosis of infective endocarditis and its diagnostic criteria
3 Sets of Blood Cultures
Echocardiography (TTE as first line)
Elevated WCC/CRP
ECG
Haematuria or Pyuria on Urinalysis
-
Modified Duke Criteria states a diagnosis of IE is definite in the presence of 2 major criteria, 1 major and 3 minor criteria or 5 minor criteria
Major Criteria: Blood Cultures +ve for IE and Evidence of Endocardial Involvement
Minor Criteria: Predisposition, Fever, Vascular Phenomena, Immunological Phenomena, Microbiological Evidence
Describe the diagnosis of an acute myocardial infarction
Clinical history consistent with ACS
ECG changes (ST elevation/depression in 2 contiguous leads)
Raised troponin
HEART score >5
Describe the pathophysiology of Tricuspid Atresia and its surgical management
Malformation of the tricuspid valve, resulting in an inability of blood flow from the right atrium to the right ventricle
Therefore, it requires both an atrial and ventricular septal defect so blood can pass from the right atrium to the pulmonary arteries
Managed surgically by the Fontan or TCPC procedure
In Fontan circulation, the single ventricle supports systemic circulation while systemic venous return is directed to pulmonary arteries (bypassing the ventricular mass)
The ASD is closed and the pulmonary aa. grafted to the RA, bypassing the RV
Describe the investigations used in the diagnosis of hypertension
Office BP Measurement
24 Hour Ambulatory BP Monitoring (BP taken every 20-30mins throughout the day)
Home BP Monitoring (2 readings, twice a day, taken over 4-7 days)
Other tests include U&Es, Glucose, Lipid Profile, TFTs, LFTs, Urinalysis, ECG, Echo, Renal Ultrasound, Renin, Aldosterone
Assess CV risk, presence of secondary HTN or end organ damage
Describe the pharmacological management of hypertension
- ACE Inhibitor
- e.g. Lisonipril
- Angiotensin II Receptro Blocker
- e.g. Candesartan
- Ca Channel Blocker
- e.g. Amlodipine
- Thiazid-Like Diuretics
- e.g. Bendroflumothiazide
- Beta-Blocker
- e.g. Atenolol
Comment on this CXR
Consolidation in the right middle lobe consistent with pneumonia
Comment on this CXR
Right lower lobe collapse
Comment on this CXR
A well defined thick walled cavitatory lesion is noted in the right para-hilar area in the midzone of right lung
aka Pulmonary TB
Describe the clinical features, prognosis and management of Basal Cell Carcinoma
Most common type of skin cancer
Usually very indolent, rarely metastases or kills
Nodular BCC - >0.5cm raised lesion with a shiny pearly lesion, telangiectasia (blood vessels), and is often ulcerated centrally
Superficial BCC - Often involves only the most superficial layers of the epidermis
Pigmented BCC
Morphoeic/Sclerotic BCC
Managed by surgical excision with a 3-4mm margin
Excellent prognosis, 100% for BCC that has not progressed
Describe the pathology and management of cellulitis
Infection involving the dermis, most commonly beginning in the lower limbs
Often tracks through the lymphatic system and may involve local lymph nodes
Usually caused by beta haemolytic streptococci (often group A strep) or Staph. Aureus
Enron 1a - PO Flucloxacillin or Doxycycline
Enron Ib and II - IV Flucloxacillin or Vancomycin
Enron III and IV - Admission with IV Management and/or Surgical
Describe the features of erythema nodosum and state some of the diseases it may be associated with
Tender, red nodules under the skin
Inflammation of the fat underlying the skin
Commonly on the shins
Associated with EBV, Strep Infection, TB, IBD, Sarcoidosis, Pancreatic CA, Non-Hodgkin Lymphoma
Describe the features of inflammatory back disease
Onset <45 yrs
Early morning stiffness >30mins
Back stiff after rest and improves with movement
May wake in the 2nd half of the night with buttock pain
Insidious onset, less likely to be acute
Outline the different types of seizure
Focal seizures begin in one part of the brain, and may spread to become secondary generalised
Generalised involves multiple areas of the brain or spread from one area to both sides of the brain
Absence seizures are common in young children
Tonic-Clonic seizures involve LOC and a short tonic phase (muscle suddenly tense and patient falls) and a longer clonic phase (rapid convulsions)
Describe the Glasgow Coma Scale
Describe the main subtypes of multiple sclerosis
- Relapsing Remitting
- Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission
- Primary Progressive
- Steady increase in disability without attacks
- Secondary Progressive
- Initial relapsing-remitting pattern that suddenly begins to decline without periods of remission
- Progressive Relapsing
- Steady decline from onset with super-imposed attacks
Describe common hepatic neoplasms
Haemangioma - Benign blood vessel tumour
Hepatic Adenoma - Mainly affects young women and is often associated with hormonal therapy
Hepatocellular Carcinoma - Most common primary liver tumour, usually arising in cirrhosis and associated with elevated serum alpha feto-protein
The most common origin of secondary liver malignancy is the GI tract (50%), followed by breast, ovaries, bronchus and kidneys
Define chronic kidney disease and a system to classify its severity
‘kidney damage or GFR <60ml/min per 1/73m2 for three months or more’
Classified based on eGFR
Compare and contrast type 1 and type 2 diabetes
Type 1 - Immune pathogenesis with severe insulin deficiency
Type 2 - Combination of insulin resistance and insulin deficiency
Describe the different insulin regimens available
Insulin is a peptide, so cannot be given orally
Can be given as a once-daily basal, twice daily mix or basal-bolus therapy
Insulin pens are more convenient, accurate, discrete and less painful than conventional vial and syringes
Describe the treatment of hypoglycaemia
Describe the pathophysiology and management of Diabetic Ketoacidosis
Absolute insulin deficiency results in activation of the ketone pathway, used in starvation states
This results in acetone (ketone) production, which along with profound hyperglycaemia can be life-threatening
Presents with osmotic symptoms, weight loss, breathlessness, abdominal pain, leg cramps, N&V, confusion
Characterised by a Metabolic Acidosis, Hyperglycaemia and Urinary/Plasma Ketones
Manage with IV fluids, insulin and assess need for potassium
Follow national DKA pathway
Describe the pathophysiology, investigation and management of Congenital Adrenal Hyperplasia
Autosomal recessive disorder
Deficiency in 21-alpha-hydroxylase
Results in steroidogenic defects including aldosterone and cortisol deficiency
This means more pregnenolone is converted to the androgen DHEA
Can result in ambiguous genitalia (female) and adrenal crisis and early virilisation (males)
Managed with mineralocorticoid and glucocorticoid replacement
Describe the pathophysiology, clinical features, investigation and management of Polycystic Ovarian Syndrome
See figure for Pathophysiology
Presents with hirsutism, acne, male-pattern hair loss, acanthosis nigricans, obesity
Lifestyle modification - diet, exercise, weight loss
Oestrogen (combined oral contraceptive)
Metformin (reduces glucose intolerance and hyperinsulinaemia)
Clomifene (selective oestrogen receptor modulator)
Gonadotropin therapy
