Clinical Sciences

Key Facts

Mendelian inheritance patterns describe how single-gene disorders are transmitted through families. Understanding these patterns is crucial for genetic counselling, prenatal diagnosis, and risk stratification.

Epidemiology

• Approximately 1 in 25 individuals carry a pathogenic variant - most are autosomal recessive carriers
• Genetic conditions account for approximately 30% of paediatric hospital admissions
• Newborn screening in the UK tests for 9 conditions including CF, sickle cell, PKU, and congenital hypothyroidism
• Approximately 6,000 recognised single-gene disorders

Aetiology

Genetic variation types:

• Point mutations: Missense, nonsense, silent
• Frameshift mutations: Insertions, deletions
• Trinucleotide repeat expansions: Dynamic mutations causing anticipation
• Large deletions/duplications: Detected by MLPA or array CGH
• Chromosomal abnormalities: Aneuploidies, translocations, inversions

Pathophysiology

Disease mechanisms:

• Loss of function (most recessive): Both alleles must be non-functional (e.g., CF - absent CFTR chloride channel)
• Gain of function (most dominant): One mutant allele confers new/enhanced activity (e.g., achondroplasia - constitutive FGFR3 activation)
• Dominant negative: Mutant protein interferes with wild-type (e.g., osteogenesis imperfecta - abnormal collagen)
• Haploinsufficiency: One functional copy insufficient (e.g., Williams syndrome - elastin deletion)

Autosomal Dominant Conditions

• Huntington's disease: Chorea, psychiatric symptoms, dementia - onset 30-50 years
• Marfan syndrome: Tall stature, arachnodactyly, lens subluxation, aortic root dilatation
• ADPKD: Bilateral renal cysts, hypertension, berry aneurysms
• Familial hypercholesterolaemia: Tendon xanthomata, premature CVD

Autosomal Recessive Conditions

• Cystic fibrosis: Recurrent chest infections, malabsorption, male infertility
• Sickle cell disease: Vaso-occlusive crises, splenic sequestration, stroke
• Phenylketonuria: Intellectual disability if untreated, musty odour

X-linked Conditions

• Duchenne muscular dystrophy: Progressive proximal weakness, Gower's sign, calf pseudohypertrophy
• Haemophilia A: Spontaneous haemarthroses, prolonged bleeding

Red Flags for Genetic Referral

• Family history of multiple affected individuals
• Consanguinity
• Multiple congenital anomalies
• Unexplained intellectual disability
• Recurrent pregnancy loss

Bedside

• Three-generation family pedigree: Essential for identifying inheritance pattern
• Dysmorphology examination: Systematic assessment of facial features, hands, feet

Bloods

• Newborn blood spot screening: PKU, CF, SCD, congenital hypothyroidism, and others
• Haemoglobin electrophoresis: Sickle cell disease, thalassaemia
• Enzyme assays: Gaucher, Fabry, Tay-Sachs

Imaging

• Echocardiography: Marfan syndrome (aortic root), hypertrophic cardiomyopathy
• Renal USS: ADPKD screening
• MRI brain: Huntington's (caudate atrophy), metabolic disorders

Special Tests

• Karyotype: Chromosomal analysis (Down's, Turner's, Klinefelter's)
• Microarray (array CGH): Copy number variants, microdeletions/duplications
• Single gene testing: Sanger sequencing for known mutations
• Gene panels / whole exome/genome sequencing: Via NHS Genomic Medicine Service
• Prenatal diagnosis: CVS (10-13 weeks), amniocentesis (15-20 weeks), NIPT (from 10 weeks)

Non-pharmacological

• Genetic counselling: Non-directive, informed decision-making
• Cascade testing: Screen at-risk family members
• Preimplantation genetic testing (PGT): For known pathogenic variants
• Prenatal testing: CVS, amniocentesis, NIPT for high-risk pregnancies
• Newborn screening: UK blood spot programme

Pharmacological

• Disease-specific treatments:
  • CF: CFTR modulators (ivacaftor/lumacaftor, elexacaftor/tezacaftor/ivacaftor [Kaftrio])
  • Sickle cell: Hydroxycarbamide 15-30mg/kg/day, crizanlizumab
  • FH: High-intensity statin, ezetimibe, PCSK9 inhibitors
  • Huntington's: Tetrabenazine for chorea (symptomatic only)
  • Gaucher disease: Enzyme replacement therapy (imiglucerase)

Referral Criteria

• Suspected genetic condition → clinical genetics service
• Positive newborn screening → specialist paediatric service
• Family history of genetic condition and planning pregnancy → genetic counselling
• Consider genomic testing via NHS Genomic Medicine Service for rare diseases

• CF: Median survival now >50 years with modern treatments including CFTR modulators
• Huntington's disease: Progressive, fatal within 15-20 years of symptom onset; no disease-modifying therapy
• Duchenne MD: Most wheelchair-dependent by age 12; median survival to late 20s with optimal care
• Sickle cell disease: Median survival in UK ~60 years with comprehensive care
• FH: Untreated homozygous FH - CVD in childhood; heterozygous - 50% risk of CHD by age 50 without treatment
• PKU: Normal life expectancy and intelligence if dietary restriction maintained from birth

Inheritance Pattern Summary

Hardy-Weinberg Equation

p² + 2pq + q² = 1 (where p + q = 1)

• p² = frequency of homozygous dominant
• 2pq = frequency of carriers (heterozygotes)
• q² = frequency of affected individuals (homozygous recessive)
• Example: CF q² = 1/2500, so q = 1/50, carrier frequency (2pq) ≈ 1/25

Key Facts

The immune system is divided into innate (non-specific, rapid) and adaptive (specific, slower but with memory) components. Both systems work in concert to protect against pathogens.

Epidemiology

Immune system dysfunction manifests as:

• Immunodeficiency: Increased susceptibility to infection (primary: ~1 in 1200 live births; secondary: much more common - HIV, iatrogenic)
• Autoimmunity: Affects ~5-8% of the UK population
• Hypersensitivity: Allergic disease affects ~30% of the UK population at some point
• Malignancy: Immune surveillance failure

Aetiology

Innate immunity components:

• Physical barriers (skin, mucous membranes)
• Chemical barriers (lysozyme, defensins, gastric acid)
• Cellular (neutrophils, macrophages, NK cells, mast cells, dendritic cells)
• Humoral (complement, acute phase proteins, interferons)

Adaptive immunity components:

• T lymphocytes → CD4+ helper, CD8+ cytotoxic, regulatory T cells
• Antigen-presenting cells bridge innate and adaptive immunity

Pathophysiology

Immune responses are initiated by pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) on innate cells, which recognise pathogen-associated molecular patterns (PAMPs). This activates inflammatory cascades and primes the adaptive immune response through antigen presentation via MHC molecules.

Immunodeficiency

• Recurrent, severe, or unusual infections
• Infections with opportunistic organisms
• Poor response to standard antimicrobial therapy
• Failure to thrive (children)

Autoimmune Disease

• Organ-specific: Type 1 diabetes, Hashimoto's, Graves', pernicious anaemia
• Systemic: SLE, rheumatoid arthritis, systemic sclerosis

Hypersensitivity

• Type I (immediate): Anaphylaxis, asthma, hay fever
• Type II (cytotoxic): Autoimmune haemolytic anaemia, Goodpasture's
• Type III (immune complex): SLE, post-streptococcal GN
• Type IV (delayed): Contact dermatitis, TB skin test

Red Flags

• Recurrent serious infections (≥2 pneumonias/year, ≥2 systemic infections)
• Unusual organisms (Pneumocystis, atypical mycobacteria)
• Family history of immunodeficiency
• Failure to thrive with recurrent infections in children

Bedside

• Clinical assessment: Lymphadenopathy, hepatosplenomegaly, skin changes, tonsil size

Bloods

• FBC with differential: Lymphopenia, neutropenia, eosinophilia
• Immunoglobulins (IgG, IgA, IgM, IgE): Quantitative levels
• Lymphocyte subsets: CD4/CD8 count (flow cytometry)
• Complement levels: C3, C4, CH50/CH100, AP50
• Autoantibodies: ANA, anti-dsDNA, ANCA, anti-CCP, RF
• CRP and ESR: Inflammatory markers

Imaging

• CXR: Thymic shadow (absent in DiGeorge), bronchiectasis
• CT chest: Bronchiectasis, lymphadenopathy, thymoma

Special Tests

• Vaccine responses: Pneumococcal antibody levels pre/post-vaccination
• Nitroblue tetrazolium (NBT) test / DHR flow cytometry: Chronic granulomatous disease
• Lymphocyte proliferation assays: T cell function
• HIV test: Secondary immunodeficiency screening
• Genetic testing: For primary immunodeficiency syndromes

Non-pharmacological

• Infection avoidance measures
• Patient education regarding signs of infection
• Medic-Alert bracelet for severe immunodeficiency
• Avoid live vaccines in immunocompromised patients

Pharmacological

• Immunoglobulin replacement: IV (0.4-0.6g/kg every 3-4 weeks) or subcutaneous for antibody deficiency
• Prophylactic antibiotics: Co-trimoxazole for Pneumocystis prophylaxis in severe T cell deficiency
• G-CSF: For severe congenital neutropenia
• Immunosuppression for autoimmunity: Corticosteroids, azathioprine, mycophenolate, rituximab, biologics
• Antihistamines/adrenaline: For allergic conditions

Surgical/Interventional

• Haematopoietic stem cell transplant: For severe primary immunodeficiency (SCID, CGD)
• Gene therapy: Emerging for specific conditions (ADA-SCID)

Referral Criteria

• Suspected primary immunodeficiency → clinical immunology
• Recurrent serious infections → infection and immunity specialist
• Suspected autoimmune disease → rheumatology or relevant organ specialist

• SCID: Fatal within first year if untreated; >90% survival with early HSCT
• Common variable immunodeficiency: Normal life expectancy with immunoglobulin replacement; increased risk of autoimmunity and lymphoma
• XLA: Good prognosis with immunoglobulin replacement
• DiGeorge syndrome: Variable - depends on severity of thymic aplasia and cardiac defects
• Autoimmune conditions: Most are chronic and require lifelong management

Immunoglobulin Summary

Complement Deficiencies

Key Facts

The innate and adaptive immune systems are complementary defence mechanisms. Innate immunity provides the first line of defence and shapes the adaptive response, while adaptive immunity provides pathogen-specific, long-lasting protection.

Epidemiology

The clinical relevance of innate and adaptive immunity spans all medical specialties:

• Innate immune defects lead to recurrent pyogenic infections (e.g., chronic granulomatous disease, complement deficiencies)
• Adaptive immune defects lead to opportunistic infections (e.g., SCID, HIV/AIDS)
• Inappropriate immune activation causes autoimmune disease and chronic inflammation

Aetiology

Innate Immune Components:

• Barriers: Skin (keratinised epithelium), mucous membranes, cilia, gastric acid, lysozyme, defensins
• Cells: Neutrophils, monocytes/macrophages, dendritic cells, mast cells, basophils, eosinophils, NK cells
• Soluble factors: Complement system, acute phase proteins (CRP, ferritin), cytokines (TNF-α, IL-1, IL-6), interferons

Adaptive Immune Components:

• Cell-mediated: T lymphocytes (CD4+ helper, CD8+ cytotoxic, regulatory, γδ)

Pathophysiology

The innate immune response is triggered by PRR recognition of PAMPs:

• Bacterial: Lipopolysaccharide (LPS), peptidoglycan, flagellin
• Viral: Double-stranded RNA, single-stranded RNA, unmethylated CpG DNA
• Fungal: β-glucan, mannan

This triggers NF-κB signalling, cytokine release, and inflammation. Dendritic cells process antigens and migrate to lymph nodes to activate naïve T cells, initiating the adaptive response.

Innate Immunity Disorders

• Chronic granulomatous disease: Recurrent catalase-positive organism infections (Staph. aureus, Aspergillus, Serratia)
• Leukocyte adhesion deficiency: Delayed umbilical cord separation, recurrent infections without pus
• Complement deficiencies: C3 - recurrent encapsulated bacteria; C5-C9 - recurrent Neisseria
• Hereditary angioedema: C1 esterase inhibitor deficiency - episodic swelling

Adaptive Immunity Disorders

• SCID: Severe infections from birth, failure to thrive, absent thymic shadow
• X-linked agammaglobulinaemia (Bruton's): Recurrent sinopulmonary infections from 6 months (maternal IgG wanes)
• DiGeorge syndrome (22q11.2 deletion): T cell deficiency, cardiac defects, hypocalcaemia, facial dysmorphism

Red Flags

• Life-threatening infections with common organisms in infancy → suspect SCID
• Recurrent Neisseria meningitidis → test complement pathway
• Granuloma formation with recurrent Staph aureus/Aspergillus → CGD

Bedside

• Clinical assessment: Growth parameters, lymph node assessment, tonsil presence
• Vaccination history: Poor responses suggest antibody deficiency

Bloods

• FBC with differential: Neutrophil count, lymphocyte count
• Lymphocyte subsets: CD3 (total T), CD4 (helper T), CD8 (cytotoxic T), CD19/CD20 (B cells), CD56 (NK cells)
• Immunoglobulins: IgG, IgA, IgM levels
• Complement: C3, C4, CH50 (classical pathway), AP50 (alternative pathway)
• CRP, ESR: Acute phase response assessment

Imaging

• CXR: Thymic shadow (absent in SCID, DiGeorge)
• CT chest/abdomen: Lymphadenopathy, splenomegaly

Special Tests

• NBT/DHR flow cytometry: CGD (oxidative burst assessment)
• Vaccine responses: Pre/post-immunisation antibody levels
• Lymphocyte proliferation assays: T cell functional assessment
• Genetic testing: For specific immunodeficiency syndromes
• Mannose-binding lectin (MBL): Lectin pathway deficiency

Non-pharmacological

• Infection prevention (hand hygiene, food safety, environmental precautions)
• Avoid live vaccines in T cell deficiency
• Family screening and genetic counselling

Pharmacological

• Immunoglobulin replacement: For antibody deficiencies (IV or SC)
• Antibiotic prophylaxis: Co-trimoxazole (PCP), itraconazole (fungal) in severe deficiencies
• G-CSF: Neutropenia
• Interferon-gamma: CGD prophylaxis
• C1 esterase inhibitor concentrate: Hereditary angioedema (acute and prophylactic)

Surgical/Interventional

• HSCT: Curative for SCID, CGD, WAS, and other severe primary immunodeficiencies
• Gene therapy: ADA-SCID, X-linked SCID (emerging)
• Thymic transplantation: Complete DiGeorge syndrome

Referral Criteria

• Any suspected primary immunodeficiency → specialist immunology
• SCID is a medical emergency - refer immediately for HSCT evaluation
• Recurrent serious or unusual infections → infection/immunology team

• SCID: >90% survival with early HSCT (within first 3.5 months of life); fatal within 1 year if untreated
• CGD: Median survival >40 years with prophylaxis; cure possible with HSCT
• XLA (Bruton's): Near-normal life expectancy with immunoglobulin replacement
• C5-C9 deficiency: Generally good prognosis with awareness and vaccination against Neisseria
• CVID: Increased risk of autoimmunity (20%), lymphoma (5-10%); life expectancy reduced if granulomatous disease develops

Innate vs Adaptive Immunity Comparison

CD Markers - Key for Exams

Key Facts

Hypersensitivity reactions represent immune-mediated tissue damage. The Gell and Coombs classification (1963) remains the standard framework for understanding these reactions.

Epidemiology

• Allergic disease (Type I) affects approximately 30% of the UK population
• Anaphylaxis incidence is rising - approximately 20 deaths per year in the UK
• Hospital admissions for anaphylaxis have increased 7-fold over the past 20 years
• Autoimmune diseases (Types II, III, IV) affect approximately 5-8% of the population

Aetiology

Each type has a distinct immunological mechanism:

Pathophysiology

Type I: Two-phase response

1. Re-exposure: Allergen cross-links surface IgE → mast cell degranulation
2. Early phase (minutes): Histamine, tryptase, prostaglandins → vasodilation, bronchospasm
3. Late phase (4-8 hours): Leukotrienes, cytokines → prolonged inflammation, eosinophil recruitment

Type I Reactions

• Mild: Urticaria, rhinitis, conjunctivitis
• Moderate: Angioedema, bronchospasm, GI symptoms
• Severe (anaphylaxis): Airway compromise, cardiovascular collapse, shock
• Common triggers: Foods (nuts, shellfish), drugs (penicillin, NSAIDs), insect stings, latex

Type II Reactions

• Haemolytic anaemia (warm: IgG - extravascular; cold: IgM - intravascular)
• Haemolytic disease of the newborn (anti-RhD antibodies)
• Goodpasture's syndrome (anti-GBM antibodies → pulmonary haemorrhage, glomerulonephritis)
• Myasthenia gravis (anti-AChR antibodies), Graves' disease (TSH receptor stimulating antibodies)

Type III Reactions

• SLE (anti-dsDNA immune complexes → nephritis, arthritis, serositis)
• Post-streptococcal GN (immune complex deposition in glomeruli)
• Serum sickness (fever, rash, arthralgia 7-14 days after foreign protein exposure)

Type IV Reactions

• Contact dermatitis (nickel, latex)
• Tuberculin (Mantoux) test
• Granulomatous disease (TB, sarcoidosis)
• Transplant rejection (acute cellular)

Red Flags

• Stridor, wheeze, or respiratory distress → anaphylaxis
• Hypotension with urticaria/angioedema → anaphylaxis
• Rapid-onset symptoms after allergen exposure → treat immediately

Bedside

• A-E assessment: Airway, breathing, circulation in suspected anaphylaxis
• Peak flow: Bronchospasm assessment

Bloods

• Mast cell tryptase: Serial samples at presentation, 1-2 hours, and >24 hours (baseline)
• Specific IgE (RAST): To identified allergens
• C3, C4: Low in Type II and III (complement consumption)
• Autoantibodies: Coombs test (Type II), ANA, anti-dsDNA (Type III)
• Eosinophil count: Elevated in atopic conditions

Imaging

• As clinically indicated (CXR if respiratory symptoms, renal imaging if nephritis)

Special Tests

• Skin prick testing: Type I hypersensitivity - must be done in specialist setting with resuscitation facilities
• Patch testing: Type IV (contact dermatitis) - reading at 48 and 96 hours
• Component-resolved diagnostics: Specific IgE to allergen components for risk stratification
• Drug provocation testing: Specialist setting for drug allergy clarification
• Direct and indirect Coombs test: Autoimmune haemolytic anaemia

Non-pharmacological

• Allergen avoidance: Education, food labelling awareness
• Allergy action plan: Written plan for patients at risk of anaphylaxis
• Medical alert identification: Bracelet/necklace

Pharmacological

Anaphylaxis (NICE CG134 / Resuscitation Council UK):

1. Remove trigger, call for help
2. IM adrenaline 0.5mg (1:1000) into anterolateral thigh - repeat every 5 minutes if needed
3. High-flow oxygen
4. IV fluid bolus (500-1000mL crystalloid)
5. Chlorphenamine 10mg IM/slow IV and hydrocortisone 200mg IM/slow IV
6. If bronchospasm: Nebulised salbutamol 5mg
7. Observe for minimum 6-12 hours (biphasic reaction risk)

Adrenaline auto-injector doses:

• Child <6 years: 150mcg (EpiPen Jr)
• Child 6-12 years: 300mcg
• Adult/child >12 years: 300-500mcg

Chronic allergic conditions:

• Antihistamines (cetirizine 10mg OD, fexofenadine 180mg OD)
• Intranasal corticosteroids (allergic rhinitis)
• Allergen immunotherapy (specialist-led desensitisation)

Referral Criteria

• All confirmed anaphylaxis → allergy clinic within 6 weeks
• Suspected drug allergy → specialist allergy testing
• Consideration of allergen immunotherapy (venom, aeroallergens)
• Recurrent angioedema without urticaria → exclude HAE

• Anaphylaxis: Fatal in 1-2% of hospitalised cases; most deaths occur within 30 minutes
• Risk of biphasic reaction: ~5-20% - typically within 4-12 hours
• Food allergy: Many children outgrow milk and egg allergy (~80% by school age); peanut/tree nut allergy tends to persist
• Autoimmune haemolytic anaemia: Variable - depends on underlying cause
• SLE: 10-year survival >90% with modern treatment; renal involvement is main prognostic determinant

Gell and Coombs Classification Summary

Adrenaline Doses for Anaphylaxis

Key Facts

Autoimmune diseases arise when the immune system mounts a response against self-antigens. They are classified as organ-specific (targeting a single organ) or systemic (affecting multiple organs).

Epidemiology

• Prevalence: ~5-8% of the UK population
• Female:male ratio varies: SLE 9:1, RA 3:1, ankylosing spondylitis 3:1 male predominance
• Peak onset varies: Type 1 diabetes (childhood/adolescence), RA (30-50 years), SLE (15-45 years)
• Autoimmune diseases are the third most common disease category after cardiovascular disease and cancer

Aetiology

Multifactorial - genetic susceptibility + environmental triggers:

• Genetic: HLA associations, AIRE gene (APECED syndrome), FoxP3 (IPEX syndrome), CTLA-4, PTPN22
• Environmental: Infections (molecular mimicry), smoking (RA, Graves'), UV light (SLE), drugs (drug-induced lupus), gut microbiome dysbiosis
• Hormonal: Oestrogen promotes immune activation - explaining female predominance

Pathophysiology

Mechanisms of tolerance breakdown:

1. Molecular mimicry: Pathogen antigens share epitopes with self-antigens
2. Bystander activation: Tissue damage releases sequestered self-antigens
3. Epitope spreading: Immune response extends from initial epitope to other self-antigens
4. Failure of regulatory mechanisms: Treg dysfunction, defective apoptosis (Fas/FasL)
5. Superantigen-mediated: Non-specific T cell activation

Organ-Specific Autoimmune Diseases

• Hashimoto's thyroiditis: Hypothyroidism, goitre, anti-TPO antibodies
• Graves' disease: Thyrotoxicosis, ophthalmopathy, TSH receptor antibodies
• Type 1 diabetes: Hyperglycaemia, anti-GAD/anti-IA2 antibodies
• Pernicious anaemia: Megaloblastic anaemia, anti-intrinsic factor antibodies
• Myasthenia gravis: Fatigable weakness, anti-AChR antibodies
• Autoimmune hepatitis: Chronic hepatitis, anti-smooth muscle/anti-LKM antibodies

Systemic Autoimmune Diseases

• SLE: Butterfly rash, arthritis, serositis, renal disease, cytopenias
• Rheumatoid arthritis: Symmetrical polyarthritis, morning stiffness
• Systemic sclerosis: Raynaud's, skin thickening, pulmonary fibrosis
• Sjögren's syndrome: Dry eyes, dry mouth, parotid enlargement

Red Flags

• Multi-system disease with constitutional symptoms
• Renal involvement (proteinuria, haematuria, rising creatinine)
• Pulmonary haemorrhage (Goodpasture's, ANCA vasculitis)
• Rapidly progressive neurological deficit

Bedside

• Urinalysis: Proteinuria, haematuria (renal involvement)
• Blood pressure: Hypertension in renal disease

Bloods

• Autoantibodies:
  • ANA (screening), anti-dsDNA (SLE activity), anti-Sm (SLE specific)
  • RF, anti-CCP (RA)
  • ANCA (vasculitis)
  • Anti-TPO (Hashimoto's), TSH receptor Ab (Graves')
  • Anti-GBM (Goodpasture's)
  • Anti-centromere (limited systemic sclerosis), anti-Scl-70 (diffuse systemic sclerosis)
• Complement: C3, C4 (low in active SLE, Type II/III hypersensitivity)
• ESR and CRP: Inflammatory markers (ESR often raised more than CRP in SLE)
• Immunoglobulins: Polyclonal elevation common in autoimmune disease

Imaging

• X-rays: Joint erosions (RA), sacroiliac joint changes (AS)
• USS/CT/MRI: Organ-specific assessment
• HRCT chest: Pulmonary fibrosis (systemic sclerosis), alveolar haemorrhage

Special Tests

• Biopsy: Renal (lupus nephritis classification), skin, salivary gland (Sjögren's)
• Schirmer's test: Dry eye assessment (Sjögren's)
• HLA typing: HLA-B27 (spondyloarthropathy), HLA-DQ2/DQ8 (coeliac disease)
• Nerve conduction studies: Myasthenia gravis, GBS

Non-pharmacological

• Patient education and self-management support
• Sun protection (SLE)
• Smoking cessation (particularly important in RA)
• Exercise and physiotherapy
• Psychological support

Pharmacological

General principles:

• Mild disease: NSAIDs, hydroxychloroquine
• Moderate disease: Conventional DMARDs (methotrexate 7.5-25mg weekly, azathioprine 1-3mg/kg/day, mycophenolate 1-3g/day)
• Severe/refractory disease: Biological DMARDs (rituximab, belimumab, TNF inhibitors), cyclophosphamide
• Acute flares: Corticosteroids (prednisolone 0.5-1mg/kg/day) - taper to lowest effective dose

Specific therapies:

• SLE: Hydroxychloroquine (all patients), mycophenolate for nephritis (ALMS trial)
• RA: Methotrexate first-line DMARD; biologics (anti-TNF, rituximab, JAK inhibitors) for inadequate response
• ANCA vasculitis: Cyclophosphamide + corticosteroids for induction; azathioprine/rituximab for maintenance (RAVE, RITUXVAS trials)

Referral Criteria

• Suspected autoimmune disease → rheumatology or relevant specialist
• Multi-system disease → urgent assessment
• Renal involvement → nephrology
• Pregnancy planning in autoimmune disease → specialist pre-conception counselling

• SLE: 10-year survival >90%; lupus nephritis is the main cause of morbidity and mortality
• RA: Life expectancy reduced by 3-10 years; early DMARD therapy improves outcomes
• Type 1 diabetes: Lifelong insulin dependence; complications relate to glycaemic control
• Systemic sclerosis: 5-year survival 80-85%; diffuse cutaneous form has worse prognosis
• ANCA vasculitis: 5-year survival ~75-80% with treatment; relapse rate 50% over 5 years
• Cardiovascular disease is a major cause of mortality across all autoimmune conditions

Key Autoantibody Associations

HLA Associations

Key Facts

Immunodeficiency disorders impair the body's ability to fight infections and, in some cases, malignancy. They are broadly classified as primary (inherited) or secondary (acquired). Understanding the immune system's components is essential for recognising patterns of susceptibility.

Epidemiology

Primary immunodeficiencies collectively affect approximately 1 in 2,000 live births. Antibody deficiencies account for approximately 65% of primary immunodeficiencies. Secondary immunodeficiency is far more common, with HIV infecting approximately 105,000 people in the UK and iatrogenic immunosuppression affecting hundreds of thousands.

Aetiology

Primary immunodeficiencies are classified by the component affected:

• B-cell/antibody defects (65%): CVID, X-linked agammaglobulinaemia, selective IgA deficiency
• T-cell defects (15%): DiGeorge syndrome, severe combined immunodeficiency (SCID)
• Combined B and T cell (10%): SCID variants, Wiskott-Aldrich syndrome
• Phagocyte defects (5%): Chronic granulomatous disease, leucocyte adhesion deficiency
• Complement defects (5%): C2 deficiency (most common), terminal complement deficiencies

Secondary causes: HIV, malnutrition, diabetes, uraemia, immunosuppressive drugs, splenectomy, haematological malignancy

Pathophysiology

Each component of the immune system provides distinct protective functions:

• Antibodies: Opsonisation, neutralisation, complement activation - deficiency leads to encapsulated bacterial infections
• T cells: Intracellular pathogen defence - deficiency leads to viral, fungal, and opportunistic infections
• Phagocytes: Bacterial and fungal killing - deficiency leads to skin abscesses, deep-seated infections
• Complement: Opsonisation, membrane attack complex - deficiency predisposes to Neisseria infections and SLE

Antibody Deficiency

• Recurrent sinopulmonary infections (Streptococcus pneumoniae, Haemophilus influenzae)
• Chronic diarrhoea (Giardia lamblia)
• Bronchiectasis from recurrent infections

T-Cell Deficiency

• Opportunistic infections: Pneumocystis jirovecii, CMV, Candida, Cryptosporidium
• Severe viral infections (measles, varicella)
• Failure to thrive in infancy

Phagocyte Defects

• Recurrent skin abscesses (Staphylococcus aureus, Aspergillus)
• Deep-seated infections: liver abscesses, lymphadenitis
• Delayed wound healing

Complement Deficiency

• Recurrent Neisseria meningitidis infections (terminal complement C5-C9)
• SLE-like illness (early classical pathway C1-C4)
• Hereditary angioedema (C1 esterase inhibitor deficiency)

Red Flags

• Failure to thrive with recurrent infections in infancy
• Two or more severe bacterial infections (meningitis, sepsis, osteomyelitis)
• Infections with unusual organisms or unusual severity
• Family history of early childhood death from infection
• Absent tonsils/lymph nodes on examination

Bedside

• Clinical assessment: Growth charts, lymph node palpation, tonsil inspection
• HIV point-of-care test: Rapid result in secondary immunodeficiency screening

Bloods

• FBC with differential: Lymphopenia (T-cell defects), neutropenia
• Serum immunoglobulins: IgG, IgA, IgM levels - low in antibody deficiencies
• Lymphocyte subsets: CD3 (T cells), CD4/CD8 ratio, CD19 (B cells), CD56 (NK cells)
• Complement levels: CH50/CH100 (total classical pathway), C3, C4, AP50 (alternative pathway)
• Vaccine antibody responses: Measure IgG to tetanus, pneumococcal serotypes pre/post vaccination
• HIV test: Fourth-generation combined antigen/antibody

Imaging

• CXR: Absent thymic shadow in SCID/DiGeorge, bronchiectasis
• CT thorax: Bronchiectasis, lymphadenopathy, granulomata

Special Tests

• NBT/DHR test: Chronic granulomatous disease - absent oxidative burst
• Genetic testing: Targeted or whole-exome sequencing for primary immunodeficiencies
• TREC assay: Newborn screening for SCID (measures T-cell receptor excision circles)

Non-pharmacological

• Patient education on infection avoidance and early treatment-seeking
• Avoidance of live vaccines in T-cell and severe combined deficiencies
• Genetic counselling for primary immunodeficiencies
• Spleen-related precautions if asplenic/hyposplenic

Pharmacological

• Immunoglobulin replacement therapy: IV (IVIg 0.4-0.6g/kg every 3-4 weeks) or subcutaneous (SCIg weekly) for antibody deficiencies
• Prophylactic antibiotics: Co-trimoxazole 960mg OD for Pneumocystis prophylaxis in T-cell defects
• Antifungal prophylaxis: Itraconazole in chronic granulomatous disease
• Antiretroviral therapy: For HIV - start regardless of CD4 count (NICE NG142)
• Interferon-gamma: In chronic granulomatous disease to enhance phagocyte function

Surgical

• Haematopoietic stem cell transplantation (HSCT): Curative for SCID, chronic granulomatous disease, Wiskott-Aldrich syndrome
• Gene therapy: Emerging treatment for ADA-SCID, X-linked SCID
• Thymic transplantation: For complete DiGeorge syndrome

Referral Criteria

• Any suspected primary immunodeficiency - refer to clinical immunology
• Recurrent infections requiring hospitalisation
• Family history of primary immunodeficiency
• Unexplained bronchiectasis

• SCID: Fatal within first year without HSCT; >90% survival with early matched sibling transplant
• CVID: Life expectancy reduced by 10-15 years; 20% develop autoimmune complications, 10% develop lymphoma
• X-linked agammaglobulinaemia: Good prognosis with adequate IgG replacement; chronic lung disease is main comorbidity
• Chronic granulomatous disease: Median survival now >40 years with prophylaxis; HSCT offers cure
• HIV: Near-normal life expectancy with early ART initiation; CD4 count <200 cells/µL defines AIDS

Classification of Primary Immunodeficiencies

Organisms by Immune Defect

Key Facts

Inflammation is a complex biological response to harmful stimuli such as pathogens, damaged cells, or irritants. It is a protective mechanism that aims to eliminate the cause of injury, clear necrotic debris, and initiate repair.

Epidemiology

Inflammation underlies virtually all pathological processes. Chronic inflammatory diseases (e.g., rheumatoid arthritis, atherosclerosis, inflammatory bowel disease) account for a significant proportion of disease burden in the UK, with an estimated 50% of all deaths attributable to inflammation-related diseases.

Aetiology

Causes of inflammation include:

• Infections: Bacterial, viral, fungal, parasitic
• Physical agents: Trauma, radiation, heat, cold
• Chemical agents: Toxins, venoms, caustic substances
• Immune reactions: Hypersensitivity, autoimmunity
• Tissue necrosis: Ischaemia, infarction

Pathophysiology

Acute inflammation follows a stereotyped sequence:

1. Chemical mediators: Histamine, bradykinin, complement (C3a, C5a), prostaglandins, leukotrienes, cytokines (IL-1, TNF-alpha, IL-6)

Outcomes of acute inflammation: Resolution, abscess formation, chronic inflammation, or fibrosis

Chronic inflammation is characterised by simultaneous inflammation, tissue destruction, and repair. Key cells include macrophages, lymphocytes, and plasma cells.

Acute Inflammation

• Local: Redness, heat, swelling, pain, loss of function
• Systemic: Fever, leucocytosis, raised CRP/ESR, acute phase response
• Severe: SIRS, sepsis, organ dysfunction

Chronic Inflammation

• Granulomatous: Caseating (TB) vs non-caseating (sarcoidosis)
• Non-specific chronic: Lymphocyte and macrophage infiltration, fibrosis
• Autoimmune: Tissue-specific or systemic destruction

Wound Healing

• Primary intention: Clean, apposed wound edges - minimal scarring
• Secondary intention: Open wound, granulation tissue fills defect - more scarring
• Tertiary intention: Delayed primary closure after initial open management

Red Flags

• Signs of systemic inflammatory response (SIRS): HR >90, RR >20, temp >38°C or <36°C, WCC >12 or <4 ×10⁹/L
• Non-healing wounds: consider malignancy, vasculitis, pyoderma gangrenosum
• Unexplained granulomatous inflammation: exclude TB, fungal infection before diagnosing sarcoidosis

Bedside

• Temperature: Fever indicates systemic inflammatory response
• Wound inspection: Signs of infection, healing stage assessment

Bloods

• CRP: Rises within 6 hours, peaks at 48 hours - useful for monitoring acute inflammation
• ESR: Slower to rise and fall - better for chronic inflammation monitoring
• Procalcitonin: More specific for bacterial infection than CRP
• FBC: Neutrophilia (bacterial), lymphocytosis (viral), eosinophilia (parasitic/allergic)
• Serum amyloid A, ferritin, fibrinogen: Additional acute phase reactants

Imaging

• Ultrasound/CT/MRI: Identify abscess collections, inflammatory masses
• PET-CT: Detect occult inflammation, vasculitis, malignancy

Special Tests

• Histology/biopsy: Gold standard for characterising inflammation type
• Immunohistochemistry: Identify cell populations in tissue
• Flow cytometry: Lymphocyte subsets in blood/tissue

Non-pharmacological

• Wound care: debridement, appropriate dressings, offloading pressure
• Nutritional optimisation (vitamin C, zinc, protein for wound healing)
• Smoking cessation - impairs wound healing and promotes chronic inflammation

Pharmacological

• NSAIDs: Inhibit COX-1/COX-2, reducing prostaglandin synthesis - ibuprofen 400mg TDS
• Corticosteroids: Broad anti-inflammatory - inhibit phospholipase A2, NF-κB; prednisolone 5-60mg OD
• DMARDs: Methotrexate 7.5-25mg weekly for chronic autoimmune inflammation
• Biological agents: Anti-TNF (adalimumab, infliximab), anti-IL-6 (tocilizumab) for refractory inflammation
• Antibiotics: When infection is the inflammatory trigger - guided by culture and sensitivity

Surgical

• Incision and drainage: For abscess cavities
• Debridement: Removal of necrotic tissue to promote healing
• Skin grafting: For large wounds unable to heal by secondary intention

Referral Criteria

• Non-healing wounds >6 weeks - consider tissue viability or dermatology referral
• Unexplained chronic inflammation - rheumatology or immunology
• Granulomatous inflammation of unknown cause - respiratory or infectious diseases

• Acute inflammation: typically resolves within days to weeks if cause eliminated
• Chronic inflammation: may persist indefinitely - leads to tissue damage and fibrosis
• Wound healing: tensile strength reaches 80% of original by 3 months; never reaches 100%
• Keloid/hypertrophic scarring: more common in Afro-Caribbean populations, young adults, sternal/deltoid sites
• Chronic non-healing wounds affect approximately 2% of the UK population, costing the NHS an estimated £5 billion annually

Key Chemical Mediators

Phases of Wound Healing

Key Facts

Maintaining acid-base balance is critical for enzyme function, protein structure, and cellular processes. The body maintains pH within a narrow range through buffer systems, respiratory regulation, and renal mechanisms.

Epidemiology

Acid-base disturbances are extremely common in hospitalised patients. Metabolic acidosis occurs in approximately 15-25% of ICU admissions. Lactic acidosis is the most common cause of raised anion gap metabolic acidosis in the acute setting.

Aetiology

Metabolic acidosis (low pH, low HCO3⁻):

• Raised anion gap: Lactic acidosis, DKA, uraemia, toxic ingestions (MUDPILES)
• Normal anion gap (hyperchloraemic): Renal tubular acidosis, diarrhoea, Addison's disease, pancreatic fistula

Metabolic alkalosis (high pH, high HCO3⁻): Vomiting, diuretics, Conn's syndrome, Cushing's syndrome

Respiratory acidosis (low pH, high PaCO2): COPD, neuromuscular disease, sedative overdose, chest wall deformity

Respiratory alkalosis (high pH, low PaCO2): Hyperventilation, anxiety, PE, salicylate poisoning (early), high altitude

Pathophysiology

Buffer systems provide immediate defence:

• Bicarbonate system: CO2 + H2O ⇌ H2CO3 ⇌ H⁺ + HCO3⁻ (carbonic anhydrase catalysed)
• Haemoglobin: Binds H⁺ in deoxygenated state (Bohr effect)
• Phosphate: Important intracellular buffer and in urine (titratable acidity)

Respiratory regulation (minutes): Peripheral chemoreceptors (carotid/aortic bodies) sense pH/PaCO2/PaO2; central chemoreceptors (medulla) sense CSF pH via CO2 diffusion

Renal regulation (hours–days): Proximal tubule reabsorbs ~85% filtered HCO3⁻; distal tubule and collecting duct secrete H⁺ via H⁺-ATPase and generate new HCO3⁻ via ammoniagenesis

Metabolic Acidosis

• Kussmaul respiration: Deep, sighing breathing (respiratory compensation)
• Confusion, drowsiness, cardiovascular collapse in severe cases
• Underlying cause symptoms: polyuria/polydipsia (DKA), oliguria (renal failure)

Metabolic Alkalosis

• Muscle cramps, tetany, paraesthesia (reduced ionised calcium)
• Arrhythmias (hypokalaemia often coexists)
• Hypoventilation (respiratory compensation)

Respiratory Acidosis

• Headache, confusion, tremor (CO2 narcosis)
• Bounding pulse, warm peripheries
• Papilloedema in chronic hypercapnia

Respiratory Alkalosis

• Light-headedness, perioral tingling, carpopedal spasm
• Anxiety, chest tightness

Red Flags

• pH <7.1 or >7.6 - life-threatening, urgent intervention required
• Lactate >4 mmol/L with acidosis - consider sepsis, tissue hypoperfusion
• Metabolic acidosis with high anion gap in a young person - consider toxic ingestion

Bedside

• Arterial blood gas (ABG): pH, PaCO2, PaO2, HCO3⁻, base excess, lactate
• Venous blood gas: Adequate for pH and HCO3⁻ screening (pH ~0.03 lower than arterial)
• Urine dipstick: pH, ketones, glucose
• Blood glucose: Capillary - DKA screening

Bloods

• U&Es: Calculate anion gap; assess renal function
• Lactate: Type A (tissue hypoperfusion) vs type B (metabolic)
• Blood ketones: β-hydroxybutyrate >3 mmol/L in DKA
• Toxicology screen: Salicylate, ethanol, methanol levels if ingestion suspected
• Chloride: Assess for hyperchloraemic (normal AG) acidosis

Imaging

• CXR: If respiratory cause suspected (pneumonia, COPD)
• CT head: If CO2 narcosis with reduced consciousness

Special Tests

• Urine anion gap: (Na⁺ + K⁺) − Cl⁻; positive in RTA, negative in GI bicarbonate loss
• Osmolar gap: Measured − calculated osmolality >10 suggests toxic alcohol ingestion
• Urine pH: >5.3 in distal (type 1) RTA despite systemic acidosis

Non-pharmacological

• Identify and treat the underlying cause - this is the priority
• Monitor with serial ABGs to assess response to treatment
• HDU/ICU admission for severe acid-base disturbances

Pharmacological

• DKA protocol: IV 0.9% saline, fixed-rate insulin infusion (0.1 units/kg/hr), potassium replacement per protocol
• Lactic acidosis: Treat underlying cause (fluids, vasopressors for sepsis)
• Sodium bicarbonate 8.4%: Only in severe acidosis (pH <6.9 in DKA, or renal failure) - 50mmol IV over 30-60 min; controversial, can worsen intracellular acidosis
• RTA: Oral sodium bicarbonate 1-2 mmol/kg/day for type 1; higher doses for type 2
• Metabolic alkalosis: Volume resuscitation with 0.9% saline, potassium replacement; acetazolamide 250mg BD if resistant

Surgical

• Renal replacement therapy (haemodialysis) for refractory metabolic acidosis, toxic alcohol ingestion

Referral Criteria

• pH <7.1 or >7.6 - critical care
• Suspected toxic ingestion - toxicology/NPIS
• Recurrent unexplained acidosis - nephrology (RTA workup)

• DKA mortality: <1% in specialist centres; rises to 5% in elderly and those with delayed treatment
• Lactic acidosis: Mortality 50-80% when lactate >10 mmol/L, depending on underlying cause
• Type 1 RTA: Good prognosis with alkali replacement; risk of nephrocalcinosis and renal stones
• Respiratory acidosis in COPD: Acute-on-chronic respiratory acidosis requiring NIV has ~15% in-hospital mortality
• Severe acidosis (pH <7.0) is associated with cardiovascular collapse, reduced myocardial contractility, and resistance to catecholamines

Systematic ABG Interpretation (5-Step Approach)

Expected Compensation

Key Facts

Body fluid is distributed between intracellular (ICF, ~28L) and extracellular (ECF, ~14L) compartments. The ECF is further divided into interstitial fluid (~11L) and plasma (~3L). Osmolarity is the key determinant of water distribution between compartments.

Epidemiology

Electrolyte disturbances are among the most common abnormalities encountered in hospital medicine. Hyponatraemia affects 15-30% of hospitalised patients. Hyperkalaemia occurs in approximately 8% of hospitalised patients and is the most common electrolyte cause of cardiac arrest. Hypokalaemia affects approximately 20% of hospitalised patients.

Aetiology

Electrolyte disturbances arise from:

• Altered intake: IV fluids, diet, TPN
• Altered losses: GI (vomiting, diarrhoea, fistulae), renal (diuretics, RTA), insensible (fever, burns)
• Redistribution: Insulin shifts K⁺ intracellularly; metabolic alkalosis drives K⁺ into cells
• Hormonal: Aldosterone (Na⁺ retention, K⁺ excretion), ADH (water retention), PTH (Ca²⁺ regulation)

Pathophysiology

• Sodium determines ECF osmolality and volume - hyponatraemia reflects relative water excess
• Potassium determines resting membrane potential - disturbances cause cardiac arrhythmias
• Calcium is essential for muscle contraction, nerve conduction, and coagulation - 40% protein-bound
• Magnesium is a cofactor for >300 enzymatic reactions - deficiency causes refractory hypokalaemia and hypocalcaemia
• Starling forces govern fluid movement across capillaries: hydrostatic vs oncotic pressure gradients

Hyponatraemia

• Mild (130-134): Often asymptomatic
• Moderate (125-129): Nausea, headache, confusion
• Severe (<125): Seizures, coma, respiratory arrest

Hyperkalaemia

• Muscle weakness, paraesthesia, palpitations

Hypokalaemia

• Muscle weakness, cramps, constipation, ileus
• ECG: Flattened T waves, ST depression, prominent U waves, prolonged QT

Hypercalcaemia

• "Bones, stones, groans, and psychic moans": Bone pain, renal stones, abdominal pain/constipation, confusion/depression

Hypocalcaemia

• Perioral paraesthesia, carpopedal spasm, Chvostek's sign, Trousseau's sign, prolonged QT

Red Flags

• K⁺ >6.5 mmol/L or ECG changes - immediate treatment
• Na⁺ <120 mmol/L with seizures - 100mL hypertonic (3%) saline bolus
• Corrected Ca²⁺ >3.5 mmol/L - urgent hydration and bisphosphonate

Bedside

• ECG: Essential in hyper/hypokalaemia and hypocalcaemia
• Fluid balance chart: Input/output monitoring
• Weight: Daily - 1kg change ≈ 1L fluid
• Urine dipstick: Specific gravity, osmolality estimate

Bloods

• U&Es: Na⁺, K⁺, urea, creatinine, eGFR
• Bone profile: Corrected Ca²⁺, phosphate, ALP
• Magnesium: Always check in refractory hypokalaemia
• Serum osmolality: Normal 280-295 mOsm/kg
• Thyroid function, cortisol: Exclude hypothyroidism and adrenal insufficiency in hyponatraemia

Imaging

• CXR: Fluid overload assessment
• Renal USS: Obstructive uropathy, renal size

Special Tests

• Paired urine and serum osmolality: Diagnose SIADH
• Urine Na⁺: <20 mmol/L suggests pre-renal/hypovolaemic; >40 mmol/L suggests renal loss or SIADH
• Short Synacthen test: Exclude adrenal insufficiency
• PTH level: Differentiate causes of hypercalcaemia

Non-pharmacological

• Fluid restriction (750-1000 mL/day): First-line for SIADH
• IV fluid therapy per NICE CG174: Assess volume status before prescribing
• Dietary potassium restriction: In CKD with hyperkalaemia

Pharmacological

Hyperkalaemia emergency treatment:

1. Calcium gluconate 10% 10mL IV over 2 min (cardioprotection) - does NOT lower K⁺
2. Insulin 10 units + glucose 50mL 50% IV - shifts K⁺ intracellularly (onset 15-30 min)
3. Salbutamol 10-20mg nebulised - additional K⁺ shifting
4. Calcium resonium 15g TDS PO or sodium zirconium cyclosilicate 10g TDS - K⁺ binders

Hyponatraemia:

• Acute symptomatic: Hypertonic saline (3%) 100-150mL over 20 min
• Chronic: Fluid restriction, demeclocycline 300mg BD, tolvaptan 15mg OD (specialist only)

Hypocalcaemia:

• Acute symptomatic: 10mL calcium gluconate 10% IV over 10 min, then infusion
• Chronic: Alfacalcidol 0.25-1mcg OD + calcium carbonate 1.25g BD

Referral Criteria

• Refractory electrolyte disturbances - endocrinology/nephrology
• Sodium <120 mmol/L or >155 mmol/L - critical care
• Suspected endocrine cause - endocrinology

• Severe hyponatraemia (<120 mmol/L): mortality up to 50% if untreated; osmotic demyelination syndrome if corrected too rapidly (>10-12 mmol/L/day)
• Hyperkalaemia-related cardiac arrest: poor outcomes; preventable with early recognition
• SIADH: Prognosis depends on underlying cause; drug-induced SIADH resolves on drug withdrawal
• Hypercalcaemic crisis (Ca²⁺ >3.5): mortality 50% without treatment
• Chronic electrolyte disorders: increase falls risk, hospital stay, and mortality in elderly patients

IV Fluid Composition

Hyponatraemia Classification

Key Facts

Haemostasis involves a coordinated interplay between blood vessels, platelets, and the coagulation cascade, balanced by natural anticoagulant and fibrinolytic mechanisms. Disturbances lead to either bleeding or thrombosis.

Epidemiology

VTE (DVT and PE) affects approximately 1-2 per 1,000 population per year in the UK. Haemophilia A affects approximately 1 in 5,000 male births. Von Willebrand disease is the most common inherited bleeding disorder, affecting approximately 1% of the population (most mild). DIC complicates approximately 1% of hospital admissions.

Aetiology

Bleeding disorders:

• Platelet defects: Thrombocytopenia (ITP, TTP/HUS, drugs), platelet dysfunction (aspirin, uraemia)
• Coagulation factor deficiency: Haemophilia A/B, liver disease, vitamin K deficiency, DIC
• Vascular: Hereditary haemorrhagic telangiectasia, vasculitis, scurvy

Thrombotic disorders:

• Inherited thrombophilia: Factor V Leiden (~5% of Caucasians), prothrombin G20210A, protein C/S deficiency, antithrombin deficiency
• Acquired: Antiphospholipid syndrome, malignancy, immobility, oestrogen, surgery

Pathophysiology

Secondary haemostasis (cell-based model):

• Initiation: TF-VIIa complex generates small amount of thrombin
• Amplification: Thrombin activates platelets, factors V, VIII, XI on platelet surface

Natural anticoagulants: Antithrombin (heparin cofactor), protein C/S (inactivate Va, VIIIa), TFPI Fibrinolysis: Plasmin degrades fibrin → D-dimers released

Platelet/Primary Haemostasis Disorders

• Mucocutaneous bleeding: Petechiae, purpura, epistaxis, menorrhagia, GI bleeding
• Immediate bleeding after trauma
• Bruising out of proportion to injury

Coagulation/Secondary Haemostasis Disorders

• Deep tissue bleeding: Haemarthroses, muscle haematomas, retroperitoneal bleeds
• Delayed bleeding after trauma or surgery
• Prolonged bleeding from surgical wounds

DIC

• Simultaneous bleeding AND thrombosis
• Petechiae, oozing from venepuncture sites, organ failure from microvascular thrombosis
• Underlying trigger: Sepsis, obstetric emergencies, malignancy, trauma

Red Flags

• Spontaneous haemarthrosis in a child - suspect haemophilia
• New petechiae with rapidly falling platelets - consider TTP/HUS (ADAMTS13)
• Post-operative bleeding with prolonged APTT - exclude acquired factor VIII inhibitor
• Purpura fulminans - consider meningococcal sepsis, protein C deficiency

Bedside

• Observation: Pattern of bleeding (mucocutaneous vs deep tissue)
• Blood pressure: Assess haemodynamic stability

Bloods

• FBC: Platelet count - <150 × 10⁹/L is thrombocytopenia
• Coagulation screen: PT/INR, APTT, fibrinogen
• D-dimer: Raised in DIC, VTE (sensitive but not specific)
• Blood film: Schistocytes (MAHA), platelet morphology
• Mixing studies: APTT corrects = factor deficiency; does not correct = inhibitor (e.g., lupus anticoagulant)
• Factor assays: VIII, IX, vWF antigen and activity
• Thrombophilia screen: Factor V Leiden, prothrombin mutation, protein C/S, antithrombin, antiphospholipid antibodies - test >3 months after acute event, off anticoagulation

Imaging

• Ultrasound: Joint haemarthrosis, DVT assessment
• CTPA: Pulmonary embolism

Special Tests

• Thromboelastography (TEG/ROTEM): Point-of-care viscoelastic testing - guides transfusion in major haemorrhage
• PFA-100: Platelet function analyser - screens for platelet dysfunction/vWD

Non-pharmacological

• Pressure and elevation for acute bleeding
• Avoid NSAIDs and IM injections in bleeding disorders
• Medical alert bracelet for severe haemophilia
• Joint protection and physiotherapy for haemophilic arthropathy

Pharmacological

• Haemophilia A: Factor VIII replacement (recombinant); prophylaxis: 25-40 IU/kg 3×/week; emicizumab (bispecific antibody) for prophylaxis
• Haemophilia B: Factor IX replacement; prophylaxis: 25-40 IU/kg 2×/week
• Von Willebrand disease: Desmopressin (DDAVP) 0.3mcg/kg IV for type 1; vWF-containing factor VIII concentrates for type 2/3
• ITP: Observation if mild; prednisolone 1mg/kg/day; IVIg 1g/kg if urgent; rituximab or TPO-receptor agonists (eltrombopag, romiplostim) for chronic
• DIC: Treat underlying cause; replace factors (FFP, cryoprecipitate if fibrinogen <1.5g/L), platelets if <50 and bleeding
• Warfarin reversal: Vitamin K 5mg IV; prothrombin complex concentrate (Beriplex) 25-50 IU/kg for major bleeding
• VTE treatment (NICE NG158): Apixaban 10mg BD for 7 days then 5mg BD, or rivaroxaban 15mg BD for 21 days then 20mg OD

Referral Criteria

• Suspected inherited bleeding disorder - haematology
• Recurrent VTE or unprovoked VTE - thrombophilia assessment
• TTP - urgent haematology/plasma exchange

• Haemophilia A: Life expectancy near-normal with modern factor replacement; joint disease remains major morbidity
• ITP in children: >80% resolve spontaneously within 6 months; adult ITP is usually chronic
• TTP: Mortality 90% untreated; 10-20% with plasma exchange
• DIC: Mortality 40-80% depending on underlying cause; sepsis-associated DIC has highest mortality
• Factor V Leiden heterozygosity: ~4-7× increased VTE risk; homozygosity ~80× increased risk

Coagulation Cascade Summary

Vitamin K-Dependent Factors

Key Facts

The cardiovascular system delivers oxygen and nutrients to tissues while removing metabolic waste. Understanding cardiac physiology is fundamental to interpreting cardiovascular disease, pharmacology, and haemodynamic management.

Epidemiology

Cardiovascular disease is the second leading cause of death in the UK, responsible for approximately 27% of all deaths (~160,000/year). Heart failure affects approximately 900,000 people in the UK, with an incidence of 2-3 per 1,000/year.

Aetiology

Cardiovascular function depends on:

• Cardiac electrophysiology: Generation and conduction of action potentials
• Cardiac mechanics: Systolic contraction and diastolic relaxation
• Vascular function: Arterial resistance, venous capacitance, endothelial regulation
• Neurohumoral control: Sympathetic/parasympathetic, RAAS, natriuretic peptides

Pathophysiology

Cardiac action potentials:

• Pacemaker cells (SA/AV node): Phase 4 spontaneous depolarisation (funny current, If); phase 0 slow upstroke (Ca²⁺ channels); no true resting potential
• Cardiomyocytes: Phase 0 rapid depolarisation (Na⁺); phase 1 partial repolarisation (K⁺); phase 2 plateau (Ca²⁺ influx balanced by K⁺ efflux); phase 3 repolarisation (K⁺); phase 4 resting potential (−90mV)

Cardiac cycle:

• S1 (mitral/tricuspid closure) and S2 (aortic/pulmonary closure) heart sounds correspond to valve events

Pressure-volume loops demonstrate the relationship between preload, afterload, contractility and stroke volume

Heart Failure (Reduced Cardiac Output)

• Dyspnoea, orthopnoea, PND, fatigue
• Peripheral oedema, raised JVP, bibasal crackles
• S3 gallop (rapid ventricular filling), displaced apex beat

Shock States

• Cardiogenic: Low CO, high SVR, raised JVP
• Hypovolaemic: Low CO, high SVR, flat JVP
• Distributive (septic): High CO, low SVR, warm peripheries initially

Arrhythmias

• Palpitations, syncope/pre-syncope, dyspnoea
• Haemodynamic compromise if rate too fast or too slow

Red Flags

• MAP <65 mmHg - organ hypoperfusion, requires urgent intervention
• New-onset S3 gallop with dyspnoea - acute heart failure
• Syncope with exercise - consider aortic stenosis, HOCM, arrhythmia

Bedside

• ECG: Heart rate, rhythm, conduction, ischaemia
• Blood pressure: Systolic, diastolic, MAP calculation
• JVP assessment: Reflects right atrial pressure
• Pulse oximetry: Oxygen delivery assessment

Bloods

• BNP/NT-proBNP: Heart failure screening - BNP >100 pg/mL or NT-proBNP >300 pg/mL suggest HF
• Troponin: Myocardial injury marker
• Lactate: Tissue hypoperfusion indicator
• FBC, U&Es, LFTs, TFTs: Baseline cardiac assessment

Imaging

• Echocardiogram: EF, wall motion, valvular function, diastolic function
• CXR: Cardiomegaly (CTR >50%), pulmonary oedema, pleural effusions

Special Tests

• Cardiac catheterisation: Invasive haemodynamic assessment - wedge pressure, CO measurement
• Cardiac MRI: Gold standard for EF, tissue characterisation, infiltrative cardiomyopathy
• Exercise testing: Functional capacity, chronotropic response, ischaemia assessment

Non-pharmacological

• Fluid restriction (1.5L/day) and salt restriction (<6g/day) in heart failure
• Cardiac rehabilitation
• Lifestyle modification: exercise, weight management, smoking cessation

Pharmacological

Heart failure (NICE NG106):

• First-line: ACE inhibitor (ramipril 1.25-10mg OD) + beta-blocker (bisoprolol 1.25-10mg OD)
• Add: Mineralocorticoid receptor antagonist (spironolactone 25-50mg OD) if EF ≤35% and symptomatic
• Add: SGLT2 inhibitor (dapagliflozin 10mg OD) - DAPA-HF trial showed 26% reduction in CV death/HF hospitalisation
• Add: Sacubitril/valsartan (PARADIGM-HF trial) - replace ACEi if EF ≤35% and symptomatic despite optimal therapy
• Diuretics: Furosemide 20-80mg OD for congestion (symptom relief, no mortality benefit)

Shock:

• Cardiogenic: Dobutamine 2.5-10mcg/kg/min (inotrope); noradrenaline for MAP support
• Hypovolaemic: IV fluid resuscitation (250-500mL crystalloid bolus)
• Septic: Noradrenaline first-line vasopressor, target MAP ≥65 mmHg

Referral Criteria

• New heart failure diagnosis - cardiology
• Cardiogenic shock - critical care
• Consideration for CRT/ICD if EF ≤35%

• Heart failure: 5-year survival approximately 50% (worse than many cancers)
• NYHA class IV: 1-year mortality approximately 50%
• ACEi + beta-blocker + MRA therapy reduces HF mortality by approximately 50% combined
• CRT improves survival in selected patients (LBBB, QRS >150ms, EF ≤35%)
• Heart transplant: 1-year survival ~85%, 5-year ~75%

Cardiac Output Determinants

Landmark Heart Failure Trials

Key Facts

The respiratory system facilitates gas exchange between the atmosphere and blood, maintaining adequate oxygenation and CO2 elimination. Respiratory physiology underpins the understanding of common diseases such as asthma, COPD, pneumonia, and respiratory failure.

Epidemiology

Respiratory disease is the third leading cause of death in the UK. Asthma affects 5.4 million, COPD affects 1.2 million diagnosed patients, and pneumonia accounts for approximately 300,000 hospital admissions annually.

Aetiology

Ventilation depends on:

• Respiratory centre drive (medullary and pontine centres)
• Chest wall and diaphragm mechanics
• Airway patency
• Lung compliance and elastic recoil

Causes of respiratory failure:

• Type 1 (hypoxaemic): Pneumonia, PE, ARDS, pulmonary fibrosis, pulmonary oedema
• Type 2 (hypercapnic): COPD, neuromuscular disease, chest wall deformity, sedation, obesity hypoventilation

Pathophysiology

Lung mechanics:

• Compliance = ΔV/ΔP; reduced in fibrosis, ARDS, pulmonary oedema; increased in emphysema
• Surfactant (type II pneumocytes) reduces surface tension, preventing alveolar collapse - deficiency causes neonatal RDS
• Elastic recoil tends to collapse lung; chest wall tends to expand - functional residual capacity (FRC) is the balance point

Gas exchange:

• Fick's law: Diffusion ∝ (surface area × pressure gradient × solubility) / (membrane thickness × √molecular weight)
• CO2 is 20× more soluble than O2 - diffusion impairment causes hypoxia before hypercapnia

Oxygen transport: 98.5% bound to haemoglobin (1.34mL O2/g Hb), 1.5% dissolved

Type 1 Respiratory Failure

• Dyspnoea, tachypnoea, cyanosis
• Hypoxaemia responsive to supplemental O2 (unless shunt)
• Underlying cause symptoms: fever (pneumonia), pleuritic pain (PE), bilateral crackles (pulmonary oedema)

Type 2 Respiratory Failure

• CO2 retention: Headache, drowsiness, tremor, bounding pulse, papilloedema
• May have reduced respiratory drive - caution with high-flow O2 (target SpO2 88-92% in COPD)

Obstructive vs Restrictive Patterns

• Obstructive: Wheeze, prolonged expiration, hyperinflation, air trapping
• Restrictive: Reduced chest expansion, fine inspiratory crackles (fibrosis), reduced lung volumes

Red Flags

• Respiratory rate >25/min with rising PaCO2 - impending respiratory arrest
• Silent chest in asthma - life-threatening
• PaO2 <8kPa on high-flow O2 - consider ARDS, massive PE, or shunt
• Stridor - upper airway obstruction, urgent ENT assessment

Bedside

• Pulse oximetry: Continuous SpO2 monitoring
• ABG: Gold standard for assessing oxygenation, ventilation, acid-base
• Peak expiratory flow: Monitoring in asthma

Bloods

• FBC: Polycythaemia (chronic hypoxia), anaemia (reduced O2 carrying capacity)
• CRP/WCC: Infection markers
• D-dimer: PE exclusion (if low pre-test probability)

Imaging

• CXR: Consolidation, effusion, pneumothorax, hyperinflation, pulmonary oedema
• CT thorax (HRCT): Interstitial lung disease, bronchiectasis
• CTPA: Pulmonary embolism

Special Tests

• Spirometry: FEV1, FVC, FEV1/FVC ratio - obstructive vs restrictive pattern
• Full lung function tests: TLC, RV, TLCO (gas transfer)
• TLCO: Reduced in emphysema, fibrosis, PE, anaemia; increased in alveolar haemorrhage, asthma
• Cardiopulmonary exercise testing (CPET): Differentiates cardiac vs respiratory limitation

Non-pharmacological

• Oxygen therapy: Target SpO2 94-98% (88-92% in hypercapnic risk patients - BTS guidelines)
• NIV (BiPAP): First-line for acute hypercapnic respiratory failure in COPD (pH 7.25-7.35)
• Pulmonary rehabilitation: COPD, MRC dyspnoea ≥3
• Smoking cessation: Most important intervention in COPD

Pharmacological

• Bronchodilators: Salbutamol 5mg nebulised, ipratropium 500mcg nebulised (acute)
• Corticosteroids: Prednisolone 40mg OD for 5 days (acute exacerbation of COPD/asthma)
• Antibiotics: Amoxicillin 500mg TDS or doxycycline 200mg stat then 100mg OD for infective exacerbations
• LTOT: ≥15 hours/day if PaO2 ≤7.3 kPa on two occasions 3 weeks apart, when stable

Surgical

• Chest drain: Pneumothorax, large pleural effusion
• Lung volume reduction surgery: Selected emphysema patients
• Lung transplant: End-stage lung disease (COPD, IPF, CF)

Referral Criteria

• Unexplained dyspnoea - respiratory specialist
• FEV1 <50% predicted - consider specialist COPD services
• Suspected ILD - urgent respiratory referral for HRCT

• COPD: FEV1 decline 30-60 mL/year (vs 25-30 mL/year in healthy non-smokers); GOLD stage IV - 5-year survival ~20%
• ARDS: Mortality 30-40% (Berlin definition: mild 27%, moderate 32%, severe 45%)
• IPF: Median survival 3-5 years from diagnosis
• Smoking cessation reduces FEV1 decline to near-normal rates - the single most effective intervention
• NIV in acute hypercapnic COPD exacerbation reduces mortality from ~20% to ~10%

Lung Volumes and Capacities

Causes of Right-Shifted O2-Hb Dissociation Curve

Key Facts

The kidneys regulate fluid balance, electrolyte homeostasis, acid-base balance, blood pressure, and erythropoiesis. They also activate vitamin D (1,25-dihydroxycholecalciferol) and excrete metabolic waste products.

Epidemiology

CKD affects approximately 13% of the UK population (predominantly stages 1-3). Stage 3-5 CKD affects approximately 6%. AKI affects approximately 15% of hospitalised patients. Approximately 65,000 patients receive renal replacement therapy in the UK.

Aetiology

Kidney function depends on:

• Glomerular filtration: Determined by hydrostatic and oncotic pressures across the glomerular capillary
• Tubular function: Reabsorption and secretion along the nephron
• Hormonal regulation: RAAS, ADH, natriuretic peptides, prostaglandins
• Renal blood flow: 20-25% of cardiac output (~1.2 L/min), autoregulated between MAP 80-180 mmHg

Pathophysiology

Glomerular filtration barrier consists of:

1. Fenestrated endothelium (size barrier)
2. Glomerular basement membrane (charge barrier - negative charge repels albumin)
3. Podocyte foot processes with slit diaphragm (final barrier)

Juxtaglomerular apparatus: Macula densa + juxtaglomerular cells (granular cells) → renin release in response to decreased NaCl, decreased perfusion pressure, or sympathetic activation

Countercurrent mechanism: Loop of Henle creates medullary hypertonicity (up to 1200 mOsm/kg) enabling urine concentration

Acute Kidney Injury

• Oliguria (<0.5 mL/kg/hr), rising creatinine
• Fluid overload, hyperkalaemia, metabolic acidosis, uraemia
• Classified by KDIGO criteria: Stage 1-3 based on creatinine rise or urine output reduction

Chronic Kidney Disease

• Often asymptomatic until advanced (GFR <30)
• Fatigue, nausea, pruritus, restless legs
• Anaemia (erythropoietin deficiency), bone disease (CKD-MBD), acidosis

Nephrotic Syndrome

• Proteinuria >3.5g/24h, hypoalbuminaemia, oedema, hyperlipidaemia
• Podocyte damage - minimal change disease (children), membranous nephropathy (adults)

Nephritic Syndrome

• Haematuria, hypertension, oliguria, mild proteinuria
• Glomerular inflammation - IgA nephropathy, post-streptococcal GN

Red Flags

• Anuria - consider obstructive uropathy (urgent USS)
• Rapidly rising creatinine - consider rapidly progressive glomerulonephritis (urgent renal biopsy)
• Pulmonary-renal syndrome - consider Goodpasture's or ANCA vasculitis

Bedside

• Urine dipstick: Blood (haematuria), protein (proteinuria), leucocytes/nitrites (infection)
• Bladder scan: Post-void residual - exclude urinary retention
• Fluid balance: Strict input/output monitoring

Bloods

• U&Es: Creatinine, urea, eGFR, sodium, potassium
• Urine albumin:creatinine ratio (uACR): Screening for albuminuria (>3 mg/mmol is abnormal)
• Calcium, phosphate, PTH: CKD-mineral bone disease assessment
• FBC: Anaemia of CKD (normocytic, normochromic)
• Autoimmune screen: ANA, ANCA, anti-GBM, complement C3/C4 - if glomerulonephritis suspected

Imaging

• Renal USS: Size, obstruction, cysts, masses (normal kidney 10-12cm)
• CT KUB: Renal stones
• Doppler USS: Renal artery stenosis

Special Tests

• Renal biopsy: Glomerulonephritis, unexplained CKD, nephrotic syndrome
• MAG3 renogram: Differential renal function, obstruction assessment
• Cystatin C: Alternative GFR marker (less affected by muscle mass)

Non-pharmacological

• Dietary: Sodium restriction (<6g/day), potassium restriction if hyperkalaemia, adequate protein but not excessive in CKD
• Fluid management: Guided by volume status
• Nephrotoxin avoidance: NSAIDs, aminoglycosides, contrast media - hold ACEi/ARB in AKI

Pharmacological

• AKI: Treat underlying cause, optimise fluid status, correct electrolytes
• CKD (NICE NG203):
  • ACEi/ARB: Ramipril 1.25-10mg OD if diabetes or uACR >30 mg/mmol or hypertension
  • SGLT2 inhibitors: Dapagliflozin 10mg OD - DAPA-CKD trial showed 39% reduction in kidney disease progression
  • Blood pressure target: <140/90 (or <130/80 if uACR >70 mg/mmol)
  • Anaemia: ESA (epoetin alfa) if Hb <100 g/L and iron replete
  • CKD-MBD: Phosphate binders (calcium acetate, sevelamer), alfacalcidol
  • Sodium bicarbonate: If bicarbonate <20 mmol/L

Surgical

• Renal replacement therapy: Haemodialysis, peritoneal dialysis, or transplantation when eGFR <5-10 or symptomatic
• AV fistula formation: 6 months before anticipated dialysis start

Referral Criteria

• eGFR <30 (G4-G5) - nephrology referral
• Progressive CKD (eGFR decline >5/year)
• uACR >70 mg/mmol (A3)
• Suspected glomerulonephritis or vasculitis

• AKI: In-hospital mortality 20-50% depending on severity and ICU admission; 30% develop CKD within 3 years
• CKD stage 5: Dialysis patients - 5-year survival approximately 40% (worse than many cancers)
• Renal transplant: 5-year graft survival ~90% (living donor), ~85% (deceased donor)
• DAPA-CKD trial: Dapagliflozin reduced kidney disease progression by 39% regardless of diabetes status
• CKD is an independent cardiovascular risk factor - CV death is the leading cause of death in CKD patients

CKD Staging (NICE NG203)

Nephron Segment Functions

Key Facts

The GI tract processes approximately 9L of fluid daily (2L ingested + 7L secretions); only ~100mL is excreted in faeces. Each region has specialised functions in digestion and absorption.

Epidemiology

GI diseases are extremely common in UK clinical practice. Coeliac disease affects approximately 1% of the population (many undiagnosed). IBS affects 10-20% of the population. Peptic ulcer disease affects ~5-10% lifetime risk.

Aetiology

GI function depends on:

• Motility: Coordinated smooth muscle contraction (enteric nervous system - "second brain")
• Secretion: Acid, enzymes, bile, mucus, bicarbonate
• Digestion: Mechanical and chemical breakdown of macronutrients
• Absorption: Specific transport mechanisms for nutrients, electrolytes, water
• Neuroendocrine regulation: Vagus nerve, hormones (gastrin, CCK, secretin, GIP, motilin)

Pathophysiology

Gastric acid secretion has three phases:

1. Cephalic phase (30%): Vagal stimulation - sight, smell, taste of food

1. Intestinal phase (10%): Initially stimulatory, then inhibitory (secretin, GIP)

Defence mechanisms against acid: Mucus-bicarbonate barrier, prostaglandins (PGE2 promotes mucus/HCO3⁻ secretion, mucosal blood flow), epithelial cell turnover (3-5 days)

Hepatic function: Metabolism (drugs, bilirubin, ammonia), synthesis (albumin, clotting factors, bile), storage (glycogen, vitamins, iron), detoxification

Malabsorption Syndromes

• Diarrhoea, steatorrhoea, weight loss, nutritional deficiencies
• Iron deficiency (duodenal disease - coeliac)
• B12 deficiency (ileal disease - Crohn's, pernicious anaemia)
• Fat-soluble vitamin deficiency (A, D, E, K) - pancreatic insufficiency, biliary obstruction

Dyspepsia and Acid-Related Disease

• Epigastric pain, heartburn, early satiety, nausea
• Duodenal ulcer pain: Relieved by eating, worse at night
• Gastric ulcer pain: Worse with eating

Hepatobiliary Disease

• Jaundice (bilirubin >35 µmol/L), pruritus, pale stools, dark urine (obstructive)
• Coagulopathy (reduced synthesis of factors II, VII, IX, X)
• Ascites, encephalopathy (decompensated liver disease)

Red Flags

• Dysphagia - urgent 2-week-wait OGD referral
• Unexplained weight loss with GI symptoms - malignancy screen
• Haematemesis or melaena - upper GI bleeding
• Iron deficiency anaemia in men or post-menopausal women - investigate GI tract

Bedside

• Stool analysis: MC&S, faecal calprotectin (>100 µg/g suggests IBD), faecal elastase (<200 = pancreatic insufficiency)
• Urea breath test: H. pylori (stop PPI 2 weeks before)

Bloods

• FBC: Microcytic (iron), macrocytic (B12/folate) anaemia
• Iron studies, B12, folate: Malabsorption screen
• LFTs: Bilirubin, ALT, ALP, GGT, albumin
• tTG-IgA + total IgA: Coeliac disease screening
• Clotting: PT prolonged in liver disease/vitamin K deficiency

Imaging

• OGD: Upper GI pathology, duodenal biopsy (coeliac)
• Colonoscopy: Lower GI pathology, IBD assessment
• USS abdomen: Gallstones, liver assessment
• MRCP: Biliary tree, pancreatic duct assessment

Special Tests

• SeHCAT scan: Bile salt malabsorption
• Hydrogen breath test: SIBO, lactose intolerance
• Capsule endoscopy: Small bowel pathology

Non-pharmacological

• Gluten-free diet: Coeliac disease - lifelong, with dietitian support
• Low FODMAP diet: IBS symptom management
• Pancreatic enzyme replacement: Creon 25,000-50,000 units with meals for exocrine pancreatic insufficiency

Pharmacological

• PPI: Omeprazole 20mg OD for acid-related disease (NICE NG12)
• H. pylori triple therapy: PPI + amoxicillin 1g BD + clarithromycin 500mg BD for 7 days
• Loperamide: 2-4mg PRN for symptomatic diarrhoea (max 16mg/day)
• Bile acid sequestrants: Colestyramine 4g OD-QDS for bile salt malabsorption
• B12 replacement: Hydroxocobalamin 1mg IM on alternate days × 2 weeks, then every 3 months
• Iron replacement: Ferrous sulphate 200mg BD-TDS (65mg elemental iron per tablet)

Referral Criteria

• Red flag symptoms - urgent 2-week-wait referral
• Positive coeliac serology - gastroenterology for biopsy
• Suspected IBD (raised calprotectin) - gastroenterology
• Deranged LFTs >3 months - hepatology

• Coeliac disease: Excellent prognosis with strict GFD; small increased risk of enteropathy-associated T-cell lymphoma (~6-9× relative risk)
• Peptic ulcer disease: >95% cure rate with H. pylori eradication and PPI
• Chronic pancreatitis: 10-year survival ~70%; pancreatic cancer risk approximately 4%
• Pernicious anaemia: Lifelong B12 replacement required; ~5% risk of gastric carcinoma
• Untreated coeliac disease associated with osteoporosis, infertility, and neurological complications

GI Hormones

Site-Specific Absorption

Key Facts

The nervous system processes sensory information, coordinates motor output, and regulates homeostasis through complex neural circuits. Understanding neurophysiology is essential for localising neurological lesions and understanding drug mechanisms.

Epidemiology

Neurological conditions account for approximately 10% of GP consultations and 20% of acute medical admissions. Stroke affects approximately 100,000 people per year in the UK. Epilepsy prevalence is approximately 0.5-1%. Multiple sclerosis affects ~130,000 people in the UK.

Aetiology

Neurological dysfunction results from:

• Structural lesions: Stroke, tumour, trauma, demyelination
• Functional disorders: Epilepsy, migraine
• Degenerative diseases: Parkinson's, motor neurone disease, dementia
• Neuromuscular: Myasthenia gravis, Guillain-Barré syndrome
• Metabolic/toxic: B12 deficiency, alcohol, drugs

Pathophysiology

Synaptic transmission:

• Excitatory: Glutamate (NMDA, AMPA receptors) → depolarisation
• Inhibitory: GABA (GABA-A = Cl⁻ channel; GABA-B = G-protein coupled), glycine → hyperpolarisation

Motor pathways:

• Extrapyramidal system: Basal ganglia, cerebellum - modulate movement (dopamine, GABA pathways)

Sensory pathways:

Upper Motor Neurone Lesion

• Spastic paralysis, clasp-knife rigidity
• Hyperreflexia, clonus
• Upgoing plantar response (Babinski positive)
• No muscle wasting initially

Lower Motor Neurone Lesion

• Flaccid paralysis, hypotonia
• Hyporeflexia or areflexia
• Fasciculations, muscle wasting
• Downgoing or absent plantar response

Cerebellar Lesion

• DANISH: Dysdiadochokinesis, Ataxia, Nystagmus, Intention tremor, Slurred/scanning speech, Hypotonia

Spinal Cord Syndromes

• Brown-Séquard (hemisection): Ipsilateral UMN weakness + dorsal column loss; contralateral spinothalamic loss
• Anterior cord: Bilateral motor + spinothalamic loss; preserved dorsal columns
• Central cord: Upper limb weakness > lower limb (cape-like sensory loss)

Red Flags

• Acute onset bilateral weakness - consider cord compression (neurosurgical emergency)
• Bilateral LMN weakness ascending rapidly - Guillain-Barré syndrome (FVC monitoring)
• Thunderclap headache - subarachnoid haemorrhage until proven otherwise

Bedside

• Neurological examination: Power (MRC grading 0-5), tone, reflexes, sensation, coordination
• GCS: Level of consciousness assessment
• Fundoscopy: Papilloedema (raised ICP), optic atrophy

Bloods

• FBC, U&Es, glucose, calcium: Metabolic causes of neurological symptoms
• B12, folate, TFTs: Peripheral neuropathy workup
• CK: Raised in myopathy, NMS, rhabdomyolysis
• Autoantibodies: Anti-AChR (myasthenia), anti-ganglioside (GBS)

Imaging

• CT head: First-line in acute stroke, head injury, raised ICP
• MRI brain/spine: Demyelination, tumours, cord compression, structural lesions
• CT/MR angiography: Cerebrovascular disease assessment

Special Tests

• Nerve conduction studies (NCS): Demyelinating vs axonal neuropathy
• Electromyography (EMG): Myopathy vs neuropathy, denervation
• EEG: Epilepsy classification, encephalopathy
• Lumbar puncture: CSF analysis - infection, SAH, MS (oligoclonal bands), GBS (albumino-cytological dissociation)
• Evoked potentials: Visual (VEP), somatosensory (SSEP) - demyelination

Non-pharmacological

• Neurorehabilitation: Physiotherapy, occupational therapy, speech and language therapy
• Falls prevention strategies
• Driving advice (DVLA regulations for neurological conditions)

Pharmacological

• Stroke: Alteplase 0.9mg/kg IV (max 90mg) within 4.5 hours for ischaemic stroke; aspirin 300mg for 2 weeks then clopidogrel 75mg OD
• Epilepsy: Lamotrigine (focal/generalised), sodium valproate (generalised - avoid in women of childbearing age per MHRA), levetiracetam
• Parkinson's: Levodopa/carbidopa (co-careldopa), dopamine agonists (ropinirole, pramipexole)
• MS: Disease-modifying therapies (DMTs) - dimethyl fumarate, natalizumab, ocrelizumab
• Myasthenia gravis: Pyridostigmine 60mg QDS; immunosuppression (prednisolone, azathioprine)

Referral Criteria

• Acute focal neurology - emergency stroke pathway
• First seizure - neurology within 2 weeks
• Suspected cord compression - emergency neurosurgery
• Progressive neurological deficit - urgent neurology

• Ischaemic stroke: 30-day mortality ~10-15%; 50% have residual disability at 1 year
• GBS: 80% make full recovery; 5% mortality; 10% have significant residual disability
• MS: Median time to wheelchair use ~30 years from onset; DMTs significantly improve outcomes
• MND: Median survival 3-5 years from symptom onset; riluzole extends survival by ~3 months
• Myasthenia gravis: Good prognosis with treatment; myasthenic crisis mortality <5% with modern ICU care

Key Neurotransmitters

MRC Power Grading

Key Facts

The endocrine system uses hormones as chemical messengers to regulate metabolism, growth, reproduction, and homeostasis. Hormones act via endocrine (distant), paracrine (local), or autocrine (self) signalling.

Epidemiology

Endocrine disorders are common: diabetes mellitus affects approximately 4.9 million people in the UK (90% type 2). Hypothyroidism affects ~2% of women, 0.2% of men. Primary hyperparathyroidism prevalence is ~1 in 1,000.

Aetiology

Hormones are classified by structure:

• Peptide/protein: Insulin, GH, PTH, ACTH - act via cell surface receptors
• Steroid: Cortisol, aldosterone, sex hormones - act via intracellular nuclear receptors (gene transcription)
• Amine: Thyroid hormones (T3/T4) - nuclear receptors; catecholamines - cell surface receptors

Pathophysiology

Negative feedback is the dominant regulatory mechanism:

Key axes:

Hypothyroidism

• Weight gain, cold intolerance, constipation, dry skin, bradycardia, fatigue
• Myxoedema (non-pitting oedema), delayed relaxation of reflexes

Hyperthyroidism

• Weight loss, heat intolerance, tremor, tachycardia/AF, diarrhoea, anxiety
• Graves' disease: Thyroid eye disease, pretibial myxoedema, diffuse goitre

Cushing's Syndrome

• Central obesity, moon face, buffalo hump, striae, thin skin, proximal myopathy
• Hypertension, hyperglycaemia, osteoporosis

Addison's Disease

• Fatigue, weight loss, postural hypotension, hyperpigmentation, hyponatraemia, hyperkalaemia

Diabetes Mellitus

• Polyuria, polydipsia, weight loss (type 1); often asymptomatic (type 2)
• Complications: Retinopathy, nephropathy, neuropathy, cardiovascular disease

Red Flags

• Adrenal crisis: Hypotension, hyponatraemia, hypoglycaemia - IV hydrocortisone 100mg stat
• Thyroid storm: Pyrexia, tachycardia, confusion - propranolol, carbimazole, hydrocortisone
• DKA: Glucose >11, ketones >3, pH <7.3 - insulin infusion, IV fluids

Bedside

• Blood glucose: Fasting, random, or OGTT
• Blood pressure: Hyper/hypotension in endocrine disease
• BMI: Obesity assessment, Cushing's

Bloods

• TFTs: TSH (most sensitive), free T4, free T3
• HbA1c: Diabetes diagnosis and monitoring
• 9am cortisol: <100 nmol/L abnormal, >450 nmol/L normal; 100-450 = Synacthen test needed
• Short Synacthen test: 250mcg IM/IV, measure cortisol at 0 and 30 min; >450 nmol/L at 30 min = normal
• Calcium, PTH, phosphate, vitamin D: Parathyroid assessment
• Prolactin: Pituitary tumour screening
• IGF-1: GH excess/deficiency screening

Imaging

• Pituitary MRI: Adenoma detection
• Thyroid USS: Nodule assessment, FNA guidance
• CT adrenals: Adrenal masses, Cushing's localisation
• DEXA scan: Osteoporosis in endocrine disease

Special Tests

• Overnight dexamethasone suppression test: 1mg at 11pm, 9am cortisol <50 nmol/L = normal
• Insulin tolerance test: Gold standard for GH and cortisol reserve
• Water deprivation test: Diabetes insipidus diagnosis
• OGTT: Diagnosis of gestational diabetes, acromegaly (GH not suppressed <1 µg/L)

Non-pharmacological

• Lifestyle modification for type 2 diabetes: Diet, exercise, weight loss
• Sick day rules for patients on steroids or insulin
• MedicAlert bracelet for adrenal insufficiency

Pharmacological

• Hypothyroidism: Levothyroxine 50-100mcg OD (start 25mcg in elderly/cardiac disease); titrate to TSH
• Hyperthyroidism: Carbimazole 20-40mg OD (block-replace or titration regimen); propranolol 40mg TDS for symptom control
• Type 2 diabetes (NICE NG28): Metformin 500mg OD-BD titrated to 1g BD → add SGLT2 inhibitor (empagliflozin 10mg) or GLP-1 RA (semaglutide) especially if CVD or HF
• Addison's disease: Hydrocortisone 15-25mg daily (split doses, 10mg on waking) + fludrocortisone 50-200mcg OD
• Adrenal crisis: Hydrocortisone 100mg IV stat, IV 0.9% saline

Surgical

• Thyroidectomy: Graves' disease, thyroid cancer, large goitre
• Transsphenoidal pituitary surgery: Cushing's disease, acromegaly, prolactinoma (if dopamine agonist-resistant)
• Adrenalectomy: Adrenal tumours, phaeochromocytoma

Referral Criteria

• Newly diagnosed type 1 diabetes - immediate endocrinology
• Suspected Cushing's or phaeochromocytoma - endocrinology
• Thyroid nodule - 2-week-wait if malignancy suspected

• Type 1 diabetes: Life expectancy reduced by ~8-13 years; intensive control (DCCT/EDIC trial) reduces microvascular complications by 50-76%
• Type 2 diabetes: UKPDS showed intensive glucose control reduces microvascular complications by 25%
• Hypothyroidism: Excellent prognosis with levothyroxine replacement
• Graves' disease: ~50% remission after 12-18 months of carbimazole; relapse rate ~50%
• Addison's disease: Normal life expectancy with adequate replacement; risk of adrenal crisis ~8% per year

Hypothalamic-Pituitary Axis Summary

Diabetes Landmark Trials

Key Facts

The musculoskeletal system provides structural support, facilitates movement, and protects vital organs. Skeletal muscle comprises ~40% of body weight and is under voluntary control via somatic motor neurones.

Epidemiology

Osteoporosis affects approximately 3 million people in the UK, causing >500,000 fragility fractures annually. Osteoarthritis affects ~8.75 million people. Musculoskeletal conditions are the leading cause of disability and the most common reason for GP consultation.

Aetiology

Bone health depends on:

• Peak bone mass (achieved by age 25-30)
• Rate of bone loss (accelerated post-menopause due to oestrogen withdrawal)
• Risk factors: Age, female sex, family history, low BMI, smoking, alcohol, corticosteroid use, immobility

Muscle disorders:

• Inflammatory myopathies (polymyositis, dermatomyositis)
• Inherited myopathies (Duchenne, Becker muscular dystrophy)
• Metabolic myopathies (McArdle disease, mitochondrial)

Pathophysiology

Muscle contraction (sliding filament theory):

1. T-tubule activation → Ca²⁺ release from SR

1. ATP-dependent cross-bridge cycling → sarcomere shortening
2. Ca²⁺ reuptake by SERCA pump → relaxation

Bone remodelling:

• Osteoblasts (bone formation): Produce osteoid (type I collagen + hydroxyapatite); stimulated by PTH (intermittent), oestrogen, mechanical loading
• Osteoclasts (bone resorption): Multinucleated cells from monocyte lineage; activated by RANKL, inhibited by OPG (osteoprotegerin); secrete H⁺ and cathepsin K

Osteoporosis

• Often asymptomatic until fracture
• Vertebral crush fractures: Height loss, kyphosis, back pain
• Fragility fractures: Hip, wrist (Colles'), proximal humerus, vertebral

Osteomalacia

• Bone pain (diffuse), proximal myopathy, waddling gait
• Looser zones (pseudofractures) on X-ray

Inflammatory Myopathy

• Proximal muscle weakness (difficulty climbing stairs, rising from chair)
• Dermatomyositis: Heliotrope rash, Gottron's papules
• May be paraneoplastic (especially dermatomyositis in adults)

Red Flags

• Back pain with neurological deficit - caution: cord compression or cauda equina
• Proximal myopathy with weight loss - consider malignancy-associated myopathy
• Bone pain with hypercalcaemia - myeloma, bony metastases
• CK >10,000 - rhabdomyolysis risk (AKI, hyperkalaemia)

Bedside

• Clinical examination: Gait, proximal power, spine inspection
• Height measurement: Serial - loss >4cm suggests vertebral fractures

Bloods

• Bone profile: Calcium, phosphate, ALP
• Vitamin D (25-OH): <25 nmol/L = deficient, 25-50 = insufficient
• PTH: Elevated in hyperparathyroidism, vitamin D deficiency
• CK: Elevated in myopathy, rhabdomyolysis (can exceed 100,000 in severe cases)
• ESR/CRP: Inflammatory markers
• Myeloma screen: Serum protein electrophoresis, free light chains

Imaging

• DEXA scan: Gold standard for bone density - T-score at hip and spine
• X-ray: Fractures, Paget's disease, lytic lesions
• MRI: Muscle inflammation (myositis), spinal pathology

Special Tests

• FRAX score: Online tool - 10-year fracture probability
• EMG: Myopathic vs neuropathic pattern
• Muscle biopsy: Inflammatory myopathy, dystrophy
• Bone biopsy: Metabolic bone disease confirmation (rarely needed)

Non-pharmacological

• Weight-bearing exercise for bone health
• Falls prevention: Home assessment, balance training, vision correction
• Adequate dietary calcium (>700mg/day) and vitamin D
• Smoking cessation, alcohol moderation

Pharmacological

• Osteoporosis (NICE CG146):
  • First-line: Alendronic acid 70mg once weekly (take on empty stomach, remain upright 30 min)
  • If intolerant: Risedronate 35mg weekly, IV zoledronic acid 5mg annually
  • Denosumab 60mg SC every 6 months (RANKL inhibitor) - second-line
  • Teriparatide 20mcg SC daily for 24 months - severe osteoporosis with fractures
  • Calcium 1g + vitamin D 800 IU daily as adjunct
• Vitamin D deficiency: Loading dose colecalciferol 50,000 IU weekly × 6 weeks, then 800-2000 IU daily maintenance
• Paget's disease: Zoledronic acid 5mg IV single dose (if symptomatic or ALP elevated)

Referral Criteria

• Fragility fracture - fracture liaison service (FLS)
• Suspected inflammatory myopathy - rheumatology
• Suspected myeloma - haematology urgent referral

• Hip fracture: 30-day mortality approximately 6.7%; 1-year mortality ~30%; only ~50% regain pre-fracture mobility
• Osteoporosis treatment: Bisphosphonates reduce hip fracture risk by ~40% and vertebral fracture by ~50%
• Polymyositis: 5-year survival ~80%; worse if associated malignancy or interstitial lung disease (anti-Jo-1)
• Duchenne muscular dystrophy: Wheelchair-dependent by ~12 years; death typically by 20s-30s (respiratory/cardiac failure)
• Paget's disease: <1% risk of osteosarcoma; most patients have normal life expectancy

Bone Metabolism Summary

Types of Collagen

Key Facts

Microbiology is fundamental to understanding infectious disease, antimicrobial selection, and infection control. Correct identification of causative organisms guides targeted therapy and improves outcomes.

Epidemiology

Healthcare-associated infections (HCAIs) affect approximately 6.4% of hospital inpatients in the UK. Sepsis affects ~48,000 people per year, causing ~11,000 deaths. C. difficile causes ~13,000 cases per year in England. Antimicrobial resistance is a growing global threat.

Aetiology

Bacterial classification:

• Gram-positive cocci: S. aureus (clusters), S. pneumoniae (diplococci, lancet-shaped), S. pyogenes (chains)
• Gram-positive bacilli: Clostridium (anaerobic, spore-forming), Listeria, Bacillus
• Gram-negative cocci: Neisseria meningitidis, N. gonorrhoeae
• Gram-negative bacilli: E. coli, Klebsiella, Pseudomonas, Salmonella, Campylobacter
• Atypicals: Mycoplasma (no cell wall), Legionella, Chlamydia
• Acid-fast bacilli: Mycobacterium tuberculosis (Ziehl-Neelsen stain)

Pathophysiology

Virulence factors:

• Endotoxin (LPS): Gram-negative cell wall component - triggers TNF-α, IL-1, IL-6 release → sepsis cascade
• Exotoxins: Secreted proteins - e.g., Clostridium tetani (tetanospasmin), C. botulinum (botulinum toxin), S. aureus (TSST-1, PVL)
• Biofilm formation: Prosthetic device infections - protects bacteria from antibiotics and host immunity
• Immune evasion: Capsule (S. pneumoniae), protein A (S. aureus), antigenic variation (N. gonorrhoeae)

Antimicrobial mechanisms:

• Cell wall synthesis inhibitors: Beta-lactams, glycopeptides
• Protein synthesis inhibitors: Aminoglycosides (30S), macrolides, tetracyclines (30S), chloramphenicol (50S)
• Nucleic acid inhibitors: Fluoroquinolones (DNA gyrase), metronidazole, rifampicin (RNA polymerase)
• Folate synthesis inhibitors: Trimethoprim, sulphonamides

Community-Acquired Infections

• Pneumonia: Cough, fever, pleuritic pain, consolidation on CXR
• UTI: Dysuria, frequency, suprapubic pain; pyelonephritis adds flank pain, fever, rigors
• Skin/soft tissue: Cellulitis (S. aureus, S. pyogenes), abscess formation
• Meningitis: Headache, neck stiffness, photophobia, non-blanching rash (meningococcal)

Hospital-Acquired Infections

• MRSA: Wound infection, line-related bacteraemia
• C. difficile: Watery diarrhoea, abdominal pain after antibiotic exposure
• Pseudomonas: Ventilator-associated pneumonia, burns, immunocompromised
• Candidaemia: Central line infection, immunosuppressed patients

Red Flags

• Sepsis: qSOFA ≥2 (RR ≥22, altered mentation, systolic BP ≤100) - NICE Sepsis pathway
• Non-blanching petechial rash with fever - meningococcal septicaemia (give IM benzylpenicillin)
• Necrotising fasciitis: Rapidly progressive cellulitis with systemic toxicity, disproportionate pain

Bedside

• Observations: Temperature, HR, RR, BP, SpO2, GCS - NEWS2 score
• Urine dipstick: Leucocytes, nitrites, blood

Bloods

• Blood cultures: Two sets from different sites BEFORE antibiotics
• FBC: WCC (neutrophilia = bacterial, lymphocytosis = viral)
• CRP, procalcitonin: Inflammatory markers
• Lactate: >2 mmol/L raises concern for sepsis; >4 mmol/L = severe

Imaging

• CXR: Pneumonia, empyema, TB
• USS/CT: Abscess collections, source identification

Special Tests

• Gram stain and culture: Identify organism and sensitivities
• Sensitivity testing: MIC (minimum inhibitory concentration)
• PCR: Rapid detection - meningococcal PCR, TB PCR (GeneXpert), viral PCR
• Serology: HIV, hepatitis, EBV, CMV
• Lumbar puncture: CSF analysis - cell count, protein, glucose, Gram stain, culture, PCR

Non-pharmacological

• Infection control: Hand hygiene, isolation precautions (contact, droplet, airborne)
• Antimicrobial stewardship: Review antibiotics at 48-72 hours, narrow spectrum when cultures available
• Source control: Drain abscesses, remove infected lines/prostheses

Pharmacological

Common empirical regimens (local guidelines vary):

• CAP: Amoxicillin 500mg TDS ± clarithromycin 500mg BD (moderate severity)
• HAP: Co-amoxiclav 1.2g TDS IV or piperacillin-tazobactam 4.5g TDS IV
• UTI: Nitrofurantoin 100mg MR BD (lower) or co-amoxiclav (upper)
• Meningitis: Ceftriaxone 2g BD IV + dexamethasone 0.15mg/kg QDS IV (before or with first antibiotic dose)
• Sepsis: Piperacillin-tazobactam 4.5g TDS IV (+ gentamicin 5mg/kg if severe)
• C. difficile: Oral vancomycin 125mg QDS for 10 days; fidaxomicin 200mg BD for recurrence
• MRSA: Vancomycin IV (target trough 15-20 mg/L) or linezolid 600mg BD

Referral Criteria

• MDR organisms - microbiology/infectious diseases
• Suspected TB - respiratory/infectious diseases
• Sepsis with organ dysfunction - critical care
• Prosthetic joint infection - orthopaedics + microbiology

• Sepsis: Overall mortality 15-20%; septic shock mortality 40-50%
• Community-acquired pneumonia: CURB-65 score 0-1 = <3% mortality; score 4-5 = >25%
• Bacterial meningitis: Mortality 10-30% depending on organism; ~20% have significant sequelae
• C. difficile: Mortality 1-5%; recurrence rate 20-30%; fulminant colitis mortality >50%
• MRSA bacteraemia: 30-day mortality approximately 20-30%

Antimicrobial Spectrum Summary

CSF Findings in Meningitis

Key Facts

Neoplasia literally means "new growth." Tumours are classified by their cell of origin: carcinomas (epithelial), sarcomas (mesenchymal), lymphomas (lymphoid), leukaemias (haematopoietic). Understanding the molecular basis of cancer drives modern targeted therapy.

Epidemiology

Cancer affects 1 in 2 people in the UK during their lifetime. The most common cancers are breast (55,000/year), lung (48,000), prostate (52,000), and bowel (42,000). Cancer causes approximately 167,000 deaths per year in the UK. Overall cancer survival has doubled in the last 40 years.

Aetiology

Carcinogenesis is a multistep process requiring accumulation of genetic mutations:

• Chemical: Smoking (polycyclic aromatic hydrocarbons), aflatoxins (hepatocellular), asbestos (mesothelioma)
• Physical: UV radiation (melanoma), ionising radiation (leukaemia, thyroid)
• Biological: HPV (cervical), EBV (Burkitt's, nasopharyngeal), H. pylori (gastric MALT lymphoma), HBV/HCV (hepatocellular)
• Genetic: Li-Fraumeni (p53), FAP (APC), Lynch syndrome (mismatch repair), BRCA1/2 (breast/ovarian)

Pathophysiology

The adenoma-carcinoma sequence (colorectal cancer model):

Tumour grading: Based on differentiation (G1 well-differentiated to G3/G4 poorly differentiated) Tumour staging: TNM is the most widely used system; stage determines prognosis and treatment

Tumour microenvironment: Immune cells, fibroblasts, angiogenesis, extracellular matrix interactions - influences treatment response

General Cancer Presentations

• Unexplained weight loss >5% in 3 months
• Fatigue, night sweats, fever
• Lymphadenopathy (>2cm, hard, non-tender, fixed)
• Paraneoplastic syndromes: Hypercalcaemia (PTHrP), SIADH, Cushing's (ectopic ACTH)

Site-Specific Presentations

• Lung: Cough, haemoptysis, Pancoast syndrome, SVC obstruction
• Breast: Painless lump, skin tethering, peau d'orange, nipple retraction
• Colorectal: Change in bowel habit, rectal bleeding, iron deficiency anaemia
• Prostate: LUTS, bone pain (metastatic)

Red Flags (NICE NG12 - 2-Week Wait Referral)

• Unexplained lump
• Unexplained bleeding
• Unexplained weight loss
• Persistent change in bowel habit (>3 weeks)
• Post-menopausal bleeding
• Dysphagia
• Haematuria

Bedside

• Clinical examination: Lump assessment (site, size, shape, consistency, tethering, lymph nodes)
• Observations: Weight, performance status (ECOG/Karnofsky)

Bloods

• FBC: Anaemia (chronic disease, bone marrow infiltration)
• LFTs: Liver metastases, biliary obstruction
• Calcium: Hypercalcaemia of malignancy
• Tumour markers: PSA, CA-125, CEA, AFP, β-hCG, CA 19-9, LDH
• LDH: Raised in lymphoma, germ cell tumours, melanoma

Imaging

• CT TAP: Primary staging investigation for most solid tumours
• PET-CT: Staging lymphoma, lung cancer; response assessment
• MRI: Local staging (rectal, brain, sarcoma)
• Mammography: Breast cancer screening and diagnosis
• USS: Thyroid, testicular, breast lumps

Special Tests

• Histology/biopsy: Gold standard - core biopsy, excisional biopsy, FNA
• Immunohistochemistry: ER/PR, HER2 (breast), CD markers (lymphoma), Ki-67 (proliferation index)
• Molecular testing: EGFR, ALK, ROS1 (lung), BRAF (melanoma), KRAS (colorectal), microsatellite instability
• Genetic testing: BRCA1/2, Lynch syndrome mismatch repair genes

Non-pharmacological

• MDT discussion (surgeon, oncologist, radiologist, pathologist, CNS)
• Cancer staging and performance status assessment
• Palliative care referral if appropriate
• Psychological support and CNS involvement

Pharmacological

• Chemotherapy: Cytotoxic agents - platinum-based (cisplatin, carboplatin), taxanes (paclitaxel), anthracyclines (doxorubicin), antimetabolites (5-FU, methotrexate)
• Targeted therapy: Trastuzumab (anti-HER2 - breast), imatinib (BCR-ABL - CML), rituximab (anti-CD20 - lymphoma), pembrolizumab (anti-PD-1 - melanoma, lung)
• Hormonal therapy: Tamoxifen (ER+ breast), letrozole (aromatase inhibitor), enzalutamide (prostate)
• Immunotherapy: Checkpoint inhibitors (anti-PD-1, anti-CTLA-4), CAR-T cell therapy
• Radiotherapy: Curative or palliative - external beam or brachytherapy

Surgical

• Curative resection with adequate margins
• Sentinel lymph node biopsy (melanoma, breast)
• Debulking surgery (ovarian)
• Palliative surgery (bypass, stenting)

Referral Criteria

• Any suspected cancer - 2-week-wait pathway (NICE NG12)
• All cancers discussed at MDT
• Genetic risk assessment if strong family history

• Overall cancer survival: 10-year survival approximately 50% (varies widely by cancer type)
• Breast cancer: 5-year survival ~85% (UK); stage I ~98%, stage IV ~15%
• Lung cancer: 5-year survival ~15% (often late presentation)
• Colorectal cancer: 5-year survival ~60%; Dukes A ~93%, Dukes D ~7%
• Prostate cancer: 5-year survival ~86% overall; 10-year ~84%
• Pancreatic cancer: 5-year survival ~7% - poorest of common cancers
• Early detection through screening programmes (breast, cervical, bowel) significantly improves survival

Tumour Nomenclature

Paraneoplastic Syndromes

Key Facts

Epidemiology is the study of disease distribution and determinants in populations. Medical statistics provides the mathematical framework for drawing valid conclusions from clinical research. Both are essential for evidence-based medicine.

Epidemiology

Evidence-based medicine is a cornerstone of modern clinical practice and medical education. Understanding study design and statistical concepts is heavily examined in MRCP Part 1, PLAB, and UKMLA. The ability to critically appraise evidence underpins clinical guideline development, including NICE recommendations.

Aetiology

Study designs (hierarchy of evidence, ascending):

1. Expert opinion/case reports: Lowest level
2. Case-control studies: Compare cases with disease to controls without; retrospective; measure odds ratio
3. Cohort studies: Follow exposed vs unexposed groups; prospective or retrospective; measure relative risk
4. RCTs: Randomise to intervention vs control; minimise confounding; measure treatment effect
5. Systematic reviews/meta-analyses: Pool data from multiple studies; highest level of evidence

Pathophysiology

Bias types:

• Selection bias: Non-random selection of participants (e.g., Berkson's bias, healthy worker effect)
• Information/measurement bias: Systematic errors in data collection (e.g., recall bias in case-control studies)
• Confounding: A third variable associated with both exposure and outcome - addressed by randomisation, matching, or statistical adjustment
• Observer bias: Knowledge of exposure status influences outcome assessment - blinding addresses this
• Publication bias: Positive results more likely published - funnel plot detects this in meta-analyses

Reducing bias:

• Randomisation (allocation concealment)
• Blinding (single, double, triple)
• Intention-to-treat analysis
• Adequate sample size (power calculation)

Application to Clinical Decision-Making

• Screening programmes: Must meet Wilson-Jungner criteria - disease must be important, detectable early, with acceptable treatment
• Diagnostic testing: Pre-test probability × likelihood ratio = post-test probability
• Treatment decisions: Assess NNT, NNH, absolute vs relative risk reduction
• Prognosis: Survival analysis, Kaplan-Meier curves, hazard ratios

UK National Screening Programmes

• Breast cancer: Mammography, women aged 50-70, every 3 years
• Cervical cancer: Cervical screening (HPV primary), age 25-64
• Bowel cancer: FIT (faecal immunochemical test), age 60-74 (expanding to 50-74)
• AAA: USS for men aged 65
• Newborn: Bloodspot screening (PKU, CF, sickle cell, CHT, MCADD + 4 others)

Red Flags in Research Interpretation

• Relative risk reduction quoted without absolute risk reduction - may overstate benefit
• Surrogate endpoints used instead of patient-important outcomes
• Subgroup analyses not pre-specified - hypothesis-generating only
• Industry-funded trials without independent replication

Diagnostic Test Properties

• Sensitivity: Proportion of true positives correctly identified - TP/(TP+FN)
• Specificity: Proportion of true negatives correctly identified - TN/(TN+FP)
• PPV: Proportion of positive tests that are truly positive - TP/(TP+FP)
• NPV: Proportion of negative tests that are truly negative - TN/(TN+FN)
• Likelihood ratio positive: Sensitivity/(1−Specificity)
• Likelihood ratio negative: (1−Sensitivity)/Specificity

Statistical Tests

• Parametric (normally distributed data): t-test (2 groups), ANOVA (>2 groups), Pearson correlation
• Non-parametric (non-normal data): Mann-Whitney U (2 groups), Kruskal-Wallis (>2 groups), Spearman correlation
• Categorical data: Chi-squared test, Fisher's exact test
• Survival analysis: Kaplan-Meier curves, log-rank test, Cox regression (hazard ratio)

Key Statistical Concepts

• p-value: Probability of observing result if null hypothesis is true; <0.05 conventionally "significant"
• Confidence interval: Range within which true value lies with 95% probability; if CI for OR/RR includes 1, result is not significant
• Power: Probability of detecting a true effect (usually target 80%)

Non-pharmacological

• Critical appraisal skills should be applied to all clinical evidence
• NICE guidelines synthesise best available evidence for UK practice

Pharmacological

Key concepts in treatment evaluation:

• ARR (absolute risk reduction): Control event rate − treatment event rate
• RRR (relative risk reduction): ARR/control event rate
• NNT: 1/ARR - number needed to treat to prevent one event
• NNH: 1/absolute risk increase - number needed to harm one patient

Example: If a drug reduces MI risk from 8% to 6%:

• ARR = 2%, RRR = 25%, NNT = 50
• This means treating 50 patients for one to benefit

Referral Criteria

• Evidence-based practice should guide all clinical referrals
• Consider NICE guidelines, local protocols, and individual patient factors
• Use validated clinical prediction rules (Wells score, CHA2DS2-VASc, FRAX) for risk stratification

• Evidence-based medicine has transformed clinical practice, improving outcomes across all specialties
• Cochrane reviews provide the gold standard for systematic evidence synthesis
• Implementation of NICE guidelines has standardised UK healthcare quality
• The replication crisis highlights the importance of large, well-designed studies
• Approximately 85% of health research is estimated to be "avoidable waste" (poor design, non-publication, etc.)

2×2 Table for Diagnostic Tests

Levels of Evidence

Common Statistical Errors in Exams

Key Facts

Clinical trials are the cornerstone of evidence-based medicine, providing the most reliable evidence for treatment efficacy and safety. The UK has a strong clinical trials infrastructure with the NIHR coordinating much of the research activity.

Epidemiology

Approximately 600,000 people participate in clinical trials in the UK each year. The NIHR supports over 3,500 active studies. UK clinical trials legislation is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, overseen by the MHRA.

Aetiology

Trial phases:

• Phase I: First-in-human, safety, pharmacokinetics, dose-finding (20-100 healthy volunteers)
• Phase II: Efficacy and side effects in target population (100-300 patients)
• Phase III: Large-scale RCT comparing to standard care or placebo (300-3,000+ patients)
• Phase IV: Post-marketing surveillance, rare side effects, long-term outcomes

Pathophysiology

Key methodological concepts:

• Randomisation methods: Simple, block, stratified, minimisation
• Blinding levels: Open-label, single-blind, double-blind, triple-blind
• Control types: Placebo, active comparator, standard care
• Endpoints: Primary (main outcome), secondary, surrogate (biomarker proxy), composite
• Non-inferiority trials: Show new treatment is not unacceptably worse than standard (pre-specified margin)
• Adaptive designs: Allow modifications based on interim data (e.g., RECOVERY trial for COVID-19 treatments)

Applying Evidence to Clinical Practice

• Ask: Formulate a clinical question (PICO: Population, Intervention, Comparator, Outcome)
• Acquire: Search for best available evidence (PubMed, Cochrane, NICE)
• Appraise: Critically evaluate validity, results, and applicability
• Apply: Integrate evidence with clinical expertise and patient preferences
• Assess: Audit outcomes of clinical decisions

Ethical Considerations

• Informed consent - voluntary, informed, competent
• Research Ethics Committee (REC) approval required
• Declaration of Helsinki principles
• Data Safety Monitoring Board (DSMB) reviews interim data for safety

Red Flags in Trial Interpretation

• Unblinded trials with subjective outcomes - high risk of performance bias
• Large loss to follow-up (>20%) - threatens validity
• Surrogate endpoints without validated link to clinical outcomes
• Selective outcome reporting - check trial registry (ClinicalTrials.gov) for pre-specified outcomes

Critical Appraisal Framework (CASP)

• Validity: Was randomisation adequate? Was blinding maintained? Were groups similar at baseline?
• Results: What is the effect size (RR, OR, NNT)? How precise (confidence intervals)?
• Applicability: Are patients similar to mine? Are all important outcomes considered? Are benefits worth harms and costs?

Key Statistical Measures

• Absolute risk reduction (ARR): Difference in event rates between groups
• Relative risk reduction (RRR): ARR ÷ control event rate
• Number needed to treat (NNT): 1/ARR
• Hazard ratio: Instantaneous risk ratio (from Cox regression, survival analysis)
• Forest plot: Visual display of individual study and pooled results in meta-analysis
• Funnel plot: Detects publication bias in meta-analyses (asymmetry suggests bias)

Regulatory Framework

• MHRA approval for investigational medicinal products
• Health Research Authority (HRA) approval
• Research Ethics Committee (REC) review
• Sponsor responsibilities (university, NHS trust, or pharmaceutical company)

Non-pharmacological

• Shared decision-making using evidence summaries (NICE patient decision aids)
• Clinical guidelines (NICE, SIGN, RCGP) synthesise evidence for practice
• Clinical audit measures practice against evidence-based standards

Pharmacological

Landmark UK Trials (examples):

• RECOVERY trial: Dexamethasone reduces COVID-19 mortality in ventilated patients by 36%
• UKPDS: Intensive glucose control reduces microvascular complications in T2DM
• ISIS-2: Aspirin + streptokinase reduces MI mortality
• 4S trial: Simvastatin reduces CV events in hypercholesterolaemia
• NICE guidance is based on systematic review of clinical and cost-effectiveness evidence

Referral Criteria

• Consider referring suitable patients to clinical trials - all NHS trusts should facilitate research participation
• Research nurse support available through NIHR Clinical Research Network
• Patient and public involvement (PPI) is now mandatory in NIHR-funded research

• Evidence-based medicine has improved outcomes across all medical specialties
• Implementation of trial evidence into guidelines typically takes 17 years on average - a key challenge
• The RECOVERY trial demonstrated the value of large, simple adaptive platform trials during pandemics
• Approximately 50% of treatments used in clinical practice have been tested in RCTs
• UK clinical trials contribute significantly to global medical knowledge through the NIHR infrastructure

Hierarchy of Evidence

Common Biases in Clinical Research

Key Facts

Screening aims to reduce morbidity and mortality by detecting disease at an early, treatable stage. Diagnostic tests are applied to symptomatic individuals to establish a diagnosis. Understanding test properties and their interpretation is fundamental to clinical practice.

Epidemiology

The UK National Screening Committee oversees population-based screening programmes. Approximately 11 million women are invited for breast screening, 15 million for cervical screening, and 4 million for bowel cancer screening each year. Newborn screening covers all ~700,000 UK births annually.

Aetiology

Wilson-Jungner criteria for screening programmes:

1. Important health problem
2. Accepted treatment available
3. Facilities for diagnosis and treatment available
4. Recognisable latent or early symptomatic stage
5. Suitable test available
6. Test acceptable to the population
7. Natural history understood
8. Agreed policy on who to treat
9. Cost-effective (finding cases)
10. Case-finding should be a continuous process

Pathophysiology

Test properties are determined by the 2×2 table (test result vs true disease status).

Bayes' theorem underlies the relationship between pre-test probability (prevalence), test characteristics, and post-test probability:

• Post-test odds = Pre-test odds × Likelihood ratio
• PPV and NPV are directly affected by disease prevalence in the tested population

ROC curves (Receiver Operating Characteristic) plot sensitivity vs (1−specificity) for different test thresholds - area under the curve (AUC) measures overall diagnostic accuracy (1.0 = perfect, 0.5 = no better than chance)

UK NHS Screening Programmes

• Breast cancer: Mammography every 3 years, women aged 50-70 (trial age extension 47-73)
• Cervical cancer: HPV primary screening - age 25-49 every 3 years, age 50-64 every 5 years
• Bowel cancer: FIT (faecal immunochemical test) every 2 years, age 60-74 (expanding to 50+)
• AAA: Abdominal USS for men aged 65
• Diabetic eye screening: Annual digital retinal photography for all diabetics aged ≥12
• Newborn blood spot: Day 5 - PKU, congenital hypothyroidism, sickle cell, CF, MCADD + 4 others
• Newborn hearing: Automated otoacoustic emissions (AOAE)
• Newborn and infant physical examination (NIPE): Within 72 hours and at 6-8 weeks
• Antenatal: Trisomy screening (combined test 11-14 weeks), infectious disease, anomaly scan (18-21 weeks)

Red Flags in Screening Interpretation

• False-positive results cause anxiety, further invasive investigations, and potential overtreatment
• False-negative results provide false reassurance
• Consider lead-time, length-time, and selection biases when evaluating screening programme effectiveness
• PSA screening: Not recommended as population programme due to high false-positive rate and overdiagnosis

Diagnostic Test Properties

• Sensitivity = TP/(TP+FN) × 100% - proportion of disease-positive correctly identified
• Specificity = TN/(TN+FP) × 100% - proportion of disease-negative correctly identified
• PPV = TP/(TP+FP) - probability that a positive test truly has disease
• NPV = TN/(TN+FN) - probability that a negative test truly is disease-free
• Accuracy = (TP+TN)/(TP+FP+FN+TN) - overall proportion correctly classified

Likelihood Ratios

• LR+ = Sensitivity/(1−Specificity) - how much a positive test increases probability of disease
• LR− = (1−Sensitivity)/Specificity - how much a negative test decreases probability
• LR+ >10 or LR− <0.1 are very useful tests

ROC Curve Analysis

• Plots sensitivity (y-axis) vs 1−specificity (x-axis) for different test cut-offs
• AUC (area under curve): 0.9-1.0 = excellent, 0.8-0.9 = good, 0.7-0.8 = fair, <0.7 = poor
• Optimal cut-off balances sensitivity and specificity (depends on clinical consequences of FP vs FN)

Non-pharmacological

• Informed choice: Patients must understand benefits and harms of screening before participation
• Quality assurance: All NHS screening programmes have rigorous QA standards
• Failsafe systems: Ensure no patients are lost from screening pathways

Pharmacological

• Treatment pathways following positive screening results should follow NICE guidelines
• Risk-stratified approaches emerging - e.g., lung cancer screening with LDCT for high-risk smokers

Referral Criteria

• Positive screening test → appropriate diagnostic pathway
• Breast: Triple assessment (clinical, imaging, biopsy)
• Cervical: Colposcopy for positive HPV + cytological abnormality
• Bowel: Colonoscopy for positive FIT
• AAA: Surveillance schedule based on aneurysm size (small 3-4.4cm: annual USS, medium 4.5-5.4cm: 3-monthly USS, large ≥5.5cm: consider repair)

• Breast screening: Estimated to save ~1,300 lives per year in England, but ~4,000 women may be overdiagnosed
• Cervical screening: Prevents approximately 5,000 cervical cancers per year in the UK; HPV vaccination will further reduce incidence
• Bowel screening: Reduces bowel cancer mortality by approximately 16% in screened population
• AAA screening: Reduces AAA-related mortality by approximately 42% in screened men
• The balance between benefits (earlier detection, mortality reduction) and harms (overdiagnosis, false positives, anxiety) must be continually evaluated

2×2 Contingency Table

• Sensitivity = a/(a+c)
• Specificity = d/(b+d)
• PPV = a/(a+b)
• NPV = d/(c+d)

Biases in Screening Evaluation

Key Facts

Nutrition provides the substrates for energy metabolism, tissue repair, and physiological regulation. Understanding nutritional biochemistry is essential for recognising deficiency states, prescribing supplementation, and managing nutritional support.

Epidemiology

Malnutrition (undernutrition) affects approximately 3 million people in the UK, costing the NHS an estimated £19.6 billion annually. Obesity (BMI ≥30) affects ~28% of UK adults. Micronutrient deficiencies (iron, vitamin D, B12, folate) are common in both developing and developed countries.

Aetiology

Macronutrients:

• Carbohydrates (4 kcal/g): Primary energy source; glucose is the obligate fuel for brain and red blood cells
• Proteins (4 kcal/g): Structural, enzymatic, immune functions; essential amino acids must be obtained from diet
• Fats (9 kcal/g): Energy storage, cell membrane structure, hormone synthesis; essential fatty acids (omega-3, omega-6)

Micronutrients:

• Water-soluble vitamins (B complex, C): Not stored significantly; regular intake needed
• Fat-soluble vitamins (A, D, E, K): Stored in liver and adipose tissue; malabsorption causes deficiency
• Trace elements: Iron, zinc, copper, selenium, iodine - enzyme cofactors

Pathophysiology

Refeeding syndrome pathophysiology:

• Starvation → catabolic state, depletion of intracellular electrolytes, glycogen exhaustion

• Consequences: Hypophosphataemia (most dangerous), hypokalaemia, hypomagnesaemia → cardiac arrhythmias, respiratory failure, cardiac failure
• NICE CG32 criteria for high risk: BMI <16, unintentional weight loss >15% in 3-6 months, little/no nutritional intake >10 days

Vitamin Deficiencies

• Thiamine (B1): Wernicke's encephalopathy (triad: confusion, ophthalmoplegia, ataxia); beriberi (wet = cardiac failure; dry = neuropathy)
• Niacin (B3): Pellagra (dermatitis, diarrhoea, dementia - the 3 Ds)
• B6 (pyridoxine): Peripheral neuropathy, sideroblastic anaemia, seizures (isoniazid-induced)
• Folate: Megaloblastic anaemia, neural tube defects (prevention: 400mcg preconception)
• B12: Megaloblastic anaemia, SACD, glossitis, neuropsychiatric symptoms
• Vitamin C: Scurvy - bleeding gums, petechiae, poor wound healing
• Vitamin A: Night blindness, Bitot's spots, xerophthalmia, keratomalacia
• Vitamin D: Rickets/osteomalacia, proximal myopathy, bone pain
• Vitamin K: Bleeding, prolonged PT/INR

Red Flags

• Acute Wernicke's encephalopathy - medical emergency, give Pabrinex IV immediately
• Refeeding risk in malnourished patients - check phosphate, K⁺, Mg²⁺ before and during feeding
• B12 deficiency with neurological symptoms - treat urgently (neurological damage may be irreversible)