ILOs

Question 1

Describe the spirometric pattern that would be expected in obstructive versus restrictive respiratory disease

Answer 1

Obstructive (e.g. COPD/Asthma) - Reduced FEV1:FVC (<70%), Reversibility (>15% AND 400ml in Post-BD FEV1) in Asthma but NOT in COPD

Restrictive - Preserved FEV1:FVC (>70%) with Reduced % Predicted FVC

Question 2

State the Alveolar Air Equation

Answer 2

PaO₂ = FiO₂ - (1.25 x PaCO₂)

PaO₂ - Alveolar Oxygen Partial Pressure, kPa

FiO₂ - Inspired Oxygen Concentration, kPa

Question 3

Describe the clinical application of the Alveolar Air Equation

Answer 3

Arterial pO2 can be directly measured by ABG analysis, whereas Alveolar pO2 must be calculated

The difference between Alveolar pO2 and Arterial pO2 is known as the Alveolar-Arterial Oxygen Gradient

Normally, this should be less than 2-4kPa

Higher than this suggests a V/Q mismatch

Question 4

Using the Alveolar Air Equation comment on the following patient:

Man with COPD, on 28% Oxygen

pO2 - 7.6

pCO2 - 6.6

Answer 4

Alveolar pO2 = 28 - (1.25 x 6.6) = 19.75

Therefore, A-a = 19.75 - 7.6 = 12.15

Alveolar-Arterial Gradient is increased, suggesting V/Q mismatch

Question 5

Describe an approach to the analysis of blood gases in clinical practice

Answer 5

Always look at pO2 first to assess if the patient is in respiratory failure or requires additional oxygen

Next look at the pCO2 to determine Type 1 vs Type 2 Resp. Failure

Then look at the acid-base balance to determine if:

Acute Resp. Acidosis (Elevated pCO2, Normal Bicarb, Acidosis)

Comp. Resp. Acidosis (Elevated pCO2, Elevated Bicarb, Not Acidotic)

Acute on Chronic Resp. Acidosis (Elevated pCO2, Elevated Bicarb. Acidosis)

Question 6

Define COPD

Answer 6

‘a chronic disease characterised by progressive airflow limitation that is not fully reversible and characterised by chronic bronchitis and emphysema’

Question 7

Describe the pathology of COPD

Answer 7

Increased number of mucus-secreting cells

CD8 lymphocyte driven inflammation of the airways, leading to scarring and thickening

Neutrophil infiltration

Loss of defined alveolar air spaces leading to loss of elasticity and air trapping

Causes airway collapse, and blockage of airways

Question 8

State some clinically differentiating features of Asthma and COPD

Answer 8

Episodic SOB in Asthma

Nocturnal Symptoms and Diurnal Variation in Asthma

Productive Cough in COPD

Asthma is Not Progressive, Has Exacerbations and Variable Symptoms

COPD is Progressive, Has Exacerbations and Persistent Symptoms

Question 9

Describe the effects of cigarette smoke on the airways and how this leads to pathology

Answer 9

Mucus Gland and Goblet Cell Hypertrophy –> Increased Mucus Production –> Cough and Sputum

Reduced Cilial Motility –> Decreased Mucus Clearance –> Increased Infection Risk

Anti-Protease Inhibition –> Increased Protease Activity –> Inflammation

Question 10

Describe the typical features of a ‘Blue Bloater’

Answer 10

Usually in chronic bronchitis

Due to CO2 retention (becomes insensitive to it)

Low Resp. Drive and Type 2 Resp. Failure

(Low PaO2 and High PaCO2)

Cyanosis, Obesity, Crackles and Wheeze, Peripheral Oedema

Chronic Productive Cough, Purulent Sputum

Question 11

Describe the typical features of a ‘Pink Puffer’

Answer 11

Due to Emphysema

CO2 responsive with compensatory hyperventilation

Desaturates on Exercise, Pursed Lip Breathing, Use of Accessory Muscles, Wheeze, Indrawing of Intercostals, Tachypnoea, Cachectic Appearance

High Resp. Drive, Type 2 Resp. Failure

Low PaO2 and PaCO2

Question 12

Define Obstructive Sleep Apnoea Syndrome

Answer 12

Recurrent episodes of partial or complete upper airway (pharyngeal) obstruction during sleep, intermittent hypoxia and sleep fragmentation manifesting as excessive daytime sleepiness

Question 13

State risk factors which predispose to development of Obstructive Sleep Apnoea Syndrome

Answer 13

Obesity

Male Sex

Post-Menopause (Women)

Large Neck Circumference (>40cm)

Maxillomandibular Anomalies (Narrowing, Retrognathia)

Increased Tonsil/Adenoid/Tongue Size

FHx

Question 14

Describe the investigations used in the diagnosis of Obstructive Sleep Apnoea Syndrome

Answer 14

History (from Pt and Family)

Clinical Exam

Daytime Sleepiness Assessment (Epworth Score)

Limited Polysomnography (Home, 5 Channel; O2 Sats, HR, Flow, Thoracic and Abdominal Effort and Position)

Full Polysomnography (In-Hospital, Multi-Channel; EEG, Video, Audio, Thoracic/Abdominal Bands, Position, Flow, O2 Sats, Limb Leads, Snore)

Transcutaneous Oxygen Saturation and Carbon Dioxide Assessment

Question 15

Describe the methods of management of Obstructive Sleep Apnoea Syndrome

Answer 15

Weight Loss

Avoidance of Triggers (e.g. Alcohol)

Treatment of Underlying Factors

Continuous Positive Airway Pressure (Splints airway open to stop snoring and sleep fragmentation to reduce daytime sleepiness and improve quality of life)

Mandibular Advancement Device

Sleep Position Training

Question 16

Describe pathological features in the lung which lead to pneumothorax

Answer 16

Sub-Pleural Blebs (blister-like air pockets) at the apex of the lung

Diffuse, microscopic emphysema below the surface of the visceral pleura

Spontaneous rupture can lead to a tear in the visceral pleura

Question 17

Outline the diagnostic features of spontaneous pneumothorax

Answer 17

Pleuritic Chest Pain

Dyspnoea

Respiratory Distress

Reduced Air Entry on Affected Side

Hyper-Resonance to Percussion

Reduced Vocal Resonance

Tracheal Deviation (If Tension)

Question 18

Outline the initial management of spontaneous pneumothorax

Answer 18

Observation if small or not very symptomatic

Aspiration (urgently if tension) with syringe in 2nd intercostal space, midclavicular line

Intercostal drain with underwater seal

Question 19

State pathological and clinical features that predispose to pulmonary embolism

Answer 19

Surgery <12 Weeks Previously

Immobilisation >3 Days in Previous 4 Weeks

Previous DVT/PTE

FHx of PTE/DVT

Lower Limb Fracture

Pregnancy or Post-Partum

Long Distance Travel

Oestrogen-Containing OCP Use

Antithrombin Deficiency

Protein S or C Deficiency

Factor V Leiden

Question 20

Describe clinical features of pulmonary embolism

Answer 20

Tachypnoea

Crackles

Tachycardia

Fever

Signs of Peripheral DVT

Pleuritic Chest Pain

Dyspnoea

Cough

Haemoptysis

Syncope

Question 21

Describe investigations for pulmonary embolism

Answer 21

Modified Geneve Score (Risk Assessment)

D-Dimer (Raised, >230mg/L)

ABGs (Resp. Alkalosis with Reduced PaCO2)

Troponin

ECG

Echocardiogram

Radiology (CXR, CT-Pulmonary Angiogram, V/Q Scan)

Question 22

Describe the immediate management of pulmonary embolism

Answer 22

Massive:

(PE associated with SBP <90mmHg or a drop in SBP of >40mmHg in <15 Minutes)

Give Unfractionated Heparin IV

Fluid Resuscitation

Thrombolysis with Alteplase if Fails to Improve

Sub-Massive:

Initially LMWH

Then Oral Anti-Coagulant for 3 Months (Factor Xa Inhibitors or Warfarin)

Question 23

Describe the features of Usual Interstitial Pneumonia

Answer 23

Heterogenous appearance with areas of normal lung punctuated by marked fibrosis and honeycombing (mainly in subpleural areas) and fibroblastic foci (dense proliferations of fibroblasts and myofibroblasts)

Question 24

Describe the clinical diagnosis of Pulmonary Fibrosis

Answer 24

Clinical manifestation of UIP

Fibrotic lung disease, usually with no definitive cause

Progressive Breathlessness, Bibasilar Crackling, Hacking Dry Cough, Fatigue, Weakness, Finger Clubbing, Appetite and Weight Loss

Question 25

Describe the pathological processes in Sarcoidosis

Answer 25

Chronic granulomatous disorder characterised by accumulation of lymphocytes and macrophages in organs (typically the lungs and intrathoracic lymph nodes) Non-necrotising granulomas with multi-nucleated giant cells in the centre

Question 26

Describe the clinical presentation of Sarcoidosis

Answer 26

May present with pulmonary, neurological, cardiac, dermatological or ocular findings Systemic symptoms: Fever, Anorexia, Fatigue, Night Sweats, Weight Loss Pulmonary symptoms: Cough, Haemoptysis, Dyspnoea on Exertion, Chest Pain May be asymptomatic

Question 27

Describe the pathology and presentation of Extrinsic Allergic Alveolitis

Answer 27

T-Cell mediated (immunological) inflammatory reaction in the alveoli and respiratory bronchioles (N.B. EAA is NOT atopy) May present with flu-like illness, cough, fever, chills, myalgia, malaise, dyspnoea

Question 28

State the pathological classification of Lung Cancer

Answer 28

Small Cell Non-Small Cell (Large Cell, Adenocarcinoma or Squamous Cell)

Question 29

Describe the pathology of Small Cell Lung Cancers

Answer 29

Most aggressive form, often metastasising early and widely Often a good initial response to chemotherapy, but most patients relapse Appearance: Oval to Spindle Shaped Cells, Inconspicuous Nucleoli, Scant Cytoplasm, Nuclear Moulding

Question 30

Describe the pathology of Squamous Non-Small Cell Lung Cancer

Answer 30

Tends to arise centrally from major bronchi Slow growing and late to metastasise Often within dysplastic epithelium following squamous metaplasia Appearance: Malignant Epithelial Tumour showing Keratinisation and/or Intracellular Bridges

Question 31

Describe the pathology of Adenocarcinoma Non-Small Cell Lung Cancer

Answer 31

Common tumour in females Also seen in non-smokers Two-thirds arise in the periphery Appearance: Glandular, Solid, Papillary or Lepidic with Mucin Production

Question 32

Describe the pathology of Large Cell (Non-Small Cell) Lung Cancer

Answer 32

Usually arises centrally Undifferentiated malignant epithelial tumour that lacks the cytological features of SCLC and glandular or squamous differentiation

Question 33

Describe the pathological consequences of local spread of lung cancer

Answer 33

Bronchial Obstruction Lung Collapse or Consolidation (Retention Pneumonia) Pleura - Haemorrhagic Effusion Blood Vessels - Haemoptysis Pericardium - Pericardial Effusion Mediastinum - SVC Obstruction Pancoast Tumour - Horner's Syndrome, Brachial Plexus Compression

Question 34

Describe the distant spread of lung cancer

Answer 34

Haematogenous - Liver, Bone, Brain, Adrenal Lymphatic - Cervical Lymph Nodes

Question 35

State cancers which most commonly metastasise to the lungs

Answer 35

Bowel, Breast, Prostate, Bladder, Kidney

Question 36

Describe the classification of Beta-Lactam Antibiotics

Answer 36

Penicillins: Benzylpenicillin, Flucloxacillin, Amxocillin Cephalosporins: Ceftriaxone Carbapenems: Meropenem Monobactams: Aztreonam Co-Amoxiclav Tazocin

Question 37

Briefly describe normal skin anatomy

Answer 37

Question 38

Describe the embryological process of skin development

Answer 38

Epidermis is derived from the ectoderm while the dermis is from the underlying mesenchyme In the 5^th week, the skin of the embryo is covered by simple cuboidal epithelium In the 7^th week there is a single squamous layer (periderm) and a basal layer In the 4^th month an intermediate layer containing several cell layers is interposed between the basal cells and the periderm In the early foetal period, the epidermis is invaded by melanoblasts (cells of neural crest origin)

Question 39

Describe the role of the immune system in the skin

Answer 39

Langerhans Cells (dendritic cells) reside in the basal layers of the skin Acquire antigens in the periphery, transport them to regional lymph nodes to activate naive T-Cells and initiate an adaptive immune response Activated T-Cells then initiate cytokine release cascade

Question 40

Describe the effects of UV light on the skin

Answer 40

Direct effects include photoaging, DNA damage and carcinogenesis p53 tumour suppressor genes are mutated by DNA damage (implicated in development of melanoma and non-melanoma skin cancers) Chronic exposure can lead to loss of skin elasticity, fragility, abnormal pigmentation, haemorrhage of blood vessels, wrinkling and premature ageing

Question 41

Describe the aetiology of Acne Vulgaris

Answer 41

1. Sebaceous gland hyperplasia and excess sebum production, especially during puberty where androgens drive gland enlargement 2. Abnormal follicular differentiation (keratinocytes are retained and accumulate) 3. *Propionibacterium Acnes* colonisation, stimulate the production of pro-inflammatory mediators and lipases 4. Inflammation and immune response leads to development of papules, pustules, nodules and cysts

Question 42

Describe the management options for Acne Vulgaris

Answer 42

* Reduce Plugging: * Topical Retinoid * Topical Benzoyl Peroxide * Reduce Bacteria * Topical Antibiotics (Erythromycin, Clindamycin) * Oral Antibiotics (Tetracycline, Erythromycin) * Reduce Sebum Production * Hormones - Anti-Androgens (Dianette/OCP)

Question 43

Describe the role of Isotretinoin in the management of Acne Vulgaris

Answer 43

An oral retinoid (concentrated Vitamin A) for severe Acne Vulgaris Reduces sebum production, plugging and bacterial colonisation Standard course of 16 weeks at 1mg/kg Causes remission in around 80% of teenagers Trivial Side Effects - Dry Lips, Nose Bleeds, Dry Skin, Myalgia Serious Side Effects - Deranged Liver Function, Raised Lipids, Mood Disturbance, Teratogenicity (Must have regular pregnancy tests to prevent pregnancy while on therapy)

Question 44

Describe how psoriasis may present in the skin

Answer 44

Extensive erythematous, circumscribed, scaly papules and plaques

Question 45

Describe the immune mechanisms associated with psoriasis

Answer 45

Hyperproliferative disorder where cells migrate from the basal layer to the stratum corneum in just a few days T-Cell mediated autoimmune response Abnormal infiltration of T-Cells causes release of inflammatory cytokines including interferon, TNF and interleukins Causes increased keratinocyte proliferation

Question 46

Describe treatment options for psoriasis

Answer 46

* Topical Creams and Ointments * Moisturisers help to reduce flaking and dryness * Steroids reduce immune response * Phototherapy Light Treatment * Non-Specific Immunosuppressant Therapy * Reduces T-Cell Proliferation * Encourages VitD to reduce skin turnover * Risk of burning and skin CA * Acitretin * Methotrexate and Ciclosporin * Immunosuppressants * Biologics * Etanercept, Infliximab, Adalimumab * (Anti-TNF)

Question 47

Describe the different types of psoriasis

Answer 47

* Chronic Plaque * Pink-red, well-demarcated plaques with a silver scale especially seen on extensor surfaces of the knees * Guttate * Raindrop like psoriasis most commonly seen in young adults and children characterised by an explosive eruption of very small circular or oval plaques over the trunk about 2 weeks after a streptococcal sore throat * Erythrodermic and Pustular * Can be life-threatening * Sterile pustules filled with inflammatory cells * Associated with malaise, pyrexia and circulatory disturbance

Question 48

Describe the conditions associated with psoriasis, i.e. psoriatic arthritis and metabolic syndrome

Answer 48

Psoriatic Arthritis - Inflammatory disease often affecting the fingers and toes causing swelling Metabolic Syndrome - Central Obesity, HTN, T2DM, Low HDL Levels and High Serum Triglycerides

Question 49

Describe the different subtypes of eczema

Answer 49

* Atopic * Itch inflammatory skin condition * Associated with asthma, allergic rhinitis, conjunctivitys and hay fever * High IgE levels * 10-15% of infants affected, remission in 75% by 15 years * Contact * Precipitated by an exogenous agent * Type IV Hypersensitivity (Delayed T-Cell Response) * Common allergens include nickel, chromate, cobalt, fragrance * Seborrhoeic * Chronic,scaly inflammatory condition often on the scalp or face * Overgrowth of *Pityrosporum Ovale* yeast * Venous * Associated with underlying venous disease

Question 50

Describe the management of eczema

Answer 50

* Atopic * Emollients * Topical Steroids * Bandages * Antihistamines * Antibiotics/Anti-Virals * Avoidance of Exacerbating Factors * Seborrhoeic * Scalp - Mediated Anti-Yeast Shampoo * Face - Anti-Microbial, Mild Sterooid and Simple Moisturiser * Venous * Emollient * Mild/Moderate Topical Steroid * Compression Bandages/Stocking * Venous Surgical Intervention

Question 51

Describe the association between eczema and diseases such as asthma, hay fever etc.

Answer 51

Atopic diseases Associated with immune response and high IgE levels

Question 52

Define Acute Compartment Syndrome

Answer 52

‘an orthopaedic emergency resulting from elevated interstitial pressure within a closed fascial compartment resulting in microvascular compromise, most commonly in the leg, forearm or thigh which could lead to loss of function, limb or life’

Question 53

Describe the pathology of Acute Compartment Syndrome

Answer 53

Increased Internal Pressure (Bleeding, Swelling) Increased External Compression (Casts, Bandages) Pressure within the compartment exceeds the pressure within the capillaries Muscles become ischaemic and develop oedema through increased endothelial permeability Necrosis begins in the ischaemic muscles after four hours Ischaemic nerves become neuropraxic (loss of motor and sensory function) This may recover if relieved early, however permanent damage may result after only four hours In the later stages, there is a compromise of the arterial supply

Question 54

Describe the clinical features of Acute Compartment Syndrome

Answer 54

Pain (out of proportion to that expected from the injury and on passive stretching of the compartment) Pallor Paraesthesia Paralysis Pulselessness Swelling Shiny Skin Autonomic Response - Sweating, Tachycardia Reduced Consciousness Level

Question 55

Describe the management of Acute Compartment Syndrome

Answer 55

Open any constricting dressings/bandages Surgical Release: Full length decompression of all compartments Excise any dead muscles Leave wounds open Repeat debridement until pressure is down and all dead muscle has been excised Later, close the wound and graft the skin if needed

Question 56

Define Tendinopathy

Answer 56

‘chronic tendon injury of over use due to repetitive loading, characterised by degeneration and disorganisation of collagen fibres, increased cellularity and only little inflammation’

Question 57

Describe the pathology of Tendinopathy

Answer 57

Tendinopathy is likely not an inflammatory process Deranged collagen fibres and degeneration with a scarcity of inflammatory cells Increased vascularity around the tendon Failed healing response to micro-tears Inflammatory mediators including IL-1, NO and Prostaglandins are released which cause apoptosis, pain and provoke degeneration through release of Matric Metalloproteinases

Question 58

Describe the management of Tendinopathy

Answer 58

**Pharmacological:** NSAIDs GTN Patches PRP Injection Prolotherapy Steroid Injection **Non-Pharmacological:** Activity Modification Physiotherapy Extracorporeal Shockwave Therapy Radiofrequency Coblation **Operative Management:** Debridement Excision of Diseased Tissue

Question 59

Describe the features of autosomal dominant inheritance

Answer 59

e.g. Achondroplasia Affects every generation Males and Females equally affected Vertical pattern of inheritance 50% chance of child being affected if a parent is heterozygous Disease = Aa or AA, Healthy = aa

Question 60

Describe the concept of 'variable expression' in Mendelian Inheritance

Answer 60

Variable Expression: Two people in the same family, who have inherited the same mutation in the same gene, may have different disease severities or age of onset

Question 61

Describe the concept of 'incomplete penetrance' in Mendelian Inheritance

Answer 61

Complete/Incomplete Penetrance: One may inherit the mutation but this would not be enough to develop the disease (i.e. incomplete penetrance)

Question 62

Describe the concept of 'gonadal mosaicism' in Atypical Mendelian Inheritance

Answer 62

Presence of more than one cell line in the gonads (but NOT in somatic cells) due to a mutation in a gamete precursor cell

Question 63

Describe the concept of 'modifier genes'

Answer 63

Genetic variants that can affect the manifestation of a disease by altering indirectly influencing expression of another gene This may help explain the variable expressivity seen in some mutations, and may affect the age of onset, rate of disease progression and severity of symptoms

Question 64

Describe the features of autosomal recessive inheritance

Answer 64

e.g. Sickle Cell, CF, PKU Equal frequency and severity in males and females Horizontal pedigree pattern Disease expressed in homozygotes (two identical mutations) or compound heterozygotes (two different mutations in the same gene) Low risk to offspring of affected individuals Expressivity more constant in a family May suggest consanguinity in the family

Question 65

Describe X-Linked Recessive Inheritance

Answer 65

e.g. Duchenne's Muscular Dystrophy No male to male transmission 'Knights Move' pattern of inheritance Male-Female transmission = All Daughters are Carriers Female-Female Transmission - 50% of Daughters are Carriers M\>\>\>F

Question 66

Describe X-Linked Dominant Inheritance

Answer 66

e.g. Vitamin D Resistant Rickets No male to male transmission Vertical pattern of inheritance Male-Female Transmission = All Daughters Affected Female-Female Transmission = 50% of Daughters Affected F:M = 2:1

Question 67

Describe the difference between Tumour Suppressor Genes, Proto-Oncogenes and Oncogenes

Answer 67

TSG: Normally inhibit progression through cell cycle and cell prilferation, promote apoptosis or act as stability genes Mutation Results in Loss of Function Requires 2 Mutated Copies to Become Tumourigenic Proto-Oncogenes: Normally stimulate cell cycle or promote cell division/growth Activation by mutation results in Oncogenes with Gain of Function in protein Only needs one mutated copy for tumourigenic effect

Question 68

Describe the 'Two-Hit Hypothesis'

Answer 68

The Two-Hit Hypothesis states that two mutated alleles are required for progression to cancer The first may be inherited, meaning a second sporadic mutation is required to initiate tumourigenesis

Question 69

Describe Gain and Loss of Function mutations

Answer 69

LOF: Mutation causes a reduction in the activity or amount of the encoded protein GOF: Mutation results in a greater level of activity, a greater amount of protein or rarely, acquisition of a new function (e.g. BCR-ABL) LOF mutations are more common

Question 70

Describe the role of BRCA1/2 mutations in the contribution to cancer

Answer 70

BRCA1/2 proteins are large nuclear proteins and with roles including DNA repair, transcriptional regulation of other genes and cell-cycle regulation They promote double-stranded DNA repair by homologous recombination

Question 71

Describe the molecular genetic basis and clinical aspects of Huntington's Disease

Answer 71

Onset typically between 30-50 years Characterised by progressive chorea (involuntary movements), dementia and psychiatric symptoms Autosomal Dominant with Genetic Anticipation Unstable length mutation in the HTT gene Number of CAG repeats increased from 10-35 to 36-120 This repeat encodes a polyglutamine tract Expansion of tract causes insoluble protein aggregates and neurotoxicity

Question 72

Describe the concept of Genetic Anticipation

Answer 72

The phenomenon where symptoms of an inherited condition become more marked and become apparent at an earlier age in subsequent generations

Question 73

Describe the clinical aspect and molecular genetic basis of Myotonic Dystrophy

Answer 73

Progressive muscle weakness in early childhood with myotonia and cataracts Autosomal Dominant with Genetic Anticipation Unstable length mutation of a CTG repeat Affected if 50 or more repeats

Question 74

Define 'Cascade Screening'

Answer 74

Systematic identification and testing of members of the family of a proband with a particular disease of interest (aka testing the family of a patient diagnosed with a disease such as CF)

Question 75

Describe the clinical aspects and molecular genetic basis of Cystic Fibrosis

Answer 75

Characterised by recurrent lung infections and exocrine pancreatic insufficiency CFTR mutation results in defective chloride ion channels and increased thickness of secretions Most common mutation is F508del (in-frame deletion of one codon resulting in loss of phenylalanine 'F' at position 508 ) Prevents normal protein folding and insertion into the plasma membrane

Question 76

Describe the clinical aspects and molecular genetic basis of Duchenne Muscular Dystrophy

Answer 76

Onset at 3yrs, Wheelchair by 12yrs X-Linked Recessive Inheritance Serum Creatine Kinase leaks from damaged muscle fibres into serum Out-Of-Frame Deletion Mutations

Question 77

Describe the clinical and genetic consequences of Fragile X Syndrome

Answer 77

Significant Learning Disability X-Linked Recessive Inheritance With Genetic Anticipation If Full Mutations: Phenotypes in males can be severe, some carrier females also affected more mildly

Question 78

Briefly describe the main autosomal trisomies

Answer 78

Down's: Trisomy 21, Learning Difficulties, Heart Defects, Hypothyroidism Edwards's: Trisomy 18, Small Chin, Clenched Hands, Malformation of Organs, Profound Learning Difficulties if Survive Past 1 Year Patau: Trisomy 13, Congenital Heart Disease, 50% SR at 1/12, 10% at 1Yr, Profound Learning Difficulties

Question 79

State some important aspects of clinical history and examination that are especially helpful in clinical genetics

Answer 79

Hx: Age of Onset, Progression FHx: Consanguinity, Miscarriages, Stillbirths O/E: Dysmorphic Features (Head Shape/Size, Eyes, Ears, Nose, Philtrum), Unusual Features (Polydactyly)

Question 80

Describe Pre-Implantation Diagnosis and state its advantages and disadvantages

Answer 80

One or Two cells are removed from an embryo to undergo PCR or FISH to check for a mutation and only unaffected embryos are transferred into the patient Pros: Permits implantation of unaffected embryos Cons: Possible long wait, Not available to all women, Difficulty with multiple visits and procedures, Take home baby rate usually \<50% per cycle

Question 81

State the genetic conditions tested for (and the tests used) during pregnancy

Answer 81

Down Syndrome: Combined Ultrasound (Nuchal Translucency Increases in DS) and Biochemical Screening (CUBS)

Question 82

State the genetic conditions tested for (and the test method) during the neonatal period

Answer 82

Heel Spot on Guthrie Card Phenylketonuria and Medium-Chain Acyl-CoA Dehydrogenase Deficiency (Mass Spectrometry) Congenital Hypothyroidism and Cystic Fibrosis (Immuno-Assay) Sickle Cell Disorder (High-Performance Liquid Chromatography)

Question 83

State some of the genetic conditions screened for in specific adult populations

Answer 83

Tay Sachs Disease - Screened for in Jewish people, e.g. Pre-Pregnancy Thalassaemia - Population Carrier Screening

Question 84

Briefly describe Sanger DNA Sequencing

Answer 84

i.e. Fluorescent Dideoxynucleotide Sequencing Used in detection of point mutations Analyses a single gene at a time

Question 85

State the application of Array Comparative Genomic Hybridisation in DNA Analysis

Answer 85

Detection of sub-microscopic duplications and deletions

Question 86

Describe the basis of next generation DNA sequencing

Answer 86

i.e. Massively Parallel Sequencing Of many or all genes Used to find small mutations somewhere in the exome

Question 87

Describe Type I Hypersensitivity, including Anaphylaxis

Answer 87

Immediate, Atopic, IgE Mediated Response Responsible for most allergies, including asthma, eczema and hayfever Response to the challenge occurs immediately, tends to increase in severity with repeated exposure Predominantly mediated by IgE bound to mast cells Antigen binds to IgE associated with mast cell, causing degranulation and release of histamine, cytokines, prostaglandins and leukotrienes Anaphylaxis is a life-threatening severe, systemic Type I Hypersensitivity as a result of systemic exposure to an antigen and vascular permeability is the immediate danger (soft tissue swelling threatens airway and loss of circulatory volume causes shock)

Question 88

Describe Type II Hypersensitivity

Answer 88

Cytotoxic, Antibody Dependent IgM/IgG Bound to Cell /Matrix Antigen Caused by binding of antibodies directed against human cells (usually IgG) Associated with Drug Associated Haemolysis more than allergy Common cause of autoimmune disease e.g. Autoimmune Haemolytic Anaemia

Question 89

Describe Type III Hypersensitivity

Answer 89

Immune Complex IgM or IgG Bound to Soluble Antigen Mediated by immune complexes bound to soluble antigen Cause of autoimmune disease and drug allergy Aggregates in small blood vessels causes direct occlusion, complement activation and perivascular inflammation e.g. SLE or RA

Question 90

Describe Type IV Hypersensitivity

Answer 90

T-Cell Mediated Response Delayed-type hypersensitivity, presents several days after exposure Mediated by action of lymphocytes infiltrating the area e.g. Contact Dermatitis

Question 91

Describe the features of reversible cell injury

Answer 91

Changes due to stress in the environment Returns to normal once the stimulus is removed Features include: 'Cloudy Swelling' - Osmotic disturbance due to loss of energy-dependent Na pump leads to Na influx and build up of intracellular metabolites Cytoplasmic Blebs Disrupted Microvilli Swollen Mitochondria 'Fatty Change' - Accumulation of lipid vacuoles in cytoplasm caused by disruption of fatty acid metabolism, esp. in the liver

Question 92

Describe the features of irreversible cell injury

Answer 92

Permanent Cell death (usually necrosis) follows Features include: ATP Depletion Calcium Influx DNA Damage Accumulation of Oxygen Free Radicals Extensive Physical Damage

Question 93

Define apoptosis

Answer 93

Genetically programmed (physiological) or activated cell death (pathological) requiring energy and distinct pathways

Question 94

State some physiological and pathological aetiologies of apoptosis

Answer 94

* Physiological: * Deletion of cell populations in embryogenesis * Cell deletion in proliferating populations (e.g. epithelium) * Deletion of inflammatory cells after an inflammatory response * Deletion of self-reactive lymphocytes in thymus * Pathological: * Viral Infection: Cytotoxic T-Lymphocytes * DNA Damage * Hypoxia/Ischaemia

Question 95

Describe the morphological features of apoptosis

Answer 95

Cell Shrinkage Chromatin Condensation (Packaging up of nucleus, unlike in necrosis) Membranes of Cell and Mitochondria Remain Intact Cytoplasmic Blebs form and break off to form apoptotic bodies which are phagocytosed by macrophages

Question 96

Define necrosis

Answer 96

Pathological, unprogrammed cell death following injury and which is uncontrolled and due to external stimuli

Question 97

Describe the histological changes seen in necrosis

Answer 97

Cell swelling, vacuolation and disruption of membranes of cells and its organelles including mitochondria, lysosomes and ER Release of cell contents (cell lysis) including enzymes causes adjacent damage and acute inflammation DNA disruption and hydrolysis

Question 98

Describe the types of necrosis

Answer 98

Coagulative: Firm, tissue outline retained (Haemorrhagic - due to blockage of venous drainage or Gangrenous - larger area especially lower leg) Colliquitive: Tissue becomes liquid and its structure is lost (e.g. infective abscess or cerebral infarct) Caseous: Combination of coagulative and colliquitive, appearing cheese-like (caseous), classical for granulomatous inflammation, especially TB Fat: Due to action of lipases on fatty tissue

Question 99

Describe the effects of necrosis

Answer 99

Functional - Depends on the tissue/organ Inflammation - Release of cell contents activates inflammation and causes damage (either acute with removal of stimulus and then healing and repair or chronic with persistence of stimulus and chronic inflammation)

Question 100

Outline the nature, causes and effects of amyloid accumulation

Answer 100

Organisation of amyloid soluble protein fibrils into specific abnormal, insoluble aggregates Can be due to multiple myeloma or chronic inflammation (e.g. RA) Effects depend on site of deposition from renal impairment/failure, heart failure or dementia

Question 101

Outline the nature, causes and effects of pathological calcification

Answer 101

Deposition of calcium salts May be dystrophic (deposition in abnormal tissue with normal serum calcium) or metastatic (deposition in normal tissue with raised serum calcium, often in the connective tissue of blood vessels resulting in compromised tissue function) Causes include increased levels of PTH due to a parathyroid tumour or kidney disease

Question 102

Describe inflammation

Answer 102

An acute or chronic physiological response to tissue injury with vascular and cellular components, terminating in resolution, repair or continuing inflammation

Question 103

Describe the role of vascular changes in inflammation

Answer 103

1. Vasodilation 1. Transient vasoconstriction then vasodilation 2. Starts in the arterioles 3. Increased blood flow 4. Due to histamine and NO on vascular smooth muscle 2. Increased Vascular Permeability 1. Permits escape of protein-rich fluid exudate into extravascular tissue 2. Contraction of endothelial cells increases inter-endothelial spaces 3. Mediated by histamine, bradykinin and substance P 4. Endothelial injury in severe injuries 5. Injury can be caused by neutrophils 6. Increased transcytosis 3. Vascular Congestion/Stasis 1. Slower flow and increased concentration 4. Endothelial Activation 1. By mediators produced during inflammation 2. Increased levels of adhesion molecules

Question 104

Describe the cellular changes in the vasculature associated with inflammation

Answer 104

1. Margination 1. WBCs become more peripheral due to stasis 2. Rolling 1. WBCs stick and detach from wall 2. Mediated by Selectins 3. Up-regulated by IL-1 and TNF (from Macrophages/PMNs) 3. Adhesion 1. Mediated by Integrins 2. Stimulated by IL-1 and TNF 3. Chemokines also facilitate binding (directly released at site of injury) 4. Reorganisation of cytoskeleton 4. Migration (Diapedesis) 1. Chemokines act on leucocytes to stimulate migration across endothelium

Question 105

Describe the various types of exudate

Answer 105

Exudate - Extracellular fluid with a high protein and cellular content Transudate - Extracellular fluid with a low protein and cellular content Serous - Usually a transudate found in pleural, pericardial and peritoneal spaces Fibrinous Exudate - Fluid rich in fibrin, and exudate due to high protein content often on serosal surfaces such as the meninges Suppurative Exudate - Pus-forming, and exudate rich in neutrophil polymorphs (abscess) Pseudomembranous - Surface exudate on mucosal/epithelial sites

Question 106

Describe the main concepts of how infection may spread

Answer 106

* Localised Infection * Remain at initial site * Spread to local lymph nodes via draining lymphatics * Five cardinal signs! * Systemic Infection * Haematogenous - i.e. spread through blood/lymph to cause SYSTEMIC INFLAMMATOrY RESPONSE * Can track through tissue to form abscess/infection elsewhere, e.g. psoas abscess

Question 107

Describe the role of neutrophil polymorphs in inflammation

Answer 107

Opsonise and phagocytose Intra-cellular killing of micro-organisms (both oxygen dependent and independent) Release lysosomal products, propagating the response

Question 108

Describe the role of mast cells in inflammation

Answer 108

Reside in tissues Contain histamine and heparin in preformed granules Stimulated to release contents by injury, complement and IgE Play an important role in allergy/anaphylaxis Also make eicosanoids to propagate immune response

Question 109

Describe the role of macrophages in inflammation

Answer 109

Macrophages - Tissue Resident, Monocyte - Circulating Chemotaxis Synthesise TNF, IL-1, IL-6 Phagocytosis Antigen-presenting cells, link between innate and adaptive immune response

Question 110

Describe the role of complement in inflammation

Answer 110

Activated by the classical pathway (Ag/Ab complexes), alternative pathway (bacterial products), products of dying cells in tissue necrosis, components of kinin, coagulation or fibrinolytic systems C3a/C5a - Chemotactic for neutrophils, increases vascular permeability and releases histamine from mast cells C5-C9 - Cytolytic Activity C2a/C3b/C4b - Opsonisation of Bacteria

Question 111

Describe how various chemical mediators affect the inflammatory response

Answer 111

Histamine - Vasodilation, Increased Vascular Permeability, Endothelial Activation Serotonin - Vasodilation, Increased Vascular Permeability Prostaglandins - Vasodilation, Pain, Fever Leukotrienes - Increased Vascular Permeability, Chemotaxis, Leucocyte Adhesion NO - Killing of Microbes, Vascular Smooth Muscle Relaxation !L-1/TNF/IL-6 - Endothelial Activation, Fever, Pain, Shock Chemokines - Chemotaxis, Leucocyte Activation

Question 112

Describe the possible sequelae of acute inflammation

Answer 112

* Resolution (complete restoration of tissue to normal) * If minimal tissue damage * If occurs in tissue with regenerative capacity i.e. skin * If cause is rapidly removed or destroyed * If there is good vascular drainage * Healing by fibrosis * After substantial tissue damage * Tissue incapable of regeneration * Abundant fibrin exudate * Progression to chronic inflammation * Persistent stimulus * Tissue destruction leading to ongoing inflammation

Question 113

Define chronic inflammation and describe the circumstances in which it arises

Answer 113

'a physiological response characterised by infiltrates of lymphocytes, plasma cells and macrophages that persists and lacks resolution when the inflamed tissue is unable to overcome the effects of the injurious agent' Many factors are important, including site affected, type of wound, presence of infection and type of organism involved, presence of indigestible material, treatment given and background disease

Question 114

Describe granulomatous inflammation

Answer 114

A distinctive pattern of chronic inflammation with predominantly activated macrophages (with a modified epithelioid appearance) and giant cells (formed from fused epithelioid macrophages) Epithelioid macrophages are arranged in small nodules or clusters and have a mainly secretory role rather than phagocytic and multinucleated giant cells form where material is difficult to digest Granuloma formation is a manifestation of T-Cell mediated immune reaction (Delayed Type Hypersensitivity) Associated with TB, Hodgkin Lymphoma, Sarcoidosis, Crohn's Disease, Leprosy, Toxoplasmosis

Question 115

Describe the factors which may influence wound healing

Answer 115

Local - Type, size and location of wound, movement within wound, infection, presence of foreign/necrotic material, irradiation, poor blood supply Systemic - Age, Nutrition (Vit C, Zinc), Systemic Disease (Renal Failure, Diabetes), Drugs (esp. Steroids), Smoking

Question 116

Describe the various stages of cutaneous wound healing

Answer 116

* Haemostasis * Aggregation of platelets, vasoconstriction and inflammatory factor release * Inflammation * Increased vascular permeability allows migration of inflammatory cells * Tissue Proliferation * Re-Epithelialisation by keratinocytes moving into the wound * Neovascularisation by proliferation of collagen-producing fibroblasts to support new blood capillaries * Tissue Remodelling * Cross-linking of collagen into thick bundles

Question 117

Describe the various stages of fracture healing

Answer 117

1. Haematoma Formation 1. Clotted blood forms around fracture site and area becomes inflamed as phagocytic cells remove debris 2. Fibrocartilaginous Callus Formation 1. Fibroblasts and chondroblasts from the periosteum arrive at the site to roughly lay down collagen and fibrocartilage (known as a fibrocartilaginous soft callus) 3. Bony Callus Formation 1. Pre-Osteoblasts differentiate to mature osteoblasts which lay down spongy bone 2. Over time the fibrocartilage is replaced by spongy bone to form a bony (hard) callus 4. Bone Remodelling 1. Finally and remaining portions of dead bone are resorbed by osteoclasts 2. The spongy bone around the periphery of the site is replaced with compact bone

Question 118

Describe healing by primary and secondary intention

Answer 118

Primary - Wound edges are close together with minimal tissue loss so can be held together with sutures, heal quickly with minimal scar formation Secondary - Wound edges are separated with greater tissue loss, so healing occurs slowly with more scar tissue formation

Question 119

Describe the two types of Post-Mortem Examination

Answer 119

* Hospital 'Consented' PM * Usually at the request of clinicians to answer question about the patient's pathology or treatment * Requires specific consent of the family * Few cases per year (40-50 in Glasgow) * Medico-Legal PM * At the instruction of the Procurator Fiscal (Scotland) or Coroner (England and Wales) * Does not require consent of the family * Constitute the vast majority of PMs performed in the UK (110,000 per year in England and Wales, 6500 in Scotland)

Question 120

Describe the process of a Post-Mortem Examination

Answer 120

* External Examination * Identification of the deceased * Height/Weight/BMI * Skin/Hair/Eye Colour * Iatrogenic - Scars, Drains and IV Lines * Evidence of trauma * Jaundice, cyanosis, finger clubbing, oedema, lymphadenopathy * Evisceration * Single incision from sternal notch to symphysis pubis to remove thoracic, abdominal and pelvic organs * Second incision around posterior skull to reflect the scalp, remove the skull and remove the brain * Organ Dissection * Pathologist inspects each organ and carefully dissects (macroscopic assessment) * They may retain a small of tissue for microscopic assessment * Finally * Organs returned to patient's body cavity * Death certificate issued * Report prepared and sent to PF or clinician * Body is reconstructed for viewing * Body released for burial/cremation

Question 121

Define congenital anomaly and developmental anomaly

Answer 121

Congenital anomalies are ones that exist at or before birth, regardless of the cause and may be either functional/metabolic or structural Developmental anomaly is a deformity, absence or excess body parts/tissues which occur when normal growth is disturbed Developmental Anomaly = Structural Congenital Anomaly

Question 122

Describe Hamartoma

Answer 122

Malformation that may resemble a neoplasm that results from faulty growth in an organ Composed of a mixture of mature tissue elements which would normally be found at that site which develop and grow at the same rate as the surrounding tissue Chondroid Hamartoma - Benign lung lesion composed of epithelium, cartilage, fat and smooth muscle

Question 123

Describe congenital ectopias

Answer 123

An abnormal location or position of an organ or tissue, most often occurring congenitally but also as a result of injury Ectopia Cordis: Displacement of heart outside the body Ectopic Thyroid Tissue: Nodules of mature thyroid tissue located elsewhere in the neck

Question 124

Define hypertrophy, describe important physiological and pathological factors and describe stimuli responsible

Answer 124

'increase in the size of cells and therefore an increase in the size of the organ/tissue' Enlargement is due to an increased synthesis of structural proteins and organelles Occurs when cells are incapable of dividing Can be physiological (muscle hypertrophy) or pathological (LV hypertrophy) Causes by increased functional demand and/or hormonal stimulation

Question 125

Define hyperplasia, describe important physiological and pathological factors and describe stimuli responsible

Answer 125

'increase in the number of cells in an organ or tissue' Adaptive response in cells capable of replication Critical response of connective tissue cells in wound healing Physiological - Hormonal (Normal Proliferative Endometrium) or Compensatory (Occurs when a portion of tissue is removed or diseased) Pathological - Caused by excessive hormonal or growth factors stimulation (androgens; BPH or oestrogen; atypical endometrial hyperplasia)

Question 126

Define atrophy, describe important physiological and pathological factors and describe stimuli responsible

Answer 126

'shrinkage in the size/number of the cells by the loss of cell substance resulting from decreased protein synthesis and increased protein degradation' Causes include; Loss of Innervation, Diminished Blood Supply, Inadequate Nutrition, Decreased Workload, Loss of ENdocrine Stimulation, Aging (Senile Atrophy) e.g. Post-Menopausal Uterus Atrophy, Cortical Atrophy in Dementia

Question 127

Define metaplasia, describe important physiological and pathological factors and describe stimuli responsible

Answer 127

'reversible change from one fully differentiated cell type into another' Adaptation so cells sensitive to a particular stress are replaced by other cells better able to withstand the adverse environment Cigarette Smokers - Normal ciliated columnar epithelial cells of the trachea and bronchi are replaced by stratified squamous epithelial cells Chronic Gastric Reflux - Normal stratified squamous epithelium of the lower oesophagus may undergo metaplasia to gastric columnar epithelium

Question 128

Describe the effects of the mechanical tissue injury, diverticula

Answer 128

Circumscribed pouch/sac caused by herniation of the lining mucosa of an organ through defect in muscular coat * Diverticular Disease * Effects include inflammation, bleeding, perforation and fistulation * When there is chronic inflammation and healing, there will be fibrosis which in turn will cause hypertrophy of the muscle which can lead to stenosis and large bowel obstruction * Meckel's Diverticulum * Congenital * Two inches long, blind-ending duct that is a remnant of the yolk sac at the terminal ileum * Contains all layers of the intestine and often has ectopic pancreatic/gastric tissue within * Complications include inflammation, bleeding, perforation, obstruction, intussusception and pain

Question 129

Describe the effects of the mechanical tissue injury, intussusception

Answer 129

'a process by which a section of intestine invaginates into the adjoining intestinal lumen' Can result in small bowel obstruction, peritonitis or bowel perforation

Question 130

Define neoplasm

Answer 130

‘an abnormal tissue mass the growth of which is excessive (i.e. not an adaption to physiological demands) and uncoordinated compared to adjacent normal tissue that persists even after cessation of the stimuli that caused it’ i.e. Uncontrolled or Irreversible Can be Benign or Malignant

Question 131

Define dysplasia and describe its characteristic features

Answer 131

'disordered growth in which cells fail to differentiate fully, but are contained by the basement membrane, i.e. non-invasive' Cell nuclei become hyperchromic Nuclear membranes become irregular Nuclear to cytoplasmic ratio increases Dysplasia may regress, persist or progress

Question 132

Describe differences between benign and malignant neoplasms

Answer 132

* Benign Neoplasm * A neoplasm that grows without invading adjacent tissue or spreading to distant sites * Usually well-circumscribed due to lack of invasion of surrounding tissues * Malignant Neoplasm * A neoplasm that invades the surrounding normal tissue * Can spread to distant sites (metastasise) * Usually is not well circumscribed

Question 133

Describe different routes of tumour growth and spread

Answer 133

* Local Invasion * Lymphatic Spread * Most common pathway for dissemination of carcinomas (although sarcomas can also use this route) * The pattern of lymph node involvement follows the natural routes of drainage * Haematogenous Spread * Typical of sarcomas * Arteries are more difficult for a tumour to penetrate than veins * With venous invasion, the blood-borne cells follow the venous flow draining the site of the tumour * Liver and lungs are frequently involved * Seeding of Body Cavities (Transcoelomic Spread) * Occurs when a malignant neoplasm penetrates into a natural ‘open field’ such as peritoneal cavity, pleural space, pericardial cavity, etc. * Most common examples include ovarian carcinoma and gastric carcinoma

Question 134

Describe the principles of tumour grading and staging and their clinical relevance

Answer 134

As tumours become more poorly differentiated, the higher the grade Therefore, a poorly differentiated tumour is a high-grade malignancy and a well-differentiated tumour is a low-grade malignancy Tumour stage is based on its size, extent of invasion into the surrounding tissue, spread to regional lymph nodes and presence or absence of lymph nodes Grading and staging are of prognostic importance and can help determine treatment options

Question 135

Describe methods to establish a neoplastic diagnosis

Answer 135

* History & Clinical Examination * Imaging – X-Ray, US, CT, MRI * Tumour Markers Laboratory Analysis – CEA, AFP, Ca125 * Cytology – Pap Smear, FNA, Flow Cytometry * Biopsy – Histopathology, ICC * Molecular – Gene Detection * Bloods - As Appropriate * Scopes - ENT, Bronchoscopy, Gastroscopy, Colonoscopy, Cystoscopy, Colposcopy

Question 136

Describe Carcinoma in Situ

Answer 136

Full thickness epithelial dysplasia extending from the basement membrane to the surface of the epithelium Applicable only to epithelial neoplasms, if the entire lesion is no more advanced than CIS then the risk of metastasis is zero This is because there are no blood vessels or lymphatics within the epithelium above the basement membrane

Question 137

Describe the importance of the bone marrow microenvironment in haemopoiesis

Answer 137

The bone marrow microenvironment (stroma) supports developing haematopoietic stem cells It provides a rich environment for growth and development of stem cells Stromal cells are supported by an extracellular matrix Stromal cells include; Macrophages, Fibroblasts, Endothelial Cells, Fat Cells, Reticulum Cells

Question 138

Describe the major myeloproliferative disorders

Answer 138

Clonal blood disorder characterised by over effective haemopoiesis JAK2 mutation is highly prevalent Too many platelets = Essential Thrombocytosis Too many RBCs = Polycythaemia Rubra Vera Too much fibrous tissue = Myelofibrosis * ET & PRV * Good outcome * Risk of vascular events (managed with aspirin) * Managed by cytoreduction (hydroxycarbamide, venesection or interferon) * 5-10% risk of progression to AML * 10% progress to myelofibrosis * MF * Splenomegaly + Systemic Symptoms * Blood counts may be high or low * Incurable other than with SCT * New drug class - JAK2 inhibitors

Question 139

Describe myelodysplastic syndrome

Answer 139

Clonal blood disorder characterised by failure of effective haemopoiesis (low blood count) More common in the elderly Dysplastic blood and marrow appearance Approx. 25% rate of progression to AML (Blast cell % cut off for MDS vs AML is 20%) Symptoms characterised by consequences of marrow failure Incurable other than with SCT for those \<65yrs Consider supportive care and drug therapy (e.g. azacitidine)

Question 140

State the requirements for normal RBC production

Answer 140

Erythropoietin (Drive for Erythropoiesis) Genes (Recipe for Erythropoiesis) Iron, B12, Folate and Minerals (Ingredients for Erythropoiesis) Functioning Bone Marrow No Increased Loss or Destruction of RBCs

Question 141

Describe the physiology of B12 metabolism

Answer 141

Essential for DNA synthesis and nuclear maturation Required for all dividing cells B12 (Cobalamin) necessary for methionine production and methylmalonyl-CoA isomerisation Found in meats (esp. liver and kidney) Require 1ug/day Absorbed with Intrinsic Factor in the ileum Stores in the body for 3-4 years

Question 142

Describe the physiology of Folate metabolism

Answer 142

Essential for DNA synthesis and nuclear maturation Required for all dividing cells Found in green veg (but destroyed by cooking) Absorbed in the small intestine (no carrier molecule required) Only a few days store in the body but quickly used up if there is increased demand (i.e. increased cell turnover)

Question 143

Describe the effects of B12/Folate deficiency

Answer 143

Affects all tissues with rapidly growing, DNA synthesising cells (bone marrow, epithelia etc.) Blood (B12 and Folate) - Megaloblastic Anaemia Neurological (B12) - Bilateral Peripheral Neuropathy, Demyelination of the Posterior and Pyramidal Tracts of the Spinal Cord Growing Foetus (Folate) - Neural Tube Defects in first 12 Weeks

Question 144

State causes of B12 and Folate deficiency

Answer 144

B12 - Dietary, Pernicious Anaemia, Gastrectomy, Achlorhydria, Crohn's, Ileal Resection Folate - Dietary, Coeliac, Severe Crohn's, Haemolysis, Severe Skin Disorders, Pregnancy

Question 145

Define haemoglobinopathies

Answer 145

'a group of inherited conditions characterised by a relative lack of normal globin chains due to absent genes (thalassaemias) or abnormal globin chains (e.g. sickle cell disease)'

Question 146

Describe Alpha-Thalassaemia

Answer 146

Relative lack of alpha globin chains Alpha globin chains are duplicated on each chromosome for a total of 4 genes Prevalent in Meditteranean countries, Africa, South East Asia and the Indian subcontinent If missing 4 Genes - Incompatible with Life If Missing 3 Genes - HbH Disease (significant anaemia and abnormally shaped RBCs) If Missing 1/2 Genes - Alpha Thalassaemia Trait (mild anaemia, microcytosis, reduced MCV and MCH but increased RBC count)

Question 147

Describe Beta-Thalassaemia

Answer 147

Deficiency in beta globin genes (should normally two) Prevalent amongst Greek Cypriots, Turks, Asians and Africans Beta Thalassaemia Major - Missing Both Genes - Autosomal Recessive - Severe anaemia due to ineffective erythropoiesis and haemolysis renders patient transfusion dependent from early life with iron overload being the major problem Thalassaemia Intermedia Beta Thalassaemia Trait - May be a mild microcytic anaemia, is often confused for IDA

Question 148

Describe Sickle Cell Disease

Answer 148

Arises due to abnormal HbS which occurs following a single amino acid substitution in the beta-globin gene RBCs undergo sickling Results in reduced RBC survival due to haemolysis and vaso-occlusive crises leading to tissue hypoxia and infarction Complications include Stroke, Moya Moya, Acute Chest Syndrome, Retinopathy, Osteonecrosis Crisis Prevention - Hydration, Analgesia, Vaccination, Antibiotics and Folic Acid Cris Management - Oxygen, Fluids, Analgesia, Antibiotics, Transfusion Can be cured with Bone Marrow Transplantation

Question 149

Describe the Direct and Indirect Coombs Test

Answer 149

The Coombs test detects autoantibodies against antigens on the RBC membrane The direct test detects antibodies on the RBC surface and is positive in Haemolytic Disease of the Newborn and Acquired Immunohaemolytic Anaemia The indirect test detects antibodies in the plasma and is used in prenatal screening of Rh antibodies

Question 150

Describe an approach to the investigation of a patient with anaemia

Answer 150

* Is it new? * Congenital or Acquired? * History * Blood Loss * Diet * Chronic Disease * Family History * Medication * Examination * Angular Stomatitis * Splenomegaly * Lymphadenopathy * Abdominal Masses * Haematology * Size of RBCs * Are WBCs/Platelets affected? * Is marrow able to mount a reticulocyte response? * What are the haematinic results? * What does the blood film look like?

Question 151

Define Lymphoma and describe a basic classification system

Answer 151

'a group of malignancies of lymphoid tissue with accumulation of B/T-Lymphocytes' Broadly divided into Hodgkin and Non-Hodgkin Lymphomas

Question 152

Describe the pathology of Hodgkin Lymphoma

Answer 152

The malignant cells (Reed-Sternberg and Hodgkin's cells) comprise a minority of the tumour, with the remainder comprised of lymphocytes, granulocytes, fibroblasts and plasma cells Reed-Sternberg cells are bi/multi-nucleated giant cells of B-Lymphocyte origin Up to 40% of HL cases are associated with EBV

Question 153

Describe the clinical presentation of Hodgkin Lymphoma

Answer 153

Bimodal Age Incidence (20s-30s and \>50s) Painless Lymphadenopathy (Cervical or CXR Mass) Spread from one nodal group to adjacent Later there may be haematogenous spread to liver or lungs May have B symptoms (fever, drenching night sweats or weight loss) Managed by Chemo and Radiotherapy

Question 154

Describe the clinical presentation of high-grade Non-Hodgkin's Lymphomas such as Diffuse Large B-Cell Lymphomas

Answer 154

Most common subtype of NHL Increasing incidence with age Aggressive Often presents with localised or generalised painless lymphadenopathy 40% present extra-nodally with abdominal pain, anaemia, CNS disease or on the skin May also present with Pyrexia of Unknown Origin Managed by R-CHOP Chemotherapy +/- Radiotherapy

Question 155

Describe the pathology of low-grade/indolent Non-Hodgkin's Lymphomas such as Follicular Lymphoma

Answer 155

B-Cell Lymphoma 90% of follicular lymphomas are characterised by the t(14;19) translocation where the BCL2 gene on chromosome 18 is moved to the immunoglobulin heavy chain This leads to excessive expression of BCL2, an oncogene known to inhibit apoptosis it is likely that further change (e.g. activation of a proto-oncogene or an antigenic stimulus) produces the clonal malignancy

Question 156

Describe the clinical presentation of low-grade/indolent Non-Hodgkin's Lymphomas such as Follicular Lymphoma

Answer 156

Increasing incidence with age Median presentation between 60-65 years Often presents with late-stage disease due to its indolent course Local disease may be managed with radiotherapy but most cases require a rituximab-containing regime (e.g. R-CVP or R-CHOP) Average survival of 15-20 years Responsive to treatment but tendency to relapse or transform to DLBCL

Question 157

Describe the staging of Lymphoma

Answer 157

Ann-Arbor Staging System I - Single Lymph Node Group II - More than one LN group on the SAME side of the diaphragm III - LN groups on BOTH sides of the diaphragm IV - Extranodal involvement (e.g. liver, bone marrow) A or B is added to signify absence or presence of B symptoms (fever, night sweats, weight loss) Early Stage = 1 or 2A Advanced Stage = 2B or 3 or 4

Question 158

Describe the diagnosis of Lymphoma

Answer 158

Excision or Core Biopsy of Lymph Node, Other Tissue or Bone Marrow CT Neck, Chest, Abdomen and Pelvis PET-CT

Question 159

Define Multiple Myeloma

Answer 159

'a clonal malignancy characterised by uncontrolled proliferation of plasma cells in the bone marrow and production of monoclonal immunoglobulin'

Question 160

Describe the pathophysiology of Multiple Myeloma

Answer 160

MM is preceded by a clinical syndrome known as Monoclonal Gammopathy of Undetermined Significance Plasma cells in the bone marrow secrete paraprotein (monoclonal immunoglobulin or immunoglobulin fragments) Most produce IgG or IgA or light chains only Occasionally myelomas may be non-secretory Myeloma Triad = Increased Plasma Cells in the Bone Marrow + Clonal Immunoglobulin/Paraprotein + Lytic Bone Lesions

Question 161

Describe the clinical presentation of Multiple Myeloma

Answer 161

Back Pain Rib Pain Pathological Fractures Vertebral Collapse Anaemia Thrombocytopenia Frequent Infection Hypercalcaemia Renal Failure

Question 162

Describe the main differences between Hodgkin's (HL) and Non-Hodgkin's (NHL) Lymphoma

Answer 162

NHL is a monoclonal proliferation of B/T-Lymphocytes and HL is a lymph malignancy of proliferating germinal centres EBV is associated with both HL has a bimodal age distribution HL is characterised by presence of Reed-Sternberg Cells Both present with painless lymphadenopathy and possibly B symptoms and HL may also present with pruritis Contiguous LN spread in HL, Non-Contiguous LN spread in NHL Radiation and Chemotherapy for both

Question 163

State techniques used to diagnose Lymphoma

Answer 163

Morphology Immunohistochemistry Flow Cytometry Karyotyping Fluorescence in situ Hybridisation PCR Clonality Assays Gene Sequencing/Array Based Technologies

Question 164

Describe lymphocyte development

Answer 164

B-Cells are produced in bone marrow from a committed stem cell progenitor Mature B-Cells circulate in peripheral blood and populate lymphoid and other organs T-Cells originate in bone marrow from committed stem cell progenitor Precursor T-Cells migrate to thymus where they develop into mature T-Cells Mature T-Cells circulate in peripheral blood and populate lymphoid and other organs

Question 165

Describe the physiological processes involved in the coagulation system

Answer 165

* Blood Vessel Damage * Endothelial Disruption * Exposure of Tissue Factor and Collagen * Primary Haemostasis * Recruitment of Platelets * Secondary Haemostasis * Activation of Coagulation Factors * Cascade: * Initiation - Extrinsic Pathway * Propagation - Intrinsic Pathway * Thrombin Generation * Fibrin Production (The Clot) * Each step in the cascade requires phospholipids from the platelet surface and calcium

Question 166

State the laboratory tests used to assess the coagulation system

Answer 166

* Assessment of Primary Haemostasis * In Vivo - Bleeding Time * Ex Vivo - FBC, Platelet Count, Platelet Function * Assessment of Secondary Haemostasis * Prothrombin Time (PT) * Activated Partial Thromboplastin Time (APTT) * Thrombin Clotting Time (TCT) * Individual Coagulation Factor Assays

Question 167

Describe the use of Prothrombin Time (PT) to assess the coagulation system

Answer 167

Simulates activation via the extrinsic pathway Add patient's plasma and thromboplastin, warm to 37C, add calcium and time taken to form clot Normal range is 10-13 seconds Ratio is the patient's PT/average of 20 normal PTs (normal ratio is 1 - 1.2) PT depends on factors in the extrinsic and common pathways (Factors VII, X, V, II and Fibrinogen)

Question 168

Describe the use of International Normalised Ratio (INR) to assess the coagulation system

Answer 168

The standardised form of prothrombin time Used in the monitoring of oral coumarins such as Warfarin A patient's INR is identical in any laboratory Patient's PT/Average of 20 Normal PTs Result factored by the International Sensitivity Index (ISI) Every thromboplastin preparation has its own ISI

Question 169

Describe the use of Activated Partial Thromboplastin Time (APTT) to assess the coagulation system

Answer 169

Stimulates activation via the intrinsic pathway Add the patient's plasma, contact factor and phospholipid Warm to 37C and add calcium and time the taken to form a clot Normal range is 26-38 seconds Ratio of Patient/Average of 20 Normals APTT depends on factors in the intrinsic and common pathways (Factors VIII, IX, XI, XII, X, V, II and Fibrinogen)

Question 170

Describe the use of Thrombin Clotting Time (TCT) to assess the coagulation system

Answer 170

Measures conversion of fibrinogen to fibrin clot At 37C, add the patient's plasma and bovine thrombin Less calcium or phospholipid-dependent Measure the time taken to clot Normal range is 10-16 seconds Depends on how much fibrinogen is present in the plasma and how well it functions Will also be prolonged by inhibitors of thrombin (heparin, dabigatran), FDPs or inhibitors of fibrin polymerisation (paraprotein)

Question 171

State and briefly describe the three classes of anti-thrombotics

Answer 171

Anti-Coagulants (inhibit one or several components of the coagulation cascade) Fibrinolytic Agents (enhance lysis of the fibrin clot) Anti-Platelet (inhibit platelet activation or aggregation)

Question 172

Describe some of the acquired disorders of the coagulation system

Answer 172

* Disseminated Intravascular Coagulation * Acquired, consumptive process with activation of the coagulation cascade (resulting in microthrombi) and subsequent exhaustion of the coagulation cascade (resulting in bleeding) * Caused by sepsis, malignancy, massive haemorrhage, severe trauma or complications in pregnancy * Treat the underlying cause and give FFP +/- platelets if bleeding or at high risk * Warfarin-Induced Bleeding * If INR is too high, stop warfarin or reduce dose, give Vitamin K or give coagulation factors * Coagulopathy in Liver Disease * Poor coagulation factor synthesis due to liver damage

Question 173

Describe some of the inherited disorders of the coagulation system

Answer 173

* Haemophilia A * Classical Haemophilia * Factor VIII Deficiency * Prolonged APTT * X-Linked Inheritance * Replacement with Recombinant Produced Factor Concentrate * Von Willebrand Disease * VW Factor facilitates platelet adhesion and aggregation in primary haemostasis * Binds Factor VIII and prolongs its half-life in the plasma * Thrombophilia * Deficiencies of natural anticoagulants such as antithrombin, Protein C or Protein S * May be due to specific gene mutations such as Factor V Leiden (resistance to APC) or the prothrombin gene (which results in increased prothrombin)

Question 174

Describe developmental abnormalities involving the breast

Answer 174

* Ectopic (Heterotopic) Breast Tissue * Commonest congenital abnormality * Most often on 'milk line' between axilla and groin * Absent Nipple * Nipple with Little Glandular Development * Breast Hypoplasia * Macromastia * Stromal overgrowth leading to excessive breast size, occasionally begins at puberty (juvenile hypertrophy) or during pregnancy (gestational hypertrophy) * Nipple Inversion * Asymmetry

Question 175

Describe periductal mastitis

Answer 175

Periductal Mastitis/Plasma Cell Mastitis/Duct Ectasia A dilation of central lactiferous ducts, periductal chronic inflammation and scarring Often asymptomatic but there may be discomfort, a mass, nipple retraction or inversion Calcified luminal secretions may be seen on mammogram It is commonest in middle age and is associated with smoking

Question 176

Describe fat necrosis of the breast

Answer 176

The initial change is disruption of fat cells where vacuoles with the remnants of necrotic fat cells are formed They then become surrounded by lipid-laden macrophages, multinucleated giant cells, and acute inflammatory cells Fibrosis develops during the reparative phase peripherally enclosing an area of necrotic fat and cellular debris Eventually, fibrosis may replace the area of degenerated fat with a scar, or loculated and degenerated fat may persist for years within a fibrotic scar May follow trauma Benign, but biopsy may be required to exclude cancer

Question 177

Describe intraduct papilloma of the breast

Answer 177

A benign tumour of the epithelium lining of the mammary ducts Solitary central papillomas are thought to be innocuous if there is no epithelial atypia Multiple papillomas (papillomatosis) are thought to be slightly more likely to be associated with malignancy elsewhere in the same or the contralateral breast

Question 178

Describe fibroadenoma of the breast

Answer 178

About 25% of asymptomatic women have at least one fibroadenoma in which there is characteristic overgrowth of epithelium and stroma Symptomatic fibroadenomas are commonest in young women Usually regarded as a benign neoplasm, hormone-sensitive and regress after the menopause Usually firm, non-tender, mobile, usually \<25-30mm Rare fibroadenomas in adolescent girls may become very large

Question 179

Describe the ranges of fibrocystic change in the breast

Answer 179

Very common and frequent benign breast condition Tends to be multifocal and bilateral and may cause breast tenderness and nodularity Ranges from small/large cysts, increased amounts of glandular tissue (adenosis), increased fibrous stroma, epithelial hyperplasia (of usual or occasionally atypical type)

Question 180

State factors modifying breast cancer risk

Answer 180

Early Menarche Late Menopause Being Older at First Pregnancy Oral Contraceptive Use HRT Obesity Alcohol Family History (BRCA1/BRCA2) Protective factors include Exercise and Breast Feeding

Question 181

Describe signs and symptoms of breast cancer

Answer 181

* New lump or thickening in breast or axilla * Altered shape, size or feel of the breast * Pain * Skin changes: * Puckering * Dimpling * Skin oedema (orange peel) * Rash * Redness * Nipple changes: * Tethering/inversion * Discharge * Eczema-like change * Widespread inflammation * Redness

Question 182

Describe the diagnosis of breast cancer

Answer 182

* Clinical Examination * Imagine * USS * X-Ray Mammography * MRI * Fine Needle Aspiration Cytology * Core Biopsy * Excisional Biopsy * May be diagnostic, therapeutic or both * Women between 47 and 73 are invited for triennial 2-view mammography breast screening and may self-refer after 73

Question 183

Describe the importance of steroid hormone receptors in breast cancer

Answer 183

About 80% of breast cancers overexpress oestrogen receptors (ER) and progesterone receptor (PR) ER/PR positive carcinomas are likely to respond to endocrine treatment (e.g. with Tamoxifen which in breast is predominantly an ER antagonist) In endometrium and bone, Tamoxifen has a significant agonistic effect and there is elevation of endometrial cancer risk in women treated with Tamoxifen

Question 184

Describe the importance of Her2 status in breast cancer

Answer 184

As a group, cancers which overexpress Her2 have a worse prognosis than other breast cancers But treatment with the monoclonal antibody Trastuzumab (Herceptin) and other Her2 targeted therapies has improved outcomes Adjuvant Herceptin reduces the risk of relapse in women with Her2 +ve breast cancer and prolongs survival in women with metastatic breast cancer

Question 185

Describe the grading of breast cancers

Answer 185

Based on Nuclear Pleomorphism, Number of Mitoses per mm2 and Degree of Gland Formation by the Cancer Cells Grade 1 - Well-Differentiated and Slow Growing Grade 2 - In Between Grade 3 - Poorly Differentiated and Fast Growing

Question 186

Describe the Nottingham Prognostic Index

Answer 186

Prognostic index for breast cancer, following surgery (Tumour Size x 0.2) + Grade + LN Involvement 0 Nodes = 1 1-3 Nodes = 2 4+ Nodes = 3 Higher the NPI, the lower the 5 Yr SR

Question 187

Describe the molecular classification of breast cancer

Answer 187

The main distinction is still between ER -ve and ER +ve cancers Luminal A ER+ cancers tend to be low grade, less proliferative and have a better prognosis Luminal B ER+ cancers tend to be high grade, more proliferative and potentially do less well In the ER- cancer group, there are three subtypes; normal breast-like, Her2 or basal-like

Question 188

Describe the management options for breast cancer

Answer 188

Surgery (wide local excision plus radiotherapy or mastectomy for larger cancers) Endocrine targeted treatment can help prevent relapse at distant sites in triple negative cancers especially, adjuvant chemotherapy is important 1 in 3 potential episodes of metastatic relapse can be prevented by adjuvant chemotherapy

Question 189

Describe cervical intraepithelial neoplasia (CIN)

Answer 189

Replacement of normal squamous epithelium by neoplastic squamous cells Basement membrane remains intact The neoplastic cells have the usual morphological features, abnormally intense staining (hyperchromasia), greater variability (pleomorphism) and fail to mature properly (and go on proliferating with mitotic cells visible) as they migrate from the base of the epithelium to its surface Immature and dividing cells are confined to the basal 1/3 of the epithelium in CIN 1, the basal 2/3 in CIN 2 and persist into the surface 1/3 in CIN 3 Invasive squamous carcinoma of the cervix almost always develops from pre-existing CIN, but not all CIN will become squamous cancer CIN 2 and CIN 3 are more likely to progress than CIN 1

Question 190

Describe squamous metaplasia of the cervical transformation zone

Answer 190

Prior to puberty, the ectocervix is covered by non-keratinising stratified squamous epithelium and the endocervix is lined by columnar (glandular) epithelium With growth of the cervix after puberty, the squamo-columnar junction is everted into the vagina and the squamous epithelium adapts to the vaginal environment by squamous metaplasia in the 'transformation zone' These changes are reversed at the menopause This zone of unstable differentiation is where most cervical neoplasia develop

Question 191

Describe the effect of HPV on the cervix

Answer 191

More than 99% of cervical carcinomas are associated with HPV infection Even in the absence of CIN, HPV infection does visibly affect the cells of the cervical squamous epithelium Even in the absence of productive infection, viral DNA can persist extra-chromosomally or integrated into the host's cells High risk HPV types 16 and 18 are strongly associated with CIN 2, CIN 3 and cervical cancer

Question 192

State the outcomes of cervical smear reporting

Answer 192

* Negative * Repeat Routinely in 3 Years * Borderline Nuclear Abnormality * Repeat 6 Months * (If 3 x BNAs - Refer to Colposcopy) * Mild, Moderate or Severe Dyskaryosis * Refer to Colposcopy * Features SUggestive of Invasion * Urgent Referral to Colposcopy

Question 193

Describe the features and effects of Salpingitis

Answer 193

Part of the spectrum of pelvic inflammatory disease Most commonly infective (mainly bacterial - chlamydia trachomatis, mycoplasma, coliforms, streptococci, staphylococci, Neisseria gonorrhoea) Usually considered to be an ascending infection Symptoms include fever, lower abdominal/pelvic pain and pelvic mass (if tubes distended with exudate or secretions) Complications: Adherence of tube to ovary (tubo-ovarian abscess); Adhesions involving tubal plicae increase risk of ectopic pregnancy; Damage or obstruction of tube lumen may produce infertility which may be difficult to treat

Question 194

Describe the features and effects of non-neoplastic cysts of the ovaries

Answer 194

Non-neoplastic cysts include inclusion, follicular and luteal cysts Symptoms include oligomenorrhoea, hirsutism, infertility, over-production of androgens by cystic follicles, high LH and low FSH Effects include enlarged ovaries, multiple subcortical cysts (5-15mm), thickened and fibrotic outer surface, absence of corpus lutea and corpus albicans (as ovulation is not occurring) and insulin resistance (which may lead to T2DM)

Question 195

Describe the processes, features and effects of ovarian surface epithelial tumours

Answer 195

Thought to arise from coelomic mesothelium on the surface of the ovary Benign lesions usually cystic (cystadenoma) with or without a solid stromal component (cystadenofibroma) Malignant epithelial tumours (carcinomas) may be cystic (cystadenocarcinoma) or solid (adenocarcinoma) Carcinomas may be high grade serous (HGSC), endometroid, clear-cell, low grade serous (LGSC) or mucinous HGSC is closely associated with p53 and BRCA1 mutations Most women with ovarian cancer present late and in many the prognosis is poor (Surface epithelial tumours also have an intermediate, borderline category called tumours of low malignant potential which have limited invasive potential and a much better prognosis)

Question 196

Describe ovarian sex cord/stromal tumours

Answer 196

These include granulosa and theca cell tumours which often secrete oestrogen and (uncommonly) Sertoli-Leydig cell tumours which may secrete androgens Granulosa cell tumours usually occur in post-menopausal women and are not rare (oestrogen overproduction may lead to endometrial hyperplasia or endometrial carcinoma) Ovarian fibromas and thecomas are usually benign and not rare

Question 197

Describe the features of ovarian germ cell tumours

Answer 197

95% of ovarian germ cell tumours are mature cystic teratomas (dermoid cysts) Totipotent germ cells differentiate into mature tissues of all 3 germ cell layers Mostly found in young women as ovarian masses or found incidentally on abdominal scans May contain foci of calcification associated with bone or teeth Approx. 10% are bilateral Grossly they appear smooth, filled with sebaceous secretions and matted hair Sometimes foci of bone and cartilage, nests of bronchial or GI epithelium, teeth and other recognisable lines of development may be present About 5% of ovarian teratomas in adult are immature cystic teratomas, associated with more aggressive behaviour

Question 198

Describe endometrial carcinoma

Answer 198

Usually in older women, over 50 years of age May be accompanied by background endometrial hyperplasia and oestrogen excess Lynch syndrome is also a risk factor Must be excluded in cases of post-menopausal bleeding Investigations include endometrial biopsy, transvaginal ultrasound or hysteroscopy Bilateral salpingo-oophorectomy is usually appropriate as well as hysterectomy Prognosis is stage dependent, but other factors include grade, lymphovascular space invasion and tumour cells in peritoneal washings Carcinosarcoma (Malignant Mixed Mullerian Tumour) are high grade serous carcinomas of the endometrium with a worse prognosis

Question 199

Describe leiomyomas (fibroids) of the uterine smooth muscle

Answer 199

Extremely common, often multiple, almost always benign smooth muscle tumours of the uterine body Symptoms include dysmenorrhoea, menorrhagia and discomfort Most active during the reproductive years and involute following the menopause Hormonal treatments may relieve symptoms but occasionally surgery is appropriate Uterine artery embolisation by interventional radiology is an alternative option

Question 200

Describe leiomyosarcomas of the uterus

Answer 200

Rare, but the most common non-epithelial malignancy Soft mass, poorly circumscribed outline May cause haemorrhage and necrosis Much more abnormal histology Vascular invasion may spread via the bloodstream to the lungs Poor long-term prognosis

Question 201

Describe adenomyosis

Answer 201

Basal endometrium extends abnormally into hyperplastic myometrium May co-occur with endometriosis Peaks between 35 and 50 Pts often present with dysmenorrhoea and menorrhagia May be focal or diffuse In diffuse involvement, the uterus becomes bulky and heavier

Question 202

Describe endometriosis

Answer 202

Presence of endometrial glands and stroma outside the body of the uterus Mechanisms are not fully understood but include retrograde menstruation, local metaplasia of surface epithelium and dissemination via the bloodstream Inflammation, cysts and scarring associated with endometriosis can cause significant symptoms and compromise fertility

Question 203

Describe Gestational Trophoblastic Disease

Answer 203

A group of conditions characterised by excessive proliferation of trophoblasts The classical hydatidiform mole is a mass of large oedematous chorionic villi Complete Mole - No Foetus - Unispermis or dispermic fertilisation of an 'empty' egg (genotype 46XX or 46XY) Partial Mole - Foetus Usually Present - Haploid egg fertilised by one sperm which reduplicates, or by 2 sperm (genotype 69XXY or 92XXXY) Risk of progression to chorioncarcinoma Requires monitoring of hCG levels

Question 204

Describe the Alkylating Agent class of chemotherapy drug

Answer 204

e.g. Cyclophosphamide, Cysplatin, Melphalan Form irreversible covalent bonds with DNA to interfere with transcription and replication Used in a range of cancers from lymphoma (mechlorethamine), multiple myeloma, ovarian and breast cancer (melphalan)

Question 205

Describe the Anti-Metabolite class of chemotherapy drug

Answer 205

e.g. Methotrexate, 5-Fluorouracil, Mercaptopurines, Cytarabine |nterfere with nucleotide or DNA synthesis Methotrexate - Folate Antagonist 5-Fluoriuracil - Pyrimidine Analogue Mercaptopurines - Purine Analogues

Question 206

Describe the Cytotoxic Antibiotic class of chemotherapy drug

Answer 206

e.g. Dactinomycin, Doxorubicin Act mainly by direct action on DNA as intercalators Dactinomycin disrupts function of RNA polymerase by inserting itself into the minor groove of the DNA helix Doxorubicin inserts itself between base pairs to impair DNA and RNA synthesis

Question 207

Describe the Microtubule Inhibitor class of chemotherapy drug

Answer 207

e.g. Vincristine Binds to microtubular protein, blocks tubulin polymerisation and normal spindle formation to disrupt cell division

Question 208

Describe the Steroid Hormone and Antagonist class of chemotherapy drug

Answer 208

Tumours may be responsive to a hormone which make it regress, or it may be relient on a hormone to grow, in which case an antagonist of the hormone will suppress growth Prednisolone - Suppressed lymphocyte growth Tamoxifen - Oestrogen receptor antagonist used in ER+ve breast cancers Casodex (Bicalutamide) - Testosterone receptor antagonist used in prostate cancers which are testosterone dependent

Question 209

Describe the principles of cancer chemotherapy

Answer 209

Cell cycle drugs are only effective on the subset of the cell population currently undergoing cell division Resting (G) phase cells are therefore less sensitive to these drugs and care the cause of many relapses The aim must be for a total kill and prolonged treatment is required to reduce the chance of relapse from resting cells Chemotherapy drugs do not reverse de-differentiation, invasiveness or metastasis General side effects include bone marrow suppression, hair loss, damage to GI epithelium, organ damage, sterility, teratogenicity and depression of growth in children

Question 210

Describe the basic physics underlying an ECG

Answer 210

ECG records the electrical activity of the heart from the skin This is usually done by a 12-Lead ECG, where a lead is an electrical vector Unipolar Leads measure the potential variation at a single point (Limb Leads aVR, aVL and aVF and Chest Leads V1-V6) Bipolar Leads measure the potential difference between two points (Leads I, II and III)

Question 211

State a systematic approach to interpreting an ECG

Answer 211

1. Consider clinical context 2. Check date, time and patient details 3. Assess technical quality (artefaxct, paper speed (normal is 25mm/s) and gain (normal is 10mV/mm) 4. Identify P wave, QRS complex and T wave 5. Measure HR 6. Check intervals 7. Look at P/QRS/T morphology N.B - Do not rely on automatic interpretation and look at old ECGs if possible

Question 212

Describe features of a normal ECG

Answer 212

Sinus Rhythym (each P wave is followed by a QRS complex) Normal HR PR interval \<1 large square (\<200ms) QR interval \<3 small squares (\<120ms) QT interval \<11 small squares (\<440ms) Positive QRS complex in leads I and II P wave upright in inferior leads ST segment flat T wave has same polarity as QRS complex

Question 213

Describe the common bradyarrhythmias

Answer 213

* Sinus Bradycardia * Rate \<60bpm * Regular, Narrow QRS * P Waves Present * P:QRS - 1:1 * Junctional Bradycardia * Rate \<60bpm * Regular, Narrow QRS * No P Waves * Second Degree AV Block * Slowest Rate (\<60bpm) * Irregular, Narrow QRS * P:QRS is not 1:1 * Complete AV Block * Rate \<60bpm * Regular, Broad QRS * No Relation Between P and QRS

Question 214

Describe and diagnose this ECG

Answer 214

Regular Rhythym No Relation Between P and QRS HR \<60bpm Complete Heart Block

Question 215

Describe and diagnose this ECG

Answer 215

Regular, Sinus Rhythm Rate = 56bpm P:QRS is 1:1 Sinus Bradycardia

Question 216

Describe the narrow complex tachyarrhythmias

Answer 216

* Sinus Tachycardia * Rate \>100bpm * Regular, Narrow QRS * P Waves Present * P:QRS is 1:1 * Atrial Fibrillation * Variable Rate (Fast) * Irregular, Narrow QRS * No P Waves * Atrial Flutter * Rate approx. 300bpm * Regular, Narrow QRS * May Get Variable AV Block * Sawtooth Atrial Activity * Supraventricular Tachycardia * Rate \>150bpm * Regular, Narrow QRS * P:QRS is 1:1 * P Waves May be Present

Question 217

Describe and diagnose this ECG

Answer 217

Regular, Sinus Rhythm 150bpm P Waves followed by QRS Complex (1:1) Narrow QRS = Sinus Tachycardia

Question 218

Describe and diagnose this ECG

Answer 218

Irregular Rhythym Narrow QRS No discernible P waves = Atrial Fibrillation

Question 219

Describe and diagnose this ECG

Answer 219

Irregular Rhythm Saw Tooth Pattern No discernible P waves = Atrial Flutter

Question 220

Describe and diagnose this ECG

Answer 220

Regular Rhythym Rate - 83bpm ST elevation in V1-4 Reciprocal ST depression in III Hyperacute peaked T waves in V2-4 = (Anterior) STEMI

Question 221

State which lead in a standard 12 lead ECG represents each position in the heart (i.e. Anterior, Lateral, Inferior, Septal)

Answer 221

Question 222

Describe the radiological signs of heart failure

Answer 222

Pleural Effusions Cardiomegaly Kerley B Lines (horizontal lines of the periphery of the lower posterior lung fields) Upper Lobe Pulmonary Venous Congestion Interstitial Oedema

Question 223

Describe the pathophysiology of heart failure

Answer 223

Dysfunction of the ventricles begins with myocardial damage which may be due to infection or ischaemia This results in a perceived reduction in the circulating volume and pressure Compensatory mechanisms are initiated to correct this, including increase in sympathetic tone, RAS activation, adrenaline and natriuretic peptide release Angiotensin II is produced, which increased sodium and water retention which initially helps to increase the blood volume and pressure to maintain cardiac output However, in the long term these mechanisms perpetuate the disease Increased HR = Increased Oxygen Demand Increased Total Peripheral Resistance = Increased Workload - Contributes to Underperfusion and Ischaemia of the heart Increased Stretching of Ventricular Wall = Reduced Contractility - Leads to fluid transudation into interstitial tissue causing peripheral and pulmonary oedema

Question 224

Describe the clinical presentation of heart failure

Answer 224

Symptoms: Dyspnea, Orthopnoea, PND, Fatigue, Exercise Intolerance, Cough, Ankle Swelling Signs: Peripheral Oedema, Elevated JVP, 3rd Heart Sound, Displaced Apex (Cardiomegaly), Lung Crackles (Pulmonary Oedema), Pleural Effusion

Question 225

Describe the mechanism of action of drugs used to manage heart failure

Answer 225

* ACE Inhibitors or Angiotensin II Receptor Blocks * e.g. Enalapril or Valsartan * Reduce activity of AngII to reduce afterload and fluid retention to slow progression of LV dysfunction * Beta Blockers * e.g. Carvedilol * Reduces afterload and HR to reduce work on the heart * Mineralocorticoid Receptor Antagonist * e.g. Spironolactone * Inhibits sodium resorption to reduce retention of sodium and water * Ivabradine * Acts on the 'funny channel' to reduce HR * Digoxin * Increases force of contraction while reducing rate of conduction through the AV node

Question 226

Describe options for non-pharmacological management of heart failure

Answer 226

Lifestyle Modification Implantable Cardioverter Defibrillator Cardiac Resynchronisation Therapy CABG Ventricular Assist Device Transplant

Question 227

Describe the pathogenesis of and pathological changes seen in aortic stenosis

Answer 227

Stenosis arises from thickening and calcification of the valve leaflets Stenosis results in a pressure overload in the LV leading to LV hypertrophy May arise congenitally, or due to rheumatic valve disease Symptoms include SOB, (pre)syncope, chest pain and reduced exercise capacity Signs include an ejection systolic murmur and slow rising pulse

Question 228

Describe the pathogenesis of and pathological changes seen in aortic regurgitation

Answer 228

Can arise due to a variety of reasons, including degeneration, rheumatic valve disease, aortic root dilation, Marfan's. SLE or endocarditis Backflow of blood into the LV causes a volume overload and LV dilation Symptoms include SOB and reduced exercise tolerance Signs include a diastolic crescendo murmur

Question 229

Describe the pathogenesis of and pathological changes seen in mitral stenosis

Answer 229

Almost always caused by rheumatic valve disease Obstruction of the mitral valve leads to pressure overload in the left atrium and pulmonary circulation which can result in atrial/pulmonary hypertension, AF and secondary right heart failure Symptoms include SOB, palpitations, chest pain, syncope, RH failure symptoms and haemoptysis Signs include a loud S1 and an opening snap close to S2

Question 230

Describe the pathogenesis of and pathological changes seen in mitral regurgitation

Answer 230

May be due to endocarditis, rheumatic valve disease, Marfan's syndrome, cardiomyopathy or Ehlers-Danlos syndrome Causes pressure overload in both the LA and LV, causing LA and LV dilation Can lead to pulmonary hypertension, secondary right heart dilation and atrial fibrillation Symptoms include SOB, palpitations, RH failure symptoms Signs include a pan-systolic murmur, heave, displaced apex

Question 231

Describe the management of common valvular heart disorders

Answer 231

Symptomatic medical management of heart failure symptoms, AF, oedema etc with Beta Blockers, ACE Inhibitors, Digoxin, Diuretics, Nitrates Surgical valve replacement is an option for some, with either a tissue or mechanical valve (the latter requires life-long anticoagulation but generally lasts longer) Procedural options include TAVI (transcatheter aortic valve implantation), MitraClip (transcatheter mitral valve repair) or valvuloplasty (widening of a stenotic aortic valve using a balloon catheter)

Question 232

Describe the clinical features of infective endocarditis

Answer 232

May be acute or sub-acute onset Fever Breathlessness Night Sweats Fatigue Anorexia Dyspnea Weight Loss New Heart Murmur Symptoms of Heart Failure Embolic Phenomena (Stroke, Pleuritic Chest Pain, Abdominal Pain, Back Pain) Splinter Haemorrhages Janeway Lesions Petechial Rash Osler's Nodes Roth Spots (Retina)

Question 233

Describe the diagnosis of infective endocarditis and its diagnostic criteria

Answer 233

3 Sets of Blood Cultures Echocardiography (TTE as first line) Elevated WCC/CRP ECG Haematuria or Pyuria on Urinalysis - Modified Duke Criteria states a diagnosis of IE is definite in the presence of 2 major criteria, 1 major and 3 minor criteria or 5 minor criteria Major Criteria: Blood Cultures +ve for IE and Evidence of Endocardial Involvement Minor Criteria: Predisposition, Fever, Vascular Phenomena, Immunological Phenomena, Microbiological Evidence

Question 234

Describe the microbiology of organisms associated with infective endocarditis

Answer 234

* In descending order of frequency * Staph. Aureus * Associated with IVDU * Staph Epidermis * Device/Line Related IE or Early PVE * Strep Viridans (oral Streptococci) * NVE * Strep Gallolyticus (non-oral Streptococci) * Enterococci The above account for more than 85% of all cases of IE Most commonly S. Aureus (26.6%) The remainder below account for a small minority * HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella Corrodens, Kingella) * Candida Species * Other/Polymicrobial

Question 235

Describe the management of infective endocarditis

Answer 235

Empirical antibiotics should be given as soon as blood cultures are obtained NVE: Amoxicillin + Flucloxacillin + Gentamicin PVE: Vancomycin + Gentamicin + Rifampicin IV treatment give for at least 4-6 weeks 40-50% of patients undergo cardiac surgery due to valve dysfunction leading to heart failure, uncontrolled infection or to prevent embolism

Question 236

Describe the main imaging techniques used in cardiology and their indications

Answer 236

* ECG * Representation of electrical activity of the heart, showing abnormalities of rhythm, conduction or repolarisation * Used in myocardial infarction, AF * CXR * Can give information on the cardiac silhouette, pulmonary vasculature and great vessels * Can be used to detect pulmonary oedema and pleural effusions * Echocardiography * Transthoracic or Transoesophageal * Gives information on blood flow through the heart (function), valves and chambers (structure) * Can be used in conjunction with doppler * Indications include valve assessment, pericardial assessment and assessment of inducable ischaemia * Nuclear Perfusion Imaging * Used to assess ischaemia and ejection fraction * Cardiac CT * Used to assess coronary artery or great vessel anatomy * Requires low heart rate and radiation dose * Angiography * Both diagnostic and therapeutic * Used to assess ischaemia, valves, ventricular pressure or in Primary PCI * Risks include CVA, MI or death * Cardiac MRI * Indications include assessment of structure and function, great vessel assessment and tissue characterisation (e.g. infiltrative cardiomyopathies or previous infarction)

Question 237

Describe the pathophysiology of acute coronary syndromes

Answer 237

ACS is a spectrum of disease from Unstable Angina on one end to STEMI at the other, with NSTEMI in the middle The typically arise on a background of atherosclerosis and coronary artery disease When a plaque in the coronary arteries ruptures and disrupts blood flow, heart muscle supplied by that vessel will become ischaemic and soon will infarct and necrose These are typically Type 1 MIs Type 2 MIs are due to an increased oxygen demand or decreased oxygen supply (e.g. due to heart failure, sepsis etc.)

Question 238

Describe the clinical presentation of coronary artery disease

Answer 238

Chest, Back or Jaw Pain (typically crushing) Sweatiness, Clamminess SOB Tachycardia Distress Crackles Elevated JVP Shock Arrhythmia

Question 239

Describe the diagnosis of an acute myocardial infarction

Answer 239

Clinical history consistent with ACS ECG changes (ST elevation/depression in 2 contiguous leads) Raised troponin HEART score \>5

Question 240

Describe the management options for acute myocardial infarction

Answer 240

Oxygen and ECG Aspirin 300mg PO Morphine 5-10mg IV Metoclopramide 10mg IV (Anti-Emetic) Ticagrelor 180mg PO Heparin 5000U IV Activate Primary PCI Team and Arrange Immediate Transfer to GJNH If not suitable for PPCI, thrombolysis should be given with Tenecteplase (and Clopidogrel in place of Ticagrelor)

Question 241

Describe complications of an acute myocardial infarction

Answer 241

Arrhythmias (AF, VT, VF) Heart Failure Cardiogenic Shock Myocardial Rupture Psychological Effects (Anxiety and Depression)

Question 242

Describe long term management following an acute myocardial infarction

Answer 242

Monitor in Coronary Care Unit Secondary prevention pharmacotherapy (ACEi, Beta Blockers, Statins, Nitrates, Aspirin Echocardiogram for assessment of LV function Cardiac Rehabilitation

Question 243

Describe the pathophysiology and treatment of an Atrial Septal Defect

Answer 243

Acyanotic defect with a left to right shunt Most common defect is a Secundum ASD (basically a patent foramen ovale) followed by a Primum ASD (basically a partial AVSD) Can result in arrhythmias, heart failure, wheeze, split-second heart sound and an ejection systolic murmur Percutaneous catheterisation is most often used for secundum defects with surgical closure reserved for more complex defects

Question 244

Describe the pathophysiology and treatment of Coarctation of the Aorta

Answer 244

‘a narrowing in the aorta, most commonly at the site of insertion of the ductus arteriosus, just distal to the left subclavian artery’ Acyanotic defect with a left to right shunt Typically presents at Day 3, when ductus arteriosus closes Upper body hypertension and lower body hypotension May require surgical balloon opening and stenting

Question 245

Describe the pathophysiology and treatment of Tetralogy of Fallot

Answer 245

Ventricular Septal Defect + Overriding Aorta + RV Outflow Obstruction (Pulmonary Stenosis) + RV Hypertrophy Cyanotic defect with right to left shunt Curative open heart surgery to repair various defects Management of acute 'tet spells' with beta-blockers and oxygen

Question 246

Describe the pathophysiology and treatment of Transposition of the Great Arteries

Answer 246

Pulmonary Artery and Aorta are switched LV --\> Pulmonary A. RV --\> Aorta Treated by prostaglandins to keep the ductus arteriosus patent followed by an arterial switch operation

Question 247

Describe the pathophysiology of Tricuspid Atresia and its surgical management

Answer 247

Malformation of the tricuspid valve, resulting in an inability of blood flow from the right atrium to the right ventricle Therefore, it requires both an atrial and ventricular septal defect so blood can pass from the right atrium to the pulmonary arteries Managed surgically by the Fontan or TCPC procedure In Fontan circulation, the single ventricle supports systemic circulation while systemic venous return is directed to pulmonary arteries (bypassing the ventricular mass) The ASD is closed and the pulmonary aa. grafted to the RA, bypassing the RV

Question 248

State causes/precipitants of Atrial Fibrillation

Answer 248

Coronary Artery Disease, Structural Heart Disease, Heart Failure, Valvular Disease, Hypertension Thyroid Dysfunction, COPD, Diabetes, Obesity, Electrolyte Disturbance, Pulmonary Emboli Infection, Smoking, Caffeine, Alcohol Excess

Question 249

Describe investigations used in the diagnosis of Atrial Fibrillation

Answer 249

ECG: Irregularly Irregular Rhythm, No Discernible P Waves, Absence of Isoelectric Baseline, Fibrillatory Waves TFTs, Echocardiogram, LFTs, U&Es, CRP, Blood Cultures

Question 250

Describe the pharmacological management of Atrial Fibrillation

Answer 250

Strategies include Rate versus Rhythm control NICE recommends rate control as the first line strategy in most patients * Rate Control * Class IV: Calcium Channel Blockers (e.g. Verapamil or Diltiazem) * Class II: Beta Blockers (e.g. Carvedilol or Bisoprolol) * Class V: Other (e.g. Digoxin) * Rhythm Control * Class I: Na Channel Blockers (e.g. Flecainide) * Class III: K Channel Blockers (e.g. Amiodarone)

Question 251

Describe the non-pharmacological management of Atrial Fibrillation

Answer 251

* Acute Rhythm Control * Synchronised Direct Current Cardioversion * 3 weeks of anticoagulation prior to DCCV followed by 4 further weeks of anticoagulation * Transcatheter Therapy * Isolation of pulmonary veins by Radio Frequency Ablation or Cryoballoon * Surgical Therapy * Maze procedure (channelled impulse propagation) * Rate Control * Transcatheter Therapy * Ablation of AV node/His bundle, resulting in iatrogenic 3rd-degree heart block * Controls ventricular rate in AF, however, renders patient Pt pacemaker dependent for life

Question 252

Describe the principles of thromboembolism prevention in Atrial Fibrillation

Answer 252

Risk of stroke and systemic embolism should be assessed using the CHA₂DS₂-VASc Score Men with a score of 1 or more and women with a score of 2 or more are more likely to benefit from oral anticoagulation OACs prevent the majority of ischaemic strokes in AF and can prolong in life, a net clinical benefit is almost universal Vitamin K Antagonists (e.g Warfarin) - Only treatment to be used in patients with mitral stenosis or mechanical valve prosthesis DOACs (e.g. Dabigatran, Apixaban, Rivaroxaban) - Predictable onset and offset without need for regular monitoring Non-pharmacological approaches include transcatheter occlusion of the left atrial appendage, where it is endothelialised by the cardiac tissue (it has been shown to be non-inferior to VKAs for stroke prevention in non-valvular AF)

Question 253

Describe the causes of hypertension

Answer 253

Primary HTN is by definition idiopathic (risk factors include age, gender, ethnicity, diet, physical activity, obesity, alcohol excess and stress) Secondary HTN accounts for 5-10% of cases and causes include hyperaldosteronism, thyroid disorders, phaeochromocytoma, renal artery stenosis, NSAIDs and cocaine use

Question 254

Describe the complications of hypertension

Answer 254

Stroke, MI, Heart Failure, Renal Failure HTN doubles cardiovascular disease risk for every 20mmHg increase in systolic pressure

Question 255

Describe the investigations used in the diagnosis of hypertension

Answer 255

Office BP Measurement 24 Hour Ambulatory BP Monitoring (BP taken every 20-30mins throughout the day) Home BP Monitoring (2 readings, twice a day, taken over 4-7 days) Other tests include U&Es, Glucose, Lipid Profile, TFTs, LFTs, Urinalysis, ECG, Echo, Renal Ultrasound, Renin, Aldosterone Assess CV risk, presence of secondary HTN or end organ damage

Question 256

Describe the non-pharmacological management of hypertension

Answer 256

Exercise Weight Loss Reduction in Na Intake Reduction in Alcohol Intake Smoking Cessation

Question 257

Describe the pharmacological management of hypertension

Answer 257

* ACE Inhibitor * e.g. Lisonipril * Angiotensin II Receptro Blocker * e.g. Candesartan * Ca Channel Blocker * e.g. Amlodipine * Thiazid-Like Diuretics * e.g. Bendroflumothiazide * Beta-Blocker * e.g. Atenolol

Question 258

Describe the clinical manifestations and natural history of peripheral vascular disease

Answer 258

PVD is associated with atherosclerosis and arterial narrowing in the periphery, resulting in reduced blood and oxygen supply to muscles and other tissues Intermittent Claudication is a muscle pain (ache, cramp or fatigue) on mild exertion, usually in the calf, that is relieved by rest Chronic Limb Ischaemia (i.e. Stable Angina) may present with dry skin, diminished or absent pulse, ulceration or peripheral discolouration Acute Limb Ischaemia is an acute thrombotic occlusion of a pre-existing stenotic arterial segment or by an embolus

Question 259

Describe features of critical ischaemia in the imminently non-viable limb

Answer 259

'limb pain that occurs at rest, or impending limb loss that is caused by severe compromise of blood flow to the affected extremity' Clinically presents with 6 Ps: Pain Pallor Paraesthesia Paralysis Pulseless Perishing Cold

Question 260

Describe the investigation and treatment of acute limb ischaemia

Answer 260

Investigations: MRI, CT Angiography or Invasive Arteriogram Management: Angioplasty, Bypass Surgery, Thrombolysis or Embolectomy

Question 261

Discuss strategies for prevention and treatment of peripheral vascular disease

Answer 261

Smoking Cessation Control of Hypertension Statins (should be prescribed to all patients with symptomatic coronary artery disease, regardless of cholesterol levels) Improve Glycaemic Control Weight Management

Question 262

Describe the clinical features and prevention of typhoid

Answer 262

Enteric fever caused by S. Typhi or S. Paratyphi Clinical features include fever, myalgia, headache, cough, abdominal pain, constipation, diarrhoea, rectal bleeding, bowel perforation, bradycardia, bacteraemia Main preventative measure is bite avoidance and pre-travel vaccination

Question 263

Describe the clinical features and prevention of Dengue fever

Answer 263

Clinical features include a headache, fever, retro-orbital pain, arthralgia, myalgia, rash, cough, sore throat, nausea and diarrhoea Laboratory features include leukopenia, thrombocytopaenia and transaminitis

Question 264

Describe the clinical features and prevention of Malaria

Answer 264

Clinical features include fever, malaise, headache, myalgia, diarrhoea, anaemia, jaundice, renal impairment In severe malaria there is parasitaemia, cerebral malaria, severe anaemia, renal failure, shock, DIC, acidosis and pulmonary oedema Prevention is by bite avoidance and chemoprophylaxis Mefloquine - Once Weekly, Psychiatric Side Effects Doxycycline - Daily, Photosensitisation Malarone - Minimal Side Effects, High Cost

Question 265

Describe the clinical features of severe skin and soft tissue infection

Answer 265

Systemic signs of infection (fever, tachycardia, tachypnea, leukocytosis) Organ dysfunction Redness Swelling Pain Hot

Question 266

Describe the microbiology of severe skin and soft tissue infection

Answer 266

* Type I * Synergistic infection with anaerobes (e.g. bacteroides, peptostreptococcus) and aerobes (e.g. streptococci, enterobacteriaciae) * More common in elderly diabetics * Type II * Infection with group A streptococci (s. pyogenes or s. aureus) * Mediated by toxin production * Type III * Vibrio Vulnificus * Type IV * Fungal

Question 267

Describe the management of severe skin and soft tissue infection

Answer 267

Necrotising Fasciitis is a surgical emergency and requires urgent debridement of all infected and necrotic tissue IV fluids for management of hypotension and decompensation IV antibiotics: Flucloxacillin + Benzylpenicillin + Gentamicin + Clindamycin + metronidazole (or Vancomycin + Gentamicin + Clindamycin + Metronidazole)

Question 268

Describe the investigation and management of Clostridium Difficile infection

Answer 268

Investigations: Toxin Tests and Incubation Management: Oral Metronidazole or Vancomycin, Isolation, Stop any Laxatives and PPIs

Question 269

Describe the clinical features and management of septic arthritis

Answer 269

Hot, swollen, tender and restricted joint with fever If methicillin-sensitive, IV flucloxacillin and gentamicin If methicillin-resistant, IV vancomycin and gentamicin Joint aspiration

Question 270

Describe the presentation of viral vesicular rashes

Answer 270

* Herpes Simplex Virus 1/2 * Clustered orofacial, genital and/or rectal with painful vesicles * Varicella Zoster Virus * Primary Varicella - Itchy vesicular rash with macules, papules, vesicles and crusting lesions * Reactivation Herpes Zoster - Painful, itchy/tingly maculopapular rash * Coxsackievirus A16/A6/A10 and Enterovirus 71 * Non-itchy red rash, spots or vesicles, painful mouth ulcers or posterior oropharyngeal besicular rash

Question 271

List the viruses which cause viral gastroenteritis and how their incidence relates to age

Answer 271

Norovirus and Sappovirus (Calciviridae) - Can affect all ages and healthy individuals but often most serious in the young and elderly Rotavirus, Adenovirus and Astrovirus - Affects mainly children under 2 years, the elderly and the immunocompromised

Question 272

Describe the transmission and immunity to norovirus

Answer 272

Spread via the faecal-oral route and is also food and waterborne Requires only a very small infectious dose Continues to be shed by the body for three weeks post-infection Immunity lasts only 6-14 weeks and there is no vaccine (so there is no lifelong immunity)

Question 273

Describe the diagnosis of viruses in viral gastroenteritis

Answer 273

All the viruses are detected by PCR which detects the viral DNA or RNA Testing is done at the virology lab at GRI From a sample of vomit or stool

Question 274

Describe the diagnosis of bone and joint infection

Answer 274

Clinical History: Fever, Hot, Swollen Joint, Loss of Movement (may be polyarticular involvement) Blood Cultures Joint Aspirate (Gram stain and microscopy for crystals and culture) FBC CRP Imaging

Question 275

Describe optimal antibiotic management of native and prosthetic joint septic arthritis

Answer 275

At least 2 weeks of IV antibiotics, but usually 3 weeks of IV antibiotics followed by 3 weeks of oral therapy Native Joint: IV Flucloxacillin + IV Gentamicin or IV Vancomycin + IV Gentamicin Prosthetic Joint: IV Vancomycin + IV Gentamicin

Question 276

Describe the emergency surgical management of prosthetic joint infection

Answer 276

1. DAIR to Leave the Infected Joint In * Debride, Antibiotics, Implant Retained * If prosthesis infection is acute (\<30 days since insertion) then it is still mechanically function and can be retained but all infected tissue should be debrided and the joint washed out to reduce burden of infection followed by IV antibiotics for 4-6 weeks 2. Take the Infected Joint Out * If the infection occurs over 30 days since surgery it may no longer be fully functional and may need removal * Removal involves taking out the prosthesis and all the cement 3. Revision Arthroplasty

Question 277

Describe the microbiology of mycobacterium tuberculosis

Question 278

Describe the serum biochemical adaptations to acute and chronic respiratory failure

Answer 278

In acute resp. failure, there is insufficient time for full renal compensation so the pH is low with a high/normal bicarbonate In chronic resp. failure the kidneys are able to compensate with a raised bicarbonate and normal pH

Question 279

State indications for the use of non-invasive ventilation in COPD

Answer 279

Acute Exacerbations of COPD with Persistent Hypercapnic Respiratory Failure (should be considered in the presence of respiratory acidosis with pH \<7.35 or if acidosis persists despite maximal medical management)

Question 280

Comment on this CXR

Answer 280

Consolidation in the right middle lobe consistent with pneumonia

Question 281

Comment on this CXR

Answer 281

Right lower lobe collapse

Question 282

State potential drug interactions and pitfalls when using theophylline

Answer 282

Side effects include GI upset, palpitations, tachycardia/arrhythmias, headache, insomnia and hypokalaemia Caution in liver disease and with concomitant use of enzyme inducers (rifampicin) and inhibitors (clarithromycin, ciprofloxacin) Smoking increases theophylline clearance – dose may need to be adjusted following smoking cessation

Question 283

Describe the mechanism of action of anti-fungal drugs

Answer 283

* Azoles * e.g. Miconazole, Imidazole, Triazole, Thiazole * Inhibitors of 14-methylsterol alpha-demethylase which produces ergosterol * Ergosterol is an essential component of the fungal plasma membrane * Does not occur in animal or plants cells * Amphotericin B * Also exploits the ergosterol/cholesterol difference * It is not an enzyme inhibitor * Binds to ergosterol to form a pore in fungal membranes, leading to cell death

Question 284

Comment on this CXR

Answer 284

A well defined thick walled cavitatory lesion is noted in the right para-hilar area in the midzone of right lung aka Pulmonary TB

Question 285

Describe how eczema may present in the skin

Answer 285

Pruritic, erythematous and dry patches of skin Often with a remitting/relapsing course

Question 286

Describe the effect of UV light on the skin

Answer 286

Direct action of UV light on target cells (keratinocytes) for neoplastic transformation via DNA damage or Effects of UV light on the host's immune system (mainly immune suppression)

Question 287

Describe the clinical features, prognosis and management of Basal Cell Carcinoma

Answer 287

Most common type of skin cancer Usually very indolent, rarely metastases or kills Nodular BCC - \>0.5cm raised lesion with a shiny pearly lesion, telangiectasia (blood vessels), and is often ulcerated centrally Superficial BCC - Often involves only the most superficial layers of the epidermis Pigmented BCC Morphoeic/Sclerotic BCC Managed by surgical excision with a 3-4mm margin Excellent prognosis, 100% for BCC that has not progressed

Question 288

Describe the clinical features, management and prognosis of Squamous Cell Skin Carcinoma

Answer 288

Papule/nodule, often eroded at the centre and crusty Usually in a sun-exposed area Often a hard, scaly, dome-like structure Can itch or bleed Surgical Excision and/or Radiotherapy \<4 risk of metastasis

Question 289

Describe the clinical features, management and prognosis of malignant melanoma

Answer 289

Malignant tumours of melanocytes resulting in DNA damage, most commonly on the skin but also in the bowels or eyes Features: Asymmetry Borders (irregular) Colour (variable, multi-pigmented) Diameter (greater than 6mm) Evolving over time For nodular melanoma; Elevated, Firm and Growing Managed by surgical excision; If Breslow \<1mm - 1cm Margin If Breslow \>1mm - 2cm Margin Adjuvant chemotherapy if metastatic spread 97% 5Yr SR for Breslow \<1mm 71% 5Yr SR for Breslow \>4mm

Question 290

Describe some tumour syndromes with cutaneous presentations

Answer 290

* Gorlin’s Syndrome * Multiple BCCs, Jaw Cysts, Risk of Breast CA * Brook Spiegler Syndrome * Multiple BCCs, Trichoepitheliomas * Gardner Syndrome * Soft Tissue Tumours, Polyps, Bowel CA * Cowden’s Syndrome * Multiple Hamartomas, Breast CA

Question 291

Describe the emergency medical and surgical management of patients with severe skin and soft tissue infection

Answer 291

i.e. Necrotising Fasciitis An immediately life-threatening soft tissue infection with deep tissue involvement Presents with severe pain and systemic upset, visible necrotic tissue and fascial oedema and gas in soft tissues on imaging Medical management with IV Flucloxacillin, Benzylpenicillin, Gentamicin, Clindamycin, Metronidazole Emergency surgical intervention with extensive debridement

Question 292

Describe the pathology and management of cellulitis

Answer 292

Infection involving the dermis, most commonly beginning in the lower limbs Often tracks through the lymphatic system and may involve local lymph nodes Usually caused by beta haemolytic streptococci (often group A strep) or Staph. Aureus Enron 1a - PO Flucloxacillin or Doxycycline Enron Ib and II - IV Flucloxacillin or Vancomycin Enron III and IV - Admission with IV Management and/or Surgical

Question 293

Describe the range of skin and soft tissue infections and their optimal management

Answer 293

* Impetigo * Golden encrusted skin lesions with inflammation localised to the dermis * Caused by S. Aureus and is usually mild and self-limiting * Can treat with topical fusidic acid or systemic antibiotics * Tinea * Superficial fungal infection of the skin or nails, very common particularly on the feet * Most common causes include Microsporum, Eidermophyton and Trichophyton * If skin alone, treat with topical terbinafine and if severe or hair/nail involvement then systemic itraconazole or terbinafine * Soft Tissue Abscess * Infection within the dermis or fat layers with development of walled off infection and pooled pus * Best treatment is surgical drainage

Question 294

Give examples of skin changes seen in endocrine disease

Answer 294

* Thyroid * Dry Skin (Hypo) * Thyroid Dermopathy (Pretibial Myxedema, Grave's Disease) * Thyroid Acropachy * Diabetes * Necrobiosis Lipoidica * Waxy, yellow * Often affects the shins and may ulcerate and scar * Scleredema * Leg Ulcers * Granuloma Annulare * Cushing's * Acne, Striae, Erythema, Gynaecomastia * Addison's * Hyperpigmentation, Acanthosis Nigracans

Question 295

Describe the features of erythema nodosum and state some of the diseases it may be associated with

Answer 295

Tender, red nodules under the skin Inflammation of the fat underlying the skin Commonly on the shins Associated with EBV, Strep Infection, TB, IBD, Sarcoidosis, Pancreatic CA, Non-Hodgkin Lymphoma

Question 296

Give examples of skin changes seen in nutritional deficiencies

Answer 296

* Vit B6 - Dermatitis * Vit B12 - Angular Chelitis * Vit B3 - Pellagra * Zinc - Acrodermatitis Enteropathica * Pustules, bullae or scaling * Vit C - Scurvy * Punctuate Purpura * Corkscrew Spiral Curly Hair * Dry Skin and Hair * Inflamed Gums * Patchy Hyperpigmentation

Question 297

Describe the features of pyoderma gangrenosum and state the disease it is associated with

Answer 297

A rare, severe skin disease in which progressive ulceration develops spontaneously or after skin trauma Causes deep ulcers, usually on the legs Associated with IBD, RA and Myeloma

Question 298

Describe the skin changes seen in internal malignancy

Answer 298

* Necrolytic Migratory Erythema * Erythematous, scaly plaques on acral, intertriginous and periorificial areas * Associated with an islet cell tumour * Erythema Gyratum Repens * Reddened concentric bands in a whirled woodgrain pattern * Severe pruritic and peripheral eosinophilia * Strongly associated with lung CA * Acanthosis Nigricans * Smooth, velvet-like, hyperkeratotic plaques in intertriginous areas

Question 299

Describe Steven Johnson Syndrome and Toxic Epidermal Necrolysis

Answer 299

A severe, mainly drug-induced, blistering disorder Dermatological emergency Disease spectrum from SJS --\> TEN (SJS if \<10% skin involvement) Stop offending drug For TEN: Inpatient derm management, analgesia, fluid balance, infection prophylaxis, special mattress, non-adherent dressing (TEN may have an up to 50% mortaility)

Question 300

Describe Erythema Multiforme

Answer 300

A self limiting allergic reaction Associated with HSV, EBV and occasionally drugs Characterised by target lesions on the skin Never progresses to TEN

Question 301

Describe the acute blistering disorders

Answer 301

* Bullous Pemphigoid * Tense and blood filled blisters * Typically on flexure surfaces * Pemphigus * Superficial and flaccid blisters * Typically on the trunk, scalp, mouth * Treatment of Above * Immunosuppression (azathioprine, oral steroids) * Infection control * Burst any blisters * Dermatitis Herpetiformis * Associated with coeliac * Common on elbows, knees, upper back * Treated with gluten free diet, topical steroid and oral dapsone

Question 302

Describe urticaria

Answer 302

Non-scarring, itchy wheals with each lesion lasting \<24 hours Most common skin disorder presenting to A&E Acute \<6 weeks, Chronic \>6 weeks May be immune-mediated (type IgE immune response) or non-immune-mediated (direct mast cell degranulation) Causes include viral infection, NSAIDs, parasitic infection, opiate Treated with antihistamines, steroids, immunosuppression or omiluzimab

Question 303

Describe the presentation, diagnosis and management of large vessel vasculitis

Answer 303

* Takayasu's Arteritis * Pulseless disease or aortic arch syndrome * Systemic features include fever, malaise, night sweats, weight loss, myalgia, arthralgia and fatigue * Late features include bruits, absent/reduced pulses, claudication, ischaemic heart disease, headaches, BP variability * Diagnosed by CT/MR Angiography * Managed with Prednisolone for all patients, and further immunosuppression (e.g. methotrexate) in some * Giant Cell (Temporal) Arteritis * Presents with scalp tenderness, jaw claudication, fatigue and headache * Diagnosed by high ESR or biopsy * Managed with PO Prednisolone

Question 304

Describe the presentation, diagnosis and management of medium vessel vasculitis

Answer 304

* Polyarteritis Nodosa * Severe systemic manifestations with fibrinoid necrosis of the vessel wall with microaneurysm formation, thrombosis and infarction * Systemic features include fever, weight loss, malaise, myalgia and arthralgia * Associated with infarction and ischaemia of organs including the gut, brain, heart, liver, skin, PNS, limbs and kidneys * Investigated with CRP/ESR and CT/MR angiography and biopsy * Treated with PO/IV Prednisolone with or without DMARD * Kawasaki Disease * Vasculitis of young children characterised by aneurysm formation in medium to large sized arteries, including the coronary, axillary, iliac and popliteal arteries * Early features include high fever, mucositis and conjunctivitis * Late features include (fatal) aneurysms * Investigated with bloods, USS of testes and gallbladder and lumbar puncture * Managed with IV immunoglobulin or methylprednisolone plus aspirin

Question 305

Describe Henoch-Schonlein Purpura

Answer 305

An immune complex mediated small vessel vasculitis Most common vasculitis in childhood Characterised by deposition of IgA Diagnostic triad of palpable purpura, abdominal pain and arthritis Investigations include urinalysis, IgA levels, U&Es Treated with analgesics only if simple If renal involvement, add corticosteroids and/or immunosuppressants

Question 306

Describe ANCA associated small vessel vasculitis

Answer 306

cANCA or pANCA Granulomatous Polyangiitis (classically involves the upper and lower respiratory tracts and kidneys) Eosinophilic Granulomatous Polyangiitis - Churg-Strauss (Associated with eosinophilia, asthma, eosinophil-rich granulomata, peripheral neuropathy, pulmonary infiltrates) Microscopic Polyangiitis (common manifestations are glomerulonephritis, weight loss, skin lesions, peripheral neuropathy, fever) Investigations include ANCA, CT Chest, biopsy, bloods and urinalysis Corticosteroid and Cyclophosphamide/Methotrexate

Question 307

Describe the presentation and investigations of secondary bone tumours

Answer 307

Found in up to 60% of patients dying from cancer Most often from the bronchus, breast, prostate, kidney and thyroid Bones with a good blood supply are most often affected, including the long bones and vertebrae Effects include bone pain, destruction and hypercalcaemia May result in pathological fractures in the long bones In the vertebrae there may be vertebral collapse, spinal cord/nerve root compression and back pain Investigated with MRI and/or PET-CT

Question 308

Describe the difference between lytic and sclerotic metastatic bone lesions

Answer 308

* Lytic * Most common * Tumour replaces bone marrow * Tumour cells produce cytokines which activate bone resorbing osteoclasts * These patients are therefore more prone to pathological fracture * Bisphosphonates inhibit bone resorption so can be used to treat this * Sclerotic * Thickening of the bone * Most common cause is Prostate CA but also seen in breast carcinoma * Tumour cells promote deposition of immature woven bone by osteoblasts * Appears sclerotic (thickened and white) on x-ray

Question 309

Describe myeloma, its presentation and management

Answer 309

Most common malignant primary bone tumours Monoclonal proliferation of plasma cells Effects include: Bone Lesions (generalised osteopenia and punched out lytic foci) Marrow Replacement (anaemia, leukopenia, thrombocytopenia and pancytopenia) Diagnosed by Immunoglobulin Excess (ESR \>100, Serum Electrophoresis and Urine Bence Jones Protein), Biopsy and Pepper Pot Skull on X-Ray High dose chemotherapy with a bortezomib regimen and autologous SCT

Question 310

Describe benign tumours of the bone

Answer 310

Osteoid Osteoma Small, benign osteoblastic proliferation Common in any age, especially adolescents Can affect any bone, including long bones and spine C/F include pain (worse at night, relieved by aspirin) and may cause scoliosis Managed with analgesia and surgical resection

Question 311

Describe malignant tumours of the bone

Answer 311

Osteosarcoma; a malignant tumour with cells arising from osteoid or bone and a peak age of 10-25yrs. Highly malignant with early lung metastases Chondrosarcoma; central, within the medullary canal or peripheral on the bone surface. Predominantly affects middle-aged and elderly, more commonly men Ewing's Sarcoma; Peaks at 5-15yrs, usually in the diaphysis/metaphysis of the long bones or flat bones of the limb girdles. Early metastases to lung, bone marrow and bone

Question 312

Describe septic arthritis, its presentation, investigation and management

Answer 312

'inflammation of the synovium due to pathogenic inflammation of the joint' Common organisms include Staph. Aureus, Neisseria Gonorrhoea and Haemophilus Influenzae Presents with a hot, red, swollen and painful joint Investigations include joint aspirate, blood cultures and FBC Manage with IV antibiotics for 1-2 weeks (Flucloxacillin or Erythromycin)

Question 313

Describe reactive arthritis, its presentation and management

Answer 313

'sterile inflammatory synovitis occurring following an infection' Trigger organisms include salmonella, shigella, yersinia and chlamydia trachomatis Preceding illnesses include gastroenteritis, urethritis and chlamydia infection Presents with acute, asymmetrical lower limb arthritis, days to weeks after the initial infection Also associated with enthesitis, sacroiliitis, spondylitis, anterior uveitis, conjunctivitis, keratoderma blemorrhagica Managed with analgesia (NSAIDs or intra-articular steroids) Usually self-limiting with occasional chronic progression or cardiac complications

Question 314

Describe gout, its presentation and management

Answer 314

Excess levels of uric acid leads to deposition of urate crystals in joints or soft tissue Commonly affects the big toe Risk factors include obesity, diabetes, high alcohol consumption and high protein diet Severely painful, red, hot, swollen joint Investigate with aspirate or serum urate levels Manage with NSAIDs, colchicine, corticosteroids or allopurinol

Question 315

State indications for allopurinol in the prophylaxis of gout

Answer 315

Urate-lowering drug Recommended for gout prophylaxis after one attack Usually lifelong treatment NSAID/Colchicine may need to be taken in conjunction for the first 4-6 weeks

Question 316

Describe the investigation of a patient presenting with acute joint pain and swelling, as per BSR guidelines

Answer 316

All patients presenting with a hot, red, swollen, tender and restricted joint should be regarded as having septic arthritis until proven otherwise (even in the absence of fever) Synovial fluid should be aspirated, gram-stained and cultured prior to antibiotics Infected prosthetic joints should be referred to an orthopaedic surgeon Blood cultures should be taken ESR, WCC and CRP should all be measured X-Ray should be conducted as a baseline

Question 317

Describe the pathophysiology of osteoporosis

Answer 317

* Osteoporosis results from a cellular process imbalance, i.e. an increase in bone resorption by osteoclasts and decrease in bone formation by osteoblasts * In younger patients, it is usually a decrease in bone formation, while in post-menopausal women, it is usually increased bone resorption * Oestrogen Deficiency * Oestrogen levels decrease greatly in females during the menopause * This can cause increased osteoclast recruitment, differentiation and prolonged osteoclast survival * This is achieved by increased activity of Interleukin-1 (increases production of osteoclasts) and Interleukin-6 (normally inhibited by oestrogen and secreted by osteoblasts to induce osteoclast formation) * The RANK receptor is normally expressed on pre-osteoclasts, where binding of the RANK-Ligand causes differentiation to mature osteoclasts, while Osteoprotegerin (OPG) inhibits the RANK receptor * Oestrogen deficiency causes increased RANK expression and decreased OPG secretion, resulting in increased osteoclast formation (i.e. increased bone resorption) * Age Related * The efficiency of calcium absorption in the intestines diminishes with age, meaning many elderly people are at risk of hypocalcaemia * This can be worsened by a vitamin D deficiency, which reduces the amount of calcium that can be absorbed * The above factors cause low bone density and quality, leading to an increased fracture risk

Question 318

State the role of DEXA scanning in osteoporosis and indications for its use

Answer 318

Measurement of bone mineral density DXA scan should be offered to patients over the age of 50 with a history of fragility fracture, or to those under 50 with a major risk factor for fragility fracture Major risk factors include frequent oral corticosteroid use, low BMI, premature menopause, hypogonadism, COPD, CKD, excess alcohol intake T-Score (number of standard deviations below average BMD for a young female): ≥ -1 = Normal -1 to -2.4 = Osteopenia ≤ -2.5 = Osteoporosis

Question 319

Describe the mechanism of action of bisphosphonates

Answer 319

PO - Alendronate, Risedronate IV - Zalendronate (Zoledronic Acid) Bisphosphonates are absorbed into hydroxyapatite crystals on bone, thereby slowing their rate of growth and dissolution to reduce the rate of bone turnover Alendronic Acid is given once weekly PO Zoledronic Acid is given by a 6-monthly IV infusion

Question 320

State indications for the use of bisphosphonates

Answer 320

Treatment of osteoporosis with a T-Score \<2.5 and Paget's Disease

Question 321

Describe other treatments to reduce fracture risk in osteoporosis

Answer 321

* Denosumab * A monoclonal antibody that inhibits osteoclast formation, function and survival to deserve bone resorption by binding to RANKL to prevent osteoclast activation * Given by 6 monthly subcutaneous injection * Major side effects include atypical femoral fractures and osteonecrosis of the jaw * Teriparatide * Intermittently high levels of PTH, in the form of Teriparatide, stimulates osteoblast activity at the pluripotent stem cell level to increase bone formation * Given by daily, self-administered subcutaneous injection * Only anabolic treatment * Given for a two-year course only * Raloxifene * Selective Serotonin Reuptake Inhibitor * Binds to oestrogen receptors, exerting both agonistic and antagonist effects * In bone, this causes increased osteoblast and decreased osteoclast activity to reduce bone turnover * Given by daily tablet

Question 322

Describe the spectrum of autoimmune connective tissue disease

Answer 322

Arises from dysfunction of the immune system SLE, Myositis and Scleroderma Can be Undifferentiated CTD or Mixed CTD

Question 323

Describe the presentation, diagnosis and management of Systemic Lupus Erythematosus

Answer 323

Causes include genetics, EBV exposure, some drugs, UV light and sex hormone status (post-menopausal women) SLE is characterised by auto-antibody production, complement/neutrophil activation and abnormal cytokine production Deposition of IgG and complement and influx of neutrophils in the skin and kidneys Fever, malaise, symmetrical small joint arthralgia, myalgia, butterfly face rash, recurrent pleurisy, pleural effusions, pericarditis, nephritis, psychiatric disturbance (depression), migraine, retinal vasculitis, mouth ulcers FBC, U&Es, ANA, anti-dsDNA, Urinalysis, PCR, Low Complement, Excess Total Ig NSAIDs, Topical/Parenteral/Oral Corticosteroids Immunosuppressant; Cyclophosphamide, Azathioprine, Rituximab

Question 324

Describe the presentation, diagnosis and management of Polymyositis

Answer 324

Inflammation of striated muscle, causing proximal muscle weakness When the skin is also involved, it is known as Dermatomyositis General malaise, weight loss and fever during the acute phase Cardinal symptom is proximal muscle weakness (sparing of face and distal limb muscles) Movements such as squatting and climbing stairs become difficult As the disease progresses, involvement of pharyngeal, laryngeal and respiratory muscles can lead to dysphonia and respiratory distress In Dermatomyositis, there is often arthralgia, polyarthritis, Raynaud's, Gottron's Papules (purple-red, raised vasculitic patches) over the knuckles Investigated with serum creatine kinase, raised ESR/CRP, serum autoantibodies, MRI, needle muscle biopsy Managed with bed rest, exercise programme, prednisolone, steroid-sparing agents and biologics

Question 325

Describe the presentation, investigation and management of Scleroderma

Answer 325

Widespread vascular damage in small arteries, arterioles and capillaries with endothelial and intimal damage Damage produces widespread obliterative arterial lesions and chronic ischaemia Fibroblasts synthesise increased collagen I and III Causes fibrosis of the lower dermis and internal organs Clinical features include Raynaud's Phenomenon, Limited Cutaneous Scleroderma, Myocardial Fibrosis, Dysmotility/Stricture of Oesophagus Autoantibodies; LcSSC, DcSSC, ANA, RF Imaging with CXR, HR-CT, Barium Swallow Oral Vasodilators (ACEi, CCB) for Raynaud's PPIs for Oesophageal Symptoms Immunosuppression for Pulmonary Fibrosis ACEi for Renal Involvement

Question 327

Describe the MOA and potential side effects of Methotrexate

Answer 327

Folate antagonist with an affinity for many of the enzymes of folate metabolism Principally inhibits dihydrofolate reductase to inhibit thymidylate synthase and arrest DNA synthesis, stopping the cell cycle at G1 Adverse include nausea, vomiting, diarrhoea, hepatitis, stomatitis, leukopenia, pulmonary fibrosis, frequent infections

Question 328

Describe the MOA and potential side effects of Azathioprine

Answer 328

Converted within cells into a nucleoside analogue which is incorporated into DNA and RNA, leading to termination of nucleic acid strands Cell growth and metabolism halts, especially in lymphocytes Adverse effects include nausea, vomiting, diarrhoea, hepatitis, cholestasis, leukopenia, thrombocytopenia, frequent infection, hair loss

Question 329

Describe the MOA and potential side effects of Cyclosporine

Answer 329

Small molecule inhibitor of calcineurin Inhibits signal transduction from the activated TCR complex, resulting in profound inhibition of T-Cell activation Adverse effects include nephrotoxicity, HTN, hepatotoxicity, anorexia, lethargy, hirsutism, paraesthesia

Question 330

State common indications for immunosuppressants and biologic therapies

Answer 330

RA Psoriasis UC/Crohn's Eczema Post-Organ Transplant

Question 331

Describe the broad categories of biologic therapies used in auto-immune conditions and risk associated with their use

Answer 331

Anti-TNF agents (e.g. Infliximab), monoclonal antibodies that target a soluble cytokine Anti-CD20 (e.g. Rituximab), monoclonal antibodies that target surface markers Side effects include hypersensitivity reactions, infusion reactions and mild GI toxicity Risk of infectious complications (e.g. activation of disseminated TB with Anti-TNF, increased pneumonia/RTI risk with Abatacept and Anti-IL1 therapy)

Question 332

Describe the features of mechanical back pain

Answer 332

Onset at any age Generally worsens with prolonged standing or movement Better with rest Morning stiffness lasting less than 30 mins Causes include lumbar strain/sprain, degenerative discs/facet joints, disc prolapse, spinal stenosis, and compression fractures Managed with an exercise programme, physiotherapy and simple analgesia

Question 333

State red flags for serious causes of back pain

Answer 333

New Onset Age \<16 or \>50 Following Significant Trauma Previous Malignancy Systemic Symptoms (fever, weight loss, malaise, rigours) Previous Steroid Use IV Drug Use, HIV or Immunosuppression Recent Significant Infection Urinary Retention Non-Mechanical Pain (e.g. Worse at Night) Thoracic Spine Pain Saddle Anaesthesia Reduced Anal Tone Hip/Knee Weakness Generalised Neurological Deficit Progressive Spinal Deformity

Question 334

Describe the features, natural history and management of acute disc prolapse

Answer 334

Acute onset, worse with coughing, typically leg and back pain (sciatica/radiculopathy), straight leg raise test +ve, dermatomal pain distribution, reduced reflexes Most resolve spontaneously \<10% need surgery (helps leg pain)

Question 335

Describe the features of inflammatory back disease

Answer 335

Onset \<45 yrs Early morning stiffness \>30mins Back stiff after rest and improves with movement May wake in the 2nd half of the night with buttock pain Insidious onset, less likely to be acute

Question 336

Define spondylolisthesis

Answer 336

Slippage of one vertebra over the one below Increased pain with extension Pain may radiate to posterior thigh

Question 337

Define spondylosis

Answer 337

Degeneration of the spinal column, usually with age but possibly from other causes Increases with flexion, sitting and sneezing

Question 338

Define spinal stenosis

Answer 338

Anatomical narrowing of the spinal canal May be congenital or degenerative Often presents with 'claudication' in the legs/calves Worse when walking, rest in the flexed position

Question 339

State the benefits of exercise in the healthy individual

Answer 339

* Regular physical activity can help reduce the risk of: * Cardiovascular – Stroke, IHD, PVD, Congenital HD, Heart Failure * Respiratory – Asthma, COPD, CF * MSK – RA, OA, Hip Fx, Low Back Pain, Fibromyalgia * Endocrine – Diabetes * Psychiatric & Neurological – Depression, Dementia, Schizophrenia, Parkinson’s * Cancer – Breast, Prostate, Colon * Other – Obesity, BP, Cholesterol

Question 340

Describe the epidemiology and presentation of Rheumatoid Arthritis

Answer 340

Affects 0.5-1% of the European and North American population F:M - 3:1 Usually presents with symmetrical joint involvement (usually small joints of the hands and feet) with pain, erythema and swelling Late joint features include swan neck, z-thumb and boutonniere deformities, ulnar deviation of the digits and radial deviation of the wrist

Question 341

State the serological investigations for patients presenting with joint pain and swelling

Answer 341

FBC, U&Es, LFTs ESR and CRP RF (60% Sens, 80% Spec) APCA (60% Sens, 80-90% Spec) - prognostic marker; associated with smoking ANA

Question 342

Describe Juvenile Idiopathic Arthritis

Answer 342

Disease of childhood-onset characterised primarily by arthritis persisting for at least 6 weeks and currently having no known cause Chronic inflammatory arthropathy Clinical diagnosis

Question 343

Describe the difference between primary and secondary headache

Answer 343

Primary headaches are those where the headache and its associated features are the disorder (i.e. there is no underlying cause), for example; migraine, tension headache, cluster headache Secondary headaches are secondary to an underlying cause, for example, subarachnoid haemorrhage, space-occupying lesion, meningitis, temporal arteritis etc.

Question 344

State important features of taking a headache history

Answer 344

Onset (time to maximal symptoms and circumstances at onset) Severity and Quality of Pain Location/Radiation of Pain Presence of Aura/Prodrome Periodicity (Duration and Frequency) Associated Features (Photophobia, Nausea, Phonophobia etc) Age at Onset Triggers/Exacerbating/Relieving Factors FHx Social/Employment Hx Mediation Hx Co-Morbid Depression and Sleep Disturbance

Question 345

State red flag signs and symptoms for headache

Answer 345

Age \>50yrs Thunderclap Headache Focal/Non-Focal Neurological Deficit Worsening of Symptoms with Posture, Valsalva or Physical Exertion Early Morning Headaches Fever Weight Loss Seizures Meningism Temporal Artery Tenderness/Jaw Claudication Specific Situations - Cancer, Pregnancy, Post-Partum, HIV, Immunosuppression

Question 346

State features of high and low pressure headaches

Answer 346

* Raised Pressure * Worse on lying flat, in the morning, on Valsalva and physical exertion * Improved on sitting/standing * Persistent N/V * Optic disc swelling, impaired visual acuity, restricted visual fields * 3rd and 6th CN Palsy * Caused my mass effect, increased venous pressure, obstruction to CSF flow * Reduced Pressure * Worse on sitting/standing * Relieved by lying down * Results from CSF leak

Question 347

Describe the presentation and management of migraine

Answer 347

Triggers include hormones, weather stress, hunger, sleep disturbance, exertion, alcohol excess, foods Prodrome in up to 60% of patients up to 48 hours before headache (could include mood disturbance, restlessness, hyperosmia, photophobia, diarrhoea) Aura reported in up to 30% of cases and is a recurrent, reversible focal neurological symptoms (visual, sensory or motor) Character often throbbing/pulsatile, moderate to severe, unilateral in 60%, gradual onset, lasting 4-72 hours Associated symptoms include N/V, photophobia, phonophobia, osmophobia, mood disturbance, diarrhoea Lifestyle management includes avoidance of triggers, reduction of caffeine/alcohol intake, encourage regular meals/sleep patterns Acute management with simple analgesia, triptans and anti-emetics Prophylaxis with beta-blockers, TCAs and anti-epileptics

Question 348

Describe the assessment and investigation of thunderclap headache

Answer 348

'abrupt onset of severe headache which reaches maximal intensity in \<5 mins and lasts \>1 hour' worst headache of my life/like being hit over the head Causes include SAH, ICH, Arterial Dissection, Cerebral Venous Sinus Thrombosis, Bacterial Meningitis, Primary Headache Investigate with Bloods, ECG, Urgent CT Head and Lumbar Puncture (after 12 hours)

Question 349

Describe the pathophysiology of stroke

Answer 349

After stoppage of blood flow to the brain, neurons depolarise within minutes (causing instant onset of early symptoms) and irreversible brain tissue death occurs within 12 hours Therefore, the sooner the blood flow is restored the more brain death is prevented

Question 350

Describe the clinical presentation of stroke/TIA

Answer 350

Visual Loss Weakness Slurred Speach Ataxia Aphasia

Question 351

Describe the management of stroke

Answer 351

* Ischaemic Stroke * IV Thrombolysis (within 4.5h) +/- Thrombectomy (within 6-8h) * Aspirin * Stroke Unit * Hemicraniectomy * Haemorrhagic Stroke * Aggressive BP Control * Stroke Unit * Neurosurgical Evacuation

Question 352

Define 'seizure'

Answer 352

'a transient occurrence of signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity in the brain'

Question 353

Define 'epilepsy'

Answer 353

'a disorder of neuronal activity in the brain defined as two or more unprovoked seizures, or one unprovoked seizure with a lesion in the CNS that increases the probability of a second unprovoked seizure'

Question 354

Outline the different types of seizure

Answer 354

Focal seizures begin in one part of the brain, and may spread to become secondary generalised Generalised involves multiple areas of the brain or spread from one area to both sides of the brain Absence seizures are common in young children Tonic-Clonic seizures involve LOC and a short tonic phase (muscle suddenly tense and patient falls) and a longer clonic phase (rapid convulsions)

Question 355

Describe investigations for epilepsy

Answer 355

Diagnosis is largely based on a detailed history from the patient and eyewitness ECG to check for underlying cardiac problems EEG is not generally diagnostic but may assist in classification MRI

Question 356

Describe the management of epilepsy

Answer 356

1. Reduce Pre-Synaptic Excitability 1. Voltage Gated Na⁺ Channel Antagonists 1. **Carbamazepine** 2. **Lamotrigine** 2. Voltage Gated K⁺ Channel Agonist 1. **Retigabine** 2. Stops Neurotransmitter Release 1. SV2A Vesicle Antagonist 1. **Levetiracetam** 2. Voltage Gated Ca²⁺ Channel Antagonist 1. **Pregabalin** 2. **Gabapentin** 3. GABA-ergic System Agonists 1. GABA Metabolism Inhibitor 1. **Valproate** 2. **Vigabatrin** 2. GABA Transporter Antagonists 1. **Tiagabine** 4. Reduces Post-Synaptic Excitability 1. GABA Receptor Agonist 1. **Benzodiazepines** 2. AMPA and NMDA Receptor Antagonist Usual treatment for Focal is Lamotrigine, Carbamazepine or Levetiracetam and for Generalised it is Valproate, Levetiracetam and Lamotrigine

Question 357

Describe the management of Status Epilepticus

Answer 357

'a single clinical seizure lasting more than 30 minutes or repeated seizures over a period of time greater than 30 minutes without intervening recovery of consciousness' MEDICAL EMERGENCY May cause profound systemic/neurological damage if left untreated Immediate management includes assessing and securing the airway, administering oxygen and assessing pulse, BP and RR If seizures continue for more than 5 minutes, the seizure should be treated with IV benzodiazepines If seizures continue, the patient may need sedated and intubated

Question 358

State causes of loss of consciousness

Answer 358

Epilepsy (Seizures) Syncope Stroke/TIA Drugs Hypoglycaemia Alcohol Hypoxia

Question 359

Describe the pathogenesis of subarachnoid haemorrhage

Answer 359

Most SAH are caused by aneurysms which form under haemodynamic stress Extensive inflammatory and immunological reactions are common in unruptured intracranial aneurysm and may be related to aneurysm formation and rupture A small number (15-20%) are due to other causes. e.g. Arterio-Venous Malformation or Neoplasia

Question 360

Describe the presentation of subarachnoid haemorrhage

Answer 360

Sudden Onset Thunderclap Headache LOC Seizures Visual, Speech and Limb Disturbance Sentinel Headache Photophobia Meningism Subhyaloid Haemorrhages Vitreous Haemorrhages Pulmonary Oedema

Question 361

Describe the investigation of subarachnoid haemorrhage

Answer 361

CT - Confirms diagnosis and may give clues to aetiology - Very accurate LP - For presence of xanthochromia (bilirubin or OxyHb) in the CSF - Conducted at least 12 hours after onset of symptoms CT/MRI Angiography Digital Subtraction Angiography

Question 362

Describe the management of subarachnoid haemorrhage

Answer 362

Bed Rest Fluids (2.5-3 Litres of Normal Saline) Anti-Embolic Stockings Nimodipine Analgesia Surgical Clipping (10-15%) Endovascular Repair (Coils, Stents and Glue) (80-85%)

Question 363

Describe the complications of subarachnoid haemorrhage

Answer 363

* Rehaemorrhage * 5-10% incidence in the first 72 hours * Immediate repair reduces risk * Delayed Ischaemia * At Days 3-10 * Progressive deterioration in LOC associated with new deficit * Managed with fluid resus, nimodipine, inotropes, angioplasty * Hydrocephalus * Hyponatraemia * ECG Changes * LRTI * PE * UTI * Seizures * 1-7% of patients * DVT * SAH induces a prothrombotic state

Question 364

Describe the Glasgow Coma Scale

Answer 364

Question 365

Describe the clinical presentation of radial nerve mononeuropathy

Answer 365

Wrist and Finger Drop Usually Painless Motor Weakness; Wrist/Finger Extension and Elbow Flexion in Mid-Pronation Sensory Change: Radial Part of Dorsum of Hand

Question 366

Describe the clinical presentation of ulner nerve mononeuropathy

Answer 366

Weak Grip Usually Painless Motor Weakness: Index Finger/Pinkie Abduction, Wrist Flexion and Thumb Adduction Sensory Change: Medial 1.5 Fingers

Question 367

Describe the clinical presentation of median nerve mononeuropathy

Answer 367

Hx of Intermittent Nocturnal Pain, Numbness and Tingling Weak Grip +ve Tinel's Sign/Phalen's Test Motor Weakness: MCP/Thumb Flexion, Thumb Opposition and Thumb Abduction Sensory Change: Lateral 3.5 Fingers on Palm and Tips of Those Fingers on Dorsum

Question 368

Describe the clinical presentation of femoral nerve mononeuropathy

Answer 368

Weakness of Quadriceps Weak Hip Flexion Numbness in Medial Shin Motor Weakness: Knee Extension, Hip Flexion, Hip Adduction Sensory Change: Medial Lower Limb

Question 369

Describe the clinical presentation of common peroneal nerve mononeuropathy

Answer 369

Acute Onset Foot Drop and Sensory Disturbance Usually Painless Motor Weakness: Ankle Dorsiflexion, Great Toe Extension Sensory Change: Shin and Dorsum of Foot

Question 370

Describe the epidemiology of multiple sclerosis

Answer 370

UK prevalence of 1.2/1000 More prevalent in Scotland and in northern latitudes Twice as common in women than men

Question 371

Describe the pathophysiology of multiple sclerosis

Answer 371

Plaques of demyelinating lesions are the cardinal features of MS Plaques can occur anywhere in the CNS white matter, however, they have a predilection for distinct sites: optic nerves, the periventricular region, the corpus callosum, the brainstem and its cerebellar connections and the cervical cord Grey matter of the cortex and the sub-pial meninges are also affected in the early stages however peripheral nerves are not Acute relapses are caused by focal inflammation causing myelin damage and conduction block and recovery follows as inflammation subsides and re-myelination occurs In severe damage, secondary permanent axonal destruction occurs which is the pathological basis of the progressive disability in progressive forms of MS

Question 372

Describe the clinical presentation of multiple sclerosis

Answer 372

Optic Neuritis Spinal Cord Lesions (Paraparesis, Difficulty Walking, Limb Numbness, Tingling) Brainstem Demyelination (Diplopia, Vertigo, Facial Numbness/Weakness, Dysarthria, Dysphagia) Visual Change, Sensory Symptoms, Clumsy Hand or Limb, Unsteadiness, Ataxia, Urinary Symptoms, Pain, Fatigue, Spasticity, Depression, Sexual Dysfunction, Temperature Sensitivity

Question 373

Describe the investigation of multiple sclerosis

Answer 373

MRI Brain and Spinal Cord - To investigate for demyelinating lesions Bloods to exclude other inflammatory conditions such as Sarcoidosis and SLE Visual Evoked Response LP - IgG Oligoclonal Bands in 85-90%

Question 374

Describe the main subtypes of multiple sclerosis

Answer 374

* Relapsing Remitting * Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission * Primary Progressive * Steady increase in disability without attacks * Secondary Progressive * Initial relapsing-remitting pattern that suddenly begins to decline without periods of remission * Progressive Relapsing * Steady decline from onset with super-imposed attacks

Question 375

Describe the pathology of Parkinson's Disease

Answer 375

Loss of dopaminergic neurones within substantia nigra PD manifests clinically after loss of approximately 50% of dopaminergic neurons Surviving neurones contain Lewy Bodies (aggregates of misfolded proteins in the cytoplasm) Progresses from Stage 1/2 (Medulla/Pons), to Stage 3/4 (Midbrain, Substantia Nigra, Pars Compacta - Parkinsonism) to Stage 5/6 (Neocortex - PD Dementia)

Question 376

Describe the clinical features of Parkinson's Disease

Answer 376

Bradykinesia, Muscular Rigidity, Postural Instability, 5-6Hz Rest Tremor Dementia, Depression, Anxiety Constipation, Urgency, Nocturia, Erectile Dysfunction, Excessive Salivation, Postural Hypotension, Sweating REM Sleep Behaviour Disorder, Restless Leg Syndrome, Daytime Somnolence Reduced Olfactory Function, Fatigue, Pain and Sensory Symptoms

Question 377

Describe the differential diagnosis of Parkinson's Disease

Answer 377

Benign Tremor Disorders (e.g. Essential Tremor) Dementia with Lewy Bodies Vascular Parkinsonism Parkinson Plus Disorders Drug Induced Parkinsonism/Tremor

Question 378

Describe the pharmacological management of Parkinson's Disease

Answer 378

* L-Dopa * Taken up by dopaminergic neurones and decarboxylated to dopamine within presynaptic terminals * Adverse effects include nausea, vomiting and postural hypotension (peripheral) and confusion and hallucinations (central) * Prescribed with a dopa-carboxylase inhibitor * Dopamine Agonists * e.g. Ropinirole, Pramipexole * Acts directly on post-synaptic striatal dopamine receptors (D2) * Longer half-life, lower efficacy but fewer motor complications than L-Dopa * MAO-B Inhibitors * e.g. Selegiline, Rasagiline * Prevents dopamine breakdown by binding irreversible to monoamine oxidase * COMT Inhibitors * e.g. Entacapone, Tolcapone * Inhibiting COMT results in longer L-Dopa half-life/duration of action

Question 379

Describe Myasthenia Gravis

Answer 379

Autoimmune disorder with auto-antibodies to acetylcholine receptor at post-synaptic neuromuscular junction Association with other autoimmune disorders May be associated with thymic hyperplasia or thymoma Affects young women in 20’s and older men in 70’s Causes fatigable weakness of ocular, bulbar, neck, respiratory and/or limb muscles Investigated with antibodies to AChR (present in 85% of cases) and abnormal single fibre EMG Managed with Pyridostigmine (anti-acetylcholine esterase) and immunosuppressive therapies (e.g. steroids and intravenous Immunoglobulin)

Question 380

Describe the pathogenesis and clinical presentation of length-dependent axonal neuropathy

Answer 380

Most common cause in the western world in Diabetes Mellitus Severely damaged axons degenerate distally Within a week the nerve becomes electrically inert Muscle fibres supplied by damaged motor nerves atrophy EMG records show fibrillation potentials Undamaged motor fibres sprout to supply more muscle fibres Demyelination: Demyelination of peripheral nerve fibres initially leaves the axon intact The result is blockage or slowing of conduction Pressure or entrapment neuropathies are primarily caused by demyelination Inflammatory processes e.g. Guillain-Barre are caused by demyelination Presents with tingling, numbness and in the peripheries, typically in a gloves and stocking pattern

Question 381

Describe the pathology of common dementias

Answer 381

Alzheimer - Generalised atrophy, beta-amyloid plaques and neurofibrillary tangles Vascular - Strokes, lacunar infarcts and white matter lesions Lewy Body - Generalised atrophy with lew bodies in the cortex and midbrain Frontotemporal - Frontotemporal atrophy and pick cells/bodies in the cortex

Question 382

Describe the clinical presentation of common dementias

Answer 382

Alzheimers - Memory loss, aggression, language deficit, impaired visuospatial Vascular - Focal neurological deficits, evidence of vascular disease Lewy Body - Fluctuating cognition, visual hallucinations, shuffling gait, increased tone, tremors Frontotemporal - Disinhibition, socially inappropriate behaviours, poor judgement and cognitive function

Question 383

Describe the investigation of common dementia syndromes

Answer 383

All patients should have a routine dementia screen, including FBC, U&Es, LFTs, TFTs, Glucose, VitB12 and Folate Cognitive function should be assessed using the Mini Mental State Exam (

Question 384

Describe the management of Multiple Sclerosis

Answer 384

Education from an MS Nurse Specialist Immunisations (avoid live vaccines if on disease-modifying drugs) Early management of infections Symptomatic treatment (e.g. pain, spasticity and urinary features) Physiotherapy/Occupational Therapy Short courses of steroids such as IV Methylprednisolone for 3 days (or high dose oral steroids) are used for severe relapses

Question 385

Describe the clinical and histological appearance of acute hepatitis and its most common causes

Answer 385

Signs and symptoms may be specific to the underlying disease process Jaundice, malaise, nausea, vomiting, diarrhoea Appearances include diffuse hepatocyte injury characterised by swelling, cytoplasmic granularity, vacuolation and necrosis Causes include viruses (Hepatitis A-E and EBV), drugs, alcohol and Wilson's Disease

Question 386

Describe the clinical and histological appearance of chronic hepatitis and its most common causes

Answer 386

Characterised by inflammatory cell infiltrate, lobular change, focal lytic necrosis, apoptosis, focal inflammation and fibrosis Specific causes have specific appearances (e.g. ground glass appearance in hepatitis B) Specific clinical features will reflect the underlying disease process Causes include hepatitis B/C, autoimmune disease, Wilson's disease and haemochromatosis

Question 387

Describe the clinical and histological appearance of acute cholestasis and its most common causes

Answer 387

Histological hallmarks include brown bile pigments and features of acute hepatitis May present with jaundice, signs of gallstones etc. Causes include extrahepatic biliary obstruction or drug injury (e.g. by antibiotics)

Question 388

Describe the clinical and histological appearance of Fatty Liver Disease and its common causes

Answer 388

Risk factors include obesity, HTN, T2DM and hyperlipidaemia May present with hepatomegaly, nausea, vomiting, diarrhoea, jaundice, ascites, ankle oedema Histological features include steatosis, alcoholic hepatitis (infiltration by polymorphonuclear leucocytes and hepatocyte necrosis, with giant mitochondria and Mallory bodies) Mallory bodies are suggestive of alcoholic damage Alcoholic cirrhosis may also be seen (classically micronodular) Most common cause is alcohol, however, fatty liver disease may be independent of alcohol

Question 389

Describe drug-induced liver disease

Answer 389

Common Drugs can cause almost any pattern of liver disease Most drug hepatotoxicity is idiosyncratic (rare but usually a single clinical pattern) thus difficult to investigate, e.g. Augmentin Occasionally there is predictable liver damage, e.g. Paracetamol or Methotrexate Non-prescribed drugs are important too, e.g. over the internet, illicit or herbal

Question 390

Describe the features of liver cysts

Answer 390

Usually developmental or degenerative in origin Most common is the Von Meyenberg complex (a simple biliary hamartoma) Usually no treatment required

Question 391

Describe common hepatic neoplasms

Answer 391

Haemangioma - Benign blood vessel tumour Hepatic Adenoma - Mainly affects young women and is often associated with hormonal therapy Hepatocellular Carcinoma - Most common primary liver tumour, usually arising in cirrhosis and associated with elevated serum alpha feto-protein The most common origin of secondary liver malignancy is the GI tract (50%), followed by breast, ovaries, bronchus and kidneys

Question 392

State the constituents of gallstones and risk factors for their development

Answer 392

Stones may be pure cholesterol or bile pigment, but most are mixed Bile becomes lithogenic for cholesterol if there is excessive secretion of cholesterol or decreased secretion of bile salts Excessive secretion of bilirubin can cause its precipitation in concentrated bile Risk factors include increased BMI, increased age, female sex, multiparity and Caucasian race (5 F's)

Question 393

Describe the features of acute and chronic cholecystitis

Answer 393

Arises due to obstruction of gallbladder emptying, usually due to gallstones, resulting in distention, compromised blood supply and inflammation Presents with severe RUQ pain, tenderness and fever Chronic cholecystitis may be a sequel to repeated attacks of acute cholecystitis Inflammation in chronic is secondary to chemical damage Gallstones are virtually always present in chronic cholecystitis

Question 394

State the LFT pattern expected in obstructive jaundice

Answer 394

Marked elevation in ALP Mild elevation in ALT/AST Raised Bilirubin

Question 395

Describe the clinical presentation, investigation and management of cholelithiasis/acute cholecystitis

Answer 395

Jaundice, severe RUQ pain, tenderness and fever USS, X-Ray (only detects 10%), and Bloods (high bilirubin/CSR/ESR, leucocytosis and obstructive LFTs) Manage with cholecystectomy if does not resolve spontaneously

Question 396

Describe the presentation, investigation and management of biliary sepsis (ascending cholangitis)

Answer 396

‘infection of the biliary tree, usually originating at the junction with the duodenum and ascending to the gall bladder, which usually contains gallstones’ Charcot's Triad (Fever, Jaundice and RUQ Pain) Reynolds Pentad (Fever, Jaundice, RUQ Pain, Mental Confusion and Septic Shock) Investigate with raised amylase, obstructive LFTs, raised bilirubin and positive blood cultures Manage with broad-spectrum antibiotics and ERCP

Question 397

Describe the presentation, investigation and management of Primary Sclerosing Cholangitis

Answer 397

‘chronic progressive cholestatic liver disease, characterised by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts, resulting in diffuse, multi-focal stricture formation’ Presents with RUQ pain, pruritis, fever, jaundice, weight loss and fatigue Investigate with obstructive LFTs, low albumin, prolonged PT, positive ANCA, abdominal USS, MRCP and ERCP Manage with pruritis relief, immunosuppression, ERCP with stenting of strictures

Question 398

Describe the presentation, investigation and management of acute pancreatitis

Answer 398

Aetiology - I GET SMASHED: Idiopathic, Gallstones, Ethanol, Trauma, Steroids, Mumps/Malignancy, Autoimmune, Scorpion Sting, Hyperlipidaemia, Hypercalcaemia, ERCP/EUS, Drugs (e.g. Azathioprine) Presents with acute, severe upper abdominal pain (may radiate to back, partially relieved by sitting/bending forward), jaundice, or signs of severe pancreatitis (multi-organ failure, pleural effusions, ascites) Investigate with serum amylase (3x ULN), serum lipase (remains elevated for longer than serum amylase), AXR, contrast CT and MRCP Manage with fluid replacement, analgesia, PO/enteral nutrition and antibiotics if septic for mild cases Treat underlying cause (e.g. abstinence from alcohol or cholecystectomy) Symptomatic fluid collections may need draining

Question 399

Describe the presentation, investigation and management of chronic pancreatitis

Answer 399

‘a progressive inflammatory condition of the pancreas marked by replacement of the normal parenchyma with fibrous tissue’ Aetiology - TIGAR-O Toxic/Metabolic, Idiopathic, Genetic, Autoimmune, RAP/SAP Associated, Obstructive Presents with epigastric pain, weight loss, malabsorption, diabetes, jaundice Investigations include elevated serum amylase and lipase, serum Ig4, abnormal faecal elastase, calcification on CT, MRCP, EUS, biopsy and labelled carbon breath test for exocrine insufficiency Manage with lifestyle modification (smoking and alcohol cessation), analgesia, management of exocrine needs (e.g. pancreatic enzyme supplements) and endocrine needs (e.g. diabetes) May require surgical intervention, such as duct drainage or distal pancreatectomy

Question 400

Describe the presentation, investigation and management of exocrine pancreatic insufficiency

Answer 400

May arise due to pancreatitis, CF, pancreatectomy Main presenting feature is malnutrition Investigate with direct pancreatic function test or indirect (faecal elastase/fat) Aim of management is to ensure a normal nutritional stats and avoid steatorrhea, weight loss and maldigestion-related symptoms Treat with pancreatic enzyme supplementation (enteric coated pancreatin) and a PPI

Question 401

Describe the presentation, investigation and management of pancreatic cancer

Answer 401

3% five year survival rate Risk factors include smoking, male, alcohol, history of chronic pancreatitis, high BMI, family history Presents with jaundice, abdominal/back pain, weight loss, acute pancreatitis, double duct sign, recent diagnosis of diabetes Investigate with CT or MRI Management may be surgical (Whipple's resection or duct stenting or gastrojejunostomy) or medical (chemotherapy, pancreatic enzyme replacement therapy)

Question 402

Describe the causes of upper GI bleeding

Answer 402

Varices - Oesophageal varices arise due to cirrhosis of the liver, which leads to portal hypertension and shunting of blood to the porto-systemic circulation. This causes distention of the blood vessels in the oesophagus, which may become prone to rupture and severe bleeding Peptic Ulcers - Commonly associated with h. pylori infection and increased gastric acid secretion Gastritis/Duodenitis/Oesophagitis Malignancy Mallory-Weiss Tear

Question 403

Describe the investigation of upper GI bleeding

Answer 403

Risk assessment with Admission Rockall or Glasgow Blatchford score High Risk - Emergency Endoscopy Moderate Risk - Admit and Next Day Endoscopy Low Risk - Consider Out-Patient Management

Question 404

Describe the management of acute upper GI bleed

Answer 404

Resuscitation (fluids, oxygen, check bloods) IV PPIs (reduces re-bleed risk and mortality if given post-endoscopy) Endoscopic Therapy (adrenaline injection, heater probe and endoscopic clips) Restrictive Transfusion if Hb \<7-8g/dL Platelets if active bleeding and platelet count \<50x10⁹/L FFP if INR\>1.5 Prothrombin Complex Concentrate if on Warfarin and active bleeding

Question 405

Describe the specific management of acute variceal bleeding

Answer 405

Resus: restore circulating volume, transfuse if Hb\<7-8 and consider airway protection Therapy: Prophylactic antibiotics, early vasopressors (e.g. Terlipressin) and/or endoscopic band ligation Primary and Secondary Prevention with Beta-Blockers and/or Banding

Question 406

State functions of the kidneys

Answer 406

Metabolic waste excretion Endocrine functions Drug metabolism/excretion Control of solutes and fluid status Blood pressure control Acid/base balance

Question 407

State methods of assessing kidney function and their uses and limitations

Answer 407

* 24hr Urine Collection (g/24h) * Cumbersome, not routinely used in clinical practice * Protein:Creatinine Ratio (PCR) (mg/mmol) * Albumin:Creatinine Ratio (mg/mmol) * Estimation of GFR * Based on plasma creatinine concentration * Not suitable in AKI * Affected by muscle mass

Question 408

Define nephrotic syndrome

Answer 408

3.5g Proteinuria per 24h (Urine PCR\>300) Serum Albumin \<30 Oedema (Hyperlipidaemia)

Question 409

Define glomerulonephritis

Answer 409

Glomerulonephritis (GN) is a renal disease characterised by inflammation and damage to the glomeruli that allows protein (+/- blood) to leak out into the urine

Question 410

State the aetiology of acute and chronic glomerulonephritis

Answer 410

Group A Strep Systemic Inflammatory Diseases (SLE, RA) Drugs (e.g. NSAIDs) Diabetes Hypertension Amyloidosis

Question 411

Describe IgA nephropathy, its diagnosis and management

Answer 411

Most common type of GN in adults worldwide Proliferative Characterised by mesangial proliferation, increased IgA production and IgA deposition Often presents 24-48hrs after a URTI Can present with haematuria, hypertension and proteinuria (nephritic syndrome) Biopsy needed for definitive diagnosis Managed with anti-hypertensives, ACEi, steroids

Question 412

Describe membranous glomerulonephritis, its diagnosis, management and prognosis

Answer 412

Presents with nephrotic syndrome Non-proliferative Caused by immune complex deposition, which results in complement activation against glomerular basement membrane proteins Microscopic analysis shows thickened glomerular basement membrane Immunofluorescence shows diffuse uptake of IgG Treat underlying disease if secondary Supportive non-immunological - ACi, statin, diuretics, salt restriction Immunotherapy can be used if disease progresses (steroids, cyclosporin) 1/3rd spontaneously remit, 1/3rd have chronic membranous GN, the remaining 1/3rd progress to end-stage renal failure

Question 413

Describe minimal change glomerulonephritis

Answer 413

Non-proliferative Most common GN in children Presents with nephrotic syndrome Often idiopathic, but can be secondary to malignancy Electron microscopy shows fused podocyte foot processes Manage with supportive care (e.g. to reduce oedema) and prednisolone

Question 414

Describe post-infectious glomerulonephritis, its diagnosis and management

Answer 414

Proliferative Can occur after almost any infection, particularly after strep. pyogenes Anti-body production and sub-epithelial deposition of immune complexes Presents with oliguria, haematuria, proteinuria, oedema and hypertension May require dialysis or antibiotics Usually resolves over weeks, and almost always a benign prognosis

Question 415

Describe rapidly progressing (cresentic) glomerulonephritis, its diagnosis and management

Answer 415

An aggressive form of GN Progresses to end-stage renal failure over a few weeks if left untreated Common Causes: Goodpasture's - Antibodies against glomerular basement membrane (anti-GBM), present with nephritic syndrome and haemoptysis, require high dose immunosuppression (IV Prednisolone and Cyclophosphamide) Microscopic Polyangiitis - MPO Antibody, +ve pANCA Granulomatosis with Polyangiitis - PR3 Antibody, +ve cANCA

Question 416

Describe the pathophysiology, presentation and management of diabetic nephropathy

Answer 416

Hyperglycaemia leads to volume expansion, intra-glomerular hypertension, hyperfiltration, proteinuria, hypertension and renal failure Diabetic disease induces structural changes, thickening of glomerular basement membrane, fusion of podocyte foot processes and loss of podocytes Often presents after retinopathy with proteinuria as a hallmark Mainstay of treatment is tight glycaemic control, good BP control (with ACEi/ARB) and SGLT-2 inhibitors

Question 417

Describe the pathophysiology, presentation and management of renovascular disease

Answer 417

Progressive narrowing of the renal arteries with atheroma causes reduced perfusion. GFR falls but tissue oxygenation of the cortex and medulla is maintained Progression of RA stenosis to 70% causes cortical hypoxia and microvascular damage and activation of inflammatory and oxidative pathways. Parenchymal inflammation and fibrosis progress and become irreversible and at this point, restoration of blood flow has no benefit Presents with hypertension, pulmonary oedema, bruits, hx of vascular disease Manage with BP control (not ACEi/ARB), statins, good glycaemic control if diabetic, smoking cessation, exercise, low sodium diet Angioplasty only used if rapidly deteriorating renal failure, uncontrolled HTN or flash pulmonary oedema

Question 418

Describe the pathophysiology, presentation and management of amyloidosis

Answer 418

Deposition of highly stable insoluble protein material in extracellular space in the kidney, heart, liver and gut AA = Systemic Amyloidosis - Treat underlying source of inflammation/infection AL = Immunoglobulin fragments from haematological conditions (e.g. myeloma) - Treat the underlying haematological condition

Question 419

Describe the pathophysiology, presentation and management of SLE

Answer 419

Auto-immune disease with immune complex mediated glomerular disease Multiple autoAbs, directed against DNA, histones etc. Form intravascular immune complexes or attach to GBM Complement is activated leading to renal damage Can present with elevated creatinine, proteinuria, nephritic syndrome Treated with immunosuppression - steroids, rituximab, cyclophosphamide

Question 420

Describe adult polycystic kidney disease, its presentation and management

Answer 420

Autosomal dominant Most common inherited kidney disorder Most are associated with PKD-1 gene mutation, some with PKD-2 gene mutation These genes code for Polycystin 1 and 2, located in renal tubular epithelia and overexpressed in cyst cells, membrane proteins involved in intracellular calcium regulation Cysts gradually enlarge, kidney volume increases and there is some compensation eGFR falls, usually 10yrs before the kidney fails Diagnosed with USS: If FHx - Age 15-30, 2 Unilateral or Bilateral Cysts. Age 30-59, 2 Cysts in Each Kidney. \>60, 4 Cysts in Each Kidney If No FHx - 10 or More Cysts in Both Kidneys, Renal Enlargement, Liver Cysts Complications: End stage renal failure, hypertension, hernias, liver/pancreas cysts Management is supportive, BP control, treat complications and extra-renal associations May require renal replacement therapy Tolvaptan - Vasopressin V2 receptor antagonist, can delay onset of RRT by around 4-5yrs. S/E include hepatotoxicity and hypernatraemia

Question 421

Describe other inherited cystic disorders of the kidneys

Answer 421

* Von Hippel Lindau * Autosomal dominant * Causes multiple benign and malignant neoplasms * Renal cysts and multifocal renal cell carcinomas * Tuberous Sclerosis * Autosomal dominant * Benign hamartomas of multiple systems (brain, eyes, heart, lung, liver, skin, kidney) * Up to 80% have renal involvement with multiple cysts, angiomyolipomas (high risk of bleeding) and renal cell carcinoma * Replacement of renal tissue leads to kidney failure * Medullary Cystic Kidney Disease * Autosomal dominant * Cysts at the cortico-medullary junction * Causes hyperuricaemia and gout

Question 422

Describe other inherited renal disease

Answer 422

* Alport's Syndrome * Usually X-Linked * Abnormality in Collagen IV (found in basement membranes, so associated with anti-GBM disease) * Presents with haematuria, proteinuria and progressive renal insufficiency * Results in renal failure * Often associated with sensorineural hearing loss * Fabry's Disease * X-Linked * Lysosomal storage disorder due to deficiency of alpha-glucosidase * Causes proteinuria, end-stage renal failure, lipid deposits in urine * Manage with IV enzyme replacement therapy

Question 423

Describe the pathophysiology and clinical presentation of pyelonephritis

Answer 423

UTI refers to infection anywhere along the urinary tract, from kidney to urethra Pyelonephritis specifically refers to infection of the kidney/renal pelvis Presents with dysuria, frequency, urgency, suprapubic pain, haematuria, fever, chills/rigor, flank pain, costovertebral angle tenderness, nausea, vomiting

Question 424

State risk factors for UTI

Answer 424

Infancy (\<1 yr) Abnormal Urinary Tract (Congenital or Other) Female Sex Bladder Dysfunction/Incomplete Emptying Foreign Body (Catheter, Stone) Diabetes Mellitus Renal Transplant Immunosuppression

Question 425

Describe the diagnosis of UTI/Pyelonephritis

Answer 425

* Multistix * Useful for children \>3 years * +ve LE & Nitrite = UTI in 90% * Microscopy/Flow Cytometry * If -ve for pus cells and bacteria = No UTI * Urine Culture * Single Organism \>= 10⁵ CFU/ml

Question 426

Describe the management of UTI

Answer 426

Treatment with antibiotics empirically while awaiting cultures and sensitivities Oral therapy should be used unless severely ill, vomiting or in infants \<3 months Oral - Trimethoprim, Cephalosporin, Co-Amoxiclav, Nitrofurantoin IV - 3rd Gen Cephalosporins (Ceftriaxone) or Aminoglycosides (Gentamicin)

Question 427

Describe the two main congenital abnormalities of the kidneys and urinary tract

Answer 427

* Vesico-Ureteric Reflux * Retrograde passage of urine from the bladder into the upper urinary tract * May present with UTI and pyelonephritis * Can result in renal scarring * Low-grade VUR is more likely to spontaneously resolve * Manage with antibiotic prophylaxis or STING procedure or open ureteric re-implantation surgically * Bladder Outlet Obstruction * Posterior Urethral Valve * Antenatal hydronephrosis, UTI, poor urinary stream, renal dysfunction * Manage with valve resection, antibiotic prophylaxis, CKD care * Pelvi-Ureteric Junction Obstruction * Abdominal mass, pain, haematuria, UTI * Manage with pyeloplasty * Vesico-Ureteric Junction Obstruction * Anatomical or functional narrowing * Antenatal dilation, UTI, abdominal mass, pain, haematuria * May improve or resolve spontaneously * May need resection

Question 428

Define acute kidney injury and describe factors contributing to its development

Answer 428

‘decline of renal excretory function over hours or days, recognised by the rise in serum creatinine and drop in urine output’ Pre-Renal - Circulatory Failure/Shock - Reduced Perfusion of the Glomerulus Renal - Cells of the Kidney Post-Renal - Obstruction

Question 429

Describe the diagnostic process in acute kidney injury

Answer 429

Rise in serum creatinine \>26micromol/L Rise in serum creatinine \>1.5x baseline Urine output \<0.5ml/kg/h for \>6 consecutive hours 1. CKD or AKI? 2. History and Exam (Sepsis, Haemoptysis, Rhabdo) 3. Drugs 4. Urinalysis 5. Renal USS 1. Exclude obstruction 2. Info on kidney size 6. GN Screen 1. ANCE, ANA, Ig, Complement, aGBM, Urine Bence Jones Protein 7. Other Blood Film

Question 430

Describe the emergency management of acute kidney injury

Answer 430

Protect Airway and Breathing Restore Renal Perfusion Assess for Pulmonary Oedema Treat Hyperkalaemia if \>6.5 (Calcium Chloride, IV Insulin, Salbutamol or Renal Replacement) Treat Sepsis Remove Offending Drugs Correct Acidosis Indications for RRT - Persistent Hyperkalaemia, Acidosis, Uraemia (pericarditis, encephalopathy), Toxins

Question 431

Define chronic kidney disease and a system to classify its severity

Answer 431

'kidney damage or GFR \<60ml/min per 1/73m² for three months or more' Classified based on eGFR

Question 432

Describe the clinical consequences of progressive chronic kidney disease

Answer 432

Albuminuria Pruritis, Nausea, Anorexia, Weight Loss, Fatigue, Leg Swelling, Breathlessness, Nocturia, Joint/Bone Pain, Confusion Peripheral/Pulmonary Oedema, Pericardial Rub, Rash, Hypertension, Tachypnoea, Cachexia, Pallor

Question 433

Describe the medical management of chronic kidney disease

Answer 433

* Treatment to slow renal disease progression * Aggressive BP control (ACEi/ARB) * Improved glycaemic control * Exercise * Sodium restriction * Treatment of renal complications * Manage anaemia (iron, B12, folate, EPO stimulator) * Acidosis (sodium bicarb supplements) * Oedema (fluid/sodium restriction, diuretic) * Bone mineral disorders (Vit D supplements, phosphate binders) * Other * Statins

Question 434

State indications for renal replacement therapy

Answer 434

Hyperkalaemia Acidosis Uraemia Fluid Overload (hypertension, pulmonary oedema)

Question 435

Describe haemodialysis and its potential complications

Answer 435

Aims to remove solutes (potassium, urea) by diffusion and fluid by convection Blood is passed over a semi-permeable membrane against dialysis fluid flowing in the opposite direction DIffusion of solutes occurs down the concentration gradient Access is usually through an arteriovenous fistula Most commonly hospital-based Standard regimen is 4 hours, 3 times a week Problems include access complications, hypotension, cramps, fatigue, infection, dialysis disequilibrium

Question 436

Describe peritoneal dialysis and its potential complications

Answer 436

Uses the peritoneal membrane as a semi-permeable membrane Catheter inserted into the peritoneal cavity and fluid is infused Glucose is used as an osmotic agent to achieve ultrafiltration Continuous process, home based Requires patient to drain and refill Complications include peritonitis, infection, hernia, loss of membrane function, glucose load

Question 437

Describe the short and long-term consequences of renal transplantation

Answer 437

Far better outcome than dialysis Cadaveric waiting list of approx. 3 years * Pros * No dialysis * Better level of renal function * Can live much more independently * Better life expectancy * Better fertility * Cons * Immunosuppressive medication for duration of transplant * Increased CV risk * Increased infection * Post-transplant diabetes * Skin malignancies and others * Risk of acute/chronic rejection, surgical bleeds Immunosuppression with monoclonal antibodies, calcineurin inhibitors antimetabolites, glucocorticoids

Question 438

State the range of organisms that cause UTI

Answer 438

Usually anaerobes and gram -ve bacteria from bowel/vagina E.coli is the most common community organism Staphylococcus saprophyticus and klebsiella pneumonia are other organisms involved

Question 439

Describe the pathophysiology, presentation and management of prostate cancer

Answer 439

Most are primary adenocarcinoma, usually arising in the peripheral zone of the prostate May be asymptomatic or present with painful/slow micturition, UTIs, haematuria, retention, lymphoedema Metastatic features may include bone pain and renal failure due to ureteric obstruction Diagnosed by digital rectal examination, prostate-specific antigen and trans-urethral guided needle biopsy Note that PSA is tissue, not tumour specific and tends to rise with age Manage localised disease with surveillance, radiotherapy, radical prostatectomy, cryotherapy For advanced cancer, androgen ablation therapy (medical or surgical castration), chemotherapy, radiotherapy

Question 440

Describe the pathophysiology, presentation and management of bladder cancer

Answer 440

Majority are transitional cell carcinomas Can be squamous carcinomas and adenocarcinomas Classically presents with painless frank haematuria Diagnosed with flexible cystoscopy Manage with mitomycin, chemotherapy, radical cystectomy, radiotherapy If metastatic, treat with M-VAC chemotherapy (methotrexate, vinblastine, doxorubicin, cisplatin)

Question 441

Describe the pathophysiology, presentation and management of renal cancer

Answer 441

Renal cell carcinoma is the most common, others include transitional cell carcinoma, sarcoma and metastases 80% are found incidentally Systemic symptoms include night sweats, fever, fatigue, weight loss, haemoptysis 10% present with the classic triad (mass, pain, haematuria) Initial diagnosis is made with USS, CT, MRI or renal biopsy Manage with partial or radical nephrectomy, cryotherapy

Question 442

Describe the pathophysiology, presentation and management of testicular cancer

Answer 442

Most are germ cell tumours (seminoma, teratoma) but can be stromal (leydig or sertoli) or lymphoma Majority present as a painless lump, or may be found after incidental trauma Investigate with scrotal USS, alpha-fetoprotein, Beta-hCG, LDH Treat with radical orchidectomy, chemotherapy, nodal radiotherapy

Question 443

Describe the epidemiology of renal stone disease

Answer 443

10-15% Lifetime Risk Peak Incidence of 30-50 Yrs Males \> Females Caucasian\>Asian\>Black\>Hispanic More common in hot, dry climates Risk of further stone is 50% at 10 years and 90% at 30 years

Question 444

Describe the pathophysiology of renal stone disease

Answer 444

* Abnormal Urine * Too much calcium * Too much acid * Hypercalciuria * Hyperoxaluria * Stone inhibitors (citrate, magnesium) * Obstruction * Congenital or Acquired * Infection * Particularly urease-producing organisms * Raises urine pH

Question 445

State common types of renal stones

Answer 445

* Calcium (80%) * Calcium Oxalate Monohydrate or Dihydrate * Calcium Phosphate * Infection (10%) * Struvite * Uric Acid Stone (5%) * Not seen on X-Ray * Others (1%) * Cystine, Xanthine, Silica

Question 446

Describe the presentation of renal stones

Answer 446

Incidental Pain (colic, radiates from loin to groin, cannot settle, unable to stay still) Haematuria UTI Sepsis Investigate with CT, Bloods (U&Es, CRP, FBC), Urinalysis, Urate, Calcium

Question 447

Describe the management of renal stone disease

Answer 447

Analgesia (NSAIDs, e.g. Diclofenac) Small stones are likely to pass spontaneously Larger stones or if non-remitting pain, may require medical expulsive therapy (alpha-blocker - tamsulosin) Surgical options include Extracorporeal Shockwave Lithotripsy, Ureteroscopy with Basket Extraction or Percutaneous Nephrolithotomy

Question 448

Describe the pathophysiology of Inflammatory Bowel Disease

Answer 448

* Ulcerative Colitis * 'relapsing and remitting inflammatory disorder of the colonic mucosa which may affect just the rectum or extend to involve part of the colon' * Caused by an inappropriate immune response to colonic flora in genetically susceptible individuals * Pathological features include hyperaemia, haemorrhagic colonic mucosa with/without pseudopolyps * Continuous inflammation is limited to the mucosa * Crohn's * 'a chronic inflammatory disease characterised by transmural granulomatous inflammation affecting any part of the gut from mouth to anus' * Unlike UC, there is unaffected bowel between areas of active disease (skip lesions)

Question 449

Describe the clinical presentation of Inflammatory Bowel Disease

Answer 449

Diarrhoea Abdominal Pain Weight Loss Fever, Malaise, Anorexia, Fatigue Tenesmus Crohns - Fistulae, Obstruction UC - Distended Abdomen, Clubbing, Erythema Nodosum, Pyoderma Gangrenosum

Question 450

Describe the diagnosis of Inflammatory Bowel Disease

Answer 450

FBC, CRP, ESR, U&Es, LFTs Blood Cultures Stool Cultures Faecal Calprotectin AXR Colonoscopy and Biopsy Crohn's - MRI, Endoscopy

Question 451

Describe the management of Inflammatory Bowel Disease

Answer 451

* Common Treatments * Corticosteroids * IV Hydrocortisone/Methylprednisolone or Oral Prednisolone * Rapid induction of remission * Poor evidence for maintaining remission * Thiopurines * Azathioprine and Mercaptopurine are unlicensed for IBD therapy * Effective maintenance therapy * Steroid-sparing agent for those requiring 2+ courses a year or relapse on \<15mg prednisolone * Prevents T-cell clonal expansion in response to antigenic stimuli * Biologics * Infliximab * Murine Anti-TNF Alpha * Severe or fistulating Crohn's or rescue acute severe UC * Adalimumab or Golimumab * For UC Alone * Aminosalicylates * Anti-inflammatory * Mesalazine most widely used * Can cause renal impairment * For Crohn's Alone * Methotrexate * Anti-inflammatory immunosuppressant * Anti-metabolite * Side effects include GI upset, hepatotoxicity, immunosuppression, sepsis

Question 452

Define diabetes

Answer 452

“a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, protein and fat metabolism resulting from defects in insulin secretion, insulin action, or both”

Question 453

State the WHO diagnostic criteria for diabetes

Answer 453

Fasting Plasma Glucose \>/= 7mmol/L Random Plasma Glucose \>/= 11.1mmol/L One Abnormal Value if Symptomatic Two Abnormal Values if Asymptomatic Should not be diagnosed on the basis of HbA1c or glycosuria alone

Question 454

Describe symptoms of diabetes

Answer 454

* Glycosuria - Depletion of Energy Stores * Tiredness, Weakness, Weight Loss, Difficulty Concentrating, Irritability * Glycosuria - Osmotic Diuresis * Polyuria, Polydipsia, Dry Mucous Membranes, Reduced Skin Turgor, Postural Hypotension * Glucose Shifts - Swollen Ocular Lenses * Blurred Vision * Ketone Production * Nausea, Vomiting, Abdominal Pain, Heavy/Rapid Breathing, Acetone Breath, Drowsiness, Coma * Depletion of Energy Stores * Weakness, Polyphagia, Weight Loss, Growth Retardation in Young * Complications * Macrovascular, Microvascular, Neuropathy, Infection

Question 455

Compare and contrast type 1 and type 2 diabetes

Answer 455

Type 1 - Immune pathogenesis with severe insulin deficiency Type 2 - Combination of insulin resistance and insulin deficiency

Question 456

Describe the pathogenesis of type 1 and type 2 diabetes mellitus

Answer 456

* Type 1 DM * Chronic, progressive metabolic disorder characterised by hyperglycaemia and the absence of insulin secretion * Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans * Occurs in genetically susceptible subjects and is probably by one or more environmental agents * Type 2 DM * Chronic, progressive metabolic disorder characterised by hyperglycaemia, insulin resistance and relative impairment of insulin deficiency * Common with a prevalence that rises markedly with increasing levels of obesity * Most likely arises through a complex interaction among many genes and environmental factors

Question 457

Describe MODY

Answer 457

Maturity Onset Diabetes of the Young 1-2% of all DM Caused by a change in a single gene (monogenic) Autosomal dominant Main features include \<25yrs onset, runs in families from one generation to next, managed by diet, OHAs and insulin

Question 458

Describe Latent Autoimmune Diabetes of Adulthood

Answer 458

Age of onset \>25yrs Obesity is rare Insulin usually required within months or years of diagnosis Polygenic inheritance GAD antibodies

Question 459

Define gestational diabetes

Answer 459

Carbohydrate intolerance with onset, or diagnosis, during pregnancy Risk factors include high body mass index, previous macrosomic baby or gestational diabetes, or family history of, or ethnic prevalence of, diabetes All women with risk factors should have an OGTT at 24 to 28 weeks Internationally agreed criteria for gestational diabetes using 75 g OGTT: Fasting venous plasma glucose ≥ 5.1 mmol/l, or One hour value ≥ 10 mmol/l, or Two hours after OGTT ≥ 8.5 mmol/l

Question 460

List causes of Secondary Diabetes

Answer 460

Genetic defects of beta-cell function Genetic defects in insulin action Disease of exocrine pancreas (pancreatitis, carcinoma, CF, haemochromatosis) Endocrinopathies (acromegaly, cushings) Immunosuppressive Agents (glucocorticoids, tacrolimus, ciclosporin) Anti-Psychotics (clozapine) Genetic Syndromes Associated with DM (Down's, Turner's, Kleinfelter's)

Question 461

Describe the different insulin regimens available

Answer 461

Insulin is a peptide, so cannot be given orally Can be given as a once-daily basal, twice daily mix or basal-bolus therapy Insulin pens are more convenient, accurate, discrete and less painful than conventional vial and syringes

Question 462

Describe the rationale for Continuous Subcutaneous Insulin Infusion treatment

Answer 462

Can potentially provide significant improvement in glycaemic control and quality of life for some people with T1DM Potentially make it easier to achieve glucose control with less danger of severe and incapacitating hypoglycaemia Complications include reactions, infections at cannula site, tube blockage, pump malfunction

Question 463

Define hypoglycaemia and describe symptoms

Answer 463

Insulin-Treated DM - \<4mmol/L Normal People - \<2.8mmol/L Autonomic - Sweating, Palpitations, Shaking, Hunger Neuroglycopenic - Confusion, Drowsiness, Visual Disturbance Nausea + Headache

Question 464

Describe the treatment of hypoglycaemia

Answer 464

Question 465

Describe the pathophysiology and management of Diabetic Ketoacidosis

Answer 465

Absolute insulin deficiency results in activation of the ketone pathway, used in starvation states This results in acetone (ketone) production, which along with profound hyperglycaemia can be life-threatening Presents with osmotic symptoms, weight loss, breathlessness, abdominal pain, leg cramps, N&V, confusion Characterised by a Metabolic Acidosis, Hyperglycaemia and Urinary/Plasma Ketones Manage with IV fluids, insulin and assess need for potassium Follow national DKA pathway

Question 466

Describe the pathophysiology and management of Hyperglycemic Hyperosmolar State

Answer 466

Occurs in a relative insulin deficiency No ketoacidosis More insidious onset Marked dehydration and hyperglycaemia Rehydrate with saline and give insulin if glucose does not fall with fluids alone LMWH prophylaxis and consider K+

Question 467

Describe the pharmacology of Pioglitazone

Answer 467

Acts on PPAR receptors to increase peripheral insulin sensitivity SE include hypoglycaemia, fractures, oedema

Question 468

Describe the pharmacology of DPP4 inhibitors

Answer 468

e.g. Sitagliptin Blocks the action of DPP4, which destroys the enzyme incretin Increased incretin levels inhibit glucagon, which increases insulin secretion

Question 469

Describe the pharmacology of SGLT-2 inhibitors

Answer 469

e.g. Empagliflozin, Canagliflozin Inhibits sodium-glucose co-transporter in the renal tubules Blocks glucose reabsorption and promotes loss of glucose in the urine

Question 470

Describe the pathophysiology, investigation and treatment of Cushing's Syndrome/Disease

Answer 470

Cushing's syndrome is the clinical state produced by chronic glucocorticoid excess and loss of the normal feedback mechanisms Causes include exogenous steroid use, and a pituitary adenoma (specifically known as Cushing's disease) Symptoms include weight gain, mood change (depression, lethargy, irritability), proximal myopathy, gonadal dysfunction, acne Signs include central obesity, moon face, buffalo hump, skin/muscle atrophy, bruises, abdominal striae, hypertension, hyperglycaemia Investigate with MRI for pituitary mass, raised plasma cortisol, 24hr urinary free cortisol and dexamethasone suppression test (give dexamethasone at night and measure cortisol in the morning, should normally be suppressed but will not be in Cushing's) Manage by stopping offending medication, surgical removal of pituitary adenoma or adrenalectomy

Question 471

Describe the pathophysiology, investigation and management of Congenital Adrenal Hyperplasia

Answer 471

Autosomal recessive disorder Deficiency in 21-alpha-hydroxylase Results in steroidogenic defects including aldosterone and cortisol deficiency This means more pregnenolone is converted to the androgen DHEA Can result in ambiguous genitalia (female) and adrenal crisis and early virilisation (males) Managed with mineralocorticoid and glucocorticoid replacement

Question 472

Describe the pathophysiology, investigation and management of Phaeochromocytoma

Answer 472

Rare catecholamine-producing tumours arising from sympathetic paraganglia cells (collections of chromaffin cells) in the adrenal medulla Often associated with hard to control hypertension Episodes of headache, palpitations, pallor and sweating Also associated with tremor, anxiety, nausea, vomiting, chest and abdominal pain Diagnose with at least two 24 hour urinary catecholamines, CT abdomen and MIGB scan (chromaffin seeking analogue) Medical management with alpha-blockade (phenoxybenzamine) first, then with beta blocker (bisoprolol) if tachycardic Followed by surgical resection

Question 473

Describe the pathophysiology, investigation and management of Primary Hyperaldosteronism

Answer 473

Excess production of aldosterone, independent of the RAS system, causing sodium and water retention and reduced renin release Mostly caused by a solitary aldosterone-producing adenoma (Conn's syndrome) Other causes include bilateral adrenocortical hyperplasia or adrenal carcinoma Often asymptomatic, may have hypokalaemia, weakness, cramps, paresthesia, polyuria, polydipsia, hypertension Investigations include a raised aldosterone and aldosterone:renin ratio and suppressed renin Confirm with a saline suppression test (2L saline over 4 hours followed by a 4h aldosterone \>270pmol/L is highly suspicious) Manage with MR antagonists or amiloride Surgical management with unilateral laparoscopic adrenalectomy (only if adrenal adenoma)

Question 474

Describe the pathophysiology, investigation and management of adrenal insufficiency

Answer 474

Primary adrenal insufficiency (Addison's disease) is rare and characterised by destruction of the adrenal cortex leads to glucocorticoid and mineralocorticoid deficiency Causes include autoimmunity, adrenal TB, lymphoma, opportunistic infection Symptoms include anorexia, weight loss, fatigue, lethargy, dizziness, hypotension, hyperkalaemia, abdominal pain, vomiting, diarrhoea, skin and mucous membrane pigmentation Investigations include; Biochemistry - hyponatraemia, hyperkalaemia and hypoglycaemia High ACTH levels Adrenal auto-antibodies Renin (high) and aldosterone (low) levels Short Synacthen Test - Measure plasma cortisol before and 30 minutes after IV ACTH injection. In normal situations, ACTH should increase cortisol levels. A normal result is a baseline of \>250nmol/L and post-ACTH of \>480. In Addison's, there would be minimal cortisol response after ACTH injection

Question 475

Describe the pathophysiology, investigation and management of Kallmann's syndrome

Answer 475

A cause of primary hypogonadotropic hypogonadism Most common form of isolated gonadotropin-releasing hormone deficiency Due to a failure of cell migration of GnRH cells to the hypothalamus from the olfactory placode Associated with anosmia and colour blindness May have micropenis and cryptorchidism Familial with variable penetration (X-Linked, Autosomal Dominant or Autosomal Recessive) Diagnosed with clinical exam (usually due to delayed puberty) and hormone profile (LH, FSH, GnRH) Treat with testosterone

Question 476

Describe the pathophysiology, investigation and management of Primary Gondal Disease

Answer 476

PGD is due to testicular failure Causes include chromosomal defects (e.g. Kleinfelters), cryptorchidism or adult leydig cell/seminiferous tubule failure (due to trauma, chemotherapy, radiotherapy or multi-system disorders) Characterised by low testosterone, high/normal LH and FSH and normal prolactin Manage with testosterone replacement

Question 477

Describe the pathophysiology, investigation and management of Kleinfelters

Answer 477

Most common genetic cause of male hypogonadism XXY Manifests clinically at puberty High LH and FSH, but seminiferous tubules regress and Leydig cells do not function normally Wide clinical variation, including delayed puberty, suboptimal genital development, reduced secondary sexual characteristics, gynaecomastia, azoospermia and behavioural issues Manage with androgen replacement, psychological support and fertility counselling

Question 478

Describe testosterone replacement therapy, its advantages and disadvantages

Answer 478

Can be given orally, IM or topically Best option for androgen replacement in deficiency Side effects include mood issues (aggression/behaviour changes), libido issues, increased haematocrit, acne, sweating, gynaecomastia Testosterone is a drug of abuse in sports

Question 479

Describe the pathophysiology, investigation and management of hyperthyroidism

Answer 479

Most commonly due to an autoimmune disease (Grave's) Symptoms include diarrhoea, weight loss, sweats, heat intolerance, palpitations, tremor Signs include tachycardia, AF, lid lag, lid retraction, goitre, bruit, thyroid eye disease, pretibial myxoedema, thyroid acropachy Investigate with TSH (suppressed) and Free T4 (elevated) May also consider thyroid auto-antibodies and iodine uptake scan Manage with beta-blockers and 'block and replace' with carbimazole and levothyroxine simultaneously May require radio-iodine or thyroidectomy

Question 480

Describe the pathophysiology, investigation and management of thyroid eye disease

Answer 480

Typically associated with Grave's, but patients can be euthyroid, hypothyroid or hyperthyroid at presentation Can be worsened by treatment, particularly radioiodine Retro-orbital inflammation and lymphocyte infiltration results in swelling of the orbit Eye discomfort, diplopia, exophthalmos, proptosis, lid retraction Diagnose clinically Treat hyper or hypothyroidism, avoid smoking, artificial tears, treat other symptoms In later disease, high dose steroid may be used and surgery may be required

Question 481

Describe the pathophysiology, investigation and management of hypothyroidism

Answer 481

Common primary autoimmune causes include Hashimoto's Thyroiditis (destruction of lymphocytic and plasma cell infiltration) Other primary causes include iodine deficiency or post-thyroidectomy Secondary hypothyroidism arises due to hypopituitarism (low TSH) Causes fatigue, cold intolerance, weight gain, constipation, menorrhagia, bradycardia, dry skin/hair, goitre Diagnosed with low TSH and low T4 Manage with levothyroxine replacement

Question 482

Describe the pathophysiology and management of thyroid carcinoma

Answer 482

Papillary, Follicular, Medullary, Lymphoma or Anaplastic Manage with thyroidectomy with or without radiotherapy

Question 483

Describe the pathophysiology, investigation and management of hyperprolactinaemia

Answer 483

Can be caused by prolactin-releasing pituitary tumours Clinical features include galactorrhoea, headaches, mass effect, visual field defects, amenorrhoea, erectile dysfunction Diagnose with serum prolactin (usually \>6000) and pituitary MRI Remaining pituitary function should also be tested (gonadal and thyroid hormones) Treat with dopamine agonists (e.g. cabergoline, bromocriptine) as dopamine has a negative feedback mechanism on prolactin secretion Surgery only indicated if medical therapy fails

Question 484

Describe the pathophysiology, investigation and management of acromegaly

Answer 484

Hypersecretion of growth hormone, most commonly due to a pituitary tumour GH stimulates bone and soft tissue growth through increased secretion of insulin-like growth factor Features include sweats and headaches, altered facial features (coarse features, macroglossia, frontal bossing, protruding jaw), spade-like hands, increased foot size, visual impairment, cardiomyopathy, increased inter-dental spaces Diagnose with GH measurements with OGTT (glucose should suppress GH) Measure IGF-1 and then Pituitary MRI First line treatment is surgery May require medical therapy such as somatostatin analogues, dopamine agonists or GH receptor antagonists Radiotherapy may be used for residual tumour or if ongoing symptoms

Question 485

Describe Whipple's triad

Answer 485

collection of three criteria that suggest a patient's symptoms result from hypoglycemia that may indicate insulinoma 1. Low Plasma Glucose 2. Symptoms Consistent with Hypoglycaemia 3. Relief of Symptoms when Glucose is Raised to Normal

Question 486

State differential diagnoses for non-diabetes hypoglycaemia

Answer 486

Drugs Critical Illness (hepatic/renal/cardiac failure, sepsis) Hormone Deficiency (e.g. Cortisol) Non-Islet Cell Tumour Endogenous Hyperinsulinism (Insulinoma, Functional Islet Cell Disorders, Insullin Autoimmune Hypoglycaemia) Accidental, Surreptitious, Malicious Hypoglycaemia

Question 487

Describe insulinoma

Answer 487

A rare neuroendocrine tumour, often benign Presents as fasting hypoglycaemia with Whipple's triad Test with IV insulin and measure c-peptide (should normally be suppressed but this will not happen in insulinoma) Image with CT/MRI and endoscopic USS Manage with excision

Question 488

State causes of amenorrhoea

Answer 488

* Primary * Chromosomal or Genetic Abnormalities (e.g. Turners) * Problems with Hypothalamus or Pituitary * Secondary * Pregnancy * Menopause * Chemotherapy * Certain Medications * PCOS * Thyroid Problems

Question 489

Describe causes of hirsutism

Answer 489

Male pattern hair growth in women Causes are familial, idiopathic or due to increased androgen secretion by the ovary (e.g. PCOS, ovarian cancer), adrenal (e.g. CAH, Cushing's, cancer) or drugs (e.g. Steroids) Manage with oestrogens (combine contraceptive pill), metformin Clomifene can be used for infertility

Question 490

Describe the pathophysiology, clinical features, investigation and management of Polycystic Ovarian Syndrome

Answer 490

See figure for Pathophysiology Presents with hirsutism, acne, male-pattern hair loss, acanthosis nigricans, obesity Lifestyle modification - diet, exercise, weight loss Oestrogen (combined oral contraceptive) Metformin (reduces glucose intolerance and hyperinsulinaemia) Clomifene (selective oestrogen receptor modulator) Gonadotropin therapy

Question 491

Describe the normal physiological role and regulation of calcium

Answer 491

Functions include muscle contraction, membrane stabilisation, bone growth and remodelling, enzyme co-factor, secondary signalling messenger, hormone secretion Most calcium is found in the skeleton, some intracellularly and some extracellularly (free or albumin-bound) Regulated chiefly by parathyroid hormone, which raises blood calcium by increasing reabsorption at the renal distal tubule; increasing osteoclast activity; and increasing Vit D synthesis which increases calcium absorption from the gut

Question 492

State signs and symptoms of hypercalcaemia

Answer 492

May be asymptomatic if mild Symptoms more common when calcium \>3mmol/L Muscle Weakness, Bone Pain, Osteoporosis Anorexia, Nausea, Constipation, Pancreatitis Confusion, Depression, Fatigue, Coma Shortened QTc, Bradycardia, Hypertension Polyuria, Nephrogenic DI, Stones

Question 493

State important causes of hypercalcaemia

Answer 493

* PTH-Mediated (i.e. Elevated/Normal PTH) * Primary Hyperparathyroidism * Familial Syndromes (MEN-1, MEN-2) * Familial Hypocalciuric Hypercalcaemia * PTH-Independent (i.e. Undetectable PTH) * Malignancy * Granulomatous Disorders * Drugs (thiazides, lithium, calcium supplements) * Adrenal Insufficiency * Milk-Alkali Syndrome * Immobilisation

Question 494

Describe the clinical effects of vitamin D deficiency

Answer 494

Can be due to poor sunlight exposure, malabsorption, gastrectomy, renal disease or enzyme-inducing drugs Can result in osteomalacia in adulthood Failure to ossify bones in adulthood as a result of Vit D deficiency Presents insidiously with bone pain, proximal myopathy and hypocalcaemia Characterised by low calcium, low phosphate, high ALP, low Vit D, elevated PTH Treat with vitamin D replacement (cholecalciferol or alfacalcidol)