2 Oxygen dissociation curve shifts Right - Raised oxygen delivery - Raised acidity,

temp, 2-3 DPG shifts Left - Lower oxygen delivery - Lower acidity,

temp, 2-3 DPG - also HbF, carboxy/methaemoglobin

Oxygen dissociation curve

The oxygen dissociation curve describes the relationship between the percentage of saturated haemoglobin and partial pressure of oxygen in the blood. It is not affected by haemoglobin concentrationBasics

shifts to right = for given oxygen tension there is reduced saturation of Hb with oxygen i.e. enhanced oxygen delivery to tissues

shifts to left = for given oxygen tension there is increased saturation of Hb with oxygen i.e. decreased oxygen delivery to tissues

20n Pulmonary arteries vasoconstrict in the presence of hypoxia (1st to do so) Respiratory physiology: hypoxia A fall in the partial pressure of oxygen in the blood leads to vasoconstriction of the pulmonary arteries. This allows blood to be diverted to better aerated areas of the lung and improves the efficiency of gaseous exchange

1

58 Respiratory physiology Chloride shift

CO2 diffuses into RBCs CO2 + H20 carbonic anhydrase HCO3- + H+ H+ combines with Hb HCO3- diffuses out of cell,- Cl- replaces it

Bohr effect

increasing acidity (or pCO2) means O2 binds less well to Hb

Haldane effect

increase pO2 means CO2 binds less well to Hb

59 Respiratory physiology: lung compliance Lung compliance is defined as change in lung volume per unit change in airway pressureCauses of increased compliance

age emphysema (but decreased elastic recoil)

Causes of decreased compliance

pulmonary oedema pulmonary fibrosis pneumonectomy kyphosis

82 Respiratory physiology: lung volumes Tidal volume (TV) = 10 ml\kg (USMLE)

2

volume inspired or expired with each breath at rest 500ml in males, 350ml in females

Inspiratory reserve volume (IRV) = 2-3 L

maximum volume of air that can be inspired at the end of a normal tidal inspiration

inspiratory capacity = TV + IRV

Expiratory reserve volume (ERV) = 750ml

maximum volume of air that can be expired at the end of a normal tidal expiration

Residual volume (RV) = 1.2L

volume of air remaining after maximal expiration increases with age RV = FRC - ERV

Vital capacity (VC) = 5L

maximum volume of air that can be expired after a maximal inspiration

4,500ml in males, 3,500 mls in females decreases with age VC = IC + ERV

Total lung capacity (TLC) is the sum of the vital capacity + residual volume

3 DiGeorge syndrome is a primary immunodeficiency disorder caused by T-cell deficiency and dysfunction. It is an example of a microdeletion syndrome. Patients are

3

consequently at increased risk of viral and fungal infections.

Primary immunodeficiency Primary immunodeficiency disorders may be classified according to which component of the immune system they affectNeutrophil disorders

chronic granulomatous disease Chediak-Higashi syndrome leukocyte adhesion deficiency

B-cell disorders

common variable immunodeficiency Bruton's congenital agammaglobulinaemia

absence of B-cells IgA deficiency commonest humoral def (thought to

be AD), high association with lupus & RA, increased incidence of cancers, anti IgA ab (transfusion anaphylaxis)

T-cell disorders

DiGeorge syndrome Nzolof’s syndrome Purine nucleoside phosphorylase deficiency

Combined B- and T-cell disorders

severe combined immunodeficiency

4

ataxic telangiectasia ch 11,autosomal recessive. CD8

Wiskott-Aldrich syndrome IgM

84DiGeorge syndrome DiGeorge syndrome is a primary immunodeficiency disorder caused by T-cell deficiency and dysfunction. It is an example of a microdeletion syndrome (ch22q11.2 found in majority)Features

Defect in 3rd and 4th pharyngeal arches at risk of viral and fungal infections parathyroid gland hypoplasia hypocalcaemic tetany thymus hypoplasia T-lymphocyte deficiency/dysfunction Cogenital heart diease(VSD,ASD),dysmorphic

features, bifid uvulu, oesophageal atresia, microagnosia & fish mouth

GVHD from non radiated blood transfusion Tests PCR-based genotyping, FISH22 test

191 Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome causes primary immunodeficiency due to a combined B- and T-cell dysfunction. It is inherited in a X-linked recessive fashion and is thought to be caused by mutation in the --Features

recurrent bacterial infections (e.g. chest) eczema (high IgA & IgE) thrombocytopenia

5

Igs high IgA & IgE due to eczema, normal IgG, low IgM

Hepatomegally, splenomegally & cervical LN may be present.

4 Metabolic acidosis Metabolic acidosis is commonly classified according to the anion gap. This can be calculated by: (Na+ + K+) - (Cl- + HCO-3). If a question supplies the chloride level then this is often a clue that the anion gap should be calculated. The normal range = 10-18 mmol/LNormal anion gap

gastrointestinal bicarbonate loss: diarrhoea, ureterosigmoidostomy, fistula

renal tubular acidosis (hyperchloraemic metabolic acidosis)

drugs: e.g. acetazolamide ammonium chloride injection Addison's disease

Raised anion gap

lactate: shock, hypoxia ketones: diabetic ketoacidosis, alcohol urate: renal failure acid poisoning: salicylates, methanol

Metabolic acidosis secondary to high lactate levels may be subdivided into two types:

lactic acidosis type A: shock, hypoxia, burns lactic acidosis type B: metformin

6

5Around 70% of patients with rheumatoid arthritis (RA) are HLA-DR4. Patients with Felty's syndrome (a triad of RA, splenomegaly and neutropaenia) are even more strongly associated with 90% being HLA-DR4

HLA associations HLA antigens are encoded for by genes on chromosome 6. HLA A, B and C are class I antigens whilst DP, DQ, DR are class II antigens (class 3= complement C2,C4 & factor B). Questions are often based around which diseases are associated with one another. The most important associations are listed below:

HLA-A3

haemochromatosis

HLA-B5

Behcet's disease

HLA-B27

ankylosing spondylitis Reiter's syndrome acute anterior uveitis

HLA-DR2

narcolepsy (if decreased) Goodpasture's

HLA-DR3

7

coeliac disease (HLA-DQ2 95% commonest.HLA-B8 (80%) as well as HLA-DR3 and HLA-DR7)

dermatitis herpetiformis Sjogren's syndrome primary biliary cirrhosis

HLA-DR4

type 1 diabetes mellitus* rheumatoid arthritis

*type 1 diabetes mellitus is associated with HLA-DR3 but is more strongly associated with HLA-DR4. MrcpassHLA ASSOCIATIONS The HLA system plays a role in antigen presentation and self recognition. HLA A, B and C are all encoded by MHC class I, not class II. Class II MHC molecules encode HLA D, which serve as antigen recognition molecules for T helper cells. HLA B8, DR3 and DW3 are associated with autoimmune hepatitis and Sjogren’s syndrome. HLA-B5, HLA -B51 and HLA-DR5 are associated with Behcet’s syndrome. Decreased HLA DR2 is associated with narcolepsy, HLA DR3 is associated with many autoimmune conditions, autoimmune adrenalitis (Addison’s) Increased HLA DR4 is associated with rheumatoid arthritis, autoimmune adrenalitis (Addison’s) The most commonly found HLA in coeliac disease (almost 90%) is HLA DQ2 and HLA DQ8.

8

HLA B27 is commonly associated with ankylosing spondylitis, reactive & psoriatic arthritis, Reiter's syndrome and Whipple's disease.

6 Causes of a low ESR

polycythaemia afibrinogenaemia/hypofibrinogenaemia sickle anemia

154 Given the history of anaphylaxis it would not be appropriate to perform a skin prick test Allergy tests Skin prick test Most commonly used

test as easy to perform and inexpensive. Drops of diluted allergen are placed on the skin after which the skin is pierced using a needle. A large number of allergens can be tested in one session. Normally includes a histamine (positive) and sterile water (negative) control. A wheal will typically develop if a patient has

9

an allergy. Can be interpreted after 15 minutes Useful for food allergies and also pollen and wasp/bee venom

Radioallergosorbent test (RAST)

Determines the amount of IgE that reacts specifically with suspected or known allergens, for example IgE to egg protein. Results are given in grades from 0 (negative) to 6 (strongly positive) Useful for food allergies inhaled allergens (e.g. pollen) and wasp/bee venom Blood tests may be used when skin prick tests are not suitable, for example if there is

10

extensive eczema or if the patient is taking antihistamines, history of anaphylaxis

Skin patch testing Useful for contact dermatitis. Around 30-40 allergens are placed on the back. Irritants may also be tested for. The results are read 48 hours later by a dermatologist

7 Transfer factor

raised: asthma, haemorrhage, left-to-right shunts, polycythaemia

low: everything else

Transfer factor (imp)The transfer factor describes the rate at which a gas will diffuse from alveoli into blood. Carbon monoxide is used to test the rate of diffusion. Results may be given as the total gas transfer (TLCO) or that corrected for lung volume (transfer coefficient, KCO)

Causes of a raised KCO

asthma

Causes of a lower KCO

11

pulmonary haemorrhage (Wegener's, Goodpasture's)

left-to-right cardiac shunts polycythaemia hyperkinetic states male gender, exercise, adult >

child

pulmonary fibrosis

pneumonia pulmonary

emboli pulmonary

oedema emphysema anaemia low cardiac

output decreases with

ageing

Some conditions may cause an increased KCO with a normal or reduced TLCO

pneumonectomy/lobectomy scoliosis/kyphosis neuromuscular weakness ankylosis of costovertebral joints e.g. ankylosing

spondylitis

10 Altitude related disorders There are three main types of altitude related disorders: acute mountain sickness (AMS), which may progress to high altitude pulmonary edema (HAPE) or high altitude cerebral edema (HACE). All three conditions are due to the chronic hypobaric hypoxia which develops at high altitudes

Acute mountain sickness is generally a self-limiting

12

condition. Features of AMS start to occur above 2,500 - 3,000m, developing gradually over 6-12 hours and potentially last a number of days:

headache nausea fatigue

Prevention and treatment of AMS

the risk of AMS may actually be positively correlated to physical fitness (i.e. the physical fitness associated with more risk of AMS)

gain altitude at no more than 500 m per day acetazolamide (a carbonic anhydrase inhibitor) is

widely used to prevent AMS and has a supporting evidence base

treatment: descent

A minority of people above 4,000m go onto develop high altitude pulmonary oedema (HAPE) or high altitude cerebral oedema (HACE), potentially fatal conditions

HAPE presents with classical pulmonary oedema features

HACE presents with headache, ataxia, papilloedema

Management of HACE

descent dexamethasone

Management of HAPE

13

descent dexamethasone, nifedipine, phosphodiesterase type V

inhibitors* oxygen if available

*the relative merits of these different treatments has only been studied in small trials. All seem to work by reducing systolic pulmonary artery pressure

136 Pulmonary histology Surfactant

a mixture of phospholipids, carbohydrates and proteins

functioning component = dipalmitoyl phosphatidylcholine (DPPC)

released by Type 2 pneumocytes reduces alveolar surface tension hypoxia may lower levels first detectable around 28 weeks as alveoli decrease in size, surfactant concentration is

increased, helping prevent the alveoli from collapsing reduces the muscular needed to expand the lungs

(work of breathing) lowers the elastic recoil at low lung volume (FRC),

an thus helps to prevent the alveoli from collapsing at the end of each expiration

163 Respiratory physiology: control Control of respiration

central regulatory centres

14

central and peripheral chemoreceptors pulmonary receptors

Central regulatory centres

medullary respiratory centre apneustic centre (lower pons) pneumotaxic centre (upper pons)

Central and peripheral chemoreceptors

central: raised [H+] in ECF stimulates respiration peripheral: carotid + aortic bodies, respond to

raised pCO2 & [H+], lesser extent low pO2

Pulmonary receptors

stretch receptors, lung distension causes slowing of respiratory rate (Hering-Bruer reflex)

irritant receptor, leading to bronchoconstriction juxtacapillary receptors, stimulated by stretching of

the microvasculature

141 Cystic fibrosis Cystic fibrosis (CF) is an autosomal recessive disorder causing increased viscosity of secretions (e.g. lungs and pancreas). It is due to a defect in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which codes a cAMP-regulated chloride channelIn the UK 80% of CF cases are due to a deletion at delta F508 on the long arm of chromosome 7. Cystic fibrosis affects 1 per 2500 births, and the carrier rate is c. 1 in 25Common organisms

15

Staph aureus Pseudomonas aeruginosa 5-10% colonized with Burkholderia cepacia* Aspergillus

*previously known as Pseudomonas cepacia

31 Despite a normal chest x-ray an ex-smoker with shortness of breath, weight loss and hyponatraemia should be investigated on an urgent basis for lung cancer. This approach is supported by current NICE guidelines. Whilst gastrointestinal cancer is a possibility the normal MCV is not entirely consistent with chronic blood loss Lung cancer: referral The 2005 NICE cancer referral guidelines gave the following advice: Consider immediate referral for patients with:

signs of superior vena caval obstruction (swelling of the face/neck with fixed elevation of jugular venous pressure)

stridorRefer urgently patients with:

persistent haemoptysis (in smokers or ex-smokers aged 40 years and older)

a chest X-ray suggestive of lung cancer (including pleural effusion and slowly

16

resolving consolidation) a normal chest X-ray where there is a high

suspicion of lung cancer a history of asbestos exposure and recent

onset of chest pain, shortness of breath or unexplained systemic symptoms where a chest x-ray indicates pleural effusion, pleural mass or any suspicious lung pathology

Refer urgently for chest x-ray for patients with any of the following:

haemoptysis unexplained or persistent (longer than 3

weeks): chest and/or shoulder pain, dyspnoea, weight loss, chest signs, hoarseness, finger clubbing, cervical or supraclavicular lymphadenopathy, cough, features suggestive of metastasis from a

lung cancer (for example, secondaries in the brain, bone, liver, skin)

underlying chronic respiratory problems with unexplained changes in existing symptoms

11 Hypersensitivity The Gell and Coombs classification divides hypersensitivity reactions into 4 types

Type I - Anaphylactic

antigen reacts with IgE bound to mast cells ,basophils anaphylaxis, atopy

17

Type II - Cell bound

IgG or IgM binds to antigen on cell surface autoimmune haemolytic anaemia, RH incompatibility,

ITP, Goodpasture's

Type III - Immune complex

free antigen and antibody (IgG, IgA) combine serum sickness, systemic lupus erythematosus, post-

streptococcal glomerulonephritis, extrinsic allergic alveolitis (especially acute phase)

Type IV - Delayed hypersensitivity

T cell mediated tuberculosis, tuberculin skin reaction, graft versus

host disease, allergic contact dermatitis, scabies, extrinsic allergic alveolitis (especially chronic phase)

In recent times a further category has been added:

Type V - Stimulated hypersensitivity

IgG antibodies stimulate cells they are directed against Grave's, myasthenia gravis

80 Whilst the majority of IgA is found in secretions there is a significant quantity present in blood. IgE makes up less than 0.1% of immunoglobulins

Immunoglobulins The table below summarises the characteristics of the 5

18

types of immunoglobulin found in the body:

IgG 75% Monomer Enhance phagocytosis of bacteria and viruses, pass to fetal circulation

IgA 15% Monomer/ dimer

Found in secretions, provide localized protection on mucous membranes

IgM 10% Pentamer

first to be secreted, anti-A, B blood antibodies

IgD 1% Monomer Involved in activation of B cells

IgE 0.1% Monomer Involved in allergic reactions

14 Acute phase proteins Acute phase proteins

CRP ferritin fibrinogen alpha-1 antitrypsin caeruloplasmin

19

serum amyloid A serum amyloid P component* haptoglobin complement

During the acute phase response the liver decreases the production of other proteins (sometimes referred to as negative acute phase proteins). Examples include:

albumin transthyretin (formerly known as prealbumin) transferrin retinol binding protein cortisol binding protein

*ESR is not a part of acute phase response

15w Erythrocyte sedimentation rate (ESR) The ESR is a non-specific marker of inflammation and depends on both the size, shape and number of red blood cells and the concentration of plasma proteins such as fibrinogen, alpha2-globulins and gamma globulins Causes of a high ESR

temporal arteritis myeloma other connective tissue disorders e.g. systemic

lupus erythematosus other malignancies infection other factors which raise ESR: increasing

age, female sex, anaemia

20

Causes of a low ESR polycythaemia afibrinogenaemia/hypofibrinogenaemia sickle cell anemia

*ESR is not a part of acute phase response

*ESR = Men: < (age / 2) mm/hr Women: < ((age + 10) / 2) mm/hr15, 23n The nitric oxide receptor is a soluble, intracellular guanylate cyclaseNitric oxide

Previously known as endothelium derived relaxation factor, nitric oxide (NO) has emerged as a molecule which is integral to many physiological and pathological processes. It is formed from L-arginine and oxygen by nitric oxide synthetase (NOS). An inducible form of NOS has been shown to be present in macrophages. Nitric oxide has a very short half-life (seconds), being inactivated by oxygen free radical

Effects

acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca2+ levels

vasodilation, mainly venodilation inhibits platelet aggregation

Clinical relevance

underproduction of NO is implicated in hypertrophic pyloric stenosis

lack of NO is thought to promote atherosclerosis

21

in sepsis increased levels of NO contribute to septic shock

organic nitrates (metabolism produces NO) is widely used to treat cardiovascular disease (e.g. angina, heart failure)

sildenafil is thought to potentiate the action of NO on penile smooth muscle and is used in the treatment of erectile dysfunctions

*MRCPASSMHC class I proteins are present on all nucleated cells. MHC class I molecules (rather than class II) allow self recognition. MHC class II proteins are only expressed on dendritic cells, macrophages, B-cells as antigen presenting cells.17Complement deficiencies Complement is a series of proteins that circulate in plasma and are involved in the inflammatory and immune reaction of the body. Complement proteins are involved in chemotaxis (C3a, C5a), cell lysis and opsonisation (C3b)

C1 inhibitor (C1-INH) protein deficiency

causes hereditary angioedema C1-INH is a multifunctional serine protease inhibitor probable mechanism is uncontrolled release of

bradykinin resulting in oedema of tissues

C1q, C1rs, C2, C4 deficiency (classical pathway components)

predisposes to immune complex disease

22

e.g. SLE, Henoch-Schonlein Purpura

C3 deficiency

causes recurrent bacterial infections

C5 deficiency

predisposes to Leiner disease recurrent diarrhoea, wasting and seborrhoeic

dermatitis

C5-9 deficiency

encodes the membrane attack complex (MAC) particularly prone to Neisseria meningitidis infection

43 Hereditary angioedema Hereditary angioedema is an autosomal dominant condition associated with low plasma levels of the C1 in (esterase)hibitor (C1-INH) protein. C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissuesTypes: 1\quantitave 2\ qualitative(dysfunctional)Investigation

C1-INH level is low low C2 and C4 levels are seen, even between attacks

predisposes to SLE

Symptoms

23

attacks may be preceded by painful macular rash (rash distinguishes it from carcinoids)

painless, non-pruritic swelling of subcutaneous/submucosal tissues

may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)

urticaria is not usually a feature (distinguishes it from anaphylaxis)

Management

acute: IV C1-inhibitor concentrate anabolic steroid Danazol may help

*MRCPASS Systemic Mastocytosis is due to excessive mast cell stimulation. It leads to anaphylactic like -states - urticaria, flushing and also GI symptoms such as diarrhoea and nausea. Mast cells are Ig E mediated but can be triggered by injury, drugs and complements. It is caused by mast cell release of histamine in the skin or connective tissue. Diagnosis can be confirmed by raised serum tryptase, raised levels of urinary histamine & N-methyl imidazole, blood eosinophilia and thrombocytopenia. It classically presents with episodes of flushing, vomiting, diarrhoea and abdominal pain.64 T-Helper cells There are two major subsets of T-Helper cells:Th1

24

involved in the cell mediated response and delayed (type IV) hypersensitivity

secrete IFN-gamma, IL-2, IL-3 ( also IL-12 &TNF-B)

suppressed by IL-10 stimulated by IL-12

Th2

involved in mediating humoral (antibody) immunity e.g. stimulating production of IgE in asthma secrete IL-4, IL-5, IL-6, IL-10, IL-13 suppressed by interferon- gamma stimulated by IL-10

67 IL-1

Interleukin 1 (IL-1) is a key mediator of the immune response. It is secreted mainly by macrophages and monocytes and acts as a costimulator of T cell and B cell proliferation. Other effects include increasing the expression of adhesion molecules on the endothelium. By stimulating the release by the endothelium of vasoactive factors such as PAF, nitric oxide and prostacyclin it also causes vasodilation and increases vascular permeability. It is therefore one of the mediators of shock in sepsis. Along with IL-6 and TNF, it acts on the hypothalamus causing pyrexia.

115 Leukotrienes Function

25

mediators of inflammation and allergic reactions cause bronchoconstriction, mucous production increase vascular permeability, attract leukocytes leukotriene D4 has been identified as the SRS-A

(slow reacting substance of anaphylaxis)(also LTC4,mLTE4)

LTB4 = chemotaxis & mucus production

Production

secreted by leukocytes formed from arachidonic acid by action of

lipoxygenase it is thought that the NSAID induced bronchospasm

in asthmatics is secondary to the express production of leukotrienes due to the inhibition of prostaglandin synthetase (pseudo-allergic reaction)

135 Tumour necrosis factor Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with multiple roles in the immune systemTNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion:

activates macrophages and neutrophils acts as costimulator for T cell activation key mediator of bodies response to Gram negative

septicaemia similar properties to IL-1 anti-tumour effect (e.g. phospholipase activation)

26

angiogenesis

TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis. It also cause activation of NFkBEndothelial effects include increase expression of selectins and increased production of platelet activating factor, IL-1 and prostaglandinsTNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is thought fragments of receptors act as binding points in serum

Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading to cachexiaTNF is important in the pathogenesis of rheumatoid arthritis - antibodies to TNF (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoidTNF blockers

etanercept: s/c administration, can cause demyelination

infliximab: IV administration, risks include reactivation of TB

Infliximab is also used in active Crohn's disease (fistulating) unresponsive to steroids*N.B, TNF stimulates synthesis of NO.21n Tumour necrosis factor & RATNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoid

27

TNF blockers infliximab: monoclonal antibody, IV

administration etanercept: fusion protein that reversibly binds

soluble TNF receptors, subcutaneous administration

adalimumab: monoclonal antibody, subcutaneous administration

adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination

Infliximab is also used in active Crohn's disease unresponsive to steroids or fistulating

139 Interferon Interferons (IFN) are cytokines released by the body in response to viral infections and neoplasia. They are classified according to cellular origin and the type of receptor they bind to. IFN-alpha and IFN-beta bind to type 1 receptors whilst IFN-gamma binds only to type 2 receptors.IFN-alpha

produced by leucocytes antiviral action useful in hepatitis B & C, Kaposi's sarcoma,

metastatic renal cell cancer, hairy cell leukaemia, cutaneous T-cell lymphoma, codylomata acuminate, melanoma.

adverse effects include flu-like symptoms and

28

depression, impaired glucose tolerance

Side-effects are dose-related, but commonly include anorexia, nausea, influenza-like symptoms, and lethargy. Ocular side-effects and depression (including suicidal behaviour) have also been reported. Myelosuppression may occur, particularly affecting granulocyte counts. Cardiovascular problems (hypotension, hypertension, and arrhythmias), nephrotoxicity and hepatotoxicity have been reported. Hypertriglyceridaemia, sometimes severe, has been observed; monitoring of lipid concentration is recommended. Other side-effects include hypersensitivity reactions, thyroid abnormalities, hyperglycaemia, alopecia, psoriasiform rash, confusion, coma and seizures (usually with high doses in the elderly).IFN-beta

produced by fibroblasts antiviral action reduces the frequency of exacerbations in patients

with relapsing-remitting MS

*both interferon alpha & beta enhance expression of MHC 1.

IFN-gamma

produced by T lymphocytes & NK cells weaker antiviral action, more of a role in

immunomodulation particularly macrophage activation

may be useful in chronic granulomatous disease

29

and osteopetrosis enhance expression of MHC 1 & 2

55w Human genome The human genome is stored on 23 chromosome pairs. The haploid human genome has a total of 3 billion DNA base pairs, making up an estimated 20,000-25,000 protein-coding genes Only 2% of human genome are genesRBCs contain incomplete genome

88 Vincristine inhibits formation of microtubules and arrests mitosis Cell cycle M - Mitosis - cell divisionG1 - Gap phase 1 - determines length of cell cycle - under influence of p53S - DNA SynthesisG2 - Gap phase

123 myc is an oncogene which encodes a transcription factor

Tumour suppressor genes Basics

genes which normally control the cell cycle exhibit a recessive effect so both copies have to be

mutated before tumourigenesis (opposite to oncogene dominant) - both copies must be mutated before cancer occurs

30

Examples

p53 : Li Fraumeni syndrome chromosome 17p APC: colorectal cancer ch5 NF-1: neurofibromatosis WT-1: wilm’s tumour Rb: retinoblastoma DCC gene (ch18q) ca colon (80%), pancreatic &

oesophageal ca

*mrcpass: Tumour suppressor genes examples: BRCA-1 in breast and ovarian cancer VHL gene in von Hippel Lindau ch 3P53 – Li Fraumeni syndromeDCC gene (ch18q) ca colon, pancreatic, oesophageal

*Oncogenes Oncogenes are viral in originProto-oncogenes and oncogenes encode growth factors. A single mutation is enough to change the proto-oncogene into an oncogene. expresses dominant inheritance Mutated proto-oncogenes that cause cancer are called oncogenes. Examples of oncogenes are: Ras oncogene is involved in sporadic tumours (colon and lung) and rhabdomyosarcomas. c-myc translocation occurs in Burkitt's lymphoma t (8:14). N-myc proto-oncogene is seen in neuroblastoma. SRC oncogene is associated with sarcoma. BCR-ABL fusion gene (t 9:22) code for tyrosine kinase

31

CMLRET : MEN-2 encodes a receptor tyrosine*Ras is the commonest oncogene (others include myc, fos and jun) Fas ligands and caspases trigger apoptosis. Bax, Bad and Bak are members of the oncogenes which promote cell death. Bcl-2 inhibits apoptosis Bcl-2 prevents cell death by blocking apoptosis, preventing p53 mediated cell destruction and prevent cell death.61 p53 Down regulate cell cycle, causes apoptosis of cells with damage DNAp53 is a tumour suppressor gene located on chromosome 17p, it encodes for transcription factor. It is the most commonly mutated gene in breast, colon and lung cancer, but mostly ca lungp53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase (DNA synthesis phase) until DNA has been checked and repaired. It may also be a key regulator of apoptosisLi-Fraumeni syndrome is a rare autosomal dominant (yet tumor suppressor genes are recessive) disorder characterized by the early onset of a variety of cancers such as sarcomas and breast & brain cancer. It is caused by mutation in the p53 gene

*it is commonest genetic mutation in lung cancer

32

56 Monoclonal antibodies

Monoclonal antibodies have an increasing role in medicine. They are manufactured by a technique called somatic cell hybridization. This involves the fusion of myeloma cells with spleen cells from a mouse that has been immunized with the desired antigen. The resulting fused cells are termed a hybridoma and act as a 'factory' for producing monoclonal antibodies. The main limitation to this is that mouse antibodies are immunogenic leading to the formation of human anti-mouse antibodies (HAMAs). This problem is overcome by combining the variable region from the mouse body with the constant region from a human antibody.Clinical examples of monoclonal antibodies:

infliximab (anti-TNF): used in rheumatoid arthritis and Crohn's

rituximab (anti-CD20): used in non-Hodgkin's lymphoma and rheumatoid arthritis

trastuzumab (anti-HER2, an EGF receptor): used in metastatic breast cancer

alemtuzumab (anti-CD52): used in chronic lymphocytic leukaemia

abciximab (anti-glycoprotein IIb/IIIa receptor): prevention of ischaemic events in patients undergoing percutaneous coronary interventions

OKT3 (anti-CD3): used to prevent organ rejection Pexelizumab: anti-C5 (complement) - anti-

inflammatory: reduces MI and death following CABG.)

Monoclonal antibodies are also used for:

33

medical imaging when combined with a radioisotope identification of cell surface markers in biopsied tissue diagnosis of viral infections

97Molecular biology techniques SNOW (South - NOrth - West) DROP (DNA - RNA - Protein)

Molecular biology techniques The following table shows a very basic summary of molecular biology techniques

Southern blotting

Detects DNA

Northern blotting

Detects RNA

Western blotting

Detects and quantifies proteins

45 PCR Polymerase chain reaction (PCR) is a molecular genetic investigation technique. The main advantage of PCR is its sensitivity: only one strand of sample DNA is needed to detect a particular DNA sequence. It now has many uses including prenatal diagnosis, detection of mutated oncogenes and diagnosis of infections. PCR is also extensively used in forensics. Prior to the procedure it is necessary to have two DNA oligonucleotide primers. These are complimentary to specific DNA sequences at either end

34

of the target DNAInitial prep

sample of DNA is added to test tube along with two DNA primers

a thermostable DNA polymerase (Taq) is added

The following cycle then takes place

mixture is heated to almost boiling point causing denaturing (uncoiling) of DNA

mixture is the allowed to cool: complimentary strands of DNA pair up, as there is an excess of the primer sequences they pair with DNA preferentially

The above cycle is then repeated, with the amount of DNA doubling each timeReverse transcriptase PCR

used to amplify RNA RNA is converted to DNA by reverse transcriptase gene expression in the form of mRNA (rather than the

actually DNA sequence) can therefore be analyzed

47 The management of management thrombotic thrombocytopenic purpura involves steroids and immunosuppressants. Plasma exchange is also commonly used (no IGs)

Immunoglobulins: therapeutics Uses

primary and secondary immunodeficiency

35

idiopathic thrombocytopenic purpura myasthenia gravis Guillain-Barre syndrome Kawasaki disease

Basics

formed from large pool of donors (e.g. 5,000) IgG molecules with a subclass distribution similar to

that of normal blood half-life of 3 weeks

155 Hyperacute graft rejection is due to preexistent antibodies to HLA antigens and is therefore IgG mediated

Renal transplant : graft failure Graft survival

1 year = 90%, 10 years = 60% for cadaveric transpants

1 year = 95%, 10 years = 70% for living-donor transplants

Post-op problems

ATN of graft vascular thrombosis urine leakage UTI

Hyperacute acute rejection

due to antibodies of IgG against donor HLA type 1 antigens (MHC-1)

36

rarely seen due to HLA matching

Causes of acute graft failure (< 6 months)

acute rejection: give steroids, if resistant use monoclonal antibodies

Causes of chronic graft failure (> 6 months)

chronic allograft nephropathy ureteric obstruction recurrence of original renal disease (MCGN > IgA >

FSGS)

157 HIV: immunology The following immunological changes are seen in progressive HIV:

reduction in CD4 count increase B2-microglobulin decreased IL-2 production polyclonal B-cell activation

hyperimmunoglobulinemia decrease NK cell function reduced delayed hypersensitivity responses

197 Thymidine kinase phosphorylates aciclovir which then inhibits viral DNA polymerase

Antiviral agents Aciclovir

aciclovir is phosphorylated (activated)by thymidine kinase which in turn inhibits the viral

37

DNA polymerase

Ribavirin

effective against a range of DNA and RNA viruses interferes with the capping of viral mRNA

Interferons

inhibit synthesis of mRNA, translation of viral proteins, viral assembly and release

Amantadine

used to treat influenza not effective for swine flu (picks)

inhibits uncoating of virus in cell

Anti-retroviral agent used in HIVNucleoside analogue reverse transcriptase inhibitors (NRTI)

examples: zidovudine (AZT), didanosine, lamivudine, stavudine, zalcitabine

Protease inhibitors (PI)

inhibits a protease needed to make the virus able to survive outside the cell

examples: indinavir, nelfinavir, ritonavir, saquinavir

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

38

examples: nevirapine, efavirenz

198 ANCA There are two main types of anti-neutrophil cytoplasmic antibodies (ANCA) - cytoplasmic (cANCA) and perinuclear (pANCA)For the exam, remember:

cANCA - Wegener's granulomatosis pANCA - Churg-Strauss syndrome + others (see

below)

cANCA

most common target serine proteinase 3 (PR3) level of cANCA may be used to monitor disease

activity Wegener's granulomatosis, positive in > 90% microscopic polyangiitis, positive in 40%

pANCA

most common target is myeloperoxidase (MPO) cannot use level of pANCA to monitor disease

activity associated with immune crescentic (rapidly

progressive) glomerulonephritis (positive in c. 80% of patients)

microscopic polyangiitis, positive in 50-75% Churg-Strauss syndrome, positive in 60% Wegener's granulomatosis, positive in 25%

39

Other causes of positive ANCA (usually pANCA)

inflammatory bowel disease (UC > Crohn's) connective tissue disorders: RA, SLE, Sjogren's autoimmune hepatitis

193 Cod liver oil provides around 1,300 IU of vit D per 15 ml serving ,so it is best source for it

Vitamin deficiency The table below summarises vitamin deficiency states

Vitamin

Chemical name

Deficiency state

A Retinoids Night-blindness (nyctalopia)

B1 Thiamine Beriberi polyneuropathy,

Wernicke-Korsakoff syndrome

heart failure

B3 Niacin Pellagra dermatitis diarrhoea dementia depression dilated

cardiomyopathy

40

B6 Pyridoxine Anaemia, irritability, seizures

B7 Biotin Dermatitis, seborrhoea

B9 Folic acid Megaloblastic anaemia, deficiency during pregnancy - neural tube defects

B12 Cyanocobalamin

Megaloblastic anaemia

C Ascorbic acid Scurvy gingivitis bleeding,

macrocytosis

D Ergocalciferol, cholecalciferol

Rickets, osteomalacia

E Tocopherol, tocotrienol

Mild haemolytic anaemia in newborn infants, ataxia, peripheral neuropathy

K Naphthoquinone

Haemolytic disease of the newborn, bleeding diathesis

109 Pellagra

41

Pellagra is a caused by nicotinic acid (niacin) deficiency. The classical features are the 3 D's - dermatitis, diarrhoea and dementiaPellagra may occur as a consequence of isoniazid therapy (isoniazid inhibits the conversion of tryptophan to niacin)Features

dermatitis (brown scaly rash on sun-exposed sites - termed Casal's necklace if around neck)

diarrhoea dementia dilated cardiomyopathy death if not treated

*Depression is quite a common early finding in patients with pellagra

48 Vitamin C deficiency Vitamin C deficiency (scurvy) leads to defective synthesis of collagen resulting in capillary fragility (bleeding tendency) and poor wound healingFeatures

gingivitis, loose teeth poor wound healing bleeding from gums, haematuria, epistaxis general malaise macrocytic anaemia is occasionally noted

214 Gingivitis is more commonly seen in vitamin C deficiency

42

Zinc deficiency Features

perioral dermatitis: red, crusted lesions acrodermatitis alopecia short stature hypogonadism hepatosplenomegaly geophagia (ingesting clay/soil) cognitive impairment

19 Vitamin D increases plasma calcium and plasma phosphate levels by promoting renal tubular absorption and gut absorption of calcium and increasing renal phosphate reabsorption

Calcium metabolism The two hormones which primarily control calcium metabolism are:

parathyroid hormone (PTH) vitamin D

Other hormones include

calcitonin: secreted from the C cells of the thyroid gland

thyroxine growth hormone

Actions of parathyroid hormone

43

increases plasma calcium, decreases plasma phosphate increases renal tubular absorption of calcium increases osteoclastic activity increases renal conversion of 25-hydroxy vitamin D to

1,25 dihydroxy vitamin D decreases renal phosphate reabsorption

Actions of vitamin D

increases plasma calcium and plasma phosphate increases renal tubular absorption and gut absorption

of calcium increases osteoclastic activity increases renal phosphate reabsorption and gut

absorption

34 One of the key differentiating features between monoclonal gammopathy of uncertain significance (MGUS) and myeloma is the absence of complications such as immune paresis, hypercalcaemia and bone pain

Hypercalcaemia: causes The most common causes of hypercalcaemia are malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) and primary hyperparathyroidism (secondary hyperparathyroidism is not a cause)Other causes include

sarcoidosis* vitamin D intoxication acromegaly

44

thyrotoxicosis Milk-alkali syndrome drugs: thiazides, Ca2+ containing antacids dehydration Addison's disease Paget's disease of the bone**

*other causes of granulomas may lead to hypercalcaemia e.g. tuberculosis and histoplasmosis

**usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation

165 Hypercalcaemia: management The initial management of hypercalcaemia is rehydration with normal saline, typically 3-4 litres/day. Following rehydration bisphosphonates may be used. They typically take 2-3 days to work with maximal effect being seen at 7 daysOther options include:

calcitonin - quicker effect than bisphosphonates steroids in sarcoidosis

There is a limited role for the use of frusemide in hypercalcaemia. It may be useful in patients who cannot tolerate aggressive fluid rehydration (to avoid fluid overload)

49 Parathyroid hormone is the single most useful test in determining the cause of hypocalcaemia Cisplatin, often used in the management of non-small

45

cell lung cancer, is a well known cause of magnesium deficiency. Without first correcting magnesium levels it is difficult to reverse hypocalcaemia

Hypocalcaemia: causes It is useful to split the causes of hypocalcaemia into those associated with low and high phosphate levels respectivelyIf phosphate low

osteomalacia

If phosphate high

chronic renal failure hypoparathyroidism (e.g. post thyroid/parathyroid

surgery) pseudohypoparathyroidism (target cells insensitive to

PTH) rhabdomyolysis (initial stages), tumour lysis

syndrome magnesium deficiency (due to end organ PTH

resistance)

Acute pancreatitis may also cause hypocalcaemia

Management acute management of severe hypocalcaemia is

with intravenous replacement. The preferred method is with intravenous calcium gluconate, 10ml of 10% solution over 10 minutes

intravenous calcium chloride is more likely to cause local irritation

46

ECG monitoring is recommended further management depends on the underlying

cause

77 Hypocalcaemia: Trousseau's sign is more sensitive and specific than Chvostek's sign

Hypocalcaemia: features As extracellular calcium concentrations are important for muscle and nerve function many of the features seen in hypocalcaemia seen a result of neuromuscular excitability Features

tetany: muscle twitching and spasm perioral paraesthesia if chronic: depression, cataracts ECG: prolonged QT interval

Trousseau's sign carpal spasm if the brachial artery occluded by

inflating the blood pressure cuff and maintaining pressure above systolic

wrist flexion and fingers drawn together seen in around 95% of patients with

hypocalcaemia and around 1% of normocalcaemic people

Chvostek's sign tapping over parotid causes facial muscles to

twitch seen in around 70% of patients with

47

hypocalcaemia and around 10% of normocalcaemic people

71Vitamin D-resistant rickets Vitamin D-resistant rickets is a X-linked dominant condition which usually presents in infancy with failure to thrive. It is caused by impaired phosphate reabsorption in the renal tubulesFeatures

failure to thrive normal serum calcium, low phosphate, elevated

alkaline phosphotase x-ray changes: cupped metaphyses with widening of

the epiphyses

Diagnosis is made by demonstrating increased urinary phosphateManagement

high-dose vitamin D supplements oral phosphate supplements

95 Osteogenesis imperfecta Osteogenesis imperfecta (more commonly known as brittle bone disease) is a group of disorders of collagen metabolism resulting in bone fragility and fractures. The most common, and milder, form of osteogenesis imperfecta is type 1Overview

autosomal dominant

48

abnormality in type 1 collagen due to decreased synthesis of pro-alpha 1 or pro-alpha 2 collagen polypeptides

Features

presents in childhood fractures blue sclera deafness secondary to otosclerosis conductive

deafness

108 The low calcium and phosphate combined with the raised alkaline phosphatase point towards osteomalacia

Osteomalacia Basics

normal bony tissue but decreased mineral content rickets if when growing osteomalacia if after epiphysis fusion

Types

vitamin D deficiency e.g. malabsorption, lack of sunlight, diet

renal failure drug induced e.g. anticonvulsants vitamin D resistant; inherited liver disease, e.g. cirrhosis

Features

49

rickets: knock-knee, bow leg, features of hypocalcaemia

osteomalacia: bone pain, fractures, muscle tenderness, proximal myopathy

Investigation

low Ca2+, PO34-, 25(OH) vitamin D raised ALP x-ray: children - cupped, ragged metaphyseal

surfaces; adults - translucent bands (Looser’s zones or pseudofractures)

Treatment

calcium with vitamin D tablets

186 Both decreased renal excretion and decreased 1-alpha hydroxylation of vitamin D (i.e. not 25-alpha hydroxylation) result in increased phosphate levels

Chronic kidney disease: bone disease Basic problems in chronic kidney disease

low vitamin D (1-alpha hydroxylation normally occurs in the kidneys)

high phosphate low calcium: due to lack of vitamin D, high

phosphate secondary hyperparathyroidism: due to low calcium,

50

high phosphate and low vitamin D

Several clinical manifestations may result:Osteitis fibrosa cystica

hyperparathyroid bone disease

Adynamic

reduction in cellular activity (both osteoblasts and osteoclasts) in bone

may be due to over treatment with vitamin D

Osteomalacia

due to low vitamin D

OsteosclerosisOsteoporosis

91n Paget's disease of the bone Paget's disease is a disease of increased but uncontrolled bone turnover. It is thought to be primarily a disorder of osteoclasts, with excessive osteoclastic resorption followed by increased osteoblastic activity. Paget's disease is common (UK prevalence 5%) but symptomatic in only 1 in 20s patient Predisposing factors

increasing age male sex northern latitude family history

51

Clinical features - only 5% of patients are symptomatic

bone pain (e.g. pelvis, lumbar spine, femur) classical, untreated features: bowing of tibia,

bossing of skull raised alkaline phosphatase (ALP) - calcium*

and phosphate are typically normal skull x-ray: thickened vault, osteoporosis

circumscriptaIndications for treatment include bone pain, skull or long bone deformity, fracture, periarticular Paget's

bisphosphonate (either oral risedronate or IV zoledronate)

calcitonin is less commonly used nowComplications

deafness (cranial nerve entrapment) bone sarcoma (1% if affected for > 10 years) fractures skull thickening high-output cardiac failure

*usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation 118 Hypokalaemia and acid-base balance Potassium and hydrogen can be thought of as competitors. Hyperkalaemia tends to be associated with acidosis because as potassium levels rise fewer hydrogen ions can enter the cellsECG small or inverted T wave, prominent u wave ,

52

prolong PR-interval, depressed ST-segment, prolong QT intervalHypokalaemia with alkalosis

vomiting diuretics Cushing's syndrome Conn's syndrome (primary hyperaldosteronism)

Hypokalaemia with acidosis

diarrhoea renal tubular acidosis acetazolamide theophyline partially treated diabetic ketoacidosis

*Bendroflumethiazide - mechanism of hypokalaemia: increased sodium reaching the collecting ducts

(most imp) activation of the renin-angiotensin-aldosterone

Increased delivery of sodium to the collecting ducts causes the sodium-potassium exchanger to release more potassium into the urine. Another cause is activation of the renin-angiotensin-aldosterone system secondary to hypovolaemia

5w Hyperkalaemia Plasma potassium levels are regulated by a number of factors including aldosterone, acid-base balance and insulin levels. Metabolic acidosis is associated with hyperkalaemia as hydrogen and potassium ions

53

compete with each other for exchange with sodium ions across cell membranes and in the distal tubule. ECG changes seen in hyperkalaemia include tall-tented T waves, small P waves, widened QRS leading to a sinusoidal pattern , VF and asystoleCauses of hyperkalaemia (>6.5 mmol):

acute renal failure drugs*: potassium sparing diuretics, ACE

inhibitors, ciclosporin metabolic acidosis Addison's Rhabdomyolysis, tumour lysis syndrome massive blood transfusion

*beta-blockers interfere with potassium transport into cells and can potentially cause hyperkalaemia in renal failure patients - remember beta-agonists, e.g. salbutamol, are sometimes used as emergency treatment *31(o\e) Common causes of hyperkalaemia include 1. Impaired renal excretion: renal failure, hyporeninaemic hypoaldosteronism (type IV renal tubular acidosis), Addison's, C-21 hydroxylase deficiency. 2. Cellular changes: acidosis, rhabdomyolysis, tumour lysis, malignant hyperthermia, burns. 3. Drugs: potassium retaining diuretics, ACE inhibitors, NSAIDs = (inhibit rennin), cyclosporin, succinyl choline, beta-blockers (inhibit rennin)31 HyponatraemiaHyponatraemia may be caused by water excess or sodium depletion. Causes of pseudohyponatraemia include

54

hyperlipidaemia, hyperprotenemia (decrease in serum volume) or a taking blood from a drip arm. Hyperglycemia(increased serum osmolarity)Urinary sodium and osmolarity and levels ECF volume state aid making a diagnosisUrinary sodium > 20 mmol/lSodium depletion, renal loss (patient often hypovolaemic)

diuretics Addison's diuretic stage of renal failure

Patient often euvolaemic

SIADH (urine osmolality > 500 mmol/kg) hypothyroidism

Urinary sodium < 20 mmol/lSodium depletion, extra-renal loss (GIT or skin)

diarrhoea, vomiting, sweating burns, adenoma of rectum

Water excess (patient often hypervolaemic and oedematous)

secondary hyperaldosteronism: CCF, cirrhosis reduced GFR: renal failure IV dextrose, psychogenic polydipsia

204 Hypernatraemia Causes of hypernatraemia

55

dehydration osmotic diuresis e.g. hyperosmolar non-ketotic

diabetic coma diabetes insipidus excess IV saline

33 Metabolic alkalosis Metabolic alkalosis may be caused by a loss of hydrogen ions or a gain of bicarbonate. It is due mainly to problems of the kidney or gastrointestinal tractCauses

vomiting / aspiration (e.g. peptic ulcer leading to pyloric stenos, nasogastric suction)

diuretics liquorice, carbenoxolone hypokalaemia primary hyperaldosteronism Cushing's syndrome Bartter's syndrome congenital adrenal hyperplasia

Mechanism of metabolic alkalosis

activation of renin-angiotensin II-aldosterone (RAA) system is a key factor

aldosterone causes reabsorption of Na+ in exchange for H+ in the distal convoluted tubule

ECF depletion (vomiting, diuretics) Na+ and Cl- loss activation of RAA system raised aldosterone levels

56

in hypokalaemia, K+ shift from cells ECF, alkalosis is caused by shift of H+ into cells to maintain neutrality

83 Iron metabolism

Absorption

upper small intestine (duodenum & upper jejenum) about 10% of dietary iron absorbed Fe2+ (ferrous iron) much better absorbed than Fe3+

(ferric iron) absorption is regulated according to bodies need increased by vitamin C, gastric acid, alcohol decreased by proton pump inhibitors, tetracycline,

gastric achlorhydia, tannin (found in tea), oxalate

Distribution in body

total body iron = 4g haemoglobin = 70% ferritin and haemosiderin = 25% myoglobin = 4% plasma iron = 0.1% (4mg\dl)

Transport

carried in plasma as Fe3+ bound to transferrin

Storage

stored as ferritin in tissues

57

Excretion

lost via intestinal tract following desquamination

85 Methaemoglobinaemia Methaemoglobinaemia describes the oxidation of Fe2+ in haemoglobin to Fe3+. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the leftCongenital causes

haemoglobin chain variants: HbM, HbH NADH - methaemoglobinaemia reductase

deficiency

Acquired causes

drugs: sulphonamides, nitrates, dapsone, sodium nitroprusside, primaquine

chemicals: aniline dyes

Features

'chocolate' cyanosis SOB, anxiety, headache severe: acidosis, arrhythmias, seizures, coma normal pO2 but decreased oxygen saturation

Management

NADH - methaemoglobinaemia reductase deficiency: ascorbic acid

IV methylene blue if acquired

58

20 Rheumatoid factor Rheumatoid factor (RF) is a circulating antibody (usually IgM) which reacts with antigenic sites on the Fc portion of the patients own IgGRF can be detected by either

Rose-Waaler test: sheep red cell agglutination Latex agglutination test (less specific)

RF can be any Ig but usually IgM, but the tests detect only IgM.RF is positive in 70-80% of patients with rheumatoid arthritis, high titre levels are associated with severe progressive disease (but NOT a marker of disease activity)Other conditions associated with a positive RF include:

Sjogren's syndrome (<= 100%) Felty's syndrome (<= 100%) infective endocarditis (= 50%) SLE (= 20-30%) systemic sclerosis (= 30%) general population (= 5%) rarely: TB, HBV, EBV, leprosy

21 Gastrointestinal hormones Below is a brief summary of the major hormones involved in food digestion:

Source Stimulus Actions

Gastrin* G cells in Distension Increase

59

antrum of the stomach

of stomach, extrinsic nerves amino acidInhibited by: low antral pH, somatostatin

HCL, pepsinogen and IF secretion, increases gastric motility, trophic effect on gastric mucosa

CCK I cells in upper small intestine

Partially digested proteins and triglycerides

Increases secretion of enzyme-rich fluid from pancreas, contraction of gallbladder and relaxation of sphincter of Oddi, decreases gastric emptying & gastrin, trophic effect on

60

pancreatic acinar cells, induces satiety

Secretin S cells in upper small intestine

Acidic chyme, fatty acids

Increases secretion of bicarbonate-rich fluid from pancreas and hepatic duct cells, decreases gastric acid secretion, trophic effect on pancreatic acinar cells

VIP Small intestine, pancreas

Neural Stimulates secretion by pancreas and intestines, inhibits acid and pepsinogen secretion

61

Somatostatin

D cells in the pancreas & stomach

Fat, bile salts and glucose in the intestinal lumen

Decreases acid and pepsin secretion, decreases gastrin secretion, decreases pancreatic enzyme secretion, decreases insulin and glucagon secretioninhibits trophic effects of gastrin, stimulates gastric mucous production

*8 physiology(o\e) its production is stimulated by neural reflex pathways and also by the direct effect of digested peptides on the G cells themselves. It also stimulates the production of bicarbonate from pancreas.

62

68w Gastrointestinal physiology: enzymes Amylase is present in saliva and pancreatic secretions.It breaks starch down into sugar The following brush border enzymes are involved in the breakdown of carbohydrates:

maltase: cleaves disaccharide maltose to glucose + glucose

sucrase: cleaves sucrose to fructose and glucose lactase: cleaves disaccharide lactose to glucose +

galactose

*mrcpass : Eukaryotes (higher organisms) have muliple chromosomes in a genome which is separated from the rest of the cell by a nuclear membranes. ;Prokaryotes lack a membrane bound nucleus, their DNA occurs in a circular form.23 Mitochondrial diseases Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is present in the mitochondria. It encodes protein components of the respiratory chain and some special types of RNAMitochondrial inheritance has the following characteristics:

inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote

all children of affected males will not inherit the disease

63

all children of affected females will inherit it generally encode rare neurological diseases poor genotype:phenotype correlation - within a

tissue or cell there can be different mitochondrial populations - this is known as heteroplasmy)

Histology

muscle biopsy classically shows 'red, ragged fibres' due to increased number of mitochondria

Examples include:

Leber's optic atrophy MELAS syndrome: mitochondrial

encephalomyopathy lactic acidosis and stroke-like episodes

MERRF syndrome: myoclonus epilepsy with ragged-red fibers

NARP neuropathy, ataxia, retinitis pigmentosa Kearns-Sayre: onset in patients < 20 years old,

external ophthalmoplegia, retinitis pigmentosa. Ptosis may be seen

sensorineural hearing loss HOCM with myopathy Diapetes with deafness Aminoglycoside induced deafness

52 Trinucleotide repeat disorders Trinucleotide repeat disorders are genetic conditions caused by an abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides. These expansions

64

are unstable and may enlarge which may lead to an earlier age of onset in successive generations - a phenomenon known as anticipation*.Examples - note dominance of neurological disorders

Fragile X (CGG) Huntingdon's (CAG) myotonic dystrophy (CTG) Friedreich's ataxia* (GAA) spinocerebellar ataxia spinobulbar muscular atrophy dentatorubral pallidoluysian atrophy DIDMOAD

*Friedreich's ataxia do not usually demonstrate anticipation (Anticipation refers to increase in the number of trinucleotide repeats somearlier age of onset)**They are unstable in somatic mitosis24 Adrenoceptor antagonists Alpha antagonists

alpha-1: doxazosin alpha-1a: tamsulosin - acts mainly on urogenital

tract alpha-2: yohimbine non-selective: phenoxybenzamine (previously used in

PVD)

Beta antagonists

beta-1: atenolol, metropolol, non-selective: propranolol

65

Carvedilol and labetalol are mixed alpha and beta antagonists

50 Adrenoceptors agonistsAlpha-1

vasoconstriction relaxation of GI smooth muscle salivary secretion hepatic glycogenolysis uterus contraction decrease in pancreatic exocrine secretion phenylephrine

Alpha-2

mainly presynaptic: inhibition of transmitter release (inc NA, Ach from autonomic nerves)

inhibits insulin platelet aggregation colonidine

Beta-1

mainly located in the heart increase heart rate + force dobutamine

Beta-2

vasodilation bronchodilation relaxation of GI smooth muscle

66

salbutamol

Beta-3

lipolysis

Pathways

all are G-protein coupled alpha-1:activate phospholipase C IP3 DAG alpha-2: inhibit adenylate cyclase all beta: stimulate adenylate cyclase

14 w Protein degradation in eukaryotes is also carried out by protein complexes called proteasomes Cell organelles The table below summarises the main functions of the major cell organelles: Organelle/macromolecule Main function

Endoplasmic reticulum Translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)

Golgi apparatus Sorting and

67

modification of proteins

Mitochondrion Energy production. Contains mitochondrial genome as circular DNA

Nucleus DNA maintenance and RNA transcription

Lysosome Breakdown of large molecules such as proteins and polysaccharides

Nucleolus Ribosome production

Ribosome Translation of RNA into proteins

Peroxisome Breakdown of metabolic hydrogen peroxide

68

30 Autosomal recessive conditions are 'metabolic' - exceptions: inherited ataxias

Autosomal dominant conditions are 'structural' - exception: hyperlipidaemia type II, hypokalaemic periodic paralysis

Autosomal recessive conditions

The following conditions are autosomal recessive:NB autosomal recessive conditions are often thought to be 'metabolic' as opposed to autosomal dominant conditions being 'structural', notable exceptions:

mucopolysaccharidoses: Hunter's (X-linked recessive)

G6PD (X-linked recessive)

AlbinismAtaxia telangiectasia ch 11 Alkaptonuria APS type 1 (MEDAC ) mutation of AIRE1 gene on chromosome 21Congenital adrenal hyperplasiaCystic fibrosis ch 7(80% are due to a deletion at delta F508 on the long arm of chromosome 7,i.e not inherited)Cystinuria ch 2: genes SLC3A1, ch 19: SLC7A9 Endemic goitrous cretinismFamilial Mediterranean Fever polyserositisFanconi anaemia

69

GalactosaemiaFriedreich's ataxia defect on gene X25 on ch 9 (frataxin)Gilbert's syndrome*Glycogen storage diseaseHaemochromatosis ch 6(HFE gene, code for glycoprotein that modulate iron uptake)Homocystinuria cystathione beta synthetase def Jervell and Lange-Nielsen syndrome Mutations in the KCNE1 and KCNQ1 genesLipid storage disease: Tay-Sach's ch5, Gaucher, Niemann-PickMucopolysaccharidoses: Hurler's syndrome (corneal opacity, gibbus deformity) (MPS-0) Phenylketonuria phenylalanine hydroxylase gene defect on ch 12Pseudoxanthoma elasticumSickle cellThalassaemias beta =ch 11, alpha =16Wilson's disease ch 13 (defective gene is ATP 7B) Xeroderma pigmentosa

*this is still a matter of debate and many textbooks will list Gilbert's as autosomal dominant

53X-linked recessive conditions The following conditions are inherited in a X-linked recessive fashion:

70

Becker muscular dystrophyColour blindnessDuchenne muscular dystrophyFabry's disease lysosomal alpha galactosidase A def Fragile X- syndrome FMR 1 gene on the X chromosome.G6PD deficiencyHaemophilia A,BHunter's disease (MPS-2)Lesch-Nyhan syndromeNephrogenic diabetes insipidusOcular albinismRetinitis pigmentosaTesticular feminisation syndromeWiskott-Aldrich syndrome WASP gene mutationKallman's syndrome failure of GnRH-secreting neurons to migrate to the hypothalamus.

The following diseases have varying patterns of inheritance, with the majority being in an X-linked recessive fashion:Chronic granulomatous disease (in > 70%)

50 Autosomal recessive conditions are 'metabolic' - exceptions: inherited ataxias

Autosomal dominant conditions are 'structural' - exception: hyperlipidaemia type II, hypokalaemic periodic paralysis

71

Autosomal dominant conditions

The following conditions are autosomal dominant:

NB autosomal dominant conditions are often thought to be 'structural' as opposed to autosomal recessive conditions being 'metabolic', notable exceptions:

hyperlipidaemia type II hypokalaemic periodic paralysis

AchondroplasiaAdult polycystic disease type1 = ch 16, type 2 = ch 4 Alpha-1 antitrypsin (A1AT) deficiency ch 14 (co dominant = M, S, Z) Antithrombin III deficiencyCADASIL ch 19 (associated with migraine) Hereditary angioneurotic edema C1 esterase deficiency Ehlers-Danlos syndromeFamilial adenomatous polyposis defect in (APC)gene, chromosome 5 Hereditary haemorrhagic telangiectasiaHereditary spherocytosisHereditary non-polyposis colorectal carcinoma hMLH1 and hMSH2 genes’ mutationsHereditary angioedema autosomal dominant C1 in (C1-INH) protein (esterase) defHSMN type IPMP-22 gene (which codes for myelin) demylinating neuropathyHuntington's disease trinucleotide CAG Hyperlipidaemia type II

72

Hypokalaemic periodic paralysis Idiopathic hypoparathyroidismMalignant hyperthermia Marble bone disease osteopetrosisMarfan's syndromes (a defect in the fibrillin-1 gene on chromosome 15)Myotonic dystrophyCTG DM1:DMPK gene on chromosome 19,DM2:ZNF9 gene on chromosome 3 MODY 3 HNF-1 alpha gene (Hepatocyte Nuclear Factor) 60 % of cases MODY 2 defect in the glucokinase gene 20 % of cases

NeurofibromatosisNF1:17,NF2:22Noonan syndrome normal karyotyping defect in a gene on chromosome 12 (PTPN11 gene protein tyrosine phosphatase non receptor type 11)Osteogenesis imperfecta1abnormal collagen type 1(pro α-1 or 2 collagen polypeptide)Peutz-Jeghers syndrome gene encodes serine threonine kinase LKB1 or STK11 Pseudohypoparathyroidism short stature, short 4 & 5th, mental retardation maternal porphyriasRetinoblastomaRomano-Ward syndrome long QT interval K-channel disorder

73

Tuberose sclerosis Treacher Collins syndromeVon Hippel-Lindau syndrome VHL-gene on ch 3Von Willebrand's disease*

*type 3 von Willebrand's disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease

170 X-linked dominant The following conditions are inherited in a X-linked dominant fashion*:

Alport's syndrome (in around 85% of cases - 10-15% of cases are inherited in an autosomal recessive fashion with rare autosomal dominant variants existing) a defect in the gene which codes for type IV collagen resultingRett syndromeVitamin D resistant rickets (X linked Hypophosphataemic rickets)defect in PO4 reapsorption in the renal tubules

*pseudohypoparathyroidism was previously classified as an X-linked dominant condition but has now been shown to be inherited in an autosomal dominant fashion in the majority of cases

198 Autosomal dominant

74

In autosomal dominant diseases:

both homozygotes and heterozygotes manifest disease (there is no carrier state)

both males and females affected only affected individuals can pass on disease disease is passed on to 50% of children normally appears in every generation (although see

below) risk remains same for each successive pregnancy

Complicating factors:

non-penetrance: lack of clinical signs and symptoms (normal phenotype) despite abnormal gene. E.g. 40% otosclerosis

spontaneous mutation: new mutation in one of gametes e.g. 80% of individuals with achondroplasia have unaffected parents (so parents are not always affected)

33 n X-linked recessive In X-linked recessive inheritance only males are affected. An exception to this seen in examinations are patients with Turner's syndrome, who are affected due to only having one X chromosome. X-linked recessive disorders are transmitted by heterozygote females (carriers) and male-to-male transmission is not seen. Affected males can only have unaffected sons and carrier daughters Each male child of a heterozygous female carrier

75

has a 50% chance of being affected whilst each female child of a heterozygous female carrier has a 50% chance of being a carrier The possibility of an affected father having children with a heterozygous female carrier is generally speaking extremely rare. However, in certain Afro-Caribbean communities G6PD deficiency is relatively common and homozygous females with clinical manifestations of the enzyme defect are seen *44(o\e) X-linked recessive diseases can occur with the same severity in females in certain situations – having an affected father and carrier mother (seen in G6PD deficiency), Turners syndrome, X-chromosome isodisomy, unequal lyonisation, in an XY individual with testicular feminisation syndrome and where there is an X/autosome translocation through a gene (DMD). Fragile X syndrome shows anticipation with triplet repeat expansion. Y-linked diseases can be associated with male infertility (but not obsolete).

55G protein-coupled receptors span the cell membrane

Membrane receptors There are four main types of membrane receptor: ligand-gated ion channels, tyrosine kinase receptors, guanylate cyclase receptors and G protein-coupled receptors

Ligand-gated ion channel

76

generally mediate fast responses e.g. nicotinic acetylcholine, GABA-A & GABA-C,

glutamate receptors

Tyrosine kinase receptors

contain intrinsic enzyme activity e.g. insulin, growth factors, interferon

Guanylate cyclase receptors

contain intrinsic enzyme activity e.g. ANP, nitric oxide receptors

G protein-coupled receptors

generally mediate slow transmission and affect metabolic processes

activated by a wide variety of extracellular signals e.g. peptide hormones, biogenic amines, lipophilic hormones, light

consist of 3 main subunits: alpha, beta and gamma ligand binding causes conformational changes to

receptor, this induces exchange of GDP for GTP e.g. muscarinic acetylcholine, adrenergic receptors,

GABA-B

* Cholera toxin has two parts, A and B. B binds while A activates G protein, which activates adenylate cyclase. Elevated CAMP results in unrestricted chloride secretion from villous crypts.

77

*T3 acts by binding to intracellular (nuclear) receptors.steroids (progesterone, testosterone, oestradiol and cortisol) = pass through cell membrane

110 Second messengers Overview

many different types allow amplification of external stimulus

Cyclic AMP

e.g. adrenaline, noradrenaline, glucagon, LH, FSH, TSH, calcitonin, parathyroid hormone

Protein kinase activity

e.g. insulin, growth hormone, prolactin, oxytocin, erythropoietin, growth factors

Calcium and/or phosphoinositides

e.g. ADH, GnRH, TRH

Cyclic GMP

e.g. ANP, nitric oxide

78 Down syndrome: epidemiology and genetics Risk of Down syndrome with increasing maternal age

risk at 30 years = 1/1000 35 years = 1/350 40 years = 1/100

78

45 years = 1/30

One way of remembering this is by starting at 1/1,000 at 30 years and then dividing by 3 (i.e. 3 times more common) for every extra 5 years of age Cytogenetics

Mode % of cases

Risk of recurrence

Non-dysjunction 94% 1 in 200 if under mother < 35 years

Robertsonian translocation(usually onto 14)

5% 10-15% if mother is translocation carrier 2.5% if father is translocation carrier

Mosaicism 1%

93 Down syndrome: features Clinical features

face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in (speckled) iris, protruding tongue, small ears, round/flat face

flat occiput single palmar crease, pronounced 'sandal gap' between

big and first toe hypotonia congenital heart defects (40-50%, see below) duodenal atresia

Cardiac complications

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multiple cardiac problems may be present endocardial cushion defect (c. 40%, also known as

atrioventricular septal canal defects) ventricular septal defect (c. 30%) secundum atrial septal defect (c. 10%) tetralogy of Fallot (c. 5%) isolated patent ductus arteriosus (c. 5%)

Later complications

subfertility:males are almost always infertile due to impaired spermatogenesis. Females are usually subfertile, and have an increased incidence of problems with pregnancy and labour

learning difficulties short stature repeated respiratory infections (+hearing

impairment from glue ear) acute lymphoblastic leukaemia hypothyroidism Alzheimer's duodenal atresia Hirschsprung's disease atlantoaxial instability

101Klinefelter's syndrome Klinefelter's syndrome is associated with karyotype 47, XXYFeatures

often taller than average

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lack of secondary sexual characteristics small, firm testes (normal testicular volume is 15 ml) infertile gynaecomastia - increased incidence of breast

cancer (20 folds) elevated gonadotrophin levels (hypergonadotrophic

hypogonadism) pyromania (fascination with fire setting)

Diagnosis is by chromosomal analysis Cryptorchidism (undescended testes) is more suggestive of Kallman's than Klinefelter's syndrome

120

Klinefelter's - LH & FSH raisedKallman's - LH & FSH low-normal

The LH and FSH levels are inappropriately low-normal given the low testosterone concentration, which points towards a diagnosis of hypogonadotrophic hypogonadism. In Klinefelter's syndrome the LH and FSH levels are raised

Kallman's syndrome Kallman's syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic hypogonadism. It is usually inherited as an X-linked recessive trait. Kallman's syndrome is thought to be caused by failure of GnRH-secreting neurons to migrate to the hypothalamus.The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty

81

Features

'delayed puberty' Hypogonadotrophic hypogonadism, cryptorchidism

(undescended testes is more suggestive of Kallman's than Klinefelter's syndrome)

anosmia sex hormone levels are low LH, FSH levels are inappropriately low/normal patients are typically of normal or above average

height

Cleft lip/palate and visual & hearing defects are also seen in some patientsDiagnosis is by chromosomal analysis

57 Turner's syndrome Turner's syndrome is a chromosomal disorder affecting around 1 in 2,500 females. It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. Turner's syndrome is denoted as 45,XO or 45,XFeatures

short stature shield chest, widely spaced nipples webbed neck coarctation of the aorta (commonest CVS

anomaly), bicuspid aortic valve primary amenorrhoea gonodal agenesis high-arched palate short fourth metacarpal

82

multiple pigmented naevi, hyperconvex nail skeletal manifestation : cubitus valgus and hip

dislocation lymphoedema in neonates (especially feet and cyctic

hygroma) horseshoe kidney blue sclera, cataracts, mental retardation ovarian agenesis (no increased risk of ca ovary)

There is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn's disease

Estrogen therapy is indicated.*The commonest cause of hypertension in turner syndrome is essential hypertension (10%) & not aortic coarctation.

134 n contrast to Turner's syndrome, the karyotype is normal

Noonan's syndrome Often thought of as the 'male Turner's', Noonan's syndrome is an autosomal dominant associated with a normal karyotype. It is thought to be caused by a defect in a gene on chromosome 12(PTPN11 geneprotein tyrosine phosphatase non receptor type 11)As well as features similar to Turner's syndrome (webbed neck, widely-spaced nipples, short stature), a number of characteristic clinical signs may also be seen:

cardiac: pulmonary valve stenosis ptosis

83

triangular-shaped face low-set ears coagulation problems: factor XI deficiency (also

factors 8, 12 &von willebrand), thrombocytopenia 30%

mental retardation30% small genitalia or undescended testes

130 Although fibrillin is the primary protein affected (due to a defect in the fibrillin-1 gene) it should be noted that fibrillin is used as a substrate of elastin

Marfan's syndrome Marfan's syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the fibrillin-1 gene on chromosome 15.intelligence is usually normalFeatures

tall stature with arm span > height ratio > 1.05 high-arched palate arachnodactyly pectus excavatum or carinatum joint laxity pes planus scoliosis of > 20 degrees heart: dilation of the aortic sinuses (seen in 90%)

which may lead to aortic regurgitation, mitral valve prolapse (75%), aortic dissection

lungs: repeated pneumothoraces (apical blebs on CXR)

eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera, myopia

84

radiological: protrussio acetabulae, dural ectasia on spinal MRI

147 Pseudoxanthoma elasticum Pseudoxanthoma elasticum is an inherited condition (usually autosomal recessive*) characterised by an abnormality in elastic fibresFeatures

retinal angioid streaks 'plucked chicken skin' appearance - small yellow

papules on the neck, antecubital fossa and axillae cardiac: mitral valve prolapse, increased risk of

ischaemic heart disease, aortic dissection gastrointestinal haemorrhage

*there are reports of autosomal dominant inheritance in a minority of cases

151 Fragile X Fragile X is a trinucleotide repeat disorder C GGFeatures in males

learning difficulties = commonest cause of inherited mental retardation

large low set ears, prominent jaw (prognathism,), long thin face, large head, high arched palate

macroorchidism , cryptorchidism, hypotonia autism is more common mitral valve prolapse

85

Features in females (who have one fragile chromosome and one normal X chromosome) range from normal to mildDiagnosis

can be made antenatally by chorionic villus sampling or amniocentesis

analysis of the number of CGG repeats using restriction endonuclease digestion and Southern blot analysis

201 Prader-Willi syndrome Prader-Willi syndrome is an example of genetic imprinting where the phenotype depends on whether the deletion occurs on a gene inherited from the mother or father:

Prader-Willi syndrome if gene deleted from father = hypotonia

Angelman syndrome if gene deleted from mother = hyprertonia

Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the long arm of chromosome 15. This may be due to:

microdeletion of paternal 15q11-13 (70% of cases) maternal uniparental disomy of chromosome 15

Features

hypotonia during infancy dysmorphic features short stature hypogonadism and infertility

86

learning difficulties childhood obesity behavioural problems in adolescence

*Conditions with genomic imprinting: • myotonic dystrophy • Beckwith-Wiedemann syndrome • Prader Willi syndrome • Angelman syndrome•Pseudohypoparathyroidism matrenal•pseudopseudohypoparathyroidism paternal

164 Macroglossia Causes

hypothyroidism acromegaly amyloidosis Down's syndrome Duchenne muscular dystrophy glycogen storage disease

*Turner’s syndrome is not acause*MRCPASS Enzyme deficiencies Gaucher’s disease – Glucocerebrosidase deficiency (-glucosidase deficiency)Tay Sachs disease - Hexosaminidase A deficiency Niemann Pick disease - Sphingomyelinase deficiency Metachromatic leukodystrophy - Arylsulphatase A deficiency Hurler's & hunter’s

87

syndrome - Iduronidase deficiency

79 The cyanide-nitroprusside test would also be positive in homocystinuria & cystinuria

Cystinuria Cystinuria is an autosomal recessive disorder characterised by the formation of recurrent renal stones. It is due to a defect in the membrane transport of cystine, ornithine, lysine, arginine (mnemonic = COLA)Genetics

chromosome 2: SLC3A1 gene, chromosome 19: SLC7A9

Features

recurrent renal stones are classically yellow and crystalline, appearing semi-

opaque on x-ray

Diagnosis

cyanide-nitroprusside test

Management

hydration D-penicillamine urinary alkalinization

NB cystinosis (klara page 390):

no renal stones, but progressive renal disease and fanconi syndrome, lympadenopathy, bone marrow failure,

88

conjunctival and corneal opacity, hypothyroidism, insulin deficiency & CNS involvement. It is lysosomal storage disease of cystine due to defect in CTNS gene which encodes for protein called cystinosin, on ch 17p13 defect in cola transport. treated by cysteamine bitartrate(intolerable), renal transplant(renal disease does not recur but extra renal is progressive). test : neutrophil cystine content

172 Cystinuria not homocystinuria is associated with recurrent renal stones

Homocystinuria Homocystinuria is a rare autosomal recessive disease caused by deficiency of cystathione beta-synthetase. This results in an accumulation of methionine & homocysteine which is then oxidized to homocystine.Features

often patients have fine, fair hair musculoskeletal: may be similar to Marfan's -

arachnodactyly etc, osteoprosis neurological patients may have learning difficulties,

seizures, spastic paraplegia ocular: downwards dislocation of lens, retinal

detachment increased risk of arterial and venous

thromboembolism also malar flush, livedo reticularis

Diagnosis is made by the cyanide-nitroprusside test, which

89

is also positive in cystinuriaTreatment is vitamin B6 supplementsOther treatment (klara): restriction of methionine but cystine supplement, some repond to folate & vit b12174 Galactosaemia Galactosaemia is a rare autosomal recessive condition caused by the absence of galactose-1-phosphate uridyl transferase. This results in intracellular accumulation of galactose-1-phosphateFeatures

jaundice failure to thrive hepatomegaly & splenomegally cataracts hypoglycaemia after exposure to galactose Fanconi syndrome E.coli sepsis may be the Initial manifestation

Diagnosis

urine reducing substances (galactose is a reducing sugar)

Management is with a galactose free diet, breast feeding is contraindicatedIt does not cause peripheral neuropathy

175 Phenylketonuria Phenylketonuria (PKU) is an autosomal recessive condition caused by a disorder of phenylalanine metabolism. This is due to defect in phenylalanine

90

hydroxylase, an enzyme which converts phenylalanine to tyrosine. High levels of phenylalanine lead to problems such as learning difficulties and seizures. The gene for phenylalanine hydroxylase is located on chromosome 12.The incidence of PKU is c. 1 in 10,000 live birthsFeatures

usually presents by 6 months e.g. with developmental delay

child classically has fair hair and blue eyes fair skin (reduced melanin formation

hypopigmentation) learning difficulties seizures 25%, typically infantile spasms, but 50%

has EEG abnormalities eczema 'musty' odour to urine and sweat*

Diagnosis

Guthrie test(bacterial inhibition test): the 'heel-prick' test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism

hyperphenylalaninaemia phenylpyruvic acid in urine

Management

poor evidence base to suggest strict diet prevents learning disabilities (provide normal physical growth but not mentality)

dietary restrictions are however important during

91

pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levels

*secondary to phenylacetate, a phenylketone

*38(o\e) Deficiency of phenylalanine hydroxylase (Chromosome 12) or of the cofactor tetrahydrobiopterin (Genes on Chromosome 10 and 4) causes accumulation of phenylalanine in body fluids. Diagnosis of classic PKU requires raised Phe levels, normal plasma tyrosine levels, increased urinary Phe metabolites and normal cofactor (tetrahydrobiopterin) concentrations

*41(o\e)Gaucher's disease is the most frequent of the lysosomal storage diseases. The condition is usually due to a catalytic deficiency of glucocerebrosidase (beta glucosidase). It is accompanied by many ill-understood plasma and metabolic abnormalities. These include a polyclonal immunoglobulin response that may progress to monoclonal gammopathy, amyloidosis, or even frank myeloma. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol fractions are abnormal in the plasma. Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease.

40 Splenectomy

92

Following a splenectomy patients are particularly at risk from pneumococcus, Haemophilus, meningococcus and Capnocytophaga canimorsus* infectionsVaccination

if elective, should be done 2 weeks prior to operation pneumococcal, Hib, meningitis A & C and annual

influenza vaccination

Antibiotic prophylaxis

penicillin V: unfortunately clear guidelines do not exist of how long antibiotic prophylaxis should be continued. It is generally accepted though that penicillin should be continued for at least 2 years and at least until the patient is 16 years of age (may be for life)

*usually from dog bites

41sThe adrenal medulla secretes virtually all the adrenaline in the body as well as secreting small amounts of noradrenaline. It essentially represents an enlarged and specialised sympathetic ganglion

44 Folic acid is also present in green vegetables and nuts (liver is best source)

Folate metabolism Drugs which interfere with metabolism (inhibit DHF reductase)

93

trimethoprim methotrexate pyrimethamine

Drugs which can reduce absorption

phenytoin

54 AIP - porphobilinogen deaminase; PCT - uroporphyrinogen decarboxylase

Porphyrias

Overview

abnormality in enzymes responsible for the biosynthesis of haem

results in overproduction of intermediate compounds (porphyrins)

may be acute or non-acute

Acute intermittent porphyria (AIP) autosomal dominant , defect in porphobilinogen

deaminase female and 20-40 year olds more likely to be affected

(AIP is more common in females (5:1) typically present with abdominal symptoms,

neuropsychiatric symptoms hypertension and tachycardia common urine turns deep red on standing (oxidation of

colorless porphobilinogin)

94

skin signs are not seen(photosensitivity,blisters,scarring with milia,hypertricosis)

Features

abdominal: abdominal pain, vomiting neurological: motor neuropathy psychiatric: e.g. depression hypertension and tachycardia common

Diagnosis

classically urine turns deep red on standing raised urinary porphobilinogen (elevated between

attacks and to a greater extent during acute attacks) assay of red cells for porphobilinogen deaminase raised serum levels of delta aminolaevulinic acid

and porphobilinogen

Porphyria cutanea tarda (PCT)

the commonest, 80% are acquired

most common hepatic porphyria defect in uroporphyrinogen decarboxylase may be caused by hepatocyte damage e.g. alcohol,

oestrogens, HCV, iron ,lead, certain aromatic hydrocarbon, pregnancy, menstruation, stress, infection.

95

classically photosensitive rash with bullae, skin fragility on face and dorsal aspect of hands (commonest feature)

hypertricosis hyperpigmentation urine: elevated uroporphyrinogen and pink

fluorescence of urine under Wood's lamp manage with chloroquine , venesection,

desferroxamine

Variegate porphyria

autosomal dominant defect in protoporphyrinogen oxidase photosensitive blistering rash abdominal and neurological symptoms more common in South Africans

92 (pharma)Acute intermittent porphyria: drugs Drugs which may precipitate attack

barbiturates halothane benzodiazepines alcohol oral contraceptive pill sulphonamides

Drugs considered safe to use paracetamol aspirin codeine morphine chlorpromazine(imp)

96

beta-blockers penicillin metformin

65n Glycaemic index The glycaemic index (GI) describes the capacity of a food to raise blood glucose compared glucose in normal glucose-tolerant individuals. Foods with a high GI may be associated with an increased risk of obesity and the post-prandial hyperglycaemia associated with such foods may also increase the risk of type 2 diabetes mellitus High GI White rice (87), baked potato (85),

white bread (70)

Medium GI

Couscous (65), boiled new potato (62), digestive biscuit (59), basmati rice (58)

Low GI Fruit and vegetables, peanutsThe glycaemic index is shown in brackets. Glucose, by definition, would have a glycaemic index of 100 *MRCPASS Causes of Retinitis pigmentosa are: Kearn Sayre's syndrome Usher's disease Refsum's disease Lawrence Moon Biedl syndrome Alports's syndrome Friedrich's ataxia

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Abetalipoproteinemia (Bassen Kornzweig syndrome)Acanthocytes are seen (abnormal RBCs morphology)

62 Epidermis The epidermis is the outermost layer of the skin and is composed of a stratified squamous epithelium with an underlying basal laminaIt may be divided in to five layers:

Layer Description

Stratum corneum Flat, dead, scale-like cells filled with keratinContinually shed (determine mechanical properties)

Stratum lucidum Clear layer - present in thick skin only

Stratum granulosum

Cells form links with neighbours

Stratum spinosum Squamous cells begin keratin synthesis

Thickest layer of epidermis

Stratum germinativum

The basement membrane - single layer of columnar epithelial cellsGives rise to keratinocytesContains melanocytes

*(o\e) The stratum corneum is the last layer and provides a mechanical barrier to the skin therefore determines the mechanical functions of the skin. The hands and feet have thich stratum corneum as compared to the lips and

98

eyelids. The thicker the stratum corneum is the more protection there is for the skin. The dermis also has some factor to play with its elastic fibres and fibrous tissue. The rest of the layers are also important but the mechanical properties are primarily determined by the stratum corneum.

27 w The RET oncogene encodes a receptor tyrosine kinase and is associated with MEN type 2. Papillary thyroid cancer also appears to be associated with the RET oncogene

Multiple endocrine neoplasia The table below summarises the three main types of multiple endocrine neoplasia (MEN) MEN type I MEN type IIa MEN type IIb

Mnemonic 'three P's': • parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia• pituitary (70%)• pancreas (50%, e.g. gastrinoma) • also: adrenal and

• phaeochromocytoma (95%, e.g. phaeochromocytoma)• medullary thyroid cancer (70%)• parathyroid (60%)

• medullary thyroid cancer• phaeochromocytoma• marfanoid body habitus• neuromas

99

thyroid

MEN1 gene Most common presentation = hypercalcaemia

RET oncogene RET oncogene

MEN is inherited as an autosomal dominant disorder

66 Hyperuricaemia may be associated with both hyperlipidaemia and hypertension, so lipid profile is next test to be done.74 Renin-angiotensin-aldosterone system Adrenal cortex (mnemonic GFR - ACD)

zona glomerulosa (on outside): mineralocorticoids, mainly aldosterone

zona fasciculata (middle): glucocorticoids, mainly cortisol

zona reticularis (on inside): androgens, mainly dehydroepiandrosterone (DHEA)

Renin

released by JGA cells in kidney in response to reduced renal perfusion, low sodium

hydrolyses angiotensinogen to form angiotensin I

Factors stimulating renin secretion

low BP hyponatraemia

100

sympathetic nerve stimulation catecholamines erect posture

*Factors reducing renin secretion : drugs: beta-blockers, NSAIDs

Angiotensin

ACE in lung converts angiotensin I angiotensin II vasoconstriction leads to raised BP stimulates thirst stimulates aldosterone and ADH release

Aldosterone

released by the zona glomerulosa in response to raised angiotensin II, potassium , and ACTH levels

causes retention of Na+ in exchange for K+/H+ in distal tubule

15n Upper limb anatomy The information below contains select facts which commonly appear in examinations: Deltoid muscle

supplied by the axillary nerve (C5,C6) actions: mainly shoulder abduction

76 Radial nerve Overview

101

arises from the posterior cord of the brachial plexus (C5-8)Motor to

extensor muscles (forearm, wrist, fingers, thumb) C7

Sensory to

dorsal aspect of lateral 3 1/2 fingers however, only small area between the dorsal aspect of

the 1st and 2nd metacarpals is unique to the radial nerve

Patterns of damageWrist damage

wrist drop sensory loss to small area between the dorsal aspect of

the 1st and 2nd metacarpals

Axillary damage

as above paralysis of triceps

25 Ulnar nerve Overview

arises from medial cord of brachial plexus (C7-8, T1)

Motor to

102

medial two lumbricals adductor pollicis interossei hypothenar muscles: abductor digiti minimi, flexor

digiti minimi flexor carpi ulnaris, ulnar part of flexor digitorum

profundus

Sensory to

medial 1 1/2 fingers (palmar and dorsal aspects)

Patterns of damage

Damage at wrist

'claw hand' wasting and paralysis of intrinsic hand muscles

(except lateral (1st)two lumbricals) wasting and paralysis of hypothenar muscles sensory loss to the medial 1 1/2 fingers (palmar and

dorsal aspects)

Damage at elbow

as above (clawing is less obvious due to flexor digitorum profundus paralysis )

radial deviation of wrist (flexor carpi ulnaris paralysis)

85 Median nerve Overview

arises from lateral and medial cords of the brachial

103

plexus (C6-8, T1)

Motor to (LOAF)

Lateral two lumbricals Opponens pollis Abductor pollis brevis Flexor pollis brevis the above three form the thenar eminence muscles also supplies flexor muscles of the forearm

Sensory to

palmar aspect of lateral 3 1/2 fingers

Patterns of damageDamage at wrist

e.g. carpal tunnel syndrome paralysis and wasting of thenar eminence muscles sensory loss to palmar aspect of lateral 3 1/2 fingers

Damage at elbow, as above plus:

unable to pronate forearm weak wrist flexion ulnar deviation of wrist

Anterior interosseous nerve (branch of median nerve)

leaves just below the elbow results in loss of pronation of forearm and weakness

of long flexors of thumb and index finger

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92 Sensory loss over the dorsum of the foot and the lower lateral part of the leg is seen in a common peroneal nerve palsy. The degree of wasting would of course depend on how long the nerve palsy had been present

Common peroneal nerve lesion (L4-S3)The sciatic nerve divides into the tibial and common peroneal nerves. Injury often occurs at the head of the fibulaThe most characteristic feature of a common peroneal nerve lesion is foot dropOther features include:

weakness of foot dorsiflexion weakness of foot eversion weakness of extensor hallucis longus sensory loss over the dorsum of the foot and the lower

lateral part of the leg wasting of the anterior tibial and peroneal muscles

94n Foramina of the skull Questions asking about foramina of the skull have come up in the exam in previous years. Below is a brief summary of the major foramina, please see the Wikipedia link for a full list. Foramen

Bone Vessels Nerves

Optic canal

Sphenoid Ophthalmic artery

Optic nerve (II)

105

Superior orbital fissure

Sphenoid Superior ophthalmic veinInferior ophthalmic vein

Oculomotor nerve (III)Trochlear nerve (IV)lacrimal, frontal and nasociliary branches of ophthalmic nerve (V1)Abducent nerve (VI)

Inferior orbital fissure

Sphenoid and maxilla

Inferior ophthalmic veinsInfraorbital arteryInfraorbital vein

Zygomatic nerve and infraorbital nerve of maxillary nerve (V2)Orbital branches of pterygopalatine ganglion

Foramen rotundum

Sphenoid - Maxillary nerve (V2)

Foramen ovale

Sphenoid Accessory meningeal artery

Mandibular nerve (V3)

Jugular foramen

Occipital and temporal

Posterior meningeal artery

Glossopharyngeal nerve (IX)Vagus nerve (X)

106

Ascending pharyngeal arteryInferior petrosal sinusSigmoid sinusInternal jugular vein

Accessory nerve (XI)

28 w Obesity hormones leptin decreases appetite ghrelin increases appetite

Whilst thyroxine can increase appetite it does not fit with the clinical picture being described Obesity: physiology LeptinLeptin is thought to play a key role in the regulation of body weight. It is produced by adipose tissue and acts on satiety centres in the hypothalamus and decreases appetite. More adipose tissue (e.g. in obesity) results in high leptin levels.Leptin stimulates the release of melanocyte-stimulating hormone (MSH) and corticotrophin-releasing hormone (CRH). Low levels of leptin stimulates the release of neuropeptide Y (NPY) Ghrelin

107

Where as leptin induces satiety, ghrelin stimulates hunger. It is produced mainly by the fundus of the stomach and the pancreas. Ghrelin levels increase before meals and decrease after meals 87 Atrial natriuretic peptide Basics

secreted mainly from myocytes of right atrium and ventricle in response to increased blood volume

secreted by both the right and left atria (right > left) 28 amino acid peptide hormone, which acts via

cGMP degraded by endopeptidases

Actions

natriuretic, i.e. promotes excretion of sodium lowers BP antagonises actions of angiotensin II, aldosterone

100 BNP has a good negative predictive value rather than positive predictive value

B-type natriuretic peptide brain-type natriuretic peptide (BNP) hormone produced mainly by the left ventricular myocardium in response to strainWhilst heart failure is the most obvious cause of raised BNP levels any cause of left ventricular dysfunction such as myocardial ischaemia or valvular disease may raise levels. Raised levels may also be seen due to reduced

108

excretion in patients with chronic kidney disease. Factors which reduce BNP levels include treatment with ACE inhibitors, angiotensin-2 receptor blockers and diuretics. Effects of BNP

vasodilator diuretic and natriuretic suppresses both sympathetic tone and the renin-

angiotensin-aldosterone system

Clinical uses of BNPDiagnosing patients with acute dyspnoea

a low concentration of BNP(< 100pg/ml) makes a diagnosis of heart failure unlikely, but raised levels should prompt further investigation to confirm the diagnosis

NICE currently recommends BNP as a helpful test to rule out a diagnosis of heart failure

Prognosis in patients with chronic heart failure

initial evidence suggests BNP is an extremely useful marker of prognosis

Guiding treatment in patients with chronic heart failure

effective treatment lowers BNP levels

Screening for cardiac dysfunction

not currently recommended for population screening

109

121 Antidiuretic hormone Antidiuretic hormone (ADH) is secreted from the posterior pituitary gland buy synthesized in the hypothalamus. It promotes water reabsorption in the collecting ducts of the kidneys by the insertion of aquaporin-2 channels

36 Cardiac enzymes Interpretation of the various cardiac enzymes has now largely been superceded by the introduction of troponin T and I. Questions still however commonly appear in the MRCP Key points for the exam

myoglobin is the first to rise CK-MB is useful to look for reinfarction as it

returns to normal after 2-3 days (troponin T remains elevated for up to 10 days)

Begins

to risePeak value

Returns to normal

Myoglobin

1-2 hours

6-8 hours

1-2 days

CK-MB 2-6 hours

16-20 hours

2-3 days

CK 4-8 hours

16-24 hours

3-4 days

Trop T* 4-6 12-24 7-10 days

110

hours hours

AST 12-24 hours

36-48 hours

3-4 days

LDH 24-48 hours

72 hours

8-10 days

*9 physiology (o\e) troponin T is a contractile protein.Troponin is a component of thin filaments (along with actin and tropomyosin), and is the protein to which calcium binds to accomplish this regulation.

114 Electrical activity of the heart Myocardial action potential

Phase Description Mechanism

0 Rapid depolarisation

Rapid sodium influxThese channels automatically deactivate after a few ms

1 Early repolarisation

Efflux of potassium

2 Plateau Slow influx of calcium

3 Final repolarisation

Efflux of potassium

4 Restoration of ionic concentrations

Resting potential is restored by Na+/K+ ATPaseThere is slow entry of Na+ into the cell decreasing the potential difference until the threshold potential is reached, triggering a

111

new action potential

NB cardiac muscle remains contracted 10-15 times longer than skeletal muscleConduction velocity

Atrial conduction

Spreads along ordinary atrial myocardial fibres at 1 m/sec

AV node conduction

0.05 m/sec

Ventricular conduction

Purkinje fibres are of large diameter and achieve velocities of 2-4 m/sec (this allows a rapid and coordinated contraction of the ventricles

138 Coronary circulation Arterial supply of the heart

posterior aortic sinus left coronary artery (LCA) anterior aortic sinus right coronary artery (RCA) LCA LAD + circumflex RCA posterior descending RCA supplies SA node in 60%, AV node in 90%

Venous drainage of the heart

coronary sinus drains into the right atrium

63 Exercise: physiological changes

Blood pressure

systolic increases, diastolic decreases

112

leads to increased pulse pressure in healthy young people the increase in MABP is only

slight

Cardiac output

increase in cardiac output may be 3-5 fold results from venous constriction, vasodilation and

increased myocardial contractibility, as well as from the maintenance of right atrial pressure by an increase in venous return

heart rate up to 3-fold increase stroke volume up to 1.5-fold increase

39n In long QT syndrome QT prolongation is due to overload of myocardial cells with positively charged ions during ventricular repolarisation. Around 90-95% of inherited causes are due to defects in potassium channels Long QT syndrome Long QT syndrome is associated with delayed repolarization of the ventricles. It is important to recognise as it may lead to ventricular tachycardia and can therefore cause collapse/sudden death. A normal corrected QT is less than 440 ms in males and 450 ms in femalesCongenital

Jervell-Lange-Nielsen syndrome (includes deafness and is due to an abnormal potassium channel) autosomal recessive

113

Romano-Ward syndrome (no deafness) autosomal dominant

Drugs amiodarone sotalol class 1a antiarrhythmic drugs, & class 3 tricyclic antidepressants antipsychotic e.g. haloperidol chloroquine terfenadine - a non-sedating antihistamine and

classic cause of prolonged QT in a patient especially if also taking P450 enzyme inhibitor, e.g. patient with cold takes terfenadine and erythromycin at same time

erythromycin grape fruit juice

Other causes electrolyte: hypocalcaemia, hypokalaemia,

hypomagnesaemia acute MI myocarditis hypothermia subarachnoid haemorrhage

Management beta-blockers* implantable cardioverter defibrillators in high

risk cases*note sotalol may exacerbate long QT syndrome 30w Hypertension in pregnancy

114

The classification of hypertension in pregnancy is complicated and varies. Remember, in normal pregnancy:

blood pressure usually falls in the first trimester (particularly the diastolic), and continues to fall until 20-24 weeks

after this time the blood pressure usually increases to pre-pregnancy levels by term

Hypertension in pregnancy in usually defined as: systolic > 140 mmHg or diastolic > 90 mmHg or an increase above booking readings of >

30 mmHg systolic or > 15 mmHg diastolicAfter establishing that the patient is hypertensive they should be categorised into one of the following groups Pre-existing hypertension

Pregnancy-induced hypertension (PIH, also known as gestational hypertension)

Pre-eclampsia

A history of hypertension before pregnancy or an elevated blood pressure > 140/90 mmHg before

Hypertension (as defined above) occurring in the second half of pregnancy (i.e. after 20 weeks) No proteinuria,

Pregnancy-induced hypertension in association with proteinuria (> 0.3g /

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20 weeks gestation No proteinuria, no oedema Occurs in 3-5% of pregnancies and is more common in older women

no oedema Occurs in around 5-7% of pregnancies Resolves following birth (typically after one month). Women with PIH are at increased risk of future pre-eclampsia or hypertension later in life

24 hours) Oedema may occur but is now less commonly used as a criteria Occurs in around 5% of pregnancies

72w Severe pre-eclampsia is associated with hyperreflexia and clonus. A low platelet count may indicate the patient is developing HELLP syndrome Pre-eclampsia Pre-eclampsia is a condition seen after 20 weeks gestation characterised by pregnancy-induced hypertension in association with proteinuria (> 0.3g / 24 hours). Oedema used to be third element of the classic triad but is now often not included in the definition as it is not specific Pre-eclampsia is important as it predisposes to the following problems

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fetal: prematurity, intrauterine growth retardation

eclampsia haemorrhage: placental abruption, intra-

abdominal, intra-cerebral cardiac failure multi-organ failure

Risk factors* > 40 years old nulliparity (or new partner) multiple pregnancy body mass index > 30 kg/m^2 diabetes mellitus pregnancy interval of more than 10 years family history of pre-eclampsia previous history of pre-eclampsia pre-existing vascular disease such as

hypertension or renal diseaseFeatures of severe pre-eclampsia

hypertension: typically > 170/110 mmHg and proteinuria as above

proteinuria: dipstick ++/+++ headache visual disturbance papilloedema RUQ/epigastric pain hyperreflexia platelet count < 100 * 106/l, abnormal liver

enzymes or HELLP syndromeManagement

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consensus guidelines recommend treating blood pressure > 160/110 mmHg although many clinicians have a lower threshold

oral methyldopa** is often used first-line with oral labetalol, nifedipine and hydralazine also being used

for severe hypertension IV labetalol and IV hydralazine are used in addition to the above

*smoking is not a risk factorAvoid in HELLP syndrome (liver damage)61w Progesterone is secreted by the corpus luteum following ovulation (so peak in luteal phase). Menstrual cycle The menstrual cycle may be divided into the following phases: Day

s

Menstruation 1-4

Follicular phase (proliferative phase)

5-13

Ovulation 14

Luteal phase (secretory phase)

15-28

Further details are given in the table below

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Follicular phase (proliferative phase)

Luteal phase (secretory phase)

Ovarian histology

A number of follicles develop. One follicle will become dominant around the mid-follicular phase

Corpus luteum

Endometrial histology

Proliferation of endometrium

Endometrium changes to secretory lining under influence of progesterone

Hormones A rise in FSH results in the development of follicles which in turn secrete oestradiol When the egg has matured, it secretes enough oestradiol to

Progesterone secreted by corpus luteum rises through the luteal phase. If fertilisation does not occur the corpus

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trigger the acute release of LH (LH surge). This in turn leads to ovulation

luteum will demise and progesterone levels fall Oestradiol levels also rise again during the luteal phase

Cervical mucus

Following menstruation the mucus is thick and forms a plug across the external os Just prior to ovulation the mucus becomes clear, acellular, low viscosity. It also becomes 'stretchy' - a quality termed spinnbarkeit

Under the influence of progesterone it becomes thick, scant, and tacky

Basal body temperature

Falls prior to ovulation due to the influence of

Rises following ovulation in

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oestradiol response to higher progesterone levels

107 Prolactin is unique amongst the pituitary hormones in being tonically inhibited by the hypothalamus

Prolactin and galactorrhoea Prolactin is secreted by the anterior pituitary gland with release being controlled by a wide variety of physiological factors. Dopamine acts as the primary prolactin releasing inhibitory factor and hence dopamine agonists such as bromocriptine may be used to control galactorrhoea. It is important to differentiate the causes of galactorrhoea (due to the actions of prolactin on breast tissue) from those of gynaecomastia

Features of excess prolactin

men: impotence, loss of libido, galactorrhoea women: amenorrhoea, galactorrhoea

Causes of raised prolactin

prolactinoma pregnancy oestrogens physiological: stress, exercise, sleep acromegaly: 1/3 of patients

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polycystic ovarian syndrome primary hypothyroidism (due to thyrotrophin releasing

hormone (TRH) stimulating prolactin release)

Drug causes of raised prolactin

metoclopramide, domperidone phenothiazines haloperidol very rare: SSRIs, opioids

124 Endothelin Endothelin is a potent, long-acting vasoconstrictor and bronchoconstrictor. It is secreted initially as a prohormone by the vascular endothelium and later converted to ET-1 by the action of endothelin converting enzyme. It acts via interaction with a G-protein linked to phospholipase C leading to calcium release. Endothelin is thought to be important in the pathogenesis of many diseases including primary pulmonary hypertension, cardiac failure, hepatorenal syndrome and Raynaud's. act in a paracrine fashionPromotes release

angiotensin II ADH hypoxia mechanical shearing forces

Inhibits release

nitric oxide prostacyclin

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Raised levels in

MI heart failure ARF asthma primary pulmonary hypertension

137 Fanconi anaemia Autosomal recessiveFeatures

aplastic anaemia increased risk of AML, myelodysplasia, PNH neurological skeletal abnormalities skin pigmentation Café-au-lait spotsi splenic atrophy short stature & hypogonadism & mental retardation congenital heart & kidney diseases

Diagnosis deb’s test incubation with diepoxybutane impaired DNA release 143 Clubbing The causes of clubbing may be divided into cardiac, respiratory and otherCardiac causes

cyanotic congenital heart disease (Fallot's, TGA) bacterial endocarditis atrial myxoma

Respiratory causes*123

lung cancer pyogenic conditions: cystic fibrosis, bronchiectasis,

abscess, empyema asbestosis, mesothelioma fibrosing alveolitis

Other causes

Crohn's, to a lesser extent UC cirrhosis, primary biliary cirrhosis Grave's disease (thyroid acropachy) rare: Whipple's disease

*COPD & celiac’s disease are not a cause of clupping

145 Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin (A1AT) deficiency is a common inherited condition caused by a lack of a protease inhibitor (Pi) normally produced by the liverGenetics

located on chromosome 14 A1AT deficiency is inherited in an autosomal co-

dominant fashion alleles classified by their electrophoretic mobility -

M for normal, S for slow, and Z for very slow normal = PiMM homozygous PiSS (50% normal A1AT levels) homozygous PiZZ (10% normal A1AT levels)

Features

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patients who manifest disease usually have PiZZ genotype

lungs: panacinar emphysema, most marked in lower lobes

liver: cirrhosis and hepatocellular carcinoma in adults, cholestasis in children

Investigations

A1AT concentrations

*MRCPASS

Prions are glycoproteins which codes for a membrane protein. Prion proteins are usually resistant to protease digestion and are not broken down by heat. Prions do not contain genetic material. CJD, Kuru and scrapie are prion diseases. Prions are thought to have a role in cell signalling rather than DNA replication. Normal prion proteins are encoded by chromosome 20. PrPsc is characterised by increased β pleated sheets. PrPsc proteins are anchored by glycoproteins (GPI).

35n Colorectal cancer - most common site: rectum Colorectal cancer Colorectal cancer is the third most common type of cancer in the UK and the second most cause of cancer deaths Location of cancer (averages)

rectal: 40%

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sigmoid: 30% descending colon: 5% transverse colon: 10% ascending colon and caecum: 15%

9n Any patient of this age with an unexplained microcytic anaemia should have a lower gastrointestinal tract investigation to exclude colorectal cancer Colorectal cancer: referral guidelines NICE recommend the following patients are referred urgently (i.e. within 2 weeks) to colorectal services for investigation:

patients > 40 years old, reporting rectal bleeding with a change of bowel habit towards looser stools and/or increased stool frequency persisting for 6 weeks or more

patients > 60 years old, with rectal bleeding persisting for 6 weeks or more without a change in bowel habit and without anal symptoms

patients > 60 years old, with a change in bowel habit to looser stools and/or more frequent stools persisting for 6 weeks or more without rectal bleeding

any patient presenting with a right lower abdominal mass consistent with involvement of the large bowel

any patient with a palpable rectal mass

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unexplained iron deficiency anaemia in men or non-menstruating women (Hb < 11 g/dl in men, < 10 g/dl in women)

2n This is a classic presentation of spinal stenosis. Whilst peripheral arterial disease is an obvious differential the characteristic relieving factors of the pain and normal vascular examination point away from this diagnosis.

Lower back pain Lower back pain (LBP) is one of the most common presentations seen in practice. Whilst the majority of presentations will be of a non-specific muscular nature it is worth keeping in mind possible causes which may need specific treatment. Red flags for lower back pain

age < 20 years or > 50 years history of previous malignancy night pain history of trauma systemically unwell e.g. weight loss, fever

The table below indicates some specific causes of LBP: Facet joint

May be acute or chronicPain worse in the morning and on standingOn examination there may be pain over the facets. The pain is typically worse on extension

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of the back

Spinal stenosis

Usually gradual onsetUnilateral or bilateral leg pain (with or without back pain), numbness, and weakness which is worse on walking. Resolves when sits down. Pain may be described as 'aching', 'crawling'.Relieved by sitting down, leaning forwards and crouching downClinical examination is often normalRequires MRI to confirm diagnosis

Ankylosing spondylitis

Typically a young man who presents with lower back pain and stiffnessStiffness is usually worse in morning and improves with activityPeripheral arthritis (25%, more common if female)

Peripheral arterial disease

Pain on walking, relieved by restAbsent or weak foot pulses and other signs of limb ischaemiaPast history may include smoking and other vacular diseases

6n Lower back pain: prolapsed disc

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A prolapsed lumbar disc usually produces clear dermatomal leg pain associated with neurological deficits. Features

leg pain usually worse than back pain often worse when sitting

The table below demonstrates the expected features according to the level of compression: L3 nerve root compression

Sensory loss from anterior thigh to medial aspect of lower legWeak quadricep musclesReduced knee reflexPositive femoral stretch test

L4 nerve root compression

Sensory loss anterior aspect of kneeWeak quadricep musclesReduced knee reflexPositive femoral stretch test

L5 nerve root compression

Sensory loss dorsum of foot including big toeWeakness in foot and big toe dorsiflexionReflexes intactPositive sciatic nerve stretch test

S1 nerve Sensory loss posteriolateral

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root compression

aspect of leg and lateral aspect of foot including the little toeWeakness in plantiflexion of footReduced ankle reflexPositive sciatic nerve stretch test

Management similar to that of other musculoskeletal lower

back pain: analgesia, physiotherapy, exercises

if symptoms persist then referral for consideration of MRI is appropriate

12n Antiphospholipid antibodies (APL) are present in 15% of women with recurrent miscarriage, but in comparison, the prevalence of APL in women with a low risk obstetric history is less than 2%

Antiphospholipid syndrome: pregnancy Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia. It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)In pregnancy the following complications may occur:

recurrent miscarriage IUGR

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pre-eclampsia placental abruption pre-term delivery venous thromboembolism

Management low-dose aspirin should be commenced once

the pregnancy is confirmed on urine testing low molecular weight heparin once a fetal

heart is seen on ultrasound. This is usually discontinued at 34 weeks gestation

these interventions increase the live birth rate seven-fold

14n SIADH: causes Malignancy

especially small cell lung cancer also: pancreas, prostate, thymoma

Neurological stroke subarachnoid haemorrhage subdural haemorrhage meningitis/encephalitis/abscess

Infections TB pneumonia

Drugs opiates sulphonylureas SSRIs, tricyclics carbamazepine vincristine

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cyclophosphamideOther causes

positive end-expiratory pressure (PEEP) porphyrias

* ethanol decrease ADH release

onexamination

10 Natural selection is the likely explanation as it appears that heterozygous for CF may offer some protection against diarrhoeal illnesses particularly typhoid. Offers survival advantage against cholera (because the toxin cannot open the chloride channels in the small intestine.) and enteropathogenic bacteria. perhaps an initial increase in CF herterozygosity was a response to a different diarrheal infection.

15 Current guidelines suggest that a resting ECG and TTE (transthoracic ECHO) are the most effective screening strategy for relatives of patients with HOCM. Genetic testing is not recommended as a first line screening tool given varying rates of penetrance

18 The exertional thigh cramps, the presence of myoglobin and change in colour of urine after exercise (turning to burgundy colour) suggests glycogen storage disease type V – McArdles syndrome. The most appropriate investigation for this is muscle biopsy which reveals

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subsarcolemmal deposits of glycogen appear at the periphery of fibres.

20 A popular question for the exam but simple physiology gets the right answer here. The effects of neurotransmitter release are principally terminated by neuronal uptake. Intraneuronal NA is usually taken back up into the neurosecretory granules and a small amount is metabolised by MAO. Even smaller quantities that escape into the circulation are metabolised by COMT.

21 Thyroid hormones enhance insulin-dependent entry of glucose into cells (Enhance inslin sensitivity), myocardial oxygen consumption, nerve conduction, gluconeogenesis and oxidation of fatty acids

22 Black ethnicity is associated with a higher risk of prostate cancer than caucasian. A family history of breast cancer increases the risk of prostate cancer, as does a family history of prostate cancer. An occupation in farming also seems to increase the risk of prostate cancer. High intake of animal fats, and low selenium intake, as well as exposure to radiation and cadmium all increase the risk of prostate cancer

31 Lactase acts on lactose to generate glucose and galactose. Lactose intolerance is least common in white northern Europeans, and is more common in Asian, and

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East Asian races. Lactose intolerance may be diagnosed with a DNA assay of the Lactase gene, along with a Hydrogen breath test. Any GI infection may reveal lactose intolerance, as gut flora may be altered by large bowel bacterial or viral load, as well as the treatment of infection. A change from an Eastern to a Western, high lactose, diet, may also reveal lactose intolerance. Many patients labelled as having IBS may suffer from undiagnosed lactose intolerance, and many medications use lactose as a binding and stabilising agent. Treatment of lactose intolerance is with careful replacement of lactase.

33honer & anhydrosis

Because the sympathetic plexus accompanying the internal carotid artery innervates sweat glands only to the medial forehead, facial anhydrosis does not occur significantly with postganglionic Horner syndrome

42 reiew

43 (review) Loss of locus hetrogeneity characterises autosomal dominant breast cancer which is due to mutations in BRCA1 and BRCA2 (inherited in an autosomal dominant pattern).

44 X-linked recessive diseases can occur with the same severity in females in certain situations – having an affected father and carrier mother (seen in G6PD

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deficiency), Turners syndrome, X-chromosome isodisomy, unequal lyonisation, in an XY individual with testicular feminisation syndrome and where there is an X/autosome translocation through a gene (DMD). Fragile X syndrome shows anticipation with triplet repeat expansion. Y-linked diseases can be associated with male infertility. There are several X-linked immune deficiency syndromes – severe combined immune deficiency, chronic granulomatous disease, agammaglobulinaemia (Brutons disease), and Wiscott-Aldrich syndrome. Hypophosphataemic rickets is X-inked dominant, and Von Willebrands disease is inherited in an autosomal dominant manner

Biochemistry

5 The hypokalaemic hypertension with hypomagnesaemia suggests primary hyperaldosteronism. The most reliable assessment for this would be renin to aldosterone ratio.

9 This smoker has a good history of angina and a strong family history of IHD. The most appropriate investigation would be a troponin T concentration would is highly specific and sensitive for IHD if elevated. An exercise test is relevant only after an acute coronary event has been excluded (by troponin T). If positive then angiography should be performed

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10 IgE is responsible for allergen-mediated diseases such as anaphylaxis, asthma and atopy. Total serum IgE is frequently increased in those with atopy but serum IgE does not rise acutely during an asthmatic attack.

25 This gent is intoxicated. He has a normal acid base balance slight hyponatraemia reflecting dilution and very high osmolality reflecting the presence of ethanol. Methanol would produce an acidosis. Diazepam is not an osmolyte nor would the other agents produce this picture.

*gilbert syndrome presentation is mild no treatment, while crigler najar type 2 may respond to phenoparpitone ; enzyme inducers (1 =recessive, 2 = dominant)

45 CD40 and CD40L are required for co-stimulation by T-cells. Deficiency of either CD40 or CD40L impairs class switching.

Some T-cell independent antigens can cause proliferation of B-cells regardless of their specificity - polyclonal B-cell activation. B cell responses to T-independent antigens consist mainly of IgM antibodies of low affinity without the production of memory cells. The influenza virus will activate T- and B-cells, and result in memory cell production. Genetic mutation in the virus is responsible for immune evasion and repeated infections.

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57 The Single radial haemolysis (SRH) test is used to screen for rubella antibodies in pregnant womenis NOT employed in the laboratory diagnosis of respiratory viral infections

62 MENTAL RETARDATION. Fragile X syndrome-commonest male cause. Hypoxia at birth, intaventricular haemorrhage, rhesus disease, Congenital infections -toxoplasmosis, CMV, rubella, herpes), hypoglycaemia, meningitis, hypothyroidism (cretinism, tuberous sclerosis, Down's, Tay-Sach's, Cornelia De Lange, (Hartnup - biochemical, treatable with diet). -homocystinuria, phenylketonuria -maple syrup urine disease, tryptophanuria –galactosaemia

Glycogen storage, Alkaptonuria, Cystinuriado not cause MR

64 There is a marked hypernatraemia with elevated chloride but normal potassium and urea in a patient with severe head injuries. The likely cause of this presentation is Diabetes Insipidus. Urine osmolality is therefore likely to be low.

65 Mickuliz’s syndrome

This condition is sarcoidosis. Serum calcium, Serum phosphorus, Chem7 and Chem 20 and Quantitative

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Immunoglobulins are all used in establishing the diagnosis. Gallium scan is helpful in sarcoidosis. (Radiology of extrathoracic sarcoid ...) NB sarcoidosis punched out lesion on finger X-ray

Gallium scan vs. Thallium scan.

Gallium scan (radioactive 67Ga) is used to detect inflammation - such as in inflammatory disorders or malignancy.

Thallium (radioactive 201Tl) is a potassium analogue and is used to demonstrate areas of poor perfusion. It is particularly used in cardiology to detect areas of ischaemia.

66 gamma glutamyl transferase found in muscle, prosate as well as liver. Increased levels of GGT are found in cholestatic liver disease and in hepatocellular disease when there is an element of cholestasis. Levels are increased with chronic intake of excess alcohol and with certain drugs (esp phenytoin), as a result of enzyme induction. Pancreatitis and prostatitis may also be associated with increased levels. Levels may be normal early in the course of acute hepatocellular damage eg acute viral hepatitis, paracetamol hepatotoxicity. Elevations in pregnancy would suggest liver disease. Increased GGT is found in fatty liver

71 The patient appeasr to have develop the refeeding syndrome. Refeeding malnourished patients increases

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basal metabolic rate, with glucose being the predominant energy source. This anabolic response causes intracellular movement of minerals, and serum levels may fall significantly. These rapid changes in metabolism and electrolyte movement may lead to severe cardiorespiratory and neurological problems resulting in cardiac and respiratory failure, oedema, lethargy, confusion, coma, convulsions, and death. The symptoms of the refeeding syndrome are thought to be due predominantly to hypophosphataemia, but metabolic changes in potassium, magnesium, glucose, and thiamine can also contribute. The probable answer here is therefore phosphate as

73 Acanthocytes are seen in abetalipoproteinaemia.abnormal RBCs morphology

Retinitis pigmentosa is seen in abetalipoproteinaemia. Neurodegenerative changes are seen such as ataxia but IQ is normal.

*asbestosis: The risk of mesothelioma is not affected by smoking but smoking and asbestos exposure greatly increases the risk of lung cancer.

Anatomy

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3 De Quervains's tenosyunovitis is thought to be related to overuse and is common in golfers and raquet sport players. Most affected are females 30-50 years old. Finkelstein's test (flexion of the thumb into the palm, making a fist over the thumb and ulnar deviation of the wrist causes pain in the first dorsal extensor complartment) is diagnostic.

4 The pure sensory loss makes the diagnosis of Meralgia paraesthetica and is a consequence of damage to the lateral cutaneous nerve of the thigh. It is usually a consequence of entrapment at the lateral inguinal ligament or less likely, trauma, ischaemia or a retroperitoneal lesion.

9 heart anatomy

The pulmonary trunk lies posterior to the aorta. The ascending aorta lies completely within the pericardium as does the pulmonary trunk. The left atrium is the most posterior chamber of the heart, the right atrium is just anterior and to the right of the left atrium. The left atrial appendage is not readily seen on transthoracic echocardiography and requires transoesophageal echocardiography.

13 The patient presents with a history in keeping with hemiballism. The presence of severe flinging movements affecting proximal muscles and following no particular

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pattern is typical for hemiballism. The site of the lesion is in the contralateral subthalamic nucleus, infarction being the commonest cause. The patient has several arteriosclerotic risk factors including hypertension, hyperlipidaemia, ischaemic heart disease and diabetes. Usually the flinging movements stop spontaneously in the next 4-8 weeks and tetrabenazine is the treatment of choice. Bilateral ballismus is rare and implicates a metabolic cause usually non-ketotic hyperosmolar coma.

18 This is a classic story of a lower brachial plexus injury; sudden upward movement of the abducted arm. This causes features of an ulnar nerve palsy which is supplied by the lower brachial plexus roots C8 and T1.

The median and radial nerves can be excluded because of the typical ulnar nerve findings. The ulnar nerve can be damaged at the elbow from chronic pressure, leaning on the elbows, and direct trauma. However, this injury is a stretching injury of the arm. A cervical spine injury would be expected to have other associated neurological signs.

28 Unilateral occlusion (distal to Ant. Comm. origin) of Anterior Cerebral Artery produces contralateral sensorimotor deficits mainly involving the lower extremity with sparing of face and hands (think of the humunculus).The Lateral Lenticulostriate artery is a branch of the middle cerebral artery. Occlusion causes damage to the internal capsule resulting in contralateral hemiparesis and

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sensory deficit. Speech may be affected (medial temporal lobe) as well as visual function (Meyer's loop: optic radiations affected).

Middle Cerebral Artery: Occlusion at the stem (proximal segment) results in:

Contralateral hemiplegia affecting face, arm, and leg (lesser).

Homonymous hemianopia - Ipsilateral head/eye deviation.

If on left: global aphasia.

Posterior cerebral artery: A variety of neurological syndromes including:-

Pure hemisensory loss visual field loss- a variety Visual agnosia Disorders of reading (alexia, dyslexia) and more..........

31 review

Median and ulnar nerve lesions would not cause absent reflexes in the arm. Lower trunk brachial plexus (C8/T1) would not cause absent reflexes in the arm. Neuralgic amyotrophy affects the upper blexus (C5-6) and therefore does not cause wasting of small muscles of hand. Thoracic outlet syndrome will not cause absent reflexes. Syringomyelia typically causes loss of reflexes,

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spinothalamic sensory loss, and weakness. It can be asymmetrical initially.

Epidemiology

2 risks of ca prostate:

Black ethnicity is associated with a higher risk of prostate cancer than caucasian. A family history of breast cancer increases the risk of prostate cancer, as does a family history of prostate cancer. An occupation in farming also seems to increase the risk of prostate cancer. High intake of animal fats, and low selenium intake, as well as exposure to radiation and cadmium all increase the risk of prostate cancer

3 "Individuals with blood group O are more susceptible than other individuals to severe cholera, although the mechanism underlying this association is unknown." also risk of peptic ulcer

4 The prevalence of Rheumatoid Arthritis is approximately 1%. Thus in a practice of 20,000, the number of patients with RhA would be 200,

SLE.2% Ak.1%

6 The prevalence of the cystic fibrosis gene at around 1 in 20 of the population would suggest that this provides some evolutionary survival advantage. Like sickle cell trait

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offering a survival advantage to malaria, it is belived that the cystic fibrosis gene offers a possible survival advantage against cholera and enteropathogenic bacteria.

"Cholera opens chloride channels, letting chloride and water leave cells. The CFTR protein does just the opposite, closing chloride channels and trapping salt and water in cells, which dries out mucus and other secretions. A person with CF cannot contract cholera, because the toxin cannot open the chloride channels in the small intestine.

Physiology

3 Mast cells are basophilic cells in the connective and subcutaneous tissues, which are involved in inflammatory and immune responses. They contain storage granules that contain lytic enzymes (e.g. tryptase) and inflammatory mediators, e.g. histamine, heparin, 5-HT, leukotrienes, platelet aggregating factor, leucocyte chemotactic factor and hyaluronidase. Release of these mediators occurs during mast cell degranulation, which can be triggered by: tissue injury, drugs, complement activation, and foreign antigenic material but maily IgE

4 A low partial pressure of oxygen (PO2) causes HbS to polymerise and precipitate, resulting in sickling of the erythrocyte. HbSS patients sickle at PO2 of 5 ? 6 kPa and HbAS patients sickle at PO2 of 2.5 - 4 kPa. A mild disease is produced when heterozygotes for HbS combine with other

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haemoglobins e.g. Haemoglobin C, thus creating HbSC. Sickling occurs at around 4 kPa.

6 A popular question for the exam but simple physiology gets the right answer here. The effects of neurotransmitter release are principally terminated by neuronal uptake. Intraneuronal NA is usually taken back up into the neurosecretory granules and a small amount is metabolised by MAO. Even smaller quantities that escape into the circulation are metabolised by COMT.

7 Thyroid hormones enhance insulin-dependent entry of glucose into cells (enhance insuin sensitivity), myocardial oxygen consumption, nerve conduction, gluconeogenesis and oxidation of fatty acids

10 Renal blood flow is approximately 25% of cardiac output. The 'Fick principle' can be used to estimate RBF through clearance. RBF is higher in the cortex than medulla as one might expect with the increasing glomeruli in this region. Sympathetic stimuli produce vasoconstriction and RBF should be increased in response to hypoxia.

11 The normal pulmonary circulation is characterised by low pressures, low flow rates, high compliance vessels.

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15 Myosin drives striated muscle (not smooth muscle)contraction, and can be divided into 2 groups – conventional (class II myosins) which form filaments in a hexameric array of 2 heavy chains and two pairs of light chains. Unconventional myosins do not form filaments and perform varied functions in a broad range of cells (eg organelle transport, endocytosis). Myosin contains an ATP and actin-binding sites. Other myosin related genetic disorders besides the heavy chain mutations in cardiomyopathy(HOCM) include Carney complex (trismus-pseudocamptodactyly), Type 1b Usher syndrome and non-syndromic deafness.

Pathology

16 Carcinoid tumours so called Argentafinomas as they take up Silver are neuroendocrine cells and are derived from the K cells (Kulchitsky (K) cell) in the lung.

17 these histological features are typical of Coeliac disease with villous atrophy, crypt hyperplasia/hypertrophy, inflammatory infiltrate of the lamina propria and intra-epithelial lymphocytes. Tropical aprue may produce the same histology

19 Most of the cells that fill the alveoli in desquamative interstitial pneumonitis (DIP) are which of the following? Macrophages

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20 Non-atherosclerotic angina would be associated with conditions such as thyroxicosis, aortic regurgitation, aortic stenosis, hypertrophic cardiomyopathy and anaemia to name but a few

22 Progressive Massive Fibrosis Complicated silicosis (not sarcoidosis). In silicosis a more accurate term is 'conglomurate nodules'. Silicosis TB

Coalworker pneumoconiosis COPD

Metabolic

4 Lithium can produce Diabetes Insipidus and also raise calcium.

10 Which of the following conditions is most likely to be detectable by growth monitoring? Hypothyroidism

15 Hunter's Syndrome (MPS-2) is of X-linked recessive

inheritance. The cornea are clear. The skeletal involvement tends to be mild with no gibbous present, though scoliosis is often found. Mental retardation and heart involvement are less severe than in Hurler's Syndrome. Hurler's Syndrome (MPS0) is autosomal recessive in inheritance and is associated with cloudy cornea. There is severe mental retardation, and gibbous deformation of the spine is characteristic. There is the characteristic coarse facies with hepatosplenomegaly.

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17 Gaucher's disease is the most frequent of the lysosomal storage diseases. The condition is usually due to a catalytic deficiency of glucocerebrosidase. It is accompanied by many ill-understood plasma and metabolic abnormalities. These include a polyclonal immunoglobulin response that may progress to monoclonal gammopathy, amyloidosis, or even frank myeloma. Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol fractions are abnormal in the plasma. Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease.

19 Which of the following suggests a diagnosis of familial combined hyperlipidaemia (FCHL) rather than heterozygous familial hypercholesterolaemia (FH)? Presence of glucose intolerance

The genetic dislipidaemias occur in one third of patients who have suffered from their first myocardial infarction below the age of 50 years in men. The commonest is familial combined hyperlipidaemia (two thirds), with a fifth due to familial hypercholesterolaemia. The former can be diagnosed only on family studies, and there is

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elevation of fasting plasma tricglycerides not associated with hypercylomicronaemia. It is autosomal dominant, and some family members may have hypercylomicronaemia. Only 20% of children have elevated triglycerides before the age of 25. Obesity, insulin resistance, hyperinsulinaemia, glucose intolerance, and hyperuricaemia are associated. Heterozygous familial hypercholesterolaemia is dominantly inherited, and results from defects in the LDL receptor. The most important clinical manifestation is premature coronary artery disease, particularly with onset between the third or fourth decade. Tendon xanthomata and arcus cornea are rarely present in children, but are very important signs to identify.

20 Which of the following would be most in keeping with a diagnosis of ploymyalgia rheumatica? increased alkaline phosphotase

Liver enzymes are elevated in most patients. Visual disturbances are suggestive of temporal arteritis not PMR, and are due to ischaemic changes in ciliary arteries (optic neuritis/infarction) and less commonly due to central artery occlusion. Raised CK in polymyositis. PMR is rare before the age of 50 years.

*differential diagnosis of livedoreticularis cholesterol embolism, antiphospholipid syndrome, homocystinuria, PAN, malignancy

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Immunology

7 Xenotransplantation is the transfer of organs between species - particularly the transfer of animal organs to humans. Compare this with allotransplantation which is the transfer of organs within the same species.

There have already been several documented cases of xenotransplantation - baboon heart, chimpanzee kidneys. A close HLA match is not possible of course unless a transgenic species is used that express human major histocompatability complexes (HLA). Early immune response is humoral - IgM.

8 Systemic mastocytosis is a disease which usually affects the elderly and is associated with urticaria pigmentosa, diarrhoea, hypotension, sclerotic bone changes and mast cell infiltration of organs such as spleen, liver kidneys.

23 Which of the following is a cause of isolated B-cell immune deficiency? Multiple myeloma

Excessive production of myeloma paraprotein is associated with progressive reduction in normal immunoglobulin levels and impairment of immune function. Azathioprine, cyclophosphamide, corticosteroids and measles infection all cause reversible impairment of cell mediated immunity.

25 This lady is likely to have asteatotic eczema (dry, pruritic rash affecting the upper back and shins) which is a

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common problem and will improve just with plain emollients. Xerotic skin is commoner in the elderly population especially in the winter months due to the dry heat from central heating. All the other suggestions may be appropriate in a patient resistant to first line treatment but the first line is to try emollients.

26 B-cells (review)

CD40 and CD40L are required for co-stimulation by T-cells. Deficiency of either CD40 or CD40L impairs class switching. Certain antigens can activate B-cells in the absence of T-cell help - thymus independent antigen. T-cell independent B-cell responses are mainly to carbohydrate antigen e.g. pneumococcal polysaccharide. These antigens are not processed and presented in association with MHC molecules, and therefore cannot activate T-helper cells. Most TI antigens have highly repetitive epitopes (e.g.LPS/endotoxin), which are able to cross link B-cell surface immunoglobulin and activate these cells. Some T-cell independent antigens can cause proliferation of B-cells regardless of their specificity - polyclonal B-cell activation. B cell responses to T-independent antigens consist mainly of IgM antibodies of low affinity without the production of memory cells.

27 Waldenstrom's Macroglobulinaemia

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This elderly man has a very raised IgM level, pancytopaenia, Raynaud's phenomenon and a foot ulcer.

The most likely diagnosis here is Waldenstrom's Macroglobulinaemia (WM). WM refers to a condition that presents in the seventh or eighth decade of life.

It is characterized by the presence of a high level of a macroglobulin (immunoglobulin M [IgM]), elevated serum viscosity and the presence of a lymphoplasmacytic infiltrate in the bone marrow, resulting in pancytopenias.

Raynaud phenomenon may herald the onset of this condition and is due to cryoglobulinemia.

The monoclonal IgM causes hyperviscosity syndrome; cryoglobulinemia types 1 and 2; coagulation abnormalities; polyneuropathies; cold agglutinin disease and anaemia; primary amyloidosis; and tissue deposition of amorphous IgM in skin, the GI tract, kidneys, and other organs.

29 review

The most appropriate next test(to RAST testing if -ve) would be skin allergen testing as a food provocation test is often unecessary and can prove rather dangerous although is the gold standard.

31 Type I hypersensitivity, also known as immediate or anaphylactic hypersensitivity, usually takes 15 - 30

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minutes from the time of exposure to the antigen. The reaction may cause a range of symptoms from minor inconvenience to death. The reaction involves preferential production of IgE, in response to certain antigens, which in turn initiates a sequence of events leading to the release various pharmacologically active substances that are responsible for the clinical features. Diagnostic tests include skin tests, measurement of total IgE and specific IgE antibodies against the suspected allergens. However, this question asks which of the following tests would provide confirmatory information and that would be Tryptase.

Tryptase is a neutral protease stored in mast cell secretory granules that is secreted by human mast cells. Levels in normal blood are undetectable (< 1 ng/ml). Elevated serum levels demonstrate that mast cell activation with mediator release has occurred whether triggered by IgE-mediated anaphylaxis or non-IgE-mediated anaphylactoid reactions. The greater the severity of anaphylaxis, the more likely that serum -tryptase levels will be elevated.

32 The BCG vaccine is an attenuated strain - it provides approximately 70% protection against leprosy

39 Thymocytes whose TcR bind with high affinity to self Ag/MHC complexes are clonally deleted by a process of negative selection.

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42 Farmer's lung

Commonest occupational extrinsic allergic alveolitis, due to thermophillic actinomycetes. Crackles are typically heard at the bases. Eosinophilia can be seen but is not typical. Immunoglobulin levels are frequently elevated but not a paraprotein. P02 may be decreased particularly with exercise. Arestrictive pattern on LF studies is seen. (Dr Shu Ho)

43 asthma There is a contribution from HLA alleles

There may be genetic linkage of atopic trait to chromosome 11, with association between response to antigen and HLA haplotype. IgE concentrations are influenced by genetic factors.

52 Infection is the commonest cause of death in multiple myeloma because of immunoparesis. Lytic bone lesions commonly occur due to increased osteoclastic activity, rarely sclerotic lesions occur. Vigorous hydration and diuresis are cornerstones of the treatment of severe hypercalcaemia in myeloma. Interferon alpha is the only agent found to prolong plateau phase of disease (used in maintenance therapy) Treatment with interferon alpha improves survival

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*aspirin & opiate mast cell degranulator ,so avoid in eczema & mastocytosis

Molecular Biology

2 Plasmids are circular molecules of bacterial DNA separate from the bacterial chromosome. They are usually small consisting of a few thousand base pairs, carry one or a few genes, and have a single origin of replication. Genes on plasmids with multiple copies are usually expressed at higher levels. In nature these genes often encode for proteins such as those needed for bacterial resistance. Plasmids can be used to clone genes by splicing a particular gene into a plasmid and then allowing the bascteria to multiply - this is then called recombinant plasmid DNA.

3 A key event in the initiation of apoptosis is the activation of a cascade of cysteine-aspartate specific proteases known as caspases

5 The structure of mRNA is similar to DNA except that uracil replaces thymine as one of the bases. Both coding (exons) and non-coding regions of DNA are initially transcribed into mRNA. Splicing is required for mature mRNA to be produced only consisting of introns. Translation occurs in the cytoplasm. Southern blotting is a

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technique that uses denatured fragments of DNA in a gel to bind to DNA probes in order to detect the presence of particular genes or sequences of DNA. The enzyme reverse transcriptase can be used by viruses to insert viral mRNA into the host genome.

6 The level of cellular telomerase activity will affect? The number of cell divisions a cell is capable of undergoing

The telomere is a DNA sequence at the end of each chromosome which becomes progressively shorter with each division the cell undergoes. When it is reduced to a critical length the cell is not capable of dividing, the enzyme telomerase is able to lengthen the telomere thus preventing this occurring.

8 Phosphorylation of specific tyrosine residues of components of cell signalling pathways is often a key event in the activation of the pathway.

9 To the small sample of DNA are added two oligonucleotides with sequences that have affinity for both ends of the area of DNA that is being studed A thermostable DNA polymerase is also added. At 94°C DNA literally melts into two single strands and with cooling the oligonucleotides bind to the areas surrounding the particular area of DNA that is being analysed. These act as primers for the DNA polymerase and a new double helix of

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DNA is formed. The cycle is repeated doubling the amount of DNA each time.

10 Which molecule is produced in the nucleus, matures in the cytoplasm, binds to the ribosome and initiates protein synthesis? messenger RNAProtein synthesis consists of two phases. Transcription is where one strand of the DNA double helix is used as a template by RNA polymerase to synthesize messenger RNA from RNA nucleotides. The mRNA then migrates into the cytoplasm maturing - for example by the splicing of non-coding sequences. Translation occurs when the ribosome binds to mRNA at the start codon and transfer RNA brings amino acids into position along the mRNA template. The ribosome moves from codon to codon along the mRNA producing a polypeptide sequence.

11 Restriction enzymes cut DNA at sequences specific for each restriction enzyme, they are vital tools for molecular biology and molecular genetic research.

16 mRNA has codons which are bound by the anticodons on tRNA (Transcription RNA) during translation of protein synthesis. Exons are coding sequences in the mRNA and introns are areas of unknown function. Transposons are genetic sequences that have been transposed from one part of DNA to another.

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17 Cyclins are key regulators of the cell cycle, different cyclins are expressed at different stages of the cell cycle

19 Which one of the following conditions is DNA analysis the most useful diagnostic test? Huntington's chorea

Klinefelter's syndrome and Down's syndrome are diagnosed principally by chromosomal analysis/karyotype – XXY in the former and trisomy C21 or translocation in the latter. A trinucleotide CAG repeat expansion in the huntingtin gene is diagnostic of Huntington disease. The majority of cases of HOCM are autosomal dominantly inherited yet defective genes are located on a variety of chromosomes.DNA linkage analysis is used to assist in the diagnosis of adult PCKD but the presence of multiple copies continues to complicate the development of reagents for direct genetic testing, at least of the 70% of PKD1 that is replicated elsewhere.

21 Coding sequence is interrupted by non-coding sequences. Removal of the introns in RNA transcript modification is called RNA splicing. Splicing occurs in the nucleus before transport to the cytoplasm. Exons are expressed sequences: these sequences are those present in mature mRNA.

24 Thyrotropin (TSH) is glycosylated, cortisol is a steroid hormone and the others are peptide hormones/neuropeptides which as a group are rarely glycosylated.

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25 The technique described is 'in situ hybridization'.

Sothern blotting is a laboratory procedure in which DNA fragments that have been electorphoresed through a gel are transferred to a solid membrane, such as nitrocellulose. The DNA can then be hybridized with a labeled probe and exposed to X-ray film. somatic cell hybridization is a physical gene mapping technique in which somatic cells from two different species are fused and allowed to undergo cell division. Chromosomes from one species are selectively lost, resulting in clones with only one or a few chromosomes from one of the species. FISH is a molecular cytogenetic technique in which labelled probes are hybridized with chromosomes and then visualized under a fluorescence microscope. SSCP is a technique for detecting variation in DNA sequence by running single-stranded DNA fragments through a non-denaturing gel. Fragments with differing secondary structure (conformation) caused by sequence variation will migrate at different rates.

Genetics

2 Gaucher's and Marfan syndrome do not present with infertility. Noonan's is associated with short stature. Kleinfelter's is a sex chromosome disorder affecting 1:400 - 1:600 male births typically with 47 XXY, XXXYY or XXYY. Andropause is the term for the gradual decrease in serum

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testosterone concentration with age, but does not occur, usually, until after the age of 50.

7Over 250 X-linked recessive disorders have been described. The commonest include red/green colour blindness, Duchenne and Becker muscular dystrophies, Fragile X Syndrome, G6PD deficiency, haemophillias A&B, and Hunter's Syndrome. The abnormal gene is carried on he X chromosome, and in the carrier female, the normal allele on her other X chromosome protects her from the disease. Since the male does not have this protection, he manifests the disease. In X-linked inheritance therefore:

Males are all affected. Females only occasionally show mild sign of disease. Each son of a female carrier has a 1:2 chance of being

affected. Each daughter of a female carrier has a 1:2 risk of

being a carrier. Daughters of affected males will all be carriers, but

sons of affected males will not be affected since the Y chromosome is derived from father.

The family history may be negative, however, since new mutations are fairly common. Carrier females can be identified from time to time from mild clinical manifestations and from specific tests such as biochemical markers, e.g. CK in DMD

9 Type 1 collagen gene defects are found in osteogenesis imperfecta and type 3 in Ehler's Danlos syndrome. TypeII

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procollagen defect is found in hereditary spodyloarthropathy.

29 The suggestion here is that this man has coronary artery disease with an impending myocardial infarction. Infarction of the LAD would cause necrosis of the left ventricle. Thrombus may form on an area of dyskinetic ventricle. Therefore he is most at risk of embolus of thrombus from the LV.

42 Nephrogenic DI is usually X-linked. While cranial DS is autosomal dominant

55 Linkage analysis. Sothern blotting is a laboratory procedure in which DNA fragments that have been electorphoresed through a gel are transferred to a solid membrane, such as nitrocellulose. The DNA can then be hybridized with a labeled probe and exposed to X-ray film. somatic cell hybridization is a physical gene mapping technique in which somatic cells from two different species are fused and allowed to undergo cell division. Chromosomes from one species are selectively lost, resulting in clones with only one or a few chromosomes from one of the species. FISH is a molecular cytogenetic technique in which labelled probes are hybridized with chromosomes and then visualized under a fluorescence microscope. SSCP is a technique for detecting variation in

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DNA sequence by running single-stranded DNA fragments through a non-denaturing gel. Fragments with differing secondary structure (conformation) caused by sequence variation will migrate at different rates.

58 Parkinson's disease Mutations in either the parkin gene or UCHL1 lead to impaired protein degradation. The other genetic abnormalities concern other disease not Parkinson's. Impaired protein degradation is also seen in other neurodegenerative conditions.

60 Ehler-Danlos syndrome The mutations in the COL1A1 gene that cause the arthrochalasia type of Ehlers-Danlos syndrome lead to a pro-alpha1(I) chain that is missing a critical segment. The absence of this segment interferes with the assembly and structure of type I collagen molecules and their processing into collagen fibrils. Tissues that are rich in type I collagen, such as the skin, bones, and tendons, are affected by this change, which leads to the characteristic features of this type of Ehlers-Danlos syndrome.

69 A patient presents with acute promyelocytic leukaemia (AMLM3). What is the likely mechanism underlying leukaemogenesis? aberrant fusion of 2 genes In APL, one of the Retinoic Acid Receptor genes, RARA, is fused to

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PML in the great majority of patients as a result of the chromosomal translocation t (15; 17).

70 Pyruvate kinase deficiency is a rare congenital haemolytic anaemia inherited as an autosomal recessive. Generation of ATP within the red cell is impaired resulting in an abnormally high concentration of 2,3,DPG in the red cell, which inhibits the enzymes of the pentose phosphate pathway. Clinical manifestations vary from severe neonatal haemolysis, to a mild well compensated haemolysis first noted in adulthood.

73 Common variable immunodeficiency involves low levels of most or all of the immunoglobulin classes, a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and is associated with frequent bacterial infections. The cause of CVID is unknown but a family member may be affected in approximately 20%, but there is no clear pattern of inheritance.

79 Mutations in the COL4A5 gene cause approximately 80 percent of Alport syndrome cases. Several hundred different mutations have been identified, the majority of which cause a change in the sequence of amino acids (the building blocks of proteins) in a region of the alpha5(IV) collagen chain that is critical for combining with other type IV collagen chains. Other mutations severely decrease or prevent the production of the alpha5(IV) chains. As a

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result, there is a serious deficiency of the type IV collagen network in the basement membranes of the kidney, inner ear, and eye

84 CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) It may present with migraine

It is a diffuse disease of small arteries predominating in the brain. It starts during mid adulthood and is characterized by recurrent ischaemic events (transient or permanent), attacks of migraine with aura, severe mood disorders, sub cortical dementia and a wide spread leukoencephalopathy on MRI. CT brain is not diagnostic. Characteristic MRI changes include T2 weighted hyperintensity of the periventricular white matter. A family history is almost always present, as it is an autosomal dominant condition, located to chromosome 19. Infarcts are subcortical, and the thalami and basal ganglia are usually involved.

88 The following disorders can be accurately detected prenatally except?Short limbed dwarfism. Anomalies of the skeletal system may be extremely difficult to diagnose and may not manifest until after 20 weeks

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