Unlock-The Only MRCP Notes You Will Ever Need 4ed

Autosomal RECESSIVE conditions are ' METABOLIC ' - exceptions: inherited ataxias Autosomal DOMINANT conditions are ' STRUCTURAL ' - exception: hyperlipidemia type II, hypokalaemic period

Hani Abuelgasim M

MRCP, The Only Notes You Will Ever Need, 4th edition © January 2012

3rd edition © October 2010

2nd edition © January 2010

1st edition © September 2009

Copyright © 2012 SudaMediCa Publications

ISBN: pending issuance

All rights reserved No part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher

PREFACE

These notes intended to target those who are appearing in MRCP exam The idea behind it was collecting the most commonly tested topics and facts in the exam for my personal revision The data has been collected from many sources

This book was not prepared to be the primary studying source but it can help you after finishing your primary reading by arranging the thoughts in your mind and making every topic as short as possible by highlighting the most important points about it You may use it just before going through your favorite MCQs book or internet site

A friend of mine appeared in part one for couple of times, he reached to a conclusion and gave me a valuable advice that said ‘when preparing for MRCP, study MRCP! Don’t study medicine!’ this book helps you to study MRCP rather than studying medicine But at the end, you have to be a good physician otherwise MRCP will be a less valuable recognition, this is why I would advise to study medicine before you study MRCP and for sure before you say that you are a member of the Royal College you have to be upto the expectations

This edition contains the latest guidelines including 2011 guidelines and recommendations It is more organized than ever

In the 4th edition we have added topics that matters for part two, we have added many pictures, we claim that it’s just enough to get you through the second part comfortably

The study pattern we recommend is:

1 Study one chapter of your choice from this book

2 Solve the same chapter’s questions either on www.passmedicine.com, www.onexamination.com

or www.pastest.co.uk

3 Study another chapter and go online to solve its question, continue until you finish all the chapters in the book and questions on your website of choice

4 Revise the whole book

5 Start solving questions randomly from another website (other than the website you have chosen

to solve chapter by chapter)

6 Now you have probably solved at least 4000 BOF questions, you have seen all the question patterns in MRCP, now you need to stabilize the information you have gained through your journey

7 The most important step is to revise this book again just before the exam, this should be the

last thing you do just before going to the exam Solving question till the last moment is not recommended, you have probably gathered enough amount of information in your study, try to fix the information by reading this book

All candidates who followed this pattern have passed comfortably and no single one gave us a negative feedback in both parts

Hani Abuelgasim M., MD

Author

DEDICATION

To Mehiara, my late daughter who stole my heart and left

To my lovely Ahlam, who kept being patient and kind while I was studying

To my parents who always supported me

Hani Abuelgasim M

CONTRIBUTORS Dr.Hussam Albanna

MBBS, MRCP, Nephrology Diploma (Sheffield, UK)

To contribute to the next edition, please send your contributions to

admin@sudamedica.com

ALL BOXES WITH THIS COLOR

ARE FOR MRCP PART II WRITTEN EXAM

Contents

Basic Medical Science ……… ……… 9

Biostatistics & EBM ……… ……… 53

Miscellaneous ……… ……… 65

Neurology ……… ……… 83

Hematology ……… ……… 131

Endocrinology ……… ……… 167

GIT ……… ……… 203

Nephrology ……… ……… 245

Locomotor System ……… ……… 269

Rhematology ……… ……… 287

Cardiovascular System ……… ……… 309

Respiratory Sytem ……… ……… 357

Infectious & STD Diseases ……… ……… 389

Gyne & Obs ……… ……… 425

Dermatology ……… ……… 437

Psychiatry ……… ……… 459

Ophthalmology ……… ……… 475

Pharmacology 491 • General Pharma ……… ……… 492

• Nervous Pharma ……… ……… 509

• Cardiac Pharma ……… ……… 515

• Other Medications ……… ……… 523

• Antibiotics ……… ……… 535

Commonly tested facts in MRCP ……… ……… 541

BASIC SCIENCES

HLAs: 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 Questions are often based around which diseases have strong HLA associations The most important associations are listed below

HLA and autoimmune diseases

HLA-B27

Ankylosing spondylitis Postgonococcal arthritis Acute anterior uveitis Reiter's syndrome (reactive arthritis)

Goodpasture's

HLA-DR3

Autoimmune hepatitis Primary biliary cirrhosis Diabetes mellitus type 1 Dermatitis herpetiformis Coeliac disease (95% associated with HLA-DQ2) Primary Sjögren syndrome

HLA-DR4 Rheumatoid arthritis

Diabetes mellitus type 1 (> DR3) HLA-DR3 + DR4 combined Diabetes mellitus type 1

HLA-B47 21-hydroxylase deficiency

HLA-B5 Behcet's disease HLA B51 is a split of B5

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

Clusters of Differentiation (CD): The table below lists the major clusters of differentiation (CD) molecules

CD1 HLA molecule that presents lipid molecules

CD2 Found on thymocytes, T cells, and some natural killer cells that acts as a ligand for CD58 and CD59 and is involved in signal transduction and cell adhesion

CD3 The signalling component of the T cell receptor (TCR) complex

CD4 Co-receptor for HLA class II; also a receptor used by HIV to enter T cells

CD8 Co-receptor for HLA class I; also found on a subset of myeloid dendritic cells

Type II - Cell bound

• IgG or IgM binds to antigen on cell surface

• Autoimmune hemolytic anemia, ITP, Goodpasture's

Type III - Immune complex

• Free antigen and antibody (IgG, IgA) combine

• Serum sickness, SLE, 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

• Graves', myasthenia Gravis

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 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 extensive eczema or if the patient is taking antihistamines

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

Immunoglobulins

IgG 75% Monomer Enhance phaGocytosis of bacteria and viruses

IgA 15% Mono+Dimer Found in secretions, provide localized protection on mucous membranes IgM 10% Pentamer first to be secreted, anti-A, B blood antibodies → Blood Transfusion

IgD 1% Monomer Involved in activation of B cells

IgE 0.1% Monomer Involved in allergic reactions

Each day an average adult produces approximately 3gm of antibodies, about two-thirds of this IgA

1 IgG

• IgG makes up approximately 75% of the serum antibodies

• IgG has a half-life of 7-23 days depending on the subclass

• IgG is a monomer and has 2 epitope-binding sites

• The Fc portion of IgG can activate the classical complement pathway

• The Fc portion of IgG can bind to macrophage and neutrophils for enhanced phaGocytosis

• The Fc portion of IgG can bind to NK cells for antibody-dependent cytotoxicity (ADCC)

• The Fc portion of IgG enables it to cross the placenta (IgG is the only class of antibody that

can cross the placenta and enter the fetal circulation)

2 IgA

• IgA makes up approximately 15% of the serum antibodies, it has a half-life of ≈ 5 days

• IgA is found mainly in body secretions (saliva, mucous, tears, colostrum and milk) as secretory IgA (sIgA) where it protects internal body surfaces exposed to the environment

by blocking the attachment of bacteria and viruses to mucous membranes

• Secretory IgA is the most immunoglobulin produced

• IgA is made primarily in the mucosal-associated lymphoid tissues (MALT)

• IgA appears as a dimer of 2 "Y"-shaped molecules and has 4 epitope-binding sites and a secretory component to protect it from digestive enzymes in the secretions

• The Fc portion of secretory IgA binds to components of mucous and contributes to the

ability of mucous to trap microbes

• IgA can activate the alternative complement pathway (IgA ≈ Alternate)

3 IgM

• IgM makes up approximately 10% of the serum antibodies and is the first antibody produced during an immune response

• IgM has a half-life of about 5 days

• IgM is a pentamer and has 10 epitope-binding sites

• The Fc portions of IgM are able to activate the classical complement pathway (most efficient)

• Monomeric forms of IgM are found on the surface of B-lymphocytes as B-cell receptors or sIg

4 IgD

• IgD makes up approximately 1% of the serum antibodies

• IgD is a monomer and has 2 epitope-binding sites

• IgD is found on the surface of B-lymphocytes (along with monomeric IgM) as a B-cell receptor or sIg where it may control of B-lymphocyte activation and suppression

• IgD may play a role in eliminating B-lymphocytes generating self-reactive autoantibodies

5 IgE

• IgE makes up about 0.002% of the serum antibodies with a half-life of 2 days

• Most IgE is tightly bound to basophils and mast cells via its Fc region

• IgE is a monomer and has 2 epitope-binding sites

• IgE is made in response to parasitic worms (helminths) and arthropods It is also often made in response to allergens

• IgE may protect external mucosal surfaces by promoting inflammation, enabling IgG,

complement proteins, and leucocytes to enter the tissues

• The Fc portion of IgE can bind to mast cells and basophils where it mediates many allergic reactions Cross linking of cell-bound IgE by antigen triggers the release of vasodilators for an

• Bruton's congenital agammaglobulinemia

• Common variable immunodeficiency

T-cell disorders = DiGeorge

• DiGeorge syndrome is an example of a microdeletion syndrome Patients are consequently at ↑ risk of viral and fungal infections

Combined B- and T-cell disorders

• Severe combined immunodeficiency

• Ataxic telangiectasia (Autosomal recessive - 10% risk of developing malignancy, lymphoma or leukaemia, but also non-lymphoid tumours - recurrent chest infections)

• Wiskott-Aldrich syndrome inherited in an X-linked recessive fashion and is thought to be

caused by mutation in the WASP gene Features include recurrent bacterial infections (e.g chest), eczema and thrombocytopenia with low IgG

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)

• Some correlation between cANCA levels and 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 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%

Other causes of positive ANCA (usually pANCA)

• Inflammatory bowel disease (UC > Crohn's)

• Connective tissue disorders: RA, SLE, Sjogren's

• Autoimmune hepatitis

Whilst C3 deficiency is associated with recurrent bacterial infections, C5 deficiency is more

characteristically associated with disseminated meningococcal infection

Complement 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, cell lysis and opsonisation

C1 inhibitor (C1-INH) protein deficiency

• Causes hereditary angiedema

• C1-INH is a multifunctional serine protease inhibitor

• Probable mechanism is uncontrolled release of bradykinin resulting in edema of tissues

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

• Predisposes to immune complex disease

• E.g SLE, Henoch-Schonlein Purpura

C3 deficiency

• Causes recurrent bacterial infections

C5 deficiency

• Predisposes to Leiner disease

• Recurrent diarrhea, wasting and seborrhoeic dermatitis

• Disseminated meningococcal infection

C5-9 deficiency

• Encodes the membrane attack complex (MAC)

• Particularly prone to Neisseria meningitidis infection

Electrolytes and Its Imbalance 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/L

Normal anion gap (hyperchloraemic metabolic acidosis)

• Gastrointestinal bicarbonate loss: diarrhea, ureterosigmoidostomy, fistula

• Renal tubular acidosis

• Drugs: e.g Acetazolamide

• Ammonium chloride injection

• Addison's disease

Renal tubular acidosis (RTA) causes a normal anion gap Raised anion gap

• Lactate: shock, hypoxia

• Ketones: DKA, 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

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 tract

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

• In Hypokalemia, K+ shift from cells → ECF Alkalosis is caused by shift of H+ into cells to maintain neutrality

Hyponatremia may be caused by water excess or sodium depletion Causes of

arm Urinary sodium and osmolarity levels aid making a diagnosis It is important to note that every 100mg/dL increase of blood glucose will lower the Na as much as 1.6 meq

Hypertonic Isotonic Hypotonic

Urinary sodium > 20 mmol/L Urinary sodium < 20 mmol/L

Sodium depletion, renal loss (patient often

hypovolaemic)

• Diuretics

• Diuretic stage of renal failure

• Addison's

Patient often euvolaemic

• SIADH (urine osmolality > 500 mmol/kg)

• Hypothyroidism

Sodium depletion, extra-renal loss

• Diarrhea, vomiting, sweating

• Burns, adenoma of rectum Water excess (patient often hypervolaemic and edematous)

• Secondary hyperaldosteronism: CCF, cirrhosis

• ↓ GFR: renal failure with volume overload

• IV dextrose, psychogenic polydipsia

↓ Volemic

↑ Volemic ↔ Volemic

Causes of Hyperkalemia:

• Acute renal failure

• Drugs*: potassium sparing diuretics, ACE

inhibitors, Cyclosporin

• Metabolic acidosis

• Addison's

• Rhabdomyolysis

• Massive blood transfusion

*β-blockers interfere with potassium transport

into cells and can potentially cause Hyperkalemia

in renal failure patients - remember β-agonists,

e.g salbutamol, are sometimes used as

emergency treatment for hyperkalemia

Untreated hyperkalaemia may cause

life-threatening arrhythmias Precipitating factors

should be addressed (e.g acute renal failure) and

aggravating drugs stopped (e.g ACE inhibitors)

Management may be categorised by the aims of

treatment

Stabilisation of the cardiac membrane

• intravenous calcium gluconate

Short-term shift in potassium from extracellular

to intracellular fluid compartment

• combined insulin/dextrose infusion

• nebulised salbutamol

Removal of potassium from the body

• calcium resonium (orally or enema)

• loop diuretics

• dialysis

• Conn's syndrome (primary hyperaldosteronism)

Hypokalemia with acidosis:

• Diarrhea

• Renal tubular acidosis

• Acetazolamide

• Partially treated DKA

ECG features of hypokalemia:

• ECG features similar to those of Hypokalemia

• Exacerbates digoxin toxicity

• Red blood cell hemolysis

• White blood cell and platelet dysfunction

• Muscle weakness and rhabdomyolysis

• Central nervous system dysfunction

Calcium Metabolism

Vitamin D ↑ plasma calcium and plasma phosphate levels by promoting renal tubular absorption

and gut absorption of calcium and increasing renal phosphate reabsorption

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 (↑ plasma Ca from bones and kidneys and activation of Vit-D)

• ↑ plasma calcium, ↓ plasma phosphate

• ↑ renal tubular reabsorption of calcium

• ↑ osteoclastic activity

• ↑ renal conversion of 25-hydroxy vitamin D to 1,25 dihydroxy vitamin D

• ↓ renal phosphate reabsorption

Actions of vitamin D (↑ plasma Ca from bones and kidneys and GIT)

• ↑ plasma calcium and ↑ plasma phosphate

• ↑ renal tubular reabsorption and gut absorption of calcium

• ↑ osteoclastic activity

• ↑ renal phosphate reabsorption

FYI Corrected Ca + = measures Ca + (mmol/l) + [40 - S.Albumin (g/dl) ] x 0.027

Hypocalcemia

The clinical history combined with parathyroid hormone levels will reveal the cause of hypocalcemia in the majority of cases

Causes

• Vitamin D deficiency (osteomalacia)

• Chronic renal failure

• Hypoparathyroidism (e.g Post thyroid/parathyroid surgery)

• Pseudohypoparathyroidism (target cells insensitive to PTH)

• Rhabdomyolysis (initial stages)

• Magnesium deficiency (due to end organ PTH resistance)

Acute pancreatitis may also cause hypocalcemia Contamination of blood samples with EDTA may also give falsely low calcium levels

Hypocalcemia causes Prolonged QT in ECG Osteomalacia causes hypocalcemia associated with a low serum phosphate

Cisplatin, often used in the management of non-small cell lung cancer, is a well known cause of magnesium deficiency Without first correcting magnesium levels it is difficult to reverse hypocalcemia

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

Features

• Tetany: muscle twitching and spasm

• Perioral paraesthesia

• If chronic: depression, cataracts

• ECG: prolonged QT interval

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

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 hypocalcemia and around 1% of normocalcaemic people

Chvostek's sign

• Tapping over parotid causes facial muscles to twitch

• Seen in around 70% of patients with hypocalcemia and around 10% of normocalcaemic people

Management

• Acute management of severe hypocalcemia 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

• ECG monitoring is recommended

• Further management depends on the underlying cause

• Paget's disease of the bone**

Parathyroid hormone levels are useful, as malignancy and primary hyperparathyroidism are the two most common causes of hypercalcemia A parathyroid hormone that is normal or raised

suggests primary hyperparathyroidism

Hypercalemia causes short QT in ECG

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

**usually normal in this condition but hypercalcemia may occur with prolonged immobilization

Management

The initial management of hypercalcemia 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 days

Other options include:

• Calcitonin - quicker effect than bisphosphonates

• Steroids in sarcoidosis

There is a limited role for the use of furosemide in hypercalcemia It may be useful in patients who cannot tolerate aggressive fluid rehydration

Hyperuricemia ↑ levels of uric acid may be seen secondary to either ↑ cell turnover or ↓ renal excretion of uric acid Hyperuricemia may be found in asymptomatic patients who have not experienced attacks of gout

Hyperuricemia may be associated with both hyperlipidemia and hypertension It may also be

seen in conjunction with the metabolic syndrome

Body & Diseases Markers

Acute Phase Proteins:

The following proteins ↑:

• retinol binding protein

• cortisol binding protein

Rheumatoid factor is an IgM antibody against IgG

Rheumatoid Factor (RF) is a circulatinjg antibody (usually IgM) which reacts with antigenic sites on the Fc portion of the patients own IgG

RF can be detected by:

• Rose-Waaler test: sheep red cell agglutination

• Latex agglutination test (less specific)

RF is positive in 70-80% of patients with rheumatoid arthritis; high titre levels are associated with severe progressive disease (prognosis but NOT a marker of disease activity)

Other conditions associated with a positive RF include:

• Sjogren's syndrome (around 100%)

• Felty's syndrome (around 100%)

Nitric 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 radicals

Effects

• Acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing

Ca++ 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

• In sepsis ↑ 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

Atrial Natriuretic Peptide (ANP) is a powerful vasodilator, and a protein (polypeptide)

hormone secreted by heart muscle cells It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue) ANP acts to ↓ the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure

Basics

• Secreted mainly from myocytes of right atrium and ventricle in response to ↑ 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

Nitric Oxide: vasodilation+inhibits platelet aggregation

BNP - actions:

• Vasodilator

• Diuretic and natriuretic

• Suppresses both sympathetic tone and the renin-angiotensin-aldosterone system

B-type Natriuretic Peptide (BNP) hormone produced mainly by the left ventricular

myocardium in response to strain

Whilst heart failure is the most obvious cause of raised BNP levels any cause of left ventricular dysfunction such as myocardial ischemia or valvular disease may raise levels Raised levels may also

be seen due to ↓ excretion in patients with chronic kidney disease Factors which ↓ BNP levels include: treatment with ACE inhibitors, angiotensin-2 receptor blockers and diuretics

Clinical uses of BNP

Diagnosing patients with acute dyspnea

• 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

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 (endothelin antagonists are now used), cardiac failure, hepatorenal syndrome and Raynaud's

• Primary pulmonary hypertension

Tumour Necrosis Factor (TNF) is a pro-inflammatory cytokine with multiple roles in the immune system

mainly in a paracrine fashion:

• Activates macrophages and neutrophils

• Acts as costimulator for T cell activation

• Key mediator of bodies response to gram NEGATIVE septicemia

• Similar properties to IL-1

• Anti-tumour effect (e.g Phospholipase activation)

TNF-α binds to p55 and p75 receptors, these receptors can induce apoptosis It also cause activation of NFkB

Endothelial effects include ↑ expression of selectins and ↑ production of platelet activating factor, IL-1 and prostaglandins TNF 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, ↑ acute phase proteins and disordered metabolism leading to cachexia TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g infliximab, etanercept) are now licensed for treatment of severe rheumatoid

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

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- α

and IFN- β bind to type-1 receptors, whilst IFN-gamma binds only to type-2 receptors

IFN-α (a L pha)

• Produced by Leucocytes

• Antiviral action

• Useful in hepatitis B & C, kaposi's sarcoma, metastatic renal cell cancer, hairy cell leukemia

• Adverse effects include fLu-Like symptoms and depression

• Produced by T lymphocytes & NK cells

• weaker antiviral action (inhibit viral duplication), more of a role in immunomodulation particularly macrophage activation

• May be useful in chronic granulomatous disease and osteopetrosis

Leukotrienes are fatty molecules of the immune system that contribute to inflammation in asthma and bronchitis Leukotriene antagonists are used to treat asthma and bronchitis

Function

• Mediators of inflammation and allergic reactions

• Cause bronchoconstriction, mucous production

• ↑ vascular permeability, attract leukocytes

• Leukotriene D4 has been identified as the SRS-A (slow reacting substance of anaphylaxis)

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

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 While TNF

is secreted mainly by macrophages, it is a key mediator of body response to gram NEGATIVE septicemia and it is a costimulator of T cell.

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 ↑ 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

T-Helper Cells: There are two major subsets of T-Helper cells:

Th1

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

• Secrete IFN-gamma, IL-2, IL-3

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

Cardiac and Protien Markers: 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

The components of thin filaments are troponin, tropomyosin and actin Thick filaments are

primarily composed of myosin 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 rise Peak 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 hours 12-24 hours 7-10 days

AST 12-24 hours 36-48 hours 3-4 days

LDH 24-48 hours 72 hours 8-10 days

Alkaline Phosphatase (ALP)

Causes of raised alkaline phosphatase (ALP)

• Liver: cholestasis, hepatitis, fatty liver, neoplasia

• Physiological: pregnancy, growing children, healing fractures

The table below splits the causes according to the calcium level

Raised ALP and raised calcium Raised ALP and low calcium

Causes of a high ESR

Causes of a low ESR

• Steroids, Cushing's syndrome

• Pregnancy, oral contraceptive pill

Genetic & Heridetary Disorders

Definitions:

• Gene: a region of DNA that encodes protein

• Genome: complete set of gene of an organism and the intervening DNA sequence

• Locus: site of gene on a chromosome

• Chromosome: Self-replicating genetic structure of cells containing the cellular DNA that bears

in its nucleotide sequence the linear array of genes Chromosomes are normally found in pairs; human beings typically have 23 pairs of chromosomes (22 autosome + 1 sex chromosome)

• Alleles: Alternative form of a gene found at the same locus on a chromosome; a single allele for each locus is inherited separately from each parent

• Haploid: a single set of chromosomes (half the full set of genetic material), present in the gamete (egg or sperm) = (23)

• Codon: sequence of amino acid

• Karyotype: number and appearance of chromosomes in the nucleus, in human there are 44

autosome + 2 sex chromosomes

• Autosome: any chromosome other than sex chromosome (22 pairs)

Autosomal RECESSIVE conditions are ' METABOLIC ' - exceptions: inherited ataxias Autosomal DOMINANT conditions are ' STRUCTURAL ' - exception: hyperlipidemia type II,

hypokalaemic periodic paralysis

Autosomal Recessive Conditions

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)

In autosomal recessive inheritance

• Only homozygotes are affected

• ♂s and ♀s are equally likely to be affected

• Does not manifest in every generation - may 'skip a generation'

If two heterozygote parents (Carrier Parents)

• 25% chance of having an affected (homozygote) child

• 50% chance of having a carrier (heterozygote) child

• 25% chance of having an unaffected (i.e Genotypical)

Autosomal recessive disorders are often metabolic in nature and are generally more life-threatening compared to autosomal dominant condition

Both parents are cariers → each offspring has risk of 25% being affected and 50% being carier

Results from mutation of 2 copies (alleles) of the autosomal gene The following conditions are autosomal recessive: (most of Cs andGs are recessive)

• Gilbert's syndrome (this is still a matter of debate and many textbooks will list Gilbert's as AD)

• Glycogen storage disease

• Gunther disease (congenital erythropoietic porphyria CEP)

• Hemochromatosis

• Homocystinuria

• Limb-girdle muscular dystrophy

• Lipid storage disease: Tay-Sach's, Gaucher, Niemann-Pick

• Maple Syrup Urine Diease

• Mucopolysaccharidoses like Hurler's (all of them except Hunter’s)

Autosomal Dominant Conditions:

AD conditions: all offsprings of an affected person have 50% chance of inherting the mutation

Results from mutation of 1 copy (allele) of the autosomal gene The following conditions are autosomal dominant: (most of Hs, MNs and Vs are dominant)

• Achondroplasia

• Acute intermittent porphyria (all hepatic porphyrias except congenital erythropoietic porphyria)

• Adult polycystic disease

• Antithrombin III deficiency

• Ehlers-Danlos syndrome

• Familial adenomatous polyposis (including Gardner syndrome)

• Familial hypercholesterolemia

• Hereditary hemorrhagic telangiectasia

• Hereditary motor and sensory neuropathy (HMSN) including Charcot–Marie–Tooth

• Von Hippel-Lindau syndrome

• Von 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

In autosomal dominant diseases:

• Both homozygotes and heterozygotes manifest disease (THERE IS NO CARRIER STATE)

• Both ♂s and ♀s 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

Hemophilia is an X-linked recessive dis

Turner's syndrome only have one X chromosome however, they may develop X

examinations is patients with Turner's syndrome, w

chromosome X-linked recessive disorders are transmitted by heterozygote

transmission is not seen Affected ♂

X-linked recessive

Each ♂ child of a heterozygous ♀ carrier has a 50% chance of being affected whilst each

heterozygous ♀ carrier has a 50% chance of being a carrier

The possibility of an affected father having children with a he

speaking extremely rare However, in certain Afro

relatively common and homozygous

Sons of carier ♀ have 50% chance of being affected while daughters have 50% chance of being cariers.

Daughters of affected Father is affected and mother is carrier then all kids have 50% chance of being affected.

The following conditions are inherited in

• Androgen insensitivity syndrome

• Becker muscular dystrophy

B+T primary immunodeficiency and

is thought to be caused by mutation in

the WASP gene Features include

recurrent bacterial infection

chest), eczema and thrombocytopenia

with low IgG

The following diseases have varying patterns of inheritance, with the majority being in an X

recessive fashion:

• Chronic granulomatous disease (in > 70%)

linked recessive disorder and would hence be expected only to occur in Turner's syndrome only have one X chromosome however, they may develop X-linked recessive conditions

inheritance: only ♂s are affected An exception to this seen in patients with Turner's syndrome, who are affected due to only having one X linked recessive disorders are transmitted by heterozygote ♀s (carriers) and

♂s can only have unaffected sons and carrier daughters

recessive conditions - no ♂-to-♂ transmission

carrier has a 50% chance of being affected whilst each carrier has a 50% chance of being a carrier

The possibility of an affected father having children with a heterozygous ♀

speaking extremely rare However, in certain Afro-Caribbean communities G6PD deficiency is relatively common and homozygous ♀s with clinical manifestations of the enzyme defect are seen

of being affected while daughters have 50% chance of being cariers.

Daughters of affected ♂ are carriers (100%)

Father is affected and mother is carrier then all kids have 50% chance of being affected.

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

Androgen insensitivity syndrome

Duchenne muscular dystrophy

Linked Trait) iabetes insipidus

Severe combined immunodeficiency

Aldrich syndrome combined B+T primary immunodeficiency and

is thought to be caused by mutation in

the WASP gene Features include

recurrent bacterial infections (e.g

chest), eczema and thrombocytopenia

The following diseases have varying patterns of inheritance, with the majority being in an X

Chronic granulomatous disease (in > 70%) – (Primary Immunodeficiency, Neut

order and would hence be expected only to occur in ♂s As patients with

linked recessive conditions

An exception to this seen in

ho are affected due to only having one X

s (carriers) and ♂-to-♂

s can only have unaffected sons and carrier daughters

carrier has a 50% chance of being affected whilst each ♀ child of a

carrier is generally Caribbean communities G6PD deficiency is

s with clinical manifestations of the enzyme defect are seen

of being affected while daughters have 50% chance of being cariers

Father is affected and mother is carrier then all kids have 50% chance of being affected

The following diseases have varying patterns of inheritance, with the majority being in an X-linked

, Neutrophil disorder)

X-linked Dominant: ♀s have two X chromosomes, while

chromosome If a child has inherited the mutation from the X chromosome of one of their parents they will have the condition A woman with an X

affected daughter or son with each pregnancy The sons of a man with an X

will not be affected (since they inherit their only X chromosome from their mother), but his daughters will all inherit the condition

XLD:

• Vit D resistant Rickets

• Alport syndrome (85% XLD)

• Rett syndrome

(Anticipation) in trinucleotide repeat disorders =

The 'classic' definition of anticipation is earlier onset in successive generations However, in most

cases, an ↑

Trinucleotide Repeat Disorders

repeats (expansions) of a repetitive sequence of three nucleotides These expansions are unstable and may enlarge which may lead to an earlier age of onset in successive generations

known as anticipation* In most cases, an

Examples - note dominance of neurological disorders

• Dentatorubral pallidoluysian atrophy

*Friedreich's ataxia is unusual in not demonstrating anticipation

s have two X chromosomes, while ♂s have one X and one Y chromosome If a child has inherited the mutation from the X chromosome of one of their parents they will have the condition A woman with an X-linked dominant disorder has a 50% chance of having an affected daughter or son with each pregnancy The sons of a man with an X-linked dominant disorder will not be affected (since they inherit their only X chromosome from their mother), but his daughters

Alport syndrome (85% XLD)

(Anticipation) in trinucleotide repeat disorders = earlier onset in successive generations

The 'classic' definition of anticipation is earlier onset in successive generations However, in most

in the severity of symptoms is also noted

isorders are genetic conditions caused by an abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides These expansions are unstable and

ay lead to an earlier age of onset in successive generations known as anticipation* In most cases, an ↑ in the severity of symptoms is also noted

note dominance of neurological disorders

muscular atrophy pallidoluysian atrophy

*Friedreich's ataxia is unusual in not demonstrating anticipation

s have one X and one Y chromosome If a child has inherited the mutation from the X chromosome of one of their parents they

linked dominant disorder has a 50% chance of having an

linked dominant disorder will not be affected (since they inherit their only X chromosome from their mother), but his daughters

in successive generations

The 'classic' definition of anticipation is earlier onset in successive generations However, in most

are genetic conditions caused by an abnormal number of repeats (expansions) of a repetitive sequence of three nucleotides These expansions are unstable and

ay lead to an earlier age of onset in successive generations - a phenomenon

in the severity of symptoms is also noted

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 RNA

Mitochondrial inheritance have the following characteristics:

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

• All children of affected ♂s will not inherit the disease

• All children of affected ♀s will inherit it

• Generally encode rare neurological diseases

• Poor genotype:phenotype correlation

• Heteroplasmy: within a tissue or cell there can be different mitochondrial populations

Histology

• Muscle biopsy classically shows 'red, ragged fibres' due to ↑ 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 fibres

• Pearson syndrome: characterized by sideroblastic anemia and exocrine pancreas dysfunction It

is usually fatal in infancy The few patients who survive into adulthood often develop symptoms

of Kearns-Sayre syndrome

• Kearns-Sayre syndrome: onset in patients < 20 years old, external ophthalmoplegia, retinitis pigmentosa Ptosis may be seen

• Sensorineural hearing loss

• Neuropathy, ataxia, and retinitis pigmentosa (NARP)

Tumour Suppressor Genes

Basics

• Genes which normally control the cell cycle

• Exhibit a recessive effect - both copies must be mutated before cancer occurs

myc is an oncogene which encodes a transcription factor

P53 Gene is a tumour suppressor gene located on chromosome 17p It is the most commonly mutated gene in breast, colon and lung cancer

P53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase until DNA has been checked and repaired It may also be a key regulator of apoptosis

Li-Fraumeni Syndrome is a rare autosomal dominant disorder characterized by the early onset of a variety of cancers such as sarcomas and breast cancer It is caused by mutation in the p53 gene

Down Syndrome: trisomy 21 or G, is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome The condition is characterized by a combination of major and minor differences in structure Often Down syndrome is associated with some impairment of cognitive ability and physical growth, and a particular set of facial characteristics Down syndrome in a fetus can be identified with amniocentesis during pregnancy or in a baby at birth

• Multiple cardiac problems may be present

• Endocardial cushion defect (40%, also known as atrioventricular septal canal defects)

• Ventricular septal defect (30%)

• Secundum atrial septal defect (10%)

• Repeated respiratory infections (+hearing impairment from glue ear)

• Acute lymphoblastic leukemia

Cytogenetics

Non-dysjunction 94% 1 in 100 if mother < 35 years

There is ↑ incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn's disease

• Short fourth metacarpal

• Multiple pigmented naevi

• Lymphedema in neonates (especially feet)

Klinefelter Syndrome (Hypogonadotropic hypogonadism) is associated with karyotype 47, XXY

Features

• Often taller than average

• Lack of secondary sexual characteristics

• Small, firm testes (hypogonadism)

• Infertile

• Gynaecomastia - ↑ incidence of breast cancer

• Elevated gonadotrophin levels

Diagnosis is by chromosomal analysis

↓ Karyotyping

Klinefelter's - LH & FSH raised Kallman's - LH & FSH low-normal

If the LH and FSH levels are inappropriately low-normal with a low testosterone concentration, that points towards a diagnosis of hypogonadotrophic hypogonadism

Kallman 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

Features

• 'Delayed puberty'

• Hypogonadism, cryptorchidism (including undescended tests)

• 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 patients

Marfan Syndrome is an autosomal dominant connective tissue disorder It is caused by a defect

in the fibrillin-1 gene on chromosome 15

Features

• Tall stature with arm span > height ratio > 1.05

• High-arched palate

• Arachnodactyly (spider fingers; fingers are abnormally long, in some cases all or few fingers

can be bent backwards of 180 degrees)

• Pectus excavatum

• 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

• Eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera

Noonan Syndrome: Often thought of as the '♂ Turner's', Noonan's syndrome is an autosomal dominant condition associated with a normal karyotype It is thought to be caused by a defect in a gene

on chromosome 12 As well as features similar to Turner's syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum), a number of characteristic clinical signs may also be seen:

• Cardiac: pulmonary valve stenosis

• Ptosis

• Triangular-shaped face

• Low-set ears

• Coagulation problems: factor XI deficiency

Fragile X is a trinucleotide repeat disorder, complex X-linked inheritance

Features in ♂s

• Learning difficulties

• Large low set ears, Long thin face, High arched palate

• Macroorchidism (Large testes)

• Hypotonia

• Autism is more common

• Mitral valve prolapse

Features in ♀s (who have one fragile chromosome and one normal X chromosome) range from normal

to mild

Diagnosis

• 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

Patau Syndrome, also known as trisomy 13 and trisomy D, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a non-disjunction of chromosomes during meiosis Some are caused by Robertsonian translocations The extra chromosome

13 disrupts the normal course of development, causing the characteristic features of Patau syndrome Like all non-disjunction conditions (Down syndrome, Edwards syndrome, etc.), the risk of this syndrome in the offspring ↑ with maternal age at pregnancy, with about 31 years being the average Patau syndrome affects approximately 1 in 25,000 live births

♂ infant with Patau, demonstrating alobar

holoprosencephaly with cyclopia A) Facial

features included sloping forehead with a

proboscis superior to a single central palpebral

fissure B) Close-up of the fused eyelids and

proboscis showing a single nostril C) Polydactyly

showing six digits D) Posterior view of the brain

showing indistinct gyri, fusion of the hemispheres,

and occipital encephalocele.E) Transposition of

the aorta (A), and hypoplastic pulmonary trunk

(P) F) Trisomy 13 [47, XY, +13] (karyotype by

Giemsa-banding)

Of those embryos that do survive to gestation and subsequent birth, common abnormalites include:

• Mental & motor challenge

• Polydactyly (extra digits)

• Cleft palate

• Meningomyelocele (a spinal defect)

• Omphalocele (abdominal defect)

• Abnormal genitalia

• Abnormal palm pattern