Panorama

MRCPass Notes

د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Stimulation of α receptors leads to:

• Vasoconstriction
• decrease in gut motility
• uterus contraction
• decrease in pancreatic exocrine secretion

Cholera toxin: activates G protein, which activates adenylate cyclase. Elevated cAMP

results in unrestricted chloride secretion from villous crypts.
Iron is absorbed in upper small intestine. Iron absorption is increased with ascorbic acid.
The sulfate form contains more elemental iron per dosage unit than gluconate.


achondroplasia
antithrombin III deficiency
C1 esterase inhibitor deficiency
Ehlers-Danlos syndrome
Familial hypercholesterolaemia
Gilbert's disease
hereditary haemorrhagic telangiectasia
hereditary elliptocysis,
hereditary spherocytosis
Huntington's disease
idiopathic hypoparathyroidism
intestinal polyposis
marble bone disease
Marfan's syndrome
neurofibromatosis
Peutz Jegher’s syndrome
polycystic kidney disease (adult)
protein C deficiency
osteogenesis imperfecta
Treacher Collins syndrome
tuberous sclerosis
Von Willebrand's disease
The list of autosomal dominant disorders are:


oculocutaneous albinism
alkaptonuria
Bartter's syndrome
cystic fibrosis
endemic goitrous cretinism
The list of autosomal recessive conditions are:

galactosaemia

Gaucher's disease
glycogen storage disease
homocystinuria
phenylkeonuriat
Sickle cell disease
Wilson's disease
xeroderma pigmentosa

The features of X linked inheritance are: Males are all affected Females only

occasionally show mild signs of disease Each son of a carrier a 1:2 chance of being
affected Each daughter of a carrier has a 1:2 risk of being a carrier Daughters of affected
males will all be carriers Sons of affected males will be affected


X linked dominant (rare)
X linked Hypophosphataemic rickets
von Willebrand's disease

X linked recessive

Becker’s muscular dystrophy
Duchenne’s muscular dystrophy
Fabry’s disease
Hunter’s syndrome
Glucose 6 Phosphate denydrogenase deficiency
red-green colour blindness
haemophilia A and B
Testicular feminisation syndrome
Wiskott Aldrich syndrome

Mitochondrial DNA is inherited from the mother. Mitochondrial DNA codes for

proteins in the oxidative phosphorylation / electron transport chain. Leber's optic atrophy
is a form of mitochondrial disease.
DNA
Bases are paired with hydrogen bonds but the ribose-phosphate complexes are paired
with covalent bonds. Histones allow DNA to twirl round it to form stable nucleoprotein
Complexes.Coding sequences (exons) are interspersed with introns.


In RNA, uracil represents the thymine residues in DNA.
mRNA translation into proteins occur in the cytoplasm. RNA polymerase II transcribes
mRNA
Transfer RNA (tRNA) is a small RNA chain (74-93 nucleotides) that transfers a specific
amino acid to a growing polypeptide chain at the ribosomal site of protein

synthesis during translation. It has sites for amino-acid attachment and codon (a

particular sequence of 3 bases) recognition.
The codon recognition is different for each tRNA and is determined by the anticodon
region, which contains the complementary bases to the ones encountered on the mRNA.

Each tRNA molecule binds only one type of amino acid, but because the genetic code is

degenerate, more than one codon exists for each amino acid.
Both coding (exons) and non coding regions (introns) exist on RNA. Reverse
transcription involves transcription of RNA to DNA (used by retroviruses).

Only about 5% of DNA codes for proteins.

Multiple codons (triplets of nucleotides) code for the same amino acid.
Antisense oligonucleotides are sequences of DNA which are complementary to RNA.
They bind to RNA and stops it from processsing.


PCR
In PCR, two primers are required for a start and stop sequence to amplify the DNA
strand.
DNA polymerase needs to be stable at high temperatures and hence thermostable enzyme
from T. aquaticus is used. The mixture is heated to below 100°C.

DNA polymerase causes synthesis of DNA between two primers

Reverse transcriptase PCR is used to amplify RNA,
whilst conventional PCR is used to
amplify DNA

Restriction enzymes cut DNA at nucleotide sequences specific to each restriction

enzyme. HindIII and EcoRI are examples of restriction enzymes
DNA ligase and polymerase are involved in joining and linking DNA together.
Plasmids are circular molecules of bacterial DNA separate from the bacterial
chromosome. They are usually small, consisting of a few thousand base pairs. They carry
one of a few genes and have a single origin of replication.

A Barr body is an inactivated X chromosome.

The human karyotype consists of 22 pairs of autosomes and 1 pair of sex chromosomes
totalling 23 pairs altogether.
Heterochromatin contains mostly inactivated genes.
Telomeres are distal extremities of chromosomal arms but centromeres provide a point
of attachment for the mitotic spindle.


Northern blotting detects RNA
Southern blotting detects DNA.
Western blotting can be used to detect and quantify proteins

The karyotype 46 XX, t (4;8)(q26;p21.3) describes a female with a normal number of

chromosomes but a translocation between the long arm of chromosome 4 (q) and the
short arm of chromosome 8 (p).

Genomic imprinting refers to the difference in phenotypic presentation depending on

the origin of the disease chromosome from either maternal or paternal.
Conditions with genomic imprinting:
• myotonic dystrophy
• Beckwith-Wiedemann syndrome
• Prader Willi syndrome
• Angelman syndrome

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.

Oncogenes

Proto-oncogenes and oncogenes encode growth factors. A single aa mutation is enough to
change the proto-oncogene into an oncogene.
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.


N-myc proto-oncogene is seen in neuroblastoma.
SRC oncogene is associated with sarcoma.
*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.

Tumour suppressor genes examples (different from oncogenes):

NF-1 gene in neurofibromatosis
BRCA-1 in breast and ovarian cancer
Rb gene in retinoblastoma
VHL gene in von Hippel Lindau
P53 – Li Fraumeni syndrome

p53 : The p53 Gene is a tumor suppressor gene. If a person inherits only one functional

copy of the p53 gene from their parents, they are predisposed to cancer and usually
develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. Li Fraumeni syndrome predisposes patients to breast cancer and sarcoma. p53 is also a transcription factor and is not found only in malignant cells. It has a role in downregulating cell division and
apoptosis.


Fragile X syndrome is typified by delayed mental and motor development with
associated seizures. Phenotypic features are prognathism, long face, high arched palate,
large ears, cryptorchidism, hypotonia and mitral valve prolapse.

Marfan's syndrome is an autosomal dominant condition associated with ocular

abnormalities such as upwards lens dislocation and retinal detachment. Aortic
regurgitation may occur due to aneurysmal dilatation a feature. Upper to lower body ratio
(head- symphysis pubis : Symphysis pubis- toes) is decreased in Marfan Syndrome.

Homocystinuria is an autosomal recessive disorder. Reduced activity of cystathionine

synthase results in accumulation of homocysteine methionine. Osteoporosis and
osteopetrosis are also seen in homocystinuria.
In pre renal failure / Acute Tubular Necrosis (hypovolaemia, dehydration), the kidney
attempts to retain sodium, hence urine sodium is <20mmol/l.

The anion gap

is normal (Na + K - Cl - Bicarb) - normal range is 10 - 16.
Serum osmolality
[2(Na + K) + urea + glucose].

Enzyme deficiencies

Gaucher’s disease – Glucocerebrosidase deficiency
Tay Sachs disease - Hexosaminidase A deficiency Niemann Pick disease -
Sphingomyelinase deficiency Metachromatic leukodystrophy - Arylsulphatase A
deficiency Hurler's syndrome - Iduronidase deficiency


Fabry's disease is an X-linked lysosomal storage disorder. It is caused by a deficiency of
alpha-galactosidase A. Ceramide accumulation occurs in various organs including the
heart, skin and nerves. The skin lesion is known as angiokeratoma corporis diffusum.
Gaucher's disease is associated with the enzyme glucocerebrosidase. As a result,
glucocerebroside accumulates, principally in the phagocytic cells of the body but also
sometimes in the central nervous system neurones.

Maple syrup urine disease (MSUD) is an aminoacidopathy secondary to an enzyme

defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine,
and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads
to encephalopathy and progressive neurodegeneration in the infant who is not treated for MSUD.

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

G protein second messenger abnormality is found in:

Cholera
pituitary adenoma
McCune Albright syndrome
lbright's hereditary osteodystrophy (pseudohypoparathyroidism)
Examples of tyrosine Kinase receptors:
• Insulin • PDGF• VEGF
• Epidermal Growth Factor
• IGF-1• Macrophage colony stimulating factor


Complements
C3 is activated by classical and alternative pathways.
Classical pathway
C1 (q,r,s), C2, C3, C3 are components
C43b cleaves and activates C3
Activated by Ab-Ag complexes
Alternative pathway
C3, factor D, factor B, properdin are components
C3bBb activates C3
Activated by endotoxin, bacterial cell wall

natural killer cells express adhesion molecules which allow

adhesion to target cells. CD94 receptor is located in Natural Killer (NK) cells and is
bound to the cell membrane. It enables NK cells to discriminate between healthy cells and pathogen infected cells

T cells

Cytotoxic (CD8) T cells recognise MHC class I molecule antigens
T helper (CD4) cells recognise MHC class II molecule antigens.

MHC 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 .


B cells usually require T cell help for full activation. B cells are activated in primary
immune response which initially produce IgM. Deficiency of CD40 impairs class
switching. Most T cell antigens have repetitive epitopes (e.g.LPS/endotoxin), which are
able to cross link to B cell surface immunoglobulin to activate these cells.

IL-1 causes pyrexia and local inflammation. Recombinant forms of interleukin receptor

antagonists (IL-1Ra) are useful as disease modifying drugs in rheumatoid arthritis.
IL-2, IL-4, IL-5 and IL-10 are commonly produced by T helper cells. Antibody
production is promoted. Immature dendritic cells are stimulated to mature by T helper.

Tumour necrosis factor can bind to either p55 or p75 receptors and activates nuclear

factor kappa B (NFkB) transcription factor. It promotes interleukin activity and can
induce apoptosis. TNF α is procoagulant and can lead to thrombosis. TNF is produced by
natural killer, T cells and macrophages. It enhances dendritic cell migration. It also
increases adhesion molecule expression on vascular endothelium, allowing for increased permeability.

IFN α and IFN β are antiviral cytokines.

IFN γ is produced by natural killer and T cells.
IFN α and IFN β (not γ) bind to the same receptor known as type I receptors.
IFN β is used therapeutically in multiple sclerosis.


IgG is the commonest antibody in the serum. There are 2 light and 2 heavy chains,
making a total molecular weight of 150,000 kDa. It comprises 2 Fab fragments, and is
divalent rather than monovalent. The reference range is 8-20 g/l.

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 levels of urinary N-methyl imidazole, blood eosinophilia and thrombocytopenia. It classically presents with episodes of flushing, vomiting, diarrhoea and abdominal pain.

Hypersensitivity reactions

Anaphylaxis is a type I reaction (atopic diseases).
Good pasture's syndrome and Coomb's positive haemolytic anaemia are type II reaction (antibody to antigenic components).
Serum sickness is a type III reaction (immune complex disease). An example of type IV
reaction is contact dermatitis or allograft rejection (T cell mediated response).

Common Variable Immunodeficiency (CVID) is a disorder characterized by low levels

of serum immunoglobulins and an increased susceptibility to infections. A clear mode of
inheritance is not defined (there are multiple modes) and there is a <10 % chance of
passing on the disease.

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).


O2-Hb dissociation curve
is shifted to the right when there is: an increase in CO2
increase in hydrogen ions (fall in pH) increase in temperature
increase in lactate
The curve is shifted to the left by
increased carboxyhaemoglobin
methaemoglobin
fetal haemoglobin.

Bioavailability refers to absorption of the drug. Increased gastric emptying and induction

of liver enzymes increases first pass metabolism and reduced bioavailability.
Potency refers to the amount of drug usually needed to produce an effect, such as relief
of pain or reduction of blood pressure. For instance, if 5 milligrams of drug A relieves
pain as effectively as 10 milligrams of drug B, drug A is twice as potent as drug B.

Efficacy refers to the potential maximum therapeutic response that a drug can produce.

Frusemide eliminates more salt than hydrochlorothiazide, hence it has higher efficacy
than hydrochlorothiazide.
The difference in speed of acetylation is due to the amount (or activity) of the enzyme Nacetyltransferase available. Fast acetylation is a trait which is autosomal dominant inherited.

Drugs with zero order kinetics

Alcohol
Phenytoin
Fluoxetine
LIVER ENZYME INDUCERS (PCBRAS)
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol
Sulphonylureas


LIVER ENZYME INHIBITORS (OAAK DEVICCES)
Omeprazole
Amiodarone
Allopurinol
Ketoconazole
Disulfram
Erythromycin
Valproate
Isoniazid
Ciprofloxacin
Cimetidine
Ethanol
Sulphonamides

Drug induced lupus:

procainamide
isoniazid
chlorpromazine
penicillamine
sulfasalazine
hydralazine
methyldopa
quinidine


Drugs which can cause gynaecomastia are : digoxin oestrogens spironolactone
cimetidine verapamil nifedipine
Drugs causing galactorrhoea are:
Oral contraceptive pills
Phenothiazines such as chlorpropramide and thioridazine
Metoclopramide
Bromocriptine

The drugs most commonly implicated in SIADH are: cyclophosphamide

chlorpromamide carbamazepine clofibrate thiazide diuretics vincristine vinblastine
phenothiazines tricyclic antidepressants SSRIs

Drugs producing hypercalcemia include:

lithium, alkaline antacids
DES,
Thiazides
estrogens
progesterone

MISCELLANEOUS DRUGS

Common side effects of Selective Serotonin Reuptake Inhibitors (SSRIs) are nausea,
vomiting, diarrhoea, appetite and weight loss, sexual dysfunction and deranged liver
function tests. Similarly, the common side effects of fluoxetine are :anxiety or
nervousness; decreased appetite; diarrhoea; drowsiness; headache; increased sweating;
nausea; tiredness or weakness; trembling or shaking; insomnia.


Amiodarone blocks conversion of T4 to T3 and affects pituitary thyroid axis.
The following changes in thyroid function tests occur within 3 months of starting
amiodarone and are not indicative of thyroid disease: increase in TSH up to 20mU/L
increase in T4 to upper limit of normal decreased T3 levels.

Anticholinergic syndrome occurs following overdose with drugs that have

anticholinergic activity.
Examples of these are tricyclic antidepressants, antihistamines and atropine. Features
include flushed skin, urinary retention, tachycardia, mydriasis (dilated pupils) and
Agitation.Physostigmine, a reversible inhibitor of acteylcholinesterase, is effective in treating
anticholinergic symptoms but there is a significant risk of cardiac toxicity (bradycardia,
AV conduction defects and asystole) with the drug.

Bisphosphonates acts at the cellular level. They act directly or indirectly on the

osteoclasts. The effect can be on the formation of osteoclasts and/or on their activity. A
decrease in osteoclast number can occur either through direct action on osteoclast
precursors, or indirectly by stimulating the osteoblasts to produce an inhibitor of
osteoclast formation. Osteoclast inactivation is associated with bisphosphonate uptake
from the bone surface.

β-interferon is a long term treatment (as opposed to steroids for acute relapses) which is
of benefit only in the relapsing remitting form (about 40% of MS patients have this
form), and slows progression of disability and reduces demyelinating lesions.


Aspirin toxicity causes symptoms of nausea, vomiting, headache, confusion and tinnitus or hearing difficulties.

Major side effects of carbimazole are: agranulocytosis, thrombocytopaenia, acute

hepatic necrosis, cholestatic hepatitis, lupus-like syndrome and vasculitis. It may cause
neutropenia in 1 in 800 patients.

Clozapine induced agranulocytosis occurs in about 1% to 10% of patient who take

clozapine. Patients who have experienced agranulocytosis with prior treatment of
clozapine should not receive clozapine again.
Hyperkalaemia, hirsutism, tremors, hypertension, nausea and vomiting, headache, gum hypertrophy, parasthesiae and hypomagnesaemia are side effects of ciclosporin.

Disulfiram (antabuse) acts by causing raised acetaldehyde levels. This causes unpleasant

effects. Metronidazole and disulfram synergism may lead to psychosis.

Digoxin is slowly absorbed, hence peak effects can be delayed for up to half a day after an overdose. Visual disturbance, nausea and vomiting, tachy and bradyarrhythmias can
occur with an overdose. Activated charcoal decreases absorption.

Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding

portion of the tumor necrosis factor receptor (TNFR) linked to a human IgG1. The
receptor binds to TNF, it is not a monoclonal antibody. It is licensed for juvenile
rheumatoid arthritis and juvenile idiopathic arthritis. Side effects are septic arthritis,
demyelination, pancytopenia, aplastic anaemia and congestive heart failure.
Infliximab is a monoclonal anti-TNF antibody.


Ezetimibe acts by prevent cholesterol absorption from the small intestine. Typically it
reduces LDL-cholesterol by approximately 20%, triglycerides by up to 5% and raises
HDL-cholesterol by approximately 5%.
Ezetimibe is currently licensed for use in combination with a statin in patients who fail to reach desired lipid profiles or as monotherapy in patients intolerant to a statin.

Thiazides block Na+ and Cl- reabsorption in the distal tubule. There is usually passive

Na+ and Cl- co transport. With this blocked, natriuresis occur. The distal convoluted
tubule accounts for 5% of total sodium chloride reabsorption. Thiazides elevate LDL
cholesterol, reduce urinary calcium excretion and can cause impotence. Hypercalciuria
can be treated with thiazides.
Thiazides can cause thrombocytopaenia, hypokalaemia (blocking NaCl channels), and
hyperuricaemia.

Frusemide acts on the thick portion of the ascending loop of Henle. It inhibits Na+ and

Cl- reabsorption there via Na+, K+, -ATPase-dependent pump. Owing to the large NaCl
absorptive capacity of the loop of Henle, agents that act at this site produce a diuretic
effect much greater than that seen with other diuretic groups.

Insulin glargine is a long-acting insulin analogue, there is a smooth, prolonged

absorption profile with no peaks. As such, it is a long-acting agent, suitable for providing
a basal level of insulin which mimics the normal physiological state.
Its smooth profile reduces the risk of hypoglycaemia, and when given at night, provides good control of the fasting blood glucose.


Penicillamine is a DMARD which can is used in Rheumatoid arthritis, Juvenile chronic
arthritis and as a copper binder in Wilson’s hepatolenticular degeneration. It is also used
in PBC, chronic active hepatitis and cystinuria. It can cause aplastic anaemia and
thrombocytopenia, proteinuria and loss of taste.
Penicillamine is associated with drug-induced lupus, Goodpasture’s syndrome,
myasthenia, myositis and Stevens-Johnson syndrome.

Orlistat is an inhibitor of gastrointestinal lipases, leading to reduced fat absorption. It is
licensed for patients with BMI > 28 with associated risk factors, a weight management
programme should be in place. Use is not recommended for more than 2 years.

Theophylline is metabolised in the liver. Plasma theophylline levels are increased in

heart failure, cirrhosis of the liver, viral infections, elderly patients, and by drugs that
inhibit metabolism of theophylline. The plasma levels of theophylline are decreased in
smokers, chronic alcoholism and by drugs that induce liver metabolism.

Metformin a biguanide. Its mode of action is thought to be multifactoral and includes

delayed uptake of glucose from the intestinal tract, increased peripheral glucose
utilisation mediated by increased insulin sensitivity and inhibition of increased hepatic
and renal gluconeogenesis.


In metformin overdose, main symptoms of toxicity include gastrointestinal upset due to
a severe lactic acidosis. Hypoglycaemia is not often seen in metformin overdose. If lactic
acidosis occurs following overdose, mortality can be high. Management is gastric
decontamination and use of activated charcoal if appropriate, and correction of acidosis
with 8.4% sodium bicarbonate. Haemodialysis can be considered in severe cases.

Selective estrogen receptor modulators (SERMs) characterized by estrogen agonist activity in some tissues with estrogen antagonist activity in other tissues. The first widely used SERM, tamoxifen, has estrogen antagonist activity in breast tissue but shows estrogen-like activity in other tissues. Raloxifene is another SERM in clinical use, and it was developed to avoid some of the undesirable estrogen agonist actions of other SERMs to improve the drug safety profile. Raloxifene has been introduced for clinical use in treatment and prevention of postmenopausal osteoporosis.

Sumatriptan is a 5HT1 agonist and may be useful in the treatment of acute migraine

attacks. is available in injectable, intranasal, and oral formulations. Ergotamine tartrate
is also effective in acute migraine. Propanolol, valproate, NSAIDs, amitriptyline, pizotifen and gabapentin are effective as prophylactic drugs in migraine.

Immunosuppresants: Corticosteroids act on cytosolic rather than cell membrane

receptors. Both mycophenolate and azathioprine Approximately 1 in 300 Caucasians have thiopurine methyl transferase (TPMT) deficiency. TPMT is the enzyme that metabolises 6-mercaptopurine and its deficiency results in high risk of azathioprine toxicity.

Azathioprine is used when steroid withdrawal causes recurrent relapse. Bone marrow

suppression (low white cell count) and pancreatitis are side effects of azathioprine
Methotrexate: Binding of methotrexate to dihydrofolate reductase reduces nucleotide
synthesis as well as amino acids serine and methionine. Folinic acid rescue is usually
given after methotrexate therapy (e.g. 24 hours) to reduce myelosuppression side effects.


Methotrexate is associated with interstitial pneumonitis. This is rare but a serious
complication. Chest radiography reveals a diffuse interstitial or mixed interstitial and
alveolar infiltrate, with a predilection for the lower lung fields.
Common side effects of gold are mouth ulceration, leucopenia, proteinuria and
skin rashes.

Hydroxychloroquine can cause renal toxicity. Sulphasalazine causes nausea and

vomiting, leucopenia and deranged liver function.
Allopurinol specifically inhibits xanthine oxidase and prevents metabolism of
azathioprine to mercaptopurine. This action causes increased toxicity of azathioprine

lithium toxicity (can occur at levels greater than 1.1 mmol/l)nausea and vomiting, diarrhoea, disorientation, tremors and ataxia.
Lithium can cause hypercalcaemia and hypothyroidism along with a goitre, fine tremor,weight gain, diabetes insipidus and cardiac arrhythmias.

Gammahydroxybutyric acid causes hypernatraemia, metabolic acidosis, hypokalaemia,hyperglycaemia.
Hypotension/shock, glucose >8.3 mmol/l, white cell count > 15, haemetemesis and
decreased consciousness are features of severe iron poisoning.

mercury poisoning are vague psychiatric ones. Short-time memory can deteriorate. Organic mercury can cross the blood-brain barrier and cause irreversible nervous system and brain damage, e.g., loss of motor control, numbness in limbs, blindness, and inability to speak.

Methaemoglobinaemia can be caused either by a genetic defect in red cell metabolism or haemoglobin structure, or acquired by a variety of drugs and toxins. Common drugs dapsone, nitrates, prilocaine, antimalarials, sulphonamides and dyes. Domestic causes of acquired methaemoglobinaemia include ingestion of food and water high in nitrites and nitrates exposure to aniline dyes in dyed blankets, laundry markings, freshly dyed shoes,red wax crayons and cleaning solution.Standard pulse oximeters give spuriously low readings in the presence of excess methaemoglobin.


Methylene blue is indicated in any patient with symptoms and/or signs of hypoxia (mental changes, tachycardia, dyspnoea, chest pain). It is contraindicated in G6PD
deficiency. High flow oxygen should be administered.

Carbon monoxide poisoning is produced by the incomplete combustion of carbon containing fuels such as gas, coal, oil, wood and coke. Headache is the most common symptom (90%) followed by nausea & vomitting, vertigo, alteration in consciousness and weakness. The cherry red skin colour occurs when COHb concentration exceeds 20% but it is rarely seen in life. Pulse oximetry gives falsely high oxygen saturation sand it is not
recommended.

Phenytoin toxicity can cause: sedation slurred speech nystagmus ataxia vertigo Long term side effects of phenytoin are: gingival hypertrophy hirsutism acne coarseness of facial features
Common drugs which can precipitate a porphyria attack are:
Barbiturates
Sulfonamides
chloroquine
steroids

Barbiturate withdrawal in an habitual abuser a well recognised cause of fits.Benzodiazepine elevates the level of an inhibitory neurotransmitter, GABA, therefore it serves as a tranquilizer. Barbiturates are prescribed as anticonvulsants, sedatives, and general anesthetics. Commonly abused barbiturates include amobarbital (Amytal),pentobarbital (Nembutal), and secobarbital (Seconal). These drugs depress the respiratory and nervous system functions.

Symptoms of withdrawal syndrome appear 12-20 hours

after the last dose; they include anxiety, irritability, elevated heart
and respiration rate, muscle pain, nausea, tremors, hallucinations, confusion, and
seizures.

Chronic cocaine use can result in erectile dysfunction, ejaculatory dysfunction,

hypersomnia, excitement, emotional instability, restlessness, irritability, apprehension,
inability to sit still, teeth grinding, cold sweats, tremors, twitching of small muscles
Severe anxiety and paranoid hallucinations, mania, and psychosis can also occur with
cocaine use.


Theophylline poisoning results in profound Hypokalaemia, SVT and VT, vomiting,
agitation and convulsions. Activated charcoal is the method of choice for elimination.
Diazepam may be used to control convulsions and Propanolol may help tachycardia and
reversal of hyperglycaemia (however, beware of using it in asthma).
Agents not adsorbed by activated charcoal include: metals (lithium, iron) hydrocarbons
and solvents alcohols

Neuroleptic malignant syndrome is characterized by fever, muscular rigidity, labile

blood pressure, altered mental status, decreased conscious level and autonomic
dysfunction. Although potent neuroleptics (eg, haloperidol, fluphenazine) are more
frequently associated with NMS, all antipsychotic agents may precipitate the syndrome.For example, these agents are prochlorperazine, promethazine , clozapine , risperidone .

Dystonic reactions usually subsides within 24 hours following cessation of treatment

and can be treated with procyclidine 5-10 mg i.m.They are well-recognized with dopamine receptor antagonists (neuroleptics).
Phenothiazines, prochloperazine, haloperidol and metclopramide are examples of drugs
which can cause dystonic reactions.

Oculogyric Crisis is one of the acute dystonic reactions. It is the most common of the ocular dystonic reactions (which include blepharospasm, periorbital twitches, and
protracted staring episodes).
Priapism as a side effect is associated with phenothiazines (chlorpromazine),
haloperidol, trazodone and alpha blockers (prazosin).


MORPHINE EQUIVALENT DOSES
100 mg of MST has the equivalent dose of 25 ug/hr of fentanyl over a day.
A 24 hour diamorphine dose should be 1/3 of the 24 hour morphine dose.
The breakthrough dose of short acting morphine such as oramorph should be 1/6th of the total 24 hour dose of morphine.
The equivalent dose of oral oxycodone 0.833 is to diamorphine SC 1.3 (about 2/3).

PREGNANCY

Trimethoprim is a folate antagonist and can increases the risk of neural tube defects.There is relative contraindication for ciprofloxacin in pregnancy due to the possible teratogenic effect. Augmentin, cefaclor, nitrofurantoin and metronidazole are safe in pregnancy.

Carbimazole crosses the placenta and can cause nail/finger abnormalities.

Propylthiouracil is commonly used in pregnancy instead of carbimazole due to the risks
of neonatal hypothyroidism with carbimazole.

Warfarin in the first trimester can cause fetal hypoplasia of the nose and limbs. After

this period warfarin is associated with neurological damage – mental retardation,
microcephaly, optic atrophy and blindness. There is an option to convert from heparin to warfarin in the third trimester, but the patient will have to be re-converted back to heparin before delivery.

Assuming normal distribution - 99% of subjects are within 3 standard deviations of the mean 95% of patients within 2 standard deviations 68% are within 1 standard deviation
Example: The mean Hb value for a group of 150 patients is 15 g/dl. The standard
deviation is 2 g/dl. 95% of patients would have a Hb between 11 and 19.


Z scores can be used instead of standard deviation to estimate distribution. If an
observation lies 1 standard deviation away from the mean, its z score is 1. Hence, a score of 2 is 2 standard deviations more than the population, and a score of -2 is to standard deviations less than the mean.

Standard Deviation is the square of variance.

Standard error of the mean is the standard deviation of the sampling distribution of the
mean - which gives an estimate of how close the sample mean is to the true population
mean. It increases with sample size and increases with stand deviation.
The S.E.M. is the standard deviation divided by the square root of the sample size SEM
= σ / √N where σ is the standard deviation of the original distribution and N is the sample size).

Coefficient of variation is expressed in %. The definition coefficient of variation V =

SD/mean. In this example 15/150 = 10%. It is a statistical measure of the deviation of a
variable from its mean.

Sensitivity is the probability that a test will be positive when a patient has the condition.
Alternatively, it is the number of true positives detected by the test divided by the number
of all true positives in the population tested.
Specificity is the probability that a test will be negative when a patient does not have the
condition. Alternatively it is the number of true negatives detected by the test divided by
the number of all true negatives in the population.


Positive predictive value suggests the probability that if a test is positive, it is true
The null hypothesis states that there is no difference between treatments.
A type 1 error
occurs when ‘the null hypothesis is falsely rejected’. This means that the study claims to
find a difference that does not really exist.

A type 2 error occurs when ‘the null hypothesis is falsely accepted’. This means that although it is suggested that there is no difference between two groups, the study is
actually too small to detect a difference.

Comparing two groups, all who have a risk factor, the relative risk is the ratio of those

who had the disease, compared to those who did not have a disease. For example, the
relative risk in a group of patients is the ratio of those who had CVA in a hypertension
group compared to those who had CVA without hypertension (e.g. 10 patients / 2 patients = 5).

The attributable risk is the difference in incidence of a disease, among patients who

have or do not have a risk factor. It is expressed in %. For example, 20% with
hypertension had CVA and 5% without hypertension had CVA, hence 20% - 5% - 15%.

Another example, if a drug reduces the incidence of stroke from 10% to 5%.

The relative risk reduction (RRR) is 50%. The absolute risk reduction (ARR) is 5%.
The number needed to treat (NNT)
is the total divided by the absolute risk reduction,
which is 100% / 5% = 20. NNT is defined as number needed to treat to prevent 1 death.


Secondary prevention does treat patients with pre-existing disease, such as heart attack.It also involves identification of patients who are high risk of further development of cardiovascular disease

Chi-squared tests are used to compare percentages or proportions of categorical data.

Data such as the above can be organised into a 2 x 2 contingency table. From the chisquared value a p value is read off a statistical table (depends on degree of freedom) to give the degree of significance.

The paired students t test can be used to compare two groups of patients with

parametric data (Null hypothesis being that any difference is due to chance).
Parametric means that the data will be of normal distribution and parallels the normal or
bell curve). In addition, it means that numbers can be added, subtracted, multiplied, and
divided. Normally distributed data can be compared with a Student’s t-test.

Skewed continuous data can be compared with a Wilcoxon rank-sum test or a Mann-

Whitney U-test. They should be described with a median and range, but NOT a mean.
The tests are also known as non parametric tests.

Logistic regression allows one to predict a discrete outcome, such as group membership,

from a set of variables that may be continuous, discrete, dichotomous, or a mix of any of
these. ANOVA is an example of a logistic regression analysis.

Case control studies are not good at identifying rare causes. In order to identify whether

a rare exposure causes a disease then the appropriate design is a large cohort study, where
one group with the particular exposure of interest is compared with a control group
without that exposure. The advantage of case control studies is that they can be used with
rare diseases and can examine multiple risk-factors. Poor control selection often makes a
case control study uninterpretable.


Crossover trials are designed where a patient can have one drug, have a washout period
and then a second drug. It is applicable to chronic conditions, such as multiple sclerosis
and not acute conditions such as MI requiring thrombolysis.
Intention to treat reduces bias by including the data from original allocation of
treatment, e.g. analyzing the patient in a treatment group even if they did not complete
the trial (dropped out because of side effects).

The second heart sound comprises of aortic (A2) and pulmonary (P2) component. In

LBBB, the aortic closure is delayed because the left ventricle contracts later. This then
causes reversed splitting (A2P2 → P2A2) if the second heart sound.BBB and left heart strain in HCM and aortic stenosis can cause reversal of A2P2 second heart sounds. Also, in type B wolf parkinson white syndrome, early activation of the right ventricle through an accessory pathway can cause P2 to close prematurely.Patent ductus arteriosus is another cause.

The third heart sound is caused by early diastolic filling due to ventricular relaxation,

shortly after closure of the aortic valve (corresponds to Y descent in JVP).It may be normal in children and young /middle aged adults.Causes of an abnormal third heart sound
Left ventricular failure
Severe MR and TR,VSD, PDA
Constrictive pericarditis,
Hypertrophic cardiomyopathy
Dilated cardiomyopathy
AV fistula,thyrotoxicosis

The left internal mammary artery supplies the anterior chest wall. It has been shown to

be superior to saphenous vein grafts (from aorta to LAD) in staying patent and hence is
now the choice artery (LIMA to LAD) graft. Although circumflex and right coronary
arteries are usually grafted with veins, the right internal mammary arteries (RIMA) are
sometimes used to graft the RCA.


The circumflex artery gives off obtuse marginal branches and the LAD gives off
diagonal branches.
The intermediate artery is not always present, it is a variant artery which is between the
LAD and circumflex artery, and occasionally dominant instead of the circumflex.

The coronary sinus predominantly drains venous blood from the left ventricle and

receives approximately 85 percent of coronary venous blood. It receives blood from the
the marginal, posterior left ventricular, anterior interventricular veins and the great
cardiac vein. The blood finally drains into the right atrium.

The posterior descending artery is often (85%) a branch of the right coronary artery.

The sinus node artery is a branch of the right coronary artery in 60% of cases.
The AV node is supplied by the posterior descending coronary artery.

Differentiating SVT from VT

Features that favour VT are :
QRS of > 140ms,
cannon a waves on JVP fusion and/or capture beats
dissociated p waves,
history of ischaemic heart disease,
right bundle branch block with left axis deviation,
concordance of the QRS complexes in the chest leads
HR >170 beats per minute.


In a patient who is stable with sustained ventricular tachycardia, the options are
intravenous lignocaine, intravenous amiodarone. IV magnesium sulphate (18 / 20 mmols or 5g) is often helpful in helping to cardiovert. If the patient were unstable then he needs
to be DC cardioverted immediately (with or without general anaesthetic)

The criteria for ICD insertion are:

1) patients with LVEF <40% with non sustained VT
2) patients with sustained VT
3) patients who have had any VT or VF leading to cardiac arrest
4) cardiomyopathy and ventricular arrhythmias
5) patients with previous MI and ejection fraction <30%

PROLONGED QT

A QT interval of >0.45
DRUGS causing PROLONGED QT
tricyclic antidepressants
quinidine,
erythromycin,
amiodarone,
phenothiazines
chlorpropramide,
antihistamines (terfenadine) grapefruit juice
sotalol


METABOLIC causes
Hypokalaemia
Hypocalcaemia
Hypomagnesaemia
Hypothermia
Hypothyroidism

A dominant R in lead V1 on the ECG is associated with : -

• primary pulmonary HT -
• Right bundle branch block (RBBB) (including Ebstein's anomaly )
• Wolf-Parkinson-White syndrome Type A
• Dextrocardia
• Posterior MI
• Duchene muscular dystrophy

MYOCARDIAL INFARCTION

Absolute contraindications to thrombolysis include:
• previous haemorrhagic stroke
• ischaemic CVA within 1 year
• suspected aortic dissection
• active bleeding <10 days
• BP>180/110
• neurosurgical procedure < 6 months ago


Troponins tend to be elevated for up to 14 days.
CK-MB comes down to normal level
within 48-72 hours, and is the most specific of the CK enzymes.
Pulmonary embolus, arrhythmias, myocarditis and right heart disorders are also known to elevate troponins.

Relative contraindications include

• major surgery or bleeding within 6 weeks
• pregnancy
• known bleeding diathesis
• severe uncontrolled hypertension Proliferative diabetic retinopathy

THE PRIMARY HYPERLIPIDAEMIAS

THE FREDERICKSON CLASSIFICATION

Type II hyperlipidaemia the most common primary hyperlipidaemia. The picture is

similar to familial hypercholesterolaemia but milder. It is characterised by increased
levels of LDL-cholesterol (> 4.0 mmol/L). Triglyceride levels are < 2.3 mmol/L.

Type IIa hypercholesterolaemia causes heart disease as there is predominantly raised

cholesterol and high LDL. There is also increased triglycerides cause eruptive skin
xanthomas, lipaemia retinalis (white TG deposits in the retina) and pancreatitis.
Cholesterol has an affinity for deposition around the tendons, tendon xanthoma is
characteristic of hypercholesterolaemia.
Type II b hypercholesterolaemia also causes elevated cholesterol and triglycerides.


Type III hyperlipidemia is when cholesterol and triglyceride are both increased, and is
associated with atherogenesis. Homozygosity for the E2 genotype (E2/E2) is found in
most patients with type III hyperlipidemia. The palmar striae (palmar xanthomata) are
considered pathognonomic for the disorder and occur in less than 50% of patients but
tubero-eruptive xanthomata, typically on the elbows and knees, as well as xanthelasma have been described. The underlying biochemical defect is one of a
reduced clearance of chylomicron and VLDL remnants.

Type IV hyperlipidemia causes an isolated hypertrigIVceridaemia. There is normal or

slightly raised plasma cholesterol. There are increased triglyceride levels due to increased
VLDLs
Type I and V hyperlipidaemia have lipoprotein lipase defects, and lead to raised
chylomicrons and triglyceride levels.

Eruptive xanthomas in the skin are typical of triglyceridaemia. Alcohol abuse,

pancreatitis and hypertriglyceridaemia are associated. Both type I and type IV are
triglyceridaemic states. Triglycerides cause turbid serum.

Causes of raised triglycerides are:

• nephrotic syndrome
• hypothyroidism
• Biliary obstruction
• steroids
• diabetes mellitus
• renal failure
• thiazide diuretics
• oral contraceptive pill
• lipodystrophies and glycogen storage disease (Von Gierke's)


Chylomicrons are triglyceride-rich lipoproteins (75%-95% of their core lipid is
triglyceride) made in the small intestine from ApoB-48 (apoliproprotein).
VLDL are made in the liver from ApoB-100.

Ventricular septal defect (VSD) is the commonest form of congenital heart disease.

Maladie de Roger is a loud systolic murmur despite a small VSD. The systolic murmur does become softer as right heart
pressures increase and a right to left shunt may develop in Eisenmenger's syndrome
(leading to cyanosis).

In hypertrophic cardiomyopathy there is decreased compliance due to the disorientation of myosin fibres. 40% of patients carry mutations of cardiac beta Myosin heavy chain on chromosome 14.
Maneouvres which decrease venous return will increase the intensity of the murmur
(valsalva – baroreceptor mediated fall in cardiac output, standing, nitrates).
Maneouvres which increase venous return will decrease the murmur as this overcomes
the obstruction (squatting, long term beta blockers).

In summary, the murmur in HCM: increases in valsalva Maneouvre ,standing .decreases with exercise decreases with squatting. Nitrates are best avoided
because they are vasodilators which may cause hypotension with the condition. Beta
blockers and calcium channel blockers help increase end diastolic filling and treat
symptoms but have no effect on risk reduction of sudden death. Amiodarone improves
survival.


Restrictive cardiomyopathy:
Echocardiography showing no pericardial effusion and
stiffness suggests restrictive rather than constrictive cardiomyopathy. The transmitral
dopplers on the echo may show E/A wave reversal and high velocities which may suggest
restrictive picture. This may be due to infiltration due to haemochromatosis,
endomyocardial fibrosis, sarcoidosis, myeloma, lymphoma or connective tissue disease.

ENDOCARDITIS

Osler’s nodes, which are small reddish tender areas on the pulp of fingers or toes.
Janeway lesions are reddish spots on fingers or toes, but are painless.
A definite diagnosis of endocarditis
(Duke's criteria) is achieved when 2 major criteria are present, or 1 major and 3 minor criterias.

Major criteria:

blood culture positive for
typical organisms persistent bacteremia
positive ECHO for vegetations abscess or valve
dehiscence
Minor criteria:
valvular heart disease or IV drug user
fever greater than 38°C
vasculitis skin lesions suggestive ECHO (but not definite) positive blood culture


In a patient with prosthetic valve, staph epidermidis (one of the coagulase negative
staph) and Strep viridans are most common. Strep bovis, and enterococcus are the other
organisms which commonly cause endocarditis.
One of the major dangers with aortic valve endocarditis is an aortic root abscess. This
can lead to prolonging of the PR interval by erosion into the adjacent AV node, hence
daily ECGs are useful for monitoring.

Marantic endocarditis:

this disorder results in the deposition of fibrin on the valve leaflets on either side of the heart, but especially the left side.
The vegetations are sterile and small (1-5 mm). This form of noninfective endocarditis
can be seen in persons who are very debilitated or in those who have a hypercoagulable state.

DRUGS

Digoxin toxicity can occur especially with renal impairment. It typically causes nausea &
vomiting. ST depression occurs along with bradycardia on the ECG. The patient may also
get xanthopsia (yellow vision).
Aspirin blocks the synthesis of COX1 and COX2 enzymes. This leads to a reduction in
the prostaglandin PGG2, PGH2 →thromboxane TXA2 synthesis↓ . This leads to ↓platelet aggregation. Aspirin does reduce urate secretion in the renal tubules and can increase risk of gout.

Brain or B type natriuretic peptide

is increasingly used as a marker of congestive heart failure. It has high specificity for the condition.
Heart failure trials
Bisoprolol (CIBIS II trial), spironolactone (RALES trial), enalapril (CONSENSUS) and
nitrates and hydralazine (V-HEFT) have all been shown to improve mortality in chronic
heart failure.


Dissection of the aorta is associated with hypertension, cocaine abuse, trauma,pregnancy, aortitis as seen in syphilis, Marfan’s, Ehlers-Danlos and other connective
tissue disorders.

ASD:

APrimum defect causes RBBB and LAD whilst
Secundum causes RBBB and RAD on the ECG. Secundum ASD is associated with Holt-Oram syndrome(triphalangeal
thumb and radial abnormalities).

Flight Rules:

A patient should be fit to fly 14 days after an uncomplicated myocardial infarct, after
normal activities have been resumed. For complicated MIs, the patient has to wait until
symptoms stabilise.
Patients are only allowed to fly once resolution of pneumothorax has been demonstrated
radiographically and 6 weeks after the event

A decrease in diffusion capacity (DLCO) indicates interstitial lung disease.

Forced Expiratory Flow (FEF) 25%-75% primarily reflects the status of the small airways and is more sensitive than the FEV1 for identifying early airway obstruction. It is
impaired in bronchiolitis obliterans, smokers, and in patients with lung and heart transplant.
FRC is raised due to increased air trapping in bronchiectasis.Residual Volume is equal to Total Lung Capacity minus Vital Capacity. Residual Volume is usually 20% of the TLC.

Restrictive lung disorders are characterised by reduced FEV1 & FVC, FEV1/FVC >70%, reduced TLC & RV and reduced TLCO.
Causes : - neurogenic or psychogenic causes -
abnormalities of the thoracic wall - stiff parenchyma (pulmonary fibrosis) - loss of lung
tissue, e.g. pneumonectomy - displacement


Obstructive lung disorders
reduced FEV1 & FVC, FEV1/FVC <70%,
raised TLC & RV (gas trapping) and reduced TLCO (emphysema) or normal or
raised TLCO (asthmatics).

Severity of emphysema is defined by the British Thoracic Society (BTS) in relation to

FEV1, not FEV1:FVC ratio. Mild is 60-80% predicted; moderate 40-60% and severe
<40%.
Severe COPD is diagnosed if the FEV1 is less or equal to 30% predicted.
In infective exacerbations of COPD, Streptococcus pneumoniae and Haemophilus
influenzae, as well as Moraxella are the commonest organisms.

Extrinsic allergic alveolitis causes a neutrophilia due to cell mediation and eosinophils

are normal. Bronchoalveolar lavage shows lymphocytes and mast cells. EAA is a delayed
hypersensitivity reaction which may be immune complex (III) mediated or cell mediated
(type IV) in chronic disease. Precipitins to micropolyspora faeni in farmer’s lung or
aspergillus are seen. Upper zone fibrosis and crackles can be heard. Symptoms are
typically of breathlessness but not wheeze.

Extrinsic Allergic Alveolitis is a type III or type IV response. There is no eosinophilia.

IgG and lymphocytes are involved in immune response. As in extrinsic allergic alveolitis, haemoptysis and wheeze are uncommon in cryptogenic fibrosing alveolitis. Dry cough and breathlessness is common. Rheumatoid factor and anti nuclear antibody may be raised. Neutrophils are raised in CFA, Rheumatoid arthritis and asbestosis. Lymphocytes are raised in granulomatous and drug induced lung disease.


Cystic Fibrosis The abnormality is the chloride transporter, which is encoded by the
cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is cAMP driven.
The commonest CFTR gene mutation is due to deletion of 3 base pairs affecting the delta
508 position (phenylalanine) on chromosome 7 (mnemonic : cystic seven). The condition
is autosomal recessive.

Pulmonary disease develops over a few months after birth. Common infective organisms are pneumoccocus, Haemophilus influenzae and Pseudomonas aeruginosa. Pneumothorax is relatively common over the age of 10 years (5%).Diabetes (20% of patients) occurs due to occlusion and fibrosis of pancreatic ducts.Pancreatic gland occlusion causes malabsorption (diarrhoea). Occlusion of intrahepatic ducts cause cirrhosis and obstruction of bile ducts (pale stools)

The sweat test

remains the gold standard for confirming the diagnosis of cystic fibrosis.
A chloride value of >60 mmol/l is considered positive, between 40 and 60 mmol/l equivocal and less than 40 mmol/l negative.

PULMONARY FIBROSIS

The causes of upper zone fibrosis are
TB ,Extrinsic allergic alveolitis,
ankylosing spondylitis radiation sarcoidosis ,silicosis

Causes of lower zone lung fibrosis

are: Asbestosis ,bronchiectasis cryptogenic fibrosing alveolitis, drugs

Drugs which can cause lung fibrosis.

Busulphan, bleomycin and methotrexate,
Amiodarone, azathioprine,
antibiotics (nitrofurantoin, sulfasalazine), penicillamine, gold,
phenytoin.


LUNG CARCINOMA
The overall survival is 20% and 5 year survival is 6% for all lung cancers. Small cell lung cancer has the worst outcome.
Squamous cell carcinoma accounts for approximately one-third of all cases. Unlike adenocarcinoma, it is strongly linked with a history of cigarette smoking. Its histogenesis may be related to chronic inflammation and
injury of the bronchial epithelium, which leads to replacement of the normal ciliated columnar epithelium by a squamous epithelium.

SIADH is most comonly seen with small cell carcinoma rather than non-small cell

carcinoma.
HPOA and hypercalcaemia without bone metastasis is more common in squamous cell
carcinoma.

Light's criteria

(suggests exudate) is satisfied if pleural fluid protein/serum protein ratio greater than 0.5 Pleural fluid lactate dehydrogenase (LDH)/serum LDH ratio greater than 0.6 Pleural fluid LDH
greater than two-thirds the upper limit of normal for serum LDH (a cut-off value of 200
IU,/L was used previously)

Any pleural effusion associated with bacterial pneumonia, lung abscess or

bronchiectasis is a parapneumonic effusion. Streptococcus infection is common. These
effusions can be monitored by the pH: pH<7 - absolute indication to insert an intercostal drain pH>7.20 - usually does not need drainage pH 7-7.20 - should be monitored.

Allergic Broncho Pulmonary Aspergillosis: commoner among asthmatics

Eosinophilia and high IgE levels are suggestive
RAST test for antibodies towards Aspergillus confirms the diagnosis.


Aspergillomas are masses of fungal mycelia that grow in preexisting lung cavities.
Haemoptysis is a common symptom.
They do not require treatment with either antifungals or steroids and are not associated with bronchiectasis (unlike allergic
bronchopulmonary aspergillosis).

Acute respiratory distress syndrome is characterised by hypoxaemia, reduced lung

compliance, pulmonary hypertension and infiltrates on chest X ray. There is
damage to the capillary endothelial cell linings resulting in oedema leakage of proteins
cells into interstitial alveolar spaces. It is associated with profound hypoxia and increased
vascular permeability (causing a V/Q mismatch). A normal PCWP differentiates the
condition from pulmonary oedema. It does not respond to steroids.

Alpha 1 antitrypsin is a glycoprotein synthesized in the liver and comprises 90% of the serum alpha 1 globulin seen on electrophoresis. It is an anti-protease which inhibits neutrophil elastase.
The production of alpha1 antiprotease is controlled by a pair of genes at the protease
inhibitor (Pi) locus. The phenotypes are M, S or Z. The most common (90%) allele is M
(PiM), and homozygous individuals (MM) produce normal amounts of alpha1
antiprotease (serum levels of 20-53 mmol/L).

Deficient levels of alpha1 antiprotease are associated with allele Z (MZ or ZZ). Serum

levels of the enzyme greater than 11 mmol/L appear to be protective against emphysema.
Emphysema develops in most (but not all) individuals with serum levels less than 9
mmol/L.


Byssinosis is caused by cotton dust, and is commoner among smokers. Immunologically,
it is different from farmer’s lung but is more akin to occupational asthma – wheeze
occurs after exposure to cotton and hemp. The condition typically worse on Mondays
when work begins and lung function stabilises throughout the week. The CXR is normal,
unlike extrinsic allergic alveolitis, where mottling is seen on CXR (interstitial pneumonitis).

Churg-Strauss syndrome

triad of
1) asthma,
2) hypereosinophilia, and
3) Necrotizing vasculitis
can present with gastrointestinal involvement may sometimes present as
bloody diarrhea or simulating ulcerative colitis and is caused by bowel ischemia.

Apart from obesity, obstructive sleep apnoea is associated with acromegaly,

hypothyroidism, jaw and craniofacial abnormalities, and alcohol.
During the sleep study or polysomnography, a cessation of breathing for 10 seconds with
desaturation in oxygen saturation would help to confirm obstructive sleep apnoea. The
hallmark clinical symptom of OSA is excessive snoring.

Lofgren's syndrome is a self limiting subset of sarcoidosis. It consists of the

triad of
fever, bilateral hilar lymphadenopathy and erythema nodosum. Therefore, the prognosis is good and steroids are not required.


Legionella pneumophila is an obligate aerobic gram negative bacilli. The natural habitat
of the bacterium is water and it is spread through contaminated aerosols. The incubation period is 2-10 days and the spectrum of the disease varies from asymptomatic seroconversion to severe life-threatening pneumonia. Symptoms such as headache, fever,
rigors, myalgias and lethargy are frequent.

Erythromycin or doxycycline are the drugs of choice and treatment should be continued for at least 3 weeks.
Rifampicin (600mg) should be added to the treatment in patients who
are severely ill or who have cavitation.

Mycoplasma pneumonia is the commonest atypical pneumonia. Approximately 15% of

pneumonias in adults are due to Mycoplasma pneumoniae. Transmission occurs from
person to person by infected droplets. The incubation period is 9-21 days, higher during the winter months. Fever, chills, cough and headache. Dyspnoea, chest pain and haemoptysis are rare. Small pleural effusions may occur but are rare. Cold agglutinins are usually present in a titre greater than 1:32.

Hypereosinophilic syndrome is a rare condition where there is an idiopathic eosinophil

count of > 15 x 10^9/dl. It generally affects young men ages 20-50. Thrombotic
tendency, neurological involvement and restrictive cardiomyopathy occur There is
response to steroids.

Achalasia: Botulinum injections are most effective of all the options for relieving a lower oesophageal sphincter restriction which leads to achalasia. Nifedipine, nitrates or
sildenafil can also be used, but are less effective. Surgically, Heller’s oesophageal
myotomy is the best treatment option, it can be done via an abdominal incision or
laparascopically.


A Mallory-Weiss tear occurs in the mucous membrane typically in the lower
oesophagus. Mallory-Weiss tears are usually caused by forceful or prolonged vomiting or coughing. They may also be caused by epileptic convulsions. The tear may be followed
by vomiting bright red blood or by passing blood in the stool. The incidence is 4 in
100,000 people.

HBeAg (not HBcAg) is the best marker of infectivity, and is used as an important criteria

for selection of patients who have chronic hepatitis B for interferon (α-2B)
therapy. HBV DNA and HBeAg levels are measured in response to the therapy and
undetectable levels would be considered successful treatment.
HbsAb is a sign of previous infection or immunisation

10% of patients with hepatitis B develop chronic infection

(as compared to hepatitis C where 80% develop chronic infection).
30% of patients with hepatitis C develop hepatocellular carcinoma over 30 years. 20% develop cirrhosis over 20 years.

The treatment options are ribavirin or PEG (polyethylene glycolated) interferon.

IFN α is only effective in clearing the virus in 25%.
Meta-analysis of data strongly suggests a two to three-fold enhanced efficacy of interferon-ribavirin combination therapy over interferon monotherapy in all major subgroups of chronic hepatitis C patients.
In hepatitis C, response to therapy is determined by normalisation of hepatic transaminases and undetectability of hepatitis C RNA in plasma.

Hepatitis G virus or GBV-C does not appear to cause progressive liver disease.

In hemochromatosis, the commonest mutation is C282Y. It is found in approximately 90% of cases. The mutation is on chromosome 6, affecting the HFE gene. There is an increased incidence in males.
The serum Fe is elevated (> 300 mg/dL).The serum transferrin saturation is a sensitive parameter of increased Fe and merits evaluation when > 50%.
The serum ferritin is increased ferritin of >1000 μmol/l is suggestive (normal <200).

Urinary Fe excretion is markedly increased

(> 2 mg/24 h) by the chelating drug deferoxamine (500 to 1000 mg IM based on the size of the patient), and this has been used as a diagnostic test.In addition, when the Fe content in the liver is significantly increased, an MRI may
reflect this change.
Liver biopsy had been the gold standard in diagnosis; it now serves only to provide evidence of fibrosis (cirrhosis). Gene assay (Homozygosity C282y mutations) is the also an excellent diagnostic test.

In haemochromatosis , joint deposition of iron occurs, causing arthropathy. Increased

iron deposition in the skin stimulates increased melanin production.
Haemochromatosis is a recognised cause of restrictive cardiomyopathy.
Cardiac damage is commonly seen with ferritin >2,000 ng/l. Iron infiltrates the parathyroid glands and can cause hypoparathyroidism.

Venesection is preferred therapy . Treatment consists of bi-weekly venesection removing

approximately 500 ml per week. Desferrioxamine infusion (another iron chelator) can also be used.

Wilson disease : The abnormal gene is the ATP7B gene on chromosome 13. It is

autosomal recessive. Kayser-Fleischer rings are often seen on slit lamp, but not always.
The best test is hepatic copper concentration
(> 250 μg /g of dry weight). . Typically
there is low serum copper levels but high urine excretion of copper. There is low liver
production of caeruloplasmin (< 20 mg/dl) in 95% of patients.
Copper deposits can occur in the liver and kidney, hence affecting vitamin D metabolism
leading to osteomalacia/osteopenic changes.


Hepatorenal syndrome (HRS) is the development of renal dysfunction in patients with
severe liver disease (acute or chronic) in the absence of any other identifiable causes of
renal pathology.

Coeliac Disease: Folate levels are usually normal but not B12 in coeliac disease

(in Crohns both are decreased).

Whipple’s disease, may be confirmed by small bowel biopsy. This will show large,

foamy PAS positive macrophages in the lamina propria. Whipple's disease affects mainly
men aged 30 to 60. It is caused by an infection with Trophyrema whippelii.
Symptoms of Whipple's disease include diarrhea, inflamed and painful joints, fever, and skin darkening.

Severe malabsorption results in weight loss along with fatigue and

weakness caused by anemia. Antibiotics such as tetracycline, co-trimoxazole and penicillin can be used for treatment (6-12 months).

Chlorpromazine, tricyclic antidepressants, azathioprine, augmentin and erythromycin

cause cholestatic jaundice and also associated hepatitis.

MALT lymphoma is the third most common type of non-Hodgkin lymphoma, although

it only accounts for about 7-8% of these tumours. MALT lymphomas have been
described at almost all extra-nodal sites, but are most commonly found in the
gastrointestinal tract (stomach is the commonest).


Low grade gastric MALT tumours which are associated Helicobacter Pylori infection
respond in over 80% of cases to helicobacter eradication. A proportion of patients will
not respond to eradication therapy alone and will go on to more conventional antilymphoma
therapies such as such as cyclophosphamide, chlorambucil, nucleoside analogues, or radiotherapy.

poor prognostic indicators in acute pancreatitis:

Calcium < 2.0
WCC > 15
Urea >16
ALT >200
PaO2 <8
Age > 55 years
Glucose > 10

Chronic Pancreatitis

Cullen's sign (periumbilical discolouration,
Grey Turner's sign (flank discoloration) can be present
Purtscher's retinopathy (ischaemic areas in the retina) can be present
lack of digestive enzymes leads to steatorrhoea
In chronic pancreatitis, trypsin secretion is reduced. Trypsin is required in the
processing of dietary B12 which enables absorption and hence B12 deficiency is the most
likely.


Causes of a raised amylase are:
acute/chronic pancreatitis pancreatic cysts and carcinoma
perforated duodenal ulcer
ovarian carcinoma ectopic pregnancy gallstones
salivary tumour
adenitis
mumps
diabetic
ketoacidosis
anorexia

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder. The cause of

Peutz-Jeghers syndrome appears to be a germline mutation of the STK11 (serine
threonine kinase 11) gene in most cases. It is characterized by intestinal hamartomatous
polyps in association with mucocutaneous melanocytic macules.
A 15-fold elevated relative risk of developing cancer exists in this syndrome over that of
the general population.

Carcinoid syndrome is diagnosed by raised urinary 5-HT levels. A precursor of 5HT,

tryptophan is highly metabolised and consequently niacin deficiency (pellagra) occurs.
The three D's dementia, dermatitis (a photosensitive rash) and diarrhoea occur.


Gut Hormones
Secretin is produced by the jejunum. It relaxes the oesophageal sphincter and also stimulates pancreatic enzyme secretion.
Gastrin is secreted by the G cells of gastric antrum. It stimulates parietal cells produce hydrochloric acid. Its production is stimulated by neural reflex pathways and also by direct effect of digested peptides on the G cells. It also stimulates the production of bicarbonate.
Vasoactive intestinal peptide (VIP) promotes intestinal water and electrolyte secretion.

VIPomas [vasoactive intestinal peptide (VIP)] originate in amine precursor uptake and

decarboxylation (APUD) cells of the gastroenteropancreatic endocrine system and in
adrenal or extra-adrenal neurogenic sites.
Features of VIP syndrome include watery diarrhea, hypochlorhydria, hyperglycemia ,
hypercalcemia, flushing and hypokalaemia due to diarrhoea.

Initial treatment is directed toward correcting volume and electrolyte abnormalities by

using potassium chloride and sodium bicarbonate. Octreotide controls diarrhea in 80% of cases. Glucocorticoids reduce symptoms in 50% of patients with VIPoma.

The symptoms of fevers, weight loss and lower back pain are classical for

retroperitoneal fibrosis. There is an association with inflammatory conditions such as
SLE, rheumatoid arthritis, ankylosing spondylitis, Hashimoto's thyroiditis and glomerulonephrosis.
CT or MRI shows can fibrotic para-aortic masses causing ureteric obstruction.

Drugs associated with retroperitoneal fibrosis include:

methysergide
beta-adrenergic blockers
lysergic acid diethylamide (LSD)
Methyldopa
amphetamines phenacetin pergolide cocaine
Azathioprine is used to treat retroperitoneal fibrosis.


Retroperitoneal organs are
kidneys,
aorta,
pancreas
ascending colon
most of duodenum

Acute Tubular Necrosis ,urinalysis usually shows granular casts. Urine sodium

is typically high due to tubular sodium loss, concentration is typically above 30 mmol/l.
The urine to plasma osmolality ratio <1:1, the ability to concentrate urine is preserved
despite sodium loss.
Acute Tubular Necrosis is associated with accelerated hypertension, hypotension,
diabetes, liver failure, eclampsia, aminoglycosides, Cephalosporins, Cisplatin,
Amphotericin and Ciclosporin.

Haemodialysis is useful for

salicylates and NSAIDs, lithium, and in particular, Antifreeze poisioning.

It is not useful for tricyclics, amiodarone and paraquat,paracetamol and digoxin, which is mostly tissue bound (use digoxin binding antibodies).

NEPHRITIC SYNDROME

Infectious causes are:
staphylococcus pneumococcus
chickenpox ,malaria
Non infectious causes :
Membranoproliferative glomerulonephritis
IgA nephropathy
Henoch-Schonlein purpura
systemic lupus erythematosus mixed cryoglobulinemia
Goodpasture's syndrome
Wegener‘s granulomatosis


Microalbuminuria is protein >30 mg/l but dipstick testing can detect protein >300mg/l.
2+ proteinuria approximates to 1g/l of prtein.
3+ proteinuria approximates to >3g/l.

GLOMERULONEPHRITIS

Granular casts, red cell casts and selective proteinuria suggest glomerulonephritis.
Minimal change nephrotic syndrome is responsible for 90% of the cases of nephrotic
syndrome in children less than 5 years of age. It also occurs in adults - approx 20%. The
name is derived from the fact that the only detectable abnormality histologically is fusion
and deformity of the foot processes under the electron microscope.

Minimal Change

Disease is steroid responsive and in general, does not lead to chronic renal failure. There is response to corticosteroids usually within the first month. 90% of patients with minimal change disease in the younger age group achieve remission after 8 weeks of steroids.

Membranous glomerulonephritis characterised by subepithelial

deposits of immune complexes in the glomerular basement membrane. It is associated with malignancy (CLL, NHL),
connective tissue disease (SLE, RA),
infections (Hep B, malaria) and
drugs (gold,penicillamine, captopril).

Membranous nephropathy is the commonest cause of the nephrotic syndrome in adults Overall, 1/3 rapid decline, 1/3 respond to steroids and chlorambucil, 1/3 remit spontaneously. Often, corticosteroids or immunosuppressive medications may be used to reduce symptoms and progression of the disorder. Note: membranous GN is associated with Non-Hodgkin’s lymphoma but Hodgkin’s lymphoma is associated with minimal change GN.


Focal Segmental Glomerulonephritis In infective endocarditis, immune complexes
form and may lead to Focal segmental proliferative glomerulonephritis. ACE
inhibitors usually reduce proteinuria and lipemia, and may slow the progression towards renal disease.

Mesangio Capillary Glomerulonephritis occurs in post streptococcal infection and caused by immune complexes depositing sub endothelially (capillary). The two most
common variants are type I MCGN and type II MCGN (also called dense deposit
disease). Type I is much more common than type II, which is a rare disease.

MCGN is characterized by capillary basement membrane thickening and mesangial cell proliferation. associated with low levels of C3. Mesangiocapillary glomerulonephritis is a significant cause of nephrotic syndrome in children (accounts for about 8% of cases) and adults (accounts for about 14%).

Immune complex deposition is predisposed to by C3 nephritic factor rise in MCGN type II, which stabilises C3bBb and activates the complement pathway.In post streptococcal glomerulonephiritis, oliguria, proteinuria and haematuria occurs.

Diffuse proliferative glomerulonephritis is the commonest glomerulonephritis in SLE.

There is mesangial and endothelial cell proliferation, polymorphonuclear cell infiltrate
and granular subepithelial deposits of C3. It also carries the worst prognosis with
progression towards renal failure.

The currently recommended therapy is pulse intravenous corticosteroids in combination

with pulse cyclophosphamide continued for at least 12 months after remission. Newer
regimes include combinations of prednisolone and mycophenolate


Radiopaque stones
Calcium oxalate, calcium phosphate, triple phosphate, cystine stones.
Radiolucent stones
Uric acid, xanthine stones.

Bartter’s syndrome

is hypokalaemic alkalosis due to hyperaldosteronism. The defect is
due to reduced resistance to angiotensin II.
Liddle’s syndrome
is a rare condition in which there is hypokalaemic alkalosis but low
aldosterone levels are found. It is seldom necessary to treat metabolic alkalosis by
acidification, fluids often help to correct it.

Causes of nephrogenic Diabetes Insipidus hypercalcaemia ,hypokalaemia ,sickle

cell disease ,lithium carbonate, amyloidosis, myeloma ,malnutrition, analgesic nephropathy,
Pregnancy, demeclocycline ,methicillin
Diabetic nephropathy
In type I diabetes, there is a 50% chance of progressing towards ESRD.
In type II diabetics, there is a 15% chance of doing so.

Multiple myeloma: Proteinuria is present in 90% of patients and abnormal light chains

(Bence Jones protein) are found in 80% of patients. At diagnosis, the creatinine level is
elevated in 50% of patients. Proximal tubules are increasingly damaged by the large protein load, and large obstructing casts frequently form within the tubules. The combination of interstitial fibrosis and hyaline casts surrounded by epithelial cells or multinucleate giant cells constitutes myeloma kidney.


Additionally, hypercalcemia and hypercalciuria as well as hyperuricemia contribute to
kidney damage. Renal amyloidosis (usually lambda light chains) and light chain
deposition disease (usually kappa light chains) occurs. Cryoglobulinaemia is uncommon
but may cause a membranoproliferative glomerulonephritis

von Hippel Lindau

disease is transmitted as an autosomal dominant condition. Affected
individuals may have renal cysts, Clear cell renal cell carcinoma (CCRCC), retinal
angiomas, central nervous system haemangioblastoma, phaeochromocytoma.

Rhabdomyolyis causes myoglobinuria, which must be differentiated from haematuria.

Causes of rhabdomyolysis are falls, drugs (metals, gasoline, alcohol), viral infections &
malaria.rhabdomyolyis causes myoglobinuria, which must be differentiated from Haematuria.Ultrasound is a good method of detecting renal scars. DMSA, which is taken up by tubular cells can be used to detect scars (as opposed to DTPA which is filtered by the glomerulus and not taken up by tubular cells, hence not good for detecting scarring).

Growth Hormone usually decreases following an elevation in blood glucose after a

meal. It is usually increased during sleep or during starvation. It causes both retention of
sodium and potassium which are required for growth metabolism.
Elevated GH levels increase IGF-1 blood levels. Because IGF-1 levels are much more
stable over the course of the day, they are often a more practical and reliable measure
than GH levels. Elevated IGF-1 levels almost always indicate acromegaly.


The oral glucose tolerance test is also used to diagnose acromegaly, because ingestion
of 75 g of the sugar glucose lowers blood GH levels less than 2 ng/ml in healthy people.
In patients with acromegaly, this reduction does not occur.

In acromegaly, hypertension, diabetes and goitre are associated. A damaged pituitary

stalk reducing the dopamine suppression signal, stimulates prolactin secretion.
Pseudogout (calcium pyrophosphate deposition) is also associated. Patients have normal calcium but increased phosphate levels. Patients with acromegaly have an increased risk of colorectal neoplasia.

The best treatment option for a large pituitary tumour in acromegaly is transphenoidal removal of the tumour. Octreotide (somatostatin analogue) and pegvisomant (growth hormone receptor blocker) are effective forms of treatment. Bromocriptine (dopamine agonist) is less effective.

Prolactin secretion is inhibited by dopaminergic pathway. Hyperprolactinaemia can be

caused by Dopamine receptor antagonists (many antipsychotic drugs e.g. phenothiazines, risperidone), hypothyroidism, liver or renal failure, pituitary adenoma /acromegaly. It
leads to galactorrhoea and osteoporosis/osteopenia.

Treatment is with dopamine

receptor agonists (bromocriptine, cabergoline).
Microprolactinoma: The most frequent symptoms at onset are oligoamenorrhoea (60%)
and galactorrhoea (50%), and headaches. Treatment is with bromocriptine (e.g. 5 mg od).

Cushing's syndrome is a non-specific name for any source of excessive glucorticoids.

There are four main causes:
1) Exogenous glucocorticoids
2) Pituitary Cushing’s syndrome known as Cushing’s disease, due to a pituitary
adenoma secreting excessive ACTH
3) Ectopic production of ACTH. Two varieties; one due to malignant tumours usually of
the lung , these patients present with hypertension, hypokalaemia and hyperpigmentation.
The second type is due to carcinoid tumours.


The inferior petrosal sinus sampling test, an elevated central ACTH concentration
compared to a peripheral value (from arm veins) indicates pituitary dependent
Cushing's disease. The test involves a microcatheter being advanced through initially the femoral vein and eventually into the inferior petrosal sinuses which lie along the internal
aspect of the skull base which drain blood from the pituitary gland.

Metyrapone is an inhibitor of 11 beta hydroxylase, inhibiting the conversion of 11 deoxycortisol to cortisol, and can be used as treatment in Cushing’s syndrome.
In ectopic ACTH syndrome, hypokalaemic alkalosis is typical. Ectopic ACTH is not suppressed by high doses of steroids such as 8 mg dexamethasome.It is typically caused by small cell carcinoma of the lung. Thymoma, carcinoid tumour,medullary carcinoma of the thyroid, pancreatic carcinoma and phaeochromocytoma are associated with ectopic ACTH secretion.

• Small cell carcinoma of the lung.

• Thymoma,
• carcinoid tumour,
• medullary carcinoma of the thyroid,
• pancreatic carcinoma and
• phaeochromocytoma .
Ectopic ACTH

Clomiphene is used as a fertility drug in hypopituitarism.

It stimulates ovulation through
the release of gonadotropins from the pituitary gland.
It can also be used in PCOS
and in treating male infertility.


Diabetic neuropathy
Autonomic neuropathy to the gut, bladder and sexual organs (impotence) can occur. A
3rd nerve mononeuropathy can occur. Motor neuropathy can cause muscle wasting, and
sensory neuropathy causes vibration sensory loss.

Graves disease

thyroid autoantibodies are increased. Almost 80% of patients have exopthalmos. Medical treatment such as carbimazole or radioiodine
treatment are recommended rather than surgery. There will be increased uptake on the
thyroid radioisotope scan.

Toxic thyroid nodules are best treated with radioactive iodine as this concentrates on the

overactive adenoma cells. Radioiodine treatment is contraindicated in young children,pregnant and lactating women. The major complication of treatment with radioactive iodine is the progressive incidence of hypothyroidism and thyroid replacement may be necessary in the future.

Medullary thyroid carcinoma produces peptides and neurohormones which lead to

symptoms of irritability, diarrhoea and sweating. It can be inherited in association with MEN type II.
Anaplastic thyroid carcinoma is commoner in female patients. It can present with
dysphagia, cough and neck pain. It is more invasive than papillary carcinoma.

Poor prognostic factors in thyroid carcinoma advanced age (>50), male,

prior neck surgery, and associated multiple endocrine neoplasia.
Overall, papillary carcinoma has a 30-year cancer-related death rate of 6%. Follicular
carcinoma has a 30-year cancer-related death rate of 15%.


Parathyroid hormone levels rise with hypocalcaemia. It increases plasma calcium by:
increasing osteoclastic resorption of bone (rapid effect)
increasing intestinal absorption of
calcium (slow effect) an
increase in tubular resorption of calcium and increased excretion of phosphate

Primary hyperparathyroidism. The radiograph of the skull commonly shows

osteopenia with a speckled appearance - the so called "pepper pot skull".
primary hyperparathyroidism, typically there is hypercalcaemia, low phosphate and raised
alkaline phosphatase.
Causes of hyperparathyroidism are:
1.Diffuse hyperplasia 10-40%
2.Single adenoma 50-80%
3.Multiple adenomas 10%.
4.Parathyroid Carcinoma 2%

Pseudohypoparathyroidism is a genetic disorder that resembles hypoparathyroidism

(lowered levels of parathyroid hormone) but is caused by a lack of response to parathyroid hormone rather than a deficiency in the hormone itself. A picture very similar to hypoparathyroidism develops with hypocalcaemia in the blood and high phophate
Levels.This defect also causes short stature, round face and short hand bones and is also called Albright's hereditary osteodystrophy.

When Albright's hereditary osteodystrophy occurs

without hypocalcemia, it is known as pseudopseudohypoparathyroidism.


MULTIPLE ENDOCRINE DISORDERS
MEN 1 [pituitary tumour, parathyroid hyperplasia/tumour, pancreatic tumours (most commonly gastrinoma / insulinoma)]. Also known as Wermer’s syndrome.
Hyperparathyroidism is the most common and earliest feature of MEN1 ( 80-95%).Usually all four glands become hyperplastic.

Neoplastic transformation of pancreatic islets is the second most common manifestation of MEN1 (80%). Gastrinomas are the most common (presenting with peptic ulcer disease and diarrhoea. Insulinomas are the second most common.
Pituitary tumours occur in 50-70% of cases.

Familial multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant

disorder. The MEN1 gene on chromosome 11q13 has been cloned and mutations
identified. The gene emcodes a protein called menin which acts as a tumour suppressor gene.

MEN 2

MEN 2a is associated with medullary thyroid carcinoma (MTC), parathyroid tumours
(10-20%) and pheochromocytoma (20-50%).
MEN 2b is associated with presentation of medullary thyroid carcinoma, parathyroid
tumours and pheochromocytoma + ganglioneuromatosis (pathognomonic), and marfanoid habitus.

Conn's syndrome, renin levels are low, and excretion of potassium is high due to

increased sodium retention. There is autonomous aldosterone secretion in the presence of
low or suppressed renin activity. A low potassium (< 3.5 mmol/L) accompanied by
metabolic alkalosis is characteristic


Adrenal adenoma is the commonest cause of Conn's syndrome.
Sodium chloride infusion
is a diagnostic test, aldosterone levels are suppressed in the normal population but not in Conn's syndrome patients.

Addison’s disease as suggested by hyperpigmentation, hyponatraemia and hypotension.

A high 9 am plasma ACTH level with low or normal cortisol will confirm the diagnosis
of primary hypoadrenalism.
A low cortisol response with the short ACTH (synacthen) test would also show that the adrenal gland is not responding to ACTH.

Associations with Addison’s disease:

• pernicious anaemia
• primary ovarian failure
• vitiligo
• diabetes
The short synacthen test is done via the following:
1) take a basal sample for cortisol at time 0 min.
2) give 250 microgramme Synacthen i.v. or i.m.
3) sample for cortisol are taken at 30 mins. There should be a significant response unless
the patient is addisonian.

The equivalent ratio of

prednisolone: hydrocortisone
is 1:4.
The ratio for dexamethasone : rednisolone
is 1:10.


Kallman's syndrome describes the occurrence of hypothalamic gonadotrophin releasing
hormone deficiency and deficient olfactory sense - anosmia. It is usually inherited as an
X-linked or autosomal recessive disorder with greater penetrance in the male. More than
half of patients have associated nerve deafness, colour blindness,

mid-line cranio-facial deformities such as cleft palate or harelip, and renal abnormalities.
Most are of normal or above average stature. Females may present with primary
amenorrhoea; males with cryptorchidism. LH and FSH levels are typically low.

Klinefelter's syndrome is the most common cause of male hypogonadism with an

incidence of 1 in 1000 male births. Individuals have an extra X chromosome. Usually, the
karyotype is 47, XXY. Accelerated atrophy of germ cells before puberty results in sterility with small, firm testes. Many patients are tall with relatively long legs.Behavioural disorders and delayed speech development are common. Testosterone
therapy may be used to improve the development of secondary sexual characteristics.

Testicular feminisation is a cause of primary amenorrhoea rather than secondary

amenorrhoea. Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals.
Most patients with complete androgen insensitivity have a female gender.

Some patients

are first seen in the teenage years for evaluation of primary amenorrhea, but most are identified in the newborn period by the presence of inguinal masses, which later are
identified as testes during surgery.


Vasopressin (Anti Diuretic Hormone) acts on the distal tubule and collecting ducts to
increase permeability to free water. Deficiency of this hormone in diabetes insipidus
results in the excretion of dilute urine (increased water clearance) and hypernatraemia.

In a normal response to the water deprivation test the maximum urine osmolality

exceeds plasma osmolality and the urine osmolality does not increase > 5 % after
administration of vasopressin. The plasma osmolality normal range is 278-300
mosmol/kg and urine osmolality normal range is 350-1000 mosmol/kg.

In diabetes insipidus, patients are unable to concentrate their urine to greater than

plasma osmolality but after administration of vasopressin the urine osmolality increases
by > 50 %.
Patients with nephrogenic diabetes insipidus are unable to concentrate their urine and
they show no response to vasopressin

In psychogenic diabetes insipidus or compulsive water drinking, fluid deprivation

would stop the polyuria. Plasma and urine osmolality (<300 msom/kg) should be low in
psychogenic diabetes insipidus.
SIADH is confirmed by inappropriately elevated urine osmolality (often above 300
mOsm/kg) and urine sodium concentration (usually above 40 mEq/liter).


Phaeochromocytoma is a tumour of the adrenal medulla. The adrenal cortex produces
aldosterone, cortisol (glucocorticoid) and adrenal androgens.
The medulla produces adrenaline and noradrenaline. Phaeochromocytoma is associated with MEN II and von
Hippel Lindau syndrome. There is an association with retinal, cerebral and renal haemangiomas. Diagnosis is with raised urinary catecholamines over 24 hours, and also MIBG scan of the adrenals.

The treatment of hypertension in phaeochromocytoma is with alpha blockade prior to beta blockade. Alpha blockade reverses the peripheral vasoconstriction whereas beta blockade prevents tachycardia. The preferred alpha-blocker phenoxybenzamine, as it is
not a selective alpha 1 blocker but an irreversible alpha-blocker whose effects cannot be
overcome by an increase of catecholamines.

Hypertension should be managed with

phenoxybenzamine initially, increasing up to 80 mg per day, with addition of propanolol
after 3-4 days of alpha blockade.
Surgery without adequate alpha and beta blockade can result in hypertensive crisis (leading to high CVA, MI complications).

Polycystic Ovarian Syndrome (PCOS) is characterized by irregular ovulation and

menses, obesity, insulin resistance, acne, and hirsutism (excessive hair growth). Impaired
fertility is a prominent feature of PCOS. This is believed to result from elevated insulin
levels that stimulate excess androgen production by the ovaries.
Biochemically, PCOS is associated with:
a raised LH:FSH ratio ,insulin resistance
hyperandrogenism (raised androstenedione levels and raised testosterone).


Causes of hirsutism include:
• cyclosporin A
• Risperidone
• Minoxidil
• Phenytoin
• Ovariantumours
• Polycystic Ovary syndrome
• Congenital adrenal hyperplasia

Alopecia is associated with

SLE
hypopituitarism
zinc and iron deficiency
hyper and hypothyroidism

Hyperpigmentation is associated with

pellagra
porphyria cutanea tarda
Nelson's syndrome
Haemochromatosis
Addison's disease
Whipple's disease
primary biliary cirrhosis.


Congenital adrenal hyperplasia:
Hirsutism, ambibuous genitalia and precocious puberty in boys (normal puberty is seen in girls).
Premature epiphyseal closure is a
classical feature of CAH. It is also associated with hyperpigmentation and
hyperreninaemia due to sodium loss and hypovolaemia.

21-hydroxylase deficiency is the commonest cause of congenital adrenal hyperplasia.

This leads to excess androgen production due to shunting of 17 OH progesterone into
testosterone and androstenedione production. Increased 17 (OH) progesterone or
pregnanetriol in the urine is diagnostic of 21 hydroxylase deficiency.
Virilisation may result in clitoromegaly and labial fusion in the female at birth.

11-beta-hydroxylase is the second most common variant of CAH and accounts for

approximately 5% of cases. Deficiency of 11 beta-hydroxylase results in a loss of cortisol; hence, due to feedback mechanisms, there is an increase in ACTH and asubsequent increase in production of 11-deoxycorticosterone. Diagnosis is made by measuring 11-deoxycortisol, which is typically high. In the classic form, other hormones that may be elevated include DOC (a potent mineralocorticoid), urinary 17-ketosteroids,and urinary tetra hydrometabolites.

Congenital Adrenal Hyperplasia : There is also cortisol deficiency and replacement

with dexamethasone or hydrocortisone is appropriate. Efficacy of treatment is best
monitored by 17OH progesterone and androstenedione levels. Renin activity levels can be used monitor adequacy of mineralocorticoid replacement. Hypertension and hypokalaemia suggest excess treatment.

Alkaptonuria is an autosomal recessive disease due to deficiency of the homogentisate oxidase enzyme. It causes accumulation of homogentisic acid which deposits in cartilage
and connective tissue (causing sacroiliac joint and knee pains). It is one of the causes of
pseudogout. Oxidation of homogentisate causes urine to turn dark on standing.


PORPHYRIA
Infection, pregnancy, stress (eg argument) and drugs can precipitate an acute porphyria
attack.
Common drugs which can precipitate a porphyria attack are:
• Barbiturates
• Sulfonamides
• chloroquine
• steroids

Drugs which are safe in porphyria are: Aspirin

Atropine
Glucocorticoids
Insulin
Narcotic analgesics
Phenothiazines
Ranitidine
Serotonin Reuptake Inhibitors
Streptomycin

Hypokalaemic periodic paralysis is a condition associated with hypokalaemia and

episodes of weakness which may be profound. The weakness does not usually involve
bulbar and respiratory function.
This disorder is commonly caused by medication, especially diuretics. Potassium should
be given before bicarbonate as bicarbonate can precipitate further hypokalaemia. Other
ways of preventing acute exacerbations are avoiding heavy carbohydrate meals, a very
low sodium diet and spironolactone.


Normal anion gap metabolic acidosis:
8-16 Na+K-(Cl+HCO3) .
The causes of a normal anion gap metabolic acidosis are
renal tubular acidosis,
ileal conduit,
carbonic anhydrase inhibitors,
ammonium chloride ingestion.
Ureterosigmoidostomy

The causes of a increased anion gap metabolic acidosis are

• toxicity with salicylates
• ethylene glycol
• toluene
• lactic acidosis
• diabetic ketoacidosis

Nephrocalcinosis is related to type I (distal) renal tubular acidosis. It also causes

hyperchloraemic metabolic acidosis (it is one of the causes of normal anion gap
metabolic acidosis).
Type II (proximal) renal tubular acidosis is typically related to a Fanconi syndrome
(loss of amino acids, glucose, phosphate and uric acid into the urine).


Type 4 RTA is caused by a defect in the distal tubule, but it is different from classic
distal RTA and proximal RTA because it results in hyperkalaemia rather than
hypokalaemia. RTA type 4 is in effect hyporeninaemic hypoaldosteronism.
It occurs when blood levels of aldosterone are low or when the kidneys do not respond to
it. Fludrocortisone is usually effective as a form of treatment.

Type IV RTA may result from may result from sickle cell disease,

urinary tract obstruction, lupus, amyloidosis, or transplantation.

Liddle's syndrome is an autosomal dominant condition leading towards increased renal

tubular (collecting tubule) resorption of Na and in most cases potassium loss. There are
classically low renin and aldosterone levels and normal cortisol levels. The cause is
increased activity of luminal membrane Na channels.
Treatment is with triamterene or amiloride.

Bartter's syndrome is an autosomal recessive renal disorder. Presentation is often in

childhood with gastrointestinal upset and polyuria. There is associated hypokalaemic
alkalosis, elevated renin and aldosterone levels. Vomiting, constipation, polyuria and
polydipsia are common symptoms.

Plasmodium vivax and ovale are the only ones which have liver parasite dormancy.

Hypnozoites in the liver spread to the bloodstream and become trophozoites in the RBC


Plasmodium vivax and ovale only infect reticulocytes whilst falciparum infects
erythrocytes of all stages and malariae infects mature erythrocytes.

The Duffy blood

group is essential for vivax spread as the merozoites of these attach to the Duffy receptor on red blood cells.

Quinine can be given orally to treat falciparum malaria. Intravenous quinine is indicated

in complicated malaria e.g. cerebral malaria and hyperparasitaemia (>2%).
Hypoglycaemia is an important side effect of quinine therapy (causes insulin release) and
BMs should be checked 2 hourly.

Meningococcal meningitis: Immunisation is available against strains A, C and W135 of

this bacterium, however strain B is the most often implicated in meningococcal
meningitis in the UK.
Rifampicin, ciprofloxacin and ceftriaxone can be used for prophylaxis.

Bacillus cereus food poisoning is caused by toxin release. There are two types of toxin, -

the Diarrhoeal (causing diarrhoea) and the Emetic (causing vomiting). Symptoms with
the diarrhoeal toxin are nausea, cramplike abdominal pains hours after ingestion usually
of rice and watery diarrhoea. The diagnosis is confirmed by a laboratory test on a faecal
specimen.


Cryptosporidium is water borne and is a protozoan parasite.
Swimming in hot tubs and pools, lakes, ponds are risk factors. It can also be spread via uncooked food. Treatment is
conservative. Symptoms typically last for 1-2 weeks but longer in immunocompromised
e.g. HIV.

VACCINES

Live vaccines (attenuated) – easiest to memorise these (all others=inactivated)
• BCG
• Mumps
• Measles
• Rubella
• Yellow fever
• Smallpox
• Oral polio vaccine

Meningococcal Vaccines recommended in those at high risk to exposures

• (contact or health workers),
• immunodeficiency and
• post splenectomy.

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
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

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

Osteomalacia

is characterized by a low serum calcium and phosphate with elevated serum alkaline phosphatase. Osteomalacia may be caused by deficiency of vitamin D or phosphate deficiency.
Malabsorption syndromes, renal failure and liver disease can result in vitamin D deficiency.
Looser’s zone are linear areas of low density surrounded by sclerotic borders, which are a feature of osteomalacia.
In adults, treatment is with a daily dose of calciferol (20-25 micrograms).

Causes of osteoporosis are : postmenopausal women

Cigarette smoking
eating disorders such as anorexia nervosa or bulimia hypocalcaemia
heavy alcohol consumption
corticosteroids /Cushing's syndrome anticonvulsants


Medications for Osteoporosis:
Calcium and vitamin D
oestrogen replacement
selective oestrogen receptor modulator (SERM)
bisphosphonates

Pseudogout – positively birefringent crystals

Gout – negatively birefringent crystals

Pseudogout causes are:

Haemochromatosis ,wilson's disease ,alkaptonuria (ochronosis),hypothyroidism hyperparathyroidism ,hypomagnesaemia hypophosphataemia
In gout, serum uric acid is elevated in 50% of patients, and often not so in an acute flare
up. Inflammatory markers are often raised and the patient may be pyrexial in acute gout.
Synovial fluid analysis should be undertaken without delay.

Gout is associated

with : Hypertriglyceridaemia ,diabetes obesity ,Excessive alcohol use
chronic renal failure ,hypothyroidism hyperparathyroidism, myeloproliferative
lymphoproliferative disease ,psoriasis

Drugs reducing uric acid levels in Gout:

xanthine oxidase inhibitor (allopurinol) or a uricosuric drug (sulfinpyrazone)
Uric acid results from the breakdown of purines. Purines are found in many foods, for example: Beer and other alcoholic beverages. Anchovies, sardines in oil, fish roes, herring, Yeast, Organ meat (liver, kidneys, sweetbreads), Legumes (dried beans, peas).


Rheumatoid arthritis causes subcutaneous nodules over the elbows, swelling of the
wrists, ulnar deviation at the metacarpophalangeal joints, Butoinneire’s deformity, dinner fork deformity and swelling of the proximal interphalangeal joints.Periarticular erosions on the X ray are suggestive of rheumatoid arthritis.

Felty's syndrome consists of a triad of neutropenia, hypersplenism and rheumatoid

arthritis,
The pulmonary complications of rheumatoid arthritis are : pulmonary fibrosis
(interstitial lung disease) bronchiolitis obliterans with organizing pneumonia
bronchiectasis interstitial pneumonitis secondary to drugs,exudative pleural effusions
Caplan’s syndrome (pneumoconiosis, pulmonary nodules)

Osteoarthritis

Bouchard’s nodes are proximal interphlangeal nodes.
Heberden's nodes are distal interphalangeal nodes.
X ray features of osteoarthritis are: joint space narrowing

drug induced lupus.

Hydralazine, procainamide, isoniazid, chlorpromazine, D penicillamine & methyldopa

treat SLE.

Hydroxychloroquine and chloroquine


Causes of Charcot’s joints:
diabetic neuropathy,
syphillis
syringomyelia
leprosy

Causes of avascular necrosis of the bone:

SLE
Nephritis
vasculitis
long term steroids
sickle cell disease

Causes of sacroilitis:

ankylosing spondylitis ,Crohn's disease Whipple's disease ulcerative
colitis ,septic arthritis ,TB, Wegener's granulomatosis
Causes of mononeuritis multiplex : Rheumatoid arthritis
amyloidosis ,diabetes, leprosy ,sarcoidosis Churg Strauss ,Wegener’s granulomatosis
Polyarteritis nodosa

Causes of Iritis:

Behcet's disease
Reiter's syndrome
ankylosing spondylitis
sardoidosis


Reiter’s syndrome is urethritis, conjunctivitis, seronegative arthritis (cannot see, cannot
pee, cannot climb a tree). The typical patient is a young man with recent urethritis or
dysentery. The seronegative arthritis is usually a mono or oligoarthritis.
Other features are anterior uveitis, keratoderma blenorrhagica (brown abscesses on palms
and soles), mouth ulcers, plantar fasciitis and archilles tendinitis (enthesopathy), circinate
balanitis (painless rash) and aortic incompetence. The arthritis may relapse or remain
chronic. Management is usually with rest and NSAIDs.

Complex partial seizures

may be preceded by an aura, can be associated with behavioural and cognitive signs.
Partial seizures from the temporal lobe typically causes motor movements like grimacing and sucking movements, rotation of the head and eyes. Déjà vu and Jamais vu (unreal perceptions) may occur. Visual, auditory and olfactory hallucinations may occur. An aura may occur, associated with micropsia (distorted visual perception in which objects appear smaller than their actual size) or physicial sensations in the stomach.

Internuclear opthalmoplegia can be caused by:

Multiple Sclerosis
stroke (basilar artery)
encephalitis
syphilis
lyme disease
phenothiazines ,tricyclic antidepressants

Causes of optic neuritis:

Sarcoid
Multiple sclerosis
drugs (ethambutol)
infections (syphillis, CMV, brucella, toxoplasmosis)


Causes of papilloedema:
Intracerebral haemorrhage
central retinal vein thrombosis
venous sinus thrombosis
benign intracranial hypertension

The lateral gaze centre is situated in the pons.

A lesion in the right pons will cause
impaired conjugate gaze to the right side, with consequent deviation away from the right side.(look to left)

Medial medullary syndrome

is caused by an ipsilateral 12th nerve lesion (tongue paralysis) and contralateral weakness and loss of postural sense due to lesions in the
pyramidal tract and the medial leminiscus.

Lateral medullary syndrome:

9th and 10th nerve - dysphagia and dysarthria Nucleus ambiguus - vomiting and hiccup Vestibular nuclei - vertigo Inferior cerebellar peduncle -ipsilateral cerebellar ataxia Descending autonomic fibres - Horner’s syndrome Fifth nerve nucleus - loss of pain and temperature sensation over the face (ipsilateral) Lateral leminiscus - loss of pain and temperature sensation in the contralateral limbs

Gerstmann syndrome includes four features (acalculia, agraphia, finger agnosia, left right disorientation), and is due to a lesion in the dominant hemisphere.
In a right handed patient, the left hemisphere is dominant.

Lambert Eaton myasthenic syndrome,

60% of cases are paraneoplastic
(small cell lung ca is most associated).
The clinical features are proximal weakness, loss of tendon
reflexes and autonomic dysfunction.


Myasthenia gravis can be differentiated from Eaton Lambert myasthenic syndrome
by electromyography. Repetitive stimulation in myasthenia gravis leads to a decrement of
evoked muscle action potentials, whilst in myasthenic syndrome the condition improves
by repetitive stimulation. Also, in myasthenia gravis the tendon reflexes are
characteristically normal. If the reflexes are depressed, Eaton-Lambert syndrome should
be considered.

drugs which may make myasthenia worse erythromycin streptomycin

ampicillin
Verapamil propranolol
Aminoglycosides
Quinidine Procainamide
Magnesium Lithium Phenytoin chlorpromazine clozapine

PARKINSON’S

Drugs - Reserpine, tetrabenazine, Phenothiazines Toxins -methyl-phenyl-tetrahydropyridine, Manganese, Carbon monoxide,
Viral – Encephalitis,eg. Japanese B,
Neurone damage - Supra nuclear palsy, Shy Drager syndrome (Multi system atrophy), Cerebral tumour,
Wilson’s disease,
Huntington’s disease,
Neurosyphillis


Friedreich's Ataxia
is an autosomal recessively inherited. It is multisystemic. Outside neurological abnormalities, patients may have cardiomyopathy and diabetes.Neurological abnormalities include optic atrophy and retinitis pigmentosa, nystagmus,cerebellar disease and signs, loss of dorsal column sensation and weakness. Pes cavus (high arched feet).

Anti Yo antibodies are associated with a cerebellar syndrome due to either lung, breast or ovarian carcinoma.A mnemonic for cerebellar signs is VANISH’D – Vertigo, Ataxia, Nystagmus, Intention tremor, Scanning speech, Hypotonia and Dysdiadochokinesis.

Essential Tremor:

• bilateral action tremor of the hands and forearms
• absence of other neurological signs, except the cogwheel phenomenon
• may have isolated head tremor with no signs of dystonia ,Secondary criteria include a long disease duration (more than three years), a positive family history and beneficial response to alcohol.

Discomfort in the arms and legs, arm or leg restlessness, relief with movement and

worsening symptoms in the evening are features that satisfy diagnostic criteria of restless leg syndrome.
It is associated
with Parkinsonism, iron deficiency anaemia, diabetes mellitus and hypothyroidism.

Guillain Barre syndrome

is preceded by diarrhoea (e.g. campylobacter) and chest infections (e.g. mycoplasma) in two thirds of cases. Autonomic dysfunction and
hyporeflexia re associated. Studies have shown that plasma exchange and IVIg are
equally effective in treating people within two to four weeks of onset of GBS.

The criteria for chronic fatigue syndrome are :

• severe chronic fatigue of six months longer duration
• Have four more of following
symptoms: substantial impairment in short-term, memory ,poor concentration, sore throat
tender lymph nodes, muscle pain ,multi-joint pain without swelling redness headaches of a
new type pattern severity unrefreshing sleep post-exertional malaise lasting more than 24
hours
Low dose antidepressants are used in treatment of CFS, but suggested first line therapy
should include cognitive behavioural therapy.


Target cells are red cells with central staining with precipitated haemoglobin seen in
conditions with abnormal haemoglobin as well as cell membrane.
Sickle cell disease
thalassaemia
iron deficiency anaemia
Liver disease

Howell Jolly bodies contain nuclear remnants. Causes are:

Post splenectomy
Leukaemia
Megaloblastic anaemia
Iron deficiency anaemia

Heinz bodies are precipitated, denatured Hb within red cells.

G6PD deficiency.
Methaemoglobinaemia

Reactive lymphocytes

Ebstein Barr virus infection / infectious mononucleosis
CMV infection
toxoplasmosis
HIV


Sickle cell disease is due to substitution of valine for glutamic acid (position 6 of the beta
chain). All forms of sickle cell include HbS.
Aseptic necrosis of the hip, cholecystitis, renal papillary necrosis and proliferative
retinopathy are clinical features of sickle cell disease.

THALASSEMIA

Mutations in globin genes cause thalassemias.
Alpha thalassemia affects the alphaglobin
gene(s).
Beta thalassemia affects one or both of the beta-globin genes.

Drugs causing haemolysis in G6PD deficiency are:

Sulphonamides
Antimalarials (chloroquine, quinine, primaquine)
Antipyretics (aspirin + paracetamol)
Chloramphenicol
nitrofurantoin
Dapsone
Probenecid
Vit K


Haemophilia A
(factor VIII deficiency) or
B (factor IX deficiency)
both produce aprolonged APTT. They are both X-linked recessive.
An isolated prolonged APTT will be caused by deficiencies in factors VIII, IX, XI and
XII and by von Willebrand’s disease. Factor XII deficiency is not associated with
increased bleeding.

Von Willebrand's disease is autosomal dominant. Bleeding following trauma, epistaxis

and menorrhagia are described.
The tests to diagnose vWD include: bleeding time (prolonged) factor VIII level test
(measures the level of factor VIII and its ability to function) von Willebrand factor antigen test (the disorder is considered mild if a person has 20% to 40% of the normal amount, severe if the amount is less than 10% of normal) ristocetin cofactor activity test
(measures how well the von Willebrand factor is working) Therapy includes DDAVP , Factor VIII concentrates and plasma products, and
Tranexemic acid (fibrinolytic inhibitor).

Type I heparin induced thrombocytopenia (HIT) occurs within a few days of heparin

and is usually mild.
Type II occurs slightly later (5-15 days). It is
associated with thrombosis and a low platelet count.
Alternative anticoagulation should
be used (hirudin, danaparoid sodium).


Side effects of heparin:
Alopecia
thrombocytopenia
osteoprosis

Disseminated intravascular coagulation caused by inappropriate and excessive

activation of the haemostatic systems.
60% are caused by Gram negative sepsis. Other
causes include viral infections,
metastatic carcinoma, leukaemia,
obstetric causes,
extensive trauma and burns.

APTT, PT and TT are all prolonged, platelets and fibrinogen are low, D-dimers/FDPs are

high. Treatment is of underlying causes and by control of the haemorrhagic state.
Platelets, blood, cryoprecipitate and fresh frozen plasma may all be required.

Thrombotic thrombocytopenic purpura (TTP)

is characterised by microangiopathic
haemolysis and thrombocytopenia. There is a spectrum of presentations with TTP-HUS.
Neurological features are present in 60% of patients of TTP and renal failure is often
associated in HUS (haemolytic uraemic syndrome).With the introduction of plasma exchange (recommended treatment), the survival rate hasimproved from approximately 3% prior to the 1960s to 82%.


The criteria for Polycythaemia Rubra Vera are:
• increased red cell mass
• splenomegaly
• increased platelets, leucocytes, INCREASED NAP score and B12 (increased B12 binding protein release).
Increased serum viscosity may arise from hyperglobulinaemia or from an increased red cell mass, polycythaemia.
Treatment of hyperviscosity syndrome should be with fluid replacement and venesection.

The NAP score is a semiquantitative cytochemical assessment of alkaline phosphatase in neutrophils. The NAP score is based on staining intensity, with a possible score of 0-400.
It differentiates chronic myeloid leukaemia (low) from reactive leucocytosis (high), eg
bacterial infection.
It may assist in the differentiation of polycythaemia rubra vera (high) from other causes of erythrocytosis (normal).

Cold Agglutinins:

IgM which agglutinate red cells between 0 and 4C. Causes are:
coxsackie virus, EBV, CMV, Mumps, HIV, syphilis, malaria, legionella, mycoplasma,
listeria, E coli, lymphoma, leukaemia, myeloma, Waldenstrom’s macroglobulinaemia, .

Myelodysplasia can be classified into five subtypes

Refractory anaemia
Refractory anaemia with ring sideroblasts Refractory anaemia with excess blasts Refractory anaemia with excess blasts in transformation (near AML)
CML.


Hypoxia, acidosis, high CO2, raised 2,3 DPG, raised temperature, high altitude and
anaemia all shift the oxygen dissociation curve to the right, reducing haemoglobin’s
affinity for oxygen.

Raised levels of HbF (fetal hemoglobin) shifts the curve to the left.