Medicine Long Case

Asthma
What are the clinical features?
 Classical history is that of episodic dyspnea especially on expiration, nocturnal cough, wheezing, chest tightness with diurnal variation, being worse in the
morning. Precipitating factors may be present.
 On examination, look for tachypnea, polyphonic wheeze, hyperinflation of the chest, hyperresonance and reduced air entry. Look for associated atopic
disease e.g. ezcema and allergic rhinitis.
 In terms of severity, red flag signs are silent chest, PEF < 33%, cyanosis, feeble respiratory effort and confusion.

What is your differential diagnosis?

 COPD
 CCF aka cardiac asthma
 GERD, Stridor
 Vocal cord dyskinesia
 Bronchitis

What are top 3 causes of chronic cough?

 Post-nasal drip
 Asthma
 GERD
 ACE-I

Why is this not chronic bronchitis?

In chronic bronchitis, there is the presence of cough with sputum production not attributable to other causes on most of the days for at least 3 consecutive months
in a year for at least 2 successive years.

Why is this not cardiac asthma?

Cardiac asthma means left ventricular failure in which the patient usually presents with sudden severe dyspnea and cough with profound mucoid expectoration. On
examination, there are bilateral basal crepitations and no rhonchi or wheeze.

What is bronchial asthma?

It is a chronic airway inflammatory disorder characterised by hyperresponsiveness of the airways to various stimuli presenting as breathlessness, cough, chest
tightness and wheeze. It is reversible.

What are the cardinal pathophysiologic features of bronchial asthma?

  Airflow limitation which is usually reversible spontaneously or with treatment
 Airway hyperresponsiveness
 Airway inflammation. Inflammation is central to the disease process, and symptom progression and disease control depends on successful management of
inflammation.

What are the 3 factors contributing to airway narrowing?

 Bronchospasm
 Inflammation and swelling
 Increased mucus production

How can you diagnose a case of bronchial asthma?

Typical history with cardinal features of breathlessness, cough, wheeze and chest tightness plus any of the following that is FEV1 of 12% an more and 200ml increase
post-bronchodilator treatment and PEFR of more than 20% of diurnal variation on 3 or more days in a week for 2 weeks.

What investigations would you do?

 FBC looking for eosinophils
 RP looking for hyperK from nebulised salbutamol which stimulates entry of K into the cells
 Sputum c/s and cytology looking for eosinophils
 Lung function test looking for obstructive pattern of FEV1/FVC
 Serial peak expiratory flow rates
 CXR looking for hyperinflation, and to exclude a pneumothorax or ABPA
 ABG in acute severe asthma
 Skin prick test

What is an acute severe asthma?

Status asthmaticus is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and corticosteroids that persists for days to
weeks.

How do you assess the severity of an acute bronchial asthma exacerbation?

(See Table)

How do you manage an acute exacerbation?

 Continunous inhlaed bronchodilators i.e. salbutamol with ipratroprium given via nebulisation- 1ml salbutamol with 2ml ipratropium bromide and 2ml NS
 Steroids 0.5 – 1mg/kg prednisolone PO (typically comes up to 30 – 40mg). The effect of steroids usually kicks in 4 – 6 hours later so it should be given early.
No difference between IV and PO as the effect is transcriptional i.e. it works on DNA
 If it is a mild/moderate exacerbation, continue SABA q 1hr
  If severe, repeat nebulisations 2 – 3 times with bronchodilators. If need, consider PO prednisolone or IV hydrocortisone or IV 1 – 2 g MgSO4 over 30
minutes (NB watch for hypotension, affects calcium, works by relaxing bronchial smooth muscle to increase pulmonary function

What are the features of life-threatening asthma?

Feeble respiratory effort, hardly able to talk, drowsy or confused, decreased respiratory rate, decreased paradoxical thoracoabdominal breathing, no wheeze i.e.
silent chest, bradycardia, clinical cyanosis

How do you treat acute severe bronchial asthma? (status asthmaticus)

Assess Airway Breathing Circulation. Secure the airway. Administer high flow supplemental oxygen.

How to monitor a patient with acute severe bronchial asthma?

Establish intravenous access and run IV 500ml crystalloids over 3 – 4 hours. Monitor vitals, pulse oximetry and do ECG.

What is the pathophysiology of cardiac arrest in asthma?

 Hypoxemia
 Obstructive shock (Tension PTX secondary to volume trauma or barotrauma

What are the indications of assisted ventilation?

After the initial management of the 1st presentation of asthma, how would you confirm the diagnosis?
 Diagnosing airway obstruction
 Spirometry shows FEV1/FVC < 0.7 (COPD guidelines), or 0.75 – 0.8 (GINA guidelines)
 Diagnosing airflow variability
 Increase in FEV1 post-BD by 12% and 200mls OR Variability after 4 weeks of steroid treatment OR Variability documented between clinic and hospital visits
 Peak Expiratory Flow Rate (Ask the patient to do the PEFR twice a day or multiple times and take the highest value, subtract the lowest value)  Average
diurnal variability > 10% is confirmatory
 Provocation tests are basically the reverse of the other tests. It is done either by exercise or metacholine which is a non-selective muscarinic receptor
antagonist. Provocation tests are sensitive but not specific

When is it ideal to test variability?

1) Before starting chronic asthma treatment
2) Don’t delay acute treatment for this

What if patient has already been started on some chronic treatment prior to seeing you?
Either step up or step down
What if there was no variability in airflow?
 Recently pre-medicated e.g. SABA given 4 hours ago, LABA 12 hours ago
 Severe asthma with fixed airflow limitation
 Alternative diagnosis where there is no variability

How do you assess control of asthma?

(See Table)
 Symptom control – Use GINA Table for long case, for Sg clinics we use ACT though
 Future risk  Previous intubations or ICU, Severe exacerbations in the past year, High use of reliever, Major psychiatric or socioeconomic problems, High
use of relievers, Smoking/Exposure to smoking, Pregnancy, Low FEV1
 Note that severity isnot controlled. Rather it is assessed retrospectively.

What are the broad principles for pharmacological management of asthma?

 There are 4 main aims of treatment
 Good symptom control
 Reduce future risk
 Reduce fixed airflow limitation
 Minimise side effects

What is the stepwise approach to asthma treatment?

 Bronchodilators vs Corticosteroids = Controllers vs Relievers
 LTRAs are less effective than ICS
 Tiotropium (LAMA) is added in stage 4
 SABA – Salbutamol
 LABA – all the ‘erols’ e.g. salmeterol with the exception of Fenoterol
 SAMA – Ipratropium
 LAMA – all the ‘iums’ with the exception of ipratropium
 Step 4 asthma therapy is SMART therapy i.e. Symbicort Maintenance and Reliever Therapy where Symbicort is a combination of budesonide and
formoterol. This is a combination of an ICS and LABA which can be used as both a reliever and controller. The advantage of this combination is that it has
quick onset (fast relief) but also long-acting.
 Controllers are medications taken daily on a long-term basis to prevent exacerbations of asthma and control of asthmatic symptoms. They have an anti-
inflammatory effect. The most effective controller medications currently available are inhaled glucocorticosteroids.
 Relievers are medications taken as required to relieve symptoms of wheeze or breathlessness. They act quickly and reverse the bronchospasm occurring
during attack. The most effective relievers are rapid acting inhaled beta 2 agonists such as salbutamol, but inhaled anticholinergics such as ipratropium.

What is the stepwise management of asthma?

Asthma control test (ACT)
1) ACT score ≥ 20  maintain or step down
2) ACT score < 20  step up
 Step 1 – needed reliever or controller
 Step 2 – low dose ICS
 Step 3 – low dose ICS + one “add on drug” (Montelukast)
 Step 4 – medium to high dose ICS plus one more more “add on drug/s”
 Step 5 – refractory
Add on drug
 Theophylline Slow Release

This patient is currently being treated at Step 2 but his asthma is not well-controlled. What should you do next?
If treatment is not working, don’t say step up from the get go. First, take a look at
 Compliance
 Technique
 Diagnosis
 Comorbids
 Triggers

What is the discharge criteria for asthma?

In order to decide on the patient’s disposition, reassess patient after 1 – 3 hours.
 Good response i.e. PEF at least 70%, 90% SaO2, not in respi distress  Discharge
 Partial response i.e. PEF 40 – 69%  Admit to ward
 Poor response i.e. PEF < 40%  Admit to ICU
 In asthma, you should expect the hyperventilating patient to have a low CO2. Thus, do ABG in cases where you are worried about decompensated Type 2
RF in which case the ABG is normal as the patient is tiring out.

How to step down treatment for asthma?

If patient’s asthma is well-controlled, then every 3 months, reduce the dose of inhaled corticosteroids by 25 to 50%.

What steroid-sparing drugs can be used in asthma?

Salbutamol – Beta 2 agonist, Ipratropium bromide – anti-muscarinic which blocks M3 receptors that mediate bronchoconstriction

What new therapy is available for bronchial asthma?

Omalizumab, a monoclonal antibody directed against IgE can be given subcutaneously 2 to 4 weekly.
What is rescue therapy?
If the patient develops severe asthma or loss of control at any step during therapy, a short course of oral corticosteroids is given. This is called rescue therapy. PO
prednisolone 30 to 60mg daily is given in a single morning dose or 2 divided doses for 3 to14 days. Tapering is not necessary, if it is not given for more than 3 weeks.

What is the treatment for refractory asthma?

Home nebulisation continuous or PRN
Vaccinations – influenza, pneumococcal??
Anti-IgE omalizumab

What is the non-pharmacological treatment for asthma?

 Disease education
 Smoking cessation
 Inhaler technique
 Trigger avoidance
 WAAP

What are the different phenotypes of asthma?

1) Allergic
2) Non-allergic  Less able to respond to ICS
3) Late onset asthma  Less able to respond to ICS hence requiring higher doses
4) Asthma with fixed airflow limitation due to recurrent exacerbations with fixed airway remodelling

When should you think of an alternative diagnosis?

 Isolated cough without other respiratory symptoms  Drug-induced, GERD, Post nasal drip
 Paresthesia, giddiness, lightheadedness associated with breathlessness  Hyperventilation
 Chronic sputum production  COPD, Bronchiectasis
 Inspiratory wheeze  VC dysfunction

What is intrinsic and extrinsic asthma?

Extrinsic asthma is atopic or early onset asthma. A definite external cause is present and it causes a type 1 hypersensitivity reaction. Serum IgE and eosinophils are
raised. The process is mediated by Th2 cells causing a release of IL-4 and IL-5, which triggers IgE synthesis and sensitisation of mast cells. In the early phase (within 1
hr), there is a release of leukotriene D4, PGE2, histamine, accompanied by reflex bronchoconstriction due to sitmulation of vagal receptors. In the late phase, there
is recruitment of leukocytes which damage the epithelium, reducing the production of NO and thus causing smooth muscle contraction. Eosinophils perpetuate the
inflammation. Examples of extrinsic asthma include atopic asthma, occupational asthma, ABPA. There is often a family history and it develops in childhood.

Intrinsic asthma is non-atopic or late-onset asthma where no causative agent can be identified, and it occurs via a non-immune mechanism. IgE antibodies are
normal. It is triggered by respiratory infection, aspirin, stress, exercise or the cold. It usually begins after the age of 30 years and tends to be more continuous and
more severe. Status asthmaticus is also more common.

What is cough variant asthma?

What is exercise-induced asthma?

When exercise produces asthma, 10% or more reduction of FEV1 after exercise is diagnostic. Cold dry air that enters into the lungs during exercise is the main
trigger factor. Increased ventilation results in water loss from the pericellular lining fluid of the respiratory mucosa trigger mediator release. Heat loss from the
respiratory muscosa is also involved. Treatment of exercise-induced asthma is single dose short-acting beta agonist immediately before exercise. Inhaled
corticosteroids twice daily for 8 to 12 weeks reduces severity. If abnormal spirometry and persisten symptoms, inhaled corticosteroids with long-acting beta 2
agonists.

What are the pulmonary eosinophilic disorders?

Churg Strauss (asthma, medium and small vessel autoimmune vasculitis involing mainly pulmonary but also affecting GIT and peripheral nerves, eosinophilia),
Pulmonary eosinophilia which may be tropical or chronic

What are the precipitating factors of asthma?

Environmental allergens, Varnish (isocyanate), Cigarette smoke, Cold air, Exercise (at the end of it), Emotion, Viral infections e.g. rhinovirus, parainfluenza, Drugs e.g.
aspirin causing imbalance in the metabolism of arachidonic acid, beta blockers

What do you know about aspirin-induced asthma?

Samter’s triad consists of asthma, aspirin sensitivity and nasal/ethmoidal polyposis

How to manage environmental triggers?

 Indoor allergens (house dust mites i.e. dermatophagoides pteronyssinus are allergens most commonly found in bedding and carpets. The most effective
method is to wash blankets, bed sheets, pillow cases and mattress pads at least weekly using at least 65 degrees C water and install impervious covers over
mattresses and pillows. Also remove carpets and soft toys or wash them weekly if present. Avoid prolonged contact with upholstered furniture. Cockroach
allergen is reduced by cockroach extermination followed by routine cleaning.
 Irritants from smoking should be avoided
 Avoid exertion or exposure to exercise outdoors when levels of air pollution are high (PSI > 100)
 Drugs e.g. NSAIDs or salicylates may exacerbate asthma. The concurrent useo of beta blockers may provoke wheezing

How would you counsel your patient regarding inhaler technique?

1) Remove the cap and shake the inhaler
2) Breathe out first to empty your lungs
3) Seal your lips around the mouthpiece
4) Breathe in as deeply as possible while simultaneously pressing
 5) Hold your breath for inhaled corticosteroids
6) Gently exhale
7) Wait for 30s before the next nebulisation
8) Rinse mouth after ICS
9) If the patient’s technique is very poor, suggest using a spacer. However, a spacer requires priming with warm soapy water and spray 10 puffs when
drying to prime the spacer

What are risk factors for death in asthma?

Prior intubation and ventilation, Hospitalisation or ED visit for asthma in the past 1 year, Current use of systemic steroids or recent withdrawal from systemic
steroids, Not currently using inhaled corticosteroids, Using > 1 canister of inhaled SABA, History of non-compliance, History of psychiatric or psychosocial disease

What is brittle asthma?

This is an unusual variant of asthma characterised by severe life threatening attacks that may occur within hours or even minutes with little or no warning
symptoms. Patients are at risk of sudden death although their asthma may be well controlled in between attacks.

What is the difference between bronchial asthma and cardiac asthma?

What is the difference between wheeze and stridor?

What considerations are there for asthma treatment in diabetics?

Corticosteroids can be used if necessary but regular sugar monitoring should be done. In severe acute asthma, insulin therapy may be necessary. Metformin should
be avoided in uncontrolled asthma and is contraindicated in acute severe asthma. Dose of OHGAs should be adjusted

What about asthma in pregnancy?

Uncontrolled asthma is associated with maternal complications of hyperemsis gravidarum, hypertension, preclampsia, vaginal haemorrhage, complicated labour as
well as fetal complications such as IUGR, low birth weight, preterm baby, increased perinatal mortality and neonatal hypoxia. All normal asthma medication can be
continued during pregnancy.

What about asthma with arrhythmias?

Digoxin and amiodarone may be used. Aminophylline or theophylline should be avoided.

What about asthma with heart failure?

Diuretic is the drug of choice. ACEIs should be continued if tolerated. Digoxin may be given, as well as carvedilol in low doses.

What about asthma with IHD?

GTN and CCBs (diltiazem and verapamil) is the treatment of choice. Clopidogrel is preferred to aspirin as it may trigger or aggravate asthma. Sometimes,
cardioselective beta blockers like metoprolol may be given. Asthma should be well controlled.
COPD What are the differential diagnoses for COPD?

Why is this not a case of chronic bronchitis?

What is the basic difference between bronchial asthma and COPD?

What are the findings in spirometry?

What investigations should be done?

What is COPD?
COPD is A small airway and parenchymal disease characterised by airflow limitation which is not fully reversible. It is usually progressive and associated with an
abnormal inflammatory response of the lung to noxious particles or gases. FEV1 < 80% predicted and FEV1/FVC < 70% predicted with less than 12% improvement in
FEV1 post-bronchodilators.

What are the mechanisms of airflow limitation in COPD?

Increased mucus production and reduced mucociliary clearance, loss of elastic recoil, increased muscle tone and pulmonary hypertension.

What is the presentation of COPD?

History is classically fixed, progressive exertional dyspnea.

What are the systemic features of COPD?

Muscle weakness, peripheral edema due to impaired salt and water excretion, weight loss due to altered metabolism, increased osteoporosis and increased
circulating inflammatory markers

What are the risk factors or causes of COPD?

What organisms are associated with an acute exacerbation of COPD?

Haemophilus influenza, Streptococccus pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae, Pseudomonas aeruginosa

What are the complications of COPD?

Pulmonary hypertension, cor pulmonale, respiratory failure, secondary infections, polycythemia

How do you assess the severity of COPD?

GOLD classification is Stage 0 which has normal spirometry and presence of chronic symptoms (cough, sputum production), Stage 1 (FEV1/FVC < 80%, none or mild
symptoms), Stage 2 (FEV1/FVC < 70%, mild to moderate symptoms), Stage 3 (FEV1/FVC < 70%, breathlessness on minimal exertion), Stage IV (FEV1/FVC < 70%,
 breathlessness at rest)

How do you treat COPD?

Smoking cessation, Trigger avoidance and Pharmacological treatment according to the stage of the disease.
What is the role of inhaled steroids in COPD?

What is the role of oral steroids in COPD? What are the indications for starting steroids in COPD?

What is the prognosis of COPD?

Pneumonia What is the definition?

 Clinical definition – Acute LRTI which is a/w fever, s/sx in the chest, and CXR abnormalities
 Pathologic definition – Inflammation of lung parenchyma which is characterised by consolidation due to exudate in the alveolar space
 This is different from pneumonitis which is inflammation of the interstititum which presents clinically as atypical pneumonia

What are the common organisms?

What is the etiology?

What are the clinical features?

What investigations would you do?

How do you assess the severity?

How do you manage?

What are possible complications?

What are causes of poorly resolving pneumonia?

Presenting complaints: cough, dyspnea, sputum production, pleuritic chest pain, fever – BUT all definitions of pneumonia require finding of pulmonary infiltrate on
chest radiograph

Management
Risk stratification and admission
 Decision regarding hospitalization: patient’s stability, risk of death and complications, other active medical problems, psycho-social
o Risk of worsening highest on the day of presentation  if okay after 24h, likely to be stable at home
o Absolute indications for admission: hypoxemia (O2 saturation <90% or PaO2 <60 mmHg) or serious hemodynamic instability, suppurative
or metastatic disease (empyema, lung abscess, endocarditis, meningitis, osteomyelitis), high-risk infections (e.g. Staph aureus, gram-
negative rods, anaerobes)
 Pneumonia Severity Index (PSI): stratifies patients based on 30-day mortality
Antimicrobial therapy
 Principles
 Antimicrobials: Regimens covering typical and atypical causes of death a/w lower risk of death
 Duration: 10-14/7
o Extended course: legionella, high-risk organisms (Staph aureus or GNR), suppurative complications
 Route
o PO = IV  if antibiotics have good oral bioavailability and patients have functioning GIT
o Switching to oral therapy (American Thoracic Society): T≤37.8C on 2 occasions 8h apart, ↓TW, functioning GIT, adequate oral intact
o Usually d/c within 24h after switching to oral
 Common antibiotics
o 3rd gen cephalosporins: ceftriaxone 1-2g/d, ceftizoxime 1-2g Q8-12H, cefotaxime 1-2g Q6-8H
 Ceftazadime is active against Pseudomonas, and has weak activity against gram-positive
o Doxycycline: 100mg Q12H
o Antipneumococcal fluoroquinolones: levofloxacin 500mg/d, gatifloxacin 400mg/d, moxifloxacin 400mg/d
o Macrolides: azithromycin 500mg/d, erythromycin 500mg Q6H, clarithromycin 500mg Q12H
o Ampicillin-sulbactam 1.5-3g Q6H
o Antipseudomonal beta-lactams: pip-tazo 3.375g Q6H, cefepime 1-2g Q12H

Setting Antibiotic Therapy Common organisms

Outpatient - Antipneumococcal fluoroquinolone; OR
- Advanced macrolide
General Ward - 3rd gen cephalosporin + macrolide/doxycycline
- Antipneumococcal fluoroquinolone
- Beta-lactam with beta-lactamase inhibitor +
macrolide/doxycyline
ICU - Antipneumococcal fluoroquinolone/macrolide
Typical: Streptococcus pneumonia,
Haemophilus influenza
Atypical: Mycoplasma pneumonia,
legionella, Chlamydia pneumonia
As above
 No risk of Pseudomonas + + Staph aureus, drug-resistant
aeruginosa - 3rd gen cephalosporin OR beta-lactam with Streptococcus pneumonia, GNR
beta-lactamase inhibitor
ICU - Antipseudomonal beta-lactam As above
Risk of Pseudomonas + Either + Pseudomonas aeruginosa
aeruginosa - Aminoglycoside + antipneumococcal
fluoroquinolone/macrolide; OR
- Antipseudomonal beta-lactam + ciprofloxacin

Clinical stability and discharge

 No data whether type of organism affects criteria for discharge
 Criteria for discharge
o Stable vital signs for 24h (T≤37.8, RR≤24, HR≤100, SBP≥90, SpO2≥90% on RA)
o Tolerate oral antibiotics
 Early conversion from IV to PO therapy does not adversely affect outcomes
 No need to observe patients for 24h after switch to oral therapy
o Maintain hydration and nutrition
o Mental status normal
o No other active clinical or psychosocial problems requiring hospitalization
 Adequate oxygenation on room air
 Advise: patient likely to feel unwell for a few weeks before all symptoms resolve and can revert to normal activities
 Pneumococcal vaccine if not previously immunized

Who is at the highest risk of pneumococcal disease?

Children < 2 years
Persons who have compromised antibody response to capsular polysaccharides e.g. SOT, HIV, multiple myeloma
Elderly aged > 65 years

What are the vaccines available?

PPSV (Polysaccharide) and PCV (Conjugate)
PPSV interacts directly with the B cell producing an antibody response that is T cell independent
Polysaccharide vaccines do not induce a significant and sustained antibody production in children < 18 months
Conjugation of apolysaccharide to a protein carrier enhances the immunogenecity

What are the broad principles to understand with regards to vaccination schedule?
 Studies have shown that PCV-PPSV sequence is better than receiving either vaccine alone
Patients who received PPSV23 first then PCV13 later 1 year later had lower opsonophagocytic antibody response c/w those who received PCV13 first.
PCV-PPSV sequence given within 8 weeks is a/w more local reactions
PCV-PPSV sequence is shortened in those with an immunocompromised state to reduce the windon in which they may get infected with serotypes unique to those
in PPSV23
Receiving PPSV within 5 year interval may result in hyporesponsiveness to the vaccine

Tuberculosis What is the etiology?

 Mycobacterium tuberculosis, (Mycobacterium bovis from unpasteurised cows’ milk is rare)

What is the pathology?

 Primary TB develops in previously unsensitised individuals and they are usually asymptomatic. However, elderly may lose their sensitivity to MTB and
hence develop primary TB again. The bacilli deposit near the pleura and proliferate in macrophages, forming tubercles with caseous necrosis (Ghon focus).
Bacilli drain to the regional LN which also undergo caseous necrosis (Ghon complex = parenchymal lesion + nodal involvement). Effective cell-mediated
immune response develops 2 – 6 weeks after an infection. Failure to develop CMI results in progressive destruction of the lung aka progressive primary TB.
 Latent TB occurs in the stage between primary and reactivation TB
 Secondary TB is a reactivation. It arises in a previously sensitised host, from reactivation of a dormant bacilli when host resistance is low. It is classically
localised to the apex of 1 or both upper lobes. Due to tissue hypersensitvity, bacilli excite a prompt and marked tissue response that tends to wall off the
focus, hence the regional LN are less prominently involved in early secondary TB vs early primary TB. Cavitations occur, erosion and dissemination occurs
along the airways, causing the sputum to be TB +, hence the person can spread the disease

What are the complications of primary TB?

 The foci of scarring may harbour viable bacilli for years and thus may be the nidus of reactivation in times of immunosuppresion.
 Progressive primary TB occurs where the disease develops without interruption in immunocompromised individuals.

What are the complications of secondary TB?

 Primary progressive tuberculosis
 Miliary pulmonary disease
 Pleural involvement
 Lymphadenitis
 Endobronchial/endotracheal/laryngeal TB
 Intestinal TB
 Pott’s disease (TB abscess in the vertebrae which may spread along tissue planes to form cold abscesses which present as a pelvic lump)
 Systemic miliary TB from hematogenous spread

What are the clinical types and their features?

 Pulmonary TB
  Miliary TB  (other than respi symptoms), tachycardia, anemia, hepatosplenomegaly, choroidal tubercles on opthalmoscopy, fever, LOW, night sweats,
lymphadenopathy
 Extrapulmonary TB  GI (Intestine/Periosteum), Pericardium, GU, CNS, Lymph node, Bones/Joint, Others (Adrenal gland destruction  Addison’s disease,
Skin  Lupus vulgaris, Erythema nodosum, Eyes  Iritis, Choroiditis)
 Symptoms of compression by lymph nodes e.g. monophonic wheeze, bronchiectasis, lung collapse
 Symptoms of affected organ systems e.g. headahces/seizures for TB meningitis, paraplegia for Pott disease

What investigations would you do?

 CXR, FBC, LFT, CRP, Sputum AFB smear, c/s on Lowenstein Jensen media, Early morning gastric aspiration, Nucleic acid amplification test, Tuberculin skin
test

How would you manage this patient?

Notify CDC
Contact tracing
Advise HIV testing
Isolation while infectious
Ishihara colour vision testing before initiating therapy + Liver function monitoring
Anti-TB treatment
Monitor CXR weekly, AFB smear and c/s monthly until 2 consecutive negative cultures

What are the aims of therapy?

Successful treatment requires > 1 drug to which the organisms are susceptible, of which the dose and duration of treatment should be sufficient as well with
compliance to directly observed therapy at the polyclinic. First –line TB drugs are Isoniazid, Rifampicin, Pyrazinamide, Ethambutol with Pyridoxine given to reduce
isoniazid-induced peripheral neuropathy. Pyrazinamide is geiven for the 1 st 2 months to kill the intracellular bacilli. 4 drugs are used in initial phase of treatment
when the total duration of treatment is 6 months, because of high incidence of isoniazid-resistant organisms. Usually RHZ or RHEZ followed by RH for 4/12.

Tell me about drug resistance in TB

In such cases, initial drug regimens need to be modified especially in areas with known high prevalence of MDR TB. The development of drug resistance after the
initial drug sensitivity occurs in patients who do not comply with treatment regimens, and this occurs mainly in HIV patients. Treat with 4 drugs for 2 years, then
follow up 1 year after eradication.

What are the side effects of anti-TB medication?

 Rifampicin  Liver enzyme inducer, hence to be used with caution for other medications/OCPs
 Isoniazid  Peripheral neuropathy, Skin rash, Hepatitis (STOP drug)
 Pyrazinamide  Precipitates gout, Liver toxicity
 Ethambutol  Dose related optic retrobulbar neuritis, patient presents with colour blindness, central scotoma and reduction in VA
 Streptomycin  Irreducible damage to the vestibular nerve, Allergic reactions are common
 Tell me about TB and HIV.
TB in a HIV patient is an AIDS defining condition and 4 drugs are used instead of the usual 3. Adverse reactions are common and the prognosis is poor. M. avium
intracellulare is another mycobacterium that can cause pulmonary infections in AIDS patients. It results as a negative Mantoux test, positive reactivation of TB,
atypical presentation, negative AFB smears, atypical CXR, extrapulmonary and disseminated disease is common. There is also increased toxicity from anti-TB and
anti-RV therapy.
The immune reconstitution inflammatory response occurs due to anti-RV therapy which reconstitutes CD4 counts and immune function. Therefore, there is
paradoxical worsening of TB symptoms.

How do you prevent TB?

BCG vaccination – which is a live attenuated vaccine that only protects against childhood miliary and CNS TB. Repeat vaccination is not indicated. Contact tracing to
initiate prophylaxis in others is done with CXR and Mantoux testing. Chemoprophylaxis given for contacts and HIV patients constitutes isoniazid 200mg/day PO x 9
months or rifampicin x 4 months if Mantoux is positive

Tell me about Mantoux testing.

Used to identify patients with latent TB, hence it is used for screening. A positive tuberculin test indicates infection with M. tuberculosis but it does not diagnose
active disease. It is done by givinng an intradermal injection of 0.1ml of PPD, causing a type 4 hypersensitivity reaction. 48 – 72 hours after intradermal
administration, there is a wheal and flare reaction.

How to interpret induration diameter?

- If < 5mm of induration, generally no treatment unless either patient is child/an adolescent/immunocompromised/has had close contact with TB + patient in
which case, initiate treatment for latent TB
- If 5 – 9mm of induration, generally no treatment unless either known to or suspected of having HIV infection/another cause of immunocompromise/is a
close contact of someone with TB/has a CXR suggestive of previous TB in which case initiate treatment for latent TB
- If 10mm or more, if they have risk factors for reactivation or have high demographic risk for TB, OR if NO risk factors BUT > 15mm of induration, initiate
treatment for latent TB. Otherwise, no treatment needed.

What is the treatment of pulmonary TB?

Recheck sputum c/s after 2 months of antibiotics. If
If aunable to tolerate pyrazinamide, give 2 months of RHE and 7 months of RH. Patient can be taken out of isolation once the sputum c/s is negative.

What is the treatment of extrapulmonary TB?

6 – 9 month regimen generally unless miliary/bonebrain which needs 12 months.
Adjunctive treatment includes steroids for TB pericardiitis/meningitis.
Surgery may be needed constrictive pericarditis or to relieve spinal cord compression.
Pneumothorax What is the definition?
Pneumothorax = Air in pleural space, If haemothorax = blood in pleural space, Chylothorax = Lymph in pleural space, Empyema = Pus in pleural space
 What is the etiology?
Spontaneous vs Traumatic
Spontaneous can be primary vs secondary. Primary  No underlying lung disease . Howevere, the pathogenesis is usually due to connective tissue defect in pleural
wall resulting in bleb formation and rupture. Thus, it is associated with Marfan’s/Ehler Danlos.

What are the types?

What are the clinical features?

What investigations would you do?

What is the management of a pneumothorax?

Start high flow supplemental oxygen 100% oxygen by NRM to create a concentration gradient. Nitrogen diffusion from the pneumothorax into the alveoli, thus
decreasing its size.

Tension pneumothorax is an emergency which should be managed with immediate needle decompression into the 2 nd intercostal space along the midclavicular line.

Primary spontanoues PTX is managed according to patient’s stability.

What are the complications of chest tube insertion?

Pulmonary Embolism What are the predisposing factors?
 Prolonged bed rest, immobiliation, surgery, trauma, fractures
 Previous stroke/immobilisation
 CCF
 Disemminated cancer
 Pregnancy, OCP use
 Antiphospholipid syndrome
 Smoking
 Genetic e.g. Factor V Leiden mutation, Thrombophilias

What is the pathogenesis?

 Thrombi arise from the deep veins of the leg, though 95% originate from the popliteal vein or above. Clots break off and embolise to the lungs. A large
embolus obstructing the main pulmonary artery causes increased pulmonary artery pressure due to blockage of flow and vasospasm a/w release of
mediators or neurogenic mechanism, leading to hypoxemia
 Small thrombi may be clinically silent as they are rapidly removed by fibrinolytic activity, and the bronchial circulation maintains the viability of the affected
parenchyma until this is achieved
  Smaller thrombi continue travelling distally and are more likely to produce pleuritic chest pain by initiating an inflammatory response adjacent to the
parietal pleura
 Multiple small emboli may lead to pulmonary hypertenion, resulting in decreased cardiac output

What are the clinical syndromes?

 Massive vs Submassive – Massive PE is a/w SBP < 90mmHg or a drop in SBP of at least 40mmHg from baseline for at least 15 minutes, which is otherwise
not explained. All PEs that are not massive are considered submassive
 Chronic PE occurs when an acute PE does not resolve

What are the clinical features?

 Acute SOB, Pleuritic chest pain, haemoptysis, syncope, dizziness, risk factors for PE
 Vitals, Cyanosis, Raised JVP, Loud P2, Pleural effusion, DVT, Recent surgical scars

What is the clinical scoring?

Wells Criteria (or Simplified Wells) can be classified as predisposing factors, symptoms, signs, alternative
 Predisposing factors – Previous DVT/PE, Recent surgery/immobilisation, Cancer
 Symptoms – Haemoptysis
 Signs – HR > 100, Clinical signs of DVT
 Alternative diagnosis less likely than PE

What investigations would you do?

 Lower limb Doppler ultrasound
 CTPA is the gold standard (aka Spiral CT)
 ECG – S1Q3T3, Right ventricular strain, new incomplete RBBB which is classical but rare, Atrial arrhythmias, TWI, ST changes
 ABG
 Baseline PT/PTT
 D dimer which is a degradation product of cross-linked fibrin  Negative D dimer has high negative predictive value in patients with low pretest probability
of VTE
 CXR, V/Q perfusion scan looking for perfusion defects without corresponding ventilation defects

What are your differentials?

 PE – ACS, COPD, Myocarditis
 DVT – Cellulitis, Superficial thrombophlebitis

What is your management of PE?

Resuscitate the patient’s airway, breathing and circulation. Start high flow supplemental oxygen. Initiate anticoagulation which reduces mortality by preventing
recurrent PE. In haemodynamically stable patients with PE, SC LMWH is preferred. IVC filter placement is indicated if patient has contraindications to starting
anticoagulation e.g. active bleeding. However, IVC filter only reduces the incidence of PE but not DVT. Thrombolysis should be considered once the diagnosis is
confirmed. If thrombolysis is chosen, anticoagulation should be temporarily discontinued then resumed. Persistent hypotension due to massive PE is a widely
accepted indication for thrombolysis. Embolectomy (either by catheter or surgery) is done when thrombolysis fails or if it is contraindicated.

What anticoagulation regimes do you know of?

Choice of drugs includes heparin (Unfractionated vs LMWH), Vitamin K Antagonist (Warfarin), Direct Oral Anticoagulant (Apixaban, Dabigatran, Edoxaban,
Rivaroxaban)

How does heparin work?

 Potentiates the effect of antithrombin
 Indirect inhibitor of Factor IIa (thrombin) and Factor Xa

 LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because, with a mean molecular weight of 4500–5000, at least
half of the LMWH chains are too short to bridge antithrombin to thrombin.
 LMWH are prodcued by fractionating heparin molecules into smaller chain lengths. LMWHs are indirect anticoagulants which exert their anticoagulant
effect by combining with antithrombin via 5 saccharide units – pentsaccharide and inhibiting only factors Xa and IIa
 LMWHs are given SC. They generally do not require lab monitoring but if monitored, the anti-Xa assay is used, not APTT. Its half-life is 3 – 6 hours. LMWHs
are renally-cleared thus, the half life is prolonged in patients with renal failure. To reverse electively, discontinue for 12 – 24 hours prior to planned
procedure. To reverse urgently, there is no antidote. Protamine may reverse the antithrombin (factor Iia) activity of LMWH but will not reverse the anti-Xa
activity. Furthermore, protamine would only affect the intravascular LMWH, not the SC depot

 Unfractionated heparin is a mixture of varying chain lengths of glycosaminoglycans derived from pig intestine. It is an indirect anticoagulant, exerting its
effect by combininng antithrombin and inhibiting the coagulation factors Iia, Xa, IXa, XIa, XIIa. A. Heparin binds to antithrombin via its pentasaccharide
sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate
thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units, which
corresponds to a molecular weight of 5400, are of sufficient length to perform this bridging function. With a mean molecular weight of 15,000, all of the
heparin chains are long enough to do this.
 It can be administered either intravenously or subcutaneously. Its half-life is 60 – 90 minute, which is shorter than that of SC heparin. Elective reversal of
UFH involves discontinuing it for 4 hours prior to the planned procedure. Urgent reversal in the setting of significant bleeding uses the antidote Protamine,
1g per 100 units of UFH given in the last 2 – 2.5 hours. Adverse effects include hypotension and hypersensitivity.

 LMWH and UFH are equally effective and safe

How does warfarin work?

 Warfarin is an oral Vit K antagonist. Clotting factors II, VII, IX and X as well as natural anticoagulant proteins C and S require the action of Vitamin K to
become activated so they may participate in coagulation.
What is the rationale for overlapping heparin and warfarin?
 There is a 3 fold recurrence rate for those getting warfarin alone
 Protein C and S have a short half life while Factor X have a half life of 5 days
 Therefore 5 days of overlap with heparin is required for Factor X levels to decrease sufficiently and have a true anti-thrombotic effect
 Thus, the regimen is to start LMWH and VKA together on confirmation of VTE and to overlap for at least 5 days or when INR > 2 for at least 24 hours,
whichever is longer

What are the absolute contraindications to starting warfarin?

 Active bleeding or known bleeding disorder
 Non-compliance to medication or INR monitoring
 1st trimester pregnancy
 Warfarin allergy or intolerance

What are the risk factors for bleeding or increased warfarin sensitivity?
Age 75 or older, Active peptic ulcer, history of BGIT, recent surgery, Uncontrolled HTN (>200/120), Drugs inhibiting warfarin metabolism or antiplatelet agents,
Weight < 45kg or poor nutrition, or any other bleeding risks.

What is the duration of treatment?

In patients with 1st episode of PE/DVT, treatment duration is determined by whether or not a risk factor can be identified, and if so, whether or not the risk factor is
reversible.
 Reversible risk factor found e.g. immobilisation, surgery, trauma  Warfarin x 3 – 6 months
 No identifiable risk factor found e.g. protein C/S deficiency, factor V leiden gene mutation  at least 6 – 12 months, KIV indefinite anticoagulation
 Indefinite anticoagulation for all patients with recurrent PE/DVT

What drugs interact with warfarin?

 Antiplatelets  Increase
 Analgesia  increase
 Antibiotics and Antifungals  Increase
 Cardiac drugs  Increase
 Antidepressants  Increase
 Phenytoin  Increase
 Others e.g. cimetidine, quetiapine, tamoxifen, thyroxine  Increase
 Rifampicin  Decrease
 Carbamazepine, Phenytoin  Decrease
 Anti-thyroid drugs, Azathioprine  Decrease

What are the side effects of warfarin?

 Bleeding
 Most common complication
 Mild – epistaxis, hematuria, Severe – retroperitoneal, BGIT, Life-threatening – ICH
 Rate of major bleeding is 1 – 3 % per person-year
 Half of complications occur because INR exceeds therapeutic range
 Can be minimised by keeping INR in the therapeutic range

Skin necrosis, Purple toe syndrome, Teratogenecity, Osteoporosis

How do you do warfarin reversal?

 Major – Stop warfarin, Give Vit K 5mg IV, Factor replacement with either PCC +FFP (300mls) or FFP alone at 15ml/kg, then repeat PT/PTT 30 mins after the
infusion, if adequate correction, repeat PT again in 4 – 6 hours. If inadequate correction, look for other contributory factors e.g. inadequate correction, DIC,
liver disease, lupus anticoagulant, congenital factor deficiency
 Minor – Stop warfarin, Give Vit K 2mg PO or 1mg IV then repeat INR at 24 hours or earlier if there is clinical deterioration
 If there is no bleeding, but INR is 7 or more, stop warfarin, give Vit K 2mg PO or 1mg IV, Tthen repeat INR at 24 hours
 If there is no bleeding but INR is 4.5 – 6.9, look for risk factors. If risk factors present, give Vit K 2mg PO, otherwise, withhold 1 dose or reduce the warfarin
dose.
 If preoop patient needs warfarin reversal, if op can be delayed 6 – 12 hours, give IV Vit K. If op cannot be delayed, give PCC and IV Vit K

What is the prognosis of PE?

 There is a 30% chance of developing a 2nd embolus
 Mortality rate is approx. 30% without treatment, mainly due to recurrent embolisms
 Accurate diagnosis followed by effective therapy with anticoagulation decreases the mortality rate to 2 – 8%
Pleural Effusion What are your physical exam findings?
 Decreased chest expansion
 Decreased breath sounds and stony dullness to percussion
 Decreased vocal resonance

What is your initial approach?

What are the causes of transudative pleural effusions?

DECREASED ONCOTIC PRESSURE, INCREASED HYDROSTATIC PRESSURE, LYMPHATIC OBSTRUCTION
 Left ventricular failure, Constrictive pericarditis, ARF, CRF, ESRF, Nephritic syndrome
 Liver failure, Malnutrition, Protein-losing enteropathy, Nephrotic syndrome
 SVCO, Tumor compression, RT
Others
  Hypothyroidism
 Meig’s syndrome (Benign ovarian fibroma + Ascites + Pleural effusion)
 Peritoneal dialysis
 Urinothorax (Fluid:Serum Cr >1) - Obstructive uropathy

However, if you suspect exudative cause in a patient with bilateral effusions, still Lasix first.

What are the causes of exudative pleural effusions?

INCREASED VASCULAR PERMEABILITY
 Inflammation e.g. RA, SLE, PE, Pancreatitis
 Infective e.g. parapneumonic effusion, empyema, TB
 Bronchial carcinoma / Mesothelia

 Esophageal perforation
 Post-cardiac surgery
 Chylothorax
 Drug-induced – ergot-derived drugs e.g. Cabergoline, Bromocriptine; MTX, Amiodarone
 Yellow nail syndrome (Yellow nail + Lymphatic hypoplasia)

What is Light’s criteria?

 Pleural fluid protein : Serum total protein > 0.5
 Pleural fluid LDH : Serum LDH > 0.6
 Pleural fluid LDH > 2/3 ULN of normal serum LDH

What is a discordant exudative effusion?

 When Lasix is given in CCF, it can cause the effusion to be exudative
 So how do you differentiate?
o Serum albumin gradient > 12g/dL or >1.2 g/L
o Lasix dries out the effusion
o Don’t bother talking about NT-proBNP in exam as a way to differentiate

What to send off a diagnostic pleural tap for?

 Pleural fluid pH, albumin
 Pleural fluid cell count
 Gram stain, Respiratory c/s
 AFB smear and TB c/s
 Adenosine deaminase
  Cytology
 pH
(Send blood simultaneously for protein, albumin, LDH, glucose)

What are your differentials for neutrophilic pleural fluid?

 Parapneumonic effusion
 Empyema
 Acute TB effusion
 Asbestosis
 Acute PE

What are your differentials for lymphocytic pleural fluid?

 TB
 Malignancy, Lymphoma
 Post-cardiac surgery
 CTD
 Sarcoidosis

What are your differentials for eosinophilic pleural fluid?

 Air/blood in pleural space
 Drugs
 Parasitic/fungal infections

How to manage a malignant pleural effusion?

 Inclusion critiera – adults > 18 y/o or < 80 y/o, Stable vitals, Alert, oriented and ambulant, History of malignancy with ECOG 0 – 2 (0 is fully active, 2
is ambulatory and capable of all self-care but unable to do work actitivities)

How to counsel a patient for a pleural tap?

 Insertion of a needle into the pleural activity to draw out fluid that has accumulated
 Indications – Diagnostic (to test for infection/cancer cells), Therapeutic (To relieve SOB)
 “You will be normally be sitting up during the procedure and leaning forward on a pillow on the side table. Local anesthesia will be injected into
the site of the chest wall where the needle will be inserted. The needle will then be inserted through the skin, ribs, through the chest wall.
 2 – 10% risk of pneumothorax, < 1% risk of bleeding, < 1 % splenic/liver laceration, re-expansion of lung congestion, reaccumulation, and other
minor things e.g. coughing in 10% / dry tap in 13%, temporary blood clot/fluid retention under skin in 1 – 2%
 Alternatives would include either conservative treatment or empiric treatment based on clinical assessment

What other investigations can you do?

  CT Thorax
 Not great if there are huge effusions as lung parenchyma is compressed
 Useful in identifying underlying etiology
 Also useful to guide focal area for biopsy
 Pleural biopsy
 If TB suspicion is high and ADA is non diagnostic
 Infection is not of the pleural fluid but raither the pleural tissue
 Medical thoracoscopy
 If huge effusion that is non-diagnostic
 Done under local
 Clinical indications to insert chest tube (u/s guided)
 Empyema
1. Complicated parapnuemonic pH < 7.2, septated and loculated
2. Malignant effusions
 Tend to reaccumulate quickly and become symptomatic quickly

How to manage hemothorax?

 Recognising haemothorax
 Starts to clots/sedimentation/clots within tubing
 Pleural fluid Hct: Serum Hct > 0.5

2010 BTS guidelines

Stages of empyema - defn

 Simple parapneumonic effusion
 Fibrinopurulent stage
 Organising stage with peel formation

Complicated Parapneumonic Effusion

 Low glucose
 Has septations
 Low pH

TB Effusion
ADA > 70u/l is more likely TB (Looking for ADA is best way to look for TB)
 Lymphocyte:Neutrophil ratio > 0.75 + intermediate ADA (40 – 50) is more likely TB
Differentials for high fluid ADA are RA or empyema

Pleural fluid glucose usually similar to blood

Causes of low glucose are RA and empyema

Chylothorax
 Leakage of chyle due to damage to lymphatic
 Causes:
o Trauma
o Cancer

What is Weil’s disease?
It is a leptospiral infection characterised by high fever, jaundice, haemorrhage and renal impairment. It is spread by contact with infected rat urine. There are 2
phases of the disease. The first phase lasts for 1 week where there is bacterremia. The second phase involvement development of antibdody so leptospira
disappears from the blood. It lasts for 2 – 5 days.

Chronic hepatitis What is the natural history of Hepatitis B?

1. There is an immune-tolerant phase is more frequent and prolonged in subjects infected perinatally and is associated with preserved HBV specific T cell
function at least until young adulthood. The rate of spontaneous HBeAg loss is very low in this phase. LFTs are normal, HbeAg + and viral load is high. HbeAg
is negative if pre-core mutant.
2. This is the immune clearance phase where the immune system has started recognising the virus thus causing flares. LFTs fluctuate. Most patients can
achieve HBeAg seroconversion and HBV DNA suppression and enter the HBeAg-negative infection phase. Other patients may fail to control HBV and
progress to the HBeAg-negative chronic hepatitis B phase for many years.
3. This is a non-replicative carrier phase where a patient who has had episodes of flares during which HbeAg seroconversion occurred is now flare-free with
LFTs normal, HbeAg –ve, viral load low. Some of these patients may go on to lose the HbsAg and are considered cured. Generally, there is a low risk of
progression to cirrhosis or HCC if they remain in this phase
4. HbeAg –ve chronic hepatitis is associated with low rates of spontaneous disease remission.
5. HbsAg-negative phase is also known as the occult HBV infection where the HbsAg is ive anti-Hbc or anti-Hbs is positive.

What are the indications for treatment?

 HBV DNA > 2000 IU/ml
 Elevated ALT and/or
 At least moderate histological lesions are typical indications for treatment.
 All cirrhotic patients with detectable HBV DNA should also be treated.
 Additional indications for treatment include prevention of mother to child transmission during pregnancy in mothers with high viremia as well as
 prevention of HBV reactivation in patients requiring immunosuppresion or chemotherapy.

What is the treatment for naïve chronic hepatitis B patients?

 The long-term administration of a potent nucleoside/nucleotide analogue with high barrier to resistance is the treatment of choice regardless of the
severity of liver disease.
 The preferred regimens are entecavir or tenofovir as monotherapies.

How to treat chronic HBV infection?

 Treatment is long-term to control the disease and reduce the risk of progression to cirrhosis. However, there is no cure.
 Drug treatment is given to make HbeAg seroconversion, reduction of HBV DNA and normalisation of LFTs.

How to treat a patient with an incidental finding of a positive HbsAg?

 Provided none of the indications for treatment are met, no treatment is necessary. Only regular follow-up is needed and reassurance.
 There is an annual spontaneous clearance rate of HbsAg of 1 – 2 %.

What is the treatment of decompensated cirrhosis in chronic hepatitis?

They should be immediated treated with a nucleoside/nucleotide analogue with a high barrier to resistance irrespective of the level of HBV DNA replication and
should be assessed for liver transplantation. PEG IFN alpha is contraindicated in decompensated cirrhosis.

What are the indications for treatment of chronic Hepatitis C?

There must be proven Hep C infection without either anti-HCV or HCV RNA, persistently deranged LFTs or evidence of chronic hepatitis on liver biopsy with no
contraindications to treatment.

How do evaluate patients for alcholic liver disease?

Men who ingest > 3 drinks/day and women who ingest >2drinks/day are at increased risk of alcoholic liver disease. For initial evaluation of a suspected alcoholic
liver disease, LFTs should be ordered and abdominal ultrasound should be done. Liver biopsy should not be routinely done.

What is the treatment of alcoholic hepatitis?

 Alcoholic hepatitis is a clinical diagnosis presenting with worsening jaundice and liver-related complications with documentation of chronic alcohol use until
8 weeks prior to presentation, Total serum bilirubin > 3, ALT and AST raised to > 1.5 times the upper limit of the normal but < 400 and an AST/ALT ratio >
1.5.
 In severe cases, defined as a Maddrey’s score of 32 or higher, the patient should be hospitalised to prevent acute kidney injury and a workup should be
done to exclude any infections.
 Steroids can be given to improve the patient’s 30 day survival.
 Baclofen is effective in preventing alcohol relapse in patients with alcoholic liver disease.
 What are the management options for alcohol-related cirrhosis?
Liver transplantation candidancy is assessed while managing the end-stage disease. Transplantation candidancy is not based solely on 6 month abstinence but also
factors such as social support and fitness to undergo rehabilitation therapy which is needed post-transplant.

Chronic Liver Disease What are the top etiologies for chronic liver disease?
Hep B , Hep C , NASH , Alcohol, Others: Autoimmune hepatitis, PBC, PSC – via secondary biliary cirrhosis

What is the definition of cirrhosis?

A histological diagnosis defined as architectural disruption with bridging fibrosis and nodular regeneration.

How is cirrhosis assessed?

 The extent of fibrosis in cirrhosis can be staged using a combination of serologic testing and ultrasound-based transient elastography.
 The most studied serum panels include the aspartate aminotransferase (AST) to platelet ratio (APRI), FibroTest/FibroSure, Hepascore (serology), and
FibroSpect but the AST to platelet ratio has the advantage of being most easily calculated from routine labs.
 Ultrasound-based transient elastography (Fibroscan) is the most studied radiologic method for staging hepatic fibrosis.
 The clinical scoring systems used are Childs Pugh and MELD scores.
 Hepatic venous pressure grading is also a marker of the extent of cirrhosis.

What is the function of the liver?

a. Synthetic
b. Detoxification
c. Conduit for blood flow

What are the complications of cirrhosis?

They can be classified into complications of hepatic failure as well as complications of portal hypertension.

What is acute management of a BGIT in cirrhotic patients?

 ABC, urgent fluid and blood products resuscitation
 Urgent endoscopy for diagnostic and therapeutic purposes
 Variceal band ligation if bleeding persists or haemodynamically unstable
 Causes of bleeding: esophageal or gastric varices, gastropathy, GAVE (gastric antral venous ectasia)
 If failed 2 attempts at endoscopic management of bleeding  for TIPS transjugular intra-hepatic portosystemic shunting)
 Standby Sengstaken Blakemore tube
 Avoid NGT insertion (may dislodge clot tamponading bleed)
 Correct coagulopathy
 PCT, whole blood, plt, FFP
  Aim for Hb 8-9 (don’t want too high as will elevate portal pressure)
 IV vitamin K
 Lower portal pressure by decreasing splanchnic circulation
▪ IV somatostatin, octreotide or terlipressin (improves mortality)
 Prevent encephalopathy
▪ Ensure BO 3x/day
▪ PR fleet/ducolax if NBM and no NGT
 **IV broad spectrum antibiotics for gut organisms e.g. ceftriaxone
▪ Prevent spontaneous bacterial peritonitis from gut translocation of bacteria as SBP increases mortality of patient and recurrence is high after 1 st episode
 IV proton pump inhibitor (blood clots more rapidly in an alkali environment  want blood in stomach to clot to tamponade bleed)
 Secondary prevention: endovascular band ligation + non selective B blocker (propanolol) if blood pressure permits, TIPS, transplant evaluation

What is the treatment for esophageal varices?

 If patient has never had endoscopy before, scope and if normal, repeat in 1 - 2 years
 If small varices found, look at varices, pull out scope, do nothing, repeat scope in 1 - 2 years again,
 If moderate to large varices found, one of the 2 programmes can be done.
 Beta blockers – propanolol, nadolol, or combined alpha and beta – carvedilol can be started. This requires subsequent review in clinic and titration if
needed – increase to level as can be tolerated; However, there is a point at which the benefits of beta blockers no longer outweighs the risks.
 Alternatively, can do variceal ligation – if patient has not bled, repeat scope in 2 – 4 weeks, continue doing it until all varices are banded; if patient has alr
had variceal bleed, dual therapy i.e. beta blockers and banding

What is the management of gastric varices?

a. If patient is not bleeding, DO NOT do anything to gastric varices; can put the patient on beta blockers but the evidence is less.
b. If gastric varice has bled, do not do banding. Generally instead we do glue injection, KIV TIPSS.
c. If rebleed, TIPSS
d. Remember that for variceal bleed vs non-variceal UBGIT, although they look similar the urgency is different. Variceal bleeds require scope as
soon as the patient is stable but non-variceal bleeds can be scoped within 24 hrs if Blatchford > 1.
e. TIPSS is indicated for refracotry esophageal or recurrent gastric variceal bleeding as well as diuretic resistant ascites. The risks of a TIPPS
include acute ischemia (which is why MELD cut off 15 – 18). It can also cause hepatic encephalopathy.

What is the mechanism of ascites in cirrhosis?

Splanchic vasodilatation is the main factor for ascites in the cirrhosis of liver. This is mediated by a vasodilator (mainly nitric oxide), that are released when portal
hypertension causes shunting of blood into the systemic circulation. Due to splanchnic vasodilatation, systemic arterial pressure falls, which leads to activation of
the RAAS with secondary aldosteronism, increased sympathetic activity and increased ANP secretion. All these produce salt and water retention. Other factors
include portal hypertension causing increased hydrostatic pressure, and hypoalbuminemia causing reduced oncotic pressure.
How to diagnose?
 If any patient has ascites, do diagnostic paracentesis to find out if a patient has SBP
 ANC in fluid > 250, must wait for differential count to come out OR if < 250 but culture +
 If anyone has had previous SBP, they have earned themselves lifelong SBP prophylaxis (cipro)

What is the SAAG Serum Ascites Albumin Gradient?

 This gradient correlates directly with portal pressure. It is thus the single test to differentiate ascites due to portal hypertension from non-portal
hypertension.
 If the gradient > 1.1, it indicates CLD with portal hypertension
 If < 1.1, no portal hypertension.
 Ascites protein < 25g/L and SAAG > 1.1g/dL is usually suggestive of portal hypertension

What is the management of ascites in cirrhotic patients?

 Establish status of ascites i.e.
o Ascites on diet control
o Diuretic-sensitive ascites
o Diuretic resistant/intolerant ascites
 Number of taps done before?
 Bed rest – Improves renal flow in the horizontal position and therefore increases diuresis
 Salt restriction (actually a lot more important than fluid restriction)
 Daily weights – Weight loss should be 0.5 – 1 kg/day
 Spirono, Lasix
o Started if no response after 4 days of conservative treatment
o Spirono is better because it is an aldosterone antagonist (K sparing so pulls in K so to balance high K give 20mg of Lasix) 50 spirono : 20 lasix is
the ideal ratio,
o Starting dose is 100 and 40 for spirono and frusemide
o 400 and 160 respectively is max dose you can give
o If still refractory, this is called diuretic resistant/intolerant ascites
o Prolonged use can cause gynecomastia and hyperkalemia
o Eplerenone is an appropriate alternative which does not cause gynecomastia
 Large volume paracentesis
o Indicated if there is huge ascites with cardiorespiratory complications or if diuretic resistant/intolerant
o 3 – 5 L can be removed and it is safe provided circulation is maintained. Paracentesis is followed by IV albumin (6 to 8 g/L of ascitic fluid
removed, usually 100ml of 20% human albumin solution for every 3L of ascitic fluid drained). Alternative plasma expanders include dextran or
hemaccel
 TIPSS – A stent is placed between the portal and hepatic vein in the liver to make a shunt. It is carried out under radiological guidance via the internal
 jugular vein. TIPSS is mainly used to reduce portal pressure and also variceal bleeding. Also, it is helpful to relieve resistant ascites, but it does not
prolong life. Following its use, the frequency of paracentesis and diuretic dose is reduced. It can be done provided reasonable liver function without
encephalopathy and minimal disturbance of renal function (TIPSS is ineffective with intrinsic renal disease). Encephalopathy may occur after.
 Prophylaxis
o Primary – If had previous SBP
o Secondary – If Child’s B/C, Ascitic fluid protein <1.5g/dL, Acute gastrointestinal bleed

What are the complications of ascites in CLD?

 SBP
 Hepatorenal syndrome

What is hepatorenal syndrome?

 Type 1 HRS – Progressive oliguria and rapid rise in serum Cr. Prognosis is poor and without treatment median survival is < 1 month
 Type 2 HRS – Occurs with refractory ascites, characterised by moderate and stable increase in serum Cr. Prognosis is better.
 Mechanism
o Initially there is vasodilatation possibly due to nitric oxide, leading to hypotension. As a result, there is high plasma renin, aldosterone, NE and
vasopressin, leading to vasoconstriction of the renal vasculature. This causes increased preglomerular vascular resistance. There is also reduced
GFR and also sodium and water retention.
o The renal failure in HRS is functional and the tubular function is intact. HRS may be precipitated by excess diuretic therapy, NSAIDs, diarrhea or
paracentesis and infection especially SBP.

How do we manage coagulopathy in cirrhotic patients?

o Hypersplenism and associated thrombocytopenia causes increased bleeding risk.
o However, cirrhotic patients are not always at increased bleeding risk as they are actually in a balance of procoagulant vs anticoagulant
o Note platelet effect is a real time thing
o You don’t need a large spleen to get hypersplenism, just portal HTN

How to manage hepatic encephalopathy?

 Nitrogenous waste such as ammonia build up in the circulation and pass to the brain, where astrocytes clear it by processes involving the
conversion of glutamate to glutamine
 This excess glutamine causes an osmotic imbalance and a shift of fluid into these cells and hence, cerebral edema
1. West Haven tells you the severity of the HE right now but does not predict recurrence
a. Covert (0/1) vs Overt HE(2/3/4); To differentiate Grades 0 and 1, ask about attention and concentration, if they can they read the
newspapers, and get through an article, if they are cooking/investing, if they stopped working etc.
2. Number of previous admission/ICU/HD stays for HE are important markers of
3. Treatment
 a. Lactulose – clears bowels and prevents translocation of gut bacteria
b. Rifaximin is a non-absorbable antibiotic which decreases gut bacteria and ammonia production

Palmar erythema (liver palm)

Redness in thenar and hypothenar eminence and pulp of ngers. Blanches on pressure. With glass slide, ushes synchronously with pulse. Causes of palmar erythema:

1. Physiological:
Normal people, may be familial Pregnancy.

2. Pathological:

CLD (commonly alcoholic cirrhosis) 


Thyrotoxicosis 


Polycythemia 


Prolonged rheumatoid arthritis 


Chronic leukemia 


Febrile illness. 
Mechanism of palmar erythema in CLD: 


Y Hyperdynamic circulation
Y Probably, high estrogen (controversial).

Q. Why itching in liver disease?
A. Commoninprimarybiliarycirrhosisandobstructivejaundice.Actualcauseisunknown,probably

due to upregulation of opioid receptors and increased levels of endogenous opioids.

Q. What are the vitamin K-dependent coagulation factors? A. Factors II, VII, IX and X (which are produced by liver).

Q. In which liver disease, vitamin K therapy is helpful?
A. Usually in obstructive jaundice, as bile salt is necessary for absorption of vitamin K. Less or not

helpful in parenchymal liver disease, as vitamin K is not used or less used by the diseased liver.
Flapping tremor (asterixis)

It is characterized by irregular, exion-extension movement of wrist and MCP joints, abduction- adduction of ngers, produced by dorsi exion of wrist and spreading of
the ngers. It is called apping, because of resemblance to a bird apping its wings. It is demonstrated by asking the patient to stretch out arms in front, separate the
ngers, dorsi exion of wrist with xed forearm by the examiner’s hand.

If it is present, there is:
Y Jerky, irregular, exion-extension of wrist and MCP joint (looks like goodbye). Y Accompanied by lateral movement of ngers or abduction-
adduction of ngers.

Features of apping tremor:
Y It is absent at rest, produced by intentional movement, maximum at sustained posture. Y Usually bilateral, and not necessarily
synchronous on each side.
Y Disappears during coma.
Y Occasionally arms, face, neck, tongue, jaw and eyelids are involved.

Causes of apping tremor:
Y Hepatic encephalopathy (the commonest cause) Y Severe cardiac failure
Y Respiratory failure

Note Remember the following:
PT depends on factors I, II, V, VII and X. In CLD, the PT is prolonged, when these factors fall below 30%.

Y Renal failure
Y Other causes (rare)—cerebrovascular accident (CVA), drug toxicity (phenytoin and barbiturate),

acute focal parietal or thalamic lesion (vascular) and hypoglycemia.

Mechanism of apping tremor in CLD:
Y It is due to impaired in ow of joint position sense and other afferent informations to the brainstem

reticular formation, resulting in rhythmical lapse of postural muscle tone.

Dupuytren’s contracture

It is characterized by thickening, brosis and shortening of super cial palmar fascia, causing exion contracture of ngers. The ring and little ngers are commonly
affected and also other ngers are affected. Inability to extend the ngers fully is associated with puckering of the skin and presence of palpable nodules. Usually
painless, bilateral, age related, 5 times common in male than in female, often familial with dominant inheritance. It may affect the sole of foot also. It is slowly
progressive and fasciotomy is seldom necessary.
 Causes are:
Y Cirrhosis of liver (commonly alcoholic)
Y Alcoholism (itself, not by cirrhosis)
Y Prolonged antiepileptic drug (phenytoin)
Y Manual worker (gardener)
and chronic vibration injury
Y Traumatic
Y Familial (as autosomal dominant, associated with Garrod’s patch on dorsum of hand) Y Diabetes mellitus (diabetic
cheiroarthropathy, confuses with systemic sclerosis)
Y Peyronie’s disease
Y Idiopathic (in many cases).

IBD What do you know about the epidemiology of ulcerative colitis (UC)?
Ulcerative Colitis Unlike CD, UC shows a bimodal distribution with a major peak between 20 and 40 years and a lesser one between 60 and 80.

What causes UC?

The cause is unknown, but in genetically susceptible people, antigens or microbial agents (notably gut microflora) probably trigger an inappropriate dysregulated
mucosal immune response. Postulated environmental factors have included sugar, margarine, cornflakes, toothpaste, cola drinks and even household appliances.

What do you know about the pathology and distribution of UC?

 Ulceration is usually superficial (mucosal). Granulomata are not a feature, and glands tend to be destroyed with crypt abscess formation, and the cellular
infiltrate tends to comprise neutrophils, plasma cells and eosinophils.
 UC is confined to the large bowel and always affects the rectum. 1/3 of patients have pancolitis, 1/3 proctitis and 1/3 distal colitis to the splenic flexure.
Occasionally, the terminal ileum may be involved in backwash ileitis.

What are the differential diagnoses of UC?

 Infectious causes include Yersinnia spp. and mycobacterial disease.
 If there is a clear history of inflammatory symptoms (blood, mucus, pus or slime) that are not of infective origin (history and stool culture), IBD is very likely,
usually UC but about 20% of CD is colitis. Sometimes, a non- specific diagnosis of ‘colitis’ will be made, but the underlying cause will probably be IBD.
 Other possibilities include ischaemic colitis, microscopic colitis (watery rather than bloody diarrhoea), radiation colitis, drug-induced colitis – usually due to
non-steroidal anti-inflammatory drugs with symptoms similar to UC but settling when withdrawn, diverticulitis, irritable bowel syndrome, chronic
pancreatitis and malabsorption, coeliac disease, sarcoidosis, rectal mucosal prolapse, small bowel cancer/lymphoma and colorectal cancer.

How is mild to moderate UC initially treated?

 In active UC, prompt treatment can reduce the symptoms rapidly and reduce the risk of complications.
 Mesalazine (5-ASA) remains the mainstay of treatment for mild to moderate UC for the induction and maintenance of remission.
 By contrast, 5-ASA is at best only mildly effective in CD.
 Long-term 5-ASA reduces the increased risk of developing colorectal cancer associated with long-standing, extensive UC.
 Corticosteroids remain one of the most effective ways of inducing remission. However, their inability to maintain remission and their serious side effect
profile make their use unacceptable except for short periods.

What is standard maintenance therapy in UC?

 The relapse rate is reduced from 80% to 20% at 1 year with salicylates.
  5-ASA inhibits pro-inflammatory eicosanoid release from colonic epithelial cells, but nephrotoxicity is a potential side effect when absorbed.

What is the approach to acute severe colitis?

 Acute severe colitis has a natural mortality rate of 25% that is markedly reduced by surgery and corticosteroid treatment.
 Severity is assessed with Truelove and Witt criteria. Initial investigations include stool microscopy, culture and sensitivity for bacteria (C. diff.), ova, cysts,
parasites and viruses (CMV).
 AXR should be done to rule out complications of a toxic megacolon (> 5.5cm in diameter) and mucosal islands, 75% of which would require surgery.
 The patient should be started on intravenous fluids, electrolytes monitoring and thromboembolic prophylaxis.
 Drugs to be avoided include anti-diarrheal drugs e.g. loperamide, opiods, antispasmodics e.g. buscopan, anticholinergics and NSAIDs.
 Treatment of antibiotics and corticosteroids should be instituted KIV surgical intervention.

What options are there for patients who have had an episode of severe colitis?
 Patients who have had severe colitis should start azathioprine (2–2.5mg/kg daily), e.g. for 3–5 years.
 Refractory severe colitis may be an indication for cyclosporin.

What options are there for patients with refractory UC?

 Patients with moderate colitis who relapse with a dose of prednisolone reduced to under 15 mg or within 6 weeks of stopping prednisolone should start
azathioprine as above.
 It is now standard practice to measure the activity of thiopurine methyltransferase (TPMT), an enzyme involved in thiopurine metabolism, before initiating
treatment with azathioprine. This allows identification of the 1 in 300 people who will predictably develop bone marrow suppression due to deficiency of
TPMT.
 Methotrexate is ineffective in UC, unlike CD.
 Refractory distal disease may respond to mesalazine suppositories (Pentasa 1 g at night) continued thrice weekly to maintain remission.

What are the indications for surgery in UC?

 Surgery can be elective e.g. in disease refractory to medical therapy with severe and extensive colitis, serious complications of medical therapy, malignancy
(precancerous lesions or prophylactic risk reduction) and debilitating extraintestinal manifestations e.g. thromboembolic complications.
 Surgery can be emergent e.g. in acute fulminant colitis with toxic megacolon, impending perforation (as evidenced by thumb printing or pneumatosis) or
free/walled-off perforation, and acute fulminant colitis without acute abdomen but with unremitting bloody diarrhea.

What are the surgical procedures done?

 In the emergent setting, total colectomy + end ileostomy is done and the diseased rectum is left in situ with a proctectomy and ileo-pouch anal anastomosis
is done at a later date when the patient has regained health and steroids have been withdrawn. The rectum is an extraperitoneal organ and
dissection/resection takes a long time. Foley catheter can be used to decompress the rectum for 3 – 4 days. In the elective setting, proctocolectomy with
ileo-pouch anal anastomosis is done. This is standard of care of patients with UC who ultimately require a colectomy to avoid the necessity of a long term
stoma. The alternative is a panproctocolectomy + end ileostomy.
What are the complications of surgery?

When should colonoscopic surveillance be contemplated?

 Colorectal cancer is more common with extensive and long-duration disease. The risk in patients with pancolitis is 5–10% at 15–25 years.
 Surveillance usually starts at 10 years.
 Long-term maintenance with aminosalicylates reduces the carcinoma risk.

What is microscopic colitis?

 This is defined as a triad of chronic watery diarrhoea with normal colonoscopy and characteristic microscopic inflammation of the lamina propria. It is more
common in older people. The term embraces collagenous colitis and lymphocytic colitis, and there is overlap between the two.
 Microscopic colitis has a mean age of incidence of 55–68 years and is uncommon (each entity one to five per 100 000 / year) but is the final diagnosis in 10–
15% of patients with chronic diarrhoea who present to specialist units.
 The cause is unclear, but luminal bacterial antigens may be important. Loperamide is useful for mild disease but budesonide and occasionally
immunomodulatory therapy with azathioprine are needed for more severe disease

Clinical subtypes of Crohn’s disease (CD)

 Common symptoms including diarrhoea (70–90%), abdominal pain (50%), anal lesions (50–80%), rectal bleeding, fatigue, weight loss and fever are the
hallmarks of CD.

Active ileal and ileocaecal disease

 Pain is a central feature of ileal and often ileocaecal disease, sometimes with a right iliac fossa inflammatory mass, with or without diarrhoea and weight
loss.
 The pain is constant if caused by inflammation or abscess formation, and colicky with borborygmi and abdominal distension if the result of small bowel
obstruction (strictures).
 Malabsorption may occur.

Active Crohn’s colitis

▪ Symptoms are similar to active ulcerative colitis, but frank bleeding is less common. Extraintestinal manifestations are more common with colonic disease.

Perianal CD
▪ T here may be fissuring, fistulae or abscesses, and perianal manifestations are more common with colonic disease.

What are the extraintestinal manifestations of IBD?

  Clubbing
 Episcleritis/Scleritis - May or may not be symptomatic (can ask if got burning/itching of eyes)
 Apthous stomatitis
 Erythema nodosum - Painful red lesions on shins usually, Resolves with therapy
 Pyoderma gangrenosum - Ulcerating rash that responds to immunosuppresion
 Arthritis +/- Arthralgia
 Cholelithiasis, Autoimmune hepatitis, Primary Sclerosing Cholangitis, Pancreatitis
 Kidney stones/Gallstones
 Venous thromboembolism
 Osteopenia
Other
 The rectum may be the only site of disease in elderly patients and very rarely CD may be confined to the mouth, stomach or duodenum.
Crohn’s  The Montreal classification of CD phenotype refers to age of onset (< 16 years A1, 17–40 years A2, > 40 years A3), location (ileal L1, colonic L2, ileocolonic
L3, isolated or with upper gastrointestinal disease L4) and behavior (non-stricturing non-penetrating B1, stricturing B2, penetrating B3, + ‘p’ if perianal).
 Incidence should be reduced with modern surveillance and treatment.

Consider function
Tell the examiners that inflammatory bowel disease (IBD) is a chronic, relapsing, often debilitating disease that can have profound psychological as well as physical
effects.

What do you know about the epidemiology of Crohn’s disease (CD)?

 Both CD and UC are idiopathic chronic relapsing and remitting disorders.
 They are increasing in prevalence, more commonly in North America and Europe.
 CD may present at any age, with peaks at 15–30 years and 60–80 years.

What is known about the immunological basis of CD?

Immunological responses that colonic bacte- rial antigens might normally stimulate, including B- lymphocyte-mediated antibody production and T-helper-
lymphocyte-mediated production of pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α) is increased in CD, together with nuclear factor-κB (NFκB) and
mitogen-activated protein kinases), are normally balanced by downregulatory cytokines, enhanced apoptosis in the lamina propria and absence of co-stimulatory
second signals leading to tolerance. It may be that such tolerance mechanisms are deficient in CD. However, as well as this long-held autoimmune theory involving
adaptive immunity there is increasing recognition of problems with immunodeficiency in innate immunity and it seems that patients with NOD2 genetic propensity
are less able to clear invasive bacteria whose clearance is dependent on NFκB activation via autophagy gene proteins ATG16L1 and IRGM.

What do you know about the pathology and distribution of CD?

CD is a chronic inflammatory disease with a T-helper-type- 1-mediated pro-inflammatory response at its core. It may affect the entire gastrointestinal tract from
mouth to anus, especially the terminal ileum (35%), ileocaecal region (40%) and anus / perineum. It is confined to the colon in 20%. The rectum is characteristically
spared. There may be skip lesions, with normal mucosa between affected areas. Aphthous ulceration is common, but inflammation tends to be transmural (although
predominantly submucosal), often with deep ulceration, fissuring and abscess forma- tion. Histologically, glands are preserved, non-caseating granulomata may
occur and the cellular infiltrate tends to comprise lymphocytes, plasma cells and macrophages.

What imaging may be useful in CD?

Ultrasound is sensitive and specific for diagnosing ileal CD. Magnetic resonance imaging has an increasing role.

Should particular drugs be avoided in CD?

NSAIDs and antibiotics may provoke relapse.

Is there a role for dietary advice in managing CD?

High-fat diets appear bad for CD. Elemental diets (con- taining amino acids and glucose) and polymeric diets may be effective in treating active disease, but are
unpal- atable. Vitamin supplementation may be necessary in malabsorption.

Are there any non-drug strategies that aid maintenance of remission in CD?
Not smoking reduces the risk of CD and improves maintenance of remission.

What are the treatment objectives in CD?

Treatments are conceptualised in terms of induction and maintenance of remission. Goals are sustained remission with the least toxic therapy and avoidance of
complica- tions. At 10 years 75% of patients remain in work.

What are the medical treatments for CD?

Salicylates
 5-Aminosalicylic acid (5-ASA) compounds are generally less beneficial for active CD than for active UC.
 Sulfasalazine 1 g twice daily has traditionally had a role in active colonic disease, but not in maintaining remission, and mesalazine in both active and
relapsing CD
 However evidence suggests that mesalazine in active CD is little better than placebo and may reduce the risk of relapse after surgery but not after medically
induced remission.
 No maintenance therapy is now recommended in mild disease, other than active non-smoking!

Corticosteroids
 Corticosteroids effectively induce remission but do not prevent relapse and are not used long term. CD responds to oral or, if severe, intravenous
corticosteroids, regimens similar to those in UC. For mild to moderately active CD, controlled ileal release budesonide at a daily dose of 9 mg is as effective
 as prednisolone with fewer side effects, and superior to mesalazine or placebo.

Antimicrobials
 Antibiotics are appropriate for septic complications, perianal disease in particular.
 Metronidazole may be helpful in patients with sepsis or bacterial overgrowth, and in Crohn’s colitis or fistulating disease.
 Ciprofloxacin may be helpful in fistulating disease.

Immunotherapy – immunomodulators and biological therapies

 Immunomodulators modify immune function in a generic and less specific way than biological therapies. Biological therapies utilise genetically engineered
proteins (e.g. monoclonal antibodies) that target mediators such as cytokines. They are generally administered parenterally, and typically persist in the
body for many weeks with long-lasting effects.
 Both immunomodulators and biological therapies modify disease at the expense of opportunistic infections and other complications.
 Immunomodulators such as azathioprine or methotrexate help maintain remission.
 In CD, TNF-α mediates inflammation. Infliximab and adalimumab are anti-TNF-α therapies used for induction of response, remission, and maintenance
therapy for patients with moderate or severely active CD despite (or because of intolerance to) therapy with corticosteroids and/or immunomodulators.
 Treatment decisions should be individualised, based on disease activity, previous therapy, disease complications and comorbidity. Relative or absolute
contraindications to anti-TNF-α therapy may be memorised by the mnemonic STOIC (sepsis, tuberculosis, optic neuritis, infusion reaction, cancer).
 The hope is that earlier use of immunotherapy might alter the pattern of hospital admissions, need for surgery and associated morbidity. Patients with poor
prognostic features appear to benefit from early treatment with immunomodulator drugs and/or anti-TNF therapy.

Other therapies
 The development of biological therapies continues with other anti-TNF-α agents
 Inhibition of chemokine receptor CCR9, which mediates intestine-specific migration of leucocytes, may prove useful in CD.
 Other potential therapies include agonists of intestinal growth factor glucagon-like peptide 2, leucocytapharesis and autologous stem cell transplantation.

What surgical procedures are common for CD?

 Right hemicolectomy is the most common operation, but some patients need panproctocolectomy with a permanent ileostomy.
 Seton insertion for perianal fistulae involves a suture through the fistula track that is tied around the anus to keep the fistula open and prevent abscess
formation.
 As well as enterocutaneous fistulae, fistulae may be enteroenteral, enterovesical or enterovaginal.
 Improving medical therapy, earlier use of immunosuppressives and anti-TNF agents, and conservative surgical strategies are reducing the need for radical
surgical procedures and improving quality of life.
Primary Biliary HOPC
Cirrhosis 

Stroke What are the different types of stroke?

Ischemic
 Thrombotic
- Large artery extracranial / intracranial occlusive disease
- Small artery disease (Lacunar)
- Hypoperfusion
 Embolic
 Heart
 Arterial

Haemorrhagic
 Aneurysm
 AVM
 Amyloid angiopathy
 Haemorrhagic conversion of infarction
 Hypertension
 Coagulopathies

Non-atherosclerotic vasculopathy
 Vasculitides
 Procoagulant activity e.g. Factor V Leiden Mutation
 Antiphospholipid Syndrome

What are the 6 questions you need to answer from you history, physical exam and investigations?
 Is it a stroke?
 Where is the stroke?
 Is it ischemic or haemorrhagic?
 What is the mechanism of the stroke?
 What is the functional impairment?
 What are the risk factors for stroke and co-existing medical problems?

Is it a stroke?
 Stroke is a clinical diagnosis
 Sudden acute onset
 Neurological deficits
 Pyramidal tract – Weakness, Numbness of UL and LL
 Cranial nerves – Dysarthria, Facial weakness/numbness, Dysphagia
  Cerebellar dysfunction
 Other brain functions
 Stroke mimics

(What are your differentials for a stroke?)

 Todd’s paresis (hemiplegia post-seizure, usually lasting < 3 days)
 Brain tumour (slow progression of symptoms)
 Infection (fever + seizures)
 Hemiplegic migraine (headache usually < 24hr)
 Metabolic e.g. hyponatremia or hypoglycemia
 Labyrinthine disorders e.g. Vestibular neuronitis (usu. viral), BPPV
 Multiple sclerosis
 Neuromuscular disorders e.g. Myasthenia, GBS

Where is the stroke?

 Total anterior circulation syndrome
 Homonymous hemianopia
 Hemiparesis
 Higher cortical dysfunction – aphasia (if dominant)  receptive is Wernicke’s, expressive is Broca’s, Agnosia + Gerstmann’s syndrome, Neglect
(which is common to both sides), Apraxia (when the non-dominant lobe is involved)

 Partial anterior circulation syndrome

 Any of the 2 TACs or isolated higher cortical dysfunction

 Lacunar syndrome (Can be Face Arm Leg, Face and Arm or Arm and Leg i.e. at least 2 contiguous)
 Pure motor
 Pure sensory
 Sensorimotor
 Ataxia-hemiparesis – Ataxia out of proportion to weakness
 The variant is a the clumsy hand dysarthria

 Posterior circulation syndrome

 Drowsiness
 Lower cranial nerve palsies
 Ataxia
 Crossed neurological signs
  Spastic paraparesis
 Bilateral LL sensory loss

Is it an ischemic or haemorrhagic stroke?

 Ischemic strokes can be thrombotic (old, hypertensive, smoking, hypercholesterolemia, DM) or embolic (AF, MS, Prosthetic valve)
 ICA stenosis (8%)
 Cardiac embolism – AF (20% in 2015)
 Lacunar infarction – Small vessel disease (50%)
 Thrombotic infarction – Atherosclerosis (22% in 2015)
 Haemorrhagic strokes (History of coagulopathy, drowsiness, vomiting, papiloedema, severe HTN)
 Intraparenchymal (22%)
 SAH (3%)  Look for star with bleed inside (Circle of Willis)
 CT brain without contrast is used mainly for excluding haemorrhagic strokes esp. if thrombolysis is being considered. However, only 50% of
infarctions are seen.

What is the mechanism of the stroke?

Emboli vs Extracranial thrombosis vs Intracranial thrombosis
Do History and PE looking for AF, MS to suggest emboli, carotid bruit to suggest thrombosis
 Risk factors for haemorrhagic etiology
 Age
 HTN
 Heavy alcohol consumption
 Anticoagulation
 Amyloid angiopathy
 Risk factors for ischemic etiology
 Cardiac embolism
 Large artery – Extracranial carotid artery, Intracranial LARGE artery (either caused by thrombosis or haemodynamic failure), Small artery, Other
mechanisms
 When do you suspect lacunar stroke?
 NO evidence of hemispheric or posterior circulation syndrome
 NO drowsiness
 NO cortical signs
 Rarely, signs of bilateral brainstem neurological deficit
 DOES NOT respect the motor homunculi
 When do you suspect Hemispheric syndrome?
 When do you suspect cortical dysfunction?
  When do you suspect posterior circulatory syndrome?

Do investigations
 Transthoracic/Transesophageal Echocardiography which may give information to suggest emboli e.g. patent foramen ovale, akinetic segment, poor EF <
30%, mural thrombus
 Duplex Dopple of carotids if suspecting extracranial thrombosis but this is done only for patients with non-disabling PACS who are fit to undergo op and
agreeable to endarterectomy
 Cerebral angiogram to quantify the degree of carotid stenosis and status of intracranial circulation
 However, there are no investigations to help diagnose intracranial thrombosis. Mianly from history, and suspect when carotid Doppler and 2DE are
unremarkable

What are the clinical features?

 Handedness!!!!
 Weakness and duration
 Numbness
 Upper and Lower limb involvement
 Hemianopia (knocking into things?)
 Cranial nerves (diplopia, facial asymmetry, dysphagia, dysarthria)
 Cerebellar (gait, balance)
 Functional impairment
 Risk factors (Ischemic – Age, Smoking, DM, HTN, Cholesterol, Haemorrhagic – Family history of aneurysms, Personal history of coagulopathies)
 Full neuro exam
 Higher cortical function assessment looking for receptive and expressive aphasia, neglecto, apraxia, Gerstmann’s syndrome (acalculia, agraphia,
left-right disorientation, finger agnosia), cardiovascular exam looking for AF, murmurs, carotid bruit)

TOAST Etiological Classification of Stroke

Acute Stroke Care
Acute Infarction Itself
 IV thrombolysis
 Endovascular therapy
 Hemicraniectomy
 Stroke unit
Stroke and Complication Prevention
 Early antiplatelet
 Secondary stroke prevention
 Complications prevention
Cerebral circulation
Extracranial
 Aortic arch
 Extracranial carotid arteries
 Extracranial vertebral arteries
Intracranial (aka Circle of Willis)
 ACA, MCA, PCA
 Intracranial ICA, Vertebral, Basilar

Management of symptomatic ICA

 Endarterectomy > Medical management (NASCET Trial)
 ESCT trial showed that carotid endarterectomy is beneficial for symptomatic carotid stenosis of 80 – 99%
Indications for Carotid Artery stenosis
 Carotid lesion unsuitable for surgical access
 Radiation –induced stenosis
 Re-stenosis after CEA
 Significant cardiac, pulmonary and other comorbidities that increase risk with GA

Doppler Blood Flow

 Principles – Laminar flow  wall resistance slows down flow at the side
 In the presence of significant stenosis  Turbulence due to chaotic flow
 U/S Carotids Parameters  Peak Systolic Veolicty, End Diastolic Velocity used to calculate Mean Velocity and Pulsatile Index
U/S Carotids
 B mode – 2D image of blood vessel, morphology of the plaques (whether it is mobile or non-mobile), structure of the artery and if there are any
abnormalities
 Power Angio mode – patency of lumen, good for detecting low flow velocities but does not provide information on direction of flow  Colour Doppler
mode
 Pulse wave mode/Doppler mode – shows flow velocity of the vessels, using the flow velocity ratios to grade stenosis

Transcranial Doppler
 Detects degree of vasospasm following SAH
 Detects microemboli
 Detects R to L shunnt in TCD Bubble study
 Stenosis of intracranial vessels in stroke
Antiplatelet
 Choice of antiplatelet – Aspirin, Clopidogrel, Combination of aspirin and dipyridamole, Ticlopidine
 Role of DAPT
 Resistance or non-responsiveness of antiplatelet agents
 Antiplatelets prevent clot formation via prevention of platelet aggregation and are used for patients with non-cardioembolic stroke/TIA
In comparison, anticoagulants target blood clotting factors to prevent the formation of clots and are used for patients with coexisting clots or cardioembolic
stroke/TIA
 On average, antiplatelets reduce RR of stroke/MI/vascular death by 22%

Aspirin
 Aspirin works by irreversibly inhibiting formation of PG derivative, thromboxane A2, via acetylation of platelet cyclooxygenase, thus inhibiting platelet
aggregation.
 Usual dosing is 300mg given within 24 – 48 hours after stroke onset. Maintenance dose 100mg once daily.
 For those treated with IV altepase, aspiring initiation is generally delayed until 24 hours.
 Aspirin may not be suitable for patients with asthma or known NSAID allergy. There is also a risk of bleeding, especially BGIT with an annual risk of serious
BGIT of 0.4% which is 2.5 times the risk for non-users. Risk factors include older age, PUD, H. pylori infection, concurrent chronic use of medications which
may increase the bleeding risk

Clopidogrel
 Blocks the P2Y12 component of ADP receptors on the platelet surface which prevents the activation of the GPIIb/IIIa receptor complex, thereby reducing
platelet aggregation
 Usual loading dose 300mg may be considered, maintenance 75mg once daily
 Unlike aspirin, can be used in patients with NSAID allergy
 C/w with aspirin, clopridogrel is slightly more effective in reducing the combined risk of vascular event/deaath in patients with symptomatc disease
 However, it is not superior in preventing recurrence of stroke
 S/e including rashes (including a few cases of TTP)
 Initiation with daily dose of 75mg does not produce maximal inhibition of platelet aggregation for about 5 days
 It is also a prodrug and its effectiveness may be affected by variability with CYP2C19 genotyping or drug interactions

Ticlodipine
 A platelet ADP receptor antagonist (similar to Clopidogrel)
 Usual dose is 250mg BD daily
 Can be used as an alternative to patients with aspirin allergy
 However, has possible adverse effects of neutropenia, thrombocytopenia and aplastic anemia
Long term DAPT (aspirin + clopidogrel) is no more effective than clopidogrel alone for secondary stroke prevention. It is no longer recommended for routine long-
term secondary prevention after ischemic stroke or TIA. Short term use of DAPT is recommended inn selected patient groups i.e. 21 days of DAPT begun within 24
hours of stroke onset can be beneficial for early secondary stroke prevention.

Pharmacological treatment of risk factors

 HTN, HLD, DM

Hypertension as a risk factor for Stroke

 Categories of BP are 1) normal i/e/ SBP <120 and DBP <80, 2) elevated i.e. SBP 120 – 129 and DBP < 80, Stage 1 HTN i.e. SBP 130 – 139 or DBP 80 – 89, Stage
2 HTN i.e. SBP 140 or higher or DBP 90 or higher, and Hypertensive crisis i.e. SBP > 180 and/or DBP > 120
 Immediately after an acute ischemic stroke, BP should be
 Cerebral blood flow is kept relatively constant across a wide range of cerebral perfusion presure by autoregulation. In acute ischemic stroke, autoregulation
is impaired. In moderate stroke patients, dysregulation can last for up to 2 weeks.
 In terms of the natural history of BP changes during an acute ischemic stroke, 60% of patients have an SBP > 160mmHg (lacunar strokes may be a/w higher
initial SBP c/w non-lacunar stroke). Generally, the BP has a tendency to normalise after 24 – 48 hours
 Even in markedly hypertensive patients, lower the BP in the acute phase should be avoided unless the high BP is causing hypertensive encephalopathy,
cardiac ischemia, congestive failure, compromise of vital organs or if the stroke is due to an aortic dissection
 Patients with elevated BP and who are otherwise eligible for treatment with rTPA should have their BP carefully lowered so that their SBP < 185 and their
DBP < 100 before IV fibrinolytic therapy is initiated. Thrombolysis with recombinant plasminogen tissue activator salvages brain tissue and must given
without 4.5 hours of stroke onset.

Preventing Secondary Stroke + Long Term

Non-cardioembolic stroke (intra-cranial atherosclerosis, lacunar stroke)
 Long term antiplatelet  asprin 100mg OM, or clopidogrel 75mg OM, (sometimes ticlodipine 250mg BD or aspirin + dipyridamole, but these are used more
rarely in Sg)
Cardioembolic stroke
 Warfarin for all cardio-embolic sources
 Dabigatran, Apixaban, Rivaroxaban for non-valvular AF
Extra-cranial carotid artery stenosis
 Antiplatelets
 Endarterectomy, indicated if stenosis > 70%, if not suitable for CEA  carotid angioplasty and stenting
Long Term
 CVRF control
 Smoking cessation
 Lifestyle modification
 Stroke rehab  Reduces disability and improves participation in ADLs
 Driving
 Vocational rehab
Meningitis and What is the epidemiology?
Encephalitis  Common organisms: Haemophilus influenzae, Streptococcus pneumonia, Neisseria meningitides
 Neonates (<1/12y/o): Strep agalactiae
 Children (1/12-4y/o): H. influen za  declined due to vaccination against Hib
 Old children (5-29y/o): N. meningitidies
 Adults: S. pneumonia  worldwide increase in antibiotic-resistance (alterations in penicillin-binding proteins involved in synthesis of bacterial cell walls)
What are the principles of antimicrobial therapy?
Bactericidal (not bacteriostatic) activity in CSF
 Specific Ab and complement absent in CSF of infected patients  inefficient phagocytosis  rapid bacterial multiplication

(Beta-lactams highly protein-bound)

 Permeability of blood-brain barrier
o Meningitis  increase in vesicular transport across cells in arterioles + separation of tight junctions in venules  Antibiotics reach 5-10% blood
concentration in CSF
o Liipid-soluble antibiotics (e.g. chloramphenicol, rifampicin, trimethoprim)  30-40% blood concentration in CSF (even w/o meningitis)
 Bactericidal therapy  bacteriolysis  biologically active cell-wall products  ↑cytokines in CSF  exacerbate inflammation and damage of blood-brain
barrier
o But: bacterial endotoxin released by above process < bacterial endotoxin released by untreated bacteria

What is the course of the disease?

 ? Promptly: inconclusive data  no correlation between duration of symptoms and clinical outcome
o Coma, papilloedema, or focal neurologic findings  require cranial imaging before lumbar puncture
 If indicated: blood c/s, empiric antibiotic therapy  imaging  lumbar puncture immediately after (delayed diagnosis and therapy
partially due to CT brain before lumbar puncture)
 Antibiotic therapy 1-2h before imaging LP does not decrease diagnostic sensitivity if CSF c/s + CSF bacterial Ag + blood c/s

What is the empiric treatment?

 Broad-spectrum cephalosporins (cefotaxime/ceftriaxone) + ampicillin (<3y/o or >50y/o – S agalactiae and Listeria monocytogenes)
 Immunocompromised: cephalosporin with gram-negative cover (ceftazidime) + ampicillin (possible listeria)
 Head trauma or VP shunt: broad spectrum antibiotics against gram (+) and (-) = vancomycin + ceftazidime

What is the empirical glucocorticoid therapy?

 Recommended for children <2/12 y/o, especially if suspecting H influenza (not vaccinated, gram-negative coccobacilli on Gram stain)
o First dose: 0.15mg/kg Q6H x4/7
 ? Limited use in adults – consider if high concentration in CSF, evidence of ↑ CSF pressure
 Evidence
 o Adjunctive glucocorticoid therapy found to ameliorate meningitis in laboratory animals
o Adjunctive dexamethasone reduced audiologic and neurologic sequelae
 Controversies
o Trial limited to children with H influenza  may not extend to S pneumonia
o Benefit in adults less clear

Organism-specific
Drug Duration Comments
CSF Gram-stain
GPC Vancomycin (IV 15mg/kg Q6H up to 2g/d) +
(Staph, Strep) broad-spectrum cephalosporin
GNC Penicillin G (IV 300 000 u/kg/d up to 24 Mu)
(Neisseria,
Moraxella)
GPR Ampicillin (IV 100mg/kg Q8H in kids or 2g Q4H
(Listeria, in adults) + aminoglycoside
Corynebacterium,
Bacillus)
GNR Broad-spectrum + IV aminoglycoside 21/7
(Pseudomonas,
Burkholderia,
Vibrio,
Acinetobacter,
Enterobacter,
Campylobacter)
CSF Culture
S. pneumonia Vancomycin + broad-spectrum cephalosporin 10-14/7 Antimicrobial resistance:
- High-dose penicillin (4 million units
If adults given dexamethasone: ceftriaxone + Q4H) may not >MIC if intermediate
rifampicin level or resistance
- Broad-spectrum cephalosporins
If dexamethasone given: repeat with 2nd LP in may be effective against penicillin-
24-48h (dexamethasone affects clinical resistant strains but reported clinical
assessment) failures
- If CSF isolate MIC (cefotaxime or
ceftriaxone) >0.5 ug/mL  ?
 resistance to cephalosporins
- Vancomycin may be most effective
since beta-lactam resistance
prevalent
- But Vancomycin penetration into
CSF not high enough  synergistic
effects of drugs
H. influenza Cefotaxime or ceftriaxone (found to be as 7/7 - Widespread beta-lactamase-
effective as ampicillin + chloramphenicol) producing strains
- These cephalosporins have lower
incidence of hearing loss
N. meningitides Penicillin G 7/7 - Even clinical isolates with
intermediate resistance can be
treated effectively with penicillin
- If inadequate response: consider
change to ceftriaxone
L. monocytogenes Ampicillin/penicillin + gentamicin 14-21/7
(or trimethoprim-sulfamethoxazole)
S. agalactiae Penicillin G 14-21/7
Neonates: Penicillin + gentamicin
Enterobacteriaceae Broad-spectrum + aminoglycoside
Pseudomoas Ceftazidime (IV 50-100mg/kg up to 2g Q8H) +
aeruginosa aminoglycoside
Parkinson’s
How do you approach Parkinsonian disorders?
 Primary idiopathic Parkinsonism
 Atypical Parkinsonian disorders
 Non-neurodegenerative secondary

Primary Idiopathic Parkinson’s

 Sporadic onset – look for red flags to suggest atypical PD

What are the red flags in PD?

 Symptoms that come on too early for PD
 Early dementia < 1 year (DLB, NPH)
 Early hallucinations < 3 years (DLB)
  Early prominent postural instability < 3 years (PSP, NPH)
 Early gait disorder (NPH)
 Early freezing < 3 years (MSA)
 Early severe autonomic dysfunction (MSA)
 Early saccadic slowing (PD)
 Early dysphagia (MSA)
 Absence of features atypical for PD
 Absence of resting tremor (MSA, PSP, NPH)
 Absence of asymmetry (MSA, PSP, NPH)
 Absence of levodopa response i.e. 1g/day x 1/12  no respone (MSA, PSP, CBD)
 Symptoms highly suggestive of atypical PD
 Respiratory stridor (MSA)
 Myoclonus (MSA, CBD)
 Cerebellar/Pyramidal signs (MSA, PSP, SCA, Fx TA)
 Limb apraxia (CBD)
 Rapid progression (MSA, PSP)

Tell me about rest tremors.

 65% occur at the onset of PD, 75 – 100% during the course of PD, 9% resolve i.e. lost
 3 – 5 Hz
 Unilateral, asymmetrical distal prominence (pronation-supination, pill-rolling)
 May also involve the lips, chin, jaw, legs, rarely neck, head or voice (DDx is essential tremors)
 Induce or aggravate tremors by producing stress e.g. counting backwards from 100 or asking the patient to walk
 Pure tremor i.e. benign tremulous PD is a monosymptomatic PD where there is an isolated tremor preceeding all other symptoms by years. This
should response to levodopa.
 Postural tremor occurs in addition to rest tremor in many patients. It is more prominent, and more disabling than a rest tremor. It is the 1st
manifestation of the disease. Extreme pronation or supination brings out the postural tremor better
 PD-related postural tremor is a reemergent tremor
 ET is a ddx. A tremor of the same frequency and amplitude as the rest tremor may emerge after latency during posture holding i.e. the so-called
re-emergent tremor. By contrast, ET apparent immediately with a posture-holding maneuver. ET responds to levodopa therapy. Coexistant ET
responds to propanolol.
PD Tremor ET Tremor
Frequency 4 – 6 Hz 5 – 10 Hz
Movement Supination-Pronation Flexion-Extension
Rest Increased Decreased
Action Decreased Increased (Can interfere with
 rapidly alternating movements
 cogwheel can be found in et
on distraction)
Walking Increased Decreased
Alcohol - Decreased
Distribution Face, jaws, lips, chin Head, voice
other than NB ET has no other signs of
hands parkinsonism

Tell me about rigidity in PD.

 Increased tone throughout the ROM of flexion and extension of the wrist
 Leadpipe and cogwheeling rigidity has underlying superimposed tremor
 Froment’s sign – Exercise opposite limb to bring out the rigidity but this is non-specific and is also present in benign ET
 Rigidity may also be associated with pain e.g. painful shoulder

Tell me about hypokinesia in PD.

 Decrease in speed and amplitude
 Bradykinesia refers to a decrease in speed alone
 It occurs due to a fusion of discrete movements
 Hypokinesia affects voluntary movements, associated movements of facial expression, arm swing. “Kinesia paradoxica” refers to the phenomenon of being
able to run if there is a fire
 Anatomical localisation for hypokinesia is to the putamen and globus pallidus

Tell me about postural instability in PD.

 Check all steps for gait, pull tests
 Appears late
 Important for staging the disease
 This symptom is refractory to levodopa as the non-dopaminergic pathways are involved

What is the staging for Parkinsons’s

 1 – Unilateral
 1.5 – Unilateral + Axial
 2 – Bilateral
 2.5 – Recovery on pull test
 3 – Postural instability, Physically independent
  4 – Severe disability, Able to walk or stand unassisted
 5 – Wheelchair bound or bedridden unless aided

Tell me about PSP.

The 3 features of PSP are postural instability – pedunculopontine atrophy i.e. midbrain atrophy, Parkinson’s-predominant axial rigidity, lack of asymmetry, poor
response to levodopa and lastly, supranuclear gaze palsy. Classically, it is called steele-richardson-olzschewski syndrome.

 Upright posture / Frequent falls

 Pseudobulbar emotionality
 Staring look, furrowed brow/stare
 Square wave jerks (saccadic intrusions) which are very pathognomonic – in the primary gaze, use a fundoscopy and fix and easier disc so it is easier to see
 Slow saccade ( speed affected before limitation of movement)
 Slowing affects saccades more than pursuits
 Vertical gaze is affected before horizontal
 Down before up
 Oculocephalic response – Vertical Doll’s and Horizontal Doll’s normal
 Eyelid apraxia
 Parkinsonism / Hypokinesia / Bradykinesia
 Cognitive impairment
 Motor disinhibition – Applaus sign (frontal), Luria hand sign (frontal), Go/No-Go tasks
 Executive dementia
 Early midbrain atrophy – MRI looking for humming bird / penguin sign

What is Vascular Parkinsonism?

- Acute/subacute onset with stepwise progression
- Lower body parkinsonism with shuffling gait and freezing
- Presence of vascular risk factors
- At least 2 infarcts in BG + Widespread white matter disease on MRI consistents with Binswanger’s pathology

What is Hydrocephalus-induced Parkinsonism?

 Can be communicating or obstructive
 NPH is idiopathic – Parkinsonism / Gait + Urinary/Fecal incontinence + Dementia

What is Multiple System Atrophy?

The 3 features of MSA are autonomic (urinary dysfunction i.e. frequency/urgency, impotence, erectile dysfunction, postural dysfunction  stand 3 min, systolic
30mmHg, diastolic 10mmHg), Parkinsonism which is poorly responsive to levodopa and cerebellar dysfunction. Pathologically, pyramidal signs can be classified as
supratentorial and infratentorial. Supratentorial signs include MSA P, MSA C, predominant autonomic (Shy drager involvement). Infratentorial signs include PD, PSP,
CBD, SCA, Atypical Friedrich’s ataxia, Pure autonomic failure. The hot cross bun sign refers to the MRI appearance of the pons in a variety of a neurodegenerative
diseases and on T2, a hyperintensity forms a cross on the axial images through the pons, representing the selective degeneration of the pontocerebellar tracts.

What is Corticobasal degeneration?

 Frontal atrophy (alien-hand, frontal gait d/o apraxia, dementia)
 Parietal atrophy (cortical sensory loss – 2 point discrimination, apraxia, agnosia, parietal eye fields)
 Basal ganglia  Parkinsonism, dystonia, myoclonus, tremor, chorea, blepharospasm
 Saccades  Horizontal and Vertical vs PSP Vertical mostly
 Unilateral coarse tremor/rigidity
 Limb apraxia, limb dystonia, Alien limb

What is Dementia of Lewy Body?

 Probable (2) of parkinsonism, fluctuation of cognition and hallucinations
 Possible (1) severe neuroleptic sensitivity
 DLB vs PDD  infamous 1 year rule
 Dementia < 1 year DLB, > 1 year – PDD

What is the pathophysiology of PD?
 A neurodegenerative disease characterised by loss of dopaminergic neurons in the substantia nigra with cytoplasmic inclusions (Lewy bodies) in surviving
neurons

What pharmacotherapy is available?

 Levodopa
 Gold standard  Most effective for motor symptoms, Has less cognitive S/E
 In the short-term, Levodopa is the safest, cheapest and has the 1least number of adverse reactions
 Usually combined with a DCI as in Madopar and Sinemet
 Motor , Psychiatric and Autonomic dysfunction symptoms are less responsive to L-dopa (Motor symptoms include postural instability, gait and
speech disturbances, Psychiatric symptoms include dementia, depression and apathy)
 S/E of dyskinesia  After 5 years, about 1/3 of patients develop dyskinesia (which can be more disabling that the PD itself)
 The development of dyskinesia is the main reason to delay treatment with L-dopa
 Another complication is motor fluctuations
 The L-dopa therapeutic window narrows with disease progression and lowers the dyskinesia threshold
 Short half-life
 Evidence – STRIDE (PD study) showed that COMTI increases the L-dopa half life to up to 3 hours, L-Dopa + COMTI avoids low trough levels and is
suitable for enteral infusion
  Dopamine agonist
 May be ergot derivatives (Bromocriptine, Cabergoline) or non-ergot (Ropinorole, Apomorphine)
 Dopamine agonists can be used as monotherapy or as an adjunct to L-dopa
 Advantage: Reduce dyskinesia, Long half-life which allows for reduced dosing
 Ergot derivatives cause cardiac and pulmonary fibrotic reactions
 DA more commonly causes neuropsychiatric complications and postural hypotension
 DA show a high rate of withdrawal
 Anticholinergics
 Anticholinergics have a mild antiparkinsonian effect. They are more effective on the tremor rather than the akinesia or rigidity. Neuropsychiatric
s/e have been shown in 70%. These drugs lower the threshold for the development of visual hallucinations and dyskinetic movements. They also
cause harmful anticholinergic effects especially in the elderly e.g. confusion, urinary retension, dry mouth with swallowing difficulty, blurring of
vision (glaucoma)
 Selegiline
 Selective MAO (monoamine oxidase)-B inhibitor, mild antidepressant activity, weak anti-PD effect
 Selegiline acts by decreasing the peripheral destruction of dopamine
 Advantage: Long half-life which allows for reduced dosing
 Disadvantage: Less potent, has more cognitive side effects (it metabolises to amphetamine)
 Combined treatment with L-dopa shows no benefit but in advanced PD, selegiline may help manage symptoms but it is best avoided in patients
with OH, frequent falls, confusion and dementia

 COMT Inhibitors
 Amantadine
 Surgery
 Deep brain stimulation (of thalamus, globus pallidus interna or subthalamic nucleus)
 Bilateral STN reduces off-period dystonia and is the procedure of choice, it is reversible, bilateral, expensive
 Globus pallidus internus stimulation
 Lesional surgery (Thalatomy – Ventral intermediate nucleus  Only tremor relieved, Subthalmotomy – Subthalamic nucleus  All symptoms
relieved, Pallidotomy – Globus pallidus interna  All symptoms relieved)

Nephrotic Syndrome Why is this not acute glomerulonephritis?

In acute glomerulonephritis, there should be a history of sore throats or skin lesions and no gross or generalised swelling. There may also be hypertension and
hematuria.

Why is this not congestive cardiac failure?

Why is this not cirrhosis?
In cirrhosis, there is usually only ascites but no generalised edema.

What history should be taken in nephrotic syndrome?

Diabetes mellitus, Malignancy such as lymphoma/leukemia, Drugs e.g. NSAIDs, skin rash, arthritis, arthralgia, alopecia, history of other diseases e.g. malaria,
syphilis, HBV, HCV

What investigations should be done?

What is nephrotic syndrome and what are its causes?

Nephrotic syndrome is defined as edema which can be peripheral or ansarca if severe, proteinuria > 3.5g/day and hypoalbuminemia <30g/L with ot without
hyperlipidema hypercholesterolemia with TC usually > 10mmol/L, lipiduria and hypercoagulability

The causes of nephrotic syndrome can be classified into primary renal disease i.e. minimal change glomerulonephritis, membranous glomerulonephritis,
mesagiocapillary and proliferative glomerulonephritis, focal and segmental glomerulosclerosis and IgA nephropathy. Secondary causes include diabetic
nephropathy, collagen vascular disease mainly SLE, and also RA by amyloidosis, drugs ?, certain malignancies e.g.. bronchial carcinoma, lymphoma, infections e.g.
infective endocarditis, HBV, HCV, HIV, secondary syphilis, leprosy

What is the most common cause of nephrotic syndrome in children and adults?
In children, it is most commonly caused by minimal change glomerulonephritis. In adults, it is most commonly caused by membranous glomerulonephritis.

What are the lipid abnormalities in nephrotic syndrome? What are the mechanisms?
Other than TC, TG, LDL and VLDL are also raised. However, HDL is normal or low. The mechanisms of lipid abnormalities are increased synthesis of lipoproteins by
the liver secondary to hypoalbuminemia and reduced clearance of triglyceride bearing lipoprotein in direct response to albuminuria.

It is because of these lipid abnormalities that there is an increased rate of atherosclerosis in patients with nephrotic syndrome.

What is the mechanism of proteinuria?

There is increased permeability of the glomerular capillary wall. There is reduction in the number of fixed negatively charged protein molecules in the glomerular
capillary wall which repel the negatively charged protein molecules allowing proteins to pass through the pores. There is also damage to the glomerular basement
membrane which leads to an increase in the size and number of the pores, allowing passage of larger molecules.

Why is there edema in nephrotic syndrome?

While it was previously thought to be due to hypoalbuminemia, the recent thinking is that edema is due to sodium retention in the extracellular compartment.
Also, there is a change in the extracellular compartment.
 What is the BP in nephrotic syndrome?
Usually BP is normal or low. If there is hypertension, it is usually secondary to underlying disease e.g. SLE with renal involvement, polyarteritis nodosa, diabetic
nephropathy or terminal stage of nephrotic syndrome.

What is the treatment of nephrotic syndrome?

What is the prognosis in nephrotic syndrome?

The prognosis of the disease depends on the type of nephrotic syndrome. The prognosis of minimal change disease in children is excellent. CKD does not occur. In
membranous nephropathy, 1/3 may remit spontaneously, 1/3 remain in nephrotic syndrome and 1/3 show progressive loss of renal function. In FSGS and
mesangiocapillary GN, the prognosis is poor. In IgA nephropathy, the course of the disease is indolent and ESRF occurs in 20 years.

What are the complications of nephrotic syndrome?

Hypercoagulability leading to venous thrombosis, infection e.g. pneumococcal infection, cellulitis, streptococcal infection due to loss of immunoglobulin
complements, hyperlipidemia causing atherosclerosis, oliguric renal failure, loss of thyroxine binding globulin causing free T3 and freeT4 which leads to
hypothyroidism, loss of transferrin and irone leading to iron deficiency anemia nad loss of vitamin D binding protein.

What are the mechanisms of renal vein thrombosis in nephrotic syndrome?

In nephrotic syndrome, there is hypercoagulable state due to loss of inhibitors of coagulation in urine such as antithrombin III, protein C and S and also loss of
fibrinolytic factor (plasminogen). There is also increased synthesis of clotting factors. Also, hyperlipidemia causes atherosclerosis which predisposes to increased
venous thrombosis.
Polycystic Kidney What is your differential diagnosis?
Disease Bilateral hydronephrosis with hypertension

State one single investigation for your diagnosis.

U/S Abdomen

What investigations should be done for PKD?

Bloods e.g. FBC looking for anemia, RP looking raised Cr and estimated GFR, UFEME and urine c/s and imaging including a renal ultrasound and MRI/MRA brain
looking for any berry aneurysm.

What are the U/S criteria for PKD?

In a person younger than 30 years old, presence of at least 2 renal cysts in either 1 or both kidneys is diagnostic. In a person aged between 30 and 59 years,
presence of at least 2 renal cysts in each kidney is diagnostic. In a person 60 years and older, presence of at least 4 cysts in each kidney is diagnostic.

What is PKD?
It is an inherited cystic disease of the kidney. There are 2 types of PKD. APKD is inherited as an autosomal dominant, common type, males and females are equally
affected. Gene on chromosome 16 (PKD1) and 4 (PKD2).
There is also an infantile type PKD which is an inherited autosomal recessive condition.

What are the presentations of adult PKD?

It may be asymptomatic, pain or heaviness in the loin, recurrent painful hematuria due to rupture od cyst in the renal pelvis or due to infection, recurrent UTIs,
acute loin pain or renal colic, features of hypertension and its complications, features of renal failure and stroke, usually SAH due to rupture of a berry aneurysm.

What are other features of PKD?

Cysts elsewhere including liver, spleen, pancreas, lung, ovaries, testes, ovaries, uterus, thyroid, bladder, Berry aneurysm in the circle of Willis, Mitral valve prolapse,
Aortic regurgitation, Tricuspid regurgitationn, Mitral regurgitation, Colonic diverticular disease with increased risk of perforation/anterior abdominal hernias,
Polycythemia due to increased EPO secretion, renal stones, and renal cancer rarely.

What are the causes of acute pain in PKD?

Acute haemorrhage in the cyst, Infection of the cyst, Renal stone, Renal cell carcinoma rarely

If the patient with PKD is unconscious what is the likely diagnosis?

Subarachnoid haemorrahge due to rupture of berry aneurysm, Ceberal haemorrhage as a complication of hypertension, Hyponatremia due to salt-losing
nephropathy

What are the causes of death in PKD?

Chronic renal failure, Subarachnoid haemorrhage, Myocardial infarction

How to manage the patient with PKD?

Monitor renal function with renal panel and hypertension with BP. Treat HTN with ACE inhibitors or ARBs. Screen family members. Genetic counselling. If Cr > 600,
start renal replacement therapy with PD, HD or transplant. If Cr > 800, start dialysis.

What are the causes of a unilateral renal mass?

Renal cell carcinoma, Hydronephrosis or Pyonephrosis, Renal abscess, Solitary kidney due to hypertrophy in a lean skinny person

What are the causes of bilateral renal masses?

PKD, Bilaterla hydronephrosis, Amyloidosis, Diabetic nephropathy in early stage

What are differentials for bilateral renal cysts?

Multiple simple cysts, Infantile PKD, Tuberous sclerosis (angiomyolipomas), Von Hippel Lindau Syndrome

What are the cystic diseases of the kidney?

Simple cysts (usually congenital), Acquired cysts, after dialysis in chronic renal failure, PKD, Medullary sponge kidney which is a cyst confined to the papillary
 collecting ducts occurring in those aged 40 – 60 years for which the prognosis is good. Medullary cystic disease where there are small cysts in the cortical area or
corticomedullary junction.
CKD Diabetic What is CKD and ESRF?
Nephropathy CKD is defined as the presence of either kidney damage as defined by structural or functional abnormalities (based on pathological abnormalities, markers of kidney
damage by blood, urine or imaging, or decreased kidney function with reduced GFR < 60, for 3 or more months, with or without kidney damage, irrespective of the
cause.

What is acute renal failure? What are the causes?

AKI is defined as an increase in serum Cr by at least 0.3mg/dl within 48 hours, or an increase in serum Cr to at least 1.5 times from baseline which is known or
presumed to have occurred within the prior 7 days or urine volume less than 0.5ml/kg/hr for 6 hours

What are the causes of CKD?

Common causes of CKD include diabetes mellitus, hypertension, glomerulonephritis, as well as vascular causes such as Henoch Schonlein Purpura, infections such as
Hep B and C infections, toxins and autoimmune causes such as systemic lupus erythematosus. Renal causes include renovascular disease, intestitial nephritis,
polycystic kidneys, analgesic nephropathy, pyelonephritis, reflux nephropathy and obstruction in the urinary tracts. Extrarenal causes include systemic sclerosis,
multiple myeloma and amyloidosis.

What are the clinical manifestations of CKD?

Symptoms of renal failure include urinary symptoms such as frequency, changes in volume of urine passed, frothy urine, hematuria, loin pain
CKD may also present with its complications which are symptoms of fluid overload such as dyspnea and edema of the lower limb, ascites, facial edema and
symptoms of uremia such as loss of appetite, fatigue, nausea and vomiting.

What are the different features due to involvement of different systems of the body?
Bone symptoms include
Skin symptoms include
GI symptoms include
Metabolic symptoms include
Endocrine symptoms include
Muscle symptoms
Nervous symptoms
Calciphylaxis symptoms
CVS symptoms
Respi symptoms
Malignancy symptoms
Nephrogenic systemic fibrosis

What are the stages of CKD?

 What causes anemia in CKD?

What is renal osteodystrophy?

What are the mechanisms of renal osteodystrophy?

How to treat renal osteodystrophy?

How to treat CKD?

What are the reversible factors in CKD?

What are the indications of urgent dialysis?

AEIOU
Metabolic acidosis ph<
Hyperkalemia K > refractory to medical treatment
Intoxication
Fluid overload
Uremia
Hypertension with What is your differential diagnosis?
CKD
p/w frequency of
micturition, excessive What investigations should be done in this case?
thirst, weakness and
palpitation, anorexia, What are the types of glomerulonephritis?
n/v
What is the treatment of CGN?
Lupus Nephritis
What investigations should be done?
FBC, ESR, UFEME looking for albumin, granular casts, RP, CMP, ANA, anti-dsDNA, C3 and C4 levels, AXR, CTAP, Renal biopsy

PUO in Haemodialysis How do you workup fever in CKD patients on HD?

patient
What are the causes of fever in such cases?

How will you treat a TB patient with CKD?

 How to treat TB in a HD patient?

How treat CMV infection?

Gout Long Case Gout

History
Presenting Complaint
Typical flare o Acute monoarthritis
 Severe pain, redness, warmth, swelling and disability
o Onset more often at night
 Symptoms peak within hours and reach a crescendo before gradually subsiding over 5-14
days
o Lower extremity involvement
o Signs of inflammation extend beyond the confines of the joint that is primarily involved
o Involvement in ankle or in-step or in a wrist, finger or olecranon burssa
o Uncommonly, may involve axial joints e.g. spine or sacroiliac joints
Polyarticular o More common in hyperuricemia secondary to myeloproliferative or lymphoproliferative
flare disorder or in organ tranplant recipients receiving cyclosporin or tacrolimus
o Occur in a sequential migratory pattern or simultaneously or may involve a cluster of
adjacent joints, tendons and bursas

Long Case Template

- Course
o Intercritical gout and recurrent gout flares
1. The intercritical period is that which someone enters upon resolution of a flare and between flares
2. Even after severe and incapacitating gout flares, these periods early in the course are most often entirely asymptomatic which is very
uncommon in arthritic disorders other than crystal deposition disease and palindromic rheumatism
o Chronic tophaceous gouty arthritis (CTGA)

- Cause (etiology)
o Primary: look for comorbids of DM HTN HLD
o Secondary
 Meds hx
  Chronic alcoholism -> in which case take a CLD Hx
 CKD
 Polycythemia, lymphoproliferative, myeloproliferative
 Psoriasis
- Cause (precipitatnt)
o Dietary indiscretion (alcohol, seafood, red meat, kidneys/livers, sardines)
o Thiazides, aspirin, cyclosporine, pyrazinamide, ethambutol
o Infection
o Dehydration/fasting
o Surgery/trauma

- Control
- Complications
o Renal complications of hyperuricaemia and urate crystal deposition
 Nephrolithiasis
 Chronic urate nephropathy

- Compliance
- Concerns

Physical Examination

Investigation
o Synovial fluid analyis
1. Monosodium urate crytals on polarising light microscopy
o Bloods
 Neutrophilic leukocytosis
 Rasied ESR/CRP
o Both these findings are often present in other causes and thus of little diagnostic value
 Serum urate
o Difficult to interpret during a flare
o > 6.8 can support the diagnosis but is not diagnostic
o The most accurate time for assessment of serum urate and establish a baseline value is at least 2 weeks after a flare completely subsides
o Imaging
CTGA – delicate overhanging edges of bone associated with bone erosions due to tophi
Management
 Confirm diagnosis
 o FBC, urate level
o XR: normal joint space, soft tissue swelling, periarticular punched-out erosions producing mouse bitten appearance, sclerotic overhanging edges
o Joint aspirate: needle-shaped negatively birefringent crystals
 Gram stain and c/s, AFB stain and c/s TRO ddx
 Treat
o Patient education, stop smoking/alcohol, dietary advice, avoid dehydration, lose weight
 Meat, alcohol, seafood
o Meds (acute flare) – do not start urate-lowering therapy acutely
 NSAID
 500mg TDS Colchicine, watch for diarrhoea – if on colchicine, stop statins
 Prednisolone 0.5mg/kg for 2-5/7at full dose, then tapered over 7-10/7
 Monitor CBG in diabetics
o Meds (chronic)
 Urate-lowering
 #1 allopurinol
o For any patient, initial dose should be < 100mg/day, and less than 50mg/day in patients with
CKD stage 4 or 5
o The dose should be uptitrated every 2 to 5 weeks based on serum uric acid levels and clinical
response
o The maintenance dose can be > 300 mg/day even in those with CKD, as long as patients are
educated regarding and monitored for adverse events and hypersensitivity
 Febuxostat (xanthine oxidase inhibitor)
o Avoid in patients with high cardiovascular risk
 If contraindicated to XOIs or unable to tolerate, probenecid, sulfinpyrazone (uricosuric agents)
o Probenecid is not recommended in patients with Cr clearance < 50
o , Also less effective in patients who are overproducers of urate
o Should be avoided in patients with urolithiasis and risk of uric acid nephropathy
- Prophylaxis
o Colchicine or low dose NSAIDs indomethacin as 1st line
o Low dose prednisolone considered 2nd line
o In patients with CKD, however, NSAIDs can cause acute worsening of eGFR and are contraindicated in alls stages of CKD
o Colchicine is excreted renally and can accumulate in renal impairment resulting in colchicine toxcitiy
 Leukopenia, elevation of AST, neuropathy

Management in Advanced Chronic Kidney Disease

Viva questions
Pathogenesis of Gout
o Monosodium urate crystal deposition
o Characterised biochemically by extracellular fluid urate saturation, reflected by blood hyperuricaemia with serum urate
concentrations > 6.8

Differentials of gout flare

o Septic arthritis
o Trauma
o Calcium pyrophosphate crystal deposition disease
o Cellulitis

Differentials of CTGA
 Rheumatoid arthritis
 Dactylitis
 Osteomyelitis

Indications for starting urate-lowering therapry in a patient with gout

 2 or more gout flares in a year
 Clinical or radiographic signs of joint damage
 Tophaceous deposits in soft tissues or subchrondral bone
 Gout with renal insufficiency (Cr clearance < 60)
 Recurrent uric acid nephrolitihiasis

Side effects of allopurinol

o Side effects occur in 3-5%
o Rash, diarrhea, drug fever
o Leucopenia, thrombocytopenia
o Allopurinol hypersensitivity syndrome
 Erythematous rash, fever, hepatitis, hypereosinophilia and renal failure

Case 3
Man with multiple lumps

- Gouty tophi vs rheumatoid nodule

Gout
- Men 40 – 50yr
 - Female > 60 y/o post menopausal
- Genetic causes of gout
o (Slide)
- Acquire causes of gout
o Fructose is underasked e.g. drinking excessive fruit juices
o (Slide) , occupation involving lead or metal products,
- Drugs
o (Slide)
- Gout and renal transplant
o Allopurinol CI if patient on Azathioprine (xanthine oxidase inhibitor, xanthine oxidase breaks down aza)
Rheumatoid Arthritis What is your differential diagnosis?
SLE, Mixed connective tissue disease, Seronegative arthritis

Could it be seronegative arthritis or ankylosing spondylitis?

Seronegative arthritis typically has asymmetrical involvement of the larger joints.

Which joint is spared in RA?

Distal interphalangeal joint. However, it may be involved if there is secondary OA

What is RA?

What are the mechanisms of wasting of mucles in RA?

There are multiple mechanisms and they include disuse, vasculitis, polyneuropathy, mononeuritis multiplex and entrapment neuropathy

What is Boutonniere’s deformity?

Fixed flexion deformity of the PIPJ and extension of DIPJ. It occurs because of rupture of the central slip of the extensor tendon allowing it to protrude the joint
between the two lateral slips of the extensor tendon.

What is the Swan Neck deformity?

Fixed flexion deformity of the DIPJ and extension of PIPJ. Changes in chronic synovitis cause rupture or stretching of the extensor tendon on the dorsum of the DIPJ.

What is the Z thumb deformity?

Because of chronic synovitis, there is hyperextension of the interphalangeal joints and fixed flexion and subluxation of the metacarpophalangeal joins of the thumb.

Why radial deviation?

Weakness of the extensor carpi ulnaris lead to radial deviation of the wrist as the carpal bone rotate.
Why ulnar deviation?
Ulnar deviation of the MCPJs occurs in response to radial deviation of the wrist in order to keep the tendons to the phalanges in normal line to the radius.

What is a rheumatoid nodule?

It is a painless, firm, subcutaneous nodule invariably associated with positive rheumatoid factor. It present in 20 – 30% of cases of RA. Sites of occurrence include
pressure points e.g. elbow, extensor surface of forearm and hands, scapula, scalp, sacrum, shin, Achilles tendon, toes, sclera, pleura, lungs and pericardium. A
rheumatoid nodule is significant as it is one of the ARA diagnostic criteria and is associated with high titer of rheumatoid factor, active and aggressive disease and
poor prognosis. Nodules may ulcerate and get infected. Treatment with methotrexate may increase the number of nodules. Nodules resolve when the disease is
under control. However, it causes problems, it can be removed surgically or with local injection of steroids. Differentials for a rheumatoid nodule include gouty
tophi, xanthomata, olecranon bursa in elbow, sarcoid nodule or neurofibroma.

What is a Baker’s cyst?

Cyst on the back of the knee joint which communicates with the joint but prevents fluid from returning to the joint by a valve-like mechanism. It may rupture during
knee flexion and fluid enters the calf resulting in severe pain, swelling and tenderness as in a deep vein thrombosis.
After rupture, treatment includes analgesia, elevation of the limb and rest, +/- antibiotics, intrarticular injection of steroids and surgical toileting anf removal of
cyst if necessary. A baker’s cyst occurs in RA, OA and rarely, may be congenital.

What are the diagnostic criteria for RA?

There are 7 diagnostic critertia for RA and they are morning stiffness for > 1 hr, arthritis of 3 or more joints, arthritis of hand joints and wrist, symmetrical arthritis,
rheumatoid nodule, positive Rh factor and typical radiological changes of erosions or periarticular osteopenia. The duration should be for 6 weeks or more and.
There are 14 joint areas that are included for involvement in RA and they are elbow, wrist, PIP, MCP, knee, ankle, MTP of both sides. When 4 or more criteria are
present, there is 93% sensitivity and 90% specificity.

What are the extra-articular manifestations in RA?

Eye involvement includes episcleritis, scleritis, keratoconjunctivitis sicca
Lung involvement includes pleurisy, pleural effusion, nodules in Caplan’s, bronchiolitis
Heart involvement includes pericarditis, pericardial effusion, chronic constrictive pericarditis
Vascular involvement includes digital arteritis and nail fold infarction, ulcers, Raynaud’s phenomenon, visceral arteritis, mononeuritis multiplex, pyoderma
gangrenosum
Neurological involvement includes entrapment neuropathy as in carpa tunnel syndrome or tarsal tunnel syndrome, peripheral neuropathy, mononeuritis multiples,
cervical cord compression due to atlanto axial subluxation, and progressive cervical myelopathy
Hematological involvement include anemia, thrombocytosis, eosinophilia and pancytopenia due to hypersplenism in Felty’s
MSK involvement includes muscle wasting, tenosynovitis, bursitis and osteoporosis
Other manifestations include lymphadenopathy, splenomegaly.
Persistent inflammatory process in RA may cause large B cell lymphoma
What is the rheumatoid factor?
It is an antibody directed agianst the Fc portion of IgG. It is positive in 75% of RA cases but in 100% of RA cases with extra-intestinal manifestations. Other causes of
positive Rh factor include Sjogren’s SLE, SSc, dermatomyositis, infectious mononucleosis, infective endocarditis, TB, hepatitis B, syphilis, malaria, primary biliary
cirrhosis (50%), sarcoidosis and also temporarily after a vaccination and blood transfusion. May also occur in 20% of normal populated aged > 65 years old

What are the presentations of RA?

Chronic persistent, Remitting, Rapidly progressive and Palindromic types

What is malignant RA?

It is a severe and progressive RA associated with severe extraintestinal manifestations, systemic features and vasculitis

What is palindromic RA?

Recurrent acute episodes of monoarthritis lasting 24 – 48 hours involving knee and finger joints commonly. Fever may occur but no other systemic features. There
may be many attacks without any permanent articular damage. However, 1/3 go on to develop typical RA.

What is Caplan’s syndrome?

Rheumatoid lung nodules with pneumoconiosis. Nodules are typically located in the periphery of the lung. They may rupture causing a pneumothorax and
hemoptysis.

What is Felty’s syndrome?

RA with splenomegaly and neutropenia. It occurs in longstanding seropositive deforming but inactive arthritis. Females are more often affected, age 50 – 70 years
old. Leg ulcers or sepsis are complications due to neutropenia. A splenectomy may be necessary for hypersplenism. It is associated with a high titer of rheumatoid
factor, subcutaneous nodules and other manifestations of systemic rheumatic disease.

What are the mechanisms of anemia in RA?

1. Anemia of chronic disease
2. Megaloblastic anemia either due to folate or vitamin B12 deficiency if associated with pernicious anemia
3. Hypersplenism in Felty’s syndrome
4. Hemolytic anemia (Coomb’s test may be positive)
5. BGIT due to NSAID use or vasculitis

What are the investigations done in RA?

FBC, Rh factor, anti-cyclic citrullinated peptide antibody, CRP, ESR, XR hand and other involved joints, CXR

What are the ARA criteria for disease activity?

Number of tender joints, Number of swollen joints, Patient’s global assessment, Physician global assessment, Visual analog pain scale, Duration of morning stiffness,
ESR or CRP, Functional assessment health status
What precautaion is needed before undergoing GA or OGD?
XR cervical spine should be taken to rule out atlanto-axial subluxation. Otherwise, during anestheisa, cervical cord compression may lead to sudden death.

If the patient develops nephrotic syndrome or proteinuria, what is the likely cause?
Renal amyloidosis

What is the anti-CCP antibody?

It binds to peptides in which the amino acid arginine is converted to citrulline by peptidyl arginine deaminase, an enzyme abundant in inflamed synovium. It is highly
specific in RA (95%), present in 70% of patients with RA. Unlike Rh factor, it is not positive in other autoimmune disease. It is helpful for early diagnosis and is also a
predictor of an aggressive disease.

What is the treatment for RA?

4 main principles of treatment are relief of symptoms by rest and NSAIDs/ intra-articular injection/splinting, suppression of activity and progression of disease by
disease modifying anti-rheumatic drugs, other measures such as physiotherapy/orthopedic measures and patient education. Surgical treatment is synovectomy of
the wrist or finger tendon sheath, and arthrodesis, arthroplasty and osteotomy in more severe cases.

What are the criteria for remission of RA?

At least 5 of the following criteria for at least 2 months: No joint pain, No joint tenderness, No fatigue, Morning stiffness < 15min, No soft tissue swelling, ESR <
30min in 1st hour

What are the bad and poor prognostic factors of RA?

What DMARDs are used?

First-line drugs are sulfasalazine and methotrexate. Other drugs include hydroxychloroquine, azathioprine and cyclosporine. Anti-TNF alpha and IL-1 , as well as
rituximab are more effective than other DMARDs in preventing joint erosions. If disease activity persists despite an adequate trial of 2 DMARDS, anti-TNF therapy
should be considered. DMARDs may take 4 to 12 weeks for response.

What is Sjogren’s syndrome?

An autoimmune disorder characterised by dryness of the eye (keratoconjunctivitis sicca) and dryness of the mouth (xerostomia) with non-erosive arthritis. Fibrosis
and atrophy of the salivary glands occurs. There is infiltration of lymphocytes and plasma cells in lacrimal and salivary glands. There is the primary type which is not
associated with collagen disease (sicca syndrome) or secondary which is associated with collagen disease, commonly RA.

What is the difference between rheumatic fever and RA?

RF typically occurs at 5 to 15 years while RA occurs at 20 to 40 years
RF is the sequelae of the immune response to Streptococcus beta hemolyticus sore throat whereas RA is an autoimmune process.
RF typically affects large joints whereas RA affects peripheral small joints
 RF causes a fleeting type of arthritis whereas RA causes bilateral symmetrical arthritis
RF is diagnosed by 2 major or 1 major + 2 minor criteria + signs of previous Streptococcus infection whereas RA requires 4 out of 7 crtieria for the diagnosis
RF does not have morning stiffness whereas RA does
RF does not have Rh factor whereas RA does
Extrarticular manifestations in RF are subcutaneous nodules, erythema marginatum, no joint deformity and commonly cardiac involvement whereas those in RA are
rheumatoid nodules and joint deformity.
Treatment of RF is prophylactic penicillin whereas that in RA is DMARDs.
Sequelae in RF is rheumatic valvular lesions (licks the joints, kills the heart)
SLE 1. Differentials inlclude dermatomyositis, mixed connective tissue disorder, sarcoidosis and rheumatoid arthritis
2. Presence of multiple skin rashes and butterfly rash with no deformity of the involved joints is against rheumatoid arthritis
3. SLE workup includes FBC looking for anemia, leukopenia and thrombocytopenia, Urine microscopy looking for proteinuria, hematuria, RBC or granular casts,
antinuclear antibody, anti double stranded DNA, anti-Ro and anti-La Abs, anti-Smith antibody, C3 and C4, Antiphospholipid antibodies (anticardiolipin, …) ,
Coagulation study, Renal panel
4. Antibodies found in SLE include antinuclear antibody, antidouble stranded DNA, anti-Smith DNA, Anti-Ro/La, Antiphospholipid anitbody/Lupus anticoagulant,
Anti-histone (drug-induced SLE), AntiC1q (has significance for lupus nephritis)
5. SLE is an autoimmune chronic multisystem disease characterised by production of multiple autoantibodies, immune complexes and widespread immune
mediated organ damage
6. SLE manifestations include skin involvement with malar/discoid rashes and alopecia, face involvmeent with dry eyes, dry mouth, red eyes and painless oral
ulcers, heart involvement e.g. pericarditiis, pericardial effusion, myocarditis, non-infective endocarditis aka Libman Sacks endocarditis commonly seen in anti-
phospholipid syndrome , IHD, lung involvement e.g. pleurisy, pneumonitiis, interstitial lung disease, hematological involvement e.g. anemia, thrombocytopenia,
antiphospholipid syndrome e.g. DVT, recurrent obstetrical losses, renal involvement e.g. glomerulonephritis, nephrotic syndrome, CNS involvement e.g. fatigue,
headache, poor concentration, vision loss, stroke, seizures, weakness, numbness, psychiatric issues, vascular involvement e.g. Raynaud’s, vasculitis, arterial and
venous thrombosis, constitutional symptoms e.g. fever, weight loss, fatigue, MSK symptoms e.g. arthralgia, arthritis, myalgia
7. There are 6 types of Lupus Nephritis and they are in order, minimal mesangial LN, mesangial proliferative LN, focal LN, diffuse LN, membranous LN, advanced
sclerosing LN. Treatment varies according to the type so for Type 1, no treatment is needed, for Type 2, steroids may be needed although the disease is benign,
for Types 3 to 5, immunosuppression is needed with steroids and cyclosphophamide or mycophenolate for induction and mycophenolate and azathioprine for
maintenance. Anti-CD20 biologic Rituximab may used in some patients. Symptomatic treatment for hypertension and edema may be needed also. Diagnosis of
renal involvement is made with UFEME, renal panel and renal biopsy.
8. There are 11 diagnostic criteria for SLE which are malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, pleritis/pericarditis, renal disorder,
neurologic disorder, haematologic disorder, immunologic disorder and positive Antinuclear antibody, presence of at least 4 confirms the diagnosis
9. The type of arthritis specific to SLE is a typically non-erosive and non-deforming arthritis. Rarely, a deformity may occur as in RA aka Jaccoud’s arthritis
10. Avascular necrosis in SLE occurs because of chronic steroid use or vasculitis
11. Backache in SLE may also be due to avascular necrosis
12. Differentials for a butterfly rash are SLE, Discoid lupus erythemmatosus, Dermatomyositis, MCTD, Drug rash, Sarcoidosis, Acne rosacea
13. Drugs causing SLE include hydralazine, procainamide, carbmazepine/phenytoin, isoniazid, OCPs, ACEi. Features of drug-induced lupus include equal male to
female ratio, ANA-positive but dsDNA-negative with normal complements. Anti-histone Ab positive 95% of the time. Clinical features revert with withdrawal of
drugs.
 14. Pregnancy is not contraindicated in SLE. Feritility is usually normal except in severe disease. Repeated abortions occur due to the presence of anti-phospholipid
antibody, as well as still birth and intrauterine growth retardation may occur. If mother is anti-Ro positive, there may be congenital complete heart block or the
baby due to the transplacental transfer of the antibody. With anti-Ro or anti-La Abs in mother, there is a 2% risk of giving birth to a baby with neonatal lupus
syndrome which is characterised by skin rash, hepatitis and fetal heart block. SLE flare during pregnancy is treated with prednisolone. Dexamethasone and
betamethasone should be avoided as they are broken by placental enzymes.
15. Abdominal pain in SLE include mesenteric vasculitis, peptic ulceration in steroids, splenic infarction and pancreatitis
16. Cyclophosphamide may cause haemorrhagic cystitis due to the production of a metabolite that is toxic to the mucosa of the urinary bladder.
17. Anti-Phospholipid Syndrome is characterised by the presence of the anti-phospholipid antibody associated with recurrent arterial and venous thrombosis,
recurrent fetal loss or thrombocytopenia. Some patients with the Ab may not get the syndrome. There are 2 types of antiphospholipid antibodies i.e. anti-
cardiolipin antibody and lupus anticoagulant.
18. Presence of anti-phospholipid antibodies is associated with arteiral/venous thrombosis, recurrent abortions and IUGR, thrombocytopenia, autoimmune
hemolytic anemia, epilepsy, TIA, stroke, sterile endocarditis, membranous lupus nephritis and skin ulcerations, livedo reticularis and gangrene. Antiphospholipid
syndrome is treated with lifelong warfarin if there is previous thrombosis, aspirin/clopidogrel if there is only a positive Ab w/o history of thrombosis and low
dose aspirin and subcutaneous heparin early in gestation for pregnant mothers.
PUO (HIV) 1. What is HIV?
2. What is AIDS?
3. Mode of tranmission of HIV?
4. Natural history of HIV/AIDS?
5. Common infections in AIDS?
6. HIV-related cancers?
7. Correlation between CD4 count and HIV associated diseases?
8. Cutaneous manifestations of HIV?
9. Oral cavity physical examination findings?
10. Causes of diarrhea/enteropathy in HIV?
11. Causes of pulmonary disease in HIV?
12. Neurological manifestations in HIV?
13. Seizures in HIV?
14. Ocular diseases in HIV?
15. Renal, cardiac and endocrine complications of HIV
16. Hematological complications of HIV?
17. Baseline investigations for newly diagnosed HIV?
18. How to make a diagnosis of HIV/AIDS?
19. Pre-test and Post-test counselling?
20. Immunisations for HIV infected patients?
21. Aims of HIV treatment?
22. Indications for antiretroviral therapy in HIV patients?
23. Indications to start higly-active anti-retroviral therapy on the basis of CD4 counts?
 24. AIDS treatment
25. Drugs used in HIV infected patients?
26. When to change antiretrovirals?
27. When to stop treatment?
28. Monitoring HAART?
29. CMV retiniitis treatment
30. Treatment of HIV positive pregnant woman
31. Prevention of HIV
Anemia
Definition
Hb < 13.5 in males
Hb < 11.5 in females

Physiology
EPO released by peritubular capillary lining cells within kidney
Small amount EPO produced by hepatocytes

Stimulus for EPO production

Availability of O2
Impaired O2 delivery  anemia
Impaired O2 loading  hypoxia
Impaired blood flow  renal artery stenosis

Hypoproliferative – normochromic, normocytic [reticulocyte production index RPI < 2.5]

Marrow damage Decreased EPO
Infiltration - Chronic inflammation
Fibrosis - Interleukin 1 (IL-1) directly decreases EPO
Aplasia production in response to anemia. IL-1, acting
through accessory cell release of interferon IFN
gamma
- tumor necrosis factor (TNF), acting through
release of IFN gamma also suppresses
response to EPO

- hypothyroidism [↓ tissue O2 requirement as

EPO production is sensitive to O2 demand]
 - Renal disease
- Inflammation, including many malignancies
- Hypometabolic states – hypothyroid,
malnutrition [anorexia nervosa]
- Endocrine deficiencies
- Marrow damage
Iron deficiency
Microcytic, hypochronic cells
- Mild iron deficiency
- Long-standing chronic inflammation
Maturation disorder – microcytic or macrocytic [RPI < 2.5]
Cytoplasmic defects Nuclear defects
- Iron deficiency [severe] - Folate deficiency
- Thalassemia - Vitamin B12 deficiency
- Sideroblastic anemia [abnormal - Drug toxicity – methotrexate, alkylating
production of red cells usually in agents, alcohol
myelodysplastic syndrome, incomplete - Myelodysplasia  sideroblastic anemia
haem formation iron deposition in
mitochondria around nucleus in Macrocytosis
developing RBC] Abnormal BM development
- Lead poisoning

- Anemia of chronic disease – RA and TB

Microcytosis
hypochromia
Hemolytic [RPI >= 2.5]
Intravascular hemolysis

Intracorpuscular
- Metabolic defect – G6PD deficiency
- Hemoglobinopathy – thalassemia
- Membrane abnormality – Hereditary spherocytosis (Presents not with anemia but with s/s of
prolonged increased RBC destruction – aplastic crisis, symptomatic gallstones, splenomegaly)
- Paroxysmal nocturnal hemoglobinuria
Extracorpuscular
- Autoimmune
- Infection
- Malignancy
- Drugs
- Isoimmunization

Blood loss [RPI >=2.5]

N.B. When iron-deficiency anemia is mild to moderate, erythroid marrow proliferation is ↓ and anemia
classified as hypoproliferative.
If iron deficiency anemia is severe and prolonged, erythroid marrow will be hyperplastic despite
inadequate iron supply  classified as ineffective erythropoiesis

Iron metabolism
Transferrin binds iron in plasma [monoferric or diferric]
Iron-transferrin complex interact with specific transferrin receptors on surface of marrow erythroid cells
Iron released after complex internalized
Excess iron is bound to storage protein apoferritin to form ferritin in the RBC

0.8-1.0% red cells turnover each day

men require 1.0mg elemental iron daily
women of childbearing age 1.4mg elemental iron

History
Geographic and ethnic backgrounds
Nutrition
Alcohol intake
Family history of anemia

Signs
Bleeding, fatigue, malaise, fever, weight loss, night sweats
Physical examination
Pallor – conjunctiva, palmar creases, nail bed

Hyperdynamic circulation
Forceful heartbeat
Strong peripheral pulse
Systolic “flow” murmur

Investigations
FBC Hb is high-normal in people who live at high altitude or smoke
heavily.
In smoking, because of normal compensation due to displacement
of O2 by CO
MCV
Microcytosis <80 fL
Macrocytosis > 96 fL
MCH and MCHC
Reflects defects in Hb synthesis
RDW
Raised in thalassemia
Reticulocyte Raised when there is EPO stimulation or architectural damage of
BM [tumor infiltration, fibrosis]

If reticulocyte production index <2 in established anemia, defect in

erythroid marrow proliferation or maturation must be present
Serum iron
Serum ferritin 1. Estimate of iron stores
2. Is an acute phase reactant and in presence of acute or chronic
inflammation may rise several fold above baseline
3. Rule of thumb, serum ferritin >200 ug/L means there is at least
some iron in tissue stores
TIBC Indirect measure of circulating transferrin
TIBC = Transferrin x 22
Iron saturation < 18%
Transferrin saturation Serum Fe / TIBC
 <15% = iron deficiency
Peripheral blood film Anisocytosis [size]
1. Correlates with increases in RDW
Poikilocytosis [shape]
2. Suggests defect in maturation of red cell precursors in BM or
fragmentation of circulating red cells
Reticulocytes
Nucleated red cells, Howell-Jolly bodies, target cells, sickle cells
BM examination To detect
3. Red cell maturation defect
4. Infiltrative disease

Myeloid/erythroid [M/E ratio]

5. hypoproliferative anemia and production index <2  M/E
ratio of 2:1 or 3:1
6. hemolytic disease and production index >3  M/E ratio of at
least 1:1
Serum folate Very poor indicator
Serum B12 Good indicator

Differential diagnosis
Iron deficiency anemia – microcytic, hypochromic
7. chronic inflammation [serum ferritin N or ↑]
8. thalassemia [serum iron N or ↑]
9. myelodysplastic syndromes  sideroblastic anemia [serum iron N or ↑]

Renal disease
DM – more severe EPO deficiency
Polycystic kidney disease – smaller degree of EPO deficiency for the level of RF
Renal failure – increase EPO

Hypometabolic states
- Starvation
- hypothyroidism
 Endocrine deficiency
Testosterones and anabolic steroids ↑ erythropoiesis
1. therefore males have higher Hb than females
Addison’s disease – hypocortisolism
- Hb may be masked by hypovolemia
- Hb may fall rapidly once cortisol and volume replaced
Anemia in liver disease
- folate deficiency
- blood loss – bleeding varices

Management
Iron replacement
Elemental Fe
- FeSO4
- Ferrous fumarate (less elemental iron than FeSO4)

Thrombocytopenia Approach to thrombocytopenia

** Commonest cause laboratory error

Complications
- hemorrhage
- Intracranial hemorrhage – most severe

Increased destruction
ITP 2 - 4 years
Sudden onset bleeding signs and symptoms
Otherwise healthy

> 6 months = chronic ITP

Evan syndrome Autoimmune hemolytic anemia
Thrombocytopenia
Drugs e.g. heparin
Thrombotic thrombocytopenia purpura
 Hemolytic uremic syndrome
DIC

Sequestration
Kasabach-merritt syndrome Giant hemangioma, rapidly enlarging
Thrombocytopenia + consumptive coagulopathy +
hemolytic anemia
Hypersplenism

Decreased production
Generalized depression
Viral infection (commonest cause)
Drugs e.g. chemotherapy agents Heparin (usually no bleeding)
Valproate
Quinine
Bactrim

Vitamin B12, folate deficiency

Fanconi
Aplastic anemia
Infiltration
Leukemia
Tuberculosis
Decreased platelet production
Hereditary amegakaryocytopoiesis
Congenital idiopathic amegakaryocytic
thrombocytopenia
Thrombocytopenia with absent radii

Disorder of platelet function

Uremia
Wiskott-Aldrich syndrome Immunodeficiency
Severe eczema
 Thrombocytopenia with small platelets

History

PMHx: hematological disease or malignancy

Viral or bacterial infections
Travel history: E. coli H157:H7 in HUS/TTP
Dengue, typhoid, malaria
Systemic review: infections
Drug history: Heparin (usually no bleeding), valproate, quinine, bactrim

Bleeding history: differentiate from coagulopathy

Family history: rare

Physical examination

 Sick? DIVC, HUS/TTP

 CNS: most important
 Lymphadenopathy, HSM
 Stool occult blood
 Skin examination

Investigations
FBC: look at other cell lines
PBF: fragmented red cells (MAHA: DIVC, TTP)
Abnormal platelets: hereditary conditions

CT brain if suspect ICH

Bone marrow aspirate if other cell lines affected
 Aplastic anemia: decreased megakaryocytes
 Myelodysplasia: dysplastic RBC and granulocytes
 Malignant cells: metastatic invasion

ITP diagnosis of exclusion, BM examination if >60 to rule out myelodysplastic syndrome (can progress to AML  fatal)
Respi