StatisticsPositive likelihood ratio (likelihood of a pos result if you DO have the disease) / (likelihood of a pos result if you

DON’T have the disease)

Pharmacology

Trial phases 0 = subtherapeutic doses for pharmokinetics/dynamics1 = healthy volunteers; determine safe dose, safety, tolerability2 = diseased pts for therapeutic effect + safety3 = RCT for efficacy comparison4 = post marketing monitoring

Bioequivalence AUC and Cmax (max conc) within 80-120% of each otherClearance Cl = 0.7 x Vd ÷ t(1/2)

clearance also = dose/AUCT(1/2) t1/2 = 0.693 x Vd/CLLoading dose = Vd x desired plasma concElimination clearance x plasma concentration

*Higher plasma concentration = more rapid elimination (but clearance is constant)Hysteresis curves anticlockwise = takes time for distribution

clockwise = tachyphylaxis

Renal + Metabolic

FormulaeNormal GFR ⓝ at birth: ≤15mL/min/1.73m². Adult: >120mL/min/1.73m²GFR estimation Schwartz formula: K*height ÷ serum creatinine

K = 0.45 in infants, 0.55 in children, 0.7 in adolescentsCreatinine clearance (⁵¹Cr EDTA) = “best”

FENa Sodium (urine) x Creatinine (plasma) x 100Sodium (plasma) x Urine creatinine

= “Suc P/ Spu C”

Interpretation:< 1% = conserved concentrating ability e.g. prerenal dz>1-2% = intrarenal e.g. ATN with ↑ Na loss or hypervolaemia with appropriate Na lossIntermediate = eitherIn obstruction, FENa can be low OR high

Spot urine Pr:Cr ratio For proteinuria evaluation

Should be < 0.2 (<0.5 in younger kids)0.2-2 = proteinuria. >2 = nephrotic range

Urine Ca²⁺:Cr ratio > 0.2mg/mL suggests hypercalciuria (assoc with persistent haematuria)

Acidosis + Alkalosis

Anion gap Na – (HCO₃⁻ + Cl)Normal is <12

Excess anion gap = total AG – normal AG (12)add this value to measured bicarbif > 30 (i.e. > ULN bicarb), suggests an underlying metabolic alkalosisif < 24 (i.e. < LLN bicarb), suggests ANOTHER non-AG metabolic acidosis

Osmolal gap- Useful to identify another

osmolal agent in serum

(measured serum osmolality) – [ (2xNa) + glucose + urea]normal is < 10

Urine anion gap Rough index of ammonium

excretion Used to differentiate renal

vs GI cause of hyperchloraemic (normal AG) metabolic acidosis

1. you have a metabolic acidosis2. calculated anion gap is <12 ∴ there is no extra acid; base is

being lost somewhere3. calculate (Urine Na + Urine K) – Urine Cl

If base (bicarb) is being lost in the gut; kidney will lose H⁺ (in the form of NH₄) to compensate → UAG will be negative (<0) = GIT

If base is being lost by the kidney (e.g. RTA), it won’t be able to compensate → UAG will be positive (≥0) = RTA

Emesis vs diarrhoea Emesis:- Loss of HCl and NaCl in vomitus → kidney saves Na²⁺ at the

expense of H⁺ → metabolic alkalosis (e.g. pyloric stenosis)Diarrhoea- Loss of HCO3⁻ in diarrhea → normal AG met acidosis- Except for congenital chloride diarrhea, where there is inadequate

bicarb secretion and a metabolic alkalosis with diarrhoeaMetabolic alkalosis CAUSES:

1. Volume contraction:a. Chronic dehydrationb. diuretic use or abuse,c. Bartter's or Gitelman's syndrome.

2. Loss of acid:a. Pyloric stenosis, NG tubes to suction, vomiting.

i. PS: hypochloraemic metabolic alkalosis with hypokalaemia & paradoxical acidic urine (trying to preserve K)

3. High mineralocorticoid states:a. Hyperaldosteronism, black licorice use.

DIAGNOSIS• ↑pH with ↑ HOC3• Urine chloride and BP can be used to narrow the differential.• Urine chloride can distinguish subtypes:

• Chloride responsive (urine Cl < 10): GI losses, dehydration, diuretic use.• Chloride resistant (urine Cl > 20): Mineralocorticoid states (HTN); Bartter's or Gitelman's syndrome (both normotension)

Metabolic compensation in respiratory acidosis

1. ACUTE COMPENSATIONIn acute respiratory acidosis (resp failure), HCO3 can rise by 1mmol for every 10mmHg risk in pCO₂ above 40mmHg, to max of bicarb ~38

Expected HCO3 = 24 + [(actual pCO₂ - 40)/10]

2. CHRONIC COMPENSATIONBicarb will rise by 4mmol/L for every 10mmHg rise in pCO₂ ∴ expected HCO3 = 24 + 4[(actual pCO₂ - 40)/10]

Metabolic compensation in respiratory alkalosis

1. ACUTE COMPENSATION FOR RESP ALKALOSIS△ HCO3 = 0.2 x △ pCO₂

2. CHRONIC COMPENSATION FOR RESP ALKALOSIS△ HCO3 = 0.5 x △ pCO₂

Respiratory compensation in metabolic acidosis

pCO₂ will drop in metabolic acidosis

expected pCO₂ = [△ in bicarb from normal] x 1.2

Fluids & Nutrition

Calculating fluid deficit

e.g. 5% dry, weighs 10kg= 10 x 5 x 10 = 500mL deficit

Fluid distribution ICF = 60% (K⁺ main cation)ECF = 40% (Na²⁺ main cation)

16% ¾ plasma ¼

Insensible losses 1/3 from lungs, 2/3 from skin= 40% of maintenance in infants, 25% in adolescents

Prems lose 2-3 mL/kg/hrNormal UO 2-3mL/kg in young children

0.5mL/kg/h in adultsGrading feeds Day 1: 60mL/kg

Day 2-3: 90mL/kgDay 4-6: 120mL/kgDay 7: 150mL/kgAim for:

If <33wks or <10th centile: 180mL/kg/day If >33wks and BW > 10th centile: 150mL/kg/day

Calories Human breast milk: 20kcal/30mLFortifier: 24kcal/30mL10% lipids = 1kcal/mL10% dex = 0.4kcal/mL

Energy + growth 0-1mo: 120kcal/kg/day<1yo: 90-100 kcal/kg/day1-6: 75-906-12 60-7512-18: 30-60adult: 30-40kcal/kg/day

Electrolyte disorders

Correct Na in hyperglycaemia

measured sodium + 0.3(glucose – 5.5)

Approach to hyponatraemia

1. Check serum osmolaritya. If normal, consider pseudohypoNa e.g.

hyperlipidaemia/hyperproteinaemiab. If high, consider hyperglycaemia (translocational hypoNa)c. If low, check volume status + UNa

2. Check volume status3. Hypovolaemia + hypoNa

a. UNa < 10 = extrarenal (D/V, 3rd spacing, CSW)b. UNa > 10 = renal wasting (thiazides, nephritis, RTA, hypoaldosteronism)

4. Euvolaemia + hypoNaa. UNa < 10 = 1° polydipsia, low salt intakeb. UNa > 10 = SIADH, hypoaldosteronism

5. Hypervolaemia + hypoNaa. UNa < 10 = CCF, nephrotic sy (intravasc depletion – trying to conserve

Na)b. UNa > 10 = ARF, CRF (kidneys wasting salt)

6. Managementa. Seizure

i. Aim to increase serum Na by 5mmol/Lii. Use 3% NaCl (513mmol/L = 1mmol in 1.95mL)iii. Recall TBW = 0.6iv. Give 0.6 x 1.95 x 5 x wk(kg)v. Then aim to ↑ Na by 3mmol/L in 24h for total 8mmol/L increase

in 24 (0.3mmol/L/hr)b. Asymptomatic – aim to increase by

Osmotic demyelination syndrome

In chronic hypoNa, brain cells lose solutes to maintain equilibrium w ECFWhen rapidly corrected, cells swell as they were hypotonicDamages myelin → cranial nerve sx, lethargy, comaDx: MRIAcidosis:

- Could be laxative abuse, diarrheaAlkalosis

- Vomiting (UNa < 10) or diuretic (UNa > 10)

Diabetes insipidus water deprivation test:1. pt empties bladder, calculate weight2. weigh q2h while water deprived3. endpoint = serum osm > 300 (dehydrate) or > 4% wt loss

a. If urine osm < 700 despite serum osm > 295 = DIb. Give DDAVP: if improves, = central DI, if not = nephrogenic

Hypernatraemia Mx Drop Na by max 0.5mmol/L/hourToo rapid = risk cerebral oedemaIf severe (>169) – use 0.9% NaCl + 5% dex; if moderate, can use 0.45% NaCl + 5% dex

Hypokalaemia ECG: prolonged PR, flat TW, TWI, STD, U waves (esp precordial leads)Low urine K (24h K < 30) – GI bicarb loss, skin (sweating, burns)High urine K (24h K > 30) – renal e.g. diuretics, tubular transport defects (all 3), dRTA, hyperaldosteronism

Drugs: adrenaline, B-agonists, thiazides, amphotericin, cisplatinHyperkalaemia TTKG: < 10 = insufficient renal K+ excretion

Renal scans

Ultrasound ObstructionMCUG Indications:

Dilatation or hydronephrosis on US (e.g. post-UTI) Atypical, recurrent or hard-to-treat UTI (perform in 4-6mo) Abnormal urine flow FHx of VUR Enuresis Voiding dysfunction

Looks at Anatomical problems, voiding Can see enlarged abnormal bladder

MAG3 = DTPA Radioactive tracer injected IV- 40-50% of MAG3 is excreted by PCT; can measure clearance. Need to give

frusemide.- ~20% of DTPA is excreted by glomerulus, can estimate GFR but MAG is

better (higher extraction fraction)- Counter-intuitive: maG is PcT, while dTPa is Glomerular

BOTH used to assess:- Function of kidneys e.g. differential function- Perfusion- Obstructive pathology

DMSA Looks at cortical morphology e.g. SCARRINGPart of post-UTI work-up

IVP Rarely performedObstructionEctopic ureter

CT Stones (procedure of choice)Masses, cysts

MRI Renal artery stenosisMassesNB: gadolinium is nephrotoxic; deposits in interstitium

Angiogram Definitive for vascular abnormalities e.g. fibromuscular dysplasia vs RAS

Renal Physiology

Sodium Reabsorption: 60% in PCT (coupled to glu/AA/PO₄; Na/K/ATPase; NHE₃ exchange

(coupled to H⁺ excretion) 25% in LOH (NKCC2 (side of frusemide); NHE₃; ROMK 15% in DCT (NCCT- thiazide site – NaCl cotransport); ENaC (epithelial

Na channel – site of amiloride action) Immature kidney has ↓ Na²⁺K⁺ATPase & NHE₃

Regulation Angiotensin II ↑ Na reabsorption in PCT Aldosterone ↑ Na reabsorption in DCT /CD via Na/K pump (pushes 3Na

out, 2K in, leading to gradient so Na is reabsorbed, K is excreted), also upregulates ENaCs

ANP ↑ Na excretion & suppresses RAA axis; ↑GFRPotassium 65-75% reabsorbed in PCT (Na/K/ATPase); rest in TAL via NKCC2, small

amt in DCT via H+K+ exchanger Excreted via ROMK in CD Excretion ↑ by aldosterone, urine flow, ↑ urine anions Fetus needs ↑K+ for growth ∴ 6.5mmol/L is normal in neonate; ↓ to 5.2 by

day 5Calcium Active maternal transport in utero

70% reabsorbed in PCT via passive paracellular transportPTH/1,25-OHD will ↑ epithelial Ca transporters in DCT/CD → total 98% reabsorbed↑Reabsorption with PTH, calcitonin, vitamin D, thiazides, volume depletion↑ excretion with volume expansion, ↑Na intake, mannitol, frusemide (hence stones)

Phosphate 80% reabsorbed in PCT↑ excretion w vol expansion, PTH↓ excretion w GH, volume contraction99% reabsorbed in neonate

Other Mg: 25% reabsorbed in PCT, 75% in TAL (paracellular)Glucose: >99% reabsorbed in PCT, Na coupled

Diuretics

Loop Act on NKCCT channel in TALMost potent diuretic; ↑ excretion of up to 25% of filtered Na, and inhibits

SE: ↓ BP, nephrotoxic, ototoxic, hypoK, hypoMg, alkalosis, hyponatraemia, hypercalciuria (stones)

reabsorptionEliminated via kidney/liver

Thiazide Act on NCCT (NaCl cotransport) at DCTInccrease excretion of Na, K, MgDecrease excretion of Ca

SE: hypoK, hyperglycaemia, hyperuricaemia, hyperlipidaemia, hypocalciuria can → hypercalcaemia

K+ sparing Act at CD ENaC (amiloride) or MR (spironolactone)

SE: hyperK, teratogenicity, GI upset, PUDSpironolactone = anti-androgen: gynaecomastia, nausea, lethargy, cramps

Osmotic e.g. mannitol: ↑ plasma osm to draw water out of tissues

Carbonic anhydrase inhibitors

Act on PCT to inhibit Na, HCO3 and water reabsorption

GlomerulonephritisLow complement GN

PSGN (should resolve; usually C3 only; IgG in mesangium/BM. CH50 also initially low)SLE (IF: + IgG, IgA, IgM, C3, C1q)MPGN (type 1 = IgG pos, classical complement pathway; type 2 = alternate pathway, IgG neg)Bacterial endocarditis, shunt nephritis, cryoglobulinaemia

Alport CAUSE: 80% XL; Type 4 collagen mutation (makes up GBM also in ears/eyes)CLIN: Episodic gross haematuria, SNHL, FHx of renal failureLM: mesangial proliferation > 10yo, thin BM thick cap wall, scalloped epitheilumIHC: absent α-5 chain of collagen IV, Anti-GBM Ab stain negativePROG: persistent haematuria or nephrotic = bad

RPGN Subacute nephritic syndrome with rapid ↓ renal functionMacrohaematuria, nephrotic proteinuria, oedemaLM: crescents (fibrin → fibrosis)DDx:

- immune complex (PSGN, SLE, MPGN, HSP, IgA neph, mixed cryo, idiopathic immune complex)

- anti GBM Abs (goodpasture, idiopathic)- ANCA med (Wegeners, MPAN)- Idiopathic

Mx = methylpredThin BM dz CAUSE: AD or sporadic

CLIN: Persistent or intermittent microhaematuriaIx: Don’t need biopsy – would show isolated thin BM on EM, otherwise normalMx: usually nil, only if proteinuria (rare)

Minimal △ Nephrotic syndromePodocyte effacement on EM

PSGN CLIN: Micro/macrohaematuria, HTN, oliguria, renal failureIX: ↓C3 (occ ↓C4), resolves within 2mIF: starry sky IgG/C3 in GBM + mesangiumLM: endocapillary proliferation, PMNsEM: subepithelial dense deposits, inflammation, proliferation

IgA neph CLIN: Synpharyngitic haematuria (latency 1-2wk)PATH: Abs vs galactose-def IgA1 → immune complexes in mesangium + mesangial proliferation → actvates complement cascadeLM: mesangial proliferation, IgA deposition, ± crescents/tubulointerstitial dzIF: granular IgA + C3 depositsEM: mesangial deposits

HSP CLIN: Nephritic (90% have haematuria) or nephrotic. Renal dz 12 wks after initial presentation.Features: purpuric rash (100%), arthritis (66%), abdo pain (50%), intussusception (5%), GN (25-50%). Assoc w HLA DRB1*01, FMF, IBDIX: ↑WCC, ↓Hb, ↑PLT, ↑ESR, ↑ IgA/IgM in 50%, ASOT ⊕ in 30%LM: mesangial proliferationIF: granular IgA, IgM, IgG, C3

HUS CLIN: Triad = microangiopathic haemolytic anaemia (↓Hb), thrombocytopenia, ARF. Also HSM.CAUSE:

D+: 80% assoc with ETEC (0157:H7 = shiga toxin producing). Other: shigella, salmonella, campylobacteria, S. pneumonia, Bartonella, viruses, OCP, cyclosporine, SLE, radiation nephritis

D-: complement defectIX:

↓Hb, ↓PLT, ↑WCC, ↓haptoglobin, ↑retics IgA ± IgM ↑ in 50% PBF: schistocytes (helmet- fragments), burr (spiky from uraemia) DAT neg (vs AIHA) UA: haematuria, proteinuria LM: mesangial proliferation IF: granular IgA, IgM, IgG, C3 Coags normal Renal US for RVT

AntiGBM dz (Goodpasture)

CLIN: Pulm haem + RPGN. Nephritic OR nephroticIX: Normal C3, Anti-GBM IgG +

FSGS CAUSES: idiopathic, hereditary, severe obesity, reflux nephropathy, renal dysplasia, DM, von Gierke, interferonCLIN: nephrotic sy ± haematuria/HTN/↑CrIF: IgM + C3 in sclerotic segment. EM: foot process fusionProg: 1/3 improve, 1/3 persistent proteinuria, 1/3 ESRF early

Membranous CLIN: Nephrotic sy (#1 cause in adults)IX:

IgG and C3 on epithelial side of BM No cellular infiltrate + extracellular substance serum C3 normal (unless SLE)

neonatal membranous: mat anti-neutral endopeptidase Abs (mum has no NEP)Causes: SLE, ITP, sarcoidosis, neuroblastoma, gonadoblastoma, HBV, HCVProg: 40% active dz

SLE Onset in adolescence, affects 30-70% of kids w SLEClasses:

1. Normal LM2. Hypercellular (mesangial expansion): haematuria, normal renal Fn, mild proteinuria3. Focal proliferative (nephrotic)4. Diffuse proliferative (nephrotic)5. Membranous (nephrotic)6. Sclerosing

Mx pred → AZT, cyclophosphamideMPGN PATH: circulating immune complexes deposit → cellular infiltrate + complement activation

CAUSES- Type 1: IgG +, complement + (infection, autoimmune, rheumatologic)- Type 2: IgG - , complement + (alternative complement pathway problem)- C3 Nephritic factor = IgG or IgM that binds & stabilizes C3 convertase →ongoing

complement activationIF: granular IgG, IgM, C3 in types 1 and 3.Type 2: C3 stains either smooth or granular, NO IgType 1:

- Classical complement pathway- Discrete deposits in mesangium/subendothelium- Cryoglobulins (HCV 70-90%), other infections, SBE, HBV, SLE, Sjogren, NHL, CLL- No cryoglobulins: endocarditis, abscess, shunt nephritis, viruses

Type 2- Alternate complement pathway- Intramembranous dense deposits – ribbon like thickened cap wall

Type 3- - Discrete deposits in mesangium/subepithelium

Acute severe nephritis

SLERPGN (many causes)ANCA + (PAN, Wegener, Churgh-Strauss)Some HSPAnti-GBM dz

Nephrotic sy DDx:MCD, FSGS, MPGN, MembranousCongenital: Inf (TORCH, HIV, HBV), DenysDrash (WT1 mut), Pierson sy (LAMB2 mut)

1. proteinuria = >3+ on UA (not definitive); >1g/m²/day [>3.5g/d in adult]Urine Pr: Cr >200mg/mmol on a first morning sample

2. hypoalbuminaemia (<25g/L)3. generalised oedema4. thrombotic disease (loss of factors), hyperlipidaemia (↑hepatic lipoprotein synth)5. loss of Ig, reduced vaccine take, risk w encapsulated orgs6. malnutrition, loss of TBG and other relevant proteins

PATHOPHYS: usually problem with podocyte function or endothelial/GBM/podocyte interface

MX- low sodium diet to reduce oedema- ACEi- steroids (start at 60mg/kg/m2/day)

SAFE TO START STEROIDS WITHOUT BIOPSY- age 2-12, no macrohaematuria, normal BP/Cr, no systemic dz

STEROID RESPONSIVENESS = better indicator of long term outcome vs histology- 95% will achieve remission after an 8wk course of pred (60mg/m²/day x 4 weeks, then 40mg/m² alt daily x 4 weeks)- in minimal change - 75% achieve remission by 2 wks

STEROID RESISTANCE: no remission within 4 weeks→ biopsy (likely to be FSGS)1. levamisole: antihelminthic, immunomodulator, useful for freq relapses; SE = neutropenia, rash, vasculitis2. cyclophosphamide3. calcineurin inhibitors (Cyclo or tac)4. MF5. rituximab

SIGNS OF HYPOVOLAEMIAUr Na < 10mmol/L↑ Hb, ↑ PCV

IV FLUIDSIF shocked - give 4% albumin 10mL/kg and NO diureticsNo shock - consider 20% albumin infusion ± diuretics, give 5mL/kg (1g/kg) over 4-6hAlbumin not given for hypoalbuminaemia alone

HYPERTENSIVE EMERGENCYgive nifedipine 0.25-0.5mg/kg/doseif overloaded consider diureticspersistent HTN: amlodipinelook for features of hypovolaemia + give volume resus if present

DIURETICSif overloaded - frusemide 0.5-1mg/kg daily or BDIV frusemide 1mg/kg for emergency Mx

INFECTION= main cause of deathloss of complement + Ighigh risk esp of ENCAPSULATED orgscellulitis: give 20% albumin + frusemide along with ABx to reduce oedemaVZV: treat aggressively with IV aciclovir then PO valacilovir. If exposed - give VZIG. Shingles also gets IV aciclovir (d/t immunocompromise)

RENAL VEIN THROMBOSISd/t loss of proteins e.g. AT-3 (anticoagulant), plus hypovolaemiaCLUES: ↓Hb/PLTs, macrohaematuria, ↑Cr, HTN, palpable firm kidneyprophylaxis (LMWH) only in severe NS or of other RF

MEDICATIONSPred 60mg/m²/day x 6/52 then weanPenicilin prophylaxis if asplenic, or other RF e.g. ATSIConsider PPI to protect vs steroid gastric irritationConsider anticoag prophylaxis in v. severe nephrotic sy

VACCINESgive all vaccines + 24ppv

DIETlow saltnormal protein (not high)

RELAPSED DZoften d/t intercurrent illnessrestart pred2nd line: no data - cyclophosphamide, ciclosporine, MMF, rituximab

ARF, ATN, TINCKD STAG

E DESCRIPTION GFR (mL/min/1.73 m2)

1 Kidney damage with normal or increased GFR >90

2 Kidney damage with mild decrease in GFR 60-89

3 Moderate decrease in GFR 30-59

4 Severe decrease in GFR 5-29

5 Kidney failure <15 or on dialysis

ATN Ischaemic orToxic: heavy metals, drugs (gent, NSAIDs, antivirals, diuretics, iodine, pesticides)PCT: flat, ↓brush border, necrosis, sloughed cells obstruct tubule

Brown/orange casts = key feature (myoglobin/haemoglobin)CLIN: loss of conc ability; oliguria (epithelial loss – can’t excrete water etc.), diuresis in recovery

TIN DEF: inflammation of interstitium with lymphocytesCAUSES: idiopathic, infection, hypersensitivity, drugs (ABx, AEDs, loop/thiazide diuretics), immune (IgA neph, SLE, sarcoid), Tx rejection, lymphoma.LM: eosinophils if HS. Inflammation. Normal glomCLIN: HS: ~15d post exposure → triad of fever, rash, arthralgia, with ↑Cr.Otherwise: polyuria, HTN, proteinuriaIX:Eosinophilia, eosinophis/WBCs on UA, ↑Ur/Cr, WC casts, haematuria, proteinuria

Stones XR Radioopaque: Calcium, struviteRadiolucent: cysteine, xanthine, uric acid (hence non con CT)

Stones management Hypercalciuria- Reduce dietary Na⁺- Normal dietary Ca intake- Thiazides (reduce Ca excretion)- K+ citrate- Neutral phosphate

Hyperoxaluria- Reduce dietary oxalate- K+ citrate- Mg, neutral PO4, pyridoxine

Hypocitric acidura: K+ citrate, bicarbHyperuricosuria: alkalinize urine; allopurinolCystinuria: reduce Na intake; alkalinize urine

Tubular transport defectsBartters Gitelmans LIddleAD AR ADNKCC2 (frusemide site)Or other – ROMK, combined Cl ch

NCCT (thiazide site) ENaC (amiloride site)

Hypokalaemic metabolic alkalosis Hypokalaemic metabolic alkalosis Hypokalaemic metabolic alkalosisDehydration, polyuria, FTT, stones±SNHL, FLK

Milder symptoms of dehydration Severe hypertension, FTT, polyuria

↑ urine K, Cl, Ca, PGE2↓ serum K, Cl, Mg (20%)

↑ urine Cl, Mg↓ urine Canormal urine PGE2

Activation of RAA axis (↑Na delivery to DCT)

Activation of RAA axis Supression of RAA axis (↓renin/aldosterone)

“Pseudo-Bartter” = CCD, which has faecal Cl < 90

DDx: RAS, where renin may be ↑, aldosterone ↑; or hyperaldosteronism where renin ↓, aldosterone ↑

Post Renal Transplant ComplicationsHypertension In 80% of those w decreased donor, 60% post livingCMV 1-6mo post Tx

Pneumonitis, GI dz (oesophagitis, gastro), hepatitis, pancreatitisEBV Reactivation usually ASx

PTLD (polyclonal B cell expansion)Mx: decrease immunosuppression. Use rituximab

BK virus Ubiqutious, found in uroepithelium5% will get BK nephropathy, of which 50% get graft failure

Hyperacute rejection Within hoursD/t pre-formed Ab against donor antigens e.g. HLA, AboIrreversible → nephrectomy

Accelerated acute 1st weekT cell mediatedMx = anti-T cell Abs, CTS50% salvaged

Acute Tubulointerstitial cell rejection1-2 week2nd most common after chronicT cell mediated w tubular injury↑Cr + HTN = rejection til disproven. Other: fever, malaise, oliguria, tendernessmx: CTS, anti-T cell Abs

Chronic >3moT cell mediatedInvolves tubules, capillaries, intersitiumMain cause of allograft lossSmall kidneys

Reduce risk of rejection Younger age, HLA matching, use induction immunosuppressionGVHD Rare after renal Tx

Metabolic Ix SummaryFBC: looking for cytopenias [organic acidaemias] or evidence of sepsis/infection as a triggerABG: high anion gap suggests organic acidaemia; resp alkalosis suggests UCDs

BG: hypoglycaemia typical of FAODs or other dz of ketogenesis, GSDs and DCM e.g. disorders of fructose metabolismAmmonia: high in UCDs+++, also in organic acidaemiasEUCs, BUN: calculate anion gap, hyponatraemia/hyperkalaemia suggests salt wastingUric acid: high in pts with GSD, can be abnormal in chronic IEM (low in purine metabolism, raised in Lesch-Nyhan)Ketones: HIGH in amino acidopathy, organic acidaemia. LOW in FAOD, hyperinsulinaemia. Normal in UCDsHypoglycaemia + ketosis = GSD (can't use glycogen but can make glucose), organic acidaemia, MSUDHypoglycaemia WITHOUT ketosis: FAOD, disorders of ketogenesis (HMG-CoA lyase def)

Galactosaemia – LOW ketones

Immunology

Post Transplant Complications (General)Timing Week 1-2:

- Ultra-rapid or acute rejection (T cell mediated – fever, hypertension, ↑Cr)

- N&V, mucositis, diarrhoea- VOD (1-3 weeks)

Week 2 – 3months- Acute GVHD (T cell mediated)- Viral hepatitis reactivation- CMV (highest risk = 2-3mo post Tx)- N&V, diarrhoea from drugs, infection

>Day 100 - Chronic GVHD - Chronic rejection

PCP Low grade fever, ↑RR, non-productive cough, can be insidious

CXR: bilat perihilar interstitial infiltratesHRCT: ground glass opacities in central lung

DX: need microscopy of lung fluid e.g. BAL, biopsy?black on silver stain

MX: bactrimCMV post BMT

greatest cause of transplant failuretiming: 1-3 month post transplant (i.e. NOT EARLY)can be asymptomaticpneumonia 80-90% mortalityhepatitiscolitisfever, encephalitis, retinitis, BM failure15% get pneumonitisoverall 15-20% mortality

Highest risk time = 2-3mo post Tx

VOD Onset: 1-3 weeks post BMT?Endothelial cell problem obliteration of venules/sinusoids hepatocellular necrosis fibrosis throughout liver

Sx: hepatomegaly, RUQ pain, jaundice, ascites, no feverTA-GVHD 1-2 weeks post transfusion

Fever, rash, diarrhea, pancytopenia, deranged LFTsUnlike BMT-GVHD, TA-GVHD leads to marrow aplasia, mortality > 90%

Cause: R is HLA heterozygous, D is homozygous

Ix: skin biopsy, HLA

Mx: supportive, CTS

Prevention: γ irradiation of blood e.g. PLTs (stops proliferation of WBCs)

GVHD RF: HLA mismatch, unrelated donor, older age

Timing: 2-3 wks post Tx (>100d = chronic)

PATHOPHYS: conditioning ↑ host cytokines/MHC upregulation → activation of donor T cells → inflame

GIT: “crypt cell necrosis”Liver: “vanishing bile ducts”

Clin:1. Rash (erythematous MP, palms, soles, nape,

trunk) bullae, desquamation2. GIT: secretory diarrhea, haematochezia,

cramping, PLE, N&V3. ↑ conjugated bili, ↑ALP, cholestasis (bile duct

epithelium damaged cholangitis)

Immunosuppressants

Glucocorticoids Block TNFα, IL2, IL6, T cells, IFN-γArrest cell cycle

Cyclosporin Binds immunophili/cyclophilin & inhibits calcineurin phosphataseInhibits IL-2SE:

Hypertrichosis Gingival hyperplasia Coarse facies Hypertension Seizures/CNS Hypomagnesaemia Hyperlipidaemia Nephrotoxic (ARF, TIN) No myelotoxicity Levels will ↓ with CYP inducers, ↑ with CYP inhibitors

Tacrolimus More potent than cyclosporineSE:

Tremor Hyperglycaemia

Hypertension Hypomagnesaemia Post-Tx lymphoproliferative sy Alopecia Nephrotoxic Hyperkalaemia ↓ wound healing NO: cosmetic se, NO hyperlipidaemia

Sirolimus MTOR inhibitorBlocks cytokine driven cell proliferation + maturationSE:

Thrombocytopenia Hyperlipidaemia PTLD

Antiproliferatives e.g. AZT, MMF Inhibit DNA synthesisAZT:

Converted to 6-MP, requires TPMT (thiopurine methyltransferase) 10% of population don’t have TPMT Blocks protein synthesis w fraudulent base SE = BM suppression, liver damage, PTLD

MMF Antimetabolite; prodrug of pruine synthesis inhibitor Prevents B and T cell activation SE: leukopenia, anaemia, infection, ARF, gastritis, diarrhoea, PTLD

Anti-TNFα e.g. infliximab TNF secreted by TH1 cellsUsed in Crohn’s, psoriatic arthritisSE:

TB reactivation (therefore always test) Nausea Allergic reaction

Methotrexate Folate antagonistSE:

Transaminitis N&V Renal toxicity (precipitates in tubules) Some haem toxicity Hypersensitivity pneumonitis Neuro: encephalopathy (resolves) Derm – 15% get rash

Anakinra Anti-IL-1 antibodySulfasalazine MOA unknownBasiliximab IL-2 antagnost

Can prevent acute transplant rejectionSE = hypersensitivity to it

Imatinib Used in CLL with Philadelphia chromosome

T cell summary

Th0 Immature T helper (CD4) cellTh1 Differentiation triggered by IL-12, IFN-γ

Interacts with MHC/HLA 2(NB: CD8 cells interact with MHC/HLA1)

Produces IL-2, TNFαIFN-α: activates macrophages, stimulates B cells to make AbTNF-ß: activates neutrophilsTargets virally infected cells, intracellular pathogens

Th2 Differentiation triggered by IL-4, IL-2 Triggers B cells to produce IgEIL-3: mucus productionIL-5: activates eosinophilsProduces IL-4,5,7,10,13Ab mediated immunity; extracellular parasites; asthma;allergy

Th17 Differentiation triggered by TGF-ß, IL-6 Produces IL-17, IL-21, IL22IL-17 stimulates IL6,8 + neutrophil recruitmentImplicated in Crohns + other autoimmune diseaseExtracellular bacteria, fungi, autoimmunity

T-reg Differentiation triggered by TGF-ß, IL-12 Produces TGF-ß, IL-35, IL-10Involved in immune tolerance, regulation of immune response

Immune cells + cytokines

Released by Actions DrugsIL-1 Macrophages

Monocytes (which △ into DCs or

PyrogenPro-inflammatoryActivates lymphocytes, leukocyte

IL-1ß = anakinraUsed in inflammatory disorders

macrophages)DCs

adhesionRegulates haematopoeisis

IL-2 TH1 cellsNK cells

Drives cell divisionT cell growth factor

Targeted e.g. by steroids, calcineurin inhibitors

IL-3 Released by activated T cells

Stimulates BM

IL-4/IL-13 Th2 cells, CD8 cells, mast cells, basophils

Stimulates IgE class switching

IL-5 Th2 cells, eosinophils, mast cells

Differentiation of eosinophils

IL-6 Monocytes, Th2 cells Production of plasma cellsInflammationPyrogen

IL-12 Activates NK cellsInhibits IgE response

TNF α made by macrophagesß made by Th1 cells

↑vasc permeability, fever, shock, CD8 killingSHOCK

Interferons IFNγ made by Th1 cells Antiviral, anti-tumour↑macrophages/NK cellsIFN α/β: protects cells adj to viral cells e.g .use in hepatitisIFNγ enhances specific + innate immunity

OTHER COMPONENTSOpsonins IgG bound to antigen

C4b + its fragmentsNeutrophil chemotaxis

C5a, LTB4, IL5, Il8

PAMPs Pathogen assoc. molecular patterns e.g. LPSRecognised by APCs (e.g. by TLRs)

TLRs Bind PAMPs, act via NF-kappa-betaInvolved in sepsis

MBL “universal antibody”, opsoninON activation, cleaves C1r and C1s

NK cells Granular lymphocytes, 5-15% of blood lymphocytesInitial response to virally infected cellsCD56/16 pos, CD3 negativeDeficiency herpesvirus infectionsIL-15 triggers developmentBM derived (non-thymic)Kill cells which have lost their MHC expression e.g. d/t virus, tumourRelease IFNγ to activate macrophagesKill via performin-granzyme or Fas pathway (induction of apoptosis)

Eosinophils

Have IgE receptorTarget helminths via degranulation + release of toxic proteins

Hypersensitivity

Type 1 Antigen + IgE → mast cell, basophil activation → histamine/leukotriene release → urticarial, bronchospasm, anaphylaxis

mediated by Th2/IgE/mast cells

e.g. anaphylaxisConfirm with tryptase

Late phase: mediated by eosinophils + neutrophils

Type 2 IgG/IgM/complement mediated – cytotoxic Ab reactionIgG or IgM recognises antigen → coats cell → recognised by complement → destroyed

e.g. AIHATransfusion reactionGoodpastures (anti-GBM disease)Haemolytic disease of newborn (anti-Rh)Autoimmune thrombocytopenia

Type 3 Insoluble immune complexes e.g. serum sickness, RA, SLEMostly IgG, some IgMSx 1-3 wks after last dose

e.g. SLE, GN, serum sickness (cefaclor)

Type 4 T cell mediated, delayedTh1, Th17, CD8 cells

e.g. allergic contact dermatitis, Mantoux test, drug exanthems

Haematology

Approach to positive DAT

VWD vs Haemophilia A

Diamond Blackfan

MacrocyticADA ↑Retics ↓HbF↑BM: ↓ RBC precursors

Craniofacial, thumb abnormalitiesMx: CTS

TEC Normocytic TEC vs IDA: check MCV: low

ADA ⓝPLT normal or ↑~2yo at onset

in IDA, but normal/high in TEC

Mx: nilParvovirus B19 Retics ↓

LM of BM: nuclear inclusions, loss of erythroid precursorsMx: transfuse if needed

Anaemia of chronic disease

Low serum ironnormocytic, normochromicLow retics (or normal)High WCC commonTIBC normal or low (vs IDA: high)Ferritin may be high (APR)BM: ↑ haemosiderin

May have concurrent IDAMx = control disease, EPO

Anaemia of renal disease

TIBC normalFe studies normalEPO lowMCV normalRetics normal or low

Physiologic anaemia of infancy

@ age 2-3mo

Megaloblastic anaemia

High MCVhypersegmented PMNsBM erythroid hyperplasiaGiant vacuolated metamyelocytes (megaloblasts)Retics lowNucleated RBCsNormal FeLDH ↑↑ (marks ineffective erythropoiesis)

Goats milk is folate deficientFolate def in coeliac, diarrhea, phenytoin, MTX

B12 deficiency e.g. deficiencyPernicious anaemia – IF deficiency e.g. atrophic gastritisHIGH MCVHypersegmented neutrophilsHypercellular BMLDH high

schilling test: give labeled BV12 to check its absorption + exc in urine

Sideroblastic anaemia

Impaired haem synthesis iron ring around nucleated RBCsPearson sy = variant with hypoplastic anaemiaCongenital formAcquired forms e.g. idiopathic, drugs,

Haemolytic anaemia

Retic indexnormal is 1Acute HA: 2-3Chr HA: 4-6↓ RBC survival time↑ indirect bilirubin↓ haptoglobin↑ urobilinogenHct low if severe

Spherocytosis Hb normal or lowMCV normalMCH high (d/t less membrane)HyPERchronic, microcytic, LESS central pallor than normalUsually >15-20% of RBCs are spherocytesRetics present – polychromatophilicBM: eythroid hyperplasiaXR: marrow expansionHaptoglobin: LOW (binds to free Hb)Pigment gallstonesOsmotic fragility testRBC membrane protein electrophoresisDNA analysisDAT NEGIndirect bili UP

Mx?splenectomy for all or >5yfolic acidPO penicillin after splenectomy + vaccinate against encapsulated organisms

Elliptocytosis Abnormal spectrin (vs spherocytosis: abnormal spectrin & ankyrin)Anaemia, jaundice, splenomegalyElongated RBCsHigh reticsBM: erythroid hyperplasiaIndirect bili UpProtein separation + analysis: cells lyse @ 45-46 degrees

PNH

Triad:

RBCs susceptible to complement mediated damage60% have BM failure (panycotpenia)Also get thrombosis

Mx: CTSAnticoagulaiton

HABM failureThrombosis

Ham test (alternate complement pathway), sucrose lysis test (classical pathway)Haemosiderinuria Fe lossFlow cytometry

Thalassaemia

Cardiology

Formulae + physiologyBazzett formula QT

_____√R̅R̅

Use preceding RR

Should be < 0.49s in infants, < 0.44s in older childrenFick principle Works out CO when given O₂ consumption

CO (in L/min) = VO₂ (in mL/min) / (arterial sat) – (venous sat)Poiseulle’s law Calculate PVR:

P1 – P2 (pressure difference) = flow x resistance∴ PVR = (mean PA pressure – LA pressure)/pulmonary flow

Inotropes summary of receptors: presynaptic α₂ - negative feedback for norad post-synaptic α₁ - INOTROPIC (contractility e.g. septic shock, arrest) post-synaptic α₂ - vasoconstrictor (e.g. anaphylaxis) β₁: positive inotropic, chronotropic, dromotropic (↑AV conduction) β₂: vasodilation of vasc sm muscle

KEY: think α₁/β₁ are similar (both inotropic, β₁ is chronotropic + dromotropic), α₂/β₂ are opposites (vasoconstriction vs vasodilatation)dopaminergic Ⓡs:- peripheral D1 receptors: vasodilatation of renal, coronary and mesenteric circulation. also natriuretic- presynpatic D2 receptors: inhibit norad release

INOTROPES MOA:activate cardiac β₁ Ⓡs + ↑cAMP via G protein → ↑ opening of L-type Ca2+ channels → more Ca influx → more forceful contraction

ADRENALINE:- acts on α, β₁, β₂, NOT dopaminergic- low dose = 2nd line inotropic (e.g. in sepsis - EXAM QN)- high dose = vasopressive e.g. anaphylaxis, arrest

NORAD- acts on α, β₁, less so on β₂, nil on dopaminergic

ISOPROTENEROL- acts on β₁, β₂

DOPAMINE: dose dependent- low dose: ↑ renal perfusion (dopaminergic Ⓡs)- intermediate: cardiac stimulation, renal vasodilatation (β₁, dopaminergic)- high dose: vasoconstriction, hypertension (α)

DOBUTAMINEStimulates β₁ i.e. inotropic/chronotropic onlyweak β₂ effect

Cardio clues

Infarct patterns LMCA: STE in aVR

INFERIOR- RCA occlusion- leads II, III, aVF

LATERAL- LCA (left circumflex)- I, aVL, V5, V6

ANTERIOR- LAD- precordial leads (V1-V6)

POSTERIOR- RCA- reciprocal changes in ant leads, esp. V1

LUSB murmur (pulm area)

PS: harsh systolic murmur, wide split S2, click/thrillASD: fixed split S2, mid-systolic murmur, ±heavePDA: continuous LUSB murmurVSD: can cause LUSB or LLSB murmur. Small: murmur stops early. Large: pansystolic. Very large: no turbulence, no murmur

LLSB (tricuspid area)

VSDStill’s murmur: musical/buzzing, diminished with standing, mid-systolic, softHOCM: mid-systolic murmur, ↑ with valsalva, ↓ with handgrip, laterally displacedTS: mid diastolic murmur, assoc with ARF

Mitral area (apex) MS: mid diastolic murmur, assoc with ARFMR: pansystolic, assoc. with Marfan’s, EDSAR: mid-diastolic, with bounding pulses, can cause relative MS

Pansystolic murmur VSDMRTR

Continuous murmur PDA (machine line, check below L clavicle)Venous hum: R subclavian, resolves when supineAV fistula

Late systolic murmur

MVP

Early diastolic murmur

AR (3rd LICS)PR (3rd RICS)

Mid diastolic murmur

Turbulence across MV/TVMS, TS, atrial myxoma, L->R shunt, Austin flint (AR with regurgitant jet causing diastolic murmur)

Bounding pulses PDA, AR, LR shunt e.g. large AVM (e.g. V of Galen), truncusFixed split S2 ASD (usually)

Occ. Another L-> R shunt that increases flow across PVWide split S2 = delayed PV closure

pulmonary stenosisRBBB (slow to move)

Paradoxical split S2 S2 splits in expiration rather than inspirationd/t very delayed AV closure, e.g. AS, LBBB

Prostaglandin infusion

INDICATIONS (duct dependent CHD):1. Inadequate mixing e.g. TGA2. Inadequate PBF e.g. PA + IVS, TA + IVS, critical PS3. Inadequate systemic BF e.g. critical CoA, interrupted arch, HLHSFor duct-dependent lesions: aim sats 75-85%

CHF by ageNewborn with cardiomegaly, tachypnoea, hepatomegaly

5 “A”s – AV valve (Ebstein’s), AV block, AVM, Anaemia, Arrhythmia

0-4wk w ↑HR, ↑RR, hepatomegaly HLHSTGATAPVRAV fistulaCritical AS/PSCoarctation

1-4mo: ↓feeding, ↑RR, FTT, sweating, hepatomegaly

Large L→R shunts (VSD, PDA, AVSD)SVT

ECG S2 Murmur CXR OtherD-TGA normal single or split none or sys – from

LV (pulm) flowegg on string↑PBF

Cyanosis (mixing), ↑w PDA closureMx: balloon septost.

L-TGA abnormal p wavesabnormal Q in 3, aVF, aVR, V1upright TW in precord.heart block

none

TOF RADRVH strain

single long loud ESM LUSB

Boot shaped↓ PBF

<6m: BT shunt to ↑ PBF (subclav-PA)>6m: corrective

HLHS RAD single loud Ø unless VSD ↑PBF ↓ sats then pulm

cardiomeg oedema↓LV forcesNorwood (PA→Ao; palliative)Glenn: SVC→PA

PA-IVS 30-90LVHRAE

single sys cardiomeg +

PS 30-90 or RADRVHRAE

single or split ESM LUSB (2nd/3rd LICS) ± click

cardiomeg ± post sten dilat.

TAPVR RADRAE

split sys ⓝ or cardiomeg (snowman)

Obstructed TAPVR: cyanosis, ↑RR, ↓ response to PGEIncomplete obstruction: CHF, pulm HTNNO obstruction: L→R shunt, mild/no cyanosis, no pulm HTN

Tricuspid atresia

LADLVHRAE

single sys cardiomeg Need ASD for R→LBT shunt, Fontan (RA→PA)

Truncus arteriosus

RADLVH, RVH, BVH

single sys/±dias cardiomeg, R Ao arch in 50%

“torrential” PBF

Ebstein's RAE + RBBB = classic± WPW (40%)

split systriple or quad rhythm

cardiomeg+ Early cyanosisProstaglandin

AS ⓝ or LVH, mid-sys RUSB ⓝ or prom LV, post sten. dilatation

CoA RVH/RBBB in infants (obstructed/sympatomatic type)Older: LVH

Single, loud Ø in 50%or ESM (b/w scapulae)

cardiomeg↑PBF

± lower postductal sats

Alcapa ↓Q I, aVL usually ø cardiomeg Angina 2-3moASD secundum: RAD

± RBBBprimum: LAD, sup axis

fixed split ESM LUSB (flow) cardiomeg↑PBF↑ pulm a.

mx: close age 4-5y or when Qp:Qs > 2:1

VSD ±RVH ⓝ or loud PSM (small)short SM (small)ø murmur (large)parasternal thrill

±cardiomeg (large)↑PBF

PDA RVH sys LSBolder: cont <clav

cardiomeg if large

↑ PBF: TGA, TAPVR, truncus [all have lots of flow]↓PBF (oligaemia): TOF, PA-IVS, PS, TA, Ebstein’s [all R heart obstruction]↑ pulm venous congestion: HLHS, TAPVR

vc = venous congestion

Higher preductal sats: pulmonary HTN (e.g. mec asp, CDH - >5% difference from pre- to post- due to RL shunt), ↓ sys pressure e.g. AS, CoAHigher post-ductal sats: TGA with CoA

key points:- max LV volume is at end of isovolumetric contraction

Endocrinology

HormonesADH ½ life 5-10min

MOA: bnds G-protein coupled receptors: V1 in liver (glycogenolysis, vasoconstriction), V3 (ant pit ↑ACTH), V2 basolat membrane of CD cells → G protein dissociation → adenylate cyclase activation → ↑cAMP → protein kinase 4 activated → aquaporin 2 inserted↑ release with:

Osm > 283 8% ↓ intravasc volume 25% ↓ BP nausea, pain, hypoglycaemia, stress, alcohol

↓ release with glucocorticoids

Rickets

Type Ca PO4 ALP PTH 25 OHD

1,25 (OH)2D

Urine calcium

↓Carickets

Vitamin D deficient rickets

↓ or N ↓ or N ↑ or ↑↑ ↑ ↓ ↑ or N* ↓ or N

Vitamin D dependent rickets type 1

↓ ↓ or N ↑↑ ↑ N ↓ ↓

Hereditary vitamin D resistant rickets (vitamin D dependent type 2)

↓ ↓ or N ↑↑ ↑ N ↑↑ ↓

↓ PO4 rickets

X-linked hypophosphatemia

N ↓↓ ↑ N or sl↑ N N or ↓ ↓

Hereditary hypophosphatemic rickets with hypercalciuria

N ↓ or ↓↓ ↑ N or ↓ N ↑ ↑

Nutritional phosphate deprivation

↑ or N ↓ ↑ or ↑↑ ↓ or N N ↑ ↑ or N

Calcipenic rickets refers to disorders in which intestinal absorption of calcium is too low to match the calcium demands imposed by bone growth. * In vitamin D deficient rickets, 1,25(OH)2D usually is increased or normal. Occasionally, it may be deceased.

Vitamin D deficiency Inadequate stores, nutritional, sun, malabsorption (ADEK)Mx = vitamin D

Serum: ↓ 25-OHD, ⓝ/↑ 1,25-OHD, ↓Ca, ↑PTH, ↓PO4, ↑ALPUrine: ↑PO4 (need vit D to reabsorb it), ↑Ca

Type 1 vitamin D dependent rickets = 1-α hydroxylase def

Low 1α reductaseMx = high dose vitamin D

Serum: ⓝ25-OHD but ↓1,25OHD, otherwise similar picture to vitamin D deficiency, Ca ⓝ/↓, PTH ⓝ/↑

Type 2 vitamin D dependent rickets = XLD hypophosphataemic rickets = vitamin D resistant rickets

Kidneys can’t reabsorb PO4 → ↓ conversion of 25-OHD to 1,25-OHDFemales get fasting hypophosphataemia

Mx = vitamin D, phosphate

ⓝ PTH, ⓝ Ca, ↓PO4, ↑ ALP, ↓/ⓝ 1,25-OHD (usually low PO4 would upregulate 1,25-OHD)Urine: ↑PO4

Renal osteodystrophy PO4 retention → binds Ca → hypoCa → stim PTHAlso, renal damage → 1α hydroxylase falls → worsening hypoCa 2° hyperpara, trying to ↑Ca → bone resorptionAutonomous (tertiary) hyperpara

Hypoparathyroidism Autoimmune, absence, 22q11.2, CASR mutation (see below)

Familial hypercalciuric hypocalcaemia

* Ca sensing ® mutation Serum: ↓ PTH (since thinks Ca is high), ↓Ca,

Pseudohypoparathyroidism e.g. Albright hereditary osteodystrophy = resistance to PTH function

↑ PTH, ↓Ca, ↑ PO4 (PTH isn’t working)

Fanconi syndrome Renal phosphate wasting hypophosphataemia ↓ △ 25-OHD to 1,25-OHD

T1DM autoantibodiesIslet cell antibodies (ICA) Positive in 80-90% with new dx T1DM

Insulin autoantibodies (IAA) Positive in 30-40% with new dxAfter Rx, all pts will develop these

Appears 1st

Anti-GAD antibodies Present in 80% of newly dx (most likely to be found in newly diagnosed?)

Appears 2nd

IA-2 antibodies (insulinoma assoc)

Present in 60%

Anti-21-hydroxylase Abs 1.7% of ptsSignificance 1 pos → 30% get DM

2 pos → 70% get DM3 pos → 90% get DMHigher risk with ↑ titre

Thyroid diseaseHashimotos (AD)

autoimmune lymphocytic infiltration --> goitre

90% anti-peroxidase Abs70% anti-thyroglobulin Absinitial rise in thyroid stimulating Abs

Graves Thyroid stimulating antibodiesNeonatal dz Maternal Hashimotos → thyroid blocking antibodies cross placenta [rarely can

cause thyrotoxicosis from stimulating antibodies]Maternal Graves Thyroid stimulating Abs neonatal transient

hyperthyroidismThyroid scan results

Thyroid agenesis (85% of congenital hypothyroidism)

Cold scan

Fetal radioiodine exposure ↓ uptake, small thyroidMaternal lithium in pregnancy Cold scan (lithium competes w iodine)Thyroid organification defect (dyshormogenesis)

Normal or ↑ uptake in normal or enlarged thyroid

Untreated maternal Graves’ Cold scan

Rheumatology – AntibodiesANA TESTING:

Staining pattern - correlates to different disease but many confounders e.g. speckled = smith, RNP, Ro, La.Rim pattern = ds DNA

Titre: low is < 1:80, high is > 1:640normal is less than 1:40titre refers to dilutions until no Abs detected

Drug induced lupus (100%)SLE (93%)Mixed CT disease (90%)Scleroderma (85%)Oligoarticular JIA (70%)Polymyositis/dermatomyositis (60%)Sjogren’s (50%)Rheumatoid arthritis (40%)Discoid lupus (15%)Other: Hashimoto’s, Graves, autoimmune hepatitis, PBC

Anti ds-DNA Specific for SLEBest to monitor disease activity: more sens/spec than C3/C4C4 drops more than C3 – also reflects flare

Anti-histone Drug induced lupusENA: Anti-SM Most specific for SLE, but only pos in 25%ENA: anti-Ro/La Sjogrens

40% of SLEDiscoid SLENeonatal SLE:

Ab ransferred between wk 12-16 of gestation 90% have anti SSA, also SSB, U1-RNP Annular scaly rash, haemolytic anaemia, TP, neutropenia, congenital heart

block, HSM, jaundiceAnti U1-RNP Pos in 10% of SLE

Pos in other mixed CT diseaseAnti-Scl-70 SclerodermaAntiphospholipid Ab Lupus anticoagulant (doesn’t correct on mixing studies, causes A/V thrombosis)

AnticardiolipinAnti ribosomal P SLE

99% spec, only 21% sensassoc with depression + psychosis

CRP Should be normal in SLE – if not, think sepsisESR Correlates with flare of disease in SLE

Oncology – chemotherapy

Chemo by cell cycle stage

Gap 0 Resting phase (senescence)Interphase G1, S, G2Gap 1 ↑ Cell size L-asparaginase (starves cells of this

AA that they can’t produce)Synthesis DNA replication Cytarabine

SteroidsMethotrexate6-MP

Gap 2 Continued cell growth Topoisomerase II inhibitorsAnthracyclines

Mitosis Division into daughter cellsPMAT:Prophase (DNA condenses, spindle forms)Metaphase (chromosomes LINE UP, spindles attach)Anaphase (division + migration)Telophase (membranes form, cytoplasm splits)

VincristinePaclitaxel

Phase non-specific

Alkylating agentsAntibioticsPlatinating agents

Alkalyting agents

e.g ifosfamide, cyclophosphamideMOA: alkylates guanine ∴ inhibits DNA synthesis by forming irreversible cross-links in DNAPhase non-specific

SE: AML TCC Haemorrhagic cystitis (prevent w mesna) Pulmonary fibrosis Delayed puberty Infertility

Ifosfamide: Fanconi sy N&V, dark skin/nails, metallic taste, SIADH, anaphylaxis

Requires hepatic activation ∴ less effective if liver dysfunctionEtoposide Topoisomerase inhibitor (regulates DNA winding)

Gap 2 phase

SE:N + VMyelosuppressionSecondary AML [also occurs with alkalyting agents]

Anthracyclines

e.g. doxorubicin, daunorubicin, BLEOMYCINGap 2 phase

MOA: prevents DNA double helix from rewinding after unwinding by binding to topoisomerase II ∴ prevents replication

SE:N+VCardiomyopathy (often refractory) or arrhythmiaRed urineRadiation recall dermatitisMyelosuppressionExtravasation injuryBLEOMYCIN - pulmonary fibrosis

Methotrexate MOA: folic acid antagonist; inhibits dihydrofolate reductaseSynthesis phase

SE:MyelosuppressionMucositisHepatitisLong term: osteopenia/bone #sHigh dose: renal, CNS toxicityIntrathecal: arachnoiditis, ❉leukoencephalopathy❉Exudative pulmonary effusion

Result therapy: leucovorin (folinic acid – already reduced ∴ don’t need DHFR)

INTERACTIONS:bactrim also inhibits DHFRdelayed clearance with: salicylates, penicillins, ALLOPURINOL↑ conc with NSAIDsdisplaced from protein binding sites by: PHT, salicylates

L-asparaginase

MOA: depletion of l-asparagine which is an AA that leukaemic cells can't produce, unlike normal cellsGap 1 phase

PEG-asparaginase catalyses L-asparagine → ammoniaPEG = polyethylene glycol

SE:allergic reactionpancreatitis*** - NB if abdo pain**hyperglycaemiaPLT dysfunction + coagulopathyEncephalopathyVenous thrombosis

Carboplatin, Cisplatin

alkylating-like agents; no alkyl but do form cross-linksplatinum agentsphase non specific

inhibit DNA synthesis

SE:N+Vrenal dysfunction***myelosuppression↑ risk leukaemia - which has a poor outcomeototoxic *** (SNHL)tetany

neurotoxicHUSanaphylactoidperipheranl neuropathy (vincristine more likely)seizures

Vincristine Inhibits microtubule formation (spindle stage)= during mitosis

SE:cellulitisperipheral neuropathyjaw painconstipationileusSIADHSeizuresptosisMINIMAL MYELOSUPPRESSIONmost likely to cause delayed nausea

Cytarabine Pyrimidine analogue but main action is to inhibit DNA polymeraseAKA cytosine arabinosine, Ara-CSynthesis phase

'cy' = 'py'rimidinevs. mercaptoPUrine

Indications: ALL, AML, NHL, HL

SEN+V, myelosuppression, mucositis, conjunctivitisLiver dysfunctionCNS/cerebellar dysfunctionIntrathecal complications (arachnoiditis, leukoencephalopathy, leukomyelopathy)Renal dysfunction

Neurology – AEDsCARBAMAZEPINE Blocks Na channels

Narrow therapeutic indexHepatic metabolism

CYP inducer#1 SE = MP rashHigh risk SJSIdiosyncratic agranulocytosisNeurotoxicNausea, dizzinessDrowsinessAtaxiaSIADHDRESS (MP rash, exfoliative dermatitis, oedema, LNs, fever, eosinophilia)

Phenytoin Blocks Na channelsNarrow therapeutic index (?needs most monitoring)Hydroxylated in liver

Saturable system – small △ can → toxicity

Zero order kinetics

AtaxiaDrowsinessGum hypertrophyAcneCoarse faciesHirsutismCYP inducerDRESSTeratogenic (cleft)

Lamotrigine Blocks Na channels Rash in 5-10%SJS/TEN (1:50-300)↑ risk SJS with valproateDizziness, ataxia, diplopiaGI symptoms

Valproate Blocks Na channels, GABA-ergicTherapeutic monitoring

CYP inhibitorDrowsinessWt gainPancreatitisAlopeciaLiver dysfunctionTeratogenic (?5% risk major defects)

Phenobarbitone Blocks Na channelsGABA-ergic

Drowsiness, sedationTolerance

Sudden withdrawal can → statusTopiramate GABA-ergic

Carbonic anhydrase inhibitorNausea, abdo pain, anorexiaNephrolithiasisHypochloraemic met acidosisMyopia, closed angle glaucomaCognitive dysfunctionWt loss

Vigabatrin GABA-ergic (↓ GABA breakdown) Optic neuritisConcentric vision lossRetinal atrophyDrowsiness

Benzodiazepines GABA-ergic SedationTolerance

Levetiracetam MOA unknownPartial & generalized seizures

Behavioural disturbanceSleep disturbancePsychosis

Gabapentin GABA analoguePartial seizures

Weight gainCI in myoclonus

Ethosuximide ↑ seizure threshold (non-GABA), ↓ nerve conduction in CNSAbsence seizures ONLY

AtaxiaBM suppression

Neurodegenerative diseases – MRI findingsXL ALD Parieto-occipital WM changes (towards the back)

+ may suggest pigment changes, deterioration at school

Metachromatic leukodystrophy Periventricular + deep WM (UMN + LMN signs)

NCL Periventricular rim of mildly abnormal tissue

Krabbe Symmetric ↑ densities in caudate nucleus, thalamiLeigh Deep grey matter symmetric lesions: brainstem, BG, subthalamic nucleiPKU WM changes, initially centralMSUD Deep gray matter changes + WMMPS Cortical GM + WM changes

CSF findings in ADEM, MS, GBS, ACA, TMADEM Post viral encephalitis, myelitis (weakness, long tract

si.) MRI: BG, thal, brainstem T2 enhancing lesionsCSF monocytic/lymphocytic pleocytosis ± ↑ protein

MS MRI: T2 multifocal lesions in periventricular WM Mild ↑ CSF WCC, IgG1 oligoclonal bandsGBS CSF ↑ protein without pleocytosisACA Isolated ataxia, or may have other cerebellar signs CSF not needed – may have ↑WCCTransverse myelitis

Triad: weakness, paraesthesiae/ses loss, sphincter dysfunction

CSF ↑WCC, ↑protein

Weakness

General clues Proximal usually muscular (except SMA) Distal usually neuropathy (except myotonic dystrophy) Muscle hypertrophy common in myopathy Distal atrophy/wasting common in neuropathy Floppy weak

o Neuromuscularo ↓ tone, ↓ power, ↓ reflexeso Myopathy, dystrophy, myasthenia gravis, SMA

Floppy strongo Centralo ↓ tone, ⓝ strength, ⓝ/↑ reflexeso CP, genetic (Down syndrome), metabolic

GBS Symmetric ascending paralysisNeuropathic pain↓DTRsUrinary retention50% bulbar involvement

CSF protein ↑ (cells usu < 10)NCS ↓ CV , dispersionMRI: thick/enhanced n. roots, thick cauda equina

CIDP (>2mo) Symmetrical prox & distal weaknessMotor > sensory {glove/stocking}↓DTRsRarely: CN/bulbar

CSF ↑ protein without pleocytosis

CMT Distal weakness 1st, calf pseudohypertrophy↓DTRs distallyMostly motor, but some sensory involvement

EMG ↓ CVNormal CSf

Myotonic dystrophy

Distal > proximal weaknessNormal DTRs/↑Involves face, tongue, speech

SMA Proximal weakness↓ DTRsⓝface, ⓝ cognition, bell-shaped chest

Fibrillation on EMGSpont APDenervation/renervationBiopsy: alt ⓝ/atrophic muscle

MalformationsDandy-Walker Complete or partial agenesis of cerebellar vermis

with retrocerebellar cyst that communicates with 4th ventricle

MRI: enlarged post fossa ± absent CC ± polymicrogyria or heterotopiaChiari 1 Inferiorly displaced cerebellar tonsils through foramen magnum

± hydrocephalus or hydrosyringomyelia

Chiari 2 Small posterior fossaTonsils + 4th ventricle + brainstem enter cervical canalMyelomeningocoele

Syringomyelia Cystic cavity in spinal cord, ± communication with CSFSpina bifida Midline defect of VBs/arches/laminae ± protrusion of SC/meninges (occulta vs

cystica)Diastematomyelia Bony burr splits cord @ L1-L3

Obstructive hydrocephalus Aqueductal stenosis – dilated 3rd + lateral ventricles, normal 4th ventriclePorencephalic cyst Lined by WMSchizencephaly Not lined by WM

Neuro injuriesCONGENITAL BRACHIAL PLEXUS INJURIESErb’s palsy C5 + C6

Deltoid, infraspinatus (C5)Biceps (C6)

Upper arm adducted, int rotatedForearm extendedPRESERVED hand/wrist movement

Erb’s palsy plus C5-C7 Arm adducted, int rotated, forearm extended & pronated, “waiter’s tip” flexion of wrist/fingers

Flail arm C5-T1 Whole upper limb weak± Horner sy

Klumpke’s C8-T1 Isolated hand paralysis + Horner syndrome

Nerve Motor DTRs Sensory MechanismAxillary nerve

teres minor/deltoid

lateral upper arm (inf half deltoid) surgical neck humerus, ant/inf shoulder dislocation

MedianC5-T1

LOAF (lat lumb, OPB, APB, FPB)

Finger jerk

trauma, radial/ulnar #, supracondylar #, Colles #, CTS

Radial n.C7-C8

elbow ext (triceps, brachioradialis), wrist ext, MCP, supination

TricepsSupinator jerk

Causes: # humeral shaft, sat night palsy

Ulnar C8-T1

Medial 2 interossei, hypothenar muscles (claw hand)

supracondylar #, radial/ulnar #, elbow pressure

AIN Thumb IP flexionIF DIP flexion“OK sign”

Supracondylar #Radial/ulnar #

MSK nC5-C6

Biceps, brachialis (elbow flexion)

Biceps jerk

FEMORAL L2,3,4 Hip flexion, knee extension, knee jerk

OBTURATOR L2,3,4 (same as femoral) Hip adduction

SCIATIC L4,5, S1,2,3 Hip extension, knee flexion (opposite of femoral) + all peroneal/tibial supplied muscles/sensory areasSplits in mid thigh to common peroneal + tibial

TIBIAL L4,5, S1,2,3 Supplies plantaris, gastrocnemius, popliteus, soleus, tibialis POSTERIOR, FDL, FHL, toe musclesINJURY --> intrinsic foot weakness**tibialis posterior inverts the foot ∴ in sciatic lesions you can't invert, but in common peroneal lesions you can

PERONEAL L4-S2 Superficial peroneaL: peroneus longus/brevis, med/lat cutnaneous nDeep peroneaL; tibialis ANTERIOR, EDH, EHL

SURAL originates from branches of tibial + common peronealsupplies cutaneous innervation to lateral calf + footpurely sensory

Tracts

PAIN/TEMP Lateral spinothalamicFibres decussate 1-2 levels higher ∴ lesion @ site → contralat loss of pain/temp 2 levels below

LIGHT TOUGH/PRESSURE

Anterior spinothalamic + medial lemniscus

VIBRATION Medial lemniscus

PROPRIOCEPTION Spinocerebellar, medial lemniscus

MOTOR Corticospinal: decussates @ foramen magnumCorticobulbar: decussates @ C7 + C12 level

Infectious diseasesAntibiotics

Drug MOA + spectrum of activity NOTESAminoglycosides Covers gram negs incl. Pseudomonas

NO gram pos coverConcentration dependent killing

Nephrotoxic (usually ATN) – 5-7d lagOtotoxicResistance from altered binding sites

Beta-lactams Binds PBPsGPOs (not enterococcus)Anti-staph have anti- beta-lactamaseAminopenicillins have some GNO cover e.g. E. coliTicarcillin/piperacillin are anti-pseudomonal, anti-anaerobe, and are combined with a beta-lactamase inhibitor to maximise spectrum

SE: low incidence ‘true allergy’10% cross-reactivity w cephalosporin allergy

Carbapenems Use for ESBLs e.g. enterobacter (a GNO)

Cephalosporins Bind PBPs1st gen: strep, staph (not MRSA), some GNOs (Kleb, Proteus, E. coli – PECK)

2nd gen (cefuroxime, cefaclor): BAD for GPOs, better for GNOs: PeCK, Haemophilus, Enterobacter, Neisseria

Cefaclor – serum sickness

[HEN PECK]

3rd gen: better CNS penetration. Still covers strep (but some resistance therefore vanc in meningitis), better GNO. Ceftazidime covers Pseudomonas

4th gene: good GPO and GNO coverage, good CNS penetration

LIncosamides (e.g. clindamycin)

Covers most GPOs, good anaerobe cover, covers MRSANOT enterococcus

Macrolides 50S ribosomal subunit, reducing protein synthesis

Erythromycin: CYP inhibitor, LQTS,

Metronidazole(imidazole)

Inhibits nucleic acid synthesis (DNA damage)Anaerobes e.g Bacteroides, Clostridium, GardnerellaParasites e.g. Giardia (no eosinophilia), Entamoeba (no eosinophilia), Trichomonas

Common organismsGram positive cocci

Catalase pos clusters= staph Coagulase pos = aureus (grapelike) Coag neg = epidermidis, saphrophyticus

Catalase neg diplo/chains = strep α-haemolytic (partial/green) = S. pneumonia (capsulated), S. viridans (no capsule) β-haemolytic (clear) = S. pyogenes, S. agalactiae γ-haemolytic (no haemolysis) = Enterococcus, Pseudopeptostrep

Gram positive rods

Aerobic: Bacillus (spores) Nocardia (branching) Listeria (motile) Corynebacterium

Anaerobic Clostridium (spores) Actinomyces (branching)

Gram negative rods

Aerobic: Legionella, Bordetella, Haemophilus, Campylobacter, Pseudomonas, Vibrio, Escherichia, Klebsiella, Enterobacter, Serratia, Salmonella, Shigella, ProteusAnaerobic = bacteroides

Gram negative cocci

Neisseria = bean shaped diplococci

E. Coli gastro EHEC (0157:H7) = shiga toxin, causes HUS. don’t treat with ABxETEC: watery secretory diarrheaEnteroinvasive: inflammatoryEnterohaemorrhagic: inflammatory

Enterococcus Gram pos diplococci (like strep)

Causes sepsis, necrotising enterocolitis

Ampicillin, vancomycin, linezolid, rifampin, quinolonesNOT cephalosporins

Listeria Gram pos rod

Clues: nodules on placenta, mat fever

Ampicillin, penicillin

Chlamydia C. pneumoniae causes conjunctivitis (>d5), staccato cough, pneumonia. GNO. Intracellular anaerobe. Intracytopalsmic inclusion bodies; PCR. Mx = macrolide

Clostridium Anaerobe, gram posC. tetani – tetanusC. botulinum – infant botulism (inhibits release of Ach into synapse)

Debridement, tet Ig, metronidazole OR penicillinBotulism: supportive +/- antitoxin

C. diptheriae Gram pos rodH. flu “pleomorphic” on gram stainStrep GP diplococcic (or chains) – blue on stain

Alpha = viridans, pneumonia

Beta:GAS (pyogenes)- Pharyngitis (risk ARF, PSGN)

Pharyngitis: ABx do not shorten illness, don’t prevent PSGN, but do prevent ARF

- Peritonsillar abscess (deviated uvula; cover for anaerobes too)

- Retropharyngeal: usually younger, neck hyperextended (vs tripod in epiglottitis)

– pyogenes (pharyngitis, oral abscess, skin, PSGN)GBS- Give intrapartum penicillin if: PROM >

18h; previous positive screen in same pregnancy; unknown status + complicated OR <37/40

Impetigo (less bullous than staph)TSS

Enterobacter GNOCan be ESBL – use carbapenem

Echinococcus Cestode (parasite)E. granulosus cystic diseaseE. multilocularis alveolar disease

In kids #1 site = lungs: CP, cough, haemoptysis#2 = liver – abdo distension, pain, hepatomegother: bonecan have anaphylaxis from cyst ruptureUS shows fibrous capsule +/- internal membranesBloods show eosinophiliaMx: albendazole + aspirate if accessible

EBV In B cellsCMV in monocytesHIV in follicular dendritic cellsToxin mediated Staph scalded skin

S. aureus phage 11, type 71Exfoliative toxin epidermis peels offPeri-orificial (no intra-oral lesions, vs EB where there are; also in EB the lesions may be present at birth)Benign

Staph toxic shockTSST1S aureus phage 1, type 29

Tender erythrodermaOedemaLate desquamationoral + genital mucosa redCan fulminant shock, multi org failure10% mortalityd/t suprantigen >30% T cells activatedMx: fluclox + clindamycin, IVIG in severe shock

GAS toxic-shock like syndromeGAS with exotoxin A

ErythrodermaLate desquamationSepsis more likelyOral mucosa involved30-50% mortalityMx: benpen + clinda/linco (to improve tissue penetration) + IVIG if shock

STIs Chlamydia 75% no symptomsMay have urthritis, bleedingDx: 1st pass urine PCREndocervical swab Culture, IF, NAATsMx: azithromycin stat dose, or doxy x 7 days

Gonorrhoea Purulent/copious dischargeDysuria, bleedingDx: urine pCR or endocervical swabMx: ceftriaxone IM or IV

PID PolymicrobialABdo pain, d/c, bleeding, fever, N&VMucopurulent d/cMx: ceftriaxone + flagyl + azithromycin

Trichomoniasis Itchy, yellow-green dischargemx: metronidazole stat dose

Incubation + contagious periods

Incubation Contagious periodVaricella 10-21 days from 5 days before rash appears

until all lesions crusted (~5-7days)Parvovirus 4-14 days from 7 days before rash appears

until rash appears – then don’t need to isolate

HFM 3-6 days (short) from onset of mouth ulcers until fever is gone

Impetigo 2-5 days (short) onset of sores until has had 24h of antibiotic (don’t need to isolate)

Lice 7 days onset of itch until one treatmentMeasles 8-12 days from 4 days before rash until 5 days

after rash appearsMeningitis 3-6 days (short) from onset of symptoms and lasting

1-2 weeksroseola 9-10 days onset of fever until rash disappears

(2 days)Rubella 2-3 weeks from 7 days before rash until 5 days

after rash appears (similar to measles)

Scabies ~1 month onset of rash until treatmentscarlet fever 3-6 days onset of fever or rash until 24h

treatmentshingles ~2 weeks onset of rash until all sores crusted

(~7 days) – don’t need to isolate, just cover lesions

warts 1-9 monthsbronchiolitis ~5 days from onset of cough then for 7 dayscolds 2-5 days from onset of rhinorrhoea until

afebrilecough, croup 2-5 days onset of cough until afebrileinfluenza 1-3 days onset of symptoms until afebrilestrep throat 2-5 days onset of sore throat until on ABx 24hviral sore throat 2-5 days onset of sore throat until afebrileTB 6mo – 2y until 2 wks on treatmentpertussis 7-10 days from onset of rhinorrhoea until 5

days treatmentEBV 30-50 days from onset of fever until afebrileviral conjunctivitis

Streptococcal antibodiesASOT - recent GAS pharyngitis < 2mo

- useful in diagnosing ARF- rises from 3wk on- severe strep: only ↑ in 70-80%- pyoderma: ↑ in 30-40%- PSGN: ↑ in 50%- MPGN: ↑ in 20%

Anti-DNAse B - superior for skin infections, less FPs, longer period of reactivity- useful in ARF, skin infections and PSGN- rises from 6-8wk on – stays up for 6-9mo

Anti-hyaluronidase Follows GAS infection + rheumatic feverAnti-fibrinolysin (antistreptokinase)

↑ In rheumatic fever + recent haemolytic strep infections

TORCH + other congenital infections Toxoplasmosis(protozoan)

TRIAD1. Chorioretinitis2. Hydrocephalus3. Intracranial calcifications (Scattered)

Other: ASx, HSM, ↑LNs, ↓IQ, visual defect, jaundice, anaemia, ↓PLTs, abnormal CSF findings, seizures, hearing loss

DIAGNOSIS IN UTERO1. Serology: IgG/IgM2. PCR amniotic fluid3. US: hydrocephalus, IC calcifications, microcephaly, IUGR, ascites, HS

Acquired 1st trimester: 10-25% risk + more severeConsider abortion if < 16wkAcquired 3rd trimester: 60-90% risk but less severe

PREVENT transmission w spiramycin in pregnancyIf confirmed – use pyrimethamine _ sulfadiazine after 1st trimesterAdd leukovorin (folinic acid) to ↓ BM suppressionTreat infant with pyrimethamine/sulfadiazine/leukovorin x 1-2y

Syphilis (spirochetal bacteria – T. pallidum)

CLIN - everything

DIAGNOSISMat; VDRL titre, plasma rapid regainIf positive --> agglutination + fluorescent treponemal antibody absorption tests

1°/2°/early latent disease: 50% riskEstablished latent disease: 10% risk

MANAGEMENTPenicillin x 10 days

Neonate:- IgM POS in 90% with congenital syphilis- If antibody titre ↑ 4-fold in 3mo = diagnostic (if mat Ab, will decline)- Dark ground microscopy can show organism from skin, placenta- Check CSF for evidence of neurosyphilis

HIV PRESENTATIONLympadenopathy, candidiasis, FTTAIDS defining illnesses:

PCP (median age 5mo) – perihilar infiltrates Lymphoid interstitial pneumonia/pulmonary

lymphoid hyperplasia – older age, reticulonodular bibasilar infiltrates + hilar adenopathy

Recurrent bacterial infections e.g. strep, staph, salmonella

Pseudomonas later Wasting sy (>10% wt loss, crossing 2

centiles, <5th centile) Candida oesophagitis HIV encephalopathy (DD, microcephaly) CMV pneumonia, colitis, retinitis

Dx: Mat Ab will persist for 18mo ∴ check HIV DNA PCR @ 3-4wk, 1-2m and 4-6m (± @ birth), then ELISA/western blot @ 18mUsually hypergamma, 10% hypogamma↓CD4:CD8 (normal is 2:1)Lymphopenia↓ Mitogenic response

Exclude HIV: 2 neg PCRs @ >1mo and >4mo

No treatment: 25-30% riskWith testing, counsellling, ARTs, LSCS, no BF: <2% risk

Bactrim prophylaxis for PCP

PROG: ø Rx → death by 5RNA conc predicts prog (so does CD4 count – best used together)

PREVENTART in pregnancy; IV zidovudine in labour; LSCS if ↑ viral load; infant gets ZDV x 6wk, BF CI

MX: combination ART: 2x NRTIs (nucleoside

reverse transcriptase inhibitors)

PLUS a PI or NNRTI NRTI e.g. zidovudine,

lamivudine (neutropenia, lactic acidosis)

NNRTI e.g. efavirenz

Give inactivated vaccinesMMR/VZV only when CD4 > 15

HCV (RNA virus), genotype 1 = worst

TRANS: blood, sexual, transplacentalCLIN: jaundice rare. Nausea, pain, anorexia, episodic transaminitisIX: RNA PCR, HCV Abs after 4-6wk, LFTs, fibrosis on biopsyCheck baby PCR @ 2mo, anti-HCV @ 18mo (when mat is gone)

Mum RNA pos → 5-10% risk↑Risk with ↑viral load/HIV positivity

↑Clearance if young

α-interferon & ribavirin clears in 50%

CAN breastfeed

Ribavirn SE: haemolytic anaemia, teratogenicity

HBV (DNA virus) TRANS: vertical, parenteral, sexual, BM (v low)Incubation 60-90 daysProdrome of fever, malaise, vomiting, then RUQ pain, jaundice, rash, ±arthritis, haematuriaCirrhosis in 20%, of which 10% →malignancyUS + αFP to screen for HCC q6mo

Neonate: check serology @12mo if mum positiveIf mum HBeAg pos: check LFTs, HBeAg + refer ID

Perinatal infection: usually ASx, but 90% → carriers, risk HCC later

Screening: screen all for HBsAg, if pos then HBeAg

Mum HBeAg pos: 90% riskMum HbeAg neg, HBsAg pos: 10%

PREVENT:Vaccine + Ig @ birth prevents >90%

Acquired in infancy: 90% → chronic dzAcquired in childhood: 30-90%Acquired in adulthood: 5-10%

Mx: if abⓝ LFTs→ α-interferon, nucleoside analogues (e.g. lamivudine)

CMV 0.2-2.4% of all live births

CMV syndrome: HSM, jaundice, petechiae, purpura, microcephaly, seizures, chorioretinitis, IUGR/SGA, periventricular calcifications

Risk: 1% of non-immune women get CMV in pregnancy, of which 10-20% will have congenital CMV. Most ASx, but 15% of these will develop hearing loss

DX: check mat IgM, IgG (high anti-CMV IgG avidity suggests 1° >6mo, low avidity = recent infection)US for periventricular calcificationsNeonatal cord blood IgM

Highest risk = new infection in 1st trimester (50% risk fetal infection, 20% congenital, 10-15% mortality – but majority still normal)

Reactivation: IgG protects ∴ only 10% have deafness or neuro probs

Mx: ganciclovir x 6 wks if severe dz, chorioretinitis, SNHL, microcephaly

Neonatal urine viral culture, throat swab/NPA PCR, neuroimaging

Rubella CRS: IUGR, microcephaly, eye stuff: cataracts, chorioretinitis, microphthalmia, heart stuff: pulm stenosis, PDA, SNHL, HSM, LNs, anaemia, blueberry muffin rash, pneumonitis, renal anomalies

Dx: Mat IgG/IgM, neonatal cord blood IgM, higher than expected neonatal IgG, PCR, viral culture

<12 wks: CRS in > 90% (♥/eye)12-18wk: SNHL in 20%>18wk: infection rare

Supportive Mx

Varicella Syndrome: cicatricial (scarred) skin, limb hypoplasia, ↓IQ, seizures, chorioretinitis, cataracts, microcephaly, IUGR?30-50% mortality

DX: amnio for varicella PCR

Week 8-20: highest risk<20th week: 1-2%>20th week: very low risk

Mx: give mum ZIG within 72h of any exposure if she’s seroneg. If mum had dz > 5d before delivery, no Rx for neonate if well, even if lesions.

If neonate exposed from 5d before to 2d after birth: give ZIG, give acyclovir only if Sx.

HSV Vesicles in > 50% (skin, eyes, mouth)Disseminated in 25% (sx @ 7-10d)Encephalitis in 30% (d13-16)

“Syndrome”: vesicles, chorioretinitis, microcephaly, microphthalmia

Ix: IgM takes 2 weeks to appear; IgG reflects mum. Therefore tak swabs of throat/eye/lesions for IF (quick) + PCRCSF PCR, viral cultureEEG: temporal/parietal predilection

Mat 1°: 30-50% riskMat recurrence: 1-3% risk↑ w scalp probe

Of those who got it:

5% was in utero85% intrapartum (mostly HSV2)10% postpartum

PREVENT: LSCS if active lesionsSwab infant @ 48h

Mx: acyclovir IV x 14d if sickNeonatal conjunctivitis

Gonococcal Gram neg coccobacillus D1-3 Florid exudate, risk corneal ulcer, perforation, blindness

Chlamydia Day 5-14 Purulent. May get pneumonia Mx = erythromycin x 2 weeks

HSV: presents day 4Other bacterial : use topical tobramycin or chloramphenicol

Breastfeeding contraindications

HIV, active TB, chemo, illicit drug use, radiation (temporarily), infant has galactosaemia

TeratogensWarfarin Fetal warfarin syndrome

Nasal hypoplasia, low nasal bridge, groove b/w nostrils + tip

Stippled epiphyses Hypoplastic phalanges, △ LBW C-spine abnormalities Airway compromise

Haemorrhage

6-8 weeks: fetal warfarin syndromeup to 20 wks: CNS/ocular defects e.g. Dandy Walker – likely from haemorrhage

Prevent w heparin instead

Phenytoin Fetal hydantoin syndrome IUGR, microcephaly, MR Metopic ridging,

epicanthal folds, ptosis, flat nasal bridge

Phalangeal hypoplasia Cleft lip

NSAIDs - kernicterus- 3rd trim: early closure of DA- abortion (1st trim)

¹³¹IODINE - 1st trim: severe hyperthyroidism- other time: destroys thyroid

K IODIDE - large goitre

TRIIODOTHYRONINE - goitre

Lithium Heart/great vessel defectsAlcohol Fetal alcohol syndrome

Low IQ Microcephaly Short palpebral fissures Maxillary hypoplasia Short nose Smooth philtrum Joint problems VSD > ASD

2 drinks per day → SGA≥ 4-6 drinks per day → FAS

Androgens e.g. danazol Virilisation in female fetusMethotrexate Skeletal malformations e.g. cranial

dysplaiaBroad nasal bridgeLow set ears

< 6 weeks can cause ToF

Retinoic acid DysmorphismCNS defects♥ defects

VALPROATE - 1.5% risk NTDs- other e.g. skeletal, hypospadias, heart - overall 5.7% risk major malformation- 9.1% risk major congenital malformation if mum taking high dose- fetal distress, low apgars

- highest risk 1st trimester

ACE-inhibitors - renal dysfunction, oligohydramnios sequence

- highest risk 2nd/3rd trimester

AMINOGLYCOSIDES - hearing loss (labyrinth damage)

BETA BLOCKERS - fetal hypoglycaemia, bradycardia, ?IUGR

CARBAMAZEPINE, PHENOBARB - haemolytic dz of newborncarbamazepine --> NTDs, cleft lip/palate, DD, nail hypoplasia

TRIMETHOPRIM - NTDs

ORAL HYPOGLYCAEMICS - neonatal hypoglycaemia

Tetracyclines stained teeth, enamel hypoplasia highest risk 2nd/3rd trimesterCHLORAMPHENICOL - grey baby syndrome (vasomotor

collapse)

FLUOROQUINOLONES - ?MSK defects

RADIATION microcephaly, MR- skeletal abnormalities

COCAINE - GU, limb, CNS, ocular defects (?poor evidence)

MARIJUANA - gastroschisis (v rare?)

AMPHETAMINES - IUGR, ↓ placental blood flow

HEROIN - IUGR, w̅drawal

DIGOXIN - crosses placenta

NICOTINE - IUGR, ↓placental blood flow

CCBs - phalageal defects (1st trim), IUGR (2nd/3rd trim)

THIAZIDES - ↓ placental perfusion, IUGR

CHEMOTHERAPY - malformations

BENZODIAZEPINES - withdrawal, resp depression

OPIOIDS - withdrawal (6-8d of life)- high dose: CNS depression, bradycardia

SSRIs paroxetine - CHDMETHIMAZOLE - goitre, aplasia cutisCTS Orofacial cleft 1st trimesterLoratadine hypospadiasVitamin K haemolysisPseudoephedrine GastroschisisCaffeine High dose: stillbirth, prem, LBWAspartame Avoid in PKU

Toxidromes

Drugs that cause diaphoresis

Need ‘SOAP’ to wash it off: Sympathomimetics Organophosphates + other

cholinergics Aspirin PCP (phenylcycline)

Drugs that cause nystagmus

AlcoholLithiumAEDsPCP

Charcoal useful for AAA Asthma meds (aminophylline, anti-muscarinics)Aspirin, ibuprofenAcetaminophenGive within 1h

Charcoal contraindicated

Unprotected airwayRisk aspiration e.g. hydrocarbons, oilsNot effective in: cyanide, caustic alkali, organic solvents, iron, ethanol, methanol, lithium, mineral acids

Gastric lavage contraindicated

HydrocarbonsAcid or base ingestions

Plant toxidromes Anticholinergic plants Jimson week (Datura) Deadly nightshade

Digoxin-like: oleanderCholinergic poisoning CAUSES: organophosphates, carbamates, sarin,

physostigmine, pilocarpine, edrophonium

DUMBELS (respond to atropine)

Fasciculations, weakness (nicotinic – ø response to atropine)

Mx:Decontamination (charcoal)ABCs, supportive careAtropine

Anticholinergic poisoning

CAUSES: Belladonna alkaloids, atropine, diphenhydramine, TCAs (also cause SS), deadly nightshade, Jimson weed

HOT as a hareBLIND as a bat (mydriasis)RED as a beetMAD as a hatterDRY as a bone (xerostomia, ↓ secretions, urinary retention)FAST as a something fast

Mx: cholinergics, e.g. physostigmine (anticholinesterase)

Paracetamol high risk: >200mg/kg; unknown quantity, or repeated >100mg/kg/day

D1: N&V, sweaty, malaise, pallor, anorexiaD2: RUQ pain, oliguria, transaminitis, ↑SBR/INRD3: risk multiorgan failure, death or resolves <d5

PATH: paracetamol → hepatic sulfation/glucuronidation (kids use sulphation

MX = NACGlutathione precursorSE:

anaphylactoid reaction with wheeze, rash. Stop, give antihistamines, restart more slowly

more so have more reserve for glucuronidation in OD) → non-toxic. 4% of dose → CYP450 → NAPQI (toxic to kidney, pancreas, mitochondrial injury, hepatocyte death) → combines w glutathione → non-toxic

Benzodiazepines Respiratory depression FlumazenilBeta blockers Hypoglycaemia, ?bradycardia, ?hypotension GlucagonCarbon monoxide Smoke inhalation, car fumes

constitutional sxsevere: seizure, coma, confusioncyanosis ABSENTCO has stronger affinity with HbCan have normal SpO2/pO2 (measures Hb-CO as if it were Hb-O2)

100% O₂ via NRBHyperbaric O₂

CCBs Insulin, Ca saltsCyanide Coma, seizures, apnoea, cardiac arrest Amyl nitrate, Na nitrate (these can

cause methaemoglobinaemia)Ethylene glycol (antifreeze)

Metabolic acidosis with ↑ AG, ↑ osmolal gap Fomipezole

Methanol ↑ AG met acidosisAlcohol dehydrogenase breaks it down into toxic metabolites

FomipezoleEthanol (competes for alcohol dehydrogenase)

Heavy metals DimercaprolDMSAEDTA

Iron Corrosive to GI mucosaGIB, hepatotoxicity, coagulopathy, cardiac dysfunction, gastric outlet obstructionUncouples oxidative phosphorylation → lactic acidosisToxic @ > 40mg/kg elemental iron (FGF = 80mg per tab)V&D, abdo pain, shock

Desferrioxamine (doesn’t drop level but chelates)WBI

Methaemoglobinaemia Congenital or from nitrates/sulphonamidesCyanosis

Methylene blue 1%

Opioids naloxoneOrganophosphates AtropineSalicylates Early resp alkalosis (can miss this in kids), then

metabolic acidosis, tinnitus, vertigo, V&D, AMS, diaphoresis, normal pupilsZero order kinetics @ high dose

Supportive careCharcoal or lavage

TCAs MOA: inhibit 5-HT, norad reuptake. Muscarinic ACh blockade (anticholinergic sx), peripheral α-blockade, fast Na channel blockade (♥ probs)OD: coma, convulsions, cardiac arrhythmia (wide QRS), antichol sySE: dry mouth, blurred vision, constipation, urine retention, tachycardia, postural hypoTN, arrhythmia, sudden death, ↓sz threshold

Sodium bicarb (if QRS > 120)Charcoal if early

Lead poisoning Constitutional Sx, microcytic anaemia, headaches, AMS, comaBurton line: blue/black line on gumRenal tubular dysfunction↑serum lead leve, XR shows dense metaphyseal line

Chelation

Copper N&V, blue/green vomit Supportive careArsenic V&D, colic

From contaminated foodEosinophilia

Lavage, BAL

Mushrooms Short acting: V&D, salivation, sweating,

hallucinations, vision lossLong acting

Liver failure, renal failureLSD = ergot (fungus). Not addictive. Mydriasis, nausea, flushing ↑HR/temp

Supportive care

PCP Angel dustDissociativeCramps, diarrhoea, haematemesis, miosis

Gastroenterology Coeliac antibodies

IgA endomysial 88-100% sensitive (“moderate”)91-100% specific = most specific

IgA anti-TTG 92-100% sensitive (highly sensitive)91-100% specificHighly sensitive AND specificPresent in 98% of biopsy proven CDMOST USEFUL test for those >2yo, and correlates with mucosal damageBUT:

Disappears with treatment False + with IDDM, liver disease, heart failure

IgA anti-gliadin 52-100% sensitivity (poor)92-97% specificityNot recommended – neither sens/spec are great, and poor PPV

IgG anti-gliadin 73% sensitive45% specific: also found in CMPA, CD, tropical sprue

IgA anti-DGP 73% sens, 89% specAPPROACH Always check IgA to r/o IgA deficiency (independently assoc. with CD)

In kids, IgA anti-TTG is the most useful, can also check IgA endomysialIf positive biopsy (while ON gluten)If negative check HLA DQ2/DQ8 to try and RULE OUT CD. If these are positive, consider modified gluten challenge + duodenal biopsy

Gastroenterology notesProtein losing enteropathy Low IgG, IgA, IgM

Normal IgE d/t rapid turnoverFaecal osmolar gap serum osmolarity - [2 x (faecal sodium + potassium)]

normal = 50-100mosm/kgosmotic diarrhoea = FOG > 100secretory = FOG ≤ 100 (sometimes reported as <50)

estimate as 290 - [2x (stool Na + K)]

Autoimmune hepatitis ALT, AST ↑ 3-10X normal↑ SBR (mostly direct)HypergammaglobulinaemiaHypoalbuminaemia± haemolytic anaemia, thrombocytopenia, leukopeniaType 1:

ANA pos, SMA pos Better steroid sensitivity + prognosis Can cause acute liver failure

Type 2: ANA neg, SMA neg, LKM pos More chronic, more steroid dependent

Type 3: Seronegative ?Soluble liver antibody

Respiratory stuff

Alveolar gas equation = [FiO2 x [barometric pressure – water vapour pressure] – (pCO2/0.8)barometric pressure @ sea level = 760mmHgwater vapour pressure = 47mmHgusual pCO2 = ~40mmHg

A-a gradient Normal = 2.5 + 0.2xage (in years)Laryngomalacia Variable extrathoracicObstructive spirometry findings

FEV1↓FEV1:FVC ↓Scooped out curve (see below – emphysema)TLC ⓝ nless A1AT defRV ↑↑↑RV:TLC is > 30%FRC ↑DDx: asthma, bronchiectasis, BPD, trachea-bronchomalacia

Restrictive spirometry findings FEV1 & FVC ↓ in proportionFEV1:FVC ⓝ or ↑TLC < 80%, VC < 80% predRV ⓝ or ↓FRC ↓DDx: poor effort/technique, neuromuscular diseaseChest wall deformity, scoliosis, interstitial disease (e.g. bleomycin, idiopathic fibrosis)

Neuromuscular disease normal FRChigh RVlow TLCFEV1 is reduced in proportion to FVC ∴ FEV1/FVC ⓝMost sensitive tests of resp muscle strength = max insp and max exp pressure, measured while pt breathes against closed shutter

>7% ↓ in VC from sitting to supine could suggest that diaphragmatic weakness is out of proportion to chest wall weakness

Small airway obstruction Scooped out on topNormal shaped inspiratory loop, small & scooped out expiratory loop

Restrictive disease Very pointy d/t ↑ elastic recoil

Developmental Milestones

Hearing

U shaped audiogram: think SNHL (hereditary)

BELOW: TYMPANOGRAM INTERPRETATIONA = normalAD = ↑ compliance e.g. loss of ossicular chain continuityAS = stiff e.g. otosclerosisB = little mobility e.g. middle ear effusionC = negative pressure + retracted TM

PsychiatryNMS vs SS vs MHNeuroleptic malignant syndrome d/t D2 blockade or dopamine

insufficiency e.g. from antipsychotics, antiemetics (maxalone, Phenergan)

FEATURES:hyperthermiaautonomic stimulation: tachycardia, diaphoresisEPS: RIGIDITY, bradykinesiaarrythmiaseizures**Rhabdomyolysis**

↑CK

Mx:Dopamine agonist eg. Bromocriptine, levodopa

Serotonin syndrome - less severe hyperthermia + rigidity- nausea + diarrhoea- HYPERREFLEXIA- d/t SSRIs, tramadol, TCAs

Serontonin antangonists e.g. cyproheptadine

Malignant hyperthermia AD ryanodine ® mutation (C ach)Sustained release of intracellular Ca

Triggers; inhaled anaesthetics, depolarizing muscle relaxants (e.g. sux)

Rigidity incl. masseterRhabdomyolysisTachycardiaMet acidosisSux: fasciculation

Mx: dantrolene

NeonatologyMeconium aspiration Hyperinflated Asymmetrical coarse peri-hilar

markingsGBS pneumonia Low volumes Diffuse granular opacities ± pleural

effusion(looks like RDS + effusion)

Other neonatal pneumonia High lung volumes Patchy asymmetrical perihilar densities – looks like mec asp!

RDS/HMD Low lung volumes Ground glass opacitiesAir bronchograms

TTN Normal volumes Coarse interstitial markingsPulmonary oedema with promiment vascular markings