ID / Haem / Immuno / Allergies / Genetics Flashcards
Anaemia - cause categorization? Ix? Deficiency-related anaemia - causes & relevant deficiencies?
Hb normal range: 130-175
MCV normal range: 82-98
Categorization:
- MICROcytic - IDA, thalassaemia, anaemia of chr disease (can be normocytic)
- NORMOcytic - acute bleed, aplastic anaemia, mixed anaemia (micro & macro)
- MACROcytic - B12/folate def, alcohol excess, haemolytic anaemia
Ix: FBC
- Microcytic - haematinics (Fe profile), Hb electrophoresis (thalassemia/SCD Dx)
- Macrocytic - B12, folate, DAT test (AI haemolytic anaemia Dx)
Deficiency-related anaemia:
- Poor dietary intake - Fe, B12, folate
- Malabsorption (IBD) - Fe, B12
- Pernicious anaemia (AI parietal cell destruction -> don’t prod intrinsic factor -> escorts B12 to terminal ileum for absorption) - B12
- Crohn’s disease (most common in terminal ileum where B12 is absorbed) - B12
- Bleeding (GI, menstrual) - Fe
Multiple myeloma - def? pathophysiology? Spectrum of disease? Ix? Dx? Mx?
Def: cancer of plasma cells –> excessive monoclonal Ig prod
- Plasma cell dyscrasia (humoral immune dysfunction) – clonal plasma cell population –> proliferate –> monoclonal Ig light chains (in blood = paraprotein, in urine = Bence Jones protein)
-
Pathophysiology:
- Normally e.g. 5 different types of plasma cells produce 5 different types of Ig
- In MM - one type of plasma cell outcompetes the others so lots of 1 type of Ig produced
Spectrum of disease:
-
Multiple Myeloma:
- >1 focal lesion on MRI
- BM plasma cells >60%
-
End organ damage (1+ of CRAB(S)):
-
Calcium (>2.75) - high: lytic bone lesions –> release Ca into circulation
- NOTE: stones, bones, abdo groans, thrones, psychiatric overtones
- Renal (from excess Ig) – creatinine clearance <40ml/min OR creatinine >177
- Anaemia (Hb <100g/l) - BM supression
- Bone lesions (lytic)
- Signs of amyloidosis – damage from misfolded protein prod
-
Calcium (>2.75) - high: lytic bone lesions –> release Ca into circulation
-
Smouldering/asymptomatic myeloma
- Serum monoclonal protein >3g/dL
- BM plasma cells 10-60% in marrow
- NO end-organ damage (CRABS) BUT most progress to MM untreated
-
Monoclonal gammopathy of unknown significance (MGUS)
- Serum monoclonal protein <3g/dL
- Plasma cells <10% in BM
- No end-organ damage (CRABS)
- NOTE: 1-2% progress to MM, very common in elderly (if low risk – yearly bloods)
Dx: plasma cells on BF + Rouleaux cells
Ix: ESR, Ca, U&E, serum & urine electrophoresis (to identify an excess of one type of Ig = 1 large band)
- Electrophoresis (spike in gamma region, isolated IgG Kappa):
- Normally polyclonal bands, in myeloma = monoclonal band
- CD138= diagnostic
Mx:
-
MM:
- Young –> chemo followed by autologous SCT
- Old –> chemo followed by maintenance therapy
- Smouldering myeloma – treat
- MGUS – annual blood test
Myeloproliferative disorders - characteristics? causes? Mx?
ALL = tyrosine kinase disorder (JAK2)
Essential thrombocythemia
- High Pls: >450 (other causes of raise: acute inf, chr infl, malig (5-10%), polycythaemia rubra vera)
- JAK2 mutation in 55%
- Mx: aspirin to reduce stroke risk, hydroxycarbamide to lower pl count
Polycythemia vera
- _High RBC_s:
- Haematocrit >0.52 (M) /0.48 (F)
- Often thrombocytosis – high risk of thrombotic event (MI, stroke, Budd-Chiari - hepatic vein occlusion - triad = abdo pain/ascities/hepatomegaly)
- JAK2 mutation in 90%
- Causes:
- Primary: polycythaemia rubra vera
- Secondary: altitude, chr hypoxia (severe COPD, cyanotic HD), erythropoietin-secreting renal cancers (RCC)
- NOTE: secondary polycythaemia = no JAK2 mutation
- Presentation: itchy (pruritus) after shower, peptic ulcers (increased histamine)
- If very high RBC count –> hyperviscosity Sx, splenomegaly, thrombosis, gout
- Mx:
- Aspirin to reduce stroke risk, hydroxycarbamide to lower pl count, JAK-inhibitors e.g. ruxolitinib
- Venesection (removing blood –> lowers haematocrit)
Myelofibrosis
- decrease all myeloid cell lines: MASSIVE SPLENOMEGALY
- Clonal prolif of stem cells in BM –> cytokine release + fibrosis of BM –> pancytopenia
- Features:
- JAK2 mutation in 50%
- Pancytopenia
- Massive splenomegaly (extramedullary hematopoiesis)
- Dry tap – on BM aspiration
- Tear drop poikilocytes – on BF (leucoerythroblastic film)
- Mx: stem cell transplant = only cure, ruloxitinib (JAK inhibitor)
- NOTE: CML increases all myeloid cell lines (opposite)
Myelodysplastic syndromes
Dx? Characteristics? Ix findings? Prognosis?
Myelodysplastic syndromes (MDS)
- Pre-malignant BM failure/’early AML’ (<20% blasts; NOTE: >20% blasts = AML)
- All 3 myeloid cell lines can be affected (erythroid, megakaryocyte, granulocyte)
- Asymptomatic –risk progression–> AML
- Can be secondary to chemo
- Ix:
- Hyposegmented + hypogranular neutrophils
- Present w/ incidental pancytopenia, can have macrocytic anaemia (normal ferritin/B12/folate/erythropoietin –> suspicious of MDS)
- Prognosis: 30% progress to AML, risk assessed w/ IPSS score
Classical Hodgkin’s lymphoma - peaks when? presentation? histology? most common type? assoc inf? Mx?
- Peaks: young, older adults
- Presentation: localised LNs (freq mediastinal), B-symptoms (fever, WL, NS)
- NHL = multiple nodal sites
- Pain in LNs after alcohol
- Neck node “rubbery”
- Possibly assoc w/ EBV inf
- Histology: Reed-Sternberg cells (“Owl’s eye” inclusions) = Dx (only 1 needed)
- Other findings – eosinophils/macrophages, reactive fibrosis
- Dx markers: CD30/15
- Nodular sclerosing = most common type
- Mx: ABVD chemo + radiotherapy –> good prognosis –> sometimes SCT
MICROangiopathic haemolytic anaemia (MAHA)
- Haemolytic uraemic syndrome (HUS)
- Thrombotic thrombocytopenic purpura (TTP)
- Disseminated intravascular coagulation (DIC)
MICROangiopathic haemolytic anaemia (MAHA)
- Non-immune-mediated, small vessel disease, RBC breakdown
- Damage to endothelial BV lining –> fibrin deposition + platelet aggregation –> fragmentation of RBCs (Schistocytes)
- It is a mechanism NOT a disease
Haemolytic Uraemic Syndrome (HUS)
- Post-_diarrhoeal_ illness – do NOT give abx
- E.coli O157:H7 –> Shiga-like toxin can cause glomerular endothelial injury –> platelet plug forms (platelet consumption) –> shearing of blood vessels (MAHA) + reduced renal perfusion –> renal failure
- Can get type with complement factor H deficiency
- Diarrhoea in child –> triad:
- MAHA (features on peripheral blood smear e.g. schistocytes)
- Haemolysis signs - high LDH, low haptoglobins
- Thrombocytopenia
- acute renal failure (self-limiting in children)
- MAHA (features on peripheral blood smear e.g. schistocytes)
- Supportive Mx, anti-C5 Ab (ecluzimab)
TTP
- Pathophysiology:
-
vWF multimers are normally broken down by ADAMTS13 but in TTP Abs against this –> reduced ADAMTS13
- Causes: unknown, cancer, pregnancy
- Increased vWF multimers = very sticky –> attach to endothelium & platelet plug forms (platelet consumption) –> shearing of blood vessels (MAHA) + reduced end-organ perfusion (can happen anywhere) –> confusion (brain), renal failure (kidneys)
-
vWF multimers are normally broken down by ADAMTS13 but in TTP Abs against this –> reduced ADAMTS13
- Pentad: MAHA, thrombocytopenia, acute renal failure, NEURO Sx, fever
- Case: 40yrs, fever, headache, jaundice for 1wk, temp 39, confused
- Purpura, bleeding gums, haemoglobinuria
- Bilirubin & LDH high = MAHA
- Case: 40yrs, fever, headache, jaundice for 1wk, temp 39, confused
- Ab to metalloproteinase
- Supportive Mx - plasma exchange + FFP
DIC
- Trigger (sepsis, tumour, pancreatitis) –> increased exposure to Tissue factor –> factor 7 converted to 7a = coagulation cascade –> lots of miniclots formed throughout circulation - platelet & coagulation factor consumption
- Very bad bleeding, Low platelets, PT & aPTT low (all coagulation factors low), low fibrinogen
Myelodysplasia vs Myelofibrosis
In normal BM - stem cells –> differentiate & proliferate
Myelodysplasia - abn differentiation of myeloid progenitor cells
- Def: BM disorder resulting in pancytopenia AND production of functionally immature blood cells (essentially it is ‘early AML’, <20% blasts)
- Chemo is a RF
- Key facts:
- Pancytopenia (all 3 myeloid lines can be affected)
- 1/3 cases –> AML
Myelofibrosis
- Def: clonal BM disorder characterised by deposition of fibrous scar tissue (over time, less and less tissue in BM that can produce blood cells)
- Key facts:
- Pancytopenia
- Tear drop cells
- Dry tap (due to level of fibrosis)
- Massive splenomegaly (a site where body tries to compensate for low blood cell production in BM)
Hereditary haemorrhagic telangiectasia (HHT) - Def? Dx criteria?
Aka Osler-Weber-Rendu syndrome - AD condition characterised by multiple telangiectasias over skin & mucous membranes
- 20% cases spontaneous wo/ FHx
Dx criteria (2 = possible; 3 = definitive Dx):
- Epistaxis: spontaneous, recurrent nosebleeds
- Telangiectases: multiple @lips/oral cavity/fingers/nose
- Visceral lesions: GI telangiectasia, pulmonary (increased stroke risk)/hepatic/cerebral/spinal AV malformations (AVM)
- FHx: first-degree relative w/ HHT
Haematinics - constituents? interpretation?
Iron studies - constituents? interpretation?
Haematinics - serum B12, folate, Intrinsic factor, ferritin
- Low IF –> consider pernicious anaemia (cause of B12 def)
Iron studies - MCV, Fe, ferritin, TIBC, transferrin, transferrin saturation
- Low MCV, low Fe, low ferritin & high TIBC/transferrin –> IDA (iron def anaemia)
- Normal MCV, low Fe, high ferritin & low TIBC/transferrin –> consider Anaemic of chronic disease/haemoglobinopathy (SCD)
Coagulation screen - constituents? interpretation?
PT, aPTT, Fibrinogen - light blue test tube
- PT /INR measures extrinsic pathway (factor 7) and common pathway - measures overall clotting factor consumption as factor 7 rarely def in isolation
- Raised in liver disease, DIC, vit K def, Warfarin
- aPTT measures intrinsic pathway (factor 8/9/11) & common pathways
- Raised by same as above + intrinsic pathway issues:
- Haemophilia A (factor 8 def - X-linked recessive)
- Haemophilia B (factor 9 def - X-linked recessive)
- von Willebrand disease (as vWF pairs with factor 8)
- NOTE: antiphospholipid syndrome can cause high aPTT despite causing clots as inactivates phospholipid used in intrinsic pathway
- Raised by same as above + intrinsic pathway issues:
- DIC - PT & aPTT raised, fibrinogen & platelets low
Amyloidosis - def? types? Presentation? Ix? Mx?
Def: aggregates of proteins with fibrillar morphology & beta-pleated sheet structure depositing in body tissues
Types: occurs as a complication of other conditions
-
AA - serum amyloid A - chronic inflammation
- RFs:
- Inflammatory conditions (e.g. RA, psoriatic arthritis, ankylosing spondylitis, IBD esp. Crohn’s)
- Chr infections (bronchiectasis, TB, chr UTIs, osteomyelitis)
- RFs:
-
AL - Ig light chain - multiple myeloma
- RF: monoclonal gammopathy of undetermined significance (MGUS)
- ATTR - TransThyRetin - familial, wild-type (elderly)
Presentation:
- Purpura around the eyes, eyelid petechiae, enlarged tongue
- Carpal tunnel syndrome (bilateral)
- Peripheral neuropathy (not in AA) - symmetrical sensory loss of feet initially (temp, pain –> proprioceptive)
- Autonomic neuropathy (not in AA) - erectile dysfunction/orthostatic HTN, GI/urinary dysfunction
- Fatigue (amyloid cardiomyopathy/nephrotic syndrome), weight loss (cardiac/hepatic amyloidosis), dyspnoea on exertion (amyloid cardiomyopathy)
- Exam: proteinuria, high JVP + pitting oedema (from restrictive cardiomyopathy)
Ix:
- Serum & urine immunofixation (monoclonal protein in AL)
- Ig free light chain assay (abn kappa to lambda ratio in AL)
- FBC (anaemia), metabolic profile (hypoalbuminaemia, high ALP, low Ca)
- 24hr-urine collection (>3g/day = nephrotic syndrome)
Mx: treat underlying condition
Case:
- 45yrs, tingling in arms & legs, loss of balance
- Exam: loss of vibration sense in both feet
- Ix: macrocytic anaemia, gastric antrum biopsy - achlorhydria & atrophic gastritis
Dx? Presentation? Ix? Mx?
Dx: pernicious anaemia aka atrophic gastritis/AI gastritis
Presentation: >60yrs, female
- Subacute combined degeneration of spinal cord from B12 def:
- Weakness, lethargy
- Paraesthesia, difficulty ambulating
- Ataxia, shuffling gait, decreased proprioception, decreased vibration sense
- Memory loss, irritability, depression, dementia
- Exam: koilonychia, macroglossia
- Assoc w/ AI conditions e.g. Hashimoto’s thyroiditis
- Risk of gastric adenocarcinoma
Ix:
- Bloods:
- FBC, haematinics (megaloblastic anaemia from B12 def), increased serum gastrin (increases PUD)
- Abs: anti-IF (60% but more specific) & parietal cell abs (90% but can be normal variant)
- Imaging:
- Biopsy of corpus/fundus stomach (absence of parietal cell-containing oxyntic glands, achlorhydria, atrophic gastritis) + intra-gastric pH (ph>6 @rest rules out Dx)
Mx:
- If PUD with H. pylori –> triple therapy (PPI + 2abx)
- Replace deficiency (Fe, B12, Ca/Vit D)
Sickle cell crisis - Mx?
ACUTE (PAINFUL CRISES)
- Oxygen
- IV Fluids
- Strong analgesia (IV opiates)
- Antibiotics
- Cross match blood
- Give transfusion if Hb or reticulocytes fall sharply
Blood transfusion reactions - Immediate? Delayed?
Immediate (<24hrs):
- Immune:
- Acute haemolytic transfusion reaction (ABO incompatibility)
- Anti-A/B abs activating complement pathway –> inflammatory cytokine release
- Features:
- Early - fever, low BP, anxiety, red urine
- Late - low BP, widespread haemorrhage secondary to DIC
- Transfusion-related acute lung injury (TRALI)
- Donor abs against recipient HLA antigens (neutrophil, leukocyte)
- Within 6hrs - sudden dyspnoea, severe hypoxemia, low BP, fever
- Resolves with supportive care within 2-4 days
- Anaphylaxis - allergic to protein components in donor transfusion
- Itchy rash, angioedema, SoB, vomiting, lightheaded, low BP
- Acute haemolytic transfusion reaction (ABO incompatibility)
- Non-immune:
- Bacterial infection
- Transfusion-associated circulatory overload (TACO)
- Acute/worsening resp compromise/pul oedema up to 12hrs post-transfusion
Delayed (>24hrs):
- Immune:
- Delayed haemolytic transfusion reaction (DHTR)
- Abs to antigens e.g. Rhesus/Kidd
- 3-13 days post-transfusion
- Sudden drop in Hb, fever, jaundice, haemoglobinuria
-
Febrile non-haemolytic transfusion reaction (FNHTR)
- Abs against donor leukocytes/HLA antigens
- Fever during transfusion, no haemolysis
- Normally if received multiple transfusions/women with multiple pregnancies
- Post-transfusion purpura (PTP)
- Adverse reaction to blood/platelet transfusion when body produces allo-abs to introduced platelets’ antigens –> destroy patient’s platelets –> thrombocytopenia
- 5-12 days post-transfusion
- Graft versus host disease (GvHD)
- After receiving transplanted tissue from a genetically different person
- WBCs in donated tissue (graft) recognise recipient as foreign –> attack host cells
- Can also occur in blood transfusion if blood has not been irradiated/treated with approved pathogen reduction system
- Delayed haemolytic transfusion reaction (DHTR)
- Non-immune:
- Viral infection
- Malaria
- Prions
Treatment of high INR on Warfarin? Target?
- Any bleeding: stop Warfarin AND IV vit K slowly
- If major bleed = ADD dried PCC/FFP
- INR @24hrs –> continue Tx if INR high, continue Warfarin when INR <5
- INR >8: stop Warfarin AND oral Vit K
- INR @24hrs –> continue Tx if INR high, continue Warfarin when INR <5
- INR 5-8: miss dose of Warfarin –> reduce maintenance dose
Target: 2.5 (2-3 range)
Viral families and relevant conditions
Key factors of infectious diseases
Typhoid fever - salmonella typhi
* 7-14d post-ingestion rising fever dropping by subsequent morning, 1st wk - GI Sx, 2nd wk - spenomegaly, 3rd wk - abdo distension +/- ‘pea soup’ diarrhoea
* Ix: blood culture (bone marrow aspirate culture best but painful)
Schistosomiasis - schistosoma flatworm (snail) - FRESH WATER exposure in endemic area
Amoebiasis - entamoeba histolytica - amoebic liver abscess most common manifestation
* Ix: abdo US
* Tx: metronidazole
Toxoplasmosis - toxoplasma gondii (cat)
* self-limmiting flu-like illness unless IS e.g. AIDS CNS involvement
Conditions associated with HIV
Burkitt’s lymphoma - high-grade B-cell non-Hodgkin’s lymphoma (fast & aggressive)
* Types: 1) endemic (africa) - children, chr malaria/EBV, commonly affects jaw 2) sporadic (outside africa) - affects ileocaecal region 3) Immunodef-assoc (HIV/drugs) - presents more advanced
Cryptococcosis - opportunisitic fungal inf with cryptococcus neoformans - lungs primary inf site with extrapul disemination e.g. meningoencephalitis
* Ix: LP - india ink
* Tx: oral fluconazole, if severe - amphotericin-B + flucytosine -> fluconazole
Cryptosporidiosis - protozoa cryptosporidum - watery diarrhoea
* Dx: stool oocytes + acid-fast staining/direct immunofluorescence
* Tx: nitrazoxinide (if IC >1yr), ART
Histoplasmosis - fungus histoplasma capsulatum
* Soil with bird/bat droppings - assoc with cave exploration, chicken roosts, demolition/excavation etc.
* Tx: amphotericin if severe pul infection
Pul TB - caused by mycobacterium TB
* Commonly lungs but can affect any organ system
* LEADING PROBLEM in HIV
* Tx: multiple abx as in non-HIV TB (isoniazid, rifampicin, pyrazinamide, ethambutol) but often more complex
Toxoplasmosis - toxoplasma gondii (cat)
* self-limmiting flu-like illness - life-long infection asymptomatic unless IS –> reactivation e.g. AIDS CNS involvement
* Tx: pyrimethamine + sulfadiazine + leucovorin
Inherited Immune deficiency examples
Selective IgA deficiency - lack of IgA - normally protects against inf at mucuous membranes (mouth/airways/digestive tract)
* MOST COMMON primary ab deficiency 1:300
* Increased freq of infections
* No Tx, body can develop immune response against IgA -> anaphylaxis to blood transfusion/IVIG
Severe combined Immunodef (SCID) - life-threatening recurrent inf, diarrhoea, dermatitis, failure to thrive
* Reduced number/function T-cells/B-cells/natural killer cells
* Presents <3months with mucocut candidiasis/bacterial otitis media/pneumonia/viral infection
* Tx: isolation, good hygeine, BM/stem-cell reconstitution
Hereditary angioedema - low plasma protein C1 inhibitor (C1-INH)
* Unchecked activation of classic compliment pathway
* Tx: acute - C1-INH concentrate of FFP, prophylaxis - danazol & TXA
How do you confirm anaphylaxis with blood test?
Anaphylaxis Mx (acute & chronic)
ABCDE
- Stop suspected cause
- Secure airway, give 100% oxygen, +/- intubate if respiratory obstruction imminent
- IM 0.5mg adrenaline (1:1000)
- Treat bronchospasm – salbutamol +/- ipratropium
Going forward:
- Maintain fluids + monitor pulse oximetry, ECG and BP
- If still hypotensive, may need transfer to ICU and an IVI of adrenaline (1mg/ml 1:1000 in 100ml NaCl - 0.5-1ml/kg/hr) +/- aminophylline (bronchodilator) and nebulised salbutamol
After acute episode:
- Admit to ward and monitor ECG, monitor for 6hrs for biphasic reaction
- Measure mast cell tryptase 1-6 hours after = confirm anaphylaxis
- Continue chlorpheniramine
- Suggest MedicAlert bracelet with name of culprit allergen
- Teach about self-injected adrenaline & give auto-injector
- Skin prick tests showing specific IgE to help identify allergens to avoid
Haem malignancy buzzwords
ALL - Testicular swelling, 3-5yrs
AML - Auer rods
CML - Philadelphia chr, t(9;22), BCR-ABL1, left shift
- Tx: Imatinib (BCR-ABL tyrosine kinase inhibitor)
CLL - Smear/smudge cells
Polycythaemia vera - JAK2 mut, high haematocrit, flushed appearance, strokes/budd chiari
Essential thrombocythemia - High platelets, strokes, ± JAK2 mut
Myelofibrosis - Dry tap, teardrop cells (poikilocytes), massive splenomegaly
Hodgkin’s lymphoma - Painful LNs w/ alcohol, Reed-Sternberg cells, EBV
Follicular lymphoma - t(14;18), centroblasts
Mantle cell lymphoma - t(11;14), mantle cells
Burkitt’s lymphoma - t(8;14), starry sky appearance, EBV, HIV
Myeloma - CRAB, bence jones protein, IgG/A >30
MGUS - NO CRAB, paraprotein <30
ALL - associated with what gene? Presentation? Ix? Mx?
ALL
- BCR-ABL1 t(9;22) assoc w/ 20-30% ALL in adults –> this genetic mutation also causes CML
-
Child Hx: 2-5yrs
- Hepatosplenomegaly
- Bone pain/limp
- Fevers, CNS Sx
- Testicular swelling (rare but specific)
- Adult Hx: like AML, lymphadenopathy
-
Investigations:
- Bloods - thrombocytopenia, anaemia, high WCC (blasts/lymphocytes)
- NOTE: circulating blasts = normal
- Blood film – high nucleus: cytoplasm ratio, can’t differentiate betw/ ALL/AML on BF
- Dx - BM + flow cytometry:
- TdT+
- CD19/22 = B cells (common)
- CD2/3/4/8 = T cells
- Bloods - thrombocytopenia, anaemia, high WCC (blasts/lymphocytes)
- Management (adults and children similar aim):
- Induction –> consolidation –> maintenance –> remission
- Covering all these stages = transplant ±novel targeted therapies (+ CAR T-cell therapy)
AML - Hx? Ix? Mx? AML vs CML difference on Ix?
-
Hx:
- Incidence increases w/ age
- Pre-existing myelodysplastic syndrome (MDS)
- Cytopenia Sx
- NOTE: AMML causes gingival hypertrophy (MM looks like gums)
-
Investigations:
- Bloods – anaemia (BM suppression), high WCC (neutropenia, excess circulating blasts), thrombocytopenia (BM suppression), only abnormal INR if DIC from acute promyelocytic leukaemia
- Blood film – single Auer rod = Dx, if none –> flow cytometry – MPO expression pattern
- Management:
- T(15;17) acute promyelocytic leukaemia – presents w/DIC, good prognosis, ALL-trans retinoic acid (ATRA) – causes cells to differentiate/stop prolif
- Others: manage like ALL, poor prognosis esp in elderly (can’t tolerate stem cell transplant
- AML VS CML- Basophils in CML
CML - gene associated? Hx? Ix? Disease phases? Mx?
- Most assoc w/ Philadelphia chromosome – BCR-ABL1 fusion gene from translocation of t(9;22) –> detected w/ FISH
- Hx/exam:
- Age 35-55yrs
- LUQ pain (from splenomegaly)
- Asymptomatic if Dx in chr phase ± lethargy, fever, night sweats
- Sx of acute leukaemia if in accelerate/blast phase (10%)
- Investigations:
- Bloods: raised basophils (specific), high WCC (neutrophilia), 50% thrombocytosis, low monocytes (high = CMML), unlikely sign anaemia (can be), precursor cells on blood differential (promyelocytes/myelocytes)
- High WCC causes:
- Acute bact inf (high neutrophil: lymphocyte ratio)
- Acute viral inf (low neutrophil: lymphocyte ratio BUT COVID-19 –> lymphopenia)
- Fungal/parasitic (high eosinophils)
- Monocytosis (in TB, endocarditis, inflame conditions)
- High WCC causes:
- Bloods: raised basophils (specific), high WCC (neutrophilia), 50% thrombocytosis, low monocytes (high = CMML), unlikely sign anaemia (can be), precursor cells on blood differential (promyelocytes/myelocytes)
- Features:
- Left shift – precursor cells present
- High WCC, eosinophilia, basophilia
- Hypo-lobated megakaryocytes – in BM
- Disease phases:
- Chr (90%)
- Accelerated (increased blasts in BM, poor Tx-response, additional chromosomal abn)
- Blast phase (>20% blasts in BM, behaves like acute leukaemia)
- Management:
- Chronic phase –> Tyrosine kinase inhibitors – 1st gen = Imatinib (2nd gen – Dasatinib/Nilotinib/Bosutinib, 3rd gen – Ponatinib)
- >90% 10yr survival –> small % need transplants
- Blast phase – Tx similar to AML (allogenic SCT for young)
CLL - presentation? Ix? Mx?
- Presentation:
- Asymptomatic – routine bloods
- >50yrs (incidence increases w/ age), X2 M>F
- Possible LNs/splenomegaly
- ITP (immune-mediated thrombocytopenic purpura)/haemolytic anaemia
- Investigations:
- Bloods: only anaemia if aggressive/haemolytic anaemia, high WCC (>100, mature lymphocytes)
- BF: smear cells/smudge cells, lymphocytosis
- Dx: flow cytometry – Kappa/Lambda light chains
- Mostly B cell CLL (but can be T cell)
- Same pathology as small lymphocytic lymphoma BUT different distribution (blood/BM Vs LNs)
- B-cells CD5 +ve (normal mature B-cells CD5 -ve), CD38 +ve = poor prognosis
- Immunoglobin gene mutations: IgH unmutated = worse prognosis
- FISH – 17p gene deletion (TP53 – contains p53 tumour suppressor gene) gene deletion –> worse prognosis
- Management:
- Staging:
- A – no cytopenia, <3 areas lymphoid involvement –> W&W
- B – no cytopenia, ≥3 areas lymphoid involvement –> consider Tx
- C – cytopenia –> TREAT
- BCL-2 inhibitors (Venetoclax) – allows the normal apoptosis of B-cells
- BCR-tyrosine kinase inhibitors (ibrutinib, idelalisib)
- CAR T-cell therapy (for B cell cancers e.g., B-cell lymphoma)
- NOTE: all very expensive
- Richters syndrome – transformation of CLL –> aggressive disease (ALL/high grade lymphoma)
- Staging:
Common chromosomal abnormalities
Down’s - trisomy 21 (most common trisomy)
* Epicanthic folds, protruding tongue, hypotonia, congenital heart defects, learning disability
Edwards - trisomy 18 (2nd most common trisomy, 80% female)
* Rocker bottom feet, microcephaly, low-set malformed ears, cleft lip
Patau’s - trisomy 13 (3rd most common trisomy)
* Most don’t survive to term - 80% congenital heart defects, holoprosencephaly - brain doesn’t divide into halves -> midline facial defects
Klinefelter’s - XXY
* Tall, gynaecomastia, infertile, behavioural problems
Turner’s - X
* Short, gonadal dysgenesis (prim/secondary amenorrhoea), lymphoedema
Fragile X - mutated FMR1 on X-chr
* Learning difficulties - delayed milestones
* Facial asymmetry - high forehead, long face, large jaw, long ears
* Large testes
Williams - chr 7 deletion (rare AD)
* ‘Elfin’ facial features, cardiac defects, learning disability
What is Peutz-Jeghers Syndrome? What are some differentials?
AD condition (chr 19) - pigmented lesions on buccal mucosa + GI polyps –> increased risk of intestinal cancer
* Normally Dx in early 20s with bowel obstruction from intussuception
Gardner syndrome (familial colorectal polyposis, AD) - multiple polyps in colon + tumours outside colon
Juvenile polyposis syndrome - multiple polyps in child GI tract - most benign but increased risk of adenocarcinoma
Familial adenomatous polyposis (AD, chr 5 - APC gene) - large intestine benign polyps transforming into malignant if not Tx
HIV - Acute worsening of inf after starting ART?
IRIS
HIV - Reduced visual acuity + “perivascular infiltrates”
CMV retinitis
HIV - odynophagia + “white mucosal plaques” at endoscopy
oesophageal candidiasis
Desaturation on exertion in HIV?
Pneumocystis jirovecii pneumonia
HIV - Brain MRI with “ring-enhancing lesions”?
toxoplasmosis encephalitis
HIV - Violaceous plaques + HHV8
Kaposi sarcoma
STI causes of genital ulcer - DDx?
Syphilis Tx? Name of immune reconstitution reaction? Ix?
Tx:
- Neurosyphilis –> IV aqueous benzylpenicillin 10-14 days
- Latent syphilis –> IM Benzathine benzylpenicillin STAT
- Otherwise –> IM Benzathine benzylpenicillin x3/2wks
Jarisch-Herxheimer reaction - acute febrile illness in 1st 24hrs post-Tx
- Acute headache, fever, myalgia
Ix:
- Lesion present - dark field microscopy (coiled spirochaete bacterium with corkscrew appearance with motility)
- Otherwise - Treponema serological testing (+ve active & past)
Painless ulcer, painful unilateral inguinal LNs and proctocolitis?
Lymphogranuloma venereum (LGV)
Painful ulcer + LNs
Chancroid
TB drug SEs?
TB Ix?
TB Tx durations?
Malaria Def? Ix? Tx?
Cause: plasmodium protozoa -> paroxysmal fever
Def:
* ≥10% RBCs infected
* ≥1 sign of severe disease
Ix: thick & thin blood film
Mx:
* Non-severe: oral artemisinin based combo therapy (ACT)
* Severe: artemisinin derivative IV followed by oral ACT
General malaise, relative bradycardia & rose spots?
salmonella typhi
Fever, headache, retro-orbital pain, myalgia & rash
Dengue
“Bull’s eye rash” - erythema chronicum migrans
Lyme disease
Proctitis + Lymphadenopathy + unprotected anal sex with male partner - Dx?
Lymphogranuloma venereum
STI types? Ix? Mx?
-
Chlamydia (Chlamydia trachomatis) – obligate intracellular G-ve (can’t be cultured on agar)
- Classification: Serovars A-C = trachoma; D-K = genital, ophthalmia neonatorum, L1-3 = Lympho-granuloma venereum (LGV)
- Ix: genital swab/urine sample (FCU) –> NAAT
- Mx: Azith 1g STAT/Doxy 100mg BD 7 days
- Complications: PID (infertility/ectopic/chr pain)
-
Gonorrhoea (Neisseria gonorrhoeae) – obligate intracellular G-ve diplococcus
- Ix: swabs/urine sample –> culture
- Mx: ceftriaxone 250mg IM STAT
-
Syphilis (Treponema pallidum) – obligate G-ve spirochaete
- Ix: dark-ground microscopy (from primary lesions)
- Ab non-treponemal tests (non-specific antigens): VDRL, RPR (false positives common, declines with treatment)
- Ab treponemal tests (specific antigens): EIA/FTA/TPHA/TP-PA (confirmatory, +ve for years despite treatment)
- Mx: IM Ben Pen STAT
- Ix: dark-ground microscopy (from primary lesions)
- Genital ulcers:
- Painful = herpes > chancroid
- Painless = syphilis > lymphogranuloma venereum (LGV) + granuloma inguinale
What eye condition are you at risk of if you have herpes zoster opthalmicus? What is Hutchinson’s sign? Tx?
Anterior uveitis
Hutchinson’s sign: vesicles extending to the tip of the nose. This is strongly associated with ocular involvement in shingles
Oral antivirals ± steroids
- If eye involvement –> urgent ophthalmological review
- Eye lubricant if blink reflex affected to prevent damage to corneal epithelium
Candidiasis Mx?
Miconazole
Fluconazole if invasive oesophagitis (difficulty swallowing)
HIV eye conditions in low CD4?
- With visual blurring & flashing lights - Dx? Tx?
- Pain, rapid loss of vision in 1wk - Dx?
- Also oral lesions - Dx?
CMV retinitis (very common pre-ARTs)
- Painless blurring, floaters
- Fundoscopy: yellow-white exudates + haemorrhages on back of retina
- Tx: valganciclovir
HSV
- Pain, rapid loss of vision in 1wk (acute retinal necrosis)
- Fundoscopy: peripheral lesions
Candida - oral lesions
HIV +ve, fevers, frontal headaches (around eyes), seizure, low CD4
CT has ring-enhancing lesions
DDx?
DDx:
- Toxoplasmosis - cat faeces, commonest CNS inf in HIV, flu-like illness, eye & basal ganglia involvement
- Primary CNS lymphoma
NOTE: PML - non-enhancing lesions in white matter (JC virus)
Infectious disease + rash DDx?
Viral
-
Measles
- Maculopapular rash over hairline/forehead/behind ears, spreading downwards.
- Koplik spots - white papules on buccal mucosa
-
Rubella
- Erythematous maculopapular rash on face –> spreads to extremities
- Tender lymphadenopathy
-
Infectious mononucleosis (EBV)
- Morbilliform rash, pharyngitis, fatigue, myalgia
- Hepatosplenomegaly, lymphadenopathy
Bacterial
-
Meningococcal disease
- Meningism + non-blanching rash
-
Scarlet fever
- Group A beta-haemolytic strep
- Erythema of axilla/neck/chest –> progress to pink papules on erythematous background –> 7-10 days later = hand/foots desquamation
- Pastia’s lines (linear petechial streaks in body folds), red strawberry tongue
- Ix: clinical +/- Anti-streptolysin O titre
- Mx: penicillin
Allergic contact dermatitis is an example of what type of hypersensitivity?
Type 4
See table for more types
40 yr old male patient bitten by his dog while on a walk through his farm with newly laid manure. Hx 5 doses tetanus vaccine last dose over 10 yrs ago. How to Mx?
Tetanus-prone wound (req surgical intervention delayed >6hrs, sig devitalised tissue/puncture wound contaminated soil, foreign body, compound fracture, sepsis)
Tx: Immediate reinforcing dose of vaccine and 1 dose human tetanus Ig at different site
What is G6PD deficiency?
X-linked -> haemolytic crisis after oxidant stress (viral/bacterial illness, sulfa/quinines, fava beans)
* Hb denaturated -> Heinz bodies
What is the concern post-splenectomy?
Encapsulated bacteria - SHiN KiS
* Strep pneumo & GBS
* Haemophilus influenzae type B (HiB)
* Neisseria meningitides
* Kleb pneumo
* Salmonella typhi
Vaccines 2wks post-surgery (pneumococcal, HiB, meningococcal, influenza)
Preventative abx in some - oral phenoxymethylpenicillin OD
Inborn errors of metabolism key conditions
Single gene defects block metabolic pathway
* Neonatal screening best way of detecting with heel prick test - day 5-8 (PKU, CF, congen hypothy, SCD, medium-chain acyl-CoA dehydrogenase def (MCADD), maple syrup urine disease (MSUD), homocystinuria, glutaric acidaemia T1 (GA1), isovaleric acidaemia)
Defects in amino-acid metabolism (AR)
* Phenylketonuria - learning disability, very fair + blue eyes
* MSUD - encephalopathy/prog neurodegen + ‘sweet’ urine/sweat smell
* Homocystinuria - CNS/MSK/CVS disorder in childhood
* GA1 - movement disorder by 2yrs -> Tx w/ diet
* Isovaleric acidaemia - toxic to CNS - some present in first days of life/others during childhood by inf/protein-rich food with vom/seizures = sweaty feet smell
* Hartnup disease - mostly asymptomatic but episodic neuro/derm Sx assoc w/ trigger (sunlight, fever, poor nutrition, exercise, sulfonamides)
Defects in lipid metabolism
* MCADD - inability to generate energy during high-demand (can cause hypoglyaemia/hepatic encephalopathy/death) -> preventative Tx
* Others
Galactosaemia - can’t breakdown galactose into glucose -> cataracts, hepatosplenomegaly, interlectual-disability - presents in milk-fed infants shortly after birth
Lesch-Nyhan syndrome - X-linked def - causes self-mutilation = lip/finger biting
Porphyrias - def enzymes in haem synth e.g. acute intermittent porphyria (AD) - attacks of abdo pain, GI dysfunct, neuro disturbance
Paroxysmal nocturnal haemoglobinuria overview
X-linked mutation in haematopoetic stem cells - def in GPI protein (anchor protein moieties to erythrocyte surface) - responsible for CD55/59 deactivation -> chr complement-mediated haemolysis of PNH cells (worsened if stress e.g. surgery, trauma, inflam)
Presentation:
* Haemolytic anaemia (haemoglobinuria) - dark brown first thing in morning, urine dip = bl+ (not RBC on microscopy)
* Thrombosis - hepatic/abdominal/cerebral/subdermal veins (VTE most common cause of death)
* Deficient haematopoiesis - SoB on exertion, fatigue. Neutropenia/thrombocytopenia can cause infection/purpura
NOTE: also Sx assoc w/ smooth-muscle dysfunction e.g. oesophageal dysfunction - resolve over day. Can have errectile dysfunction.
Ix: flow cytometry - blood CD55/59
Mx:
* Blood transfusion as required
* Meningococcal vaccine
* Eculizumab - prevents activation of C5
* Anticoag (reduce risk of thrombosis if not on eculizumab)
* Pred (reduces haemolysis)
* Bone marrow transplant currative (Tx-related toxicity is an issue)
- Give examples of live vaccines
- What vaccines contain egg?
- BCG, MMR, Varicella, Rotavirus, Nasal flu, Yellow fever, oral typhoid
- MMR (can still give if allegic under supervision), Influenza, Yellow fever
Cytochrome P450 inducers & inhibitors
