Path Flashcards
HLA Class II Molecules
HLA-DR
HLA-DP
HLA-DQ
HLA Class I Molecules
HLA-A
HLA-B
HLA-C
HLA Matching in Organ Donation
Clinically most important
HLA-A
HLA-B
HLA-DR
Score in series e.g. 0:0:0
Would no mismatches across HLA-A, HLA-b and HLA-DR between recipient and donor
As two alleles from each, opportunity to match 6 alleles
Maximum of 6 mismatches (MM)
6 MM= bad
0 MM = good
Sibling to sibling:
25% - 6MM
50% - 3MM
25% - 0MM
HLA matching is an important part of organ allocation procedure
Bone marrow
Kidney
HLA matching not as important (Size is more important)
Heart
Lung
T Cell Mediated Transplant Rejection
T cell mediated
Phase 1 - Recognition
Acute Rejection
Direct: donor APC presents to recipient CD8 or CD4 T cell which recognises APC as foreign and leads to destruction
Chronic Rejection
Indirect: Indirect is recipient APC finding a foreign protein (HLA molecule) and presenting to immune system
Phase 2 - T cell activation by foreign antigen
First signal is the inetreaction of APC with the T cell receptor
Second signal is co-stimulatory signals that enhance T cells activation
Third signal is when activated T cell produces cytokines, IL-2 autocrine effect
Phase 3 - Effector cells Recruited all the immune cells They recognise the HLA molecule as foreign Infiltrate organ Cause damage to the organ Produce lytic enzymes Direct cytotoxicity Antigen-dependent cell mediated cytotoxicity
Graft infiltration by alloreactive CD4+ cells Cytotoxic” T cells Release of toxins to kill target Granzyme B Punch holes in target cells Perforin Apoptotic cell death Fas -Ligand
Macrophages Phagocytosis Release of proteolytic enzymes Production of cytokines Production of oxygen radicals and nitrogen radicals
Symptoms of acute T-cell mediated rejection
Deteriorating graft function
Kidney transplant: Rise in creatinine, fluid retention, hypertension
Liver transplant: Rise in LFTs, coagulopathy
Lung transplant: breathlessness, pulmonary infiltrate
Pain and tenderness over graft
Fever
Antibody Mediated Rejection
Phase 1 – exposure to foreign antigen
Phase 2 - proliferation and maturation of B cells with antibody production
Phase 3 – effector phase; antibodies bind to graft endothelium (capillaries of glomerulus and around tubules, arterial)
Antibodies
Anti-A or anti-B antibodies are naturally occurring
Anti-HLA antibodies are not naturally occurring
Pre-formed – previous exposure to epitopes (previous transplantation, pregnancy, transfusion)
Post-formed - arise after transplantation
Path
Endothelium with foreign HLA antigens
Antibody against epitope on ENDOTHELIUM
Recruit complement
Complement is activated
(can detect complement for diagnosis on biopsy)
Cause formation of membrane attack complex –> cell lysis
Also liberate C3a and C5a –> potent chemotactic
Recruit inflammatory cells directly to the endothelium through the Fc receptors on macrophages and NK cells and polymorphs
Histology of T and B cell rejection
In T cell
Heavy monocytic infiltrates
In B cells
Discrete accumulation of inflammatory cells including polymorphs
Stain for complement
Prevention and Treatment of Transplant Rejection
Preventing rejection:
A. AB/HLA matching
B. Screening for anti-HLA antibodies
Before transplantation
At time of transplantation: when a specific deceased donor kidney has been assigned to the patient
After transplantation, repeat measurements to check for new antibody production
3 main types of assay
Cytotoxicity assays
Flow cytometry
Solid phase assays
C. Immunosuppression: dampen the immune system of the recipient
Induction agent ex. OKT3/ATG, anti-CD52, anti-CD25
Base-line immunosuppression: CNI inhibitor + MMF or Aza, with or without steroids = calcineurin inhibitor (cyclosporine) and anti-proliferative drug (micophenolate)
Treatment of episodes of acute rejection:
Cellular: steroids, ATG/OKT3
Antibody-mediated: IVIG, plasma exchange, anti-C5, anti-CD20
Always balance the need for immunosuppression with the risk of infection/malignancy/drug toxicity
Graft vs Host Disease
Eliminate hosts immune system (total body irradiation; cyclophophamide; other drugs)
Replace with own (autologous) or HLA-matched donor (allogeneic) bone marrow
Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues
Related to degree of HLA-incompatibility
Also graft-versus-tumour effect
GVHD prophylaxis: Methotrexate/Cyclosporine
Preparative regimen for haematopoietic transplant has a role to play in developing graft vs host disease
Injury in recipients GI tract
Helps to prone donor T cells
Form immune reaction against recipients tissue
Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool
Liver: jaundice
Treat with corticosteroids
Post transplantation infections
Bacterial, viral, fungal
Opportunistic
Cytomegalovirus
BK virus
Pneumocytis carinii
Post-transplantation Malignancy
Viral associated (x 100) Kaposi’s sarcoma (HHV8) Lymphoproliferative disease (EBV)
Skin Cancer (x20)
Risk of other cancers eg lung, colon also increased (x 2-3)
Causes of microcytic Anaemia
FAST Fe Iron deficiency anaemia Anaemia of chronic disease Sideroblastic anaemia Thalassaemia
Faecal calprotectin
Marker of GI inflammation
Produced by neutrophils
Coeliac Disease HLA associations
HLA-DQ2
HLA-DR8
Histopathological Changes in Coeliac Disease
Villous height is reduced and crypts become hyperplastic, resulting in reduced or reversed villous: crypt ratio
Although height of villi are reduced, mucosal thickness remains the same due to crypt hyperplasia
Villous atrophy results in decreased surface area –> malabsorption
Increased to >20 IELs/100 epithelial cells
These lymphocytes are 𝛄ƍ T cells
Causes of Increased Intra-epithelial lymphocytes
Coeliac Disease Dermatitis herpetiformis Cows milk protein sensitivity IgA deficiency Tropical sprue Post infective malabsorption Drugs (NSAIDs) (Lymphoma)
Causes of Villous Atrophy
Coeliac Giardiasis Tropical sprue Crohn’s disease Radiation/chemotherapy Bacterial overgrowth Nutritional deficiencies Graft versus host disease Microvillous inclusion disease Common variable immunodeficiency
Complications of Coeliac Disease
Malabsorption
Osteomalacia and osteoporosis (bone scan every 3 years)
Neurological disease
Epilepsy
Cerebral calcification
Lymphoma
Hyposplenism
Positive Anti-TTG on gluten free diet
The TTG antibody should be negative
It can only be positive in two cases:
Not sticking to gluten free diet
Developed lymphoma
Coeliac Associated Conditions
Dermatitis herpetiformis (prevalence = 100%)
Type 1 diabetes mellitus (prevalence = 7%)
Autoimmune thyroid disease
Down’s syndrome
Recombinant Cytokines
IFN-alpha
Hepatitis C
Hepatitis B
Kaposi’s Sarcoma (HHV-8)
IFN-gamma
Chronic granulomatous disease
T Cell Inhibiting APC
T cell expresses CTLA4, binds to CD80/CD86 on APC
Transmits inhibitory signal
Iplimumab
Block CTLA4 (inhibitory signal from T cell --> APC) Leading to great T cell response
Indications
- Advanced melanoma
APC inhibiting T cell
PD-1 is expressed on T cells
PD-1 Ligand expressed on APC
APC causes inhibition of T cell
PD-1 also expressed on some malignant cells
Pembrolizumab and Nivulomab
Antibody binds to PD-1
Blocks immune checkpoint
Allows T cell activation
Indications
Advanced melanoma
Corticosteroids
Reduces prostaglandin synthesis
Corticosteroids inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation
Inhibits phagocyte migration and function
Decreased traffic of phagocytes to inflamed tissue
Decreased phagocytosis
Decreased release of proteolytic enzymes
Inhibits lymphocyte proliferation
Sequestration of lymphocytes in lymphoid tissue
Affects CD4+ T cells > CD8+ T cells > B cells
Blocks cytokine gene expression
Decreased antibody production
Promotes apoptosis
Cytotoxic Anti-Proliferative Drugs
Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate
Inhibit DNA synthesis –> affect rapidly dividing cells
Toxicity Bone marrow suppression Infection Malignancy Teratogenic
Cyclophosphamide
Alkylates guanine base of DNA
Damages DNA –> prevents cell replication
Affects B cells > T cells
Indications: Multi-system connective tissue disease/vasculitis with severe end-organ involvement
SLE, Granulomatosis with polyangiitis,
Side Effects
Toxicity to proliferating cells (bone marrow, sterility)
Haemorrhagic cystitis
Malignancy (Bladder, haematological, Non-melnoma skin)
Infection: PCP
Azathioprine
Metabolsied by liver
Azathioprine –> 6-mercaptopurine
6-mercaptopurine blocks de novo purine synthesis –> inhibits DNA replication
Preferentially inhibits T cell
Indications
Transplant
Autoimmune
Autoinflammatory disease (IBD)
Side Effects
Bone Marrow Supression (1 in 300 have polymorphism of Thiopurine methyltransferase –> inability to metabolise azathiopurine –> accumulation)
Check TPMT levels before prescribing
Hepatotoxicity
Infection
Mycophenolate Mofetil
Blocks de novo nuceltodie synthesis –> prevents DNA replication
T cell > B cells
Indications
As alternative to azathioprine in transplants
As alternative to cyclophosphamide in autoimmune and vasculitis
Side Effects
Bone marrow suppression
Infection:
Herpves virus reactivation
Progressive multi-focal leukoencephalopathy (PML) (JC virus)
Plasmapheresis
Patient’s blood passed through cell separator
Removal of pathogenic antibody
Own cellular constituents reinfused
Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)
Problems
Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent
Indications
Severe antibody-mediated disease
Goodpastures syndrome
Anti-glomerular basement membrane antibodies
Severe acute myasthenia gravis
Anti-acetyl choline receptor antibodies
Severe vascular rejection
Antibodies directed at donor HLA molecules
Cyclosporin and Tacrolimus
Block Calcineurin (normally activates NFATc which is transcription factor for cytokines)
Prevents cytokine transcription factor –> prevents lymphocyte proliferation
Indications
Transplant –> Improves graft survival
Side effects Nephrotoxic Neurotoxic Hypertension Diabetogenic (particularly tacrolimus) Dysmorphism (Cyclosporin only)
Tofacitinib
JAK signalling inhibitor
Indications: Rheumatoid Arthitis
Apremilast
PDE4 inhibitor
Indications: Psoriasis and Psoriatic arthritis
Anti-Thymocyte Globulin
Antibody against human thymocyte
Lymphocyte depletion
Modulation of T cell activation and migration
Indications;
Allograft rejection (renal or heart)
Give daily infusion
Toxicity Infusion reactions Leukopenia Infection Malignancy
Basiliximab
Anti-CD25 (IL-2 R alpha-chain)
Prevents T cell proliferation
Indications: pre and post-transplant
Prophylaxis against transplant rejection
Toxicity
Infusion reactions
Infection
Concern over long-term malignancy
Abatacept
Fusion: Antibody-CTLA4
CTLA4 normally on CD4 cell –> binds to APC
CTLA4 binds to APC but has antibody on the other end, blocks T cell from binding –> prevents T cell activation
Indications
Rheumatoid arthritis
Weekly subcut
Monthly IV
Toxicity
Infusion reactions
Infection (TB, HBV, HCV)
Rituximab
Anti-CD20 (Mature B cell)
–> depletion of mature B cell
Indications
Lymphoma
Rheumatoid arthritis (2 doses every 6-12 months IV)
SLE
Toxicity
Transfusion reaction
Infection (progressive multifocal leukoencephalopathy, JC virus)
Exacerbated CV disease
Natalizumab
Anti-a4 integrin
a4 expressed with b1 or b7 integrin
a4b1 bind to VCAM1 and MadCAM1 on endoethelium to mediate cell rolling
Inhibits T cell migration
Indications
Multiple sclerosis
(Crohn Disease)
IV every 4 weeks
Toxicity
Infusion reaction Infection (Progressive Multifocal Luekoencephalopathy)
Hepatotoxicity
Concern over long-term malignancy
Tocilizumab
Anti-IL-6R
Reduces Activation of:
Macrophages
T cells
B cells
Indications
Castleman’s disease
Rheumatoid arthritis
IV or SC
Toxicity Transfusion reactions Infection Hepatotoxicity Elevated lipids Concern over long-term malignancy
Agents directed at cytokines
Infliximab – anti-TNFa Adalimumab – anti-TNFa Certolizumab – anti-TNFa Golimumab – anti-TNFa Etanercept – TNF receptor p75-IgG fusion protein
Ustekinumab – anti-IL-12 and IL-23
Secukinumab – anti-IL-17
Denosumab – anti-RANK ligand
Agents directed at cell surface antigens
Rabbit anti-thymocyte globulin Basiliximab – anti-CD25 Abatacept – CTLA4-Ig Rituximab – anti-CD20 Natalizumab – anti-a4 integrin Tocilizumab – anti-IL-6 receptor
Anti-TNFa Antibodies
Infliximab
Adalimumab
Certolizumab
Golimumab
Indications Rheumatoid arthritis Ankylosing spondylitis Psoriasis and psoriatic arthritis IBD SC or IV
Toxicity Infusion or injection reaction Infection (TB, HBV, HCV) Lupus-like syndrome Demyelination Malignancy
Etanercept
TNF Antgaonists
- Inhibits TNFa and TNFb
Indications and dosing Rheumatoid arthritis Ankylosing spondylitis Psoriasis and psoriatic arthritis Subcutaneous weekly
Toxicity Injection site reactions Infection (TB, HBV, HCV) Lupus-like conditions Demyelination Malignancy
Ustekinumab
Anti-p40 (IL-12 and IL-23)
IL-12: p40+p35
IL-23:p40+p19
Inhibits IL-12 and IL-23
IL-12 and IL-23 on NK cell and T cell
Indications
Psoriasis and psoriatic arthritis
Subcut every 12 weeks
Complications
Injection reaction
Infection (TB)
Concern regards long-term malignancy
Secukinumab
Anti-IL-17A
Dimer of IL-17A or IL-17A/F
Binds to IL-17RA/RC receptor
IL-17AR on keratinocyte
Indications
Psoriasis and psoriatic arthritis
Ankylosing spondylitis
SC load and then monthly
Action
Inhibits IL-17A
Toxicity
Infection (TB)
Denosumab
Anti-RANKL
Inhibits RANK mediated osteoclast
differentiation and function
Indications
Osteoporosis
Subcutaneous every 6 months
Toxicity
Infection
Avascular necrosis of jaw
HIV-1
HIV-1 Retrovirus positive sense ssRNA virus 9 genes Reverse transcriptase: RNA --> DNA DNA then integrated into host DNA Infects CD4+ T cell and CD4+ monocyte Receptor = CD4 Co-receptor = CCR5 or CXCR4
Immunity against HIV-1
Non-specific activation of NK cells and complement associated with slower disease course
Acquired immunity – B cells
Anti-gp120 and anti-gp41 (Nt) antibodies are thought to be important in protective immunity.
Non-neutralising anti-p24 gag IgG also produced.
HIV remains infectious even when coated with antibodies.
CD8+ T cells
Secrete soluble molecules (cytokines and chemokines such as MIP-1a, MIP-1b, and RANTES) which are able to prevent infection by blocking entry of virus into CD4+ T cells.
Recognise processed antigen - (peptides) - in the context of class I HLA molecules
HAART
HAART = 2NRTIs + PI (or NNRTI)
Management of Anaphylaxis
IM adrenaline 0.5mg (may repeat)
Oxygen by mask
IV Intravenous anti-histamines (10mg Chlorpheniramine)
Nebulised bronchodilators (driven by oxygen)
Intravenous corticosteroids (Hydrocortisone 200mgs)
Intravenous fluids (if hypotensive)
Causes of recurrent meningococcal meningitis
Immunological Complement deficiency (susceptible to encapsulated bacteria) Antibody deficiency (susceptibility to upper and lower respiratory tract infections)
Neurological: any disruption to BBB
Occult skull fracture
Hydrocephalus
Features of immune deficiency (SPUR)
Serious
Persistent
Unusual
Recurrent
Management of Complement Deficiency
Meningovax
Pneumovax
HIB vaccines
Daily prophylactic penicillin
Anti-CCP
Anti-citrullinated peptide antibodies
70% Sensitivity for RA
95% Specificty for RA
Antibodies against citrullinated proteins
Rheumatoid Arthritis HLA Associations
HLA-DR1
HLA-DR4
Rheumatoid Factor
IgM Antibody against Fc portion of human IgG
60-70% Sensitivity for RA
60-70% Specificity for RA
Genetic Predisposition to Rheumatoid Arthritis
5%DZ and 30%MZ twins
Peptidylarginine deaminase polymorphisms
PAD Type 2 & 4
Increase citrullination of proetins
PTPN 22: Protein tyrosine phosphatase non-receptor 22
Lymphocyte-specific tyrosine phosphatase –> supresses T cell activation activation
1858T allele increases susceptibility to rheumatoid arthritis, SLE, type 1 diabetes
HLA
HLA-DR1
HLA-DR4
Treatments for Rheumatoid Arthritis
Standard Mx Methotrexate Sulphasalazine Hydroxychloroquine Leflunomide
Further Mx
TNFalpha antagonist
Inhibits downstream events in inflammation.
Rituximab
Antibody specific for CD20
Depletes B cells (not plasma cells)
Abatacept
CTLA-4 – Ig fusion protein
Binds to ligands of CD28 (CD80 and CD86) and thereby inhibits T cell activation
Tocilizumab
Antibody specific for IL-6 receptor – widespread effects
Before Starting Biologics:
Screen for exposure to TB using CXR and TB ELISPOT
Screen for exposure to Hepatitis B
Screen for exposure to Hepatitis C
Consider possibility of HIV infection
Prior history of septic arthritis/infected joint prosthesis
Educate patient to stop drug and seek advice if acute infection
Consider need for vaccinations
Consider risk of malignancy
Prior history of malignancy
Advise re sun exposure/skin protection
Serum Sickness
Penicillin can bind to cell surface proteins
Acts as “neo-antigen”: stimulates very strong IgG antibody response
Individual is “sensitised” to penicillin
Subsequent exposure to penicillin stimulates
Formation of immune complexes with circulating penicillin
Production of more IgG antibodies
Fever
Arthralgia of large joints
Vasculitic skin rash
Renal function deteriorates
Sjögren’s syndrome
Chronic auto-immune disease of salivary glands
Primary: by itself
Secondary: as a result of connective tissue disorder
F>M Dry mouth Dry eyes Dry skin Chronic cough Muscle and joint pains Thyroid problems
Increase risk of lymphoma
ANA +ve
SA/Ro
SB/La (far more specific)
Antithrombin
Inhibits factor IIa and factor Xa
Tissue factor pathway inhibitor
Inhibits VII –> VIIa
Protein C and S
Inhibits factor Va and VIIIa
Antithrombotic Mediators on Endothelium
Endothelial expression TFPI Endothelial Protein C TFPI Heparans
Secretes Anti-platelet mediators
Prostacyclin
NO
ENDOTHELIUM DOES NOT EXPRESS TISSUE FACTOR
Pregnancy and Susceptibility to Thrombosis
Decrease Protein S
Increase Factor VIII, Increase Fibrinogen
Stasis
Compression
Malignancy and Susceptibility to Thrombosis
Tissue Factor on tumour
Increased Inflammation
Decreased Flow
Anticoagulant Drugs
Heparin
LMWH
Unfractionated
Potentiate Antithrombin, Factor IIa and Xa
Immediate acting (potentiate anti-coagulant activity)
Warfarin Vitamin K antagonist Inhibits vitamin K dependent factors: II VII IX and X Delayed action Reduce procoagulant activity
New oral anticoag (rivoraxaban) are immediate
Heparin
Three forms
LMWH (subcut)
Unfractionated (IV only)
Pentasaccharide (subcut)
Provide immediate effect (eg for treatment of thrombosis)
Disadvanatges
Long term disadvantage – have to be given by injections, risk of osteoporosis
Difficult to dose: Variable renal dependence
Low molecular weight heparin (LMWH)
Reliable pharmacokinetics so monitoring not usually required
Can use anti-Xa assay in at-risk eg:
Renal failure (CrCl<50)
Extremes of weight or risk
In anti-Xa assay you measure ability to potentiate antithrombin in its inhibition of thrombin and Xa
Unfractionated heparin
Much more complex, Variable kinetics
Variable dose-response
Always monitor therapeutic levels with APTT or anti-Xa
Direct acting anticoagulants
Anti-Xa
Rivaroxaban, apixaban, edoxaban
Anti-IIa
Dabigatran
Properties Oral administration Immediate acting –peak in approx. 3-4 hours (cf LMWH) Short half-life No monitoring
New agents
Oral admin
Reliable dose response,
No monitoring
Warfarin
Oral
Only anti-coagulant that can be used for metallic heart valves
Indirect effect by preventing recycling of Vit K
Action is delayed
II, VII, IX & X
Takes some time to fall
Levels of anticoagulant protein C and protein S also fall (also vit K factors, transient increase thrombotic risk at onset)
Reversal of Heparin
Protamine
Low molecular weight heparin (LMWH) dosing
Thromboprophylaxis
Tinzaparin 4500U
Clexane 40mg
Risk Factors for VTE
Patient Factors Age > 60yrs Previous VTE Active cancer Acute or chronic lung disease Chronic heart failure Lower limb paralysis (excluding acute CVA) Acute infection BMI>30
Procedure (circumstance) Hip or knee replacement Hip fracture Other major orthopaedic surgery Surgery > 30mins Plaster cast immobilisation of lower limb
Bleeding risk assessment
Patient Factors Bleeding diathesis (eg haemophilia, VWD) Platelets < 100 Acute CVA in previous month (H’gge or thromb) BP > 200 syst or 120 dias Severe liver disease Severe renal disease Active bleeding Anticoag or anti-platelet therapy
Procedure
Neuro, spinal or eye surgery (v high risk if bleeding occurs)
Other with high bleeding risk
Lumbar puncture/spinal/epidural in previous 4 hours
Treatment of DVT/PE
Start LMWH eg Tinzaparin 175u/kg \+ warfarin Start Warfarin at the same time, measure INR Stop Hep when OK Stop LMWH when INR >2 for 2 days
Continue for 3-6 months, takes this for patients to settle
Patients with cancer: continue LMWH not warfarin.
OR Start Rivaroxaban (NEW WAY)
DOES NOT DISSOLVE CLOT, STOPS PROPAGATION OF CLOT
Thrombolysis
About to die or critical limb
Only for life threatening PE or limb threatening DVT
Risk of haemorrhage(Intracranial Haemorrhage) 4%
Reduces subsequent post-phlebitic syndrome
Indications broadening slowly
Same treatment for stroke, potentiate fibrinolysis (TPA) tissue plasminogen activator
Risk of VTE recurrent
Higher risk (put on on long-term anticoag)
Idiopathic thrombosis (no external stimulus)
Male
Have higher d-dimer after coming off anticoagulant –> high risk of recurrence
Presentation of Anaemia in Cancer
Fe Deficiency (Occult blood loss)
GI cancer: Gastric, colonic
Urinary tract cancer: Renal cell carcinoma, bladder cancer
Anaemia of Inflammation
Leucoerythroblastic anaemia –> bone marrow infiltration
Cancer
Myrelofibrosis
Severe Infection
Haemolytic anaemias
Immune mediated
Non Immune; fragmentation (micro-angiopathic haemolytic anaemia)
Leucoerythroblastic anaemia
Bone Marrow Infiltration
Cancer
Haematopoietic: Leukaemia, Lymphoma, Myeloma
Non-Haematopoietic: Breast, Bronchus, Prostate
Severe Infection:
Miliary TB
Severe Fungal Infection
Myelofibrosis
Dry tap apriate of BM
MASSIVE Splenomegaly
Myelofibrosis
Bone marrow failure due to progressive scarring
Leukoerythroblast changes
Dry tap on BM aspirate
Massive splenomegaly
May eventually develop a serious form of acute leukaemia
Haemolytic Anaemia
Inherited: Defects of the red cell.
OR
Acquired: Defects of the environment in which the Red cell finds itself, the red cell itself is fine
Anaemia (though may be compensated) Reticulocytosis Raised Bilirubin (unconjugated) Raised LDH Reduced haptoglobins
In bone marrow failure, you can’t increase red cell output so you don’t see reticulocytosis and the anaemia is not compensated
Inherited Haemolytic Anaemias
Membrane
Spherocytosis
Elliptocytosis
Haemoglobin
Mutation of beta chain, structurally abnormal beta chain –>
Structural (sickle cell disease)
Quantitative (thallasaemias) imbalance between alpha and beta chains
Enzymes
G6PD
Continual Red Cell breakdown –> pigment stones
Acquired Haemolytic Anaemia
Immune
OR
Non-Immune
DAT test +ve –> IMMUNE
Diseases that produce autoimmune haemaolytic immune
- Cancer of immune system: lymphoma or lymphocytic leukaemias
- Disease of the immune system: SLE or Sjorgen’s
- Infection (disturbing the immune system) e.g. Mycoplasma
Mycoplasma = Cold agglutinin disease is an autoimmune disease characterized by the presence of high concentrations of circulating antibodies, usually IgM, directed against red blood cells
In autoimmune haemolytic anemia you also get acquire spherocytes
DAT NEG –> NON-immune
These diseases damage the red cells but are not immune mediated
Infection (malaria) gets into red cell
Micro-angiopathic Haemolytic anaemia (MAHA)
Red cell fragments
low platelets (activation of clotting system)
DIC/bleeding
Underlying adenocarcinoma (prostate or stomach)
Coombs Test
Direct coombs = DAT Test
Used to test for autoimmune hemolytic anemia
Tests for presence of IgG on Red cells
Blood sample is taken and the RBCs are washed (removing the patient’s own plasma) and then incubated with anti-human globulin (also known as “Coombs reagent”). If this produces agglutination of RBCs, the direct Coombs test is positive#
AND
Indirect coombs
Used in prenatal testing of pregnant women and in testing blood prior to a blood transfusion
Detects antibodies against RBCs that are present unbound in the patient’s serum
Serum is extracted from the blood sample taken from the patient. Then, the serum is incubated with RBCs of known antigenicity; that is, RBCs with known reference values from other patient blood samples. Finally, anti-human globulin is added. If agglutination occurs, the indirect Coombs test is positive.
micro-angiopathy haemolytic anaemia from an adenocarcinoma
Low grade DIC
Occult cancer secreting pro-thrombotic factors into blood
Activated coagulation pathway
Coagulation systemic throughout blood – not confined to local site
In microvasculature Blood flow slow Pro-coagulation factors At sites of slow flow, fibrin able to be formed Fibrin goes across blood vessel Causes red cell trauma Fragmented cells Platelets consumed s part of process
Polycythaemia
Appropriate e.g. high altitude
True: polycythaemia vera
Secondary: Ectopic Erythropoietin
Hepatocellular carcinoma
Renal cancer
Bronchial cancer
Causes of Neutrophilia
TIMUC
Corticosteroids (demargination of neutrophils –> apparent increase)
Underlying neoplasia
Tissue inflammation (e.g.colitis, pancreatitis)
Myeloproliferative/ leukaemic disorders
Infection -itis
Reactive:
Neutrophil count up to 15 –> infection or malignant
Presence bands, toxic granulation, and signs of infection/inflammation
Malignant:
Neutrophil count 250 –> leukaemia
Find neutrophils along with immature cells: Neutrophilia basophilia plus immature cells myelocytes, and splenomegaly. Suggest a myeloproliferative (CML)
Neutropenia plus precursors cells (Myeloblasts) (AML)
Eosinophilia
Reactive eosinophilia
Parasitic infestation
allergic diseases e.g. asthma, rheumatoid, polyarteritis,pulmonary eosinophilia.
Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia)- lymphoma secretes eosinophil secreting factor
Drugs (reaction erythema mutiforme)
Chronic Eosinophilic leukaemia
Eosinophils part of the “clone”
FIP1L1-PDGFRa Fusion gene
Monocytosis
Rare but seen in certain chronic infections and primary haematological disorders TB, brucella, typhoid Viral; CMV, varicella zoster sarcoidosis chronic myelomonocytic leukaemia (MDS)
Lymphoid Vs Myeloid Clinical Distinguishing Factor
If you have splenomegaly and hepatomegaly and no lymph nodes –> Myeloid disorder
Haemopoiesis can go back to where it occurred in fetal, in liver
If you have splenomegaly and hepatomegaly and lymphadenopathy –> lymphoid disorder
Lymphoma Associated with Antigenic Stimulation
H.Pylori : Gastric MALT (mucosa associated lymphoid tissue) lymphoma
Sjogren’s syndrome : Parotid lymphoma
Autoimmune thyroid disease –> thyroid marginal lymphomas
Coeliac disease: small bowel T cell lymphoma EATL (enteropathy associated T-Cell lymphoma)
Lymphoma Associated with Translocation
Lymphoma associated translocations
e.g. t(8,14)
Involve the Ig Locus Ig promoter highly active in B cells Bring intact oncogenes close to the Ig promoter Oncogenes may be anti apoptotic, proliferative. bcl2 bcl6 Myc cyclinD1
Risk Factors for Lymphoma
Constant antigenic stimulation
Infection( direct viral infection of lymphocytes)
Loss of T cell function
(HIV and Immunosuppression)
Lymphoma and Infectious Agents
1) Direct Viral Integration
HTLV1 infects T cells by vertical transmission
Carribean and Japan
May develop Adult T cell leukaemia lymphoma (2.5% at 70 years)
2) Immunosuppression + EBV infection
EBV infects B lymphocytes
Carrier state and regulated by healthy T cells
Iatrogenic supression of T cells (to prevent transplant rejection increase in B cell lymphomas)
3) HIV
60 fold increase in lymphoma in HIV (high grade B-NHL)
Loss of T cell regulation of EBV infected B cells
Immuno Markers
B Cell
CD20
Immature blast B cell = TDT
Cyclin D1 not normally expressed by B cells, Expression of cyclin D1 indicative of mantle cell lymphoma
CD5 expression in B cells indicative of mantle B cell lymphoma OR small lymphocytic lymphoma
(CD5 is normally a T cell marker)
T Cell
CD3
CD5
Mantle Cell Lymphoma
Middle aged male
Lymph node, GI tract
Present in mantle zone
Median survival 3-5 yrs
B cell expressing
cyclin D1
CD5
Translocation
t(11,14) = diagnostic
Follicular Lymphoma
Lymphadenopathy in the elderly
CD10
bcl-6 +ve
t(14,18) involving bcl-2 gene
Small Lymphocytic Leukaemia
Middle aged/ Elderly
Nodes or blood
Small lymphocytes, naive or post-germinal centre B cell
CD5
CD23
Indolent
Undergo Ritcher transformation into high grad elymphoma
Marginal Zone / MALT lymphoma
Arise at extranodal sites e.g. Gut, lung, Spleen
In response to chronic stimulation form antigen e.g. H.Pylori
Post germinal centre memory B cell
Indolent, but can transform into high grade lymphoma
Can treat if remove antigen stimulation early
Burkitt’s Lymphoma
Jaw or abdominal mass in Children
EBV associated
Immunodeficiency
Sporadic
Stary-sky appearance
C-myc
t(8,14)
Aggressive
Diffuse Large B Cell
Middle aged/Elderly
Lymphadenopathy
Germinal centre or post-germinal centre B cell
Sheets of large lymphoid cells
p54 positive
Peripheral T Cell Lymphoma
Middle aged/ Elderly
Lymphadenopathy and extra nodal sites
Large T lymphocytes
Associated with reactive cells e.g. eosinophils
Aggressive
Special Forms of T Cell Lymphoma
Adult T Cell Leukaemia / Lymphoma
HTLV-1 Japan and Caribbean endemic
Enteropathy associated T cel lymphoma
Longstanding Coeliac
Cutaneous T cell lymphomas
Mycosis fungiodes
Anaplastic large cell lymphoma
Anaplastic Large Cell Lymphoma
Children/ Young adults
Lymphadenopathy
Large epitheloid lymphocytes
T cell or null phenotype
t(2,5)
Alk-1
Agressive BUT alk-1 expression = better prognosis
Non-Hodgkin’s Lymphoma
Multiple nodal sites
Spreads discontinuously
B Cell
T Cell
Hodgkin’s Lymphoma
Single nodal site
Spreads continuously
Split into Classical and Lymphocyte predominant
Classical Three subtypes Nodular sclerosing Mixed cellularity Lymphocyte rich and Lymphocyte depleted
Lymphocyte predominant = some relation to non-hodgkin’s lymphoma
Classical Hodgkin’s Lymphoma
Young/Middle aged
Single site of nodes
germinal centre or post-germinal centre B cell
EBV associated
Sclerosis
Mixed cellularity
Reed-Sternberg and Hodgkin cells
with eosinophils
Rarely Alcohol-induce pain
Nodular Lymphocyte Predominant Hodgkin’s Lymphoma
Isolated lymphadenopathy
Germinal centre B cell
B cell rich nodules with scattered L&H cells
NO ASSOCIATION WITH EBV
Can transform into high grade B cell lymphoma
B Cell Non-Hodgkin Lymphomas
Low Grade Follicular lymphoma Small lymphocytic lymphoma/ Chronic lymphocytic leukaemia Marginal zone lymphoma Mantle zone lymphoma
High Grade
Diffuse large B cell lymphoma
Intermediate
Burkitt’s Lymphoma
Staging of Hodgkin Lymphoma
Stage I; one group of nodes II; >1 group of nodes same side of the diaphragm III; nodes above and below the diaphragm IV; extra nodal spread
Suffix A if none of below, B if any of below
Fever
Unexplained Weight loss >10% in 6 months
Night sweats
Treatment of Hodgkin Lymphoma
Chemotherapy for all cases (ABVD)
ABVD 2-6 cycles +/- Radiotherapy
PET CT
Interim: post x2 cycles, response assessment
End of Treatment: Guides need for radiotherapy
Relapse then Autologous Stem cell transplant as salvage
Chemotherapy ABVD Adriamycin Bleomycin Vinblastine DTIC ABVD, is given at 4-weekly intervals.
Effective treatment Preserves fertility (unlike MOPP the original chemo) Can cause (long term) Pulmonary fibrosis cardiomyopathy
Treatment of Diffuse Large B Cell Lymphoma
International Prognostic Index (IPI) Age > 60y serum LDH > normal performance status 2-4 stage III or IV more than one extranodal site
Treated by x 6-8 cycles of R-CHOP (Rituximab-CHOP)
Combination drug regimens e.g. CHOP Cyclophosphamide Adriamycin Vincristine Prednisolone
Doxorubicin
Relapse: Autologous Stem Cell transplant salvage 25% of patients
Chronic Lymphocytic Leukaemia
Proliferation of mature B-lymphocytes
Age at presentation median 72 Commonest leukaemia in the western world Lymphocytosis between 5 and 300 x 109/l Smear cells Normocytic normochromic anaemia Thrombocytopenia Bone marrow Lymphocytic replacement of normal marrow elements
Mature B cells (CD19) co-expressing CD5
Further immuno studies CLL score 4-5
CLL Score (Need 4/5) CD5 CD23 FMC7 CD79b SmIg
Binet and Rai staging
CD38 expression = bad prognosis
Deletion of 17p (TP53) = bad prognosis
unmutated IgH gene = bad prognosis
CD5 also expressed in Mantle Cell Lymphoma
Normally a T cell marker
Treatment of CLL
Prophylaxis and treatment of infections
Aciclovir
PCP prophylaxis for those receiving fludarabine or alemtuzumab (Campath)
IVIG is recommended for those with hypogammaglobulinemia and recurrent bacterial infections
Immunisation against pneumococcus, and seasonal flu
Auto-immune phenomena
1st Line Steroids
2nd Line Rituximab
Irradiated Blood products if risk of TA GVHD
Variants of CLL
Transformation to high grade lymphoma = Richter’s syndrome
~1% per year
Treat as high grade lymphoma with CHOP-R
BCR Kinase inhibitors
New drugs in CLL
Ibrutinib
Idelalisib
Myelodysplastic Syndromes
Typically a disorder of the elderly. (over 60) Common in 70s
Symptoms/signs are those of general marrow failure
Develops over weeks & months
Development of clone marrow stem cells with abnormal cell development
- -> functionally defective blood cells
- -> numerical reduction
Cytopenia
Anaemia –> tiredness, lethargy, severely anaemic –> heart failure
Neutropenia –> infection
Thrombocytopenia –> bleeding
AND Increased risk of transformation to leukaemia
Myelodysplastic Features in Bone Marrow and Blood
Pelger Huet = bilobed neutrophils
Ring sideroblast = iron arranged in ring
Dysgranulopoiesis of neutrophils = abnormal granules
Myelokathexis of neutrophils = abnormal appearance of neutrophils and pre-cursors in bone marrow
Dyserythropoiesis of red cells = Abnormal red cells in the bone marrow (bridge sand blebbing)
Dysplastic megakaryocytes = Abnormally small megakaryocytes
INCREASED PROPORTION OF BLAST CELLS (normally <5%) –> prognostic significant
More than 20% = defined as having an Acute Leukaemia
Auer rods stain deep red
They are indicative of acute myeloid leukaemia
WHO classification of MDS
Refractory anaemia (RA)
- without ringed sideroblasts
- with ringed sideroblasts (RARS)
Refractory cytopenia with multilineage dysplasia (RCMD)
Refractory anaemia with excess of blasts (RAEB)
- RAEB-I (BM blasts 5-9%)
- RAEB-II (BM blasts 10-19%)
5q- syndrome
Unclassified MDS: MDS with fibrosis, childhood MDS, others
The Revised International Prognostic Scoring System IPSS-R
BM blasts % Karyotype Hb Neutrophils Platelets
0 = Good
4=Bad
Used to predict risk of development of AML
Treatment choices
Prognosis of MDS
Deterioration of blood counts
Worsening consequences of marrow failure
Development of acute myeloid leukaemia
– Develops in 50%< 1 year
– Some cases of MDS are much slower to evolve
– AML from MDS has an extremely poor prognosis and is usually not curable
As a rule of thumb
• 1/3 die from infection
• 1/3 die from bleeding
• 1/3 die from acute leukaemia
Treatment of MDS
Prolong survival:
- allogeneic stem cell transplantation (SCT)
- intensive chemotherapy
Supportive care Blood product support Antimicrobial therapy Growth factors (Epo, G-CSF) EPO = red cells G-CSF = neutrophils
Biological Modifiers Immunosuppressive therapy Hypomethylating agents Azacytidine Lenalidomide (5q- syndrome)
Oral chemotherapy
Hydroxyurea
Low dose chemotherapy
Subcutaneous low dose cytarabine
Intensive Chemotherapy/SCT
AML type regimens
Allo/VUD standard/ reduced intensity
Bone Marrow Failure
Failure of stem cell
Depending on whereabouts in lineage the stem cell fails –> different outcome
Could fail to make lymphocytes and myeloid
Or either depending on location of failure
Results from damage or suppression of stem or progenitor cells
PLURIPOTENT HAEMATOPOIETIC CELL
- Impairs production of ALL peripheral blood cells
- rare
COMMITTED PROGENITOR CELLS
- Result in bi- or unicytopenias
Causes of Bone Marrow Failure
Primary
Congenital
Fanconi’s Anaemia –> MULTIPOTENT
Diamond-Blackfan Anaemia –> Red cell progenitor
Kostmann Syndrome –> neutrophil progenitor
Acquired Primary: Idiopathic aplastic anaemia –> MULTIPOTENT
Secondary Bone Marrow Infiltration (haematological = leukaemia, lymphoma, myelofibrosis, non-haematological = solid tumour) Radiation Drugs Chemicals (Benzene) Autoimmune Infection (Parvovirus, Hepatitis)
Drugs causing Bone Marrow Failure
Cytotoxic
Antibiotics
Chloramphenicol
Sulphonamide
Diuretic
Thiazide
Anti-Thyroid
Carbomazole
Aplastic Anaemia
Aplastic Anaemia = Pancytopenia
Subtype of Bone Marrow Failure in which all three cell lines are NOT produced
CLASSIFICATION:
- Severe aplastic anaemia (SAA)
- Non-severe aplastic anaemia (NSAA)
Camitta criteria:
2 out of 3 peripheral blood features
- Reticulocytes < 1% (<20 x 109/l)
- Neutrophils < 0.5 x 109/l
- Platelets < 20 x 109/l
AND Bone marrow <20% cellularity
MULTIPOTENT defect - “Stem cell” problem (CD34, LTC-IC
Causes Primary Idiopathic - 70% (Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita) Fanconi's Anaemia Dyskeratosis congenita Schwman-Diamond Syndrome
Secondary Radiation Drugs: chloramphenicol Infection: hepatitis SLE
Immune attack:
Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell.
Dyskeratosis Congenita
3 patterns of inheritance
Abnormal telomeric structure and function is implicated.
Telomere length is reduced
X-linked recessive trait = mutated DKC1 gene - defective telomerase function
Autosomal dominant trait = mutated TERC gene
RNA component of telomerase
Autosomal recessive trait, gene not yet been identified
Progressive bone marrow failure –> aplastic anaemia
Cancer predisposition
Somatic abnormalities
Triad of:
Reticulated skin hyperpigmentation,
Nail dystrophy
Oral leukoplakia
Tx:
Supportive
Blood/platelet transfusions
Antibiotics
Drugs to promote marrow recovery
Oxymetholone
Growth factors
Haemopoietic stem transplantation
Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita
Schwman-Diamond Syndrome
Congenital disorder characterized by:
Exocrine pancreatic insufficiency
Bone marrow dysfunction –> Aplastic anaemia
Skeletal abnormalities
Short stature
Differential Diagnoses of Pancytopenia & Hypocellular Marrow
Hypoplastic MDS / Acute Myeloid Leukaemia
Hypocellular Acute Lymphoblastic Leukaemia
Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
Management of Bone Marrow Failure
Seek a cause (detailed drug & occupational exposure history)
Supportive
Blood/platelet transfusions (leucodepleted, CMV neg, irradiated)
Antibiotics
Iron Chelation Therapy (avoid iron overload)
Drugs to promote marrow recovery
Oxymetholone (=anabolic steroid)
Growth factors
Immunosuppressive therapy (due to t cell attack of bone marrow)
Stem cell transplantation
Treatment for Idiopathic Aplastic Anaemia
Immunosuppressive therapy – older patient
Anti-Lymphocyte Globulin (ALG)
Ciclosporin
Androgens – oxymethalone
Stem cell transplantation
Younger patient with donor (80% cure)
VUD/MUD for > 40 yrs (50% survival)
Fanconi’s Anaemia
Autosomal recessive/ X-linked
- -> abnormalities in DNA repair
- -> chromosoma fragility *in vitro addition of diepoxybutane or Mitomycin –> chromosomal breakages
Normal blood count at birth
Marrow failure and pancytopenia slowly progress onset at 5-10 years
10% result in acute leukaemia
Tx:
Supportive
Androgens
full blood count in pregnancy
Mild anaemia (due to net dilution)
Red cell mass rises (120 -130%)
Plasma volume rises (150%)
Macrocytosis
Normal
Check Folate or B12 deficiency
Neutrophilia
Thrombocytopenia
increased platelet size
Incidental thrombocytopenia in third trimester
Not due to volume expansion
As plasma volume expansion finished by end of second trimester
Causes of Thrombocytopenia in Pregnancy
1) Physiological (normal to have lower platelets in pregnancy)
2) Pre-Eclampsia (HELLP)
3) Immune thrombocytopenia
4) MAHA = Schisyocytes
HELLP (remits after delivery)
TTP and HUS (do not remit after delivery)
5) All others:
Bone marrow failure
Leukaemia
Hypersplenism
Lower the platelets –> more likely pathological
*NEED >70 for epidural
Iron Deficiency in pregnancy
May Cause: Anaemia IUGR Prematurity Postpartum haemorrhage
Coagulation changes in pregnancy
Increase in:
von Willebrand
Factor VIII
PAI-2 (placenta produced)
Decrease in:
Protein S
Antiphospholipid Syndrome
Recurrent miscarriages
Lupus anticoagulant positive
Anti-cardiolipin antibody
Obstetric outcome improved with herparin and aspirin
Myeloproliferative Disorders
Ph Neg Polycythaemia vera (PV) Essential Thrombocythaemia (ET) Primary Myelofibrosis (PMF)
Ph Pos
Chronic myeloid leukaemia (CML)
Myeloproliferative Disorders Gene Mutation
JAK2 = PV
Calreticulin
MPL
Polycthaemia vera treatment
Venesection
Hydroxycarbamide
Aspirin
Essential thrombocythaemia treatment
Aspirin
Anagrelide
Hydroxycarbamide
Treatment of Primary Myelofibrosis
Anaemia –> transfusion
Splenectomy –> symtpomatic relief
Thrombocytosis –> hydroxycarbamide
Ruxolotinib = JAK2 inhibitor
Bone marrow transplant
Treatment of CML
Imatinib
2nd generation: Dasatanib, and Nilotinib
Treatment of Multiple Myeloma
Melphalan (mustard-type alkylating agent)
Steroids
Proteasome inhibitors
IMIDs“ - Thalidomide, Lenalidomide, Pomalidomide
Treatment of Graft vs Host Disease
Corticosteroids Cyclosporin A FK506 Mycophenylate mofetil Monoclonal antibodies (against T cells) Photopheresis Total lymphoid irradiation
Prevention of GvHD
Methotrexate Corticosteroids Cyclosporin A CsA plus MTX FK506
T-cell depletion
T(15,17)
T(15,17)
Translocation of retinoic acid receptor
Acute promyelocytic leukaemia
Responsive to trans retinoic acid (ATRA) aka tretinoin
AML Disease Hotspots, Mutations and Translocations
Duplication
+8
+21 gives predisposition
Loss
deletions and loss of 5/5q & 7/7q
Common mutations
NPM1
CEBPA
FLT3: internal tandem duplication = bad prognosis
Translocations = Core binding Factor Changes –> cause arrest of cell development
t(8;21) fuses RUNX1 (encoding CBFα) with RUNX1T1
15% of adult AML
inv(16) fuses CBFB with MYH11
12% of adult AML
inv(16) , t(16;16) –> eosinophilic subtype
Acute Promyelinocytic Leukaemia
t(15,17) = PML:RARA
Causes thrombocytopenia
Can present with haemorrhage of easy bruising
Because of coagulation defects and low platelets
Hyperactive fibrinolysis
Can cause DIC
Treated with ARTA – all trans retinoic acid (not chemotherapy)
Nearly all curable
Block in differentiation is further down pathway – excess of promyelocytes
AML vs CML Cytochemistry
Cytochemical stain AML ALL
Myeloperoxidase + (Gr) -
Sudan black + (Gr) -
Non-specific esterase + (Mo) -
All negative = ALL
AML vs ALL immunohistochemistry
ALL:
Precursor-B-cell: CD19, CD20, TdT, CD10 +/-
B-cell: CD19, CD20, surface Ig
T-cell: CD2, CD3, CD4, CD8,TdT
AML:
MPO, CD13, CD33, CD14, CD15 glycophorin (E), platelet antigens
Both: CD34, CD45, HLA-DR
Clinical features of AML
Bone marrow failure
Anaemia
Neutropenia
Thrombocytopenia
Local infiltration into tissues Splenomegaly Hepatomegaly Gum infiltration (if monocytic) Lymphadenopathy (only occasionally) Skin, CNS or other sites (Cranial nerve palsy)
Complications
septic shock
Complicated by renal failure
DIC
Clinical features of ALL
Bone marrow failure — effects of
Anaemia
Neutropenia
Thrombocytopenia
Local infiltration Lymphadenopathy (± thymic enlargement) Splenomegaly Hepatomegaly Testes, CNS, kidneys or other sites Bone (causing pain)
Lymphoid cells are more likely to enter lymph nodes
T cells –> thymus enlargement
Bone pain in long bones of children
Hereditary Haemolytic Anaemias
Red cell membrane defects
Hereditary spherocytosis
Hereditary elliptocytosis
Haemoglobin defects
Sickle cell anaemia
Glycolytic pathway defects
Pyruvate kinase deficiency
Pentose shunt defects
G6PD deficiency
Paroxysmal Nocturnal Haemoglobinuria
Destruction of red blood cells by the complement system
Only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to the absence of protective proteins on the membrane)
GPI anchor missing
GPI binds complement regulatory proteins
Red urine in the morning
cholelithiasis in chronic haemolytic anaemia
Coinheritance of Gilbert syndrome further increases risk of cholelithiasis in chronic haemolytic anaemia
Reduced/absent haptoglobins
Intravascular haemolysis
Hereditary spherocytosis
Vertical interaction
Band 3
Protein 4.2
Ankyrin
Beta Spectrin
Autosomal dominant
Osmotic fragilty test
Reduced binding of dye eosin-5-maleimide
Blood film
Looks spherical
Looks dense
Mean cell haemoglobin conc is increased
Hereditary elliptocytosis
Horizontal interaction
Alpha Spectrin
Beta Spectrin
Protein 4.1
Hereditary pyropoikilocytosis = homozygous form
Glucose-6-phosphate dehydrogenase deficiency
X-linked
Enzyme catalyses first step in pentose phosphate(hexose monophosphate) pathway - generates NADPH required to maintain intracellular glutathione(GSH)
Clinical effects
Neonatal jaundice
Acute haemolysis(triggered by oxidants/infection)
Chronic haemolytic anaemia(rare)
Drugs, infections or fava beans –> Acute haemolysis
Blood Film Nucleated red blood cells Bite cells Hemighosts Poikilocytes Contracted cells **Heinz bodies formed of denatured haemoglobin = Characteristic of oxidative haemolysis
Agents triggering haemolysis in G6PD
Anti-malarials
Primaquine
Antibiotics
Sulphonamides
Ciprofloxacin
Nitrofurantoin
Other drugs Dapsone Vitamin k Fava beans Mothballs
Pyruvate kinase deficiency
Echinocytes (sea urchin)
Pyrimidine 5’-nucleotidase deficiency
Pyrimidine nucleotides are toxic to red cells but red cells need to retain and salvage purine nucleotides
eliminating pyrimidine nucleotides = pyrimidine 5’ nucleotidase
Prominent basophilic stickling
Lead also inhibits this enzyme
Ham’s Test
=Flow cytometry of GPI-linked proteins
Paroxysmal nocturnal haemoglobinuria
Heinz Bodies
Marker of oxidative stress
=G6PD (and bite cells present)
JAK2 V617F
Polycthaemia vera
Idoiopathic erythrocytosis
Isolated erythrocytosis
von Willebrand’s
Type 1 Partial quantitative deficiency
Type 2 Qualitative deficiency
Type 3 Total quantitative deficiency (similar to haemophilia A as apparent factor VIII def)
Inhibitors of Cell wall Synthesis
Beta-Lactams
Penicillins
Cephalosporins
Carbapenems
Glycopeptides
Vancomycin
Teiciplanin
Penicillins
Penicillin
Gram positive organisms = streptococci, clostridia
Broken down by beta-lactamase
Amoxicillin
Gram positives and extended to cover enterococci and gram negatives
Broken down by beta-lactamse (staph aureus and many gram negs produced)
Co-amoxiclav (augmentin) = amoxicillin + clavulanic acid
Flucloxacillin
Resistant to beta-lactamase
Used for staph aureus
Piperacillin Similar to amoxicillin Extends coverage to pseudomonas and other non-enteric gram negatives Broken down by beta-lactamase Tazocin = piperacillin + tazobactam
Cephalosporins
3 Generations (increasing activity against gram negative bacilli with each gen)
Need to add in metronidazaole to cover anaerobes
First generation = Cephalexin
Second generation = Cefuroxime
Third generation = Cefotaxime, Ceftriaxone, Ceftazidime
Ceftriaxone = 1st line meningitis
Ceftazidime = psudomonas coverage, give in cystic fibrosis
Carbapenems
Meropenem, Imipenem, Ertapenem
Stable to extended spectrum beta-lactamase (ESBL)
Broad spectrum
Broken down by carbapenemase enzyme –> breaks down all three types of beta-lactams (penicillins, cephalosporins, and carbapenems)
Multi-drug resistant acinetobacter and klebsiella species
Glycopeptides
Vancomycin and Teicoplanin
Unable to penetrate gram negative outer cell wall
Active against gram positives
Inhibit cell wall synthesis
Bind to D-Ala D-Ala and prevent cross-linking
Slowly bactericidal
Nephrotoxic: must monitor levels and check for accumulation
MRSA
oral for serious C.Diff
Antibiotics inhibiting Protein Synthesis
Aminoglycosides
Gentamicin
Amikacin
Tobramycin
Tetracyclines
Doxycycline
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Linocosamides
Clindamycin
Streptogramins
Synercid
Chloramphenicol
Oxazolidinones
Linezolid
Aminoglycosides
Gentamicin
Akimacin
Tobramycin
30S ribosomal subunit Streptococci are intrinsically resistant (requires specific transporter) no activity against anaerobes Ototoxic and nephrotoxic used synergistically with beta-lactams
Bactericidal
Gentamicin and tobramycin active against pseudomonas
Tetracyclines
Doxycycline
Activity against intracellular pathogens
Chlamydia
Mycoplasma
Rickettsiae
Bacteriostatic
Reversibly bind to 30S subunit
Light-sensitive rash
Do not give to children or pregnancy women
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Bind to 50S subunit
Bacteriostatic
Minimal activity against gram negatives
USed for streptococcal infections and mild staphylococcus in penicillin-allergic patients
Also active against atypical pneumonias
Campylobacter
Legionella
Chloramphenicol
Broad spec
Used in eye preparations
Risk of aplastic anaemia
Grey baby syndrome
Bacteriostatic
50S subunit
Oxazolidinones
Linezolid
Highly active against gram positive (including MRSA and VRE)
Not active against gram negatives
Bind to 23S of 50S subunit
May cause thrombocytopenia and neurological problems
Inhibitors of DNA synthesis
Flouroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Nitroimidazoles
Metronidazole
Tinidazole
Fluoroquiniolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Act on alpha subunit of DNA gyrase
Bactericidal
Gram negatives including pseudomonas
Levofloxacin and moxifloxacin also against gram positive and intracellular bacteria e.g. chlamydia
Use for UTIs Pneumonia Atypical pneumonia Bacterial gastroenteritis e.g. salmonella
Nitroimidazoles
Metronidazole
Tinidazole
Active against anaerobes and protozoa (Giardia)
Bactericidal
Inhibitors of RNA synthesis
Rifampicin
Rifabutin
Rifampicin
Mycobacterium e.g. TB
Binds to DNA-dependent RNA polymerase
Bactericidal
Monitor LFTS
induces CYP450
Turns secretions orange
Daptomycin
Cell membrane toxin
MRSA and VRE
Antibiotics inhibiting Folate Metabolism
Sulfonamides: Sulphamethoxazole
Diaminopyrimidines: Trimethoprim
Co-trimoxazole
trimethoprim + sulphamethoxazole
Used in PCP
Eagle Effect
Penicillins don’t work unless dividing
If large bacterial burden –> no active replication as nutrient deficiency
–> penicillins won’t work
Cytomegalovirus
Usually minimally symptomatic and self-limiting
Can cause mild mononucleosis-like illness and hepatitis
Groundglass appearance on CT
Owl’s eye inclusion
Retinal haemorrhages
Remains latent in bone marrow and monocytic cells
Epstein-Barr Virus
Exudative pharyngitis
Atypical lymphocytosis
Infectious mononucleosis
Associated with lymphoproliferative disease in immunosupressed
Burkitt’s
Post-transplant lymphoproliferative disease (PTLD)
Antivirals for CMV
Ganciclovir (given to all transplant recipients)
Valganciclovir (pro-drug of ganciclovir)
Foscarnet
Cidofovir
All very toxic
Classification of Human herpesvirus
Alpha = rapid growth and latency in sensory ganglia
HSV-1 - oral
HSV-2 - genital
VZV
Beta = slow-growth restricted range
CMV
HHV-6
HHV-7
Gamma = oncogenic
EBV
HHV-8
HHV-8
Kaposi’s sarcoma
Multicentric Castleman’s disease
Timing of Vaccine Ractions
Inactivated: within 48 hours
Live attenuated, need time to replicate
Measles: rash, fever, malaise 6-11 days
Rubella: pain, stiffness, swelling of joints 2nd week
Mumps: parotid swelling 3rd week
Acellular vaccines
Pertussis
Diptheria toxoid
Hib polysaccharide
Diptheria
Bacteria = corynebacterium diptheria or corynebacterium ulcerans
Airborne
Bull neck
Early: mild fever, swollen neck glands, anorexia, malaise, cough
2-3 days: grey membrane of dead cells form in throat, tonsils, larynx or nose “pseudomembrane”
Untreated: Infectious for up to 4 weeks
5-10% extensive organ damage: neurological and heart damage
Tetanus
Clostridium tetani: forms spores that can survive in environment
Non-communicable: infection by contamination of cut with soil or manure
Incubation 4-21 days
No natural immunity, ever if you have had tetanus, need to be immunised
Muscle stiffness, lock-jaw
Followed by neck stiffness, difficulty swallowing, stiffness of stomach muscles, muscle spasm, sweating and fever
Complications: fractures, laryngospasm, PE, aspiration, Death
neonatal tetanus due to infection of umbilical cord stump
Pertussis
Whooping cough
Bordatella pertussis
3 x 2 week phases:
Catarrhal phase: URI
Paroxysmal phase: paroxysms of coughing, inspiratory whoop, vomiting, apnoeic episodes
Convalescent phase: resolution but dry cough may persist for months
Acellular pertussis vaccine
Poliomyelitis
Transmission through contact with faeces or pharyngeal secretions
Can be asymptomatic
Mild-influenza-like illness
<1% result in flaccid paralysis (develops 1-10 days after prodromal illness)
Meningococcal vaccines
Meningococcal C: conjugate vaccine (polysaccharides chemically joined to tetanus or diptheria carrier proteins)
Men B: recombinant vaccine
Men ACWY: quadrivalent
Pneumococcal vaccines
PPV:purified polysaccharide vaccine = pneumovax II
23 serotypes
PCV: conjugated pneumococcal vaccine = Prevanar 13
13 valent
Measles
Morbillivirus
negative sense SSRNA
Airborne
Incubation: 7-18 days
Prodromal period: High fever and 3Cs
Cough
Coryza
Conjunctivitis
Enanthem phase
Koplik spots
Exanthem phase
Rash develops from face and upper neck –> hands and feet over 3 days
Lasts 5-6 days
Recovery: persistent cough
Complications Severe diarrhoea Pneumonia Otitis media (supresses immune system for 6 weeks, infections occur) Convulsions Encephalitis subacute sclerosing panencephalitis (SSPE) Death 1 in 5,000
Mumps
Paramyxovirus
SSRNA
Cause epithelial cells to fuse, multi-nucleated giant cell
Airborne
Incubation: 14-25 days
Headache, fever, parotid swelling (unilateral or bilateral)
Meningism: photophobia, neck stiffness
Complications: Pancreatitis Orchitis Oophoritis Neurlogical complications: meningitis, bilateral/unilateral deafness
Rubella
Togavirus
Direct droplet contact
Incubation:14-21 days
Infectivity until 5-7 days after the rash onset
Usually mild illness
Swollen lymph glands, low grade fever, malaise
Conjunctivitis
Maculo-papular rash on face, neck, and body
Swollen joints
Congenital rubella syndrome
Cardiac defects
Auditory
Ophthalmic
Neurological
Risk
90% <10 weeks
10-20% 10-16 weeks
Rare >20 weeks
Causes of Meningitis
Acute
Neisseria meningitides = gram negative diplococci
Streptococcus pneumoniae = gram positive diplococci
Haemophilus influenzae B
Listeria monocytogenes = gram positive rod
Group B streptococcus = gram positive cocci
E.Coli = gram negative rod
Chronic
TB
Spirochetes (leptospirosis)
Cryptococcus (Cryptococcus neoformans)
Aseptic
Cocksackie B viruses
Echviruses
Septicaemia (4 processes)
1) Capillary leak
Lack of albumin and other plasma proteins –> hypovolaemia
2) Coagulopathy
Bleeding and thrombosis
Exposure to tissue factor
Activation of protein C
3) Metabolic derangement
Acidosis
4) Myocardial failure
- -> Multi-organ failure
Chronic Meningitis
4+ days
usually TB
Can result in tuberculous granulomas, tuberculous abscesses, cerebritis
CT changes = leptomeningeal enhancement
Encephalitis
HSV most common viral cause
Arboviruses (neonates, younger adults)
Western equine encephalitis (infants, children)
St Louis encephalitis (>40 yrs)
California encephalitis (school-aged)
Eastern equine encephalitis (infants/children)
Rabies
All more common in summer/autumn
Bacterial = listeria
Amoebic
Toxoplasmosis
India Ink
Cryptococcus
Ziehl-Neelsen stain
TB
Gram positive rod
Listeria
Gram negative diplococci
Neisseria Meningitdes
Gram positive diplococci
Streptococcus pneumoniae
Management of Meningitis
Ceftriaxone 2g IV BD
IF > 50 yrs OR immunocompromised add Amoxicillin 2g IV 4-hourly
Management of meningo-encephalitis
Aciclovir 10mg/kg IV TDS
Ceftriaxone 2g IV BD
IF > 50 yrs OR immunocompromised add Amoxicillin 2g IV 4-hourly
Hypoxia, worse on exertion
PCP
pneumocytis jiroveci pneumonia
Co-trimoxazole
Gram stain and Grocott stain
Branching long Gram positive rods
Actinomyces
Lung abscess
Alcoholics
Auramine stain
Mycobacterium
Microcytic Anaemia (FAST)
Fe (Iron deficiency anaemia)
Anaemia of chronic disease
Sideroblastic anaemia
Thalassaemia
Normocytic Anaemia (AHHA RAP?)
Acute blood loss
Hypothyroidism
Haemolysis
Anaplastic (bone marrow failure)
Renal failure
Anaemia of chronic disease
Pregnancy
Macrocytic Anaemia (FAT RBC M)
Fetus (pregnancy)
Anti-folates (e.g. phenytoin)
Thyroid (hypothyroidism)
Reticulocytosis (release of immature cells e.g. haemolysis)
B12 or folate deficiency
Cirrhosis (alcoholic liver disease)
Myelodysplastic syndrome
Plummer-Vinson
Oesophageal webs
Iron deficiency anaemia
Causes of Iron-deficiency Anaemia
Increased loss = blood loss
Increased utilisation
Pregnancy, lactation
Growing children
Decreased intake
Prematurity
Infants and the elderly
Decreased absorption
Coeliac
Post-gastric surgery
Intravascular haemolysis
MAHA
PNH
Cytokine driven inhibition of red cell production
Anaemia of chronic disease
IFNs, TNF and IL-1 reduce EPO production
Rheumatoid Malignancy TB, osteomylitis (chronic infection) Vasculitis (Renal Failure)
Sideroblastic Anaemia
Ringed sideroblasts in bone marrow
Treatment of Sideroblastic Anaemia
Treat cause
+ Pyridoxine (Vitmain B6) –> promotes red cell production
Hypersegmented polymorphs
Leucopenia
Macrocytosis
Thrombocytopenia
Megaloblastic blood film
IM hydroxocobalamin
Replenish vitamin B12
megaloblastic anaemia
Intravascular haemolytic anaemia
Increase free plasma Hb
Decreased haptoglobins
Haemoglobinuria
Methaemalbuminaemia
Acquired Haemolytic Anaemias
Immune
Autoimmune: warm or cold
Alloimmune - haemolytic transfusion reactions
Non-immune Mechanical e.g. metal valves, trauma Paroxysmal nocturnal haemoglobinuria MAHA Infections (malaria) Drugs
Inherited Haemolytic Anaemias
Membrane
Hereditary spherocytosis
Hereditary eliptocytosis
Enzyme defect
G6PD deficiency
Pyruvate kinase deficiency
Haemoglobinopathies
Sickle cell disease
Thalassaemias
Hereditary Spherocytosis
=spherocytes
Autosomal dominant
Spectrin or ankyrin
Extravascular=splenomegaly
Increased osmotic fragility
DAT negative
Tx: splenectomy, folic acid
Hereditary eliptocytosis
=eliptocytes
Autosomal dominant
Spectrin mutations
Ranges from hydrops fetalis to asymptomatic
South East Asian Ovalocytosis
Autosomal Recessive
heterzygoues = Protection against malaria
Glucose -6 - Phosphate Dehydrogenase deficiency
X-linked
Deficiency in G6PD
Rapid anaemia and jaundice
Heinz bodies and bite cells
Take enzyme level 2-3 months after attack as enzymes level present in new cells
Intravascular haemolysis = dark urine
Pyruvate Kinase Deficiency
Autosomal Dominant
Severe neonatal jaundice
Splenomegaly
Haemolytic anaemia
Sickle cell mutation
Codon 6 which is part of coding for beta chain
GAG ==> GTG single base mutation
Glu to Val
Vaso-occlusoive crisis of Sickle Cell Disease (SICKLED)
Stroke
Infections (hyposplenism, CKD)
Crises (splenic, sequestration, chest, and pain)
Kidney (papillary necrosis, nephrotic syndrome)
Liver (gallstones)
Eyes (retinopathy)
Dactilitis
Mesenteric ischaemia
Priaprism
Diagnosis of Sickle Cell
Sickle cells and target cells in blood film
Sickle solubility test
Hb electrophoresis
Gurthrie test
Treatment for Sickle cell
Folic acid
Penicillin V
Pneumovax
Hib vaccine
Hydroxycarbamide
Warn autoimmune haemolytic anaemia
37 C
IgG
+ve coombs
Blood film - spherocytes
Primary idiopathic Lymphoma CLL SLE Methyldopa
Mx
Steroids
Splenectomy
Immunosuppression
Cold autoimmune haemolytic anaemia
<37 C
IgM
+ve coombs
Raynaud’s
Primary idiopathic
Lymphoma
Infections: EBV, MYCOPLASMA
Mx
Avoid the cold
Chlorambucil
Donath Landsteiner antibodies
Paroxysmal cold haemoglobinuria
Paroxysmal cold haemoglobinuria
Caused by viral infection
Measles
Syphilis
VZV
Donath Landsteiner antibodies
IgG adhere in cold —> complement mediated lysis in warm
Treatment of paroxysmal nocturnal haemoglobinuria
Acquired, loss of GPI
Ham’s Test
Non-immune
Morning haemoglobinuria
Thrombosis –> Budd-Chiari syndrome
Mx Eculizimab Folate, iron supplements Antibiotics Vaccines
MAHA
Mechanical destruction
Schistocytes
TTP
DIC
HUS
Thrombotic Thrombocytopenic Purpura
Pentad
MAHA
Fever
Renal impairment
Neurological abnormalities
Thrombocytopenia
Intrinsic Pathway
APTT
Monitor: unfractionated heparin
Extrinsic Pathway
PT
Monitor: Warfarin
Factor Xa activity
Monitor LMWH in renal impairment and those who are underweight or overweight
Osler Weber Rendu
= Hereditary Haemorrhagic Telangiectasia
Autosomal dominant
Abnormal vessel formation
Nosebleeds
GI bleeds
Platelet Disorders
Reduced function
Congenital: storage pool disease and Thrombasthenia (glycoprotein deficiency)
Acquired: Aspirin, Uraemia
Low number
Decreased production: bone marrow failure
Increased destruction: ITP, drugs, HUS, DIC, TTP
Heparin
Potentiates anti-thrombin III which inactivates thrombin and factors 9, 10, 11
Treatment of DVT/PE
LMWH 175units/kg
AND
Warfarin
Continue LMWH until INR is 2.5
Monitor:
INR 3.5
Prosthetic metal valve
INR 2.5
1st episode DVT or PE
AF
Gum infiltration + Hypokalaemia
AML
Leukaemia + DIC
Acute Promyelocytic Leukaemia
Sudan Black B stain
AML
Smear cells
SMEAR CLLS =
CLL
Small mature lymphocytosis
CLL
Bad prognostic markers of CLL
LDH raised
CD38+
112q23 deletion
Good prognostic markers of CLL
Hypermutated Ig gene
Low ZAP-70 expression
13q14 deletion
Treatment of CLL
Chlorambucil
Fludarabine
Alemtuzumab (anti-CD52)
Steroids
SCT
Reed-Sternberg cells
Hodgkin’s lymphoma
Subtypes of Hodgkin’s lymphoma
Nodular sclerosing
Mixed cellularity
Lymphocyte rich
Lymphocyte depleted
Nodular lymphocyte predominant (non-classical Hodgkin’s) - NON classical = NOT EBV ASSOCIATED
Hodgkin’s lymphoma
Reed-sternberg cells
EBV-associated
Spreads continuously from single lymph node group
B symptoms
Pain in lymph nodes after alcohol
Staging of Lymphoma
Stage 1
one LN region (LN can include spleen)
Stage 2
two or more LN regions on same side of diaphragm
Stage 3
two or more LN regions on opposite sides of diaphragm
Stage 4
Extranodal sites e.g. liver, brain
A= no B symptoms
B = B symptoms
Treatment of Hodgkin’s Lymphoma
ABVD
Adriamycin
Bleomycin
Vinblastine
Decarbazine
Autologous Stem Cell Transplant
Self–> Self
Multiple myeloma
Lymphoma
Allogenic Stem Cell Transplant
Leukaemia
High Grade NH Lymphoma
V aggressive - Burkitt’s
Aggressive
Diffuse large B cell
Mantle Cell
Low Grade NH Lymphoma
Follicular
Marginal Zone
Small Lymphocytic
T(8,14)
Burkitt’s Lymphoma
Mycosis fungoides
Cutaneous T cell lymphoma
HTLV-1
Adult T cell lymphoma/leukaemia
c-myc over expression
Burkitt’s lymhoma
Alk-1 protein expression
Anaplastic Large cell lymphoma
T(2,5)
Anaplastic Large Cell lymphoma
Coeliac Disease
Enteropathy-associated T cell lymphoma
Starry-Sky appearance
Burkitt’s lymphoma
Sheets of large lymphoid cells
Diffuse large B cell lymphoma
Angular nuclei
Mantle cell lymphoma
T(14,18)
Follicular lymphoma
H.pylori lymphoma
Mucosal associated lymphoid tissue lymphoma
T(11,14)
Mantle Cell lymphoma
Ritcher’s Transformation
From chronic lymphocytic leukemia (CLL) and hairy cell leukemia —> DLBL
BLIMP1
XBP1
Markers of Plasma Cell
Chromosome 13 deletion OR Translocation at 14q32 OR Hyperdiploid affect chromosomes with uneven numbers (3, 7, 9 etc.)
MGUS
additional k-ras or classical oncogenic mutation –> multiple myeloma
Monoclonal Gammaglobinopathy of Unknown Significance
Pre-clinical abnormality
<10%plasma cells in bone marrow
<30g/l monoclonal paraprotein
No CRAB
Smouldeirng Myeloma
> 10% plasma cells in bone marrow
> 30g/l monoclonal paraprotein
BUT no CRAB
Waldenstrom’s Macroglobinaemia (Lymphoplasmacytoid Lymphoma - LPL)
Elderly men
Low grade NHL
Lymphoplasmacytoid cell sproduce monclonal IgM (unlike IgG in Multiple myeloma)
Infiltrates BM and LN
Weight loss, fatigue, hyperviscosity syndrome,
Tx: chlorambucil, cyclophosphamide,
Apple-green birefringence
Amyloidosis
Blood Film Features of Myelodysplastic Syndrome
Hypercellular bone marrow
Ring sideroblasts
Pelger-Huet anomaly (bilobed neutrophils)
Dysganulopoieses of neutrophils
Myelokathexis of neutrophils & precursors
Dyserythropoiesis of red cells
Dysplastic megakaryocytes – e.g. micro megakaryocytes
PROGNOSTIC SIGNIFICANCE: Increased proportion of blast cells in marrow (normal < 5%)
Myelokathexis of neutrophils
Shattered nuclei in bone marrow
=myelodysplastic syndrome
International Prognostic Scoring System for Myelodysplastic Syndrome
Predict development of acute myeloid leukaemia
Blast cell proportion
Karyotype: Chromosomal Abnormalities
Haemoglobin level
Platelet level
Neutrophil level
Very good: -Y, del(11q)
Good: normal, -Y, del(5q), del(12q), del(20q)
Intermediate: del(7q), +8,+19
Poor: complex (3 abnormalities), -7, double abnormalities inc. -7 or del(7q)
Very Poor: > 3 abnormalities
Treatment of MDS
Supportive care
Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF)
Biological Modifiers
Immunosuppressive therapy
Azacytidine
Lenalidomide (5q- syndrome)
Inherited Aplastic Anaemia
Fanconi’s Anaemia
Dyskeratosis Congenita
Schwachman-Diamond Syndrome
Diamond-Blackfan Syndrome
Fanoni’s Anaemia
AR
5-10 years
Skeletal abnormalities (Radii, thumbs)
Renal malformations
Microopthalmia
Short stature
Skin pigmentations
Increased AML
Dyskeratosis Congenita
C-linked
Telomere shortening (Chromosomal instability)
Triad
Skin pigmentation
Nail dystrophy
Oral leukoplakia
Bone marrow failure
Schwachman-Diamond Syndrome
AR
Skeletal abnormalities
Pancreatic dysfunction
Endocrine dysfunction
Hepatic impairment
Increased AML
Diamond-Blackfan
Pure red cell aplasia
Normal WCC and platelets
Dysmorophic
Myeloproliferative disorders
Ph positive
CML
Ph negative
Polycthaemia vera
Myelofibrosis
Essential thrombocytosis
Polycythaemia
Primary
Polycythaemia vera
Familial polycythaemia
Secondary (due to Increased EPO)
Altitude
Renal cancer
Chronic Hypoxia
Anagrelide
treatment of essential thrombocytosis
Lowenstein-Jensen Medium
TB
Gram +ve rods
Acid fast
Aerobic
Intracellular
TB
Treatment TB meningitis
1 year TB therapy
+ corticosteroids
Post infleunza infection + cavitation on CXR
Staph aureus pneumonia
Rusty sputum
Lobar pneumonia on CXR
Steptococcus pneumonia
positive diplococci
Smoker/COPD with pneumonia
Haemophilus influenzae
negative cocco-bacilli
Pneumonia in alcoholic
Klebsiella
negative rod enterobacter
negative coccus pneumonia in a smoker
M.catarrhalis
Typical Pneumonia
=signs of pneumonia on examination
Streptococcus pneumonia
Haemophilus influenza
M.catarrhalis
Staph Aureus
Klebsiella pneumonia
Atypical Pneumonia
Not classic signs of pneumonia on examination
Legionella
Mycoplasma
Chlamydia pneumonia
Chlamydia psittaci
Bordatella pertusis
TB
Air conditioning
Hepatitis
Hyponatraemia
Legionella pneumophilia
Joint pain
Cold agglutins
Erythema multiforme
Mycoplasma
Respiratory tract infections in HIV
PCP
TB
Cryptococcus neoformans
Neutropenia and Respiratory tract infections
Fungi - Aspergillus
Bone marrow transplant and Respiratory tract infections
Aspergillus
CMV
TWAR agent
Chlamydia pneumonia
Mild-moderate CAP antibiotics
Amoxicillin
OR
Macrolide
Moderate-severe CAP antibiotics
Clarithromycin
AND
Co-amoxiclav
OR
Cefuroxime
Atypical CAP Antibiotics
e.g. chlamydia , mycoplasma
Macrolide
Tetracycline
Hospital Acquired Pneumonia Antibiotics
1st Line: Ciprofloxacin +/- vancymycin
Aspiration Pneumonia Antibiotics
Cefuroxime
AND
Metronidazole
Legionella Antibiotics
Macrolide
AND
Rifampicin
Staph Aureus pneumonia Antibiotics
Flucloxacillin
Psuedomonas spp. Antibiotics
Piperacillin + tazobactam (Tazocin)
OR
Ciprofloxacin +/- Gentamicin
MRSA antibiotic
Vancomycin
Gonorrhoea Mx
Ceftriaxone IM 250 mg single dose
OR
Cefixime PO 400mg single dose
if resistant –> Spectinomycin 2g single dose (binds to the 30S subunit of the bacterial ribosome)
Spectinomysin
Treatment of resistant gonorrhoea
Binds to the 30S subunit of the bacterial ribosome
Treatment of Chlamydia
Azithromycin 1g (4 capsules) Single dose
OR
Doxycycline 100mg BD 7 days
Treatment of LGV
Doxycycline 100mg BD for 21 days
Syphilis
Gram neg spirochaete
Treponema pallidum
IM ben pen
Argyll-Robertson Pupil
Accommodates but does not react
Tertiary syphilis
Jarisch-Heimer reaction
Fever, headache, myalgia, exacerbation of syphilitic symptoms
AFTER
Treatment with IM ben Pen
Chancroid
Haemophilus ducreyi
Gram neg cocoobacillus
Painful ulcers
Granuloma inguinale
Klebsiella granulomatis
Gram neg bacilus
Large expanding ulcer
Beefy red appearance
Tx: azithromycin
Molluscum contagiosum
poxvirus
dsDNA
In adults = HIV
Cryptococcal Meningitis Tx
Amphotericin B
Herpes Encephalitis
HSV-1
Mollaret’s meningitis
Recurrent aseptic meningitis
HSV-2
Pleiocytosis
HSV meningitis
Tzank cells
Multinucleated giant cells
VZV
VZV Tx
If adult
Neonate
Immunocompromised
Eye involvement
Aciclovir 800mg TDS
Owl’s eye inclusion
= CMV
Treatment of CMV
Ganciclovir
Infectious Mononucleosis
Triad:
Fever
Pharyngitis
Lymphadenopathy
CMV in BMT
=Pneumonitis
CMV retinitis
=AIDS
Paul Bunnel monospot
=CMV
HHV-8
Kaposi’s sarcoma
Castlemann’s syndrome
Tx: ganciclovir
PUO
Fever > 38.3º C
On several occasions
persisting without diagnosis for at least 3 weeks in spite of at least 1 weeks investigation
Classical PUO
Abscesses Endocarditis Tuberculosis Complicated urinary tract infections Fever in returning traveller HIV Connective Tissue/Vasculitis Neoplasms
Fever in the Returning Traveller
Malaria 21% Dengue 6% Typhoid 2% Rickettsia 2% Bacterial diarrhoea 3% Urinary tract infections 2% Brucella (indolent) Viral heam’ fever
Neutropenic fever
Aspergillus
Roth Spots
Retinal haemorrhages
If fever think endocarditis
leukemia, diabetes, subacute bacterial endocarditis, pernicious anemia, ischemic events, hypertensive retinopathy and rarely in HIV retinopathy.
Choroid tubercle
=Intraocular TB
Histoplasmosis
Immunocompromised
Temperate climate
Dimorphic fungus
Non-specific respiratory symptoms, often cough or flu-like
Chest X-ray findings are normal in 40–70% of cases.
Chronic histoplasmosis cases can resemble tuberculosis
Disseminated histoplasmosis affects multiple organ systems and is fatal unless treated
Infective Endocarditis
Prosthetic valve –> think endocarditis
Damaged heart valve form rheumatic heart disease –> more likely to get endocarditis
Valves involved are mitral valve, aortic valve most commonly
Fever 90%
Heart murmur 85%
Changing murmur 5-10%
Fever 80%
Chills 40%
Weakness 40%
Dyspnoea 40%
Causes of endocarditis
Viridans streptococci (oral) 60-80%
Enterococci 30-40%
Staph. aureus 10-27%
Gram negative bacilli 1.2-13%
Fungi 2-4%
Rare..Rothia, Cardiobacterium, etc
Coagulase negative staphylococci (CNS) cause most cases of prosthetic valve endocarditis
Duke Criteria
Pathologic criteria
1.Microoraginsms demonstrated by culture or histologic examination of a vegetation, a vegetation that has embolised, or an intracardiac abscess specimen
- Pathologic lesions: vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis..\BIT LATE!!
B Clinical criteria
Two major criteria
One major and 3 minor criteria
Five minor criteria
Treatment of Endocarditis
For strep. viridans endocarditis
Combination of benzylpenicillin and gentamicin
For enterococcal endocarditis
Combination of ampicillin and gentamicin
MSSA endocarditis - flucloxacillin for 4-6 weeks
MRSA endocarditis – Vancomycin and gentamicin or rifampicin or fucidin
Typhoid
Salmonella typhi and paratyphi
Anaerobic gram neg bacillus
Enteric fever
Infection of Peyer’s patches
Fever, abdo pain, headache, constipation, relative bradycardia
Hepatosplenomegaly
Rose spots
Malaria Species
P. Falciparum
P. Vivax
P. Ovale
P. Malariae
Fever Patterns of Malaria
P. Falciparum = tertian 48 hr OR 24 h
P. Vivax = 48 hr
P. Ovale = 48 hr
P. Malariae = 72 hr (Quartan)
P. Falciparum complicated infections
Resists removal from spleen
Clumping of red cells in capillary beds
Blocks blood flow to organs
Haemolytic organs + reduced perfusion = bad
- cerebral malaria = confusion, seizures, coma
- bilious malaria = vomiting, diarrhoea, jaundice and liver failure
lungs
kidney
spleen
=sepsis-like clinical picture
Diagnosis of Malaria
Thick film = identifies parasites in red cells
Thin film = identifies specific plasmodium species
Treatment of P. Falciparum Malaria
Mild
Quinine + Doxycycline / Clindamycin
OR Malarone
OR Riamet
Severe
Artemisinin combination therapy
OR
Quinine + Doxycycline/Clindamycin
Treatment of P. Vivax / P. Ovale Malaria
Chloroquine and then Primaquine
Schnuffer’s dots
P. Vivax
P. Ovale
Young trophozoites (Rings)
Absence of mature trophozoites
Crescent-shaped gametocytes
P. Falciparum malaria
Antibiotics prone to causing C. Diff
The 3 Cs
Cephalosporins
Clindamycin
Ciprofloxacin
129 codon MM
CJD
Serial EEG: periodic triphasic changes
Sporadic CJD
Brucellosis
Gram negative aerobic bacilli
Facultative intracellular
Untreated diary
Undulant fever
Malaise, rigors, arthralgia, tiredness
Spinal tenderness, lymphadenopathy, splenomegaly, heaptomegaly
Epididymo-orchitis
Anti-O-polysaccharide antibody
WCC normal
Tx: tetracycline OR Doxycyline
Combined with streptomycin
Anti-O-polysaccharide antibody
=Brucellosis
Negri bodies
=Rabies
Erythema chronicum migrans
Bulls-eye rash
= Lyme disease
Treatment for Lyme Disease
Doxycycline 2-3 weks
If CNS disease –> Ceftriaxone
Q fever
Coxiella burnetii
Looks like atypical pneumonia
Painless round black lesion + rim of oedema
=Anthrax
Massive lymphadenopathy + mediastinal haemorrhage + pleural effusion (resp failure)
Pulmonary Anthrax
Leptospirosis
Gram negative aerobic motile spirochaetes
Excreted in dog, rate urine
Swimming in contaminated water
Spiking temp, headache, conjunctival haemorrhage, jaundice, malaise, myalgia, meningism, carditis, renal failure, haemolytic anaemia
Amoxicillin, Erythromycin, Doxycyline, Ampicillin
Cutaneous Leishmaniasis
Sandfly (South and Central America + Middle East)
Skin ulcer at site of bite
Multiply in dermal macropahges
Heals after 1 year –> leaves depigmented scar
Type IV reaction
L. major
L. tropica
L. braziliensis
Muco-cutaneous Leichmaniasis
L. donovani
L. infantum
L. chagasi
Visceral Leichmaniasis
Kala-Azar
Increase PR interval on ECG with bacterial endocarditis
Periventricular abscess –> need surgical intervention
Inx for bacterial endocarditis
at least 3 different blood cultures
Amantadine
Targets M2 ion channel
mutation S31N in M2 = resistance
Neuraminidae inhibitors
Oseltamivir
Zanamivir
Sialic acid
Influenza A
8 RNA segments
NA
HA
CMV complications (RCHEP)
Retinitis Colitis Hepatitis Encephalitis Pneumonitis
Guanosine analogue
Aciclovir
Activated by viral thymidine kinase
Pyrophosphate analogue
Foscarnet
Inhibits nucleic acid synthesis without requiring activation
Ganciclovir
Used to treat CMV
also EBV and HHV-6
Nucleoside analogue
Side effects: bone marrow suppression
Nucleoside phosphonate
Cidofovir
Used in CMV retinitis
And post-transplant
Treatment of HSV
IV aciclovir
If resistant Valaciclovir and Famciclovir
Act Very Fast
A
V
F
Treatment for Hepatitis B
Entecavir
Peg IFN alpha2 (subcut)
Tenfovir
Tenofovir
Inhibitor of reverse transcriptase
Treatment for Hepatitis C
Peg INF 2b/2a
Ribavirin
Works bets in genotypes 2 and 3
Ribavirin
RNA nucleoside analogue
(causes hamolytic anaemia)
Used in Hep B
AND adenovirus Tx in paediatric post-transplant
CMV pos and neg in transplant
Solid organ:
Recipient neg –> donor must be neg
BM transplant
Recipient pos –> donor must be pos
HHV-6 treatment
Ganciclovir
Foscarnet/Cidofovir
Treatment of Pyelonephritis
Co-Amoxiclav
+/-
Gentimicin
OR
Cefuroxime
+/-
Getamicin
Four mechanisms of resistance = BEAT
Bypass antibiotic-sensitive step e.g. MRSA
Enyme-mediated destruction e.g. beta-lactamase
Accumulation reduction e.g. Tetracycline
Target change (modify protein targeted by antibiotics) e.g. Quinolone resistance
Treatment of Meningitis
Ceftriaxone
Corticosteroids
Ampicillin
Hep B antibodies
HBsAntibody = chronic carrier
HBeAntibody –> low infectivity in carrier
HBcAntibody
IgM –> recent infection
IgG –> previous expsoure to HBV (cleared and chronic carriers)
Diagnosis of Diabetes
Fasting Glucose >7.0mM
If still suspicious but fasting negative –>
OGTT 2 hour >11.1
HbA1c >6.5% OR >48mmol/mol
Management of Hypokalaemia
3.0-3.5
Oral KCl Sandok Tablets for 48 hours
Recheck K+
<3.0
IV KCl
Max rate 10nmol/h
>20nmol/h highly irritant to veins
Gitelman Syndrome
Autosomal recessive kidney disorder
Hypokalaemia
Low magnesium
Decreased excretion of calcium in the urine
Elevated blood pH
Caused by loss of function mutations of the thiazide-sensitive sodium-chloride symporter
Located in the distal convoluted tubule of the kidney
Bartter Syndrome
Rare inherited defect in the thick Ascending limb of the loop of Henle
Hypokalemia
Alkalosis
Normal to low blood pressure
Polyuria, and polydipsia
Calciuria
Two types of Bartter syndrome: neonatal and classic
Management of Hyperkalaemia
U&Es, ECG, drug review
10ml 10% Calcium gluconate
50ml 50% dextrose + 10 units of insulin
Nebulised salbutamol
sgk-1
Under control of aldosterone
Inhibits Nedd4, normally tags ENac for degredation
sgk-1 –> sodium reabsorption
Elevated Anion Gap (KULT)
Ketoacidosis (DKA, alcoholism, starvation)
Uraemia (renal failure)
Lactic acidosis
Toxins (ethylene glycol, methanol, paraldehyde, salicyclate)
AST : ALT 2:1
Alcoholic liver disease
AST : ALT <1:1
Viral liver disease
GGT
Raised in alcohol and bile duct disease
Found in hepatocytes and epithelium of small bile ducts
Raised ALP and Dilated Ducts
=mechanical obstruction
Gallstones
Cancer
Raised ALP and ducts NOT dilated
=injury of the bile duct
Primary biliary cirrhosis
Primary sclerosing cholangitis
Toxic injury of bile ducts (drugs: augmentin)
Pregnancy
Low urobilinogen
Obstructive jaundice
raised in haemolysis
Decreased Albumin
Sepsis
Warfarin use
Nephrotic syndrome OR protein losing enteropathy e.g. IBD
Chronic liver disease
Triad of
Abdominal Pain
Psychiatric Symptoms
Neurological symptoms
Porphyria
PBG Synthase deficiency
ALA Dehydratase / Plumboporphyria
HMB Synthase deficiency
Acute Intermittent Porphyria
Coproporphyrinogen oxidase deficiency
Hereditary Coproporphyria
Protoporphyrinogen oxidase deficiency
Variegate Porphyria
Uroporphyrinogen III synthase deficiency
Congenital eryrthopoietic porphyria
Uroporphyrinogen decarboxylase deficiency
Porphyria cutanea tarda
Ferrochetolase deficiency
Erythropoietic protoporphyria
Glucose level cut-off for triple test
<2.2
Homovanillic acid in urine
= Neuroblastoma
Waterhouse–Friderichsen syndrome
hemorrhagic adrenalitis or fulminant meningococcemia is defined as adrenal gland failure due to bleeding into the adrenal glands
Commonly caused by severe bacterial infection
Typically the pathogen is the meningococcus Neisseria meningitidis
Treatment for Grave’s
Carbimazole
Propylthiouracol
Inhibit thyroperoxidase enzyme
Schmidt’s
Polyglandular autoimmune type II
Addison’s
Autoimmune hypothyroidism
MEN II
Thyroid (medullar carcinoma)
Parathyroid
Phaeochromocytoma
MEN I
Pituitary
Parathyroid
Pancreas
Cacitonin
Tumour marker for Medullary carcinoma of thyroid
Produced by C cells
Reduce blood calcium, opposing the effects of PTH
Medullary carcinoma
MEN II
Calcitonin tumour marker
cancer of C cells
Thyroglobulin
Tumour marker for Follicular thyroid cancers
Produced by follicular cells
Precursor of the thyroid hormones; these are produced when thyroglobulin’s tyrosine residues are combined with iodine and the protein is subsequently cleaved
Treatment of papillary and follicular thyroid cancers
T4 –> suppresses TSH (TSH dependent)
removal of thyroid gland
Radioiodine to irradicate any remaining cells
Ataxia and nystagmus
Phenytoin toxicity
Omit dose
Arrhythmias, heart block, confusion, xanthopsia
Digoxin toxicity
Digibind
Tremor, lethargy, fits, arrhythmia, renal failure
Lithium toxicity
Haemodialysis
Tinnitus, deafness, nystagmus, renal failure
Gentamicin toxicity
Omit dose
Arrhythmias, anxiety, tremor, convulsion
Theophyline toxicity
Omit dose
Normal plasma calcium
2.2-2.6
Adjusted calcium
= 40 - 0.02[albumin]
When you measure calcium you measure the albumin-bound form
If you have low albumin, you can get a falsely low Ca2+ measurement –> use adjusted calcium
3 Important causes of Hypercalcaemia
Primary hyperparathyroidism
Malignancy of bone OR ectopic PTH
Sarcoidosis
Treatment of Hypercalcaemia
(if unwell or >3.0)
FLUIDS FLUIDS FLUIDS
IV saline 0.9% (4L/24h)
Furosemide
IV Pamidronate (30-60mg) Bisphosphonates if bony metastasis (slow invasion and decrease pain)
Causes of Hypocalcaemia
Vitamin D deficiency
Chronic kidney disease
Hypoparathyroidism
Pseudohypoparathyrodism
Magnesium deficiency
DiGeorge
Looser’s zone
=vitamin D deficiency
Radial aspect cystic changes
Primary hyperparathyroidism
Management of Sarcoidosis
40mg steroids / day
Band keratopathy
=Hypercalcaemia
(Not cancer, takes too long to develop and cancer would have killed them by then)
Ca deposits in band in front of cornea
Causes of Osteomalacia
Vitamin D Deficiency
Chronic kidney disease
Anticonvulsants
Chappatis (phytic acid chelates Vit D in gut)
Causes of Hypercalcaemia
PTH raised = don’t have cancer
Primary PTH adenoma
Familial hypocalciuric hypercalcaemia
PTH NOT raised = cancer
Squamous cell carcinoma
Ectopic PTHrP (neonatal marker = poor prognosis)
Bony metastasis e.g Breast cancer
Myeloma
Familial hypocalciuric hypercalcaemia
Calcium sensing receptor (CaSR) mutation
Right shift: Higher PTH for a given Ca
More PTH –> More Ca in blood, less in urine
Diagnostic Criteria for an Acute MI
EITHER
1) Typical rise and gradual fall of troponin OR rapid rise and fall CK-MB with at least one of the following:
- ischaemic symptoms
- pathological q wave on the ECG
- ECG changes indicative of ischaemia
- Coronary artery intervention
OR
2) Pathological findings of an acute MI
PKU
Phenylaline hydroxylase deficiency
T cell deficiencies
Bare Lymphocyte Syndrome
DiGeorge’s Syndrome
Regulatory Factor X defect
Bare lymphocyte syndrome
Absent MHC Class I
Bare lymphocyte syndrome Type 1
Absent MHC Class II
Bare lymphocyte syndrome Type 2
Membranoproliferative nephritis and bacterial infections
C3 deficiency with presence of a nephritic factor
HLA B27
Ankylosing spondylitis
HLA DR15 / HLA DR2
Goodpasture’s
HLA-DR3
Graves
SLE
Type I diabetes
HLA DR3 / HLA DR4
Type I Diabetes
HLA DR4
Rheumatoud arthritis
Type I Diabetes
PTPN22
Tyrosine phosphatase expressed in lymphocytes
Associated with Rheumatoid Arthritis, SLE and Type 1 Diabetes
CTLA4
Receptor for CD80/86 expressed by T cells
Expressed in Tregs
Inhibitory control of cell activation
SLE
Type 1 diabetes
Autoimmune thyroid disease
Human Normal Immunoglobulin
Antibody replacement
Pooled from 1000s of donors
Every 3-4 weeks IV or subcut
Used for:
CVID
Bruton’s
Post-BMT
INF-alpha
Hepatitis B
Hepatitis C
Kaposi’s Sarcoma
Hairy cell leukaemia
Chronic Myelogenous Leukaemia
Malignant Myeloma
INF-beta
MS
INF-y
Chronic granulomatous disease
Dihydrofolate reductase (DHFR) inhitor
Methotrexate
GVHD Prophylaxis
Methotrexate/Cyclosporine
HIV routine treatment
Atripla =
- Emtricitabine
- Tenofovir
- Efavirenz
HIV in pregnancy
Zidovudine
CD45 RO
Memory T cells
CD45 RA
Naive T cells
Effector memory T cells
CCR7-
CD26 low
Not found in lymph nodes
Perforin and IFN-y
Central Memory T cells
CCR7+
CD26 high
Lymph nodes
IL-2
Alum
Adjuvant used in human vaccine
Activates Gr1 cells to produce IL-4
Primes naive B cells
Gas gangrene
Clostridium perfringens
Urinary 5-HIAA
Carcinoid syndrome (Bronchoconstriction, Flushing, Diarrhoea)
Metabolite of serotonin
APC gene
First hit in adenocarcinoma colon cancer
FAP
Multiple polyps
Mucocutaneous hyperpigmentation
Freckles around mouth, palms and soles
Peutz-Jeghers syndrome
AD - LKB1
Increased risk of intussusception and malignancy
Characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa (melanosis).
Juvenile polyposis
AD
< 5 yrs
May require colectomy
Duke’s Staging
A: confined to mucosa (95% 5ysr)
B1: extending into muscularis propria (67% 5ysr)
B2: transmural invasion, no lymph node involved (54% 5ysr)
C1: extending to muscularis propria, with LN metastases (43% 5ysr)
C2: transmural invasion, no lymph node involved (43% 5ysr)
D: distant metastases (<10%5ysr)
CCK
causes release of digestive enzyme
Produced by I-cells in duodenum
Secretin
Controls gastric acid secretion with HCO30 buffering
Produced by S-cells of duodenum
Coagulative necrosis
Acute pancreatitis
Raised serum Lipase
Acute Pancreatitis
Causes of Acute Pancreatitis
Idiopathic
Gallstones
Ethanol
Trauma
Steroids Mumps Autoimmune Scorpion Hyperlipidaemia ERCP Drugs (thiazides)
Causes of chronic pancreatitis
Alcoholism
Cystic fibrosis
Hereditary
Pancreatic duct obstruction (stones, tumour, autoimmune IgG4 scerlosing)
Fibrosis and loss of exocrine tissue, duct dilation with thick secretions and calcification
Chronic pancreatitis
CA19.9
Pancreatic carcinoma (acinar)
Functional neuroendocrine tumours
Insulinoma
Gastrinoma (Zollinger-Ellison syndrome)
VIPoma
Glucagonoma
Alpha fetoprotein
Hepatocellular carcinoma
Benign tumours of liver
Hepatic adenoma = OCP
Haemangioma
Bile duct adenoma
Malignant tumours of the liver
HCC
Angiosarcoma
Hepatoblastoma (in young children, primitive hepatocytes)
Cholangiosarcoma (adenocarcinoma) - PSC, Chronic liver disease, Lynch syndrome II (HNPCC), parasitic liver disease
Metastatic: most common
Usually form GI tract
/breast/ bronchus
Cirrhosis Histology
Hepatocyte necrosis
Fibrosis
Nodules of regenerating hepatocytes
Disruption of liver architecture (resistance to blood flow –> portal hypertension)
Genetic causes of liver cirrhosis
Haemochromatosis = HFE gene chromosome 6
Wilson’s disease = ATP7B chromosome 13
A1AT deficiency
Galactosaemia
Glycogen storage disease
Micronodular cirrhosis
< 3mm Uniform
Alcoholic hepatitis
Biliary tract disease
Macronodular cirrhosis
> 3mm
Viral hepatocytes
Wilson’s disease
A1AT deficiency
Modified Pugh Score
Liver cirrhosis prognosis
> 10 = v bad <20% 5yrs
Causes of Portal Hypertension
Pre-hepatic
Portal vein thrombosis (e.g. Factor V Leiden)
Hepatic
Pre-sinusoidal: Schistosomiasis, PBC
Sinusoidal: Cirrhosis
Post-sinusoidal: veno-occlusive disease
Post-hepatic
Budd-Chiari syndrome: occlusion of hepatic vein
Bile duct loss + granuloma
Primary biliary cholangitis
Low ceruloplasmin
Wilson’s
Direct Van den Bergh
Conjugated
Complete —> unconjugated
Onion-skinning fibrosis + multi-focal strictures
Primary sclerosing cholangitis
Rhodanine stain
Copper
Wilson’s
Periodic acid Schiff
Stain A1AT
Treatment of Haemochromatosis
Desforrioxamine
Venesection
Treatment of Wilson’s
Penicillamine
Macroglossia
Heart failure
Hepatomegaly
Amyloidosis
HLA-DRB1
Goodpasture’s
Thrombotic microangipathies
Thrombosis
+MAHA
+Thrombocytopenia
+renal failure (mostly in HUS)
Causes
TTP - diffuse, esp in CNS
HUS - confined to kidneys
TTP = headache, altered consciousness HUS= renal failure
Liver cysts and berry aneurysm with reduced GFR
PKD1
Chromosome 16 autosomal dominant
Sharply circumscribed, discrete, round, firm, grey-white tumours
Fibroid
Tamoxifen
oestrogen receptor antagonist/agonist
Herceptin / Trastuzumac
Monoclonal Ig to HER2 (breast cancer)
