Haematology notes Flashcards
(103 cards)
What is the mutation involved in genetic haemochromatosis?
What is the result of this?
HFE gene mutation (HFE =High Fe) which codes for hepcidin
If mutated there is impaired production of hepcidin which causes an upregulation of ferroportin 1 transporter in enterocyte. This causes unopposed absorption of iron in the gut causing increased iron uptake.
Before giving IV iron supplements what must be checked?
What complications of IV iron?
IV iron is contraindicated in active sepsis
* Siderophilic organisms that require iron to function will thrive in iron rich enviroment
Complications
* Extravasation of iron when doing IV drip if requires multiple punctures to secure IV line. Dermal level accumulation of iron. Can do saline test to see if there is adjacent swelling post test indicating leakage.
What is the classification for amyloidosis?
- Systemic amyloidosis or localized amyloidosis
- Acquired or hereditary amyloidosis
What are the types of systemic amyloidosis?
**AL amyloidosis **(light chain amyloidosis or primary amyloidosis)
* Light chains of Ig become AL amyloid protien
* Etiology: plasma cell dyscrasias (e.g. multiple myeloma)
* Typically affects the heart, kidney, tongue, peripheral and autonomic nervous system, GIT. Rapidly progressive clinical course
AA amyloidosis (reactive amyloidosis or secondary amyloidosis)
* Serum amyloid associated protein (SAA) becomes AA amyloid protein
* Etiology: chronic inflammatory conditons (e.g. IBD, RA, SLE), chronic infections (e.g. TB, osteomyelitis), RCC, lymphomas
* May occur at any age: most common in children. Typically affects the kidney, liver and spleen, GIT, adrenal glands.
* Disease progression can be slowed by managing the underlying condition
AB2M amyloidosis (B2 microglobulin amyloidosis or haemodialysis associated amyloidosis)
* B2 microglobulin becomes AB2M amyloid protein
* Etiology: long term haemodialysis, end stage renal disease
* Features: develops 10 years after starting. Typically affects joints and tendons, manifesting with scapulohumeral periarthritis, carpal tunnel syndrome, bone cysts
ATTRmt amyloidosis (mutated transthyretin amyloidosis, ATTRv (variant) amyloidosis, or hereditary transthyretin amyloidosis)
* Transthyretin is mutated transthyretin (ATTR): autosomal dominant disease
* Familial amyloid cardiomyopathy: typical age of onset: >60 years. Affects endomyocardium
* Familial amyloid polyneuropathy. Typical age of onset: >20 years, affects peripheral and autonomic nerves
ATTRwt amyloidoisis (wild type transthyretin amyloidosis or senil cardiac amyloidosis
* Normal transthyretin (ATTRwt) –> deposition in cardiac ventricles –> cardiac dysfunction (less drastic than in AL amyloidosis
* Median age of dx is 75 years. Typically affects the heart, ligaemnts and tendons, peripheral nerves
Approach to make dx of amyloidosis?
Tissue sample: target organ (kidney/nerve) preffered in patients with single organ involvement. Abd fat inspiration or rectal mucosa preferred in patients with multiorgan and/or tissue involvement
Methods
* Congo red stain to confirm amyloid deposition
* Histology shows apple-green birefringence under polarized light
* Additional findings from an affected kidney may include deposits in glomerular mesangial areas and enlarged tubular basement membranes that can be identified via light microscopy.
Gold standard is mass spectrometry
IHC light chain (if demonstrated can indicate AL amyloidosis)
What is the etiology of AL amyloidosis?
What pathophysiology
What clinical features?
Etiology: low level expansion of a plasma cell dyscrasia (e.g. multiple myeloma, Waldenstrom macroglobulinemia)
Patho: increased production of the light chains of immunoglobulins –> deposition of amyloid light chain protein A(L) in various organs
Clinical features
* Skin: cutaneous ecchymoses around the eyes (raccoon eyes), combined with yellow waxy papules
* Heart: restrictive cardiomyopathy, HFpEF, AV block
* Kidney: nephrotic syndrome, type 2 RTA, nephrogenic DI
* Tongue: macroglossia (specific to AL amyloidosis): OSA
* ANS: autonomic neuropathy
* GIT: malabsorption, hepatomegaly
* Haematopoietic system: bleeding disorders, splenomegaly
* Musculoskeletal system: carpal tunnel syndrome (may be bilateral), shoulder pad sign
What are the diagnostic Ix for AL amyloidosis and its management
Tissue biopsy
Assessment of organ involvement, including ECG, cardiac imaging
Obtains diagnostics for plasma cell dyscrasias to identify the underlying cause
* Serum electrophoresis: monoclonal gammopathy
* Urine protien electrophoresis (UPEP) with immunofixation: Bence-Jones proteins
Suspect AL amyloidosis in patients with multiple affected organs (heart failure with preserved ejection fraction, nephrotic range protienuria, peripheral neuropathy, hepatomegaly and/or noninfectious diarrhea), and/or atypical MGUS or smoldering multiple myeloma
Management
Control of underlying plasma cell dyscrasia with chemotherapy eg. melphalan + corticosteroids, thalidomide, bortezomib
Rapidly progressive clinical course if left untreated
Median survival time without treatment is 1-2 years
What is the etiology of AA amyloidosis?
Pathophysiology?
Clinical features?
AA amyloidosis is secondary to a chronic disease, such as:
* Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis, SLE, vasculitis, familial Mediterranean fever)
* Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, osteomyelitis)
* Malignancy (e.g., renal cell carcinoma, lymphomas)
Pathophysiology
Chronic inflammatory process → ↑ production of acute phase reactant SAA (serum amyloid-associated protein) → deposition of AA (amyloid-associated) protein in various organs
Clinical features
* Kidney: nephrotic syndrome, type II renal tubular acidosis, nephrogenic diabetes insipidus
* Adrenal glands: primary adrenal insufficiency
* Liver and spleen: hepatomegaly, splenomegaly
* Gastrointestinal tract: malabsorption
* Heart (rare): severe thickening of ventricular wall
Main feature of AA amyloidosis at dx is renal dysfunction (CKD, nephrotic syndrome). Cardiac involvement is rare.
What are the dx tests for AA amyloidosis and management?
Kidney tissue biopsy findings
* Global and segmental amyloid deposition
* Diffuse and/or focal glomerular involvement
* Enlargement of glomeruli
* Tubular atrophy
* Interstitial fibrosis
Assessment of organ involvement, including BMP, estimated GFR, urinalysis
For suspected cardiac involvement: multiparametric CMR (including late gadolinium enhancement imaging)
Identify the underlying inflammatory disosrder (if not yet known) consider: CXR, inflammatory markers (ESR, CRP)
Managaement
Treat the underlying condition to reduce AA production (mainstay of treatment) e.g. colchicine for FMF
Provide supportive care for associated complications (CKD)
What are the clinical phenotypes of ATTRmt amyloidosis, etiology and the affected sites?
What are the types of localized amyloidosis and organs affected?
What nuclear imaging used to assess severity of cardiac amyloidosis?
Tc-99m PYP (pyrophosphate) nuclear scan is useful for transthyretin amyloid (ATTR). Not useful for AL amyloidosis.
What amyloidosis associated with haemodialysis patients?
What clinical features may there be?
AB2M amyloidosis (B2 microglobulin)
Will accumulate amyloid protiens (misfolded proteins) that mainly deposit in the joints
May manifest as carpal tunnel syndrome
What are the general principles of management of sarcoidosis?
If there is heart involvement how does this affect prognosis?
Drugs used to stop the production of amyloid proteins.
If there is extensive adherence of proteins to the heart with heart failure –> difficulty in the amyloid protien disolving away from the organ.
What are the 2 types of transthyretin in amyloidosis?
Hereditary (hATTR-CM) and wild type (wATTR-CM) which is acquired
What is the initial Ix if suspicious of lymphoma?
PBS for lymphocytosis. If looks abnormal do flow cytometry (immunophenotype). If CD antigens are present it is clonal B cell in circulation (T cell is less common)
Can do light chain restriction
Or Ig rearrangement to prove those B cells are clonal
Plasma cell disorders will 90% elevated lambda chain, only 10% is kappa
If positive in peripheral blood –> already stage 4 lymphoma (as in systemic circulation)
How do you work up a patient with thrombocytosis?
Work up to rule out secondary thrombosis
* CXR (rule out CA lung)
* CEA +/-colonoscopy (rule out CA colon)
* CRP, ESR (underlying inflammation)
Wont do rheumatic work up (as expensive)
Causes of secondary thrombocytosis: infection, inflammation, malignancy, iron deficiency anemia)
How to do the workup for suspected PV?
- Peripheral blood do JAK2V617F (cytogenetics). If present in the blood does not require bone marrow biopsy –> indicates that its clonal (carries the same mutation)
- Minority of case (10%) without JAK2 V617F requires bone marrow biopsy: must do CALR exon 12
Used to rule out prefibrotic PMF or ET
What are the causes of reversed albumin: globulin ratio?
What are the causes for increased albumin/globulin ratio?
Not common and should raise suspicion in paeds
Patient with mechanical heart valve leak presents with leukopenia + increased LDH and urate (elevated to four digits). What could be the cause?
Valve related haemolysis
ITP
MUST RULE OUT HAEM MALIGNANCY since urate and LDH should not be this high
What Ix should be done and in what order for persistent lymphocytosis?
- PBS first to assess morphology (is there dysfunctional/morphological issue)
- Flow cytometry (protein expression on cells) to determine clonality (CD5 on T cell is less common: if its high most likely clonality). Can see light chain expression (kappa or lambda restricted than it is more compatible with clonal)
- IgH gene rerrangement and TCR gene rearrangement using PCR (peripheral blood of bone marrow aspirate): should have lots of variation in VDJ rearrangement and T cell receptors (shows functional immune system)
If clonal abnormality than do FISH (for prognosis not for proving clonal)
At this stage the diagnosis of clonality is already made. If it is leukemia than it necessitates bone marrow biopsy aspirate and trephine biopsy to confirm.
Why is chromosome 17p deletion bad prognosis for CLL?
- Short head of chromosome 17 contains TP53 tumor suppressor gene (any strain breaks will repair). If absent does not know how to do apoptosis.
- Will not respond to chemotherapy. As chemotherapy induces DNA breaks. So even if there is DNA breaks there is no apoptosis.
- Hence other therapy such as venetoclax which is a bcl2 inhibitor which activates BAK and BAX proteins which increases mitochondrial outer membrane permeabilization (MOMP) and induces apoptosis (bypasses cells inability to induce apoptosis by itself)
ddx for increased lymphocytosis?
- Chronic NK lymphocytosis
- Monoclonal B cell lymphocytosis
- Early phase HIV
