Haematology Flashcards
What are the Porphyrias?
Definition:
Porphyria = PURPLE
Group of disorders that result from defect in normal processing or porphyrins.
Porphyrins are synethesised in the manufacturing process to produce heme
Some of this occurs in liver, some in bonemarrow and kidney.
Defects of enzymatic processing at one of 8 steps gives rise to a specific porphyria
Defect is never great enough to cause anaemia
Defects cause build up of a specific porphyrin at the respective level of processing
Pophyria may never present as an acute episode.
More common in women - cyclical oestrogen variability and association of attacks with oestrous spikes
Types: Define based on attack of site of porphyrin defect
ACUTE PORPHYRIAS - 2 specific + 2 variable
- Build-up of ALA and PBG
- aminolevulinic acid and porphobilinogen
- Damage the nerves - can mimic GBS in presentation
AIP = acute intermittent porphyria (high ALA/PBG)
ADP =ALA dehydrogenetase porphyria - rare
VP - variegate porphyria (strong assoc HCC)
CP - hereditary copoporphyria
CUTANEOUS - 1 specific - 3 with manifestations
ight-sensitive porphyrins build up (A, B and E respectively),
which cause the skin problems, but they do not
cause acute attacks.
(hepatic cutaenous - secondary to iron overload)
PCT - porphyria cutanea tarda - uroporphyrinogen decarboxylase COMMONEST
(erythropoeitic porphyria)
EPP - erythropoietic porphyria (BM and renal processing)
CEP - congenital erythropoietic porphyria
MIXED - ACUTE AND CHRONIC FEATURES
VP - variegate porphyria (varied - variegate :) )
HC - hereditary copopophyria
Pathogenesis
e.g. Deficiency of URO-PORPHYRINOGEN -
DECARBOXYLASE - cutanea tarda (skin)
7 types of porphyrias - 7 enzymes affected
Each has a defect in one of the processing steps for heme leading to a different porphyrin accumulating.
Inheritance:
autosomal dominant,
autosomal recessive,
X-linked traits,
exception of the most common porphyria, porphyria cutanea tarda (PCT), which usually is sporadic.
-inherited or triggered by alcohol / drugs / COCP
Presentation: - dependent on type
Severe abdominal pain
Neurological symptoms
Light sensitive dermatitis (epidermal deposition of porphyrins)
Urine left to stand is coloured due to reaction of porphyrin with light
–>purple / brown / orange
Diagnosis:
raised urinary porphobilinogen
What are the acute porphyrias?
Acute porphyrias Symptoms of acute porphyria can vary. -abdominal pain. -muscle weakness -numbness i -agitation -mania -depression -hallucinations. -hyponatraemia and HTN may increase seizure risk
Acute intermittent porphyria AIP
-COMMONEST
Aminolaevulinic acid dehydratase porphyria ADP (rare)
-plumboporphyria
What are the cutaenous porphyrias?
Cutaneous porphyrias This type of porphyria mainly affects the skin. -hyperpigmentation -hypopigmentation -blistering -skin fragility -scarring -hypertrichosis over cheeks
Porphyria cutanea tarda. PCT
- Uro-porphyrinogen decarboxylase mutation
- SKIN BLISTERING
Erythropoietic protoporphyria. EPP
- NO BLISTERING
- porphyrins also deposited in TEETH / NAIL BED = teeth flouresce
Congenital erythropoietic porphyria CEP
-Günther’s disease
PCT is the most common, as it is the only
porphyria which can be caused by something
other than a “porphyria” gene. It can be triggered
later in life, by heavy drinking, iron supplements
or certain drugs including COCP and by liver infections.
EPP causes pain in the skin on sun exposure,
and there is no blistering and often no redness
with it, so it can be puzzling for doctors.
CEP is very rare. It can cause severe scarring.
What are the mixed porphyrias?
Mixed porphyrias
This type of porphyria can lead to symptoms of both acute porphyria and cutaneous porphyria. They can therefore cause abdominal pain, affect the skin and the nervous system and may also cause psychiatric problems. The mixed porphyrias include:
Variegate porphyria - hepatic porphyria
NEUROVASCULAR COMPLICATOINS
36-61% increased risk of HCC
Hereditary coproporphyria.
How is porphyria managed?
IX: IRON STORES URINE PORPHYRINS URINE - flouresces under WOODS LIGHT LIVER SCREEN - other causes deranged LFTs \+ AFP to exclude HCC Skin biopsy - will scar badly
Acute:
Removal of trigger
-COCP
-Alcohol
-carbemazepine / clonazepam / metoclopramide
- IV HAEM ARGINATE replaces haem and reduces prophyrin production
Chronic: sun avoidance Therapeutic phlebotomy - iron inhibits uroporphyrobilinogen decarboxylase (UROD) therefore bloodletting encourages RBC prodction and use of hepatic iron stores raising UROD activity CHRLOROQUINE
What is the pathogenic mechanism in AIP
The acute attacks result from the hepatic production of a neurotoxic substance, presumably ALA (a γ-aminobutyric acid analog) and/or PBG that may interact with γ-aminobutyric acid or glutamate receptors.
What is Haem Arginate and when can it be used
Definition
Haem coupled with arginine
When:
Any acute attack of porphyria not improving after 24 hours
Any attack complicated by severe symptoms, hyponatraemia, convulsions, indicators of incipient neuropathy (including loss of reflexes or complaints of pain in the muscles of the back, thighs and upper arms).
MOA:
Effect of haem arginate to reduce porphyrin synthesis
Replenishing haem stores within the body.
By negative feedback, this inhibits the initial rate-limiting enzyme of the haem synthetic pathway, ALA synthase,
The formation of porphyrins and the precursors ALA and PBG is almost immediately reduced to low levels, and the symptoms improve.
Haem arginate is safe.
What is the pathophysiology behind Sideroblastic anaemia
Failure to incorporate iron into heme.
Congenital or secondary to myelodysplasia
When do SMUDGE cells arise
CLL
- remnant of WCC
- no csm or nucleus hence a smudge
- CLL = old lymphocytyes
Smudge cells arise in any condition where the white ells are old or fragile or renewal is delayed
What are the features of leuco-erythroblastic anaemia
Immature WCC and RBC
Typically see RBC with nuclei
Lots of myelocytes Vs mature WC
Raised RDW
associations:
- myelofibrosis - fibrosis of BM - no maturation of T and B before ascension to secondary lymphoid tissues
- malignant marrow infiltration
- CML
- POLYCYTHAEMIA RUBRA VERA
What is polycythaemia rubra vera?
Primary polycythaemia i.e. myeloid line cancer
Primary therefore not EPO dependent - EPO suppressed
Drive is primarily from BM
Neoplastic proliferation and maturation of erythroid, megakaryocytic and granulocytic elements
= panmyelosis.
In contrast to secondary polycythemias, PCV is associated with a low serum level of the hormone erythropoietin (EPO).
Instead, PCV cells often carry activating mutation in the tyrosine kinase (JAK2) gene, which acts in signaling pathways of the EPO-receptor, making those cells proliferate independent from EPO
Diagnosis:
JAK-2 mutation
low serum EPO
BM biopsy
polycythaemia
high RDW
High platelets
Signs:
Erythromyelgia
Due to polycthaemia and thrombocythaemia get intermittent microvascular occulsions
repeated iscahemiac-reperfusion injury
Characteristic purpura
characteristic hyperaemic swollen and deformed arms and fingers
What malignancy is associated with Auer rods
AML
What information is prognostically useful in AML
Myeloblast malginancy
Prognostic depends heavily on cytogenetics
AML is curable in about 35% of people under 60 years old and 10% over 60 years old.
Older people who are not healthy enough to receive intensive chemotherapy have a typical survival of 5–10 months
- Deletion of chr 5q or 7 poorer
- t(8:21) better prognosis - 5-12%
- older age of onset poor
- previous leukaemia poor
What is the philadelphia chromosomal translocation
Typically CML t(9:22) Produces fusion protein BCR-ABL B cell receptor-ABL Tyr Kinase - uncontrolled division of myeloblast or myeloid precursor.
also found in CLL
AML rarely
ALL 25–30% of adult cases
How is CML treated?
Chr 9:22 = tyr kinase const activation
Tyr Kinase inihibitors -
imatinib = 76% remission rate - not curative
Cure = transplant
Leukophoresis if symptomatic hyperviscosity
