Haematology - Anaemia: IDA, Thalassemia, Megaloblastic anemia, Polycythemia Flashcards
S/S of anemia
Symptoms of anaemia: due to ↓O2 delivery
□ Acute/severe: SOB (esp on exertion), palpitation, dizziness/syncope (may be postural)
□ Chronic/insidious: fatigue, Low exercise tolerance, SOB on exertion, pallor
□ Symptoms from causes, eg. menorrhagia, tarry stool, bone pain, hypovolaemia
□ Complications: cardiac ischaemia, thrombocytopenic bleeding, ↑mortality
S/S of following causes of anemia
- Uremia
- Haemolysis
- Megaloblastic anemia
- Haematological malignancy
- Hypersplenism
- Marrow infiltration
□ Uremia: café au lait complexion, uremic fetor, flapping tremor
□ Haemolysis: jaundice, ± mild/moderate splenomegaly
□ Megaloblastic anaemia: premature greying of hair, skin hyperpigmentation, atrophic glossitis, jaundice, oral ulcers, SCD, PN, Psychiatric complications
□ Haematological malignancy: lymphadenopathy, hepatosplenomegaly
□ Hypersplenism: isolated splenomegaly
□ Marrow infiltration: signs of infection elsewhere (leukopenia), mucocutaneous bleeding (thrombocytopenia)
List all Red cell indices
Haemoglobin (HGB)
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
MCH concentration (MCHC)
Red cell distribution width (RDW)
RBC count (RBC)
Haematocrit (HCT)
Reticulocyte count (RET)
Haemoglobin level
- Normal ref. interval
- Definition
14.0-17.5 g/dL (M) 12.3-15.3 g/dL (F)
Concentration of haemoglobin per unit volume blood
MCV
Normal reference interval
Definition
Clinical relevance
80-96 fL
Average volume per RBC
Most important
Classifies anaemia into micro-, normo-, macrocytic
Mean corpuscular haemoglobin
Reference interval
Definition
Clinical relevance
28-33 pg/RBC
Average Hb content per RBC
Used to double check MCV as prolonged storage can lead to RBC swelling due to temperature changes
MCHC
Normal reference range
Definition
Clinical relevance
33-36 g/dL RBC
Average Hb concentration per RBC
Very high = spherocytosis
Low = Fe def anaemia, thalassaemia
Red cell distribution width
Reference interval
Definition
Clinical relevance
12-15% CV
Degree of anisocytosis, i.e. variation in RBC size
Increased in reticulocytosis, Fe def anaemia and severe thalassemia (not in trait)
RBC count
Normal reference interval
Definition
Clinical relevance
4.5-5.9×109/L (M)
4.1-5.1×109/L (F)
Number of RBCs per unit volume whole blood
Parallels HGB and HCT except in extreme microcytosis, eg. thalassemia
Haematocrit
Normal reference
Definition
Clinical relevance
42-50% (M)
36-45% (F)
Volume of intact RBC per unit volume blood (as percentage)
Usually parallels HGB
Reticulocyte count
Normal reference range
Definition
Clinical relevance
0.02-0.11×109/L
0.5-2% total RBC
Percentage of reticulocytes among RBCs
Increase signifies intact marrow compensation + adequate EPO and therefore likely ↑consumption
Causes of Falsely elevated WBC count + anemia
falsely high due to circulating nucleated RBCs
Anemia: Severe hemolysis, acute hemorrhage
Acute hypoxia
Hyposplenism
Cancer: myelofibrosis, extramedullary erythropoiesis, marrow infiltration by leukemias
Ddx Thrombocytopenia + anemia
Ddx thrombocytosis + anaemia
Thrombocytopenia + anemia: DIC and thrombotic microangiopathies (TMAs), marrow infiltration by hematological malignancies
thrombocytosis + anaemia: chronic Fe deficiency, MPN, inflammatory/neoplastic disease e.g. CML
Describe following picture and give Ddx
Microcytosis (MCV<76)
Iron deficiency
Sideroblastic aneaemia
Thalassaemia
Describe following picture and give Ddx
Macrocytosis (MCV > 100fl)
Vitamin B12/ Folate deficiency
Liver disease, Alcohol
Hypothyroidism
Drugs: Zidovudine, Trimethoprim, Phenytoin, Methotrexate
Describe following picture and give Ddx
Target cell (central area of Hemoglobinization)
Liver disease
Thalassemia
Post-splenectomy
Haemoglobin C disease
Describe following picture and give Ddx
Spherocytes (no central pallor)
Autoimmune haemolytic anaemia
Post-splenectomy
Hereditary spherocytosis
Describe following picture and give Ddx
Red cell fragments (Intravascular hemolysis)
Macroangiopathic hemolysis e.g. TTP
DIC
Describe following picture and give Ddx
Nucleated red blood cells (normoblast)
Marrow infiltration
Myelofibrosis
Severe haemolysis
Acute haemorrhage
Describe following picture and give Ddx
Howell-Jolly bodies (small nuclear remnants)
Hyposplenism
Post-splenectomy
Dyshaematopoiesis
Describe following picture and give Ddx
Polychromasia (reticulocyte present)
Haemolysis
Acute haemorrhage
Increased red cell turnover
Causes of the following poikilocytes
Rouleaux formation
Macro-ovalocytes
Tear-drop RBC
Bite cells
RBC parasite inclusion
Basophilic stippling
Rouleaux formation - Paraproteinaemia
Macro-ovalocytes - Megaloblastic anaemia
Tear-drop RBC - Myelofibrosis
Bite cells - G6PD/ oxidative haemolysis
RBC parasite inclusion - Malaria, Babesiosis
Basophilic stippling - Lead poisoning, Dyshaematopoiesis
2 major mechanisms and sub-categories that cause anaemia *****
How to differentiate?
- Decreased RBC production - Low reticulocyte count
- Inadequate RBC production by Erythroid hypoplasia in bone marrow
- Ineffective erythropoiesis by Erythroid hyperplasia in bone marrow
- Increased peripheral consumption - High reticulocyte count
- Increase destruction of circulating RBC (Hyperplastic marrow)
- Increase blood loss (Hyperplastic marrow)
Causes of inadequate RBC production (erythroid hypoplasia)
Failure of trophic mechanism:
□ Chronic renal failure (↓EPO)
□ Hypothyroidism
Inadequate iron: rate-limiting step
□ Iron deficiency anaemia
□ Anaemia of chronic disease (ACD)
Bone marrow suppression:
□ Drugs, esp chemotherapy, cotrimoxazole
□ Irradiation
Bone marrow disorders:
□ Malignant infiltration
□ Aplastic anaemia
□ Pure red cell aplasia (PRCA)
Causes of ineffective erythropoiesis (erythroid hyperplasia)
Megaloblastic anaemia
α and β-thalassaemia (*usu ↑reticulocyte count)
Myelodysplastic syndromes
Sideroblastic anaemia and lead poisoning
Congenital dyserythropoietic anaemia (CDA)
Causes of peripheral RBC destruction
Intrinsic RBC defects:
□ Enzyme deficiencies, eg. G6PD def
□ Hb defects, eg. thalassemia, Hb-pathy
□ Membrane defects, eg. hereditary spherocytosis, elliptocytosis
Extrinsic RBC defects:
□ Mechanical, eg. mechanical heart valve
□ Infections, eg. malaria
□ Immune: warm- or cold-reacting, drug-induced, alloimmune
□ Microangiopathic haemolytic anaemia (MAHA), eg. DIC, TTP
Hypersplenism
Causes of blood loss leading to anaemia
GI bleeding (most common in general)
Menorrhagia (most common in young F)
Haematuria (uncommon)
Trauma and surgery
Respiratory tract bleeding
Occult bleeding
Causes of Microcytic anaemia
Iron deficiency anaemia
Thalassaemia intermedia and major
Anaemia of chronic disease/inflammation (some)
Sideroblastic anaemia (congenital and acquired) and lead poisoning
Causes of Normocytic anaemia
Acute bleeding (haemodilution) and early/recovering iron deficiency anaemia
Anaemia of chronic disease/inflammation (ACD)
Marrow suppression, eg. cancer, aplastic anaemia, infection
Chronic renal insufficiency
Microcytic anaemia masked by reticulocytosis
Haemolytic anaemia (can be normal or high)
Causes of Macrocytic anaemia
Causes of Macrocytic RBC with no anaemia
*Causes of macrocytosis without anaemia include
Reticulopenic, macrocytic RBC:
Hypothyroidism and liver disease due to lipid abnormalities
Chronic alcoholism
Drugs interfering with nucleic acid metabolism, eg. zidovudine, methotrexate, trimethoprim, phenytoin, TKIs)
Cell swelling and water retension:
CO2 retention (e.g. COPD)
Outline investigation pathway for normocytic or microcytic anaemia
Outline investigative pathway for Macrocytic anaemia
Polycythaemia
Definition
Cut-offs
Polycythaemia: defined as abnormal elevation of haemoglobin and/or haematocrit in peripheral blood
□ Increased haemoglobin as defined as >16.5g/dL (M) and >16.0g/dL (F)
□ Increased haematocrit as defined as >49% (M) and >48% (F)
Compare relative vs absolute polycythaemia
□ Relative polycythaemia: spurious ↑Hb/Hct due to loss of plasma volume (i.e. haemoconcentration)
→ Causes: diuretics, vomiting/diarrhoea, obesity, heavy smoking, Gaisbock syndrome
□ Absolute polycythaemia: true ↑Hb/Hct due to ↑total body RBC mass, which can be divided into
→ Primary polycythaemia due to autonomous production of RBCs
→ Secondary polycythaemia due to ↑serum erythropoietin
Causes of Primary absolute polycythaemia
Primary (EPO = ↓/0)
Congenital: erythropoietin receptor mutations, congenital methaemoglobinaemia
Polycythemia rubra vera (due to JAK2 mutation)
Other myeloproliferative neoplasms (due to JAK2, MPL, CALR mutations)
Causes of secondary absolute polycythaemia
Secondary (↑EPO)
Hypoxia-associated ↑EPO:
chronic pulmonary disease, cyanotic heart diseases, obstructive sleep apnoea, high altitude, chronic CO poisoning (incl heavy smoking)
Inappropriately increased erythropoietin:
Renal diseases: renal artery stenosis, hydronephrosis, cysts, post-transplant
EPO-producing tumours: HCC, RCC, haemangioblastoma, phaeochromocytoma, uterine leiomyoma
Performance-enhancing drugs in athletes, eg. recombinant erythropoiesis-stimulatint agents, autologous transplantation, androgens/anabolic steroids
Symptoms of primary myeloproliferative neoplasms (giving primary absolute polycythaemia)
Symptoms of primary myeloproliferative neoplasms:
→ Hyperviscosity: chest/abd pain, myalgia/weakness, fatigue, headache, ↓VA, slow mentation
→ Thrombosis/bleeding: thrombosis at unusual sites, excessive bleeding/bruising
→ PV-related: unexplained fever, sweats, weight loss, aquagenic pruritus, erythromelalgia, gout
Panel of investigations for Polycythaemia
□ CBC, PBS: ↑other lineages, immature WBC, leucoerythroblastic picture → suggests MPN
□ Urinalysis, L/RFT: for possible renal diseases and HCC
□ Pulse oximetry for tissue hypoxia
□ Serum EPO: low or absent serum EPO → relatively specific for MPN and PV
□ JAK2 testing for V617F mutation in PV
□ Further screen for 2o causes if JAK2 mutation negative + no clear 2o causes
→ Total red cell mass (by radiolabeling RBCs) to confirm absolute erythrocytosis
→ Sleep study for OSA
→ USG abdomen for abdominal tumours (ectopic EPO)
→ Lung function tests for respiratory diseases
□ Bone marrow aspirate + trephine if suspicious of myeloproliferative neoplasms
Causes of hereditary microcytosis/ microcytic anaemia
Defects in globin synthesis:
Thalassaemia
Thalassaemic Hbpathies, eg. HbE
Defects of iron metabolism:
Iron-refractory iron deficiency anaemia
DMT1 mutation
Atransferrinaemia
Defects in porphyrin synthesis:
Inherited sideroblastic anaemia
Causes of hereditary microcytosis/ microcytic anaemia
Defects in globin synthesis
Thalassaemia
Thalassaemic Hbpathies, eg. HbE
Defects of iron metabolism
Iron-refractory iron deficiency anaemia
DMT1 mutation
Atransferrinaemia
Defects in porphyrin synthesis
Inherited sideroblastic anaemia
Causes of acquired microcytosis/ microcytic anaemia
Iron deficiency anaemia (IDA)
Anaemia of chronic disease (majority normocytic)
Acquired sideroblastic anaemia due to lead poisoning, alcohol, drugs
Copper deficiency (some)
Zinc toxicity
Panel of investigations for microcytosis
□ ↑RDW: non-specific
□ RBC count: ↓ in Iron deficiency anaemia (IDA), N/↑ in thalassaemia
□ Iron profile and Hb studies for IDA and thalassaemia respectively
□ Blood smear:
→ Thalassaemia: marked anisopoikilocytosis (↑variation in RBC size/morphology) incl target cells, teardrop cells
→ Fe def: anisopoikilocytosis (↑variation in size and shape), but many have normal-looking RBCs
→ Anaemia of chronic disease: majority have normal sized, shape RBCs, but a subset may have microcytosis (accounts for ↓MCV)
→ Sideroblastic anaemia: ringed sideroblasts with a ring of iron granules surrounding nucleus
→ Lead poisoning: characterized by basophilic stippling (denatured RNA)
□ BM examination: rarely necessary if isolated McHc anaemia
Iron deficiency anaemia
Outline the CBC: HBG, MCV, RDW, RBC
Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)
Reticulocyte count
CRP
Thalassaemia
Outline the CBC: HBG, MCV, RDW, RBC
Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)
Reticulocyte count
CRP
Anaemia of chronic disease
Outline the CBC: HBG, MCV, RDW, RBC
Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)
Reticulocyte count
CRP
Hepcidin
- Function
- Causes of high hepcidin state
- Causes of low hepcidin state
Function: Internalize ferroportin in gut lumen >> decrease absorption of iron from gut into blood >> decrease serum iron
High hepcidin state:
- Inflammation/ Infection >> inflammatory cytokines >> Induce hepcidin secretion from liver
Low hepcidin state:
- Anaemia
- Hypoxia
- Low iron stores
Factors that decrease iron absorption in GIT
High hepcidin state: Infection/ Inflammatory state
Low stomach acid (acid for reduction of iron): Gastrectomy, Long-term PPI use, Autoimmune gastritis
Low reducing agent: e.g. low Vitamin C
Iron overload
Duodenum/ small intestine pathologies/ resection causing malabsorption
Describe the recycling and storage of iron in body
Internal cycling of iron:
□ Transferrin (Tf): iron transported in plasma bound to transferrin → each Tf binds 2× Fe3+
□ Utilization: used to form erythroid precursors in BM
□ RBC cycling: RBCs broken down by reticuloendothelial system (liver, spleen) and iron returned into plasma as transferrin-bound form
Storage of iron:
□ Form: ferritin and haemosiderin
□ Site: reticulo-endothelial system (RES), i.e. macrophages of liver, bone marrow and spleen → derived almost entirely from phagocytosis of senescent erythrocytes or defective developing red cells
Causes of iron deficiency
Frank bleeding
*GI bleeding
*Trauma- and surgery-related bleeding
*Severe Haemoptysis
*Menorrhagia
Occult bleeding/iron loss:
Iatrogenic: frequent blood donation, excessive blood taking, haemodialysis
Occult/underestimated bleeding
Functional Iron deficiency - Post- EPO treatment
Urinary and pulmonary haemosiderosis
Malabsorption: H. pylori-related atrophic gastritis, coeliac disease, gastrectomy/gastric bypass, autoimmune gastritis
Inadequate intake (extremely rare, iron store lasts years)
Compare absolute and functional iron deficiency
Absolute deficiency: absence/severely ↓iron stores in RES
Functional deficiency (iron-restricted erythropoiesis): adequate Fe for normal erythropoiesis but iron is not available for RBC, due to
- ACD: ↑hepcidin → ↓ferroportin expression → ↓iron release into circulation
- EPO: release into circulation not rapidly enough to respond to EPO
Iron deficiency anaemia
Outline typical CBC, PBS, BM exam results
CBC:
- *McHc anaemia** with ↓RBC count, ↓reticulocyte count
- *Reactive thrombocytosis** due to ↑stimulation of platelet precursors by ↑EPO
PBS:
hypochromic microcytic red cells with anisopoikilosis
May be dimorphic in concurrent megaloblastic anaemia or iron supplement treatment
BM: not routinely done
Active erythropoiesis but poorly haemoglobinized (micronormoblastic)
Iron stain shows ↓/absent marrow iron stores
Iron deficiency anaemia
Describe typical iron profile and limitations of each metric
Iron studies:
↓serum iron: influenced by inflammatory state, dietary intake, diurnal variation → NOT diagnostic
↑serum transferrin/TIBC but ↓Tf saturation: <16% compatible with IDA (less specific than ferritin)
↓serum ferritin: diagnostic of IDA (most Spec)
- FN: acute phase reactant → FN if inflammatory state
- FP: very rarely, hypothyroidism, vit C deficiency
↑soluble Tf receptor (sTfR): reflects ↑erythropoiesis
Investigations to find cause of Iron Deficiency anaemia
□ Hx: bleeding Hx (GI, urine, menses, bleeding disorders), blood donation, RFs for GI cancers, drug Hx (NSAID, anticoagulants), previous scopes
□ P/E: as appropriate, include PR exam
□ Ix: look for occult GI bleeding first
→ FOBT×3 if >50y
→ Stool examination × ova/cyst in tropical areas
→ Upper endoscopy then colonoscopy if either IDA or FOBT+
→ Consider non-GI and small bowel causes if endoscopy –ve
Management of Iron deficiency anaemia
Indication for different options, dosing, side effects
□ Treat underlying cause
□ Oral iron for majority of patients
Dosing: 150-200mg elemental iron per day until Fe profile normalized (~3-6mo)
Choice: Iron sulphate tablet, ferrum hausmann chewable tablet
Effect: ↑Hb by ~1g/dL every 7-10d with reticulocyte response in 1w
S/E: GI S/E very common → metallic taste, dyspepsia, Nausea and vomiting, altered bowel habits, black stools
□ IV iron if refractory to oral iron, with severe ongoing blood loss or malabsorption
Choice: ferric carboxymaltose, ferric gluconate, ferumoxytol, iron sucrose, iron isomaltoside
Advantage: effective, rapid correction, ensure good compliance, no GI S/E
□ Transfusion if angina, heart failure, cerebral hypoxia or Hb <7g/dL
Anaemia of chronic disease
Pathogenesis
Pathogenesis: result from body’s normal response to limit availability of iron for invading microbes
□ Dysregulated iron homoeostasis:
Inflammation/ LPS in bacterial infection >> ↑ IL-6 and other cytokines >> Increase transcription and translation of Hepcidin in liver >> Hepcidin internalize ferroprotein in gut mucosa and macrophages in RES >> Decrease GI absorption of Fe and MQ release of Fe
□ Immune effect on erythropoiesis:
→ ↓EPO secretion by kidneys
→ ↓erythropoiesis
→ ↓RBC survival by ↑free radical formation → ↑RBC damage → ↑RBC turnover
Diseases asso. with Anaemia of chronic illness
□ Systemic inflammatory/ Autoimmune disease, eg. RA, SLE
□ Infections: related to disease severity
□ Cancer, esp haematological malignancies
□ Chronic organ impairment: heart failure, COPD
□ Chronic solid-organ rejection after transplant
□ Chronic Kidney disease/ inflammation
Anaemia of chronic disease
CBC, PNS, BM exam and Iron profile typical results
□ CBC: Mild NcNc anaemia, can be McHc (<1/4) with low reticulocyte count
□ PBS: relatively uniform population of normocytic RBCs w/o evidence of haemolysis
□ BM: iron stain shows N/↑ iron in MQ, ↓/no iron in erythroid precursors (both –ve in IDA)
□ Iron studies: ↓serum iron, ↓total Tf/TIBC, ↓Tf saturation, N/↑ ferritin
□ ↑CRP/ESR
How to differentiate anaemia of chronic illness from concomitant iron deficiency
Differentiating from or identifying concomitant Fe deficiency:
→ Suggestive features: MCV (↓ in IDA, Normal in ACD), Ferritin (↓ in IDA, ↑ in ACD)
→ Differentiating features: sTfR (↑ in IDA, ↓ in ACD), hepcidin (↓ in IDA, ↑ in ACD)
→ Therapeutic trial of iron may be given in difficult situations
Alpha thalassaemia
Gene affected and type of gene defect
Pathogenesis and effects
Genetics: HBA1/2 code for same α-globin chain in α-gene cluster (ch16)
One person has four genes → α0 (0 α genes) to α4 (4 α genes) presents with a spectrum of varying disease severity
Majority are deletions (90%)
Pathogenesis: mutated HBA1/2 resulting in ↓α-globin synthesis
α-globin required for production of both fetal (α2γ2) and adult (α2β2) Hb → affects both fetus and adults
Effects:
→ Fetus: excess γ chains form Hb Bart’s (γ4)
→ Adults: excess β chains form Hb H (β4)
→ Result: abnormal HbH tetramer unstable → ↑haemolysis
Compare the 4 phenotypes of Alpha thalassaemia
Underlying genetic defect
Effect on RBC
A-thal. minima (silent carrier) - 1 gene deletion, i.e. αα/α-; no effect on MCV and Hb analysis
A-thal minor (Thal. trait) - 2 gene deletions, i.e. αα/– (SE Asians), α-/α- (Blacks); may have hypochromia/microcytosis with mild anaemia
A-thal intermedia (HbH disease) - 3 gene deletions, i.e. α-/– → excessive HbH (β4); Transfusion-dependent, moderate McHc anaemia
A-thal major (Hb Bart’s hydrops fetalis) - 4 gene deletions, i.e. –/– → Hb Bart’s (γ4) in fetal blood; Severe fetal anaemia culminating in hydrops fetalis (fetal high-output HF)
Beta-thalassaemia
Gene affected and type of genetic defect
Pathogenesis
Genetics: single HBB gene code for β-globin chain in β-gene cluster (ch11)
Majority due to point mutations instead of deletions
Majority compound heterozygotes → clinical severity depends on combination and nature of mutation in each of the two HBB gene
Pathogenesis:
→ α-globin only required for production of adult HbA, HbA2 → only becomes manifest at ≥6y/o
→ α4 tetramer is unstable, precipitate into inclusion bodies → damage RBC membrane and ineffective erythropoiesis
→ Free α-chains in peripheral RBCs → aggregate and precipitate → ↑haemolysis
Other sources of variability in clinical severity:
- Genetic determinant of HbF level: HbF can compensate partly for function of HbA
- Configuration of α cluster: excessive α alleles → ↑imbalance → ↑clinical severity
Compare the 3 syndromes of Beta thalassaemia
Underlying genetic defect
Effect on RBC
β-thal minor (thal trait)
*β/β+ or β/β0; asymptomatic mild anaemia with marked microcytosis
β-thal intermedia
*β+/β+, β+/β0 (majority)
*transfusion-independent anaemia
(β-thal minor with exacerbating genetic variant (eg. triplicated/quadriplicated α genes, HbE) or β-thal major with alleviating genetic variant are also classed as intermedia)
β-thal major (Cooley’s anaemia)
*β0/β0, β0/β+ or β+/β+ with very low β-chain production (rare)
*lifelong transfusion-dependent anaemia with onset at 6-12mo
*Hemolytic symptoms, progress to high-output HF, FTT, Infection, iron overload…etc
Thalassaemia
Manifestations of extramedullary haematopoiesis
Splenomegaly due to extramedullary haematopoiesis and haemolysis
- Common in thal major, some thal intermedia
- Hypersplenism may exacerbate situation
Hepatomegaly due to extramedullary haematopoiesis and iron overload
- Early-life symptom, cirrhosis with long iron overload
Nephromegaly
Jaundice, dark urine, pigment gallstones
Manifestations of iron overload
Childhood onset in those with chronic transfusion w/o chelation, adult onset in those with intermedia or transfusion w/ chelation
Chronic liver disease: hepatomegaly, cirrhosis, HCC
Endocrine and metabolic abnormalities due to iron deposits in endocrine glands
Hypogonadism: delayed puberty, oligo/amenorrhoea, ↓libido, ↓2o sexual features
Hypothyroidism
Insulin resistance during 2nd decade of life and DM (bronze diabetes)
Leaden-grey skin pigmentation
Infection by sideroophilic organisms, eg. L. monocytogenes, Yersinia enterolitica, Salmonella enterica, Klebsiella pneumoniae and E. coli
Thalassaemia
Skeletal abnormalities in severe cases?
Due to marrow expansion from ineffective erythropoiesis
- ‘Chipmunk’ facies
- Change in body habitus: Convex ribs and limb bones, Shortened limbs
- Osteopenia/ Osteoporosis
- Growth impairment/ delay
- Bony masses (expanding marrow break bone cortex
Cardiovascular and pulmonary manifestations of thalassaemia
Cardiovascular:
- Major cause of death in thalassaemia
- Heart failure
- Bradyarrhythmia
- Thromboembolism due to hypercoagulation
Pulmonary:
- Pulmonary hypertension
- Asymptomatic pulmonary dysfunction: e.g. restrictive ariway/ obstructive defects, decrease VO2 max…etc
Investigations for thalassaemia
CBC:
- McHc anaemia with marked ↓MCV, N/↑ reticulocyte13 and ↑RBC
- Mentzer index (MCV/RBC count): >13 = IDA, <13 = thalassaemia trait
PBS:
- profoundly hypochromic microcytic red cells with bizarre RBC morphology (target, pencil cells)
Markers of haemolysis: ↑LDH, ↑unconj bilirubin, ↓haptoglobin, ↑methaemalbumin, DAT –ve
Iron studies: ↑serum iron, ↑Tf sat, ↑ferritin due to iron overload
Haemoglobin studies:
Hb electrophoresis for beta
Supravital stain for alpha (HbH)
DNA-based genotyping
Management of thalassemia (severe e.g. thal major/ intermedia with hemolysis)
Folate supplementation
Low iron diet, eg. avoid red meat, spinach
Regular transfusion: mainstay of treatment
- hypertransfusion to maintain stable Hb level and suppress ineffective erythropoiesis
- use leukodepleted packed cells to ↓FNHTR and TRALI
Iron chelation: for B-thal major
Splenectomy
Allogeneic HSCT
Causes of macrocytosis and macrocytic anaemia
- *Abnormal DNA metabolism**
- *- Vitamin B12 deficiency**
- *- Folate deficiency**
- Copper deficiency
- Drugs, including antiretroviral, cytotoxic agent, immunosuppressant, TKI
Primary marrow disorder
- Myelodysplastic syndrome (esp in elderly)
- Congenital dyserythropoietic anaemia
- Sideroblastic anaemia (some)
- LGL leukaemia
Reticulocytosis:
- Haemolytic anaemia
- Stress-induced erythrocytosis
Lipid abnormalities
- Liver disease
- Hypothyroidism
Others:
- *Alcohol abuse**
- *Multiple myeloma** and other plasma cell dyscrasia
Investigations for macrocytosis
CBC:
- *Severe macrocytosis (MCV >110-115) → almost exclusively megaloblastic anaemia**
- *≥1 additional cytopenias → Primary BM problem, eg. megaloblastic anaemia, MDS**
PBS:
→ Megaloblastic anaemia: macro-ovalocytes, hypersegmented neutrophils (>5 lobes)
→ Liver disease: target cells
→ Myelodysplastic syndrome: hypolobulated or hypogranular, dysplastic neutrophils
□ Ix for cause:
→ Reticulocyte count: ↑ in haemolysis, ↓ in BM disorders
→ Serum B12 and folate (± copper if gastric bypass) for megaloblastic anaemia
→ TFT for hypothyroidism
→ LFT for liver disease
□ BM examination: only when uncertain diagnosis or pancytopenia
Causes of false positive macrocytosis
Consider factitious cause, eg. RBC clumping, osmotic swelling with hyperGly or prolonged storage, EDTA tube
Megaloblastic anaemia
Cause
Pathogenesis
Megaloblastic anaemia: due to delay in maturation of nucleus relative to cytoplasm
□ Result from defective DNA synthesis → delayed M phase entry → continuous ↑cytoplasmic size without mitosis (nuclear-cytoplasmic dyssynchrony)
□ Deficiency in vitamin B12 (vast majority) or folate
Source and absorption of Folate
Found in leafy vegetables (spinach, broccoli, lettuce), fruits (banana, melon) and animal protein (liver, kidney)
Seldom deficient with any normal diet in developed countries (>50μg/d)
Absorbed folate converted to methyl tetrahydrofolate (THF) by small intestines then transported inside plasma
Total body stores small → deficiency occur in weeks
Source and absorption of Vitamin B12
Found in meat, fish, eggs, milk
Seldom deficient (>1μg/d) unless vegan diet
Bound to intrinsic factor (IF) produced by gastric parietal cells → IF-B12 complex absorbed in terminal ileum → transported in plasma while binding with transcobalamin II
Liver has 3-year stores of B12 and recycles B12 via enterohepatic cycling → takes years before deficiency manifest
Physiological Function of B12 and folate
- Methyl B12 serves as co-factor in methylation of homocysteine into methionine with demethylation of methyl THF into THF
- THF converts to 5,10-methylene THF, serves as coenzyme for conversion of dUMP into dTMP for DNA synthesis
- Deoxyadenosyl B12 also serves as co-enzyme in conversion of methylmalonyl CoA into succinyl CoA
Causes of Folate deficiency
Dietary insufficiency: usually only in poor, elderly, alcoholics
Malabsorption
High demand due to pregnancy, haemolytic anaemia, myeloproliferative diseases
Antifolate agents, eg. trimethoprim, OCP, pyrimethamine, phenytoin, methotrexate
Causes of Vitamin B12 deficiency
Dietary insufficiency in long-term vegans
Gastric causes:
Pernicious anaemia
Status post-gastrectomy: 10-20% by 5y
Bowel causes:
SBIO with bacteria consuming B12 due to motility disorder, ↓γ-globulin, stagnant loop
Terminal ileal pathology, eg. Crohn’s disease
Fish tapeworm
Pernicious anaemia
Define
Pathogenesis
Risk factors
Complications
Diagnosis
Define: Autoimmune disorder with atrophic gastric mucosa and loss of parietal cells
Pathogenesis: anti-IF or anti-parietal cell Ab (a/w chronic atrophic gastritis) attack parietal cells → ↓intrinsic factor production
Risk factors: Autoimmune diseases
Complications: Chronic atrophic gastritis, Gastric Cancer (achlorhydria)
Diagnosis: presence of auto-antibodies - Anti-Intrinsic Factor Ab and Anti-parietal cell antibody
Clinical features of megaloblastic anaemia
- Anaemia S/S
- Jaundice
- Oral: atrophic glossitis, oral ulcers, angular stomatitis
- Skin: greying of hair, skin hyperpigmentation
Neuropsychiatric:
- Subacute combined degeneration of cord: affects dorsal (DC-ML) and lateral columns (CST)
- Peripheral neuropathy: classically ↑knee jerk (from SCD) + ↓ankle jerk (from PN)
- depression, irritability, cognitive slowing, dementia, psychosis
Investigations for Megaloblastic anaemia
- CBC: macrocytic anaemia (typically >115fL) with mild leukopenia/thrombocytopenia + ↓RET
- PBS: macro-ovalocytes + hypersegmented neutrophils
- Markers of haemolysis
- Serum B12 level: deficient <200pg/mL
- RBC folate: <150ng/mL
- Anti-IF, anti-parietal cell Ab for pernicious anemia
- Metabolite testing (MMA, homocysteine)
- Upper endoscopy for atrophic gastritis and CA stomach
Management of Megaloblastic anaemia
Management: by replacement of B12 and/or folate
Urgent Folate with B12 supplement for severe anaemia/ symptomatic- Parental or oral
Oral B12 supplement: vegan diet require lifelong replacement
Oral folate supplement: indicated for folate deficiency and other conditions e.g. haemolytic anaemia with poor RBC survival
S/S of iron deficiency anaemia
S/S anaemia: SOB on exertion, Pallor, Tiredness, Dizziness , Palpitation
Pica: desire for or compulsion to eat substances not fit as food, eg. dirt (geophagia), ice (pagophagia)
Restless leg syndrome (RLS)
Nail changes: brittle nails, koilonychias (spoon-shaped nails)
Epithelial/mucosal changes:
→ Atrophic glossitis with loss of tongue papillae ± tongue pain, dry mouth
→ Cheilosis (angular cheilitis)
→ Oesophageal webs (rare) → termed Plummer-Vinson syndrome when a/w dysphagia
