GP refresher course Anaemia Peter MacCallum Consultant Haematologist Barts Health NHS Trust London January 2018
None Declarations
WHO thresholds Hb (g/l) Children 0.5 5 yrs 110 Children 5 12 yrs 115 Teens 12 15 yrs 120 Women, non pregnant 120 Women, pregnant 110 Men 130
Compensatory mechanisms Increased cardiac output Increased plasma volume Increased red cell 2,3 DPG
Anaemia 1. 30 year old female Hb 80 2. 75 year old male Hb 65 3. 65 year old female Hb 95 What is the most useful additional piece of information on the FBC?
Anaemia 1. 30 year female Hb 80 MCV 73 2. 75 year male Hb 65 MCV 115 3. 65 year old female Hb 95 MCV 90 What are the most likely causes of these anaemias?
Classification of anaemia size
Classification of anaemia mechanism
ANAEMIA: a pathophysiological approach LOSS GI Menstrual Haematuria Ch. bleeding Iron defic. ANAEMIA DESTRUCTION Anaemia & jaundice retics bilirubin LDH haptoglobin PRODUCTION 1 o /2 o marrow disorders: Bone marrow suppression: Drugs/chemo haematinics hormones EPO with CKD Hypothyroidism Anaemia of ch. inflamm: iron availability UTILISATION* Growth Pregnancy *Iron
Anaemia 1. 30 year female Hb 80 MCV 73 2. 75 year male Hb 65 MCV 115 3. 65 year old female Hb 95 MCV 90 Now what additional tests would you do to determine the likely cause of the anaemias?
Anaemia 1. 30 year female Hb 80 MCV 73 Ferritin 10 2. 75 year male Hb 65 MCV 115 B12 100 3. 65 year old female Hb 95 MCV 90 egfr 25
Case 1 81 year old female with an anaemia 2008 2013 Mar 2015 Hb 119 109 95 MCV 88 86 81 Ferritin* 36 24 Minimal symptoms WBCs, neutrophils & platelets normal; Moderate CKD egfr 50 *normal range 20 300 μg/l What are the possible cause(s) of her anaemia?
MCV and iron deficiency With IDA up to 40% may have a normal MCV MCV <80fl sensitivity for IDA ~50% 1,2 Specificity 80+% ~20% of individuals with the anaemia of chronic disease are microcytic 1. Thompson et al. Arch Intern Med 1988;148(10):2128 2. Seward et al. J Gen Intern Med 1990;5(3):187
Ferritin & iron deficiency Ferritin* (μg/l) Sensitivity Specificity <15 1 59% 99% <40 2 98% 98% *normal range 20 300 μg/l Can be falsely normal, especially in the elderly Cut off 50 μg/l 3 in elderly (?100 μg/l with ACI) 1. Guyatt et al. J Gen Intern Med. 1992;7(2):145 2. Punnonen et al. Blood 1997;89(3):1052 3. Joosten et al. 1991 Am J Med;90(5):653
Iron deficiency should always be investigated ~10% GI bleeding is from small bowel e.g. angiodysplasia Video capsule endoscopy
Endoscopy in iron deficiency anaemia 111 hospitalised patients >75 years with IDA 102 OGD 44 (43%) had a source of bleeding Only 6 (14%) had a malignancy 91 Colonoscopy 43 (47%) had a source of bleeding 31 (72%) had a colonic carcinoma Nahum et al. Gastroenterol Clin Biol. 2007;31(2):169.
Case 2 70 year old male 2008 July 2015 Oct 2015 Hb 110 120 95 MCV 91 94 85 Ferritin >75 47 egfr 45 Recently on prednisolone for PMR What do you think might be the cause of his anaemia? What other lab tests might be helpful?
Transferrin (iron) saturation TSat Normal 20% 45% Total Iron Binding Capacity TIBC Iron Transferrin Iron deficiency <20% <15% sensitivity for IDA 80% 1 With functional iron defic. CKD ACI Iron overload >50% (f); >55% (m) 1. Guyatt et al. Am J Med 1990;88(3):205
Case 2 70 year old male 2008 July 2015 Oct 2015 Hb 110 120 95 MCV 91 94 85 Ferritin >75 47 egfr 42 Recently on prednisolone for PMR Transferrin saturation 11% What is the likely cause of his anaemia?
Case 3 26 year old female student from Iran c/o ing fatigue Hb 85 g/l MCV 58fl What is the likely cause of her anaemia? What additional tests would be helpful?
Case 3 26 year old female student from Iran c/o ing fatigue Hb 85 g/l MCV 58fl Ferritin 5μg/l (normal >20μg/l) Hb A 2 4.2% (normal <2%) What is/are the diagnosis(es)?
Iron deficiency / thalassaemia t Iron Deficiency Hb. MCV + Thrombocytosis. Film pencil cells. ferritin Thalassaemia Trait Normal / Hb. MCV +++ Normal platelets. Film target cells. β thal - HbA 2 α thal normal HbA 2
Case 4 35 year old female c/o TATT FBC Hb 126 MCV 84 Ferritin 10 (>20) Does this explain her fatigue? What would you do next?
Iron deficiency without anaemia Associated with: Fatigue Exercise & work capacity Impaired cognitive performance Memory Concentration Is worth treating Should be investigated as for IDA Halterman JS et al. Pediatrics 2001:107(6); 1381.
Case 5 82 year old male Type 2 diabetic Admitted alcohol intake 20 units/week BMI 32 2012 2014 2015 Hb 135 128 115 MCV 102 101 104 WBCs 6.8 6.0 5.7 Plts 202 176 125 What are the possible causes of his anaemia? What investigations would be useful?
Case 5 B12 & folate normal LFTs ALT 54; GGT normal. TSH normal Creatinine 78; egfr >60 What do you think could be the diagnosis now? Are there any other useful tests you can ask for?
Blood film report Hypogranular neutrophils Pelger cells Large platelets What do you think the diagnosis is now?
Blood film report Hypogranular neutrophils Pelger cells Large platelets Changes suggestive of myelodysplasia
Macrocytic anaemia Common B12 or folate:* MCV often >110fl. Chronic liver disease*: LFTs (esp albumin). Myelodysplasia Cytopenias. Less common Hypothyroidism* Usually normocytic Haemolysis: retics. bilirubin. LDH. Myeloma globulins. Non MDS bone marrow disorders. * Commonest causes in Italian study, + alcohol
Isolated macrocytosis Excess alcohol History, MCV & GGT Chronic liver disease (low albumin). Pregnancy. Smokers/COPD. Drugs: Hydroxycarbamide. Methotrexate. Azathioprine. Chemotherapy. Phenytoin. COCP. Precursor of myelodysplasia Benign familial macrocytosis. Biomarkers in alcoholism MCV Lacks sensitivity Slow return to normal GGT 1 Sensitive but not specific in only ~50% More rapid return to normal 1. Niemela. Clinica Chimica Acta 2007; 377: 39-49
Case 6 73 year old male with an anaemia Nov 2013 July 2014 Hb 145 102 MCV 87 81 Ferritn 120 WBCs, neutrophils & platelets normal CKD egfr 39 to 31 Poorly controlled diabetes Last HbA 1 C 65mmol/mol ESR & CRP (under rheumatology for RA; on MTX & hydroxychloroquine) What do you think are the possible cause(s) of his anaemia?
Anaemia and CKD Normocytic ~10% at egfr <30 33 67% at egfr <15 Associated with EPO Management: Individualised Hb <100 EPO Iv iron if ferritin <100 Target Hb 110 120 Hbs >130 risk of death & stroke The InCHIANTI study. Arch Intern Med. 2005;165(19):2222
Anaemia of Chronic Inflammation Infection Inflammation Malignancy Severe trauma Diabetes Elderly Obesity Ac/ch. immune activation Normocytic ~75% Usually mild Hb <80 in 20% Hypoproliferative: Low retics Ferritin N/
Anaemia of chronic inflammation (ACI)
Functional iron deficiency Decrease in iron availability in the face of normal or increased iron stores Anaemia of chronic inflammation ~20% MCV Ferritin usually normal or TSat usually >20% ~20% TSat is functional iron deficiency In ~25% of these is true iron deficiency with a ferritin Schilling. Ann Intern Med 1991;115(7):572
Anaemia in Inflammatory Bowel Disease Reinisch et al. Journal of Crohn s and Colitis 2013;7:429
Anaemia in the elderly Nutritional deficiency: 60% iron Chronic disease: ACI CKD (egfr <30) Unexplained: ~15% myelodysplasia (MDS)
Case 7 Asymptomatic 70 year old male diabetic elderly blood screen Hb 143; MCV 90 Creatinine 92 LFTs normal TSH normal B12 203 (normal 246 900) Folate 5.6 Ferritin 120 What is the significance of the low B12 level? What further action will you take?
B12 Deficiency Subclinical deficiency common Within 25% below the low limit of normal 5 10% in individuals >65 years Repeat the levels as assay not robust & variable Lack specificity & sensitivity <200ng/l 97% sensitivity for true deficiency Holotranscobalamin ( active B12) What is the Hb and MCV? Blood film Any neurological features or glossitis? Hb and MCV normal in ~25% Check GPC and IF antibodies re pernicious anaemia. IFA +ve in ~50%; high specificity GPC +ve in ~80%; low specificity Consider a trial of B12. BCSH Guidelines for the diagnosis of cobalamin and folate disorders. Brit J Haematol 2014;166:496
B12 Deficiency causes Pernicious anaemia: Abs Vs IF Abs Vs GPC chronic atrophic gastritis IF & gastric acid production Assoc. with risk of gastric cancer Age related gastric atrophy (antibody negative PA) H.Pylori. Diet (B12 in meat & dairy products): Vegans/vegetarians Malabsorption: Terminal Ileum: IBD (Crohn s disease). Metformin. Prolonged treatment with PPIs. Gastrectomy; bariatric & gastric bypass surgery. Low levels can be seen with: Pregnancy COCP
Folate deficiency Low stores. Easily exhausted. Subclinical deficiency common. Repeat levels as assay variable <3μg/l indicative of true deficiency B12 level may also be mildly Check Hb & MCV. Diet Elderly Alcoholic Malabsorption ttg. Anticonvulsants
Combined nutritional deficiencies Other considerations Coeliac disease (anti tissue glutaminase antibodies) Capsule endoscopy for small bowel disease
Clinical approach to anaemia Length of history Ethnicity Sickle and thalassaemia NB multiple causes Family history Inherited haemolytic anaemias GI symptoms, including bleeding Detailed menstrual history (if appropriate) Jaundice & dark urine re haemolysis Drugs Antithrombotics NSAIDs Diet; especially children and the elderly Recent surgery or hospital admission
Investigation of anaemia FBC MCV; WBCs & platelets Retics & blood film DAT Creatinine & egfr (& creatinine clearance) LFTs; esp. albumin, bilirubin, GGT, LDH Hb electrophoresis B12 & folate Ferritin, iron & TIBC (Tsat) ESR/CRP Protein electrophoresis Bone marrow
Blood film