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Iron deficiency anaemia ( IDA )

Anemia may be defined as Hb ( Hemoglobin ) concentration two standard deviation below the mean Hb concentration for a normal population of the same gender and age range ( BMJ )

Iron deficiency is a state of reduced iron stores which precedes overt iron deficiency anaemia / anemia ( IDA ) or persists without progression and IDA is when low iron levels are associated with anaemia and the presence of microcytic hypochromic red cells ( from Lancet ) Anemia may be defined as Hb ( Hemoglobin ) concentration two standard deviation below the mean Hb concentration for a normal population of the same gender and age range ( BMJ )

Iron deficiency is a state of reduced iron stores which precedes overt iron deficiency anaemia / anemia ( IDA ) or persists without progression and IDA is when low iron levels are associated with anaemia and the presence of microcytic hypochromic red cells ( from Lancet )

 

Anaemia affects about a third of the world population and half the cases are due to iron deficiency Affects people of all age groups and is a global concern IDA is a common medical condition seen in everyday clinical practice WHO estimates that 42 % of children less than 5 and 40 % of pregnant women worldwide are anaemic Iron deficiency is the most common and nutritional deficiency , particularly among children in developing countries ( BMJ ) Iron deficiency is seen in both the developed and developing world In the UK iron deficiency is the most common cause of anemia seen in primary care Prevention programs have reduced incidence of IDA , but the prevalence still remains high in parts of Africa & S Asia

 

Physiology – Essential trace element which can be toxic in excess Roles – oxygen transport in haemoglobin , muscle oxygenation ( as myoglobin ) , DNA synthesis , RNA and protein cellular respiration , immune function , myelin sheath formation Main source of iron are (a ) dietary (b) macrophages which recycle iron (c ) liver stores Absorbed by mature enterocytes of the midupper villus and mainly small intestine
( particularly the duodenum and 1st part of jejunum ) Iron homeostasis is tightly regulated & typical daily elemental iron loss is 0.25-0.75 mg A daily quantity of 1-2 mg of intestinal absorption is needed for iron homeostasis Males contain about 4000 mg of iron of which 2500 mg is within erythrocytes , 1000 mg is stored in splenic and hepatic macrophages and rest in various proteins ass Mb , cytochromes or other ferroproteins Lack of iron means less hemoglobin is available for RBCs hence most common clinical sign of iron deficiency manifests as iron deficiency anaemia Liver plays an important role in fine regulation via the hormone hepcidin by controlling the release of iron from enterocytes and macrophages in circulation
Hepcidin is an acute phase reactant which tightly regulates mechanisms of iron acquisition

 

Why important – In pregnancy severe IDA is linked to LBW , increased risk pre-term delivery , increased newborn and perinatal mortality In 2010 anemia accounted for 68.4 million yrs of life lived with disability or 9 %  of the total global disability burden from all conditions Poor socioeconomic position is a risk factor for anaemia particularly among women and children Increased morbidity and mortality in children Poor birth outcomes Impaired cognitive and behavioural outcome ( developmental delays ) in children Negative effect on physical performance / productivity Longer length of stay in hospital Increased risk of falls Reduced life expectancy Increased risk of infections (in all age groups ) Severe anaemia can cause heart failure Precipitate restless leg syndrome

 

Causes of iron deficiency- Iron deficiency results when the capacity of small intestine to absorb iron is outstripped by iron losses It should be noted that the guidelines are formulated taking ino account the facts that
o IDA in adult men and postmenopausal women is often the result of chronic occult GI bleeding
o virtually any GI tract lesion that causes a mucosal defect can bleed enough to cause occult blood loss leading to IDA Endoscopic evaluation of patients has shown that
o 2/3rd of patients will have lesions identified in the GI tract responsible for occult bleeding
o cancers have been identified in IDA patients in all parts of GI tract
o most common cause of IDA are inflammatory ulcerative upper GI tract lesions

 

Inadequate intake – poor nutrition Strict vegan /vegetarian diet alcoholism eating disorder

 

Decreased absorption- coeliac disease tropical sprue previous gastrectomy ( both partial and total ) inflammatory bowel disease bariatric surgery Helicobacter infection uncommon causes e.g autoimmune gastritis , atrophic gastritis concomitant drug use for e.g PPIs ( often ignored as possible cause of malabsorption ) / antacids Chronic kidney disease / ESRF patients ( loss of blood during dialysis , reduced hepcidin clearance , inflammation and use of drugs as PPIs and anticoagulants ) Cancer chronic inflammatory conditions as inflammatory arthritis Obesity Congestive cardiac failure

 

Increased demand / blood loss – pregnancy ( up to 1200 mg is the estimated iron requirement from conception through delivery ) extra iron is needed to support expansion of blood volume / red cell mass and growth of the fetus and placenta uterine loss- menstruating women ( up to 5 % of women ) childbirth gastrointestinal bleeding ( common cause in adult men and post menopausal women ) nose bleeds haematuria blood donation hookworm infestation ( major cause globally )
I developing countries the cause may be a combination of insufficient intake + hookworm infestation intravascular hemolysis with hemoglobinuria ( e.g malaria ) childhood ( growth spurts – adolescence )

 

Differentials – lead poisoning anaemia of chronic disease hemoglobin C disease ( also called CC disease ) heterozygous Hb D disease autoimmune hemolytic anaemia hemoglobin S beta thalassemia.

 

Assessment – Low MCV ( less Hb- cells become smaller ) Low MCH ( less Hb within RBC )Note that MCH may be more reliable than MCV as it is less influenced by storage and the counting machine Hematoscopy-microcytosis , hypochromia and anisocytosisNote that microcytosis may be absent in combined deficiency for e.g folate which may be identified by a raised red cell distributionwidth ( RDW )Microcytosis may also happen with thalassemia when the red cell count is usually elevated ( MCH/ RBC index or Mentzer index is valuable in differentiating between the two causes of microcytic/ hypochromic anaemia ie ID and thalassemia ) Ferritin , iron and transferrin saturation – lowConsider the fact that ferritin ( acute-phase reactant ) level within the reference range is not a very useful guide in patients with inflammatory conditions such as malignancies and collagen disease Total iron binding capacity – increased Red Cell Distribution- measures the variation in diameter of the red cells
o high RDW indicates conditions as IDA , B12 deficiency and folate deficiency
o RDA is normal in ACD & haemoglobinopathies.

 

History- History – particularly focus of potential blood loss e.g from GI tract Women – menstrual loss Enquire any other source of blood loss – is the patient a blood donor ? Diet , alcohol , ethnic group A previous h/o IDA ( investigations as endoscopy ) & treatment Family h/o IDA / haemoglobinopathies Ask about significant family h/o colorectal carcinoma – that is one affected 1st degree relative < 50 yrs old or 2 affected 1st degree relatives Full medication history with focus on NSAID, antiplatelet medications , anticoagulants , steroids.

 

Tests – Repeat FBC ( exclude spurious cause ) Reticulocyte count Blood film -most labs automatically report blood film Ferritin , Transferrin ,B12 , Folate , U&E , Creatinine , FBC , CRP If ethnic origin points to potential haemoglobinopathy consider electrophoresis Soluble transferrin receptor ( sTfr ) – more reliable in identifying IDA than TIBC and iron but is not available widely Helicobacter pylori serology Urinalysis – r/o haematuria
Recommended in all IDA patients as about 1 % of IDA patients will have renal tract malignancy.

 

Diagnosing IDA with inflammation is challenging and cannot be determined on the basis of a single test- higher cutoffs of ferrtin are also used to diagnose IDA for e.g in presence of conditions as heart failure , CKD.

 

Symptoms – Fatigue Shortness of breath Bounding pulse or palpitations Lack of concentation
 In severe cases -
o dry and rough skin
o damaged hair
o alopecia
o koilonychia ( spoon shaped fingernails )
o atrophic glossitis Pallor is a poor marker and not usually visible unless Hb falls to 7-8 g/dL

 

Examination – Examination usually unhelpful Occasionally it may reveal a relevant abdominal mass DRE may not contribute much without presence of symptoms as rectal bleeding and tenesmus.

 

When to refer – For post menopausal women and men with IDA the standard investigation is to assess the GI tract for a bleeding lesion AGA ( American Gastroenterology Association ) says that in asymptomatic post menopausal women & in men with IDA it recommends bidirectional endoscopy over no endoscopy Shersten et al report that 9 % of patients older than 65 yrs with IDA have a GI cancer when investigated We will discuss the treatment via iron replacement / follow up in a separate chart, it is important to know the current referral guidelines as advised by NICE / CKS.

 

Anaemia- IDA 60 and over- refer colorectal appt within 2 weeks

Anaemia- IDA unexplained with rectal bleeding in adults under 50- consider a suspected cancer pathway referral for appt within 2 weeks colorectal.

Anaemia -IDA without rectal bleeding and criteria for a suspected cancer pathway referral not met offer testing with quantitative faecal immunochemical ( FIT ) test

 

Gastroenterology – all men and women with IDA unless there is a known overt non-gastrointestinal bleeding men with Hb of < 120 g/L and postmenopausal women with an Hb level of < 100 g/L all people aged 50 yrs or over with marked anaemia or a significant family h/o colorectal carcinoma ( even if coeliac dis is not found ) premenopausal women < 50 with colonic symptoms , a strong family h/o of GI cancer or persistent iron deficiency anaemia despite treatment

 

Also refer- coeliac disease serology positive profound anaemia with signs of heart failure unable to tolerate or do not respond to iron therapy or 
they develop anaemia without an obvious underlying cause after an initial response type of anaemia is not clear further investigations are indicated for e.g bone marrow biopsy.

References

  1. Iron deficiency anaemia Seminar Anthony Lopez, Patrice Cacoub, Iain C Macdougall, Laurent Peyrin-Biroulet Published online: August 24, 2015 The Lancet Iron deficiency anaemia (thelancet.com)

     

     

  2. Samuel Dickey, Don C. Rockey,
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    (http://www.sciencedirect.com/science/article/pii/S0002962919303179)
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    women in a primary care setting: a
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    Sabine Bayen1,2* , Charline Le Grand1 , Marc Bayen1 , Florence Richard3 and Nassir Messaadi1,4 Bayen et al. BMC Family Practice (2020) 21:13
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    Anaemia in Adults
    RCN guidance for nursing practice Clinical Professional Resource
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  7. Guidelines for the management of iron
    deficiency anaemia
    Andrew F Goddard,1 Martin W James,2 Alistair S McIntyre,3 Brian B Scott,4 on
    behalf of the British Society of Gastroenterology https://www.bsg.org.uk/wp-content/uploads/2019/12/Guidelines-for-the-management-of-iron.pdf
  8. CKS NHS Anaemia – iron deficiency https://cks.nice.org.uk/topics/anaemia-iron-deficiency/
  9. AGA Clinical Practice Guidelines on the GastrointestinalEvaluation of Iron Deficiency Anemia Cynthia W Ko et al Gastroenterology 2020;159:1085–1094CLINICAL PRACTICE GUIDELINES
  10. Don C. Rockey, Osama Altayar, Yngve Falck-Ytter, Denise Kalmaz,
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    Gastroenterology, Volume 159, Issue 3, 2020, Pages 1097-1119,
    ISSN 0016-5085, https://doi.org/10.1053/j.gastro.2020.06.045.
  11. Chaparro, Camila M, and Parminder S Suchdev. “Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries.” Annals of the New York Academy of Sciences vol. 1450,1 (2019): 15-31. doi:10.1111/nyas.14092
  12. Miller, Jeffery L. “Iron deficiency anemia: a common and curable disease.” Cold Spring Harbor perspectives in medicine vol. 3,7 a011866. 1 Jul. 2013, doi:10.1101/cshperspect.a011866
  13. American Society of Haematology – Iron deficiency anaemia Iron-Deficiency Anemia – Hematology.org
  14. Bouri, Sonia, and John Martin. “Investigation of iron deficiency anaemia .” Clinical medicine (London, England) vol. 18,3 (2018): 242-244. doi:10.7861/clinmedicine.18-3-242
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  17. Iron Physiology Iron Physiology | Iron Studies – MedSchool

  18. DeLoughery TG. Iron Deficiency Anemia. Med Clin North Am. 2017 Mar;101(2):319-332. doi: 10.1016/j.mcna.2016.09.004. Epub 2016 Dec 8. PMID: 28189173. ( Abstract )
  19. Iron-Deficiency Anemia Clara Camaschella, M.D. N Engl J Med 2015; 372:1832-1843 DOI: 10.1056/NEJMra1401038

  20. Logan, E C M et al. “Investigation and management of iron deficiency anaemia in general practice: a cluster randomised controlled trial of a simple management prompt.” Postgraduate medical journal vol. 78,923 (2002): 533-7. doi:10.1136/pmj.78.923.533

 

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