4. Nutritional Anaemias Flashcards
What is anaemia?
- Number of red blood cells (and consequently their oxygen-carrying capacity) is insufficient to meet body’s physiological needs; can also be less than normal quantity of haemoglobin in blood
- Insufficient oxygen carrying capacity is due to reduced haemoglobin concentration as seen with insufficient RBC
- Hb in g/L
What is haemoglobin? and what is expected on the blood film?
- Haemoglobin – iron containing oxygen transport metalloprotein within RBCs
- Varying normal concentration according the age, menstrual cycle, gender, pregnancy.
- On a blood film, if the RBC has sufficient levels of Hb, there would be a clear ring of colour
What is required for normal erythropoiesis?
• Maturation of red blood cells require:
- Vitamin B12 and folic acid for DNA synthesis
- Iron for Haemoglobin synthesis
• Also need other vitamins, cytokines (erythropoietin), healthy bone marrow environment
What mechanisms cause anaemia?
1) Failure of production: hypoproliferation -> reticulocytopoenic (decreased number of reticulocytes)
2) Ineffective erythropoiesis: (red blood cell production)
3) Decreased survival:
- > blood loss, haemolysis, reticulocytosis (increased number of reticulocytes/immature RBCs)
How is anaemia classified?
Microcytic, normocytic, macrocytic anaemia - MCV
Expand on microcytic
- Iron deficiency (haeme deficiency)
- Thalassaemia (globin deficiency)
- Anaemia of chronic disease
Expand on normocytic
- Anaemia chronic disease
- Aplastic anaemia
- Chronic renal failure
- Bone marrow infiltration
- Sickle cell disease
Expand on macrocytic
- B12 and folate deficiency
- Myelodysplasia – deficiency in the bone marrow where it makes abnormal RBCs
- Alcohol induced
- Drug induced
- Liver disease
- Myxoedema
What are the different measurements to allow anaemia classification?
- MCV (mean cell volume) – of RBC, part of complete blood count
- Reticulocyte count – caused by failure of production (reticulocytopoenic) or increased losses?
What are the key players in nutritional anaemia?
- Iron deficiency
- vitamin B12 deficiency
- folate deficiency
Expand on iron.
- Essential for O2 transport (haemoglobin synthesis)
- Daily requirement for iron for erythropoiesis varies depending on gender (little bit more in a menstruating women) and physiological needs, increases in pregnancy and lactation
- Recommended intake assumes 75% of iron is from heme iron sources (meats, seafood). Non heme iron absorption is lower (applies to those with vegetarian diets, for whom iron requirement is approx.. 2-fold greater)
What is the distribution of iron within adults body? - inc, regulation and transport/storage
- Dietary iron -> plasma transferrin, mainly absorbed in duodenum
- MAJORITY of iron is in circulating erythrocytes (also a lot utilised in bone marrow and muscle myoglobin), storage iron in liver
- Iron levels are REGULATED by hepcidin ~ tells your body how to regulate it at absorption level
• TRANSPORT:
- transferrin and lactoferin
•STORAGE ~ most in hepatocytes and reticuloendothelial macrophages.
- Ferritin = short-terM
- Haemosiderin = long-term
- (found in cells of liver, spleen and bone marrow)
Describe iron metabolism.
- Iron metabolism controlled by absorption (rather than usual excretion); only lost through blood loss or loss of cells as they slough
- More than 1 stable form of iron: Ferric states (3+) and Ferrous states (+2); these are two different oxidation states
- Reticuloendothelial macrophages ingest senescent RBCs, catabolise Hb to scavenge iron and load the iron onto transferrin for reuse
Describe iron absorption
- Regulated by GI mucosal cells and hepcidin
- Most absorption in duodenum and proximal jejunum
- Via FERROPORTIN receptors on enterocytes
- Amount absorbed depends on the type ingested ~ heme, ferrous iron-containing proteins GREATER absorption than non-heme, ferric forms which is bound to other substances
- Other factors that affect absorption: other foods, GI acidity, state of iron storage levels, bone marrow activity
How is iron concentration regulated?
HEPCIDIN
- Inhibits iron transport by binding to iron export channel ferroportin located on the BASOLATERAL surface of enterocytes and membrane of reticuloendothelial cells (macrophages), and hepatocytes
- Hepcidin causes ferroportin internalisation and degradation (lysosomal) -> decreased iron transfer into the blood plasma, from macrophages involved in recycling senescent erythroyctes and from iron-storing hepatocytes
- Hepcidin is feedback-regulated by iron concentrations in plasma and the liver and by erythropoetic demand for iron.
Describe iron transport and storage.
- From duodenum into mucosal cells ~ Iron transported from enterocytes and then either into plasma or if excess iron stored as ferritin
- Combine with apoferritin (unbound ferritin) -> ferritin
- Or cross to plasma where it binds to transferrin and enter cells via transferrin receptor (e.g. in erythroid precursors)
How can you carry out iron deficiency investigations?
- Full blood count (red blood cells): Hb, MCV, MCH, reticulocytes and blood film
- Iron studies: ferritin, transferrin saturation, TIBC (total iron binding capacity)
- Other studies: BMAT, iron stores
What are the different lab iron studies?
- SERUM Fe - Hugely variable during the day.
- BLOOD TEST: FERRITIN – measures amount of iron stored; primary storage protein, provides reserve, water soluble ~ high levels can indicate iron storage disorder,
- BLOOD TEST: TRANSFERRIN – made by liver, inversely proportional to Fe stores, vital for Fe transport,
- URINE TEST: HAEMOSIDERIN – water insoluble, Fe- protein complex/iron-storage complex in cells; haemodiserinuria (brown urine) is secondary to excess intravascular haemolysis
- BLOOD TEST: IRON BINDING CAPACITY – shows capacity to bind iron with transferrin (indirectly reflects transferrin levels)
- BLOOD TEST: TRANSFERRIN SATURATIONS – Ratio of serum iron and total iron binding capacity – revealing % of transferrin binding sites that have been occupied by iron
What would you see in a state of iron deficiency?
- Reduced Hb levels
- Reduced MCV
- Reduced MCH
- Reduced serum Fe
- Reduced ferritin
- Increased TIBC (reflecting transferrin)
- Reduced transferrin saturation
- Reduced/absent bone marrow iron studies
What are the causes of iron deficiency?
- Not enough: poor diet, malabsorption, increased physiological needs (e.g. pregnancy)
- Losing too much: blood loss, menstruation, GI tract loss, parasites
Iron deficiency occurs in several stages before anaemia develops. What are they?
- Initially normocytic and normochromic
- Moderate: microcytic (low MCV), hypochromic (low MCHC), reticulocytopoenic?
- Serum ferritin most sensitive indicator for mild iron deficiency
- Percentage saturation of transferrin with iron and free erythrocyte protoporphyrin (high levels indicate disruption of heme production?) values do not become abnormal until tissue stores are depleted of iron
- Decrease in Hb concentration -> when iron unavailable for haem synthesis
- MCV and MCH do not become abnormal for several months after tissues stores are depleted of iron.
What is the prevalence of iron deficiency?
- World’s most common nutritional deficiency
- Blood loss from GI tract – most common causes of IDA in adult men and postmenopausal women
- Excessive menstrual losses – 1st cause in premenopausal women
What are the symptoms of iron deficiency?
- Symptoms: fatigue, lethargy, dizziness
- Signs: pallor of mucous membranes, bounding pulse, systolic flow murmurs, smooth tongue, koilonychias (‘spoon nails’)
Expand on clinical results of vitamin B12 and folate deficiency.
- Both have very similar lab findings and clinical symptoms
- Can be found together or as isolated pathologies
- Cause of macrocytic anaemia – low Hb, high MCV, normal MCHC
Expand on folate
- Folate necessary for DNA Synthesis:
Adenosine, guanine and thymidine synthesis - absorbed in the Jejunum and the body
Causes of folate deficiency
=> Increase demand - e.g. pregnancy/breast feeding, infancy and growth spurts, haemolysis and rapid cell turnover (e.g. SCD), disseminated cancer and urinary losses (e.g. heart failure)
=> Decreased intake - e.g. poor diet, elderly and chronic alcohol intake
=> Decreased absorption - e.g. medication (folate antagonists), coeliac, jejunal resection and tropical sprue
Expand on vitamin B12.
- Essential co-factor for methylation in DNA and cell metabolism
- Intracellular conversion to 2 active coenzymes necessary for the homeostasis of methylmalonic acid (MMA) and homocysteine
- Animal sources: Fish, meat, dairy
- Requires the presence of Intrinsic Factor for absoprtion in terminal ileum
- IF made in Parietal Cells in stomach
- Transcobalamin II and Transcobalamin I transport vitB12 to tissues
What are the causes of B12 deficiency?
=> Impaired absorption - e.g. pernicious anaemia, gastrectomy/ileal resection, Zollinger-Ellison syndrome and parasites
=> Decreased intake - e.g. malnutrition, vegan diet
=> Congenital causes - intrinsic factor receptor deficiency, Cobalamin mutation, C-G-1 gene
=> Increase requirements - e.g. Haemolysis, HIV, pregnancy, growth spurts
=> Medication - e.g. alcohol, NO, PPI H2 antagonists, metformin
What are haematological consequences?
- Normal/raised MCV ~ megaloblastc anaemia ineffective erythropoeisis
- Normal/low Hb
- Low reticulocyte count
- Raised LDH ~ intramedullary haemolysis
- BLOOD FILM: macrocytes, ovalocytes, hypersegmented neuts
- BMAT: hypercellular, megaloblastic, giant metamyelocytes ~ unusual to need
- Increased MMA ~ not standard lab test
Clinical consequences
- Brain: cognition, depression, psychosis
- Neurology: myelopathy, sensort changes, ataxia, spasticity (SACDC)
- Infertility
- Cardiac cardiomyopathy
- Tongue: glossitis, taste impairment
- Blood: Pancytopenia (reduction in the number of red blood cells, white blood cells and platelets)
What is pernicious anaemia?
- Autoimmune disorder
- Lack of IF -> lack of B12 absorption
- From gastric parietal cell autoantibodies or IF autoantibodies
Treatments for iron, folate/B12 deficiency:
- Treat the underlying cause
- Iron – diet, oral, parenteral iron supplementation, stopping the bleeding
- Folic acid – oral supplements
- B12 – oral vs intramuscular treatment
Macrocytic anaemia: causes
• MEGALOBLASTIC: low reticulocyte count - Vitamin b12/folic acid deficiency - Drug-related - Any interference with B12/folic acid metabolism • NONMEGALOBLASTIC: - Alcoholism ++ - Hypothyroidism - Liver disease - Myelodysplastic syndromes - Reticulocytosis (haemolysis)
Megaloblastic vs. non Megaloblastic
Megaloblastic changes of blood cells are seen in B12 and Folic Acid deficiency. They are characterized on the peripheral smear by macroovalocytes and hypersegmented neutrophils.
