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Case 14: Chemical Pathology (Iron Metabolism), Acute Phase Proteins in…

- - - - Iron Uptake into the Cells
        Describe the uptake of Iron into the Cells
        
        Cells needing to take up Iron (especially Erythrocytes precursors, Growing cells or Placenta) do so by expressing Transferrin Receptors on their surfaces
        
        Transferrin carrying two molecules of Ferric iron (Fe3+) then bind to the Transferrin Receptors and become endocytosed
        
        Once endocytosed, the acidic environment inside the endosome allows for the release of Iron from the Transferrin
        
        Ferric Iron (Fe3+) is then reduced to form Ferrous iron (Fe2+)
        
        Ferrous iron (Fe2+) is then transported out of the Endosome into the Cytoplasm via the DMT1
        
        In the cytoplasm the Ferrous iron (Fe2+) is then either:
        
        Stored as Ferritin in non-erythroid cells
        
        Taken up into the mitochondria in erythroid cells to be used in the formation of Haem
        
        Haem is especially important in the RBC precursor cells in the Bone Marrow
        
        The Apo-Transferrin is then released
        
        Recycling of Iron
        Describe the Recycling of Iron
        
        Apart from the Discarding of epithelial cells, there is no know mechanism for Iron excretion
        
        The control of iron is therefore, in the uptake and release of iron into Circulation
        
        Most circulating Iron is derived from Iron already with the system
        
        Iron is mainly recovered from Senescent Red Blood cells
        
        These old, and damaged RBCs are phagocytosed by macrophages, mainly in the Spleen, where they are lysed, the Haem catabolysed and the Ferrous Iron(Fe2+) released
        
        Some of the Ferrous Iron (Fe2+) remains in the macrophages as Ferritin or Haemosiderin
        
        Most of the Ferrous Iron (Fe2+) is released into circulation via the Ferroportin
        
        In circulation, the Ferrous Iron (Fe2+) is oxidised by Caeruloplasmin to Ferric Iron (Fe3+)
        
        Ferric iron (Fe3+) the binds to Transferrin
        
        Storage of Iron
        Describe how Iron is stored in the body
        
        Iron is mainly stores as Ferritin but Iron can also be stored as Haemosiderin
        
        Ferritin
        
        Ferritin is the storage form of Iron
        
        Iron in the Ferric Form (Fe3+) is complexed with Apoferritin
        
        Ferritin is water-soluble
        
        Ferritin found in circulation does NOT contain Iron
        
        However, it correlates well with Intracellular Ferritin stores in the Liver
        
        Serum Ferritin levels are proportional to Iron Storage levels
        
        When the level of Iron in the body is low, the Serum Ferritin levels are proportionally low
        
        When the level of iron in the body is high, the Serum Ferritin levels are also proportionally increased
        
        Ferritin is a Positive Acute Phase Protein, this means that Ferritin is increased with Inflammation
        
        Ferritin can also be increased with Liver disease and is released from damaged Hepatocytes
        
        Haemosiderin
        
        Haemosiderin is a Water-Insoluble, Iron-storage complex
        
        Therefore, it is a complex of Ferritin, Denatured ferritin and other material
        
        Since Haemosiderin is Water-Insoluble, it is not found in circulation
        
        However, Haemosiderin is found in tissues and most commonly found in Macrophages
- - - - Transferrin
        List the characteristics of Transferrin
        
        Transferrin is synthesised and produced by the Liver
        
        Transferrin has the following characteristics:
        
        Transferrin is the transporter of Iron in blood
        
        Transferrin carries 2 molecules of Fe3+ Iron
        
        Transferrin is increased in Iron Deficiency and High oestrogen states
        
        Transferrin is decreased in Chronic Iron Overload
        
        Inflammation, meaning Transferrin is a Negative Acute Phase Protein
        
        Liver disease because Liver cells are damaged and cannot produce Transferrin
        
        Protein losing states (Nephrotic Syndrome)
        
        Transferrin Receptors
        Describe the characteristics of Transferrin Receptors
        
        Transferrin Receptors are on all cell surfaces
        
        Transferrin Receptors bind and internalise Iron-Bound Transferrin
        
        Transferrin Receptors are increased during:
        
        Iron-deficiency
        
        Increased RBC production (erythropoiesis)
        
        Transferrin Receptors are decreased during Iron Overload
        
        NOTE: Transferrin Receptors are NOT affected by inflammation
- - - - Iron Deficiency Anaemia
        Outline the results of Biochemical Investigations of iron Status in Iron Deficiency Anaemia
        
        Iron Deficiency Anaemia is easy to diagnose with microcytic and hypochromic anaemia due to the inability to haemoglobinise cells therefore pale and small cells
        
        %Saturation of Transferrin = (Serum Iron)/ (2XTrasnferrin) x 100%
        
        Iron Deficiency Anaemia has the following biochemical results:
        
        Serum Iron is decreased
        
        Transferrin increased
        
        Iron deficiency stimulates an increase in the uptake of iron by increasing Transferrin
        
        %Saturation of Transferrin is decreased
        
        Ferritin is decreased
        
        Soluble Transferrin Receptors (STR) is increased
        
        Iron deficiency stimulates an increase in the uptake of iron by increasing Transferrin Receptors
        
        List the causes of iron Deficiency Anaemia
        
        Blood Loss:
        
        Menstruation
        
        GIT loss
        
        Frequent pregnancies
        
        Malabsorption
        
        Anaemia of Chronic Disease/Inflammation
        Describe the characteristics of Anaemia of Chronic Disease/Inflammation
        
        Anaemia of Chronic Disease/Inflammation is characterised by:
        
        Inadequate RBC (erythropoiesis) production
        
        Inhibition of erythroid proliferation
        
        Trapping of iron into the RES
        
        Trapping of Iron into the RES is caused by the stimulation of Hepcidin secretion by IL-6
        
        IL-6 is a cytokine released during inflammation
        
        Hepcidin then prevents the uptake of iron from the Epithelial cells and the release of iron from the RES into circulation
        
        This results in a Function Iron Deficiency which limits the erythrocyte hemoglobinization, causing Anaemia
        
        Outline the results of Biochemical Investigations of Iron Status in Anaemia of Chronic Disease/Inflammation
        
        Anaemia of Chronic Disease/Inflammation has the following biochemical results:
        
        Serum Iron is decreased
        
        Transferrin is normal/decreased
        
        Transferrin decreases after 8 days
        
        %Saturation of Transferrin normal
        
        This is because Hepcidin does not affect the Transferrin and Transferrin receptors
        
        Ferritin is normal/increased
        
        Ferritin increases after 4 days
        
        Soluble Transferrin Receptors are normal
        
        NOTE: In order to differentiate between Functional iron deficiency and Real iron deficiency
        
        C-Reactive Protein is increased and Ferritin is decreased in Real Iron deficiency anaemia
        
        Ferritin is normal or increased in Functional iron deficiency
        
        Haematological test: Reticulocyte Hb Content (CHr)
- - - - Investigating Elevated Ferritin
        
        Most patients who present with elevated Ferritin, will not always have an Iron overload
        
        BUT will usually have one of the following causes:
        
        Acute or Chronic Inflammation
        
        Chronic alcohol consumption
        
        Liver disease
        
        Renal failure
        
        Metabolic syndrome
        
        Malignancy
        
        These causes must first be excluded clinically or with initial biochemical testing including:
        
        FBC, Liver and Renal functional teste and Inflammatory markers
        
        A normal Serum Transferrin Saturation usually excludes iron Overload
        
        NOTE: An Iron overload Transferrin Saturation is usually greater than 45%
- - - - African Iron Overload
        
        African Iron Overload is due to a mutation in the Ferroportin Gene in 50% of patients
        
        It results in the accumulation of Iron in the RES, and later accumulation in Hepatocytes
        
        Chronic liver disease, Cirrhosis, Hepatocellular carcinoma may develop
        
        Increased risk of TB infection
        
        Secondary Iron Absorption
        
        Secondary Iron absorption may be caused by:
        
        Repeated Blood Transfusions (Sideroblastic Anaemia): Haem synthesis defect
        
        Ineffective Erythropoiesis (Thalassaemia): Globin defect
        
        Where Hepcidin secretion is suppressed leading to an increased uptake of iron
        
        First the will be RES overloaded with Iron, then the rest will follow such as carfiomyopathy
        
        Treatment: Patients are treated using Chelation Method where a Chelator such as Desferrioxamine