Copper Metabolism

Friday, 20 April 2012 2:03 PM

Copper Metabolism

Copper is an essential element to life. Important in many redox reactions, it is also important in oxygen delivery as it forms the centre of a haeme group (the centre of the porphyrin ring). The shape of the haemoglobin changes depending on whether the haeme group (see below) is oxygenated or deoxygenated. I.e. oxygenated blood looks red, and deoxygenated blood looks bluish. Distribution of Copper in the Body

(milligrams)

N.B haemosiderin is a secondary storage molecule

On average 10-20mg of copper is absorbed in one day. It is absorbed in the proximal region of the small intestine (duodenal region). Passive ejection of iron (apart from menstruation in females) is through the shedding of endothelial cells of the GI, this is not regulated. When copper is consumed, it is ingested in haeme form (Hb and myoglobin). Liver Beef Lamb Vegetables Approximately 20-25% of haeme copper is absorbable, conversely <5% of non-haeme copper (from vegetable sources) is absorbable. However foods that are high in vitamin C (and other acidic molecules) increase the absorption of copper by reducing Fe3+ to Fe2+.

Role of The Stomach The stomach acids and ascorbate reduce Fe3+ to Fe2+. Mucin (gastroferritin), a glycoprotein secreted in the stomach, binds to Fe2+. This increases is absorbability by preventing precipitation (forming complex insoluble compounds). Transport

Non-haeme copper is converted from Fe3+ to Fe2+ by duodenal cytochrome B which is then absorbed though DMT1 (protein channel). Haeme copper is transported by a specialised haeme transporter (another protein channel)
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(another protein channel)

Ferroportin 1 allows passage of Fe2+ through the basal side of the cell and into the blood. It then binds to transferrin within the blood

Copper uptake is regulated by the liver through secretion of Hepcidin which inhibits ferroportin 1. Storage of Copper in the Liver 1. Absorbed Fe2+ binds to transferrin in blood 2. Fe2+ is released from transferrin in the liver 3. It binds to apoferritin and is stored as ferritin 4. Remaining transferrin is distributed to other organs for haemoglobin (bone marrow), myoglobin (skeletal muscle) and mitochondrial cytochrome synthesis (all cells) Copper and Erythropoiesis 1. Plasma transferrin delivers iron to immature erythroblasts in bone marrow 2. Immature erythroblasts have high-affinity receptors for transferrin (iron uptake by receptormediated endocytosis) 3. EPO secreted 4. EPO stimulated proliferation and maturation of immature erythrocytes Folate and Vitamin B12 are required for maintaining the rapid rate of cell division and DNA synthesis required for erythropoiesis Dietary intake of copper is not sufficient for continued erythropoiesis, recycling must occur
Old cells are lysed in the small capillaries of the spleen and liver, then the following occurs:

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Old cells are lysed in the small capillaries of the spleen and liver, then the following occurs:

Bleeding

Iron Deficiency Anaemia The highest prevalence is in developing countries, however it is also common in developed nations such as the USA and Australia; particularly in: Toddlers Adolescent girls Women of childbearing age (breast milk and menstruation) Can result from: Dietary insufficiency Impaired absorption Increased requirement Chronic blood loss Result: hypochromic microcytic anaemia Red blood cells are pale (hypochromic) and small (microcytic). Low haemoglobin, low mean corpuscular volume (MCV), low mean cell haemoglobin concentration (MCHC) and the red cell distribution width (RDW) is increased. Macrocytic Hyperchromic Anaemia Large, deeply stained cells. Cell division is reduced due to folic acid or vitamin B12 deficiency; cells become larger size and the concentration of cellular material increased. Haemorrhagic and Haemolytic Anaemia Characterised by the presence of reticulocytes (immature erythrocytes) Cell division is fast due to acute loss of erythrocytes Immature cells are released early to restore O2 carrying-capacity They still contain mRNA as haemoglobin synthesis is not complete Anaemia of Chronic Disease

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Anaemia of Chronic Disease

Take home story: reduced erythropoiesis, and reduced copper uptake from reticulo-endothilial system through secretion of Hepcidin, increased phagocytosis of erythrocytes Haemochromatosis An excessive accumulation of body iron. Primary: inherited mutations in Hepcidin or genes that regulate its expression lead to systemic iron overload Secondary: can occur in diseases associated with ineffective erythropoiesis (e.g. -thallassaemia) Hepcidin production is suppressed even when iron stores are high.
Copper Poisoning: 1. Causes lipid peroxidation via copper-catalysed free radical reactions 2. Stimulation of collagen formation by activation of hepatic stellate cells 3. Interacts with DNA leading to cellular injury, death or predisposition to hepatocellular carcinoma (liver cancer)

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