Essential trace elements copper, zinc and iron Introduction: • Trace elements, Inorganic elements present in the body in quantities less than 5 g are often found in complexes with proteins. Average adult daily requirements of essential trace elements. Introduction: • Trace elements can be classified as: – Essential trace elements – Nonessential trace elements • An element is considered essential if a deficiency impairs a biochemical functions and replacement of the element corrects this impairment. Whereas, excess concentrations are associated with some degree of toxicity. • The essential trace elements are usually associated with an enzyme (metallo-enzyme) or another protein (metallo-protein) as an essential component or cofactor. Introduction: • Causes of trace elements deficiency: – Decreased intake – Impaired absorption – Increased excretion – Genetic abnormalities COPPER • Copper(Cu) is an essential trace metal that is a component of a wide range of intracellular metalloenzymes, including cytochrome oxidase, superoxide dismutase. • Absorption, Transport, and Excretion – About 50% of the average daily dietary copper is absorbed from the stomach and the small intestine – Absorbed copper is transported to the liver bound to albumin where it is incorporated into caeruloplasmin, that contains 6 copper atoms per molecule, and exported into the circulation. Absorption, Transport, and Excretion • Copper is present in all metabolically active tissue of the body with the highest concentrations found in liver, brain, heart, and kidneys, with significant amounts in cardiac, skeletal muscle and in bone. • Hepatic copper accounts for about 10% of the total copper in the body. • Excess copper is excreted in bile into the gut and is lost when the mucosal cells are shed in the feces. Copper deficiency • Both children and adults can develop symptomatic copper deficiency. • In premature infants. • Copper deficiency is related to malnutrition, malabsorption, chronic diarrhea, and prolonged feeding with low-copper, total-milk diets. • Signs of copper deficiency include: 1. Neutropenia, hypochromic anemia 2. Osteoporosis and various bone and joint abnormalities that reflect deficient copper-dependent cross-linking of bone collagen and connective tissue. 3. Decreased pigmentation of the skin and general pallor 4. In the later stages, possible neurologic abnormalities Copper toxicity • Copper toxicity is uncommon and is most usually due to administration of copper sulphate solutions. • Inborn errors of copper metabolism: • Wilson’s disease: – All adolescents or young adults with otherwise unexplained neurological or hepatic disease should be investigated for Wilson’s disease. – Wilson’s disease is a genetically determined copper accumulation disease that usually presents between the ages of 6 and 40 years. Wilson’s disease • Its manifestations include neurologic disorders, liver dysfunction, and Kayser-Fleischer rings (green-brown discoloration) in the cornea caused by copper deposition. • Confirmation is by measurement of copper in a liver biopsy • Early diagnosis of Wilson’s disease is important because complications can be effectively prevented and treated using of zinc acetate or chelation therapy penicillamine. • Liver transplantation may also be considered, particularly in young patients with severe disease. Laboratory Evaluation of Copper Status • 90% of serum copper is bound to caeruloplasmin. • Total copper concentration may vary either due to changes in copper itself or to changes in the concentration of caeruloplasmin. • Serum caeruloplasmin increased greatly in the acute phase reaction. • Urinary copper. Normal excretion is <1.0 μmol/24 hours. ZINC • Zinc (Zn) is second to iron in importance as an essential trace element. • Zinc physiology • The main biochemical role of zinc is its influence on the activity of more than 300 enzymes. – – – – – – Enzymes involved in synthesis and metabolism of DNA and RNA. Zinc influences the synthesis and metabolism of proteins Participates in glycolysis Cholesterol metabolism Maintains membrane structures Effects functions of insulin ZINC • Chronic oral zinc supplementation interferes with copper absorption and may cause copper deficiency. • A high zinc intake will block the absorption of copper by inducing metallothionine in the mucosal cells. Copper has high affinity for metallothionine and is lost when the mucosal cells are shed in the faeces. • This ability to interfere with copper absorption is also the basis for using zinc to treat Wilson’s disease. • Copper status should be monitored in patients on long-term zinc therapy. Absorption, Transport, and Excretion • The body content in a normal individual is about 2.5 g zinc, which is mainly in muscles (60%) and skeleton(30%). The remaining 10% is distributed in all tissues, with highest concentrations in eyes, prostate, and hair. • Zinc absorption mainly occurs in the small intestine and especially in the jejunum. • In blood, the absorbed zinc is distributed between RBCs (80%), plasma (17%), and white blood cells (3%). • In plasma, 90% of zinc is bound to albumin and 10% to α2macroglobulin. Absorption, Transport, and Excretion • The factors increasing zinc absorption include: – Presence of animal proteins and amino acids in a meal – Intake of calcium and unsaturated fatty acids • The factors decreasing zinc absorption include: – Intake of iron – Taking zinc on empty stomach • In normal dietary circumstances, about 90% of zinc is excreted in feces. • Zinc is excreted in urine, in bile, in pancreatic fluid and in milk in lactating mothers. Zinc deficiency • Nutritional zinc deficiency is widespread all over the world. • Zinc deficiency is known to occur in patients on intravenous nutrition, old age, pregnancy, lactation, and alcoholism. • Zinc deficiency causes: – Growth retardation – Slows skeletal maturation – Testicular atrophy (delayed testicular development in adolescence delayed puberty) – Reduces taste perception – Skin rash and hair loss – Wound breakdown and delayed healing – Lymphopenia Zinc toxicity • Zinc toxicity is uncommon. Nevertheless, high doses (1 g) or repetitive doses of 100 mg/day for several months may lead to disorders, decrease in heme synthesis due to an induced copper deficiency, and hyperglycemia. • Exposure to ZnO fumes and dust may cause “zinc fume fever.” • The symptoms include: – Chemically induced pneumonia – Severe pulmonary inflammation – Fever, coughing, and chest pain – Vomiting Laboratory Evaluation of Zinc Status • Low urine zinc levels in presence of low serum zinc levels, usually confirms zinc deficiency. • Zinc concentration in red blood cells is approximately 10 times that in serum. • The concentration of zinc in plasma decreases as part of the metabolic response in inflammation such that when the CRP concentration is >20 mg/L. IRON • Introduction: • Iron is one of the most abundant element in the earth’s. • However iron is classified as a trace element in the body. • Iron ions are able to (function of iron): – Participate in redox chemistry between the ferrous (Fe (II) Fe2+) and ferric (Fe (III) Fe3+) states. – Act as a carrier of oxygen (hemoglobin and myoglobin) – Act as electron transfer reactions (cytochromes). Iron compartment • Of the 3 to 5 g of iron in the body: – Approximately 2 to 2.5 g of iron is in hemoglobin 66%, mostly in RBCs and red cell precursors in the bone marrow. – A moderate amount (4%) of iron (130 mg) is in myoglobin, the oxygen-carrying protein of muscle. – A small (8 mg), is in tissue, where iron is bound to several enzymes that require iron for full activity. – Only 3 to 5 mg of iron is found in plasma 0.1%, almost all of it associated with transferrin, albumin, and free hemoglobin. Iron compartment – 30% Iron is stored as: • Ferritin, is the major water soluble storage protein found in all cells of the body. Hepatocytes, macrophages in the bone marrow and other organs, ferritin a reserve of iron. • Hemosiderin, is an water insoluble form of intracellular storage iron protein, found predominantly in liver cells, spleen and bone marrow. – Iron is slowly released from hemosiderin. Iron compartment – In men the total body content of stored iron as ferritin 800mg . – In female the total body content of stored iron as ferritin ranges from 0-200mg. – Minute amount of water soluble ferritin are present in serum (concentrations is directly proportional to the total body stored iron). – Thus the measurement of serum ferritin is a direct indication of the amount of storage iron. – This critical pool of iron may be the first to become diminished in iron deficiency states. Absorption, Transport, and Excretion • Three major factors may influence iron absorption: 1. The state of the body iron stores, absorption increased when they are depleted and decreased when they are replete 2. Erythropoiesis, absorption is increased when erythropoiesis increased. • Absorption of iron from the intestine occurs primarily in the duodenum. Absorption, Transport, and Excretion • In the intestinal mucosal cell, ferritin and tansferrin are present in the absorptive cells of the intestinal mucosa and together regulate iron absorption. • When iron stores are high, the ferritin content of mucosal epithelia cells are high and the transferrin content is low. Iron that enters mucosal cells is trapped in ferritin and lost when the mucosal cells detached in the intestinal lumen and lost. Absorption, Transport, and Excretion • This mechanism reduces iron absorption when body stores of iron are already increased. • With iron deficiency the intestinal mucosal cells content of the ferritin is diminished and the transferrin content is increased then iron absorption is accelerated. • To be absorbed by intestinal cells, iron must be in the Fe(II) (ferrous) reduced state and bound to protein. Absorption, Transport, and Excretion • Because Fe (III) is the predominant form of iron in foods, it must first be reduced to Fe (II) by agents such as ascorbic acid vitamin C and the acidic condition of the gastric content before it can be absorbed. • In the intestinal mucosal cell, Fe (II) is bounded to apoferritin then Fe (II) re-oxidized by ceruloplasmin to Fe (III) and bound to ferritin. • Absorption and transport capacity can be increased in conditions such as iron deficiency anemia, or hypoxia. • Iron is absorbed into the blood by apotransferrin a protein synthesized by the liver, which becomes transferrin as it binds two Fe (III) ions. 30% of the transferrin molecule normally saturated with bound iron. Absorption, Transport, and Excretion • The percentage of transferrin saturation can increase or decrease depending on the iron status of the body. • In plasma, transferrin carries and releases Fe to the bone marrow, where it is incorporated into hemoglobin of RBCs. • After about 4 months in circulation, red cells are degraded by the spleen, liver, and macrophages, which return Fe to the circulation, where it is bound and carried by transferrin for reuse. • Iron is lost primarily by desquamation and red cell loss to urine, feces, bleeding, and by cancer. Absorption, Transport, and Excretion • Women lose iron: – With each menstrual cycle approximately 20 to 40 mg of iron. – 600-900 mg of each pregnancy. – Menstrual loss is the most common cause of iron loss in women • In adult male and postmenopausal female iron deficiency anemia usually results from gastrointestinal tract bleeding, can be diagnosed by stool occult blood. Disorders of iron metabolism • Iron deficiency: • Occurs when the amount of iron absorption is inadequate to meet the needs of the body, or decreased release from ferritin. • Iron deficiency anemia is considered the most common cause of anemia worldwide, leads to anemia and tissue hypoxia. • It can affect: – Persons of any age – But mostly occurs in children , women of child bearing age – Pregnant women Disorders of iron metabolism • Causes of iron deficiency anemia: – Decreased availability: inadequate intake, malabsorption, chronic diarrhea. – Increased requirements: Growth, infancy, childhood, adolescence, child bearing ages and pregnancy. – Chronic loss of blood: • Hemorrhage is the most common causative factor of iron deficiency. • Excessive menstruation, peptic ulcer, hemorrhoids, esophageal varices. Disorders of iron metabolism • Chronic diseases: – Chronic Infection, chronic inflammation, malignancies might alter the erythropoietin production resulting in decreased erythropoiesis. – Despite low serum iron levels, iron store are increased, because of block of transfer of stored iron RE sources to the plasma. – Whereas in hepatitis iron and ferritin is high may be due to hyperferritinemia from hepatocytes injury. Liver injury results in release of large amounts of ferritin into plasma. Laboratory assessment of body iron status 1. Serum iron (SI) 2. Total iron-binding capacity (TIBC) 3. Unsaturated iron binding capacity: (UIBC = TIBC-SI) 4. Percent transferrin saturation 5. Serum ferritin assay 6. The soluble transferrin receptor (sTfR) Laboratory assessment of body iron status Diagnosis of iron deficiency • The typical biochemical assessment of iron deficiency anemia includes the measurement of: • Serum Iron (SI): decreased SI is a late feature of iron deficiency – There is a marked circadian rhythm in serum iron concentrations, which can vary by 50% over 24 hours. Although it is usually accepted that iron concentration peaks in the morning and is lowest in the evening. • Total iron binding capacity (TIBC): a functional measurement of tranferrin. Diagnosis of iron deficiency • % transferrin saturation. – Transferrin increased in iron deficiency anemia as a result of increased synthesis of protein to transport more iron to the depleted tissue, but because of depleted iron stores the % saturation of transferrin decreased. • Accurate diagnosis of the cause of iron deficiency, then administration of iron in the form of iron sulfate is the usual treatment. Diagnosis of iron deficiency • The classic laboratory findings in in iron deficiency anemia are: • Decreased serum ferritin, decreased serum iron, decreased % transferrin saturation, increased TIBC, decreased red blood cell count, mean corpuscular hemoglobin concentration, and microcytic RBCs. • Whereas in iron deficiency anemia due to chronic inflammation and malignancy – Decreased serum iron, decreased % transferrin saturation and decreased TIBC, because transferrin synthesis is decreased and its catabolism is increased which contributing to lower the TIBC values and increased ferritin. Iron overload • Increased iron absorption may occur either from: – An increase in the amount of available dietary iron. – Through increased intestinal absorption. • Iron overload states are collectively referred to as hemochromatosis. • Causes of iron overload: – Increased absorption: • Primary hemochromatosis (HH) hereditary disease • Secondary due to dietary excessive iron ingestion, medicinal, and transfusional, increased red blood cell destruction, Thalassemia. Haemochromatosis • Haemochromatosis is a relatively common inherited disease characterized by: – Increased iron absorption (2–3 × normal) that leads to iron deposition in various organs. – The excess iron is highly toxic leads to free radical generation, fibrosis and organ failure. • The commonest mutation is in the HFE gene results in decreased production of a small peptide, hepcidin, which is the main regulator of iron absorption and distribution. • Hepcidin targets ferroportin, a transmembrane protein. Haemochromatosis • The latter is present in intestinal cells and binds to the absorbed iron. • Hepcidin binds to ferroportin and induces its internalization and degradation, thereby retaining the iron within the cells; this iron is then lost with cellular desquamation. • Low hepcidin production leads to dysregulated and excessive iron absorption. • Women are less severely affected than men, being protected by physiological iron loss during menstruation and in pregnancy. • Clinical features include – Chronic fatigue and skin pigmentation diabetes mellitus, cardiomyopathy hepatic cirrhosis and hepatoma. Iron overload • Laboratory diagnosis of iron overload: – – – – Increased serum iron Decreased TIBC Increased transferrin saturation of greater than 90% Increased serum ferritin • The best way to confirm hereditary haemochromatosis is genotyping, which is 99% sensitive. • Liver biopsy is also used to confirm iron overload. • Chronic iron overload is usually treated by venesection (therapeutic phlebotomy) the removal of 500 mL blood accounting for 2 ̴ 50 mg iron or administration of chelators, such as deferoxamine.
