Iron Deficiency Anemia: Symptoms, Ferritin Testing, Causes, and Clinical Management

Pathophysiology Iron is an important molecule involved in the porphyrin ring of haemoglobin and myoglobin. Patients will present with less red blood cells produced in the bone marrow as erythroid precursors cannot function as well. Microcytic (small) and hypochromic (pale) red cells result. Iron is also essential for mitochondrial cytochrome enzyme involvement in the electron transport chain, resulting in fatigue and decreased exercise tolerance. This occurs despite haemoglobin levels still being high. Clinical Manifestations: Physical signs are due to the severity of tissue iron deficiency: Fatigued, unable to complete daily tasks due to chronic fatigue and dyspnoea on exertion. Cold intolerance with cold hands and feet. Spoon shaped nails/ brittle nails (nail dystrophies such as koilonychia). Increased diffuse hair loss (telogen effluvium). Restless leg syndrome (RLS). Symptoms worsen when lying down at night. Cravings pica. Craving to chew ice (pagophagia), cornstarch, chalk or clay. Raised angular cheilitis (painful cracks in the corners of the mouth). Pale oral mucosa (conjunctiva and nail beds). Etiology: Iron deficiency is an indication of an underlying cause in p>In adults: Investigating Iron Deficiency Parameter Iron Deficiency Anaemia Anaemia of Chronic Disease Optimal Interpretation Serum Ferritin <30 ng/ml (<15 is diagnostic) Normal or Increased (>100ng/ml) td>40-150ng/ml Most sensitive but has a major flaw. Ferritin is an acute phase protein and can become raised when there is active inflammation. TSAT <16-20% <20% td>20-45% This indicates how much iron is available for erythropoiesis. Calculated from (serum Iron/TIBC)x100. TIBC Increased (>400µg/dL) Decreased or normal (<250 µg/dL) td>250-400µg/dL This monitors how much transferrin is in the blood. It will be increased to compensate for when the liver recognise low levels of iron in the body. Hb <12.0g/dL (F)/ <13.5g/dL (M) <12.0g/dL (F)/ <13.5g/dL (M) td>12.5-15.5g/dL (F)/13.5-17.5g/dL (M) Monitor total oxygen carrying capacity. Will be reduced late on in disease. Modern Oral Regimens: Recent clinical trials have changed how we prescribe oral iron supplements to help reduce hepcidin inhibition. Red flag: Any male or post-menapausal female presenting with unexplained iron deficiency anaemia should be assumed to have GI cancer (colon/gastric). Endoscopy and colonoscopy should be done to confirm. When to see your doctor: If any of these signs appear seek medical attention: New black tarry stools (melena), bright red rectal bleeding or persistent abdominal pain. Chest pain on exertion. Feeling light headed on standing or fainting. Racing heart at rest. Severe breathlessness on minimal exertion. Heavy periods. Having to change pads/tampons more often than every 1-2 hours. Ferroportin Transport in Enterocytes, Regulation by Hepcidin and Ferritin Thresholds Iron deficiency anaemia occurs in three stages; Iron Depletion, Iron-deficient Erythropoiesis and Microcytic Hypochromic Anaemia. Iron (Fe3+ non-heme) from diet is absorbed in the duodenum. The apical duodenal cytochrome B (Dcytb) reduces the Fe3+ to Fe2+. The Fe2+ then enters the enterocytes via the DMT1 transporter. The Fe2+ can only leave the enterocyte at the basolateral surface via ferroportin. Iron levels in the body are regulated by the 25AA peptide hormone hepcidin. Hepcidin is produced by the hepatocytes in response to iron overload and inflammation. Hepcidin binds to the ferroportin causing it to internalise and break down in the lysosomes. This prevents iron entering the body via the intestines. Iron is trapped within the macrophage. Modern Oral Iron Therapy, IV Forms and Synergy with Vitamin C Modern oral iron therapy uses our knowledge of hepcidin and circadian rhythms to optimally increase iron absorption in the gut.

In adults, iron deficiency is a clinical sign that always requires investigating the underlying root cause:

Recent clinical trials have revolutionized oral iron prescribing to minimize hepcidin-mediated absorption blockades:

Iron deficiency anemia (IDA) occurs due to three progressive phases of iron deficiency, namely: Iron depletion, iron deficiency erythropoiesis and microcytic hypochromic anaemia. Dietary non-heme Fe3+ is reduced to Fe2+ in the duodenum by apical duodenal cytochrome B (Dcytb). This Fe2+ enters enterocytes via DMT1. Ferroportin mediates basolateral transport across the cell membrane into the circulation. Iron in the body is regulated by the hormone hepcidin, which is produced by hepatocytes. It is 25 amino acids long and is released in response to iron loading and inflammation. This hormone binds to ferroportin causing it to be taken up and degraded in the lysosomes, this prevents iron absorption in the intestine and causes iron to become trapped in macrophages.

Modern oral iron repletion leverages chronobiological understanding of hepcidin to maximize gastrointestinal absorption while minimizing mucosal toxicity.