Suspected iron overload or high serum ferritin

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Chapter 37 SUSPECTED IRON OVERLOAD OR HIGH SERUM FERRITIN

KEY POINTS

• Iron is a component of a number of essential proteins.
• Iron surplus to body needs is stored in ferritin, while iron is transported in serum bound to transferrin. Transferrin saturation and serum ferritin increase with increasing iron stores.
• Transferrin saturation is affected by dietary iron intake. A raised random transferrin saturation should be repeated fasting. Serum ferritin is increased in inflammation and by liver disease.
• Increased body iron stores are seen in hereditary haemochromatosis, a group of diseases caused by mutations in proteins involved in iron regulation. HFE1 is the most prevalent of these disorders and is caused by mutations of HFE, particularly homozygosity for the C282Y mutation.
• Secondary iron overload occurs with repeated blood transfusion or iron infusion, chronic anaemia, chronic liver disease and inflammatory states.
• In subjects with an appropriate ancestry, HFE genotyping should be performed if fasting transferrin saturation is ≥45%. When serum ferritin is >1000 μg/L, liver biopsy should be considered.
• Treatment options rely on deceasing iron stores. This can usually be achieved by phlebotomy.

INTRODUCTION

High serum ferritin is usually detected during screening studies for causes of chronic liver disease or where iron overload is suspected, as in patients requiring repeated transfusions for thalassaemia or other causes of inadequate red cell production.

It is important to note that serum ferritin is influenced by liver injury and inflammation, so an elevated serum ferritin does not necessarily indicate increased body iron stores.

IRON METABOLISM

Iron is present at about 35–45 mg/kg body weight in men and women respectively (typically 2–3 g). Iron uptake in the gut is the key step regulating iron stores and is stimulated by iron deficiency and chronic anaemia. Approximately 10%–20% of dietary iron (1–2 mg/day) is absorbed in the proximal small intestine. Once in enterocytes, iron needs to be released into the circulation, where it complexes with transferrin to be transported around the body. Iron is used in a variety of essential proteins including haemoglobin (60%–70% of body stores); and myoglobin, cytochromes and other cellular enzymes (10% of body stores). The liver is the principal storage site for iron (typically 20%–30% of body stores), in protein, ferritin; and in haemosiderin, where it can be detected histologically with Perl’s stain. Iron is lost from the body (about 1 mg/day) in bile and urine, and with the shedding of enterocytes and skin. In women, iron is also lost with menses and pregnancy. In pathological states, iron can be depleted by gastrointestinal blood loss and excessive menstrual losses.

Serum iron studies

A request for serum iron studies usually results in measurement of serum ferritin, iron and transferrin. Ferritin is the storage protein for iron in reticuloendothelial cells and hepatocytes. The serum concentration of ferritin represents the balance between secretion/leakage from cells and hepatic clearance. It provides an indirect guide to iron stores. However, serum ferritin is an acute phase reactant and its concentration increases with inflammation, and also as a consequence of hepatocyte injury.

Serum iron is included on some routine blood tests of electrolytes and liver enzymes. It is affected by dietary intake, shows diurnal variation, and is not a reliable indicator of iron stores. Transferrin is the major iron transporting protein in the body. Transferrin saturation reflects iron stores and is usually elevated (>50%) before the serum ferritin increases. Transferrin is calculated from the serum iron and total iron binding capacity, which depends on serum transferrin concentration. Measuring fasting transferrin saturations decreases the effects of diet and diurnal variation, and a value of >45% is suggestive of iron overload.

Consequences of iron overload

Iron surplus to body needs is stored in the liver. Iron overload can result in liver injury and hepatic fibrosis that can progress to cirrhosis, which in turn can be associated with liver failure and hepatocellular carcinoma. Cirrhosis typically occurs when body iron stores are >5 g. The risk of developing cirrhosis is increased in the presence of a cofactor for liver injury, such as alcohol or non-alcoholic fatty liver disease. Iron can also accumulate in the heart, resulting in cardiomyopathy and conduction defects; the pancreas, leading to diabetes; the pituitary gland, leading to hypogonadotrophic hypogonadism; joints, causing arthritis; and skin, resulting in bronze pigmentation.

Causes of high serum ferritin

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