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

Serum ferritin is increased in iron overload, liver injury and in inflammatory states. Iron overload can occur with inherited abnormalities of iron metabolism, particularly hereditary haemochromatosis (HFE), repeated blood transfusion and dietary iron overload (including hazardous alcohol consumption). The most common cause of iron overload in Western countries is haemochromatosis. There are a number of different types of haemochromatosis. HFE1 is the most common type of haemochromatosis and is an autosomal recessive condition caused by mutation of the HFE gene, in particular a cysteine to tyrosine mutation at amino acid 282, designated Cys282Tyr or C282Y. This mutation interferes with the regulated movement of iron from enterocytes into the body, so that iron accumulation can occur despite adequate iron stores. This depends on factors like dietary iron intake, and iron depletion through blood loss or pregnancy. The C282Y mutation appears confined to populations with Northern European ancestry and in these groups the prevalence of C282Y homozygotes is about 1 in 200 to 1 in 400. Approximately 50% of C282Y homozygotes will develop significant iron overload, depending on diet, blood loss and other genetic factors. Another HFE mutation that appears to play a role in HFE1 is the H63D mutation, which seems to only be associated with iron overload in combination with C282Y. Other genes implicated in haemochromatosis include transferrin receptor 2, ferritin heavy chain, ferroportin 1, hepcidin and hemojuvelin.

ASSESSMENT

Assessment relies on history and physical examination for inflammatory conditions or liver disease; and serological studies of iron markers, liver enzymes and screening for liver disease, and inflammatory state; and HFE gene testing. In haemochromatosis, the earliest phenotypic change is in transferrin saturation, with 45% generally being considered the upper limit of normal. This occurs prior to elevation of serum ferritin. If iron overload is suspected, transferrin saturation should be repeated after an overnight fast to avoid the diurnal and postprandial changes in this measurement. A fasting transferrin saturation of >45% will detect most patients with HFE1 and is the recommended threshold for HFE genotyping. Cirrhosis is usually associated with ferritin >1000 μg/L and this is often taken as a cutoff value for liver biopsy. Confirmation of increased iron stores relies on measurement of hepatic iron. This has usually been done on liver biopsy material, but new magnetic resonance imaging (MRI) modalities have been shown to accurately measure hepatic iron stores. Liver biopsies are also undertaken to determine if cirrhosis is present as this has prognostic significance and may lead to screening for oesophageal varices and hepatocellular carcinoma.

Causes of hyperferritinaemia and iron overload include:

• Inflammatory states—including the metabolic syndrome, and chronic rheumatologic conditions
• Chronic anaemia—conditions associated with chronic anaemia, such as haemolytic anaemia, hereditary sideroblastic anaemia and thalassaemia, that stimulate erythropoiesis can also stimulate increased iron uptake
• Transfusional iron overload—these include conditions where there is a need for repeated transfusions such as thalassaemia, bone marrow failure and sickle cell disease. Iron accumulation may also occur with parenteral iron administration
• Chronic liver disease—serum ferritin is increased with liver cell damage and release of ferritin into the circulation. This can be dramatic (ferritin in the thousands) in acute liver injury. Iron overload also occurs with chronic liver disease and cirrhosis, where it is seen more commonly as hepatocellular rather than biliary injury. It is particularly associated with non-alcoholic fatty liver disease, alcoholic liver disease, chronic viral hepatitis and porphyria cutanea tarda.
• Haemochromatosis—HFE1 is an autosomal recessive condition caused by HFE mutations, particularly homozygosity of the C282Y mutation. A small proportion (several per cent) of C282Y/H63D compound heterozygotes develop mild iron overload. Other HFE genotypes are not associated with significant iron loading. HFE2 and 3 are rare, autosomal conditions associated with raised transferrin saturation. They have been identified in people from southern Europe (Italy and Portugal). HFE2 is juvenile haemochromatosis (onset of clinical manifestations <30 years). HFE2A is an autosomal recessive condition caused by mutations in hemojuvelin (HJV). HJV mutations have also been identified in Japanese populations. HFE2B is caused by mutations in hepcidin (HAMP). HFE3 is clinically similar to HFE1 and is caused by mutations in the transferrin receptor 2 (TFR2), which is present on hepatocytes. HFE4 is autosomal dominant, caused by mutations in ferroportin 1 (SLC11A3). It is associated with normal or slightly raised transferrin saturation. HFE5 occurs with ferritin heavy chain mutations (FTH1). Routine genetic testing is only available for HFE mutations.
• Other hereditary hyperferritinaemias—hereditary hyperferritinaemia cataract syndrome is an autosomal dominant disease caused by mutation in the ferritin light chain (FTL) that can be associated with congenital cataracts. Transferrin saturation is normal and iron overload does not occur. Hereditary acaeruloplasminaemia is a rare autosomal recessive condition associated with absence of serum caeruloplasmin that can result in hepatic iron overload. It can be associated with neurological disorders due to cerebral iron deposition.

MANAGEMENT OF IRON OVERLOAD

Patients with iron overload who can tolerate phlebotomy should undergo weekly or biweekly venesection of a unit of blood (500 mL) until serum ferritin is <50 μg/L. The haemoglobin should be checked prior to each venesection to ensure it has not fallen by ≥20% from the previous value. Once ‘de-ironing’ has been achieved, the frequency of venesection can be reduced to 3–4 times per year. In patients who are unable to tolerate phlebotomy (including patients with anaemia), de-ironing can be achieved by chelation. A number of chelating agents are available including desferrioxamine at a dose of 40 mg/kg body weight/day. This is expensive and cumbersome to administer, requiring infusion over 8–12 hours. Recently oral chelating agents (deferiprone) have entered clinical practice. Their role in relation to desferrioxamine is being determined.

Phlebotomy is so successful there is no need to modify intake of foods containing iron. Vitamin C increases iron absorption and should be avoided. Alcohol also appears to increase iron uptake. There are few data supporting phlebotomy for iron overload associated with chronic liver disease.

PROGNOSIS

The prognosis of hyperferritinaemia depends on the underlying condition. In transfusion-dependent patients prognosis depends on cumulative iron load and adequacy of chelation therapy. In HFE, prognosis depends on recognition and adequate de-ironing. If patients are not cirrhotic, survival is similar to patients without HFE. However, once cirrhosis has occurred, there is increased risk of cirrhosis-related complications, particularly hepatocellular carcinoma.

SUMMARY

Iron is a component of a number of important proteins including haemoglobin, myoglobin, cytochromes and other key enzymes. Body iron stores are controlled by regulating uptake from the gut. Iron surplus to body needs is stored in hepatocytes and the reticuloendothelial systems as ferritin.

Iron is transported in blood bound to the protein transferrin. Serum ferritin and the saturation of transferrin with iron both increase with increasing iron stores. However, transferrin saturation shows diurnal variation related to dietary iron intake. As a consequence, an elevated random transferrin saturation should be repeated with a fasting sample to confirm body stores are increased. Serum ferritin is an acute phase reactant, and so is increased in inflammation. It is also elevated by liver diseases and leakage from damaged hepatocytes.

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 in populations with northern European ancestry, affecting 1 in 200–400 people. It is caused by mutations in HFE, almost exclusively homozygosity for the C282Y mutation. Other genes implicated in hereditary haemochromatosis include hepcidin, hemojuvelin, transferrin receptor 2, ferroportin and the ferritin light chain. There are other rare genetic causes of hyperferritinaemia. Secondary iron overload occurs with repeated blood transfusion or iron infusion, chronic anaemia, chronic liver disease and inflammatory states.

Evaluation of suspected iron overload requires history taking, physical examination and appropriate laboratory investigations to rule out chronic inflammation or liver disease and determine if there is secondary iron overload (Figure 37.1). 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.

image

FIGURE 37.1 Clinical pathway for evaluation of suspected iron overload.

Treatment options rely on decreasing iron stores. This can be achieved by phlebotomy or chelation therapy, if phlebotomy is not possible.

FURTHER READING

Aguilar-Martinez P, Schved J-F, Brissot P. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol. 2005;100:1185-1194.

Andrews NC. Disorders of iron metabolism. N Eng J Med. 1999;341:1986-1995.

Lieu PT, Heiskala M, Peterson PA, et al. The roles of iron in health and disease. Mol Aspects Med. 2001;22:1-87.

Siah CW, Trinder D, Olynyk JK. Iron overload. Clin Chim Acta. 2005;358:24-36.

Tavill AS. Diagnosis and management of hemochromatosis. Hepatology. 2001;33:1321-1328.

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