Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

Abstract

AASLD, American Association for the Study of Liver Diseases; ALD, alcoholic liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMP6, bone morphogenetic protein-6; C282Y, Cys282Tyr mutation; GRADE, Grading of Recommendation Assessment, Development, and Evaluation; H63D, His63Asp mutation; HAMP, hepcidin; HCC, hepatocellular carcinoma; HH, hereditary hemochromatosis; HIC, hepatic iron concentration; HII, hepatic iron index; HJV, hemojuvelin; OLT, orthotopic liver transplantation; PCT, porphyria cutanea tarda; S65C, Ser65Cys mutation; TfR2, transferrin receptor-2; TS, transferrin saturation. This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association. These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic; (2) the American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; and (4) the experience of the authors in regard to hemochromatosis. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C). Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information.3, 4 Hereditary hemochromatosis (HH) remains the most common, identified, genetic disorder in Caucasians. Although its geographic distribution is worldwide, it is seen most commonly in populations of northern European origin, particularly Nordic or Celtic ancestry, in which it occurs with a prevalence of approximately 1 per 220-250 individuals.5, 6 The pathophysiologic predisposition to increased, inappropriate absorption of dietary iron may lead to the development of life-threatening complications of cirrhosis, hepatocellular carcinoma (HCC), diabetes, and heart disease. The principal HFE gene defect was first described in 1996, and is a G-to-A missense mutation leading to the substitution of tyrosine for cysteine at amino acid position 282 of the protein product (C282Y).7 C282Y homozygotes account for 80%-85% of typical patients with HH.8 There are two other regularly identified mutations, one in which aspartate is substituted for histidine at amino acid position 63 (H63D), and the other in which cysteine is substituted for serine at amino acid position 65 (S65C). These are generally not associated with iron loading unless seen with C282Y as a compound heterozygote, C282Y/H63D or C282Y/S65C (Fig. 1). Over the last 10 years, mutations of other genes coding for iron regulatory proteins have been implicated in inherited iron overload syndromes (e.g., hepcidin, hemojuvelin, transferrin receptor 2, and ferroportin). These are thought to account for most of the non-HFE forms of HH.9 Schematic representation of the protein product of HFE. Most of the protein is extracellular. There is a short cytoplasmic tail and three extracellular alpha loops. The three principal mutations are identified. Stage 1 refers to those patients with the genetic disorder with no increase in iron stores who have “genetic susceptibility.” Stage 2 refers to those patients with the genetic disorder who have phenotypic evidence of iron overload but who are without tissue or organ damage. Stage 3 refers to those individuals who have the genetic disorder with iron overload and have iron deposition to the degree that tissue and organ damage occurs. This organizational schema is important to allow clinicians to categorize patients who have positive genetic test results. The current classification of iron overload syndromes divides patients into three groups (Table 2): (1) those who have inherited causes of iron overload, (2) those who have various causes of secondary iron overload, and (3) a small miscellaneous group. Approximately 85%-90% of patients who have inherited forms of iron overload are homozygous for the C282Y mutation in HFE, with a small minority who are compound heterozygotes, meaning that one allele has the C282Y mutation and one allele has the H63D or the S65C mutation. The remaining 10%-15% of patients who have inherited forms of iron overload most likely have mutations in one of the other aforementioned genes involved in iron homeostasis.9 Causes of secondary iron overload are divided between those causes related to iron loading anemias, those related to chronic liver disease, transfusional iron overload, and miscellaneous causes. Oral iron ingestion does not lead to iron overload except in genetically predisposed individuals or those who have ineffective erythropoiesis. Other inherited forms of iron overload, classified as non–HFE-related HH, are juvenile hemochromatosis and iron overload resulting from mutations in the genes for transferrin receptor 2 (TfR2), or ferroportin (SLC40A1).9 Juvenile HH is characterized by rapid iron accumulation. Mutations in two different genes (hemojuvelin and hepcidin) have been shown to cause two forms of juvenile HH.14 The more common mutation occurs in the hemojuvelin (HJV) gene on chromosome 1q.15 Mutations in the hepcidin gene (HAMP) also produce a form of juvenile HH, but this is much less common.14 Hepcidin is a 25–amino acid peptide produced in the liver that down-regulates iron absorption. Mutations in the TfR2 gene produce an autosomal recessive form of HH that is clinically similar to HFE-related HH.16 These mutations may cause abnormal iron sensing by hepatocytes, which is the predominant site of TfR2 expression. The distribution of excess iron is similar to that in HFE-related HH, namely, primarily in hepatic parenchymal cells.16 A rare autosomal dominant form of HH results from two categories of mutations in the gene for the iron transporter protein, ferroportin. “Loss-of-function” mutations decrease the cell surface localization of ferroportin, thereby reducing its ability to export iron.17, 18 The result is iron deposition primarily in macrophages, and this disorder is called “ferroportin disease”. The second category of mutation includes “gain-of-function” ferroportin mutations that abolish hepcidin-induced ferroportin internalization and degradation18; distribution of iron is similar to HFE-related HH, concentrating predominantly in parenchymal cells. African iron overload occurs primarily in sub-Saharan Africa and is now considered to be the result of a non–HFE-related genetic abnormality that can be exacerbated by dietary iron loading.19 Some individuals with African iron overload drink an iron-rich fermented beverage, but iron overload can also occur in people who do not drink this beverage.19 Individuals who absorb excessive amounts of iron as a result of an underlying defect other than any of the previously mentioned inherited disorders have secondary iron overload.20 The most common causes of secondary iron overload are individuals with ineffective erythropoiesis, parenteral iron overload, and liver disease. Individuals who receive blood transfusions and who have transfusional or parenteral iron overload should be distinguished from those who have other causes of secondary iron overload. Parenteral iron overload is always iatrogenic, in that blood or iron (given parenterally) must be ordered by a health care provider prior to its administration. Many individuals with ineffective erythropoiesis who have decreased utilization of iron by the bone marrow also have transfusional iron overload because of a requirement for transfusions.20 Recently, it has been found that neonatal hemochromatosis is actually a form of congenital alloimmune hepatitis with subsequent iron deposition.21 In these cases, immune-mediated liver injury in the fetus is associated with the development of iron overload. of or the development of this Other rare miscellaneous disorders congenital and There are categories of of HH that should be (1) the absorption of dietary iron in the (2) decreased of the hepcidin, (3) the of HFE protein, and (4) tissue injury and by The first between HFE protein and iron from the that the HFE protein with forms a with transferrin This was in and in which have been considered to be the predominant site of of dietary iron absorption. The that HFE protein and associated to a of of the of HFE protein on iron and iron The cell of iron is now as much less important the of the of hepcidin in the of iron Hepcidin is a 25–amino acid peptide that iron is considered to be the principal in the of hepcidin an important in the of hemochromatosis. Hepcidin is predominantly in and is into the to ferroportin, which is found in and on the surface of hepcidin to ferroportin, the ferroportin is and and iron export by these two cell and is Hepcidin by excess iron or results in decreased iron absorption and iron from In hepcidin is decreased by iron ineffective erythropoiesis, and with resulting in iron absorption from the and of iron from Mutations in or of the genes for HFE, hemojuvelin, hepcidin, or TfR2 decrease hepcidin with a resulting increase in iron absorption of ferroportin in have that of hepcidin a bone morphogenetic protein 6 to a receptor on of hepcidin expression. of of is a and it the of to its of the gene in hepcidin and causes iron The extracellular of HFE protein of three with the second and (Fig. 1). The of the HFE protein is similar to that of other but evidence that HFE protein does not in HFE protein is associated with similar to other The by which HFE of hepcidin HFE can to TfR2 and to the transferrin receptor In HFE and TfR2 may with HJV, that a of HFE and TfR2 may a regulatory in that the of and HFE as an iron at the cell of the transferrin transferrin HFE from thereby HFE available to to is that the of HFE and TfR2 hepcidin expression. 2 these of between hepatocytes, and in iron by ferroportin. from iron with from pathophysiologic in HH to the liver damage that results from iron In patients with HH, hepatic and are the principal hepatic iron overload have identified damage and associated of of and is that occurs in and causes hepatocellular injury or from and produce which in hepatic to amounts of thereby leading to is by it is because it is considered a rare disorder that is by the seen in fully of cirrhosis, diabetes, and for hemochromatosis is seen in approximately one in fully with is seen in than of these The for the of phenotypic are may with gene of other proteins involved in iron or without This can the between the high of C282Y in in the of the are seen one in The is found in approximately one in 10 individuals and may be associated with iron but without associated tissue iron overload or damage. in patients in from the to the that most patients and of hemochromatosis (Table the HH was identified in patients who abnormal iron on or by patients been identified by patients with HH identified in this approximately of not have and not any of the of the disease. in approximately of C282Y homozygotes are found to have an of iron stores (Table and a small of these patients have of iron than have it is important for clinicians to be of the that patients may and the with which can patients with hemochromatosis should be considered are of of the second and decreased and of heart or (Table of an particularly in the of cirrhosis, of chronic liver disease, heart of porphyria cutanea or should the of hemochromatosis (Table Many of these are of other than but the that hemochromatosis has been considered patients who these or are most patients with HH to because of as in or by of abnormal by care In of patients with HH, patients identified by or of the disease, approximately 10 than and approximately 10 as as This is likely because of blood and iron a for with a of patients identified by the of for and has and the of and identified are 10 the of C282Y homozygous with (e.g., liver disease, is than that patients with abnormal iron should be as patients with in the of patients with evidence of liver should be for hemochromatosis. The of hemochromatosis is based on of iron by which an increase in hepatic iron HH can be by the of iron overload associated with C282Y or C282Y/H63D compound iron are and the of patients with HH are now identified and without evidence of hepatic or There are groups that should be for as those with a of HH, those with organ and those with of of the of iron overload. is generally that patients with abnormal liver have iron at in The in 3 can provide and is from the used in the AASLD can provide and for The is from the used in the AASLD guidelines. The approach to is by of iron or and (Table is from the of iron to In the is from the of the iron and the in it is from the transferrin in the A has shown no in or in the of C282Y this prior is no it is to an with a second and it is not in to do this on a Over the years, different have used a of for to patients for Although a of is for its high for C282Y it has a and positive to a of also with minor secondary iron overload as as heterozygotes, and these has less than TS, but it has a positive because of related to can be in the of iron stores in patients with liver liver chronic hepatitis and liver in and in patients with other chronic In in the iron overload is not the most common cause of an in the of other of with HH have that the a with the degree of iron In most of the of an in C282Y In a of individuals of in the in with a a of for iron In a phenotypic and in a care in a in and in was positive in and of C282Y In the and that American in in in of and of C282Y is that a of to iron overload may cause a in and in the of an TS, this may be iron overload may be in a with an and a TS, particularly in non–HFE-related iron overload or in a C282Y/H63D compound have an as a of and in have that a of is an for the of cirrhosis, of the of the A with an or aspartate and a the of in of C282Y In a with or a of and should be than on a is abnormal or the of HFE mutation analysis should be iron should groups as those with a of HH or those with organ a with HH has been identified should be for of mutation and and should be at a of an identified HFE of the other is generally because results are the is an and not because is no of iron C282Y or compound is found in of a and are increased, can be is in these with iron is identified, C282Y and H63D can be that are not at for or iron overload. H63D homozygotes can iron it should be that any of these can be a for the development of liver occur in with other liver as PCT, hepatitis ALD, or who are identified as H63D or H63D homozygotes can be that are generally not at of iron overload, may have minor in iron as or have that homozygous of and of a of approximately identified C282Y homozygotes These a prior to available of iron was in of and of and HFE mutation of of patients with HFE-related HH to and the of HFE mutation liver has less important as a in the of Liver should be considered for the of the or of or cirrhosis, which does have of may lead to in as for and other of The of liver have been with to be in the of and associated with a of less than can patients who may most from a liver have that C282Y homozygotes with a are at an of cirrhosis, with a prevalence of In than of C282Y homozygotes with a at the of have or in the of as excessive or liver A of more than C282Y homozygotes described the prevalence of hepatic In this a liver was in because of a of or abnormal liver the of or a of The of these for of HH prior to the of HFE mutation was in of and of with a hepatic iron the of A and for of with a These must be patients with HH also amounts of that of patients with HH who cirrhosis, to of those who less on these it can be that is the most important of the of hepatic in C282Y liver does not to be is in the of excess and liver with iron but who C282Y should be considered for liver have liver or other evidence of liver disease. These patients may have liver as ALD, or chronic liver is should and as as for the degree and distribution of hepatic iron In a of liver tissue can be for of should be that can also be from but at 4 of tissue should be available for and for the degree of hepatic iron have been The system an of the of that for from 1 to of 2 and 3 The of iron from 1 to with 4 iron A hepatic iron has been based on the and of iron in hepatocytes, and This can be used to a iron and this system has been and found to be to from is not used the iron was first in and was used to a of HH the was prior to the of HFE mutation HII, which the of hepatic iron is by the by the in and was based on the that homozygotes to absorb excess dietary iron those who or those with iron overload to associated use that most homozygotes with iron overload an patients with other chronic an The of genetic has now shown that phenotypic of can occur at a much and a much HII, and the is no between on liver with by by Liver is to the degree of liver in C282Y homozygotes or compound liver are or is Liver may provide and in patients with iron overload who are not C282Y iron are identified in approximately of patients with other liver as ALD, or chronic Liver is used to those patients from the of underlying disease, the of and to the degree of iron In the secondary iron overload seen with other liver iron deposition is to and generally occurs in and in in a Liver is also to the different of iron overload seen in patients with ferroportin disease, the iron deposition is predominantly in or is in a of and without a Liver is for and in patients with phenotypic of iron overload who are not C282Y homozygotes or compound that in patients with non–HFE-related HH, on hepatic iron is with iron to the degree and distribution of iron loading Although has been a of no in of HH, is evidence that of the development of the and of and of those at is generally This includes of individuals with homozygous HH and of iron overload, as as with evidence of of hepatic In is also to of organ damage. are likely to be by for and other are less to iron or do not at (Table These and In cases, hepatic and The life-threatening complications of cirrhosis, particularly HCC, to be a to patients with should to be for for approximately of complications of account for an is rare in HH, which an for preventive prior to the development of remains the of for HH (Table of blood approximately on the and should be or per as In patients with HH who may have iron stores may to to iron should be by of the or as to reducing the to of the remains iron stores are which may to with iron and is of of iron analysis should be every 3 in the of can be that excess iron stores have been the to between and the of is may be more to the development of iron is not for patients to iron and in this should be can be at the at which iron stores are and the should be for that are not patients with HH iron may not a the of to the of iron in Some patients or who iron at a may of blood per In the blood by may be used for blood in and the American and the and have that the blood is for The to HH with is and to for patients with evidence of liver or other The more is the C282Y with a of for with liver and no are patients as this to more and may not to be is and provide and is are no of who the of increase of in the to be an of tissue and organ damage. In the of results from to in those individuals who and to the In those patients with who may have or is an of with rapid of most likely to the of iron in a of of of iron to a that may resulting in an increase in should be by particularly those dietary are because the of iron absorption that an can with a is small to the with of have been described in patients with HH who these should be is not with iron and the development of liver is an to orthotopic liver In the of patients with HH who liver was than in those who liver for other causes of liver Most in patients with HH in the from or These complications related to of excess iron stores of patients with HH is to other at in because and occurs prior to with hemochromatosis and iron overload should of should be a of In the of of liver C282Y homozygotes who have an should to without a liver with damage to iron overload should to the as for HH, dietary are and iron should be with hemochromatosis and iron overload should be for of iron and of should be a of by of patients with non-HFE iron overload who have an These have primarily on the of HH, but it is to review the of forms of secondary iron overload. The causes of secondary iron overload are in is in forms of secondary iron overload (Table is in patients with PCT, and results in a in iron stores iron overload is seen in with chronic hepatitis and There is no published evidence that is of in In chronic hepatitis it has been shown that and a in but has no on is not for secondary iron overload in chronic hepatitis In have shown a of with in of and in in patients with have been In secondary iron overload associated with ineffective erythropoiesis, iron with parenteral is the of have the of in the complications of iron overload in Recently, an has been approved in the for of secondary iron overload to ineffective erythropoiesis. are its use in complications have for this in is by a at a of for for A of approximately 2 per iron to the of The of is by the for a parenteral of and iron in patients with secondary iron overload is In contrast to HH, iron can be in secondary iron overload. In it may be to liver to the of and iron is a is of a but this is a that is available in a The development of has shown in a to In patients with secondary iron overload, an for iron with or is in iron patients with syndromes or chronic In patients with HH who with cirrhosis, the AASLD for should be These recommendations should be to patients with HH who have cirrhosis, have to iron The for is approximately with an of with HH with or should be regularly for as per AASLD guidelines. the evidence to should be for the C282Y a is the of C282Y Approximately of C282Y homozygotes do not have phenotypic of excess iron stores in (Table 2). of from a for HH is not In a TS, and it was on two by genetic liver In liver and and of the prevalence of of individuals C282Y these liver was in with of three identified with and one with who associated prevalence of Other have similar that the of C282Y is This between the seen in patients and the of in patients is not to that have genetic have that for HH be of patients life-threatening The of HH has been in the patients followed for with without an that C282Y Many patients not of iron overload as by and the of positive iron in a considered This has to that a genetic test should be followed by of There have been the of genetic as genetic have that this is a for HH is not more in populations for HH is not The refers to genetically forms of inherited iron overload individuals without HFE of the genes involved are hemojuvelin ferroportin transferrin receptor 2 and hepcidin The non-HFE forms of inherited iron overload are for of and genetic is except in for non–HFE-related HH is not This guideline was produced in with the Practice Guidelines Committee of the This review of the and an review from the GRADE system of the Practice Guidelines Committee and