How can I be sure that the patient has hereditary hemochromatosis?
The term “hemochromatosis” refers to tissue injury that results from iron overload. More recently, the term “iron overload disease” has been introduced to define disease that is due to iron overload. Hemochromatosis can result from primary (inherited or genetic disorders) or secondary (exogenous administration of iron or blood products or hematological disorders) causes. Hereditary hemochromatosis (HH) is present when an inherited disturbance of iron metabolism results in iron overload, tissue injury, and disease.
The most common cause of hemochromatosis in populations of northern European origin is HH. Most cases of HH result from inherited mutations in proteins involved in iron-sensing and the regulation of iron homeostasis (Types 1-3 HH). Such mutations result in impaired production of the key iron regulatory hormone “hepcidin.” Hepcidin plays a central role in iron hemostasis by coordinating iron absorption, mobilization, and storage to meet the iron requirements of erythropoiesis and other iron-dependent processes. Hepcidin is expressed predominantly in hepatocytes and is secreted into the circulation. It binds to the iron export protein ferroportin (FPN), which is highly expressed on macrophages and the basolateral surface of enterocytes, causing FPN to be internalized and degraded, and thereby inhibits iron export (Figure 1). Hepcidin expression is regulated by iron status, erythropoiesis, inflammation, and hypoxia. Excess iron and inflammation both induce hepcidin gene (HAMP) expression and protein production, which decreases iron absorption from the gut and iron release from the bone marrow. Erythropoiesis and hypoxia inhibit hepcidin production, promoting iron absorption and iron release. Currently, four types of HH are recognized.
Type 1.HFE- related HH is an autosomal recessive inherited condition and is the most common cause of HH, accounting for approximately 90% of cases. Most commonly, a missense mutation leads to substitution of tyrosine for cysteine at amino acid 282, resulting in a C282Y mutation in the HFE-gene product. Approximately 1 in 7 individuals is heterozygous whereas 1 in 200 individuals in populations of northern European origin is homozygous for the C282Y mutation. Only homozygosity for C282Y increases the risk of iron overload. Development of iron overload disease occurs in up to 30% of male and 1% of female C282Y homozygous individuals by the 7th decade of life.
Another mutation, H63D, is more common than C282Y (1 in 3 is heterozygous while 1 in 36 is homozygous for H63D), but it does not increase the risk of development of iron overload disease. Compound heterozygosity for both C282Y and H63D affects about 1 in every 42 individuals in populations of northern European descent. It develops into clinically relevant iron overload disease in about 1% of cases, usually in the setting of other liver disease co-factors, such as excessive alcohol consumption.
HFE-related HH is characterized by impaired iron sensing and inappropriately low production of hepcidin relative to iron status of the homozygous individuals.
Type 2. Juvenile hemochromatosis-related HH is an extremely rare autosomal recessive condition that results in severe iron overload in the 2nd and 3rd decades of life. Mutations in either the hemojuvelin or hepcidin genes underly the causation of this disease. It is characterized by impaired iron sensing and low levels of hepcidin production.
Type 3: Transferin receptor 2 (TFR2)-related HH is an extremely rare autosomal recessive disorder that affects adults of Italian, Portuguese, French, or Japanese descent. It is characterized by impaired iron sensing and low levels of hepcidin production.
Type 4: Ferroportin mutations account for an extremely rare form of adult HH that is inherited in autosomal dominant fashion. It has been reported in populations of French, Solomon Islander, African, African-American, Spanish, or Indian descent. It is caused by either gain-of-function or loss-of-function mutations in the FPN gene.
For the purposes of this publication, we hereafter discuss only HFE-related HH.
What signs and symptoms of hereditary hemochromatosis are usually found?
Although C282Y homozygosity is present at birth, it demonstrates high variability in terms of development of biochemical or clinical manifestations of iron overload. Elevated serum transferrin saturation and ferritin levels develop in at least half of affected adults. At least 50% of C282Y homozygotes remain asymptomatic for long periods and well into adulthood. Many will never develop symptoms or signs of disease. In those who go on to develop iron overload disease, symptoms and signs develop primarily during mid-adult life, when iron loading reaches a critical level (usually around 10-20 g of body iron).
Patients who are at highest risk of development of iron overload disease are those who achieve transferrin saturation and ferritin levels of at least 95% and 1000 μg/L, respectively. Females present later than males as they are protected by iron loss or utilization via menstruation or pregnancy. There are multiple other genetic and environmental factors that modify the clinical and biochemical expression of C282Y homozygosity. Concomitant existence of other liver injury processes may also contribute to the development of hepatic injury. Dietary iron and fruit intake and alcohol consumption can all modify the degree of iron accumulation independently of HFE status.
Symptoms and signs are often nonspecific and have often been present for long periods prior to diagnosis (Figure 2; Table I). Common symptoms include lethargy, fatigue, arthralgia, and loss of libido. In addition, specific symptoms related to organ involvement in iron overload may also occur.
Common sites of involvement include the joints, liver, pituitary, skin, pancreas, and, rarely, the heart. Bilateral arthritis of the 2nd and 3rd metacarpophalangeal joints or lower limb large joints affects up to 25% of HFE-related HH individuals and occurs more commonly in those with more significant iron overload. It is one of the most debilitating manifestations of iron overload disease. Chronic liver disease (cirrhosis and hepatocellular carcinoma), hypogonadotropic gondadism, skin pigmentation, diabetes mellitus, and cardiac failure may all occur in decreasing order of likelihood.
Many of these clinical manifestations are directly attributable to the excessive absorption of iron, which leads to cellular injury through oxyradical formation and generation of cellular lipid peroxidation. Damage to hepatocellular lysosomes and mitochondria has been hypothesized to contribute to local hepatocyte injury, necrosis, and apoptosis. Secondary liver regenerative, liver progenitor cell and fibrogenic responses to this injury result in fibrosis, cirrhosis, and, ultimately, hepatocellular carcinoma.
A tabular or chart listing of features and signs and symptoms
See sections above for characteristic features and less common clinical presentations of HH.
Differential diagnoses of hereditary hemochromatosis
Differential diagnoses include the following:
1. Chronic liver diseases, such as
Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune cholangiopathy: diagnosed by serology and liver biopsy
Viral hepatitis B, C: identified by serology, virology, and liver biopsy
Chronic drug-induced hepatitis: drug history, serology, + liver biopsy
Alcoholic and nonalcoholic fatty liver disease: history, physical exam, exclusion of other causes of liver disease, liver biopsy
2. Secondary causes of raised serum ferritin levels, such as
renal failure patients on hemodialysis or being treated with erythropoietin and iron therapy (about 40% of such individuals)
obesity and nonalcoholic fatty liver disease (30-50% of such individuals)
chronic viral hepatitis (30-50% of such individuals).
Of these groups, only subjects with chronic renal disease are likely to have significant iron overload. Hyperferritinemia in the other disease states does not usually indicate significant iron overload.
3. Secondary iron overload syndromes, such as iron-loading anemias, parenteral iron overload, etc.
4. Causes of arthritis: usually distinguished by history, physical exam, serology, and imaging
5. Other causes of diabetes mellitus
6. Other causes of impotence: distinguished by history (and examination with exclusion), various endocrinopathies, and local causes
7 Other causes of skin pigmentation: distinguished by history, physical exam, and serum biochemistry (e.g., testing for Addison’s disease)
How can I confirm the diagnosis?
What tests should be ordered first?
Investigation of HH is dependent on the clinical situation. Two common diagnostic scenarios usually present to clinicians: (1) Individuals present for assessment on the basis of a family history of HH or iron overload, or (2) of clinical symptoms or signs that raise the possibility of HH.
For those presenting for family history assessment, initial testing should involve measurement of serum transferrin saturation and ferritin level. Individuals of northern European descent should also undergo HFE gene testing for the common C282Y mutation. These tests complement each other: normal iron studies exclude the presence of iron overload at the time, while HFE gene testing identifies any predisposition to development of iron overload disease. Homozygous C282Y individuals with normal ferritin levels should be followed periodically (at least every 2 years) to assess the evolution of biochemical expression that precedes most significant clinical sequelae of disease. Almost all C282Y homozygotes that will develop iron overload disease will have done so by the age of 65 years.
Individuals presenting clinically should initially be evaluated with measurement of transferrin saturation and ferritin level. If either is elevated, genetic testing for C282Y homozygosity is indicated. If C282Y homozygosity is confirmed, then further evaluation for evidence of iron overload disease is required, as illustrated in Figure 3.
What tests should be used to confirm the initial tests?
Assessment of the level of risk of iron overload disease is required in all C282Y homozygotes with elevated serum ferritin levels. Individuals who are less than 45 years of age, with no other liver risk co-factors, and who have a serum ferritin level lower than 1000 μg/L can safely progress to phlebotomy therapy, family screening, and counseling regarding the risk of malignancy. Those who are older than 45 years and who have serum ferritin levels above 1000 μg/L or who possess other liver disease risk factors should be further evaluated with direct assessment of hepatic iron concentration evaluation either by liver biopsy, FerriScan (R2 MRI measurement of hepatic iron concentration), or quantitative phlebotomy that provides retrospective assessment of the body iron load.
Liver biopsy has been the gold standard for the diagnosis of hepatic fibrosis and cirrhosis, as well as quantitation of hepatic iron concentration. R2 MRI has emerged as an accurate, noninvasive, and rapid method for the measurement of hepatic iron content and the possible detection of fibrosis. MRI provides a high degree of sensitivity and specificity for measurement of liver iron concentration with an area under the receiver operating characteristic curve greater than 0.98. The product of hepatic iron concentration and age is a sensitive and specific measure for the identification of subjects at risk for high-grade fibrosis. In the future, it is hoped that other noninvasive fibrosis assessment methods (e.g., FibroScan) will prove useful in the assessment and management of hepatic iron overload disease complicating HH.
For a diagnostic algorithm, see Figure 3.
What other diseases, conditions, or complications should I look for in patients with hereditary hemochromatosis?
What are the major risk factors for patients with this disease?
Thirty percent of male and 1% of female C282Y homozygous subjects develop iron overload disease by the age of 65 years, in the absence of other risk factors for liver disease. Development of liver disease can be accelerated by risk factors such as excessive alcohol consumption, chronic viral hepatitis, and, possibly, nonalcoholic steatohepatitis.
Iron stores can vary as much as tenfold among patients, and this variability is likely governed by genetic as well as environmental factors such as dietary intake of iron and fruit, alcohol consumption, blood loss, and blood donation. Genetic factors are emerging as important determinants of iron status in HH. A recent study of duodenal cytochrome B reductase activity in HH patients reported that common polymorphisms, which influence the activity of the enzyme, account for up to 11% of the variability of expression of iron overload in C282Y homozygous individuals.
Patients who exceed a hepatic iron concentration of 90 μmol/g and ferritin of 1000 μg/L are most likely to develop iron overload disease. Approximately 5% of C282Y homozygous subjects are at risk of cirrhosis. Once cirrhosis develops, and irrespective of phlebotomy treatment, C282Y homozygous subjects retain approximately a 100-fold increased risk of hepatocellular carcinoma compared with the matching age and gender population.
What diseases may occur with hereditary hemochromatosis?
Overall survival of C282Y homozygosity is similar to that of the general population, in the absence of iron overload disease.
Iron overload disease is the principal clinical manifestation of iron overload in HH. It comprises arthritis, liver disease (including cirrhosis and hepatocellular carcinoma), or any other clinical condition that cannot be ascribed to another causation in the setting of iron overload and C282Y homozygosity. Other well-documented complications of HH include increased susceptibility to infectious diseases such as salmonella, listeria, and yersina infection. C282Y homozygous individuals have a two- to threefold increased risk of bowel cancer and breast cancer compared with the general population.
What complications of hereditary hemochromatosis are commonly encountered?
The major life-threatening complications of HH are development of cirrhosis, hepatocellular carcinoma, and end-stage liver disease and the complications thereof. Dilated cardiomyopathy is a rare complication of HH. Decompensated liver disease due to HH is amenable to treatment with orthotopic liver transplantation in suitable candidates. However, patients with HH undergoing orthotopic liver transplantation have reduced survival rates compared to patients undergoing transplantation for other causes of liver disease. Other significant complications include arthritis, hypopituitarism, diabetes mellitus, impotence, and porphyria cutanea tarda.
What is the right therapy for the patient with hereditary hemocromatosis?
As the body has limited ability to excrete iron, treatment of iron overload is dependent on therapies that directly reduce iron stores: phlebotomy or chelation therapy. Concomitant hepatotoxic co-factors should also be addressed where possible. The mainstay of therapy in the majority of C282Y subjects with iron overload is removal of body iron by phlebotomy. Each unit of blood removed contains approximately 250 mg of iron. If patients cannot tolerate phlebotomy due to medical (e.g., anemia, cardiac failure) or other reasons, then chelating agents can be used. Historically, this has relied on the use of parenteral desferrioxamine. However, the more recently introduced oral deferasirox therapy provides a better tolerated alternative.
What is the most effective initial therapy?
The most effective initial therapy for hereditary hemochromatosis is phlebotomy.
Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.
Phlebotomy has remained the mainstay of therapy since it was initially described in the 1940s by Davies and Arrowsmith. It is a safe and effective way to remove iron from most HH patients. The number of weekly venesections required to return the serum ferritin level to the low normal range provides a direct measure of the degree of iron overload in an individual subject.
The aim for therapy is to return and maintain the serum ferritin level in the low normal range 50 to 100 μg/L. The frequency of venesections can be tailored to an individual’s ability to cope with the blood loss. Initially, therapy is delivered once per week. The frequency of phlebotomy is reduced as the ferritin level declines toward normal.When normal ferritin levels are achieved, the subject reverts to a maintenance phlebotomy schedule that is usually in the order of 3 to 4 times a year.
Due to the high variability of reaccumulation of iron, maintenance phlebotomy requirements also vary greatly. Many countries now accept blood from therapeutic donors for blood transfusion purposes.
A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies
The most useful second-line therapy to phlebotomy is oral iron chelation using deferasirox. This therapy offers substantial clinical benefits over the previous subcutaneous administration of desferrioxamine.
Deferasirox is taken as an oral tablet at a dose of 20 to 30 mg/kg body weight. It is generally well tolerated and has lesser adverse effects compared to desferrioxamine.
Desferrioxamine is used far less frequently, but when required it can be administered as a subcutaneous infusion at 25 to 50 mg/kg/day over 10 to12 hours.
Listing of these, including any guidelines for monitoring side effects.
Deferasirox is administered as an oral tablet and is generally well tolerated. Common side effects include nausea, vomiting, diarrhea, and abdominal pains. Dose-related rises in serum creatinine have been reported. Elevated serum transaminase is noted occasionally; therefore, renal and liver biochemical function should be monitored monthly. Adverse effects of desferrioxamine include hypersensitivity and anuria. Caution is required in renally impaired patients.
How should I monitor the patient with hereditary hemochromatosis?
Monitoring of subjects with HH is based on monitoring of (1) iron load and (2) organ injury.
Monitoring of iron load is best accomplished using serial measurements of serum ferritin levels. A low normal range serum ferritin level is the endpoint of successful initial therapy. Maintenance phlebotomy should keep the ferritin in the low normal range. In C282Y homozygotes at risk for liver disease or other iron overload diseases, initial diagnosis should consider noninvasive quantitation of hepatic iron concentration and liver injury or more invasive tests, such as liver biopsy, to ascertain the fibrotic or cirrhotic state of the liver.
In subjects with cirrhosis, management issues include screening for hepatocellular carcinoma, variceal surveillance, management of ascites, or other complications of decompensated end-stage liver disease. Identification of end-stage liver disease and decompensation mandates early consideration of suitability for orthotopic liver transplantation.
All subjects with C282Y homozygosity should be counseled regarding the risk of colorectal cancer (in males and females) and breast cancer (females only). It is not known whether the risk of malignancy is related to the genetic mutation status or iron status of the individual.
Complications resulting from extrahepatic organ damage secondary to iron overload are managed according to the underlying organ involved.
Established end-organ damage may not be fully reversible with phlebotomy therapy, but some improvements can occur. Features most likely to improve with therapy include lethargy, fatigue, skin pigmentation, and glucose intolerance. Frank diabetes mellitus requiring therapy is usually not reversed by phlebotomy therapy, although insulin doses may be able to be reduced following phlebotomy therapy.
Liver fibrosis is reversible but cirrhosis is probably not reversible. Once established, arthritis rarely improves even when normal iron status is restored. Hypogonadotropic hypogonadism may reduce in severity with therapy but often requires adjunctive hormone supplementation (Table 1).
What's the evidence?
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- How can I be sure that the patient has hereditary hemochromatosis?
- A tabular or chart listing of features and signs and symptoms
- How can I confirm the diagnosis?
- What other diseases, conditions, or complications should I look for in patients with hereditary hemochromatosis?
- What is the right therapy for the patient with hereditary hemocromatosis?
- What is the most effective initial therapy?
- Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.
- A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies
- Listing of these, including any guidelines for monitoring side effects.
- How should I monitor the patient with hereditary hemochromatosis?
- What's the evidence?