AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. It is the most common inherited liver disease in whites and the most common autosomal recessive genetic disorder.

Pathophysiology

Hereditary hemochromatosis is an adult-onset disorder characterized by inappropriately high iron absorption resulting in progressive iron overload. The organs involved are the liver, heart, pancreas, pituitary, joints, and skin.

Adults preserve a constant level of body iron by efficient conservation, maintaining rigorous control over absorption to balance losses. An adult man loses approximately 1 mg of iron daily, mostly in desquamated epithelium and secretions from the gut and skin. During the childbearing years, healthy women lose an average of an additional milligram of iron daily from menstrual bleeding (40 mL blood loss) and approximately 500 mg with each pregnancy. In addition, normal daily fecal loss of approximately 0.7 mL of blood (0.3 mg of iron) occurs. Only a small quantity of iron is excreted in urine (<0.1 mg/d).

In healthy adults, losses are balanced by absorption of sufficient dietary iron (1-2 mg) to maintain a relatively constant amount of body iron throughout life. Although excretion is quantitatively as important as absorption in the maintenance of iron balance, absorption usually plays the more active regulatory role. In hereditary hemochromatosis, dysregulation of intestinal iron absorption occurs, wherein iron continues to be efficiently absorbed even in the face of substantial elevation of body iron stores.¹

The gene responsible for the disease is called HFE and is located on chromosome 6. It is mutated in most individuals with hereditary hemochromatosis. HFE interacts with the transferrin receptor and causes a clear decrease in the affinity with which the receptor binds transferrin. This interaction also may modulate cellular iron uptake and decrease ferritin levels. When a mutant or nonfunctional variant of the HFE gene is present, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced accumulation of iron in peripheral tissues.

Findings suggestive of increased iron transport at the basolateral membrane of enterocytes in hemochromatosis have emerged from numerous studies of HFE-related hemochromatosis in humans² and in mice.

Hepcidin, a human antimicrobial peptide synthesized in the liver,³ plays a key role in the down-regulation of iron release by enterocytes and macrophages. The absence of this new peptide is associated with severe early-onset iron-loading phenotype. It is also inappropriately low in adult-onset HFE-related disease.⁴

Excess iron is hazardous because it produces free radical formation. The presence of free iron in biological systems can lead to the rapid formation of damaging reactive oxygen metabolites, such as the hydroxyl radical and the superoxide radical. These can produce DNA cleavage, impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and fibrosis.⁵

Frequency

United States

Prevalence is approximately 1 case in 300 persons. Most are of northern European origin.⁶ The carrier state is estimated to be approximately 10%.

International

Hemochromatosis has the same prevalence in Europe, Australia, and other Western countries, with the highest prevalence being noted in people of Celtic origin. Hemochromatosis is less common among Africans.

Mortality/Morbidity

Hemochromatosis results in liver cirrhosis, heart failure, diabetes mellitus, impotence, and arthritis. If untreated, hemochromatosis may lead to death from cirrhosis, diabetes, malignant hepatoma, or cardiac disease.³⁶

• Mortality is estimated to be 1.7 cases per 10,000 deaths. This number increases to 3.2 cases per 10,000 deaths in autopsy series.
• The death rate associated with hemochromatosis increased from 0.5 persons per million population in 1968 to 0.9 persons per million population in 1992 due to improved recognition of the disease.
• Mortality is higher in infants and in adults older than 50 years. Also, mortality is higher in men and in whites than in women, African Americans, and other groups.

Race

• Prevalence in whites is 6 times higher than in African Americans.
• C282Y homozygotes account for 82-90% of clinical diagnoses of hereditary hemochromatosis among persons of northern European descent.⁹
• One in 227 white people were homozygotes for the HFE C282Y mutation, a genotype seen in more than 90% of patients with typical hemochromatosis.¹⁰
• The highest reported prevalence for C282Y homozygosity is one in 83 people in Ireland.¹¹
• Recently, it has become prevalent in the Hispanic population. The frequency is much lower among Hispanic persons (0.27 in 1000), Asian Americans (<0.001 per 1000), Pacific Islanders (0.12 per 1000), and black persons (0.14 per 1000)
• The Celtic population is affected most frequently.

Sex

• Men are affected more often than women, with an estimated ratio of 1.8:1.
• Disease related to iron overload commonly develops in men (but not in women) who are homozygous for the C282Y mutation, especially when serum ferritin levels are 1000 mcg/L or more. The increased prevalence of iron-overload–related disease in C282Y homozygous men, as compared with that in women, is frequently ascribed to recurrent physiologic blood loss and the resultant slower accumulation of iron in women.¹²
• However, disparate frequencies of HLA A*03B*07 haplotypes in men and women have been reported in hereditary hemochromatosis probands, which may be relevant to sex-specific phenotypic expression of this disease.¹³
• Studies of iron regulatory pathways in African Americans have also suggested that serum ferritin levels may be genetically determined by sex differences as well as environmental factors.¹⁴

Age

• The disease usually becomes apparent after age 40 years in men and after age 50 years in women.
• Median age in women is 66 years.
• Median age in men is 51 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Symptoms usually begin between age 30 years and age 50 years, but they may occur much earlier.¹⁵ Clinical manifestations include the following:
• • Liver disease
  • Skin pigmentation
  • Diabetes mellitus
  • Arthropathy
  • Impotence in males
  • Cardiac enlargement, with or without heart failure or conduction defects
• Early symptoms include the following:
• • Severe fatigue (74%)
  • Impotence (45%)
  • Arthralgia (44%)
• Later, patients may experience the following symptoms:
• • Skin bronzing or hyperpigmentation (70%): This reflects a combination of iron deposition and melanin. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease, when total iron body content is 20 grams (ie, >5-times normal).
  • Diabetes mellitus (48%): This is due to progressive iron accumulation in the pancreas. The defect appears to be relatively selective for the pancreatic beta cells. Most patients with hemochromatotic diabetes have other signs of hemochromatosis, such as liver disease or skin pigmentation.
  • Cirrhosis: This is one of the most common disease manifestations of the tissue damage caused by hemochromatosis, and it may progress to liver cancer years later (risk >200-fold). It also is the most common cause of death in patients with hereditary hemochromatosis.
  • • Cirrhosis is due to progressive iron deposition in the liver parenchyma.
    • Reversibility with iron removal has been reported even with development of varices, but this is more likely early in the course of liver disease.
    • All patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk of variceal hemorrhage. Patients at risk for variceal hemorrhage should be considered for primary prophylaxis with propranolol or nadolol.
    • Hepatocellular carcinoma is one of the most serious complications of hemochromatosis.
    • Most hepatologists recommend periodic screening with serum alpha-fetoprotein (AFP) every 6 months in patients with cirrhosis.
    • The most cost-effective imaging test used to supplement serum AFP screening is ultrasound. The sensitivity is approximately 80% when serum AFP and ultrasound are combined for the screening of hepatocellular carcinoma.
    • Liver transplant may be used to treat patients with hepatocellular carcinoma, but careful patient selection is advised. Particularly, these patients should have a single tumor of 5 cm or smaller in diameter. If multiple tumors are present, the acceptable number is 3 or less, smaller than 3 cm. The 4-year survival rate can be approximately 90% if these criteria are respected.
    • See related CME at Diagnosis and Management of Advanced Hepatocellular Carcinoma.
• Other symptoms may include the following:
• • Fatigue and arthralgia are the most common symptoms prompting a visit to a physician.
  • Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis.
  • Cardiomyopathy is another mode of presentation, particularly in younger patients. These patients may present with congestive heart failure or arrhythmias.
  • Dilated cardiomyopathy is characterized by the development of heart failure and conduction disturbances, such as sick sinus syndrome. In the past, cardiac disease was the presenting manifestation in as many as 15% of patients; therefore, the absence of other manifestations of hemochromatosis should not preclude the diagnosis.
  • Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary involvement by iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.
  • Amenorrhea can occur in women but is less frequent than hypogonadism in men.
  • Arthropathy is due to iron accumulation in joint tissues. It is associated with characteristic radiologic findings, that is, squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints. Symptoms usually do not respond to iron removal.
  • Hypothyroidism may occur rarely.

Physical

• The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.¹⁶
• Liver function abnormalities occur in 35-75% of patients.
• Cirrhosis occurs in 13%, usually late in the disease.
• Other findings upon examination include the following:
• • Right upper quadrant tenderness with hepatomegaly or splenomegaly if cirrhosis present
  • Signs of fluid overload with congestive heart failure
  • Sick sinus syndrome with conduction abnormalities
• Patients may have susceptibility to certain bacterial infections, such as Yersinia enterocolitica liver abscess, Yersinia pseudotuberculosis sepsis, Vibrio vulnificus sepsis, and Listeria monocytogenes meningitis.
• The most commonly affected joints include the following:
• • MCP joints
  • Proximal interphalangeal joints
  • Knees
  • Feet¹⁷
  • Wrists
  • Back
  • Neck
• Chondrocalcinosis, which involves the knees and the wrists, may occur and may be asymptomatic.

Causes

• Hereditary hemochromatosis is a genetic disorder inherited as an autosomal recessive trait.
• The gene is tightly linked to the human leukocyte antigen (HLA)-A region on the short arm of chromosome 6.
• HFE, a specific gene for hemochromatosis, has been identified.¹⁸
• Homozygosity for a missense mutation, with substitution of a cysteine residue for a tyrosine residue at amino acid position 282 (C282Y) of HFE is found in 70-100% of clinically diagnosed patients.¹⁹
• A second missense mutation, with substitution of histidine for aspartate at amino acid 63 (H63D), also has been identified. The clinical effects of this mutation appear to be limited.²⁰
• C282Y homozygotes and, possibly, C282Y/H63D compound heterozygotes, appear to be at risk for clinical iron overload. The clinical significance of other rarer forms of compound heterozygosity, such as heterozygosity for C282Y and a mutation in which cysteine replaces serine at position 65 (S65C) or heterozygosity for H63D and S65C, is still controversial.²¹
• The precise mechanism by which mutations in the HFE gene lead to iron overload is unknown.
• The outcome is increased intestinal iron absorption and predominantly hepatocellular accumulation of hepatic iron.
• Although relatively few cases have been described to date, the iron-overload phenotype associated with mutations in the gene encoding transferrin receptor 2 (TfR2) appears to be very similar to that of classic HFE-related hemochromatosis.
• Rare cases of juvenile hereditary hemochromatosis have recently been linked to a homozygous mutation in the HAMP gene, which encodes hepcidin, a peptide that plays a key role in human iron metabolism.^{22, 23} However, most juvenile-onset cases have been mapped to chromosome 1q, where the gene that produces hemojuvelin, HJV (originally called HFE2), has been identified.²⁴
• Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency.²⁵ Recent studies suggest that TfR2 is a modulator of hepcidin production in response to iron; hepcidin was low or undetectable in most cases of patients homozygous for TfR2 mutation.^{26, 27, 28}

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Biliary cirrhosis

Alcoholic liver disease: Patients include those who are heavy drinkers, perhaps of iron-containing fortified wines, who have cirrhosis. Liver biopsy in these patients may show a modest increase in iron; however, contrary to patients with hemochromatosis, the hepatic iron levels are relatively normal and iron stores are less than 4 g.

Ineffective erythropoiesis with marrow hyperplasia: Patients with hyperplastic erythroid marrow absorb an increased amount of iron to the point where they may have clinical iron overload. Examples include the hereditary sideroblastic anemias, severe alpha and beta thalassemia, and the myelodysplastic syndrome variants, such as refractory anemia with ringed sideroblasts (RARS).

Iron overload associated with chronic anemia: Patients have increased effective erythropoiesis and increased iron absorption. Examples include hereditary spherocytosis and acquired sideroblastic anemia.

Multiple transfusions: Hypertransfusion is performed in patients with beta thalassemia major, sickle cell anemia, refractory aplastic anemia, and myelodysplastic syndrome. Such patients may receive as many as 100 units of red cells, which contain as much as 20-25 g of iron, similar to or more than the amount retained in many symptomatic patients with hereditary hemochromatosis.

Porphyria cutanea tarda (PCT): It primarily is a skin and liver disease that occurs in familial and sporadic forms. The cause of liver siderosis in sporadic PCT has not been established, but it may be related to a mutation in the HFE gene in most patients.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Measuring serum iron has no value in the diagnosis, but measuring transferrin saturation is necessary.
• Transferrin saturation corresponds to the ratio of serum iron and total iron-binding capacity. Similar to iron, it is influenced by liver disease (other than hemochromatosis) and inflammation; therefore, it has limitations in the diagnostic workup.
• • Hemochromatosis is suggested by a persistently elevated transferrin saturation in the absence of other causes of iron overload. It is the initial test of choice.
  • The screening threshold for hemochromatosis is a fasting transferrin saturation of 45-50%.
  • Approximately 30% of women younger than 30 years who have hemochromatosis do not have elevated transferrin saturation.
  • High transferrin saturation is the earliest evidence of hemochromatosis. A value greater than 60% in men and 50% in women is highly specific.
• Serum ferritin levels elevated higher than 200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal women indicate primary iron overload due to hemochromatosis, especially when associated with high transferrin saturation and evidence of liver disease.
• • Ferritin concentration can be high in other conditions, such as infections, inflammations, and liver disease.
  • Ferritin concentration higher than 1000 mcg/L suggests liver damage with fibrosis or cirrhosis.²⁹
  • Ferritin levels are less sensitive than transferrin saturation in screening tests for hemochromatosis.
• The Centers for Disease Control and Prevention (CDC) does not recommend universal screening for hemochromatosis but rather suggests evaluating iron overload in individuals with a family history and in individuals who are symptomatic.³⁰
• The American College of Physicians found insufficient evidence to recommend for or against the use of transferrin saturation and serum ferritin levels to help identify the early stages of hereditary hemochromatosis.³¹

Imaging Studies

• Development of noninvasive measures of hepatic iron content has generated significant interest. Many studies are focusing on the role of CT scan or MRI in the evaluation of total iron body stores.
• CT scanning is neither sensitive nor specific for the detection of mild hepatic iron overload.
• MRI may be more sensitive, but it has not been validated as a diagnostic test to help confirm hemochromatosis.
• In cases of elevated ferritin levels in the absence of homozygosity for C282Y/compound heterozygosity for C282Y/H63Asp, hepatic iron quantification with MRI might be helpful.³² However, consensus has not yet been reached regarding the technique or the possibility to reproduce the same method of calculus in different machines.

Other Tests

• Genetic testing for the HFE mutation is indicated in all first-degree relatives of patients with hemochromatosis and also in patients with evidence of iron overload³³ (eg, elevated transferrin saturation, high serum ferritin levels, excess iron staining or iron concentration on liver biopsy samples). This is particularly indicated in patients with known liver disease and evidence of iron overload, even if other causes of liver disease are present.³⁴
• • It is accomplished by searching for the 2 HFE gene mutations, C282Y and H63D. This is the next step in diagnosis after increased biochemical iron indices are present and other causes of iron overload have been excluded.
  • The finding of heterozygosity for C282Y is expected in 10% or more of subjects of northern European extraction and for the H63D mutation in approximately 15-20%, and, thus, this finding is common in any white population studied.
  • C282Y heterozygosity may contribute to iron overload due to other conditions, but it should not be considered the sole cause of iron overload and it should not be considered diagnostic of hereditary hemochromatosis. At present, only homozygosity for C282Y and compound heterozygosity for C282Y/H63D should be considered indicative of hereditary hemochromatosis.
  • HFE genotyping cannot provide information about the degree of increased body iron stores or organ damage.
  • DNA-based testing cannot replace liver biopsy to confirm the presence of end-stage liver damage.³⁵
  • The use of DNA-based tests alone may fail to identify 20-40% of white patients and most black patients with clinical evidence of hemochromatosis but without the C282Y mutation.
• Screening for hemochromatosis should be considered in the following patients⁸:
• • All first-degree relatives of subjects known to have hemochromatosis should be screened. HLA typing is no longer necessary. Family members identified as having C282Y homozygosity should be tested for transferrin saturation, serum ferritin, and liver enzymes. Screening of young children of patients with hemochromatosis does not need to be performed if the spouse is tested and does not have the C282Y mutation.
  • Individuals presenting for a standard medical check should have their transferrin saturation measured. If levels are higher than 45%, the estimation should be repeated after fasting. If the fasting level still is higher than 45%, further investigation is warranted.³⁶
  • The general population possibly should be screened, although screening is more difficult and debatable in this category.³⁷ Cost is a major consideration. A recent consensus stated that population screening is best performed by phenotype (using iron-binding capacity), and using genotype screening (using C282Y mutation) is considered premature until all unanswered questions are clarified.³⁸
  • Overall, the clinical expressivity of C282Y homozygosity appears to be much lower than previously thought, and the cost effectiveness of screening has been challenged, since many people must be screened in order to prevent severe disease in only a few. During a screening program conducted in a health appraisal clinic, classical multiorgan disease was detected in only 1 of 152 homozygotes.³⁹
  • If a proband is negative for C282Y mutation, family members must be screened by other means, such as serum iron studies or HLA typing.
• HLA typing or tissue typing has been used to detect homozygous hemochromatosis in a sibling of a proband who has hemochromatosis by other means, such as liver biopsy or quantitative phlebotomy.
• • In this setting, a sibling who is HLA-A identical and HLA-B identical to the proband is considered homozygous.
  • If only 1 haplotype is shared with the proband, the sibling is considered heterozygous.

Procedures

• Liver biopsy with determination of hepatic iron concentration and histologic evaluation with iron staining was considered the criterion standard for diagnosis. Currently, the diagnosis can be confidently based on genetic testing for the C282Y mutation. Liver biopsy is no longer essential for diagnosis in many cases.
• Liver biopsy is useful to identify liver disease and to determine the presence or absence of cirrhosis, which directly affects prognosis.
• The use of liver biopsy in hereditary hemochromatosis now can be restricted to those patients with a high probability of severe fibrosis or cirrhosis. A ferritin level of greater than 1000 mcg/L is a strong and independent predictor of fibrosis, but when alcohol intake exceeds 60 g/d, a significant proportion of patients may have severe fibrosis or cirrhosis, even if their ferritin levels are less than 60 g/d. Liver biopsy should be considered in these patients.
• According to the recently developed guidelines for the diagnosis and management of hereditary hemochromatosis, on behalf of the Dutch Institute for Healthcare Improvement³² (which is mainly expert opinion based), a liver biopsy is indicated in the following cases: (1) elevated liver enzymes in combination with hereditary hemochromatosis, and (2) serum ferritin levels greater than 1000 mcg/L. 
• Histochemical iron stains (Perls Prussian blue) and biochemical determination of hepatic iron concentration with calculation of the hepatic iron index (HII) are used with liver biopsy.
• • The HII is calculated by dividing body weight in pounds by the hepatic iron concentration (HIC) in micromoles per gram of dry weight. It is becoming less important in the era of HFE gene testing and is no longer mandatory in all cases.
  • An HII of greater than 1.9 can accurately differentiate homozygous hemochromatosis from heterozygous hemochromatosis, alcoholism, and normal controls.
  • When the HII is 1.5-1.9, the diagnosis of hemochromatosis is equivocal. Genetic testing for the C282Y mutation of HFE may help confirm the diagnosis.

Histologic Findings

Histologic evaluation with Perls Prussian blue staining shows a characteristic pattern of hepatic accumulation. In hemochromatosis, iron accumulates predominantly in hepatocytes and biliary epithelial cells, with relative sparing of Kupffer cells. Typically, a gradient of hepatocyte iron accumulation is present, with prominent involvement of periportal hepatocytes (zone 1) and decreasing intensity near the central vein (zone 3). By contrast, iron accumulation in parenteral iron overload occurs predominantly in Kupffer cells.⁴⁰

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The goal of therapy in patients with iron overload disorders is to remove the iron before it can produce irreversible parenchymal damage.⁴¹

• Because a normal life span can be expected if iron reduction is initiated before the development of cirrhosis, clinical suspicion and early diagnosis are essential.
• Once diagnosed, hemochromatosis is treated by phlebotomy to rid the body of excess iron and to maintain normal iron stores.
• Iron supplements should be avoided.
• Patients should limit alcohol consumption and should not eat raw oysters.

Surgical Care

Surgical procedures are used to treat 2 important complications: end-stage liver disease and severe arthropathy.

• When end-stage liver disease progresses despite iron-reduction therapy, orthotopic liver transplantation is the only therapeutic option.⁴²
• Another indication for liver transplantation is the development of hepatocellular carcinoma.
• After liver transplantation, 1-year and 5-year survival rates are 58% and 42%, respectively, which is significantly lower than for all other indications.
• Poor survival and increased posttransplant mortality are due to predominantly  infectious and cardiac complications. Sepsis causes most early posttransplant mortality, whereas congestive heart failure accounts for most deaths 1 year or longer after transplantation.
• Surgical arthroplasty is considered if joint destruction becomes severe despite medical therapy.

Consultations

Because of its multiorgan nature and the injury or damage to many intrinsic systems, care and treatment of patients with hemochromatosis require the collaboration of multiple physicians in different medical or surgical specialties.

• Most often, a gastroenterologist is required to confirm the diagnosis by liver biopsy and to assist in the management of end-stage liver diseases.
• An endocrinologist is helpful in treating patients with diabetes mellitus or other endocrine complications, such as thyroid and gonadal dysfunction.
• A cardiologist assists in the management of severe congestive heart failure and other cardiac complications, such as arrhythmias.
• An infectious disease specialist can treat patients with sepsis and also can choose the right antibiotic therapy for rare infectious complications.
• A rheumatologist or an orthopedist is required for the management of joint complications.
• A surgeon specializing in liver transplantation may be needed in highly advanced liver disease.

Diet

Dietary factors may influence the phenotypic expression of the disease. Some modulate absorption of iron and may affect the variability of phenotypic penetrance.

• Patients should not consume foods that contain large concentrations of bioavailable iron, such as red meats and organ meats.
• They should not use iron supplements, including multivitamins with iron.
• Substances in foods and drinks, including tannates (in tea), phytates, oxalates, calcium, and phosphates, can bind iron and inhibit its absorption.
• Dietary changes intended to minimize or eliminate iron ingestion usually are unnecessary and often are not feasible.
• Ethanol sometimes increases iron absorption, and certain alcoholic drinks, especially red wine, contain relatively high concentrations of iron. Ingestion of 30 grams or more of ethanol daily potentiates hepatic injury due to iron overload and increases the relative risk for primary liver cancer in persons with cirrhosis.
• • Patients with evidence of hepatic injury should consume little or no ethanol.
  • Other patients should consume ethanol in moderation.
• Vitamin C (ascorbic acid) increases intestinal absorption of inorganic iron. No reason exists to discourage patients from eating fresh fruits and vegetables containing vitamin C, but advising them to limit ingestion of vitamin C in supplements to 500 mg/d is prudent.
• Raw or improperly cooked shellfish sometimes is contaminated with V vulnificus and can cause sepsis in patients with hemochromatosis.
• Seafood from potentially contaminated waters must be cooked thoroughly.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Despite advances in the molecular understanding of hemochromatosis and the impact of C282Y on diagnosis, treatment remains simple, inexpensive, and safe.

Encourage patients to have weekly therapeutic phlebotomy of 500 mL of whole blood (equivalent to approximately 200-250 mg of iron).⁴³

Some patients can tolerate twice-weekly phlebotomy, but this regimen is tedious and often inconvenient. Therapeutic phlebotomy should be performed until iron-limited erythropoiesis develops, identified by failure of the hemoglobin level and/or hematocrit to recover before the next phlebotomy. It should be continued until transferrin saturation is less than 50% and serum ferritin levels are less than 50 ng/mL, preferably 20 ng/mL.

Most patients require maintenance phlebotomy in which 1 unit of blood is removed every 2-3 months. Therapeutic phlebotomy may improve or even cure some of the manifestations and complications of the disease, such as fatigue, elevated liver enzymes, hepatomegaly, abdominal pain, arthralgias, and hyperpigmentation. Other complications usually show little or no change after phlebotomy.

Among individuals with biopsy results positive for liver fibrosis, phlebotomy was associated with an improvement of 13-50%, with the greatest improvement among individuals with the least degree of liver fibrosis. Individuals served as their own controls, and improvement was based on qualitative histologic features. When liver cirrhosis is present and in its early stages, therapeutic phlebotomy appears to control or slow the progression of liver disease.

Chelation therapy with deferoxamine induced iron depletion in people with C282Y homozygosity unable to undergo phlebotomy. However, compliance and acceptability of deferoxamine therapy in patients with nonhemochromatosis iron overload is poor. The oral chelators, deferiprone and deferasirox, also remove iron from hepatocytes, the primary site of excess iron deposition in HFE-associated hemochromatosis, but there are no reports of the use of these drugs in people with C282Y homozygosity.⁴⁴

Drug Category: Antidote-iron toxicity

Used in patients with hemochromatosis associated with significant anemia or severe end-organ involvement.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admission to ICU may be warranted for patients who develop hepatic, cardiac, and infectious complications.
• Indications for inpatient care, preferably in an ICU, include the following:
• • Gastroesophageal bleeding
  • Hepatic encephalopathy
  • Sepsis
  • Congestive heart failure
  • Arrhythmias

Further Outpatient Care

• Importantly, the patient should have a primary care provider who can coordinate treatment with the other specialists involved.
• Regular follow-up visits should be scheduled with the gastroenterologist. Others, such as a cardiologist, an endocrinologist, or a hematologist, may be needed for serial diagnostic and therapeutic intervention.
• Quarterly visits may be necessary depending on the severity of the symptoms or complications.

Transfer

• In case of end-stage liver disease refractory to all methods of medical treatment, transferring the patient to a facility experienced in liver transplant is preferable.
• Transfer the patient to a cancer institution when the diagnosis of hepatocellular carcinoma is being considered or if the diagnosis is confirmed.

Deterrence/Prevention

• Avoid iron supplements.
• Consume red meats in moderation.
• Consume ethanol in moderation.
• Limit supplemental vitamin C to 500 mg daily.
• Use mineral supplements for specific deficiencies only.
• Cook shellfish from warm-water areas.

Complications

• Liver cirrhosis
• Hepatocellular carcinoma
• Congestive heart failure
• Cardiac arrhythmias
• Diabetes mellitus
• Hypogonadism
• Arthropathy
• Thyroid dysfunction
• Sepsis

Prognosis

• The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis.
• Patients without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy.
• Early diagnosis and therapeutic phlebotomy to maintain low normal body stores can prevent all known complications of hemochromatosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize that a high ferritin level may be an indicator of iron overload, not just a sign of nonspecific inflammation, especially if accompanied with elevated liver enzymes
• Failure to perform early genetic testing or liver biopsy to avoid the complications of hemochromatosis
• Failure to avoid excessive phlebotomy and the risk of hypovolemia and dehydration
• Failure to promptly refer patients to a gastroenterologist and a liver transplant center in case of end-stage liver disease, especially if refractory to treatment
• Failure to screen family members

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Conrad ME, Umbreit JN, Moore EG. Iron absorption and transport. Am J Med Sci. Oct 1999;318(4):213-29. [Medline].
2. Rolfs A, Bonkovsky HL, Kohlroser JG, et al. Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol. Apr 2002;282(4):G598-607. [Medline].
3. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. Mar 16 2001;276(11):7806-10. [Medline].
4. Fleming RE, Britton RS, Waheed A, et al. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis. Nov 2004;8(4):755-73, vii. [Medline].
5. Galbraith R. Heme oxygenase: who needs it?. Proc Soc Exp Biol Med. Dec 1999;222(3):299-305. [Medline].
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Article Last Updated: Jul 17, 2008