eMedicine Specialties > Gastroenterology > Systemic Disease

Hemochromatosis: Differential Diagnoses & Workup

Author: Hady E Sfeir, MD, Clinical Assistant Professor of Medicine, Department of Internal Medicine, OSF St Francis Medical Center
Coauthor(s): David M Klachko, MBBCh, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri
Contributor Information and Disclosures

Updated: Jul 17, 2008

Differential Diagnoses

Hemolytic Anemia
Thalassemia, Beta

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

Laboratory 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 present34
    • 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 damage35
    • 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 warranted36
    • The general population possibly should be screened, although screening is more difficult and debatable in this category37 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 homozygotes39
    • 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

More on Hemochromatosis

Overview: Hemochromatosis
Differential Diagnoses & Workup: Hemochromatosis
Treatment & Medication: Hemochromatosis
Follow-up: Hemochromatosis
References
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References

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Further Reading

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Keywords

hemochromatosis, haemochromatosis, hereditary hemochromatosis, HH, iron overload, genetic hemochromatosis, siderophilia, primary hemochromatosis, cirrhosis, hepatocellular carcinoma

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Contributor Information and Disclosures

Author

Hady E Sfeir, MD, Clinical Assistant Professor of Medicine, Department of Internal Medicine, OSF St Francis Medical Center
Hady E Sfeir, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

David M Klachko, MBBCh, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri
David M Klachko, MBBCh is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, Endocrine Society, Missouri State Medical Association, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Vivek Gumaste, MD, Chief, Clinical Associate Professor, Department of Internal Medicine, Division of Gastroenterology, Elmhurst Hospital Center, Mount Sinai School of Medicine
Vivek Gumaste, MD is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Douglas M Heuman, MD, FACP, Director of Hepatology, McGuire Veterans Affairs Medical Center, Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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