Hemochromatosis

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Diagnostic confirmation of hereditary hemochromatosis (HH) in an individual with biochemical or clinical findings of iron overload
  • Screening for adult family members of individuals with a C282Y/C282Y or C282Y/H63D genotype
  • Carrier testing for the reproductive partner of an individual with HH

Laboratory Testing

  • Initial screening tests
    • Fasting serum transferrin saturation (STS)
      • Calculated from serum iron and iron binding capacity
    • Using a saturation cutoff of 45% is more sensitive for detecting mild disease, but also identifies heterozygotes not at risk for developing clinical findings
    • Elevated serum ferritin (SF)
      • Increases progressively over time in individuals with untreated HFE-caused HH
      • SF is an acute phase reactant – elevated concentration alone is not specific for iron overload because increased levels may also be caused by inflammatory or neoplastic disorders
      • Do not use serum iron testing for evaluation of HH
  • Genetic testing
    • HFE gene – C282Y, H63D, and S65C mutations
      • HFE genotyping should be performed only for individuals (Choosing Wisely: 5 Things Physicians and Patients Should Question, 2015; American College of Medical Genetics and Genomics) with
        • Laboratory evidence of iron overload (eg, elevated fasting transferrin saturation >45%)
        • A known family history of HFE-associated hereditary hemochromatosis

Other Testing

  • Quantitative phlebotomy
    • Use to determine quantity of iron that can be mobilized
      • 1 liter of blood = ~0.5 grams of iron
    • Confirms diagnosis of HFE-HH in individuals with hemochromatosis and  no diagnostic genotype who are unwilling to undergo liver biopsy
      • Affected persons can mobilize at least 4 grams of iron

Histology

  • Liver biopsy – useful in confirming hepatic iron overload and degree of fibrosis
    • Most often used for individuals with hemochromatosis and absence of common HFE mutations
    • Testing should include
      • Measurement of hepatic iron concentration
      • Calculation of hepatic iron index and stains to assess pattern and severity of iron overload
        • Index >1.9 suggests hemochromatosis
      • Stains to determine the presence or absence of hepatitis and fibrosis – hepatitis B surface and core antigen, Alpha-1-Antitrypsin (AAT)

Imaging Studies

  • Quantitative MRI – may be used as an alternative to liver biopsy
    • Requires expertise with validation

Differential Diagnosis

  • Other forms of hereditary hemochromatosis (non-HFE)
    • Type 2B – juvenile hemochromatosis (HFE2, HAMP variants)
    • Type 3 – transferrin receptor 2 mutation (TFR2)
    • Type 4 – ferroportin disease (SLC40A1)
    • Neonatal hemochromatosis
  • Secondary iron overload
    • Iron loading anemias (eg, thalassemia)
    • Transfusion iron overload
  • Chronic liver disease
  • Other
    • Aceruloplasminemia
    • Sub-Saharan African iron overload
  • Screen with fasting serum transferrin saturation (calculated from serum iron and iron binding capacity) and serum ferritin
  • U.S. Preventive Services Task Force and EASL do not recommend widespread screening
  • American College of Physicians (ACP) recommendation – offer testing to the following
    • Adult Caucasian men of North European ancestry >25 years
    • First-degree relatives of patients with disease
  • American Association for the Study of Liver Diseases recommendation – offer testing to the following
    • All patients with evidence of liver disease without obvious etiology
    • First-degree relatives of patients with disease
  • EASL recommendation – offer testing for patients with unexplained chronic liver disease and elevated transferrin saturation
  • Depletion phase – hemoglobin/hematocrit, mean corpuscular volume (MCV), serum ferritin until ferritin <50 μg/L
    • If hematocrit drops >20% of initial level, next phlebotomy should be postponed
  • Maintenance phase – check ferritin every 6 months to maintain <50 μg/L
  • Do not base frequency of phlebotomy on transferrin concentration

Hemochromatosis is an iron overload disorder caused by excess iron being stored in the body. It can be inherited or acquired. Hereditary hemochromatosis (HH) is a genetic disorder resulting in excessive absorption and storage of dietary iron, leading to progressive iron accumulation in tissues and resulting in organ damage.

Epidemiology

  • Incidence – allele frequency varies by ethnicity; most common in Caucasians of Northern European descent(~1/200-400)
  • Age – peaks in 40s-50s
  • Sex –  M>F, 2:1

Inheritance

  • Mutations of the HFE gene are responsible for the most common form of HH (HFE-HH)

Pathophysiology

  • Pathogenesis
    • High rate of iron absorption across duodenal enterocytes
    • Increased iron stores of ferritin – most found in reticuloendothelial macrophages with limited excretion
    • Eventual deposition of excess iron in other organs, causing tissue damage
  • First biochemical manifestation is increased transferrin saturation due to the following
    • Uncontrolled influx of iron from enterocytes and macrophages
    • Inadequate synthesis of the hepatic iron-regulating hormone, hepcidin

Clinical Presentation

  • Tissue and organ damage typically appear after age 30
  • Classic HH – effects of excess iron are cumulative
    • Severe disease rarely occurs in individuals <35 years
  • Subtle, nonspecific symptoms prior to clinical diagnosis
    • Fatigue, lethargy
    • Progressive increase in skin pigmentation
    • Loss of libido
    • Arthralgias
  • Hepatic disease
  • Cardiovascular disease
    • Cardiomyopathy – dilated, restrictive or mixed
    • Arrhythmias – atrial tachycardias most common
  • Endocrine disease
  • Skeletal disease
    • Arthritis – metacarpophalangeal joint; second and third joint
    • Arthralgias
    • Porphyria cutanea tarda
  • Dermatologic disease
    • ​Melanoderma
      • Bronzing, gray, or brown discoloration – increased melanin production and iron deposition in skin
      • Not usually truncal in distribution
    • Rare

 

Clinical Background

Epidemiology

  • Prevalence – rare
  • Age – 10-30 years (for diagnosis)
  • Sex – M:F, equal

Inheritance

  • See Clinical Background tab

Clinical Presentation

  • Earlier onset – typically <30 years
    • More severe disease than adult forms
  • Typical presentation – cardiomyopathy and hypogonadotropic hypogonadism
  • Other organ involvement similar to adult onset – cirrhosis, diabetes mellitus, arthritis, increased skin pigmentation

Diagnosis

Indications for Testing

  • Arthralgias, skin pigmentation, diabetes

Laboratory Testing

  • Initial screening tests
    • Serum ferritin (SF) – ranges from 1,000-6,000 μg/L
    • Fasting serum transferrin saturation (STS) – ≥45% suggests further testing necessary
      • Normal value in children is 15-50%
  • Genetic testing
    • HFE2, HAMP genotyping may be important if HFE gene testing is negative
    • Other testing for atypical presentations (eg, TFR2)

Histology

  • Liver biopsy
    • Hepatic iron index – >1.9 suggestive of disease
    • Iron index not applicable to children <14 years
    • Utility of hepatic iron quantitation in a child is controversial

Imaging Studies

  • MRI may be used to quantify hepatic iron load

Differential Diagnosis

  • Other forms of hereditary hemochromatosis (non-HFE)
    • Type 2B – juvenile hemochromatosis (HFE2, HAMP variants)
    • Type 3 – transferrin receptor 2 mutation (TFR2)
    • Type 4 – ferroportin disease (SLC40A1)
      • A and B subtypes
    • Neonatal hemochromatosis
  • Secondary iron overload
  • Chronic liver disease
  • Other
    • Aceruloplasminemia
    • Sub-Saharan African iron overload
    • Porphyria cutanea tarda ​
    • Macrophage activation syndrome
    • Hereditary hyperferritinemia with cataracts syndrome

Monitoring

  • Refer to Monitoring tab
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Iron and Iron Binding Capacity 0020420
Method: Quantitative Spectrophotometry

Recommended Use 

Aid in the diagnosis of iron deficiency, anemia, and iron overload

Quantitate serum or plasma iron; calculates values for transferrin saturation and TIBC (STS [%] = [100 x serum iron]/TIBC)

Should be fasting sample

Ferritin 0070065
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use 

Aid in the diagnosis of iron deficiency, anemia, and iron overload

Monitor treatment for hemochromatosis

Limitations 

Elevated concentration alone not specific for iron overload

Hemochromatosis (HFE) 3 Mutations 0055656
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Recommended Use 

Confirm clinical diagnosis of hereditary hemochromatosis (HH) in an individual with biochemical findings of iron overload

Screen for adult family members of individuals with C282Y/C282Y or C282Y/H63D genotype

Carrier testing for reproductive partners of an individual with HH

Test HFE gene for C282Y, H63D, and S65C mutations

Clinical sensitivity –

  • Up to 90% for Caucasian populations
  • Lower in other ethnicities

 Analytical sensitivity/specificity – 99%

Limitations 

Test should not be used for testing at-risk asymptomatic minors, population carrier screening, prenatal diagnosis

Genotyping does not substitute for serum iron studies, which identify iron overload

Only the 3 targeted HFE gene mutations will be detected

Rare diagnostic errors may occur due to primer-site mutations

Iron, Liver 0028250
Method: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Recommended Use 

Useful in confirming hepatic iron overload, particularly in individuals with hemochromatosis and no common HFE mutations

Initial approach to diagnosis for hemochromatosis should include iron and iron binding capacity (NOTE: test includes serum transferrin saturation) and serum ferritin

Limitations 

Hepatic iron distribution may be heterogenous; verification of biopsy quality or testing multiple biopsy cores is preferred

Hepatitis B Surface Antigen by Immunohistochemistry 2003917
Method: Immunohistochemistry

Recommended Use 

Determine presence or absence of hepatitis

Stained and returned to client pathologist; consultation available if needed

Alpha-1-Antitrypsin (AAT) by Immunohistochemistry 2003424
Method: Immunohistochemistry

Recommended Use 

Identify fibrotic liver disease

Stained and returned to client pathologist; consultation available if needed

Guidelines

American College of Medical Genetics and Genomics. Choosing Wisely - Five Things Patients and Providers Should Question. An initiative of the ABIM Foundation. [Initial posting Jul 2015; Accessed: Nov 2015]

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011; 54(1): 328-43. PubMed

Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. American Association for the Study of Liver Diseases - Nonprofit Research Organization. 2001 March (Revised 2011 July). NGC: 008787

European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010; 53(1): 3-22. PubMed

Morisco F, Pagliaro L, Caporaso N, Bianco E, Sagliocca L, Fargion S, Smedile A, Salvagnini M, Mele A, University of Naples Federico II, italy. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008; 40(7): 585-98. PubMed

Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006; 145(3): 209-23. PubMed

General References

Bardou-Jacquet E, Brissot P. Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE). Hematol Oncol Clin North Am. 2014; 28(4): 625-35, v. PubMed

Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician. 2013; 87(3): 183-90. PubMed

Moyer TP, Highsmith E, Smyrk TC, Gross JB. Hereditary hemochromatosis: laboratory evaluation. Clin Chim Acta. 2011; 412(17-18): 1485-92. PubMed

Nadakkavukaran IM, Gan EK, Olynyk JK. Screening for hereditary haemochromatosis. Pathology. 2012; 44(2): 148-52. PubMed

Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010; 139(2): 393-408, 408.e1-2. PubMed

Seckington R, Powell L. HFE-Associated Hereditary Hemochromatosis. 2000 Apr 3 [updated 2015 Sep 17]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. PubMed

Zarrilli F, Elce A, Scorza M, Giordano S, Amato F, Castaldo G. An update on laboratory diagnosis of liver inherited diseases. Biomed Res Int. 2013; 2013: 697940. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kroot JJ, van Herwaarden AE, Tjalsma H, Jansen RT, Hendriks JC, Swinkels DW. Second round robin for plasma hepcidin methods: first steps toward harmonization. Am J Hematol. 2012; 87(10): 977-83. PubMed

Sumner K, Hubley L, Pont-Kingdon G, Mitchell S, Wayman T, Wilson A, Meadows C, Elenitoba-Johnson K, Pattison D, Dobrowolski S, Best H, Lyon E. Validation of an unlabeled probe melting analysis assay combined with high-throughput extractions for genotyping of the most common variants in HFE-associated hereditary hemochromatosis, C282Y, H63D, and S65C. Genet Test Mol Biomarkers. 2012; 16(7): 656-60. PubMed

Medical Reviewers

Genzen, Jonathan R., MD, PhD, Co-Medical Director, Automated Core Laboratory at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Lyon, Elaine, PhD, Medical Director, Genetics, and Co-Medical Director, Pharmacogenomics at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, Medical Director, Molecular Genetics and Genomics at ARUP Laboratories; Associate Professor of Clinical Pathology and Co-director, Clinical Medical Genetics Fellowship Program, University of Utah

Salama, Mohamed E., MD, Medical Director, Hematopathology and Immunohistochemistry Staining at ARUP Laboratories; Associate Professor of Clinical Pathology, Director of Hematopathology Fellowship Program, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Strathmann, Frederick G., PhD, MS, Medical Director, Toxicology; Director of High-Complexity Platforms, Mass Spectrometry; Interim Scientific Director, Biocomputing; Assistant Director, ARUP Institute for Clinical and Experimental Pathology® at ARUP Laboratories; Assistant Professor of Clinical Pathology and Associate Member of the Interdepartmental Program in Neuroscience, University of Utah

Last Update: August 2016

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