Hemochromatosis

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.

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Clinical Overview

Diagnosis

Indications for Testing

Biochemical or clinical findings of iron overload suggesting HH
In adult family members of individuals with a C282Y/C282Y or C282Y/H63D genotype, screening is indicated
In reproductive partner of an individual with HH, carrier testing is indicated

Laboratory Testing

Initial screening tests
- Fasting serum transferrin saturation (STS)
  - Calculated from serum iron and iron binding capacity
  - A saturation cutoff of 45% is more sensitive for detecting mild disease, but also identifies heterozygotes not at risk for developing clinically concerning findings
- Serum ferritin (SF)
  - Increases progressively over time in individuals with untreated HFE-caused HH
  - As SF is an acute phase reactant, elevated concentration alone is not specific for iron overload; increased levels may be caused by inflammatory or neoplastic disorders
  - Serum iron testing should not be used for evaluation of HH

Genetic testing

HFE gene – C282Y, H63D, and S65C variants

HFE genotyping should be performed only for individuals (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology) with
- Laboratory evidence of iron overload (eg, elevated fasting transferrin saturation >45%)
- A known family history of HFE-associated hereditary hemochromatosis

*Interpretations for Common HFE* Gene Variants**
Variant	Clinical/Biochemical Evidence of Iron Overload	Comments
C282Y, H63D, S65C heterozygosity H63D homozygosity	Elevated serum iron levels may be present Clinical symptoms present only if an additional rare, undetected HFE mutation is present	No clinical symptoms of iron overload Consider HFE or other alternative full gene sequencing and possibly deletion/duplication analysis if suspicion for HH remains high
C282Y homozygosity	Negative	High risk for iron overload Only minority develop clinical symptoms
C282Y homozygosity	Positive	Confirms diagnosis of HH Only minority develop clinical symptoms
C282Y/H63D; C282Y/S65C compound heterozygosity	Negative	Moderate risk of iron overload <2% risk of developing clinical symptoms
C282Y/H63D; C282Y/S65C compound heterozygosity	Positive	Supportive of diagnosis of HH Penetrance is low – only minority develop clinical symptoms

Other Testing

Quantitative phlebotomy
- Use to determine quantity of iron that can be mobilized
  - 1 L of blood = ~0.5 g 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 g of iron

Histopathology

Liver biopsy – useful in confirming hepatic iron overload and degree of fibrosis
- Most often used for individuals with hemochromatosis and absence of common HFE variants
- 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 – alpha-1-antitrypsin (AAT)

Imaging Studies

Quantitative magnetic resonance imaging (MRI) – may be used as an alternative to liver biopsy
- Requires expertise with validation

Differential Diagnosis

Other forms of HH (non-HFE)
- Type 2B – juvenile hemochromatosis (HFE2, HAMP variants)
- Type 3 – transferrin receptor 2 variant (TFR2)
- Type 4 – ferroportin disease (SLC40A1)
- Neonatal hemochromatosis
Secondary iron overload
- Iron-loading anemias (eg, thalassemia)
- Transfusion iron overload
Chronic liver disease
- Alcoholic siderosis
- Porphyria cutanea tarda
- Portocaval shunt
- Alcoholic liver disease
- Hepatitis
Other
- Aceruloplasminemia
- Sub-Saharan African iron overload

Screening

Screen with fasting STS (calculated from serum iron and iron-binding capacity) and SF
U.S. Preventive Services Task Force (USPSTF) and the European Association for Study of the Liver (EASL) do not recommend widespread screening
American College of Physicians (ACP) recommends testing be offered to
- Adult Caucasian men of North European ancestry >25 years
- First-degree relatives of patients with disease
American Association for the Study of Liver Diseases (AASLD) recommends testing be offered to
- All patients with evidence of liver disease without obvious etiology
- First-degree relatives of patients with disease
EASL recommendation – offer testing to patients with unexplained chronic liver disease and elevated transferrin saturation

Monitoring

Depletion phase – hemoglobin/hematocrit, mean corpuscular volume (MCV), and SF 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

Background

Epidemiology

Incidence – allele frequency varies by ethnicity; most common in Caucasians of Northern European descent (~1/200-400)
Prevalence in children – rare
Age
- Peaks in 40s-50s
- Diagnosis is typically after age 10 in children
Sex
- Adults, M>F, 2:1
- Children, M:F, equal

Inheritance

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

Types of HH and Genes Involved
Type	Gene	Inheritance	Protein	Onset	Phenotype
1	HFE	AR	HFE	~40-60 yrs Males – 40s-50s Females – postmenopausal	Moderate
2A	HFE2	AR	Hemojuvelin	~15 yrs	Severe
2B	HAMP	AR	Hepcidin	~15 yrs	Severe
3	TFR2	AR	Transferrin receptor	~30 yrs	Moderate
4	SLC40A1	AD	Ferroportin	Any age	Moderate
AD, autosomal dominant; AR, autosomal recessive Sources: Zarrilli, 2013; Bardou-Jacquet, 2014

Common HFE Variants
Variant	Homozygosity	Carrier Frequency	Type of Disease	Heterozygosity
C282Y	85% of cases Variable penetrance Most patients have biochemical abnormalities ≤2% have characteristic clinical endpoints	Caucasians – 0.11 Hispanics − 0.03 African Americans − 0.02 Asians − <0.01	Severe	C282Y – does not cause HH Compound C282Y/H63D heterozygosity – 5% of cases
H63D	1% of cases	Caucasians – 0.25 Hispanics − 0.18 Asians − 0.09 African Americans − 0.06	Mild	H63D – does not cause HH Compound H63D/C282Y heterozygosity – 5% of cases
S65C		Caucasians – 0.015 Others – unknown	Unknown	Does not cause 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
- Uncontrolled influx of iron from enterocytes and macrophages
- Inadequate synthesis of the hepatic iron-regulating hormone, hepcidin

Clinical Presentation

Earlier onset (<30 years) – more severe disease than adult forms
- Pediatric presentation typically involves cardiomyopathy and hypogonadotropic hypogonadism
- Other organ involvement similar to adult onset – cirrhosis, diabetes mellitus, arthritis, increased skin pigmentation
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
- Liver function abnormalities – >95% of patients
- Chronic abdominal pain
- Hepatosplenomegaly
- Cirrhosis
- Hepatocellular carcinoma – 200-fold increase compared to patients with cirrhosis and chronic viral hepatitis B or hepatitis C
Cardiovascular disease
- Cardiomyopathy – dilated, restrictive, or mixed
- Arrhythmias – atrial tachycardias most common
Endocrine disease
- Diabetes – deposition in pancreas
- Thyroid dysfunction – iron deposition with fibrosis
- Hypogonadism, infertility
  - Iron deposition in the pituitary
  - Relatively rare
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

ARUP Lab Tests

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 total iron binding capacity (TIBC) and STS (STS [%] = [100 x serum iron]/TIBC)

Ferritin 0070065
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Aid in the diagnosis of iron deficiency anemia and iron overload

Monitor treatment of 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 HH in an individual with biochemical findings of iron overload

Screen adult family members of individuals with known HH

Test reproductive partners of an individual with HH for carrier status

Not recommended for initial hemochromatosis testing

Tests HFE gene for C282Y, H63D, and S65C mutations

Limitations

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

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

Only the three 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 variants

Initial approach to diagnosis for hemochromatosis should include iron and iron binding capacity (NOTE: test includes STS) and SF

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

Medical Reviewers

Genzen, Jonathan R., MD, PhD, Laboratory Section Chief, Clinical Chemistry, and Medical Director, Automated Core Laboratory, at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Johnson-Davis, Kamisha, PhD, DABCC, FAACC, Medical Director, Clinical Toxicology at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

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

References

Guidelines

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
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
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jun 2018]
European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010; 53(1): 3-22. 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

Testing Algorithms

Hemochromatosis Testing Algorithm

Read more about Hemochromatosis Testing Algorithm

Last Update: July 2018


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	Hemochromatosis. ARUP Consult^©. Retrieved August 15, 2018, from: https://arupconsult.com/content/hemochromatosis

Hemochromatosis

Diagnosis

Indications for Testing

Laboratory Testing

Other Testing

Histopathology

Imaging Studies

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Inheritance

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Hemochromatosis Testing Algorithm

References from the ARUP Institute for Clinical and Experimental Pathology^®