HFE-associated hereditary hemochromatosis: Overview of genetics and clinical implications for nurse practitioners in primary care settings


  • Donna Emanuele MN, DNP, FNP-BC, FAANP,

    (Assistant Professor)
    1. College of Graduate Nursing, Western University of Health Sciences, Pomona, California
    Search for more papers by this author
  • Ivy Tuason RN, MSN, FNP-BC,

    (Assistant Professor)
    1. College of Graduate Nursing, Western University of Health Sciences, Pomona, California
    Search for more papers by this author
  • Quannetta T. Edwards PhD, FNP-BC, WHNP-BC, FAANP

    (Professor), Corresponding author
    1. College of Graduate Nursing, Western University of Health Sciences, Pomona, California
    • Correspondence

      Quannetta T. Edwards, PhD, FNP-BC, WHNP-BC, FAANP, College of Graduate Nursing, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766–1842. Tel: (909) 469–3931; Fax: (909) 469–5521; E-mail: qedwards@westernu.edu

    Search for more papers by this author

  • To obtain CE credit for this activity, go to www.aanp.org and click on the CE Center. Locate the listing for this article and complete the post-test. Follow the instructions to print your CE certificate.

  • Disclosures: The authors report no competing interests.



HFE-hemochromatosis is one of the most common genetic disorders in the United States among Caucasians of Northern European ancestry. The purpose of this article is to discuss HFE-associated hereditary hemochromatosis (HH), including the genetics, pathophysiology, phenotype and genotype, diagnostics, and management utilizing a case-based format as an exemplar.

Data sources

Online genetic resources; professional guidelines; review; and scientific articles.


HFE-HH is an autosomal recessive disorder and two major genes C282Y and H63D are associated with HH (iron overload) susceptibility particularly C282Y/C282Y mutations. It has a variable penetrance and expression. Individuals who develop iron overload may develop broad symptoms, including joint discomfort, fatigue, decreased libido, and abdominal pain; and if left untreated, HFE-HH has the potential of developing end-organ disease including liver fibrosis, cirrhosis, and cancer; cardiac arrhythmias or heart failure; and diabetes. Suspicion of the disorder begins with personal and family history, transferrin saturation, and ferritin levels, and if high, genotyping to confirm the disorder. Management consists of correcting iron overload to prevent/delay end-organ damage often consisting of intermittent phlebotomy.

Implications for practice

Knowledge of HFE-HH is essential so that nurse practitioners can identify individuals at risk and to provide appropriate management of care and referral.


G. I. is a 68-year-old Caucasian female of Irish ancestry who presented to the primary care clinic with complaints of (c/o) 6-month history of progressively worsening “fatigue” affecting her ability to work and socialize, and c/o “joint discomfort in the hands/wrists.” She denied further problems and the history is otherwise uneventful except for two spontaneous miscarriages at 6 weeks. She is menopausal for 14 years and the review of systems and physical exam were unremarkable. Only medication use is Motrin 600 mg every 6 h prn for joint discomfort × 2 weeks with some relief. Social history: married, smoker 1 pack/day for 30 years, alcohol one glass/month (social drinker). Family history is significant for two brothers age 59 and 60 with undiagnosed joint pain, the older of which also has hypothyroidism; father, prostate cancer diagnosed at age 69 and died of the disease at age 74; mother, throat cancer diagnosed at age 83 and died of it shortly after; maternal and paternal aunts, uncles, and paternal grandparents with heart disease and a paternal grandfather, colon cancer at age 92 who died of the disease the same age (Figure 1). Based upon the personal and family history, the patient underwent a complete physical exam and laboratory tests that included complete blood count, ferritin, transferrin saturation (TS) level, total iron-binding capacity, thyroid test, and a comprehensive metabolic panel. Examination findings and laboratory tests were normal with the exception of a ferritin level >300 ng/L and a TS level >55%. Based on these findings she had genetic counseling/testing to rule out HFE-HH. Findings revealed a deleterious mutation C282Y/C282Y confirming the diagnosis. She was referred to a gastroenterologist and had liver magnetic resonance imaging (MRI) that showed no heptocellular disease. She underwent therapeutic phlebotomy weekly for 3 months. Her symptoms resolved and she is currently stable with follow-up visits every 6 months with primary care and gastroenterology.

Figure 1.

Five-generation pedigree of proband (presenting fictitious case of G. I.) with confirmed diagnosis of HFE-associated HH with C282Y/C282Y genotype.


Hemochromatosis is a disorder resulting from iron overload due to an increased rate of intestinal iron absorption and iron depositions that can occur in many parenchymal organs, including liver, pancreas, heart, pituitary, testicles, joints, and skin disrupting their normal function (Moyer, Highsmith, Smyrk, & Gross, 2011). The disorder was first described in 1865 and was later named in 1889 (Moyer et al., 2011). Hemochromatosis can be a serious disorder and if left untreated the increased iron stores and its potential organ involvement may cause significant morbidity and mortality, including liver fibrosis, cirrhosis, diabetes, arthritis, hypopituitarism, cardiomyopathy, and skin hyperpigmentation (Moyer et al., 2011). Its etiology can be attributed to genetic inheritance (primary) or secondary/acquired causes. When the disorder is because of inherited causes it is attributed to a single gene mutation (alteration in the normal genetic sequence) due to one of five HFE and non-HFE genes, including: HFE, HJV, HAMP, SLC40A1, and TFR2 (Table 1; Kowdley, Bennett, & Motulsky, 2012; Online Mendelian Inheritance in Man [OMIM], 2012; Santos, Krieger, & Pereira, 2012). These genes play an important role in regulating the absorption, transport, and storage of iron and alterations in their structure because of a gene mutation affects the normal gene functioning. Of these five gene mutations that can cause HH, the most common is because of a mutation in the HFE gene, the focus of this article.

Table 1. Genes associated with hereditary hemochromatosis
 Phenotype OMIMa Inheritance 
GeneEntry No.ChromosomePatternClinical Characteristics Description
  1. AR, autosomal recessive; AD, autosomal dominant.

  2. a

    OMIM, Online Mendelian Inheritance in Man http://www.omim.org/

  3. b

    Goldberg Y. P. (2011). Juvenile hereditary HH. From GeneReviews™[Internet]. Paragon, R. A., Adam, M. P., Bird, T. D., et al. (Eds.). Seattle, WA: University of Washington, 1993–2013. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1170/

  4. c

    Camaschella & Roetto, TFR2-related hereditary hemochromatosis (2011). From GeneReviews ™ [Internet]. Paragon, R. A., Adam, M. P., Bird, T. D., et al. (Eds.). Seattle, WA: University of Washington, 1993–2013. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1349/

  5. d

    U.S. National Library of Medicine. (2013). Genetics home reference. SLC40A1. Retrieved from http://ghr.nlm.nih.gov/gene/SLC40A1

Classicb HH: HFE gene2352006p22.2ARIron overload with symptoms appearing after periods of progressive iron overloading usually middle-late adulthood or decades of progressive iron loading
HHb type 2A HJV gene (hemojuvelin)6023901q21.1ARIron loading and early age onset usually before age 30 (juvenile HH)a
HHb type 2B HAMP gene61331319q13.12ARIron loading and early age onset usually before age 30 (juvenile hemachromatosis)b
HHb type 3 TFR2 gene (tranferrin receptor 2)6042507q22.1ARIron overload with age of onset earlier than in HFE-associated HH with some presenting in second decade of lifec
HHb type 4 solute carrier family 40 (iron-regulated transporter), member 1. SLC40A16060692q32.2ADIron overload; variantd (Q248H) increased risk among people of African descent

Besides single gene mutations, noninherited factors can also cause iron overload. Examples include consequences of iron-loading anemias, parental overload, chronic liver disease, dysmetabolic syndromes, congenital atransferrinemia, neonatal iron overload, and aceruloplasminemia (defined as disorder in which iron gradually accumulates in the brain and other organs; Bacon, Adams, Kowdley, Powell, & Tavill, 2011).

The purpose of this article is to discuss HFE-HH, including the genetics and clinical implications of the disorder for nurse practitioners (NPs) in clinical practice. Specifically addressed is the genetics and pathophysiology; epidemiology; clinical characteristics (phenotype); diagnostics, including genetic testing; and disease management of HFE-HH. A summary of the case presented previously and implications of the genetics of the disorder in NP practice are also discussed.

Genetics/pathophysiology of HFE-associated HH


The HFE gene is located on the short arm of chromosome 6p21.3, an autosome. The gene is important in producing a protein that functions as a hepcidin modulator. Hepcidin is a peptide hormone secreted primarily by hepatocytes into the circulation and is integral to whole-body iron homeostasis by controlling intestinal iron absorption, mobilization, distribution, and storage (Collins, Wessling-Resnick, & Knutson, 2008; Gan, Powell, Olynyk, & Collins, 2011; Ganz, 2011; Rossi, 2005). Important is the hepcidin–ferroportin regulatory pathway whereby hepcidin binds with ferroportin, a major iron exporter that is located on enterocytes, macrophages, and hepatocytes, that modulates the release of cellular iron (Rossi, 2005). Most of the iron found in the plasma is because of reticuloendothelial macrophages important in removing senescent or damaged red blood cells (RBC) from the circulation before recycling their hemoglobin iron back into the plasma for new RBC formation (Pietrangelo, 2010). When hepcidin concentrations are low, iron enters blood plasma at a high rate (Ganz, 2011). Certain mutations in the HFE gene may result in nonfunctioning proteins, reducing hepcidin levels that have the potential to lead to inappropriate high iron absorption and recycling and consequently iron overload (Santos et al., 2012). The high levels of iron into the plasma lead to an increase in transferrin saturation (TS; iron transporter) and nontransferrin-bound iron (Brissot et al., 2010) and further elevation of ferritin level results (Moyer et al., 2011). Ferritin is a protein that stores iron and increases in serum ferritin production occur when excess iron is absorbed. As a consequence, the high iron levels can result in visceral storage leading to damage in the liver (fibrosis and cirrhosis the main pathological findings), pancreas, heart, pituitary gland, gonads, skin (pigmentation), and joints (arthritis) (Bacon et al., 2011; Kowdley et al., 2012). The liver is a major organ for pathology for HH because of the increased plasma iron, particularly in its nontranferrin-bound forms (Ganz, 2011). HFE-HH can be life-threatening as a result of cirrhosis, hepatocellular carcinoma, diabetes, and heart complications (Bacon et al., 2011).

HFE-HH is transmitted in an autosomal recessive (AR) pattern of Mendelian inheritance requiring that the offspring inherit both copies of the gene, one from each parent in order for a diagnosis of HH to occur (Kowdley et al., 2012). There is a 1:4 or 25% chance of transmitting a gene mutation to the offspring in AR inheritance when each parent is a carrier of the gene mutation (Figure 2); when one parent is diagnosed with the disorder and the other parent is a carrier there is a 50% chance of transmitting the disease and 50% chance of carrier status to the offspring. In carriers, only one chromosome with the HFE-mutated gene is affected and the other chromosome with the HFE gene is normal (wild type). Carriers of the HFE-HH gene do not develop clinical findings/symptoms (Kowdley et al., 2012).

Figure 2.

Autosomal recessive pattern of inheritance depicting 1:4 or 25% transmission of the gene to the offspring in affected parents both who are carriers of the mutation. Figure from the U.S. National Library of Medicine retrieved from http://ghr.nlm.nih.gov/handbook/illustrations/autorecessive

Genes associated with HFE-HH

HFE-HH has been attributed primarily to two HFE gene mutations resulting in alterations of either the C282Y and/or H63D proteins. Individuals with a C282Y/C282Y genetic mutations in both genes (homozygotes) and those with C282Y mutation in one gene and H63D-mutated gene on the other chromosome (heterozygote) account for the majority of individuals in the United States of European ancestry with HFE-HH (Kowdley et al., 2012). Both are missense mutations that occur as a result of a substitution in a nucleotide sequence of the gene leading to a change in an important amino acid. In C282Y, the HFE gene mutation is c845 G → A (G substituted for A) resulting in tyrosine instead of cysteine at the amino acid position 282 and in H63D, the HFE gene mutation c187 C → G (C substituted for G) resulting in aspartate instead of histidine at amino acid position 63 of the gene (Bacon et al., 2011; Kowdley et al., 2012; Pedersen & Milman, 2009). Another mutation of the gene is that of S65C. In this HFE mutation of c183 (missense mutation A → T), cysteine is substituted for serine at amino acid position 65. The mutation, however, has not been associated with iron loading unless combined with C282Y as a heterozygote (i.e., heterozygotes C282Y/S65C) (Bacon et al., 2011). Of these three mutations, C282Y is the most common gene mutation associated with HFE-HH. Approximately 82%–90% of individuals diagnosed with HFE-HH are homozygous for this gene and this genotype has the highest risk for iron overload when inherited in this state (Bacon et al., 2011; Kowdley et al., 2012). Heterozygote mutations in C282Y/H63D account for nearly 3%–8% of individuals with HFE-HH and this genotype can result in iron overload but at lesser risk than those homozygous for C282Y (Pedersen & Milman, 2009). Genetic mutations of H63D/H63D account for approximately 1% of those with the disorder (Genetrack Biolabs, 2013; Kowdley et al., 2012; Toland, 2011). The H63D and S65C mutations are less penetrant and have a lower chance of causing disease and individuals with H63D/S65C or heterozygotes for S65C have no impact or not been found to increase the risk of developing HH (Pedersen & Milman, 2009; Toland, 2011). The percentage of individuals with HH due to sequence variants or exonic and whole gene deletions causing disease is unknown (Kowdley et al., 2012).

Epidemiology of HFE-HH

HFE-HH is one of the most common inherited disorders in the United States. The overall prevalence for the disorder in the United States is estimated at 1:200 to 1:500 people (homozygotes) (Adams et al., 2005; American Hemocromatosis Society [AHS], n. d.; Duchini & Katz, 2013; Kowdley et al., 2012) with approximately 1 million people in the United States homozygous for the mutation (National Heart Lung and Blood Institute [NHLBI], 2011; Schmitt et al., 2005). The prevalence of HFE-HH in the United States, however, depends on the individual's race/ethnicity. The disorder occurs predominately among Caucasians of Northern European descent with rare occurrences found in other racial/ethnic groups. In one large population study, the frequency of C282Y homozygosity was reported as 4.4 per 1000 (0.44%) for whites, followed by Native Americans 1.1 per 1000 (0.11%), Hispanics 0.27 per 1000 (0.027%), 0.14 per 1000 for blacks (0.014%), 0.12 per 1000 for Pacific Islanders (0.012 percent), and <0.001 per 1000 for Asians (0.0039%; Adams et al., 2005; Whitlock, Garlitz, Harris, Bell, & Smith, 2006). Carrier status or heterozygosity for the gene among whites is approximately 1:8 to 1:10 (AHS, n. d.; Whitlock et al., 2006) with much lower rates found in other racial/ethnic groups (Adams et al., 2005).

Clinical characteristics—phenotype

There is not one but a spectrum of phenotypes associated with HFE-HH. These spectrums include nonexpressing HFE-HH or individuals that are homozygotes and who do not manifest clinical symptoms or iron overload but are genetic susceptible to the disease; biochemical HFE-HH manifested by laboratory findings of increased iron load specifically increased transferrin-iron saturation and increased serum ferritin; and clinical HFE-HH resulting in end-organ damage due to excessive iron overload (Bacon et al., 2011; Kowdley et al., 2012). Because of these varied spectrums, HFE-HH may go undiagnosed unless individuals present with clinical symptoms or incidental abnormal laboratory tests leads the knowledgeable clinician to further evaluate for the disorder through genetic testing.

Clinical expression of HFE-HH is highly variable even for those homozygous with a C282Y mutation. Individuals homozygous for C282Y who develop elevated serum ferritin and transferrin levels associated with HH occur in approximately 70%–90% of males and 40%–60% of females, and nearly 20% of men and 50% of women with a C282Y/C282Y mutation have normal serum ferritin levels and TS levels (Adams et al., 2005). Lower rates of elevated serum ferritin and transferrin levels occur among heterozygotes with C282Y/H63D genotype.

Organ involvement of the disorder also varies. Although nearly 1:250 Caucasians of Northern European descent are homozygous with the C282Y gene, only about 10% of these individuals will develop full expression of the disorder leading to end-organ disease (Bacon et al., 2011; Beutler et al., 2002). In one population-based study of individuals of Northern European descent conducted in Australia, iron overload related disease conditions (i.e., cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated amniotransferase levels, arthropathy) among those with C282Y genotype was 28.4% for men and 1.2% for women (Allen, 2010).

For those who develop clinical features, early symptoms of HFE-HH are because of iron overload usually emerging in late adulthood and involving a myriad of vague complaints. Common symptoms associated with the disorder include fatigue, depression weight loss, joint discomfort/pain, decreased libido, hair loss, and abdominal discomfort (Beutler et al., 2002; King & Barton, 2006; Kowdley et al., 2012). Fatigue and arthralgia are among the most common presenting symptoms of patients who present with the disorder (McCarthy et al., 2002). Women who develop symptoms of HFE-HH often do so later in life when compared to men probably as a result of blood loss due to menstruation and changes due to pregnancy from iron loss. The disorder is one of slow progression with typical age of presentation for HFE-HH symptoms due to iron overload usually occurring between 40 and 60 years for males and after menopause in females (Bacon et al., 2011; Kowdley et al. 2012).

Advanced stages of untreated individuals with iron overload who manifest clinical stages of the disorder may result in chronic and severe disease(s) and organ(s) involvement. These include liver involvement (hepatomegaly, hepatitis, cirrhosis, liver fibrosis, and hepatocellular liver cancer); diabetes (pancreas); arrhythmias; cardiac myopathy, heart failure; hypogonadism (pituitary), arthritis particularly of the metacarphophalangeal joints (particularly the second or third metacarpophalangeal joints); and progressive hyperpigmentation of the skin (Bacon et al., 2011; Beutler et al., 2002; Kowdley et al., 2012; Yen, Fancher, & Bowlus, 2006). Males homozygous for C282Y have also been found to have higher proportions of iron-overload diseases compared to females (Allen, 2010).

Laboratory/biochemical findings

Biochemical findings of HFE-HH are associated with iron overload. Individuals suspect for the disorder based upon symptoms, physical findings, or family history should have iron status markers conducted to include TS levels and serum ferritin (Bacon et al., 2011). These tests should begin prior to genetic testing for individuals with whom diagnostic work up for the disease is indicated. The TS is an early and reliable indicator of iron overload in individuals with the disorder. TS levels of ≥45% have been recommended by the American Association for the Study of Liver Disease (AASLD) as a cut-off reference warranting further genetic testing for HFE-HH (Bacon et al., 2011). This cutoff while highly sensitive for C282Y homozygotes has a lower specificity and positive predictive value than with higher cutoff values (Bacon et al., 2011; Yen et al., 2006) and adding serum ferritin level provides additional information in assessing for the disorder.

Serum ferritin is an important test to assess for iron overload. Ferritin levels >300 μg/L in men and 200 μg/L in women provide additional data to support HFE-HH (Bacon et al., 2011; European Association for the Study of the Liver [EASL], 2010; Yen et al., 2006). Elevated serum ferritin levels alone however may not be indicative of HFE-HH as serum ferritin levels particularly when TS is normal may be attributed to a wide-range of other conditions, including alcohol consumption, inflammatory or neoplastic diseases and non-HFE genetic disorders (Bacon et al., 2011; EASL, 2010; Kowdley et al., 2012; Yen et al., 2006). Thus, AASLD recommends TS and ferritin when assessing individuals for HFE-HH rather than a single test (Bacon et al., 2011).

Genetic testing

Individuals who have TS ≥ 45% and/or elevated ferritin level should have molecular genetic testing using targeted mutation analysis to detect for C282Y and H63D mutations, the two common genes associated with HFE-HH (EASL, 2010; Kowdley et al., 2012). Individuals homozygote for C282Y or heterozygote for C282Y/H63D have the genotype to develop into HFE-HH. When these two mutations are not found, additional genetic testing strategies may be warranted for individuals with TS ≥ 45 or for whom HH is strongly suspected. For example, further HFE genetic sequencing and analyses may be warranted for those with one C282Y identified (however only few individuals will have a phenotype associated with other genotypes). Consideration of genetic testing for other genes (non-HFE) associated with iron overload or assessing for secondary causes of other iron-overload conditions may be indicated for individual's suspect for hemachromatosis (EASL, 2010; Kowdley et al., 2012). Utilization of an intercollaborative team, including individuals experienced in genetic counseling and testing should be considered to assist in genetic risk assessment and counseling of the nature, inheritance and implications of the genetic disorder as well as other personal, familial, ethical, and cultural issues that may be impacted based upon genetic findings (Kowdley et al., 2012).

Disease management

Genetic testing confirms the HFE genotype and susceptibility for developing HFE-HH. Varied penetrance however may not necessarily result in iron overload even if C282Y homozygous (EASL, 2010). Heterozygotes for C282Y/H63D may have increased ferritin levels in the absence of elevated TS due to other causes. Individuals who are heterozygote for C282Y/H63D or heterozygote with non-C282Y gene should have further evaluation to exclude other liver or hematologic diseases (Bacon et al., 2011; EASL, 2010) and NPs in primary care practice should obtain expert consultation regarding this issue (i.e., specialist in HH; genetic counselor; hematologist). When the diagnosis of HFE-HH has been established, management of care is based upon the extent of disease. Serum ferritin levels provide a valuable disease predictor particularly when advanced liver disease is involved, such as in fibrosis and cirrhosis. Individuals with ferritin levels > 1000 μg/L or who have elevated liver enzymes (i.e., aspartate aminotransferase) warrant liver biopsy to assess for hepatic iron concentration, pathology, and to stage the degree of liver disease (Bacon et al., 2011).

Therapeutic phlebotomy is a major treatment for HFE-HH and a primary preventive strategy to reduce development of liver and other diseases that increase the risk for morbidity and mortality due to high iron overload from the disorder (Bacon et al., 2011; EASL, 2010). Guidelines regarding the specific serum ferritin level of which to begin phlebotomy is not clear; however, AASLD and EASL recommends the procedures for individuals with elevated iron levels among symptomatic individuals particularly those with fatigue, skin pigmentation, and abdominal pain. It is also indicated for asymptomatic homozygous C282Y individuals with iron overload as a preventive measure, and those with evidence of increased levels of hepatic iron (Bacon et al., 2011; EASL, 2010).

Therapeutic phlebotomy usually involves the removal of 500 mL or one unit of blood in weekly or monthly intervals based upon individual's tolerance resulting in an estimated loss of 200–500 mg of iron (Bacon et al., 2011). Hemoglobin and hematocrit should be tested prior to phlebotomy to reduce the risk of lowering these levels to <80% of initial or 20% of prior levels (Bacon et al., 2011). Monitoring serum ferritin levels should be done to assess for falling levels, indicating iron mobilization with depletion of iron stores usually occurring after every 10–12 phlebotomies or at 3 months (Bacon et al., 2011). The AASLD and EASL recommend targeting the phlebotomy to achieve serum ferritin levels between 50 and 100 μg/L (Bacon et al., 2011; EASL, 2010). Similarly, maintenance phlebotomy is individualized and should be considered when ferritin levels are beyond 50–100 μg (Bacon et al., 2011). In some cases, the removal of excess iron may take from 1 month to 3 years, with a mean average of 13–31 months (Laudicina, 2001), while others may need 1–2 units removed yearly (Bacon et al., 2011). Maintenance therapy regarding serum ferritin level is usually obtained according to the EASL (201) in 3–6 months of phlebotomy (EASL, 2010).

Caution should be maintained in the use of phlebotomy for individuals with cardiac arrhythmia or cardiomyopathy as rapid mobilization of iron may lead to sudden death (Bacon et al., 2011). Supplemental vitamin C should also be avoided in patients undergoing the procedure because it accelerates mobilization of iron; however, adjustments in the diet are not needed (Bacon et al., 2011). Individual homozyotes with nonexpressing C282Y and who do not have iron overload do not need phlebotomy.

Currently, therapeutic phlebotomy is the primary treatment and standard approach recommended for individuals requiring treatment for HFE-HH (i.e., iron overload or symptoms) (Abolaban et al., 2010; Bacon et al., 2011; EASL, 2010). Erythrocytapheresis has also been as an alternative management of care for select individuals with the disorder to achieve iron depletion particularly among those with severe iron overload or other problems associated with the disorder not manageable by current therapeutic phlebotomy (Adams & Barton, 2010; Poullin & Levevre, 2011; Rombout-Sestrienkova et al., 2012).

Additional laboratory, ancillary tests, and preventive measures for those with HFE-HH should be ordered based upon history. For example, assessment of liver functioning (i.e., ALT, AST) may be indicated based upon iron studies to determine liver involvement, and liver biopsy may be warranted based upon these findings or if ferritin is >1000 μg/L (Bacon et al., 2011; EASL, 2010). Routine liver biopsy is not indicated for routine diagnosis but to determine liver disease, such as cirrhosis. The use of magnetic resonance imaging (MRI) provides an additional measure to estimate iron content in the liver (Joffe et al., 2013). In addition, to minimize the risk of additional complications, patients with HFE-HC should be immunized against hepatitis A and B while iron overload. Also, raw shellfish should be avoided in patients with HH because of the potential for Vibrio(V.) vulnificus a bacterium infection that has been associated with septicemia (Barton & Action, 2009). The increased availability of iron in the blood of patients with chronic iron overload is thought to enhance susceptibility to V. vulnificus unless shellfish are thoroughly cooked (Laudicina, 2001).

Family implications and genetic testing

Genetic testing should be offered to first-degree family members of individuals diagnosed with HFE-HH (proband) for early detection of the disease and to prevent future complications (Bacon et al., 2011). Recommended screening for these family members should include HFE genetic mutation analysis and serum ferritin and TS. For children of an affected proband, testing the other parent can be conducted first and if negative denotes obligate carrier status of the child and no need for genetic testing.

Differential diagnosis

Numerous hereditary, secondary causes, and other medical conditions may result in iron overload. In fact, secondary causes are more common than primary disorders in leading to iron overload. Examples of secondary causes of iron overload include thalassemia, sideroblastic anemia, chronic liver diseases including hepatitis B and C, alcohol-induced liver disease, and parental iron overload (Bacon et al., 2011; Yen et al., 2006). While certain mutations in the HFE gene (particularly C282Y homozygotes) are susceptible to iron overload, other non-HFE genetic disorders may also lead to HH. Thus, NPs must be knowledgeable about the many causes of iron overload and provide appropriate assessment to evaluate for HH, including HFE-HH. Assessment for HFE-HH should be based on careful personal history and physical examination, including assessment of race/ethnicity, age, current and medical history, as well as a thorough evaluation of the family history preferably with a three-generation pedigree obtaining data on both the maternal/paternal lineage. Recognition of signs and symptoms indicative of HFE-HH should be followed up with appropriate laboratory testing, including serum ferritin and TS, for initial evaluation of iron overload.

Follow-up case discussion

The case of G. I. illustrates an individual with symptoms of HFE-HH and who was appropriately diagnosed and managed for the disease. G. I. is of an ancestry that is high risk for the disorder (Caucasian; Northern European) and who presented with joint discomfort and fatigue typical for the disorder. Her personal and medical history coupled with the elevated serum ferritin and ferritin saturation levels ordered by the astute NP highlighted the need for genetic testing. The five-generation pedigree did not reveal a prior history of individuals diagnosed with HFE-HH. The pedigree is not unusual given the AR mode of transmission that manifests on pedigrees with a horizontal rather than vertical pattern, however there are two additional siblings noted in the pedigree with undiagnosed joint pain suspect for the disorder. Molecular genetic testing (deleterious mutation C282Y/C282Y) of Mrs. G. I. confirmed that the iron overload was because of HFE-HH and management for the disease with an interprofessional team was initiated. Abdominal MRI revealed no hepatic heptocellular involvement/disease. Based upon her symptoms and elevated serum iron levels, she was treated appropriately with phlebotomy with resolution of symptoms and serum iron levels. Her siblings and children (father not available for testing) are recommended to have serum ferritin, ferritin saturation, and genetic testing and these tests are pending evaluation.

Final discussion—Summary

Because of the variable penetrance of the HFE-HH, routine population screening in the United States for asymptomatic individuals or individuals without known family history or genotype for the disorder is currently not recommended by most professional organizations (Bacon et al., 2011) including U.S. Preventative Service Task Force (Agency for Healthcare Research, 2011). Thus, knowledge of HFE-HH, including the genetics of the disorder, is important for all healthcare providers (HCPs), including NPs in order to recognize individuals suspect for the disorder and to prevent iron overload that can lead to adverse outcomes. Reports have shown that the disorder may be underdiagnosed and failure to diagnose the disorder may be because of numerous reasons, including lack of knowledge to recognize HH (Burke, Cogswell, Donnell, & Franks, 2000). In one study by Edwards et al. (2006), the researchers found that only 8% of NP faculty integrated the genetics of HH into curriculum and only 40% reported feeling comfortable teaching the disorder and fewer (15%) reported prior training or education on the genetics of HH. An established panel of nursing experts has obtained consensus on the genetic core competencies that are essential for advanced practice nurses, including NP (Greco, Seibert, & Tinley, 2011). This includes risk assessment to identify clients with inherited predispositions to diseases as appropriate to the nurse's practice setting. Evaluating patients for HFE-HH warrants that NPs have this genetic knowledge and skills to appropriately assess individuals at risk and to identify those with symptoms of the disorder. Commonly used genetic terms and resources about HFE-HH are available to assist NPs learning more about the disorder (Tables 2 and 3).

Table 2. Definition of common concepts used in genetics
Genetic ConceptDefinition
  1. a

    U.S. National Library of Medicine (2014) Retrieved from Genetics Home Reference Glossary http://ghr.nlm.nih.gov/glossary/browse/a

  2. b

    National Institute of Health, National Cancer Institute (NCI). NCI dictionary of cancer terms. Retrieved from http://www.cancer.gov/dictionary?expand=%23;

  3. c

    Pagon, R. A., Adam, M. P, Bird, T. D., et al. (Eds.). GeneReviews ™ [Internet]. Illustrated glossary. Seattle, WA: University of Washington, 1992–2013. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK5191/

AlleleaVariant form of a gene at a given location on a chromosome
Autosomal dominantaOne copy of the gene located on the autosomes (nonsex chromosome) is required for expression of the phenotype
Autosomal recessiveaTwo copies of the gene mutation is required to express the phenotype of which both occurs on the autosomes
Gene expressionbProcess whereby the gene is turned on to make RNA or protein
GenotypeaIndividual's collection of genes; the genetic constitution of an organism that is inherited
HeterozygoteaIndividual that has inherited two different alleles
HomozygoteaIndividual who has inherited same or identical alleles at a particular locus of the chromosome
Missense mutationaA single base pair substitution of a gene that results in a different amino acid at that position
Penetrancea, bThe proportion of individuals with a mutation who manifest clinical symptoms of the disorder, or shows signs and symptoms of the disease
PhenotypecObservable (clinical presentation) or biochemical characteristics of a disorder
ProbandcIndividual with a genetic disorder who presents with the disorder for counseling/management or primary care
Table 3. Examples of online resources to assist in the understanding of genetics/genomics pertaining to hereditary HH
Online ResourceDescriptionWeb Site
Center for Disease ControlHH web site includes “training and education,” “free materials,” “health tips,” “patient brochures”http://www.cdc.gov/ncbddd/hemochromatosis/index.html
Online Mendelian Inheritance in Man (OMIM)Comprehensive, authoritative compendium of human genes, and genetic phenotypes (including HH) that is freely available and updated dailyhttp://www.omim.org/
Gene Reviews™ University of Washington, SeattleExpert-authored, peer-reviewed disease descriptions presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions includinghttp://www.ncbi.nlm.nih.gov/books/NBK1116/
HFE-Associated Hereditary HemochromatosisHFE-associated hereditary HH. Kowdley, K. V., Bennett, R. L., Motulsky AG2000 April 3 [Updated 2012 April 19]. In: Pagon R. A., Adam, M. P., Bird, T. D., et al. (Eds.). GeneReviews™ [Internet]. Seattle, WA: University of Washington, 1993–2013.http://www.ncbi.nlm.nih.gov/books/NBK1440/
National Library for MedicineWhat is HH?http://ghr.nlm.nih.gov/condition/hemochromatosis
National Institute of Health  
Genetics Home Reference