This guideline provides recommendations for the biochemical investigation, genetic testing and management of HFE associated hereditary hemochromatosis (HFE-HH) in adults aged > 19 years. The objectives are the early identification and management of individuals at risk for iron overload caused by HFE-HH.- Screening the general population is not recommended. - Testing non-Caucasians for HFE-HH is not recommended. - Ferritin, rather than transferrin saturation, is measured as the initial marker of hemochromatosis and to determine if further testing is warranted. 1 - Revision of criteria for genetic testing of first-degree family members of individuals with HFE-HH. - Discontinuation of testing for the H63D variant in HFE.Iron overload occurs when iron absorption exceeds physiological requirements or when iron derived from repeated blood transfusions or excessive ingestion overflows normal body iron stores. Excess iron is deposited in the organs, leading to parenchymal damage and organ dysfunction. Iron overload may result from either inherited or acquired disorders.The common form of hereditary hemochromatosis is due to a (C282Y) mutation in a gene called HFE -a mutation which occurs predominantly in Caucasians, and leads to excessive absorption of dietary iron. HFE-associated hereditary hemochromatosis (HFE-HH) is an autosomal recessive disorder and therefore, both alleles of HFE must be abnormal for risk to occur (1 in 230 in Caucasians is homozygous for the C282Y mutation). 2,3 Notably, however, fewer than 10% of C282Y homozygotes develop clinical manifestations. 1  The HFE gene encodes the hereditary hemochromatosis protein. HFE-HH refers to HFE-associated hereditary hemochromatosis. For this guideline the condition will be referred to as hemochromatosis.#
There are other rare genetic conditions leading to iron overload for which genetic testing is not available. For example, Asians with elevated ferritin are very unlikely to have HFE-HH 4 and a number of mutations in other iron related genes have been identified in this population. 5 These rare disorders are outside the scope of this guideline; suspected cases should be referred to a specialist.

# Acquired (Outside the scope of this guideline)
- transfusion dependent anemias
- various liver diseases - anemia from ineffective erythropoiesis
- excessive ingestion of medicinal iron

# Signs and Symptoms
Because hemochromatosis can lead to gradual damage in a number of organs over many years, its symptoms can be confused with those of much more common diseases, such as alcoholic liver disease, diabetes, and osteoarthritis. If untreated, hemochromatosis can cause serious disease and premature death. Pre-symptomatic detection and treatment can completely prevent clinical sequelae and, in symptomatic patients, phlebotomy effectively reduces morbidity and mortality. 2,3  Most patients with hemochromatosis develop only one or a few of the above problems, with liver involvement and enlargement being the most common, occurring in most affected patients. Patients are often not diagnosed until aged > 40 years in males and even later in females. However, nonspecific symptoms such as arthralgias, fatigue, and abdominal pain may be noted years before organ dysfunction becomes apparent.
Significant end-organ damage is rare with a ferritin value < 600 g/L. The routine complete blood count (CBC) is normal in hereditary hemochromatosis.
HFE-HH is diagnosed upon demonstration of increased iron stores (with or without clinical symptoms) and C282Y homozygosity.

# Whom to Test
A. Individuals of Caucasian ethnicity with signs and symptoms that might be caused by iron overload. These include:
- enlarged liver, unexplained persistent elevation of liver enzymes, cirrhosis - arthritis (including premature osteoarthritis and classic arthropathy of thumb, index and middle fingers)
- unexplained congestive heart failure or cardiomyopathy - adult-onset, brittle diabetes - hypogonadism - increased skin pigmentation

# Test to Order: Ferritin (hemochromatosis)
Serum ferritin reflects total body iron stores, and a serum ferritin > 600 g/L provides a sensitive indicator of patients at risk for clinical manifestations of hemochromatosis 1 warranting follow-up genetic testing. Ferritin levels that are elevated but < 600 g/L are less specific due to ferritin fluctuation as an acute-phase reactant.  In these cases genetic testing will proceed only when the transferrin saturation is also elevated. Transferrin saturation alone lacks both sensitivity and specificity as an indicator of hemochromatosis. 8  Ferritin is both a maker of intracellular iron stores and an acute phase reactant. Aside from HFE-HH, some common causes of elevated ferritin include inflammation, liver disease, dysmetabolic hyperferritemia 9 transfusional iron overload, and non-HFE related genetic iron overload. Serum ferritin values may vary between laboratories and with patient age and gender. Refer to the normal reference interval provided by your local laboratory.
B. Individuals of Caucasian ethnicity with persistently elevated serum ferritin discovered incidentally and not secondary to underlying systemic disease (e.g., chronic alcohol abuse, infection, autoimmunity, malignancy).

# Test to Order: Ferritin (hemochromatosis)
For example, an elevated ferritin may be noted as part of an investigation for possible iron deficiency. Such elevations in ferritin should be followed up as patients with hemochromatosis may initially present with non-specific symptoms and upon confirmation of diagnosis would be eligible for therapy.
C. Parents, siblings, and adult children of individuals with confirmed genetic diagnosis of HFE-HH (i.e., C282Y/C282Y homozygotes).
- Parents: the results of the serum iron tests(s) determine the need for the HFE genetic testing (see Appendix A -Figure 2: Laboratory Testing Algorithm) - Siblings and adult children (> 19 years): testing for HFE C282Y mutation will proceed in all cases; if C282Y/C282Y homozygote, measure serum ferritin; treat and/or follow as indicated, based on ferritin results. Test to Order: Ferritin (hemochromatosis). Provide family history on requisition and genetic testing may proceed according to protocol. Individuals that have previously been treated for hemochromatosis should be offered genetic testing if not already performed. When ordering, indicate that the patient has previously been treated for hemochromatosis.

# Whom Not to Test
Screening the general population is not recommended. Testing non-Caucasians for HFE-HH is not recommended as the mutation is rare to non-existent in the non-Caucasian population. Non-Caucasian patients with evidence of iron overload should be referred to a specialist

# Genetic Testing
Genetic testing is currently only offered through the Molecular Genetics Laboratory (MGL) at the Children's and Women Health Centre of BC.
Genetic testing should not be offered to:
- children  19 years of age  - non-Caucasians - first-degree relatives   of individuals identified to be heterozygous (carriers) for C282Y
- first-degree relatives of individuals previously identified to be compound heterozygotes for C282Y/H63D or to have only the H63D variant Genetic testing of samples to confirm HFE-HH can be done in one of two ways:
A. The provincial standard laboratory requisition form (found on the physician secure section of the BCMA website, at www.bcma.org) a. Select HFE hemochromatosis testing within the Hematology section (see Appendix A for the testing algorithm followed by laboratories.)
B. The laboratory requisition from the Molecular Genetics Laboratory (www.genebc.ca) a. Provide reason for testing (check boxes, mid-left side of page) as in Figure 1.
As HFE-HH is an adult-onset disorder, genetic testing is not generally indicated in children <19 years of age. Genetic testing for adult-onset disorders should only be requested when an individual can, themselves, provide informed consent.   First-degree relatives: parents, siblings and children.

# Send patient (with the completed requisition) to any collection laboratory
Patients in whom iron overload is confirmed in the absence of C282Y/C282Y homozygosity should be referred to a specialist.

# Management Management and Surveillance of Hemochromatosis
Therapeutic phlebotomy is the treatment of choice for hemochromatosis and for other primary iron overload disorders. Possible exceptions include those who are already anemic, or have limited life expectancy due to other diseases or those with congestive heart failure with hemodynamic instability.
Prior to initiating a phlebotomy program, the patient should be thoroughly assessed for possible end organ damage (e.g., arthritis, liver dysfunction, diabetes, heart disease). Patients with ferritin > 1000 g/L should have liver function tests because of the increased risk of cirrhosis and hepatoma. 10,11 Phlebotomy technique is important for maintaining venous access. Refer to Appendix B: Therapeutic Phlebotomy Using an 18 Gauge Cannula.
Volume and frequency of phlebotomy need to be individualized according to the patient's age and clinical and biochemical presentation. For severely iron overloaded patients, weekly phlebotomy of 500 ml of whole blood should be continued until serum ferritin is < 50 g/L. Patients with massive iron overload may require in excess of 100 phlebotomies.
Serum ferritin and hemoglobin should be monitored regularly (e.g., every 4th phlebotomy) to assess response to therapy. It is unusual for iron overloaded patients to develop anemia early in the course of phlebotomy therapy. If this occurs, the frequency of phlebotomy needs to be reduced.
Once patients have been successfully depleted of excess iron stores (ferritin <50 g/L), a program of monitoring and maintenance should be established. The need for maintenance phlebotomy is quite variable; some patients require phlebotomy every 2-4 months to maintain a low-normal ferritin, and some may not re-accumulate for many years.
At minimum, the CBC and ferritin should be checked every 12 months, and phlebotomy should be re-initiated if the ferritin is rising toward the upper limit of normal.
End organ damage should be reassessed periodically. If liver enzymes have been abnormal, they often improve once iron stores have been depleted. There may also be improvement in iron-induced cardiac dysfunction. Diabetic patients often note improvement in blood sugars with less dependency on insulin or oral hypoglycemic agents. Conditions that often do not improve with phlebotomy include arthropathy, cirrhosis and testicular atrophy.