Investigation and Management of Iron Overload

Scope

Who to Test

How to Test

Genetic Testing

Genetic Test Followup

Management

Rationale

Investigation Flow Sheet

About This Document

Scope

This guideline provides recommendations for the investigation of iron overload and management of hemochromatosis. It applies to patients of all ages.

Iron overload refers to all conditions where excessive amounts of iron accumulate in tissues resulting in parenchymal damage and organ dysfunction. The various forms of iron overload may be classified as:

a) INHERITED

• HFE-related (occurs predominantly in people of European descent)

• Non-HFE-related (can occur in other ethnic groups)

b) ACQUIRED

• Iron loading anemias, transfusion iron overload, etc.

Note: The terminology varies in the literature. More recent references reserve the terms ‘hereditary hemochromatosis’ and ‘genetic hemochromatosis’ for HFE-related iron overload. The symbol “HFE” has been used for many years in the human genetics community to designate the gene for hemochromatosis.

Recommendation 1:: Who should be tested for iron overload

a) Patients who have symptoms or signs that might be caused by iron overload. These include patients with (unexplained):

• arthritis (including premature osteoarthritis)

• congestive heart failure or cardiomyopathy

• adult-onset diabetes

• persistent elevation of liver enzymes or cirrhosis

• secondary hypogonadism

• increased skin pigmentation

b) Patients with persistently elevated serum ferritin not explained by an underlying inflammatory/ systemic disease.

Notes: First degree relatives of a known case of HFE-related hemochromatosis should be offered genetic testing as the first step. Refer to Recommendation 3. Other groups at risk of iron overload include patients receiving long-term red cell transfusion support for chronic anemia and patients with porphyria cutanea tarda. Management of these patients should be discussed with a specialist.

Serum ferritin levels may be elevated out of proportion to total body iron stores in patients with infection, inflammation, or cancer.

Recommendation 2: How to test for iron overload (See Investgation Flow Sheet)

Patients who meet any of the criteria in Recommendation 1 should receive testing for iron overload on a fasting blood sample. Depending on the laboratory, the test can either be transferrin saturation or saturation of total iron binding capacity. For practical purposes, the two tests are equivalent. In the discussion to follow, we will use the term ‘fasting transferrin saturation’ (fTS).

a) If fTS =/< 0.45, no further testing is required.

b) If fTS is between 0.45 and 0.60, repeat test within a month.

• If repeat test is =/< 0.45, no further hemochromatosis testing is required.

• If repeat test is > 0.45, consider genetic testing.

c) If fTS > 0.60, consider genetic testing.

Note: Serum ferritin is not a reliable screening test for iron overload because it may be nonspecifically elevated as an acute-phase reactant. It is useful only for monitoring response to phlebotomy.

Recommendation 3: Who should be offered genetic testing

Persons of European descent who:

a) Fulfill criteria b) or c) in Recommendation 2.

b) Have one or more first-degree relatives with a confirmed or presumptive diagnosis of hereditary hemochromatosis.

c) Have previously been diagnosed with hemochromatosis, but have not had genetic testing.

Note: Genetic testing for the known HFE mutations is not informative for persons of non-European descent. Such patients should be evaluated by a specialist.

Recommendation 3: Follow-up based on genetic testing

a) If genetic testing confirms the presence of one or more C282Y mutations on the HFE gene, genetic testing should be offered to all first-degree relatives.

b) If genetic testing confirms the presence of two HFE mutations, at least one of which is C282Y*, further management requires a serum ferritin level. If serum ferritin is elevated, proceed to Recommendation 5. If serum ferritin is normal, then manage as follows:

• C282Y/C282Y - homozygotes: Monitor serum ferritin every two years. If ferritin becomes elevated, proceed to Recommendation 5.

• C282Y/H63D - compound heterozygotes: Less than 5 per cent will develop iron overload. Monitor ferritin every 5 years.

• C282Y/Norm - simple heterozygotes: Low risk of developing iron overload. Further ferritin testing is not required.

c) If iron overload is present, but genetic testing does not reveal the cause, then referral to a specialist is appropriate.

* Subjects with H63D/H63D or H63D/Norm are at very low risk of developing iron overload. Ferritin testing is not required and genetic testing of family members is not recommended.

Recommendation 5: : Management of hemochromatosis

Therapeutic phlebotomy is the treatment of choice for HFE-related hereditary hemochromatosis and for non-HFE-related hemochromatosis. Serum ferritin is the preferred method for monitoring response to therapy.

a) Volume and frequency of phlebotomy need to be individualized according to the patient’s age and clinical circumstances. For severely iron overloaded patients, weekly phlebotomy of 500 ml of whole blood should be continued until serum ferritin is less than 50 µg/L. Patients with massive iron overload may require in excess of 100 phlebotomies.

b) Phlebotomy technique important for maintaining venous access.

c) 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, clearly, the frequency of phlebotomy needs to be reduced.

d) Once patients have been successfully depleted of excess iron stores, a program of maintenance therapy should be established. Removal of 500 ml every 2-3 months is usually sufficient. Serum ferritin should be monitored yearly to ensure that it is maintained within the normal range.

e) Patients on maintenance therapy may be eligible to donate to the Canadian Blood Services.

f) 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. (Note: phlebotomy results in formation of new red cells; therefore, HbA1C may underestimate glycemia for up to 3 months after phlebotomy.)

Conditions that often do not improve with phlebotomy include arthropathy, cirrhosis and testicular atrophy.

Rationale

Hereditary hemochromatosis is the most common autosomal recessive genetic disorder in persons of European descent, with an estimated prevalence of 2-5 per 1000. Recent studies suggest that hemochromatosis is under-diagnosed, often misdiagnosed, and under-reported. Iron overload occurs when iron accumulation exceeds physiological requirements leading to deposition of excess iron in tissues. Subsequent parenchymal damage results in organ dysfunction.

Iron overload may result from inherited or acquired disorders. The most common form of inherited iron overload is hereditary hemochromatosis, which results from a mutation on the HFE gene on chromosome 6.

Acquired iron overload includes a variety of clinically distinct syndromes that should be distinguished from hereditary hemochromatosis. A multiply transfused patient is a common example. An increase in absorption of intestinal iron may be promoted by underlying conditions such as anemia from ineffective erythropoiesis, various liver diseases, excessive ingestion of medicinal iron, and congenital atransferrinemia.

The absorption of iron in the intestine is regulated by the body’s iron requirements. A typical diet contains 15 mg iron per day, and in the normal situation, only 1-2 mg is absorbed. In hemochromatosis, regulation of iron absorption is defective, and iron absorption is typically 3-6 mg per day. This equates to excess absorption of about 1 gram per year; consequently it may take 3 decades or more to accumulate the 20-40 grams of total-body iron needed to cause organ damage. Iron loading is even slower in women because of the “protective” effect of menstruation and pregnancy. End organ damage occurs more rapidly in juvenile and childhood forms of hemochromatosis, but these are thought to be caused by defects in genes other than HFE.

Target organ dysfunction may manifest as diabetes, complications of cirrhosis, cardiomyopathy, hypogonadism, arthropathy, or increased skin pigmentation. However, nonspecific symptoms such as arthralgias, fatigue, and abdominal pain may be noted years before organ dysfunction becomes apparent. A review of family-based screening studies reported that 52 per cent of family members in whom hereditary hemochromatosis had been diagnosed by genetic testing were asymptomatic. The other 48 per cent had at least one clinical manifestation of disease such as cirrhosis, skin bronzing, fatigue, weight loss, abdominal pain, or impotence.

Because hemochromatosis can lead to numerous chronic conditions, its symptoms can be confused with those of more common diseases such as alcoholic liver disease, diabetes, and osteoarthritis. If untreated, hemochromatosis can cause serious disease and premature death. Presymptomatic detection and treatment can completely prevent clinical sequelae and, in symptomatic patients, phlebotomy effectively reduces morbidity and mortality.

The availability of biochemical and genetic tests that allow diagnosis of hereditary hemochromatosis in the early stages has increased awareness of the importance of early diagnosis. The relatively high prevalence and low cost of diagnosis and treatment have led to pressure for population screening. Although most reviews have concluded that there is insufficient evidence to warrant population screening at this point, there is widespread consensus that efforts to increase early detection and treatment of hemochromatosis are warranted.

This guideline was developed by the Guidelines and Protocols Advisory Committee, approved by the British Columbia Medical Association and adopted by the Medical Services Commission.

Effective Date: Dec 15, 2006