GENETIC TESTING FOR HEREDITARY HEMOCHROMATOSIS

Hereditary Hemochromatosis is one of the most common genetic diseases in individuals of northern European descent, affecting one in every 200-400 persons. It is an autosomal recessive disorder of iron metabolism that leads to iron accumulation in a variety of organs, eventually resulting in organ failure. Symptomatic disease typically presents after the age of 50 and is more common in males. The lower incidence in women is partially attributable to the protective effects of menstrual blood loss and pregnancy. Early signs and symptoms may be vague and are easily overlooked. The classical findings of bronzing of the skin, cirrhosis and diabetes are associated with marked iron accumulation, usually greater than 10,000 mg/ g dry weight in liver biopsies.

A number of mutations have been discovered in the hemochromatosis (HFE) gene. Two mutations, C282Y and H63D, are responsible for the majority of patients of European ancestry with hereditary hemochromatosis. Homozygosity for the C282Y mutations accounts for up to 90% of cases with an estimated penetrance (as indicated by iron studies) of 95% for men and 70% for women over 40 years. Compound heterozygosity for the C282Y and H63D mutations has been described in some patients, but with a much lower penetrance. Significant iron overload is rare in homozygotes for H63D, heterozygotes for C282Y or H63D, or in other mutations. In these mutations, however, iron overload may occur in the setting of another risk factor, such as hepatitis. Mutations at other sites or in other genes may cause hemochromatosis in non-European patients.

The recommended initial test for patients suspected of having hereditary hemochromatosis is the fasting transferrin saturation (fTS). Genetic testing should be restricted to patients with persistently elevated results (see algorithm) and to family members of known cases. At MDS Metro, patient DNA is assayed for the C282Y and H63D point mutations in the hemochromatosis gene by polymerase chain reaction (PCR), and digestion using restriction enzymes. Sensitivity and specificity for detection of these mutations are 99.9%.

Signs and symptoms of hereditary hemochromatosis:

• Arthritis, Arrhythmia
• Bronzing or graying of the skin
• Cirrhosis
• Diabetes
• Enlarged liver
• Fatigue
• Heart disease, Hypopituitarism
• Impotence
• Jaundice
• Liver cancer
• Menstrual irregularities

Points To Remember:

• Many cases of iron overload are not HFE-related:
  - Liver disease is the principal cause with viral hepatitis and ethanol as the most common etiologies.
• Routine screening for hemochromatosis is not recommended.
• Before requesting genetic testing for Hemochromatosis screening tests fasting transferrin saturation should be performed. If clinically indicated, liver enzymes should be ordered.
• The genetic test looks for two types of HFE mutations – C282Y and H63D. The current consensus is that only homozygosity for C282Y and compound heterozygosity for C282Y/H63D are indicative of hereditary hemochromatosis.
• Once the molecular diagnosis of hereditary hemochromatosis is made, surveillance of iron status by serum ferritin is recommended for asymptomatic individuals in order to detect iron overload early.
• If a patient has iron overload and no HFE mutations:
  - Rare mutations of other iron-related genes may be involved.
  - Other causes of iron overload should be excluded.

Requisition forms for genetic testing can be ordered on our Clinic & Physician Supply Requisition or by calling 604-412-4481. Please provide the results of transferrin saturation on the form.

References:

1. Guidelines and Protocols Advisory Committee. Investigation and management of iron overload. 2001.
2. Basett ML. Analysis of the cost of population screening for hemochromatosis using biochemical and genetic markers. J Hepatol 1997; 27:517-524.
3. Beutler C. The significance of the 187G (H63D) mutation in hemochromatosis. Am J Hum Genet 1997; 61:762-764.
4. Beutler E, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 1996; 22:187-194.
5. Beutler E, et al. Penetrance of 845G®ðA (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002 Jan; 359:211-8.
6. Edwards CQ, et al. Screening for hemochromatosis: phenotype versus genotype. Sem Hemat 1998; 35:72-76.
7. Moirand R, et al. Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med 1997; 127:105-110.
8. Mura C, et al. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 1999 Apr 15; 93.
9. Harrison H., et al. Hemochromatosis; common genes, uncommon illness? Canadian Family Physician 2002; Aug. 48: 1326-33.
10. Adams PC. Population screening for haemochromatosis. Gut. 2000; 43:301-03.
11. Krikler SH. Prevalence of iron overload in the Lower Mainland of British Columbia. BC Medical Journal. 2002. March 44: 80-82
12. Whittington, C. Genetics of hereditary hemochromatosis. BC Medical Journal. 2002. Dec. 44:544-46.

ALGORITHM FOR HEMOCHROMATOSIS TESTING

INFORMATION ON LABORATORY REQUISITION FORMS

Ordering physicians are reminded of the importance of providing complete patient identification on the requisition when ordering laboratory tests. Laboratory Accreditation Standards require adequate patient identification, including patient name, date of birth, test(s), and the name of the physician requesting the testing. For specimens collected in the office, specimen source, the time and date of collection should be recorded. In all cases, providing clinical information assists in the interpretation of test results.

Please be informed that commencing on January 15, 2003, a comment will appear on patient reports when requisitions are received at MDS Metro with incomplete or no patient identification. We will continue to contact physicians’ offices to verify patient information as part of our standard operating procedure.

If you require clarification, please contact our Client Services Department at 604-431-5005 or 1-800-663-9422.

MDS METRO'S ROLE AS COURIER OF SPECIMENS TO OUTSIDE INSTITUTIONS AND REFERRAL AGENCIES

MDS Metro provides courier pick up services at many physicians’ offices and clinics across the province.

When we pick up specimens destined for testing at MDS Metro, we also pick up and transport specimens for testing at other agencies like the BC Centre for Disease Control, BC Cancer Agency and numerous hospitals. We provide this additional service at no charge to the sender, recipient or patient.

Every year, we transport hundreds of thousands of these kinds of specimens, and while we are pleased to provide this service, it is simply a transport service.

Physicians and Medical Office Staff

If you have any questions about tests performed at a facility other than MDS Metro, please contact that facility or agency directly. We do not have access to the status of testing, or to test results. If you aren’t sure which agency is doing the test(s), we would be pleased to provide you with that information.

Other Testing Facilities

If you require additional information about a specimen, such as diagnosis or patient demographics, we ask that you contact the ordering physician’s office directly.

Thank you for your cooperation.

MDS METRO WELCOMES DR. EKRAM ZAYED

MDS Metro is pleased to announce the arrival of Dr. Ekram Zayed, a hematopathologist based in our Victoria Reference Laboratory. Dr. Zayed comes from Halifax where he was the Chief of Service, Division of Hematopathology at the Queen Elizabeth II Health Science Centre and Dalhousie University. Dr. Zayed was also a Professor in the Department of Pathology and the Program Director for Hematopathology Residency Training program at Dalhousie. Dr. Zayed obtained his medical degree in Alexandria, Egypt, completed his residency training in Ottawa, Ontario and obtained his Canadian fellowship in 1982.

Dr. Zayed is looking forward to serving the medical community on Vancouver Island. He can be reached at 250-881-3109. He is very interested in hearing from clinicians, particularly if you have any comments or suggestions in relation to the diagnostic hematology services provided by MDS Metro on Vancouver Island.

BURNABY REFERENCE LABORATORY RECEIVES CAP ACCREDITATION

We are pleased to announce that our Burnaby Reference Laboratory was inspected and reaccredited by the College of American Pathologists in October 2002. It is one of the few medical laboratories in Canada to achieve this accreditation status.