Effective Date: June 30, 2021
This guideline is directed to primary care practitioners who encounter an unexplained finding of high ferritin in an adult outpatient aged >19 years. It provides recommendations for the investigation of high ferritin levels (hyperferritinemia), outlines common causes of hyperferritinemia and gives practitioners guidance on when to investigate for and treat hereditary hemochromatosis.
The guideline is not for screening for iron overload.
Hemochromatosis caused by mutations in iron-related genes other than HFE is outside the scope of this guideline. HFE (high Fe) is the gene most commonly associated with hemochromatosis. Because the non-HFE hereditary hemochromatosis causes of hyperferritinemia are so diverse, their management is out of scope. They should be managed according to the underlying condition.
*The key recommendations are adapted from the 2018 British Journal of Hematology Guideline Investigation and management of a raised serum ferritin1 and modified to fit the BC primary care context.
Hyperferritinemia: occurs when a patient’s serum ferritin is above the upper reference interval. The upper reference interval varies with age, gender, and laboratory method. Individuals of East Asian descent have ferritin values 1.5-2x higher than the reference norms reported.2 Refer to Appendix A: Suggested laboratory thresholds for addition of an abnormal result flag and addition of interpretive comments on ferritin testing. High ferritin alone does not indicate iron overload.
Iron overload: occurs when iron absorption exceeds physiological requirements, leading to excess stores because there is a limited physiological capacity (i.e., blood loss) to get rid of excess iron. This is indicated by TSAT >45% and can occur from:
HFE-associated Hereditary Hemochromatosis (HFE-HH): is an autosomal recessive genetic disorder common in individuals of European ancestry, in which an increase in the intestinal absorption of iron leads to excessive iron deposits in organs such as liver, pancreas, heart, pituitary, testicles, joints, and skin. Early detection and treatment can completely prevent clinical sequelae, and, in symptomatic patients, phlebotomy effectively reduces morbidity and mortality..3,4
HFE-HH has a relatively low clinical penetrance, with fewer than 10% of those homozygous for the C282Y variant (the most common mutation) developing clinical manifestations, which usually present by age 40-50 in men and age 50-60 in women (Appendix B: Nonspecific signs and symptoms of extreme iron overload by organ).5 Liver impairment is the most common presentation. Nonspecific symptoms such as arthralgias, fatigue, and abdominal pain may be noted years before organ dysfunction becomes apparent. If untreated, iron overload can cause serious organ damage and premature death but end-organ damage is rare with a ferritin value < 600 μg/L.
Over 80% of HFE-HH is due to homozygous mutation for C282Y in the HFE gene.3,4 Hemochromatosis caused by mutations in other iron-related genes are rare and are outside the scope of this guideline.6 Suspected cases should be referred to a specialist. Information on the epidemiology of HFE-HH is provided in Appendix C: Epidemiology of HFE hemochromatosis.
The signs and symptoms of high ferritin are due to the underlying conditions (e.g., infection) and not due to the high ferritin in and of itself.
Iron overload is often missed because its symptoms are nonspecific and gradual multiorgan damage occurs over many years. Its symptoms can mimic those of much more common diseases, such as alcoholic liver disease, diabetes, and osteoarthritis.
Nonspecific symptoms of extreme iron overload are provided in Appendix B: Nonspecific signs and symptoms of extreme iron overload by organ. Iron overload does not cause a high hemoglobin.
This may include inflammatory disorders, liver disease (particularly non-alcoholic steatohepatitis (NASH)/fatty liver), alcohol excess, malignancy, renal failure, and metabolic syndrome, which are each more common than hemochromatosis.1 Fatty liver is a very common cause of high ferritin in out-patients.7–9
Extreme hyperferritinemia >3000 µg/L can be seen in transfusional iron overload, severe liver disease, hemophagocytic syndromes, renal failure, sepsis, severe inflammation and other severe illnesses, typically in a hospital setting.
In patients with serum ferritin levels >10,000 µg/L, acute hepatitis and rare conditions such as adult onset Still disease, hemophagocytic lymphohistiocytosis and hematological malignancies should be considered.
|Not associated with significant iron accumulation
|As a result of cellular damage
|Due to iron accumulation
1May also have iron overloading.
Key questions to ask in a patient with raised serum ferritin levels:
In some cases, patients may need additional testing to confirm or rule out iron overload, which may include MRI of the heart or liver. This is arranged by a specialist and the specific MRI protocols to assess for iron are not widely available.
Genetic testing for HFE-HH is indicated in patients of European descent with a persistently elevated serum ferritin AND TSAT >45%. The tests that the laboratory will perform for each indication are described in Appendix E: Laboratory Test Procedures for HFE-HH Testing. The patient can go to any collection laboratory. Identification of HH through genetic testing will eliminate the need for liver biopsy in those with TSAT > 45% and provides diagnosis confirmation prior to initiation of phlebotomy.
HFE-HH testing is not recommended for individuals of East and South Asian descent, or those of other non-European ancestries, because HFE-HH is extremely rare in these groups. Further information on non-indications for testing HFE-HH is provided in Appendix D: Whom not to perform genetic testing for HFE-HH.
Individuals who have previously been treated for HFE-HH should be offered genetic testing if not already performed. For ordering guidance, see BCCH/BCWH Division of Genome Diagnostics webpage (www.genebc.ca) under frequently asked questions.
The following table outlines the appropriate settings for testing for HFE-HH and how to fill out the laboratory requisition. Checking the specific categories in the laboratory requisition facilitates appropriate genetic testing.
Testing for patients with clinical features of iron overload
|Indication for HFE-HH Genetic Testing
|How to fill out the standard out-patient laboratory requisition‡
|Individuals of European ancestry with raised ferritin and TSAT ≥45%
|Under HFE-Hemochromatosis, check off "Confirm diagnosis"
Cascade testing for a patient with family history of hemochromatosis
|Indication for HFE-HH Genetic Testing
|How to fill out the standard out-patient laboratory requisition‡
Patient has a child with C282Y;C282Y HFE genotype
Adult patient with family history of hemochromatosis (genotype of relative is unknown or not HFE C282Y;C282Y)
Under HFE-Hemochromatosis, check off "Confirm diagnosis"
|Adult patient’s sibling or parent has confirmed C282Y;C282Y HFE genotype
|Under HFE-Hemochromatosis, check off "Sibling/parent is C282Y/C282Y homozygote"
|Patient < 19 years old with family history of hemochromatosis
|See Appendix D: Scenarios in which genetic testing for HFE-HH is not indicated
‡ The standard out-patient laboratory requisition (SOPLR) is available from: gov.bc.ca/assets/gov/health/forms/1901fil.pdf
Genetic counselling, patient education, and testing of first-degree relatives should be performed by the primary care practitioner. Refer to Frequently Asked Questions at genebc.ca for more information. Most genetics clinics do not accept referrals for HFE-HH genetic counselling.
Patients with hyperferritinemia, TSAT > 45% and genetic testing confirming C282Y homozygosity have a diagnosis of HFE-HH. Most will require reduction of their iron stores with a phlebotomy program (can be supplemented by regular blood donation) (see Appendix F: Management and surveillance of HFE-HH). Good phlebotomy technique is important for maintaining venous access long term (see Appendix G: Therapeutic Phlebotomy Using an 18 Gauge Cannula). 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 > 1,000 µg/L should have liver function tests because of the increased risk of cirrhosis and hepatoma.10 Management and surveillance of patients with a diagnosis of HFE-HH are provided in Appendix F: Management and surveillance of HFE-HH.
Patients heterozygous for HFE C282Y are most often asymptomatic carriers. However, they may have a clinical phenotype of HH due to co-inheritance of other genetic factors (e.g., another mutation such as H63D in the same gene, or a co-inherited mutation in another gene), and/or other comorbidities (e.g., alcohol use disorder, hepatitis C).8 If the clinical phenotype strongly suggests HH, refer to a specialist to consider hepatic iron studies and/or need for additional genetic investigations. In majority of these cases, genetic testing will not affect clinical management.
The following patients should be referred to a specialist (i.e., general internist, gastroenterologist/hepatologist or hematologist) for further investigations or management:
History containing clinical features suggestive of iron overload and results from first line investigations indicated above. Genetic studies and family history should be included if available.
This guideline was adapted from the British Journal of Hematology Guideline Investigation and management of a raised serum ferritin1 to fit the BC primary care context. The working group included representatives of family medicine, hematology, gastroenterology, radiology, medical biochemistry and molecular genetics. We added guidance on diagnosis and management of hereditary hemochromatosis, based on the BC Guideline HFE-Associated Hemochromatosis Investigations and Management (2013).
For more information about how BC Guidelines are developed, please refer to the GPAC Handbook.
257.0 Disorders of iron metabolism
275.01 Hereditary hemochromatosis
275.02 Hemochromatosis due to repeated red blood cell transfusions
275.03 Other hemochromatosis
275.09 Other disorders of iron metabolism
HFE-HH HFE-associated hereditary hemochromatosis. HFE (high Fe) is the gene most commonly associated with hemochromatosis
NASH non-alcoholic steatohepatitis
TSAT transferrin saturation
This guideline is based on scientific evidence current as of the Effective Date.
This guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with the Provincial Laboratory Medicine Services, and adopted under the Medical Services Act and the Laboratory Services Act.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.
THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
The principles of the Guidelines and Protocols Advisory Committee are to:
Guidelines and Protocols Advisory Committee
PO Box 9642 STN PROV GOVT
Victoria, BC V8W 9P1
The Clinical Practice Guidelines (the guidelines) have been developed by the guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.