High Ferritin and Iron Overload – Investigation and Management

Effective Date: June 30, 2021

Recommendations and Topics

• Scope
• Key Recommendations
• Definitions and Clinical Context 
• Signs and Symptoms
• Diagnosis
• Testing for HFE-HH
• Interpreting Results from HFE-HH Testing
• Indications for Specialist Referral 
• Resources

Scope

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.

Key Recommendations*

• Ferritin is an acute phase reactant released by activated macrophages and damaged hepatocytes.
• High ferritin levels are most commonly caused by inflammation, infection, liver disease (particularly non-alcoholic steatohepatitis (NASH)/fatty liver), renal disease, alcohol excess, metabolic syndrome or malignancy. In these cases, a high ferritin level does not accurately reflect iron stores¹
• The first-line investigations for a patient with a raised serum ferritin are:
  • History taking: alcohol intake and other risk factors for liver disease, type 2 diabetes mellitus, obesity, hypertension, symptoms and signs of an underlying inflammatory or malignant disorder, transfusion history, and family history of iron overload.
  • Lab tests: repeat serum ferritin, transferrin saturation (TSAT), complete blood count, serum creatinine, liver enzymes (ALT and GGT) with consideration of viral hepatitis screening and abdominal ultrasonography (if suspected liver disease or elevated liver enzymes). Check blood glucose and lipid studies if not recently performed.
• Hereditary hemochromatosis is an uncommon cause of hyperferritinemia and testing for HFE-HH is not recommended in patients of non-European ancestry because its prevalence is very rare.
• Individuals of East Asian descent have ferritin values 1.5-2x higher than the upper limit of normal reported.
• Iron overload can generally be excluded when TSAT <45%.

_{*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.}

Definitions and Clinical 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:  

• Transfusion-dependent anemias (e.g., myelodysplastic syndromes (MDS), sickle cell anemia)
• Anemia from ineffective erythropoiesis (e.g., thalassemia, MDS)
• Chronic excessive ingestion of medicinal iron
• Hereditary hemochromatosis (HH)

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.

Signs and Symptoms 

Signs and symptoms of high ferritin levels

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.

Signs and symptoms of iron overload

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.

Diagnosis 

Differential diagnosis of high ferritin

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.

Table 1. Causes of raised serum ferritin (adapted from Table 1, Cullis 2018¹)

Not associated with significant iron accumulation	As a result of cellular damage	Due to iron accumulation
Acute and chronic infection  Chronic inflammatory disorders Autoimmune disorders  Malignancies Malignant or reactive histiocytosis Hereditary hyperferritinemia with and without cataracts Gaucher disease	Chronic excess alcohol consumption Liver Diseases including: liver failure, chronic viral hepatitis, alcoholic and non-alcoholic steatohepatitis1	Hereditary hemochromatosis Secondary iron overload from blood transfusion or excessive iron intake/administration Ineffective erythropoiesis: sideroblastic anemia, some myelodysplastic syndromes (e.g., refractory anemia with ring sideroblasts) Thalassemia Other rare genetic disorders

¹May also have iron overloading.

History taking

Key questions to ask in a patient with raised serum ferritin levels:

1. Extent of alcohol intake
2. Risk factors for viral hepatitis (e.g., travel, high risk activities such as intravenous drug use)
3. Signs and symptoms or known inflammatory condition (e.g., rheumatoid arthritis)
4. Signs and symptoms or known malignancy
5. Diabetes mellitus and risk factors
6. Metabolic syndrome (hypertension, diabetes, obesity)
7. History of blood transfusions, specifically, frequency and duration of red cell or whole blood transfusion
8. Family history of iron overload, hemochromatosis, anemia, hemoglobinopathies or other hematological conditions

Initial laboratory investigation

• If the serum ferritin is elevated and there is a potential transient cause (e.g., acute infection, flare of a chronic inflammatory condition), recheck the serum ferritin no earlier than one week after the transient cause has resolved
• Unless recently investigated, the following tests are recommended for patients with an unexplained, persistently elevated serum ferritin level: 
  • TSAT (fasting sample not required)
  • CBC
  • high sensitivity C-reactive protein (only if indicated according to BC Guidelines: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing)
  • serum creatinine
  • ALT and GGT: if elevated, investigate for common causes of hepatitis (e.g., viral, NASH, alcohol)
  • abdominal ultrasound if clinical suspicion for liver disease or liver enzymes are elevated
  • glucose and HbA1C
  • lipid studies
• If TSAT <45%, then iron overload is generally excluded and no follow-up is required. For borderline unexplained levels, there is no urgency to re-check TSAT before 6 months.
• If TSAT >45%, then investigations for causes of iron overload is indicated, unless obvious causes are apparent such as multiple transfusions (see Table 1 and Definitions and Clinical Context – Iron Overload).

Investigations to determine degree of iron overload

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.

Resources

Practitioner Resources 

• BC Children’s Hospital and BC Women’s Hospital (BCCH/BCWH) Department of Pathology and Laboratory Medicine, Division of Genome Diagnostics: genebc.ca
  • Refer to Frequently Asked Questions

Patient, Family and Caregiver Resources

• HealthLink BC: https://www.healthlinkbc.ca/family-and-home
• Canadian Hemochromatosis Society: toomuchiron.ca
• Canadian Blood Services – Information about blood donation for individuals with hemochromatosis: https://www.toomuchiron.ca/support/donating-blood/

How this guideline was developed

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.

References

1. Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW. Investigation and management of a raised serum ferritin. Br J Haematol. 2018;181(3):331–40.
2. Tahmasebi H, Asgari S, Hall A, Higgins V, Chowdhury A, Thompson R, et al. Influence of ethnicity on biochemical markers of health and disease in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2020 Mar 26;58(4):605–17.
3. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005 Apr 28;352(17):1769–78.
4. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatol Baltim Md. 2011 Jul;54(1):328–43.
5. Waalen J, Felitti VJ, Gelbart T, Beutler E. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood. 2008 Apr 1;111(7):3373–6.
6. Lok CY, Merryweather-Clarke AT, Viprakasit V, Chinthammitr Y, Srichairatanakool S, Limwongse C, et al. Iron overload in the Asian community. Blood. 2009 Jul 2;114(1):20–5.
7. Mörwald K, Aigner E, Bergsten P, Brunner SM, Forslund A, Kullberg J, et al. Serum Ferritin Correlates With Liver Fat in Male Adolescents With Obesity. Front Endocrinol. 2020;11:340.
8. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatol Baltim Md. 2012 Jan;55(1):77–85.
9. Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P, et al. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol. 2001 Aug;96(8):2448–55.
10. Guyader D, Jacquelinet C, Moirand R, Turlin B, Mendler MH, Chaperon J, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology. 1998 Oct;115(4):929–36.
11. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43.
12. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans [Internet]. Genomics; 2019 Jan [cited 2020 Jun 5]. Available from: http://biorxiv.org/lookup/doi/10.1101/531210
13. Government of Canada SC. Focus on Geography Series, 2016 Census - Province of British Columbia [Internet]. 2017 [cited 2020 Sep 3]. Available from: https://www12.statcan.gc.ca/census-recensement/2016/as-sa/fogs-spg/Facts-PR-Eng.cfm?TOPIC=7&LANG=Eng&GK=PR&GC=59
14. Guidelines for genetic testing of healthy children. Paediatr Child Health. 2003 Jan;8(1):42–5.
15. Delatycki M, Wolthuizen M, Collins V, Varley E, Craven J, Allen K, et al. Implementation of ironXS: a study of the acceptability and feasibility of genetic screening for hereditary hemochromatosis in high schools. Clin Genet. 2010 Mar;77(3):241–8.
16. Delatycki M, Wolthuizen M, Aitken M, Hickerton C, Metcalfe S, Allen K. To tell or not to tell - what to do about p.C282Y heterozygotes identified by HFE screening: Should HFE p.C282Y heterozygotes be told their genotype? Clin Genet. 2013 Sep;84(3):286–9.
17. Herbert V. Hemochromatosis and vitamin C. Ann Intern Med. 1999 Sep 21;131(6):475–6.

Diagnostic Codes

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

Abbreviations

HFE-HH HFE-associated hereditary hemochromatosis. HFE (high Fe) is the gene most commonly associated with hemochromatosis

NASH non-alcoholic steatohepatitis

TSAT transferrin saturation

Appendices 

• Appendix A – Suggested laboratory thresholds for addition of an abnormal result flag and addition of interpretive comments on ferritin testing (PDF, 91KB)
• Appendix B – Nonspecific signs and symptoms of extreme iron overload by organ (PDF, 91KB)
• Appendix C – Epidemiology of HFE hemochromatosis (PDF, 95KB)
• Appendix D – Scenarios in which genetic testing for HFE-HH is not indicated (PDF, 95KB)
• Appendix E – Laboratory Test Procedures for HFE-HH Testing (PDF, 106KB)
• Appendix F – Management and surveillance of HFE-HH (PDF, 96KB)
• Appendix G – Therapeutic Phlebotomy Using an 18 Gauge Cannula (PDF, 91KB)

Associated Documents 

• BC Guideline: Iron Deficiency – Investigation and Management
• BC Guideline Ultrasound Prioritization
• BC Guideline: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing
• BC Guideline: Viral Hepatis Testing
• Contributors List (PDF, 114KB)

 

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: encourage appropriate responses to common medical situations recommend actions that are sufficient and efficient, neither excessive nor deficient permit exceptions when justified by clinical circumstances Contact Information: Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria, BC V8W 9P1 Email: hlth.guidelines@gov.bc.ca Website:  www.BCGuidelines.ca   Disclaimer 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.