You Make the Call: When would you start phlebotomy for an asymptomatic patient with hemochromatosis?

Paul C. Adams, MD
Professor Emeritus
Western University
Ontario, Canada

CLINICAL DILEMMA

For patients with hemochromatosis, UpToDate recommends phlebotomy when ferritin levels are 1,000 ng/mL or greater, while the American Society of Hematology Self-Assessment Program (ASH-SAP) recommends phlebotomy when ferritin levels are greater than 300 ng/mL in male patients and greater than 200 ng/mL in non-pregnant female patients. Both publications indicate phenotypic manifestations are only 1% to 25% even if they are homozygotes, so my question is, when do we start phlebotomy for asymptomatic patients with hemochromatosis — at a ferritin level of 300 ng/mL or 1,000 ng/mL? Based on UpToDate, it looks like iron overload in the liver and cirrhosis can happen only when ferritin levels are greater than 1,000 ng/mL, so for patients with levels greater than 500 ng/mL, does a liver MRI need to be done? If there is no evidence of transaminase elevation or congestive heart failure and the patient is asymptomatic, when should phlebotomy be done — at a ferritin level of 1,000, 500, or 300 ng/mL? Is there a difference in when to do phlebotomy for heterozygotes versus homozygotes, and is that guideline the same for ferritin levels of 500 ng/mL or 1,000 ng/mL?

EXPERT OPINION

There are many facets to the multiple questions in this month’s clinical dilemma, so I will answer from multiple perspectives.

Patient Perspective

The patient’s perspective is the most important, and this simple fact can be forgotten. Patient-centered outcomes are an important aspect of clinical trials and drug assessments by the U.S. Food and Drug Administration (FDA). Most patients want treatment, and they want more of it than the doctor recommends. In my experience, most patients like phlebotomy treatment. The dedicated phlebotomy clinic is a friendly place that knows how to spell and treat their disease. Patients often meet other families who have been affected, and for older patients it is a day out on the town. (The only complaint we often get is hospital parking fees.) This is one area where voluntary blood donation as treatment has an advantage; the other is extended hours.

Physician Perspective

Why do some guidelines recommend treatment at 200 to 300 ng/mL, while other experts suggest waiting until the ferritin is greater than 1,000 ng/mL? The threshold of 1,000 ng/mL has been well validated to predict the risk of cirrhosis of the liver.^1,2 If you wait for that to happen, you have missed an opportunity to prevent cirrhosis. You should not wait for abnormal liver enzymes. Most C282Y homozygotes have normal liver enzyme levels,³ which is why screening in liver clinics has been low yield. Silent fibrosis has been reported in 18% of referred patients with normal AST and ALT and fibrosis or cirrhosis on liver biopsy.⁴ The objective of treating lower values of ferritin is to prevent the development of liver fibrosis and cirrhosis, which also prevents hepatocellular carcinoma.⁵ However, a new piece of this puzzle is the observation in untreated C282Y homozygotes that many do not have a rising ferritin over time, so they may never reach 1,000 ng/mL.^6-10 This pattern is more common in women.

I find it useful to observe a change in serum ferritin over a few months while other investigations are in progress (e.g., abdominal ultrasound, investigations of siblings, genetic counseling). If the ferritin has risen over several months, it is a sign that accumulation is in progress. If the ferritin is similar or falling, this patient could be further observed without treatment. The initial serum ferritin should also be interpreted in the context of the patient’s age and gender. An 80-year-old woman with a ferritin of 300 ng/mL may never need treatment, whereas a 22-year-old man with a ferritin of 500 ng/mL that has risen to 800 ng/mL over six months is a treatment candidate. This “slope” of ferritin rise over time is also useful to predict the need for maintenance therapy, which many patients do not need after iron depletion.⁹ You could consider a liver MRI in your patient at baseline for data on iron overload, fibrosis, fat, and potential tumors since they exclude iron. In practice, ultrasound would be a more common initial test. You do not need to do an MRI to determine whether iron overload is present in a C282Y homozygote with an elevated serum ferritin since the pre-test probability of having iron overload is high because of the typical genetic test.¹¹ The MRI liver iron becomes of greater value in the assessment of high ferritin with a normal genetic test, or serial assessment of a chelation patient with thalassemia.

In a patient with a mild ferritin elevation who is asymptomatic, a good compromise is to suggest voluntary blood donation four to six times per year, as allowed by your country’s regulations. Some patients are interested in being bled to a very low serum ferritin. The guidelines suggested bleeding until the serum ferritin is 50 ng/mL; this number was chosen because it was anticipated that many C282Y homozygotes would start re-accumulation of iron and move through the normal range. We know now that many patients are not starting to re-accumulate iron¹² and may have to be brought back to the baseline they were in during childhood, so it may take many years to reach their presenting serum ferritin again. Intensive phlebotomy therapy to a ferritin of 20 ng/mL and the lowering of serum transferrin saturation requires close monitoring and testing to avoid iron deficiency. C282Y heterozygotes and compound heterozygotes (C282Y/H63D) may have an elevated serum ferritin, but it is often mild, and these patients can be encouraged to be blood donors.

Public Policy Perspective

Guideline development in this field has been challenging.¹³ Most patients in the general population with an elevated serum ferritin do not have iron overload or hemochromatosis. The most common setting for an elevated serum ferritin is metabolic syndrome, often accompanied by fatty liver. A French study showed that only 25% of patients having phlebotomy for hemochromatosis were C282Y homozygotes.¹⁴ Randomized trials in hemochromatosis have been rare. It has been difficult to blind for placebo treatment effects, and some investigators feel that beneficial effects of iron depletion have been clearly established. The new information that progressive iron accumulation is not inevitable in C282Y homozygotes has led to a re-evaluation of the need for treatment in mildly ​affected patients. An Australian study used erythrocytapheresis¹⁵ and randomized patients with or without an iron removal filter to evaluate 35 measures. They found fatigue had a 6.3% improvement with iron removal, and F2-isoprostane, an oxidative stress molecule, was reduced in the urine with iron removal. The patients had mild disease and most measures did not change.

There are several new therapies in development, including synthetic mini-hepcidins,¹⁶ which decrease intestinal iron absorption, and oral compounds that can bind dietary iron.^17,18 Neither treatment mobilizes existing tissue iron like phlebotomy, so they are being developed for maintenance therapy. There could be a time when these treatments will need to undergo a registration trial against phlebotomy therapy, and ideally, there would be a third group of no treatment. This could provide meaningful information to guide future therapeutic recommendations and guidelines on the need for maintenance therapy.

References

1. Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology. 1998;115(4):929-936. 
2. Beaton M, Guyader D, Deugnier Y, Moirand R, Chakrabarti S, Adams P. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology. 2002;36(3):673-678. 
3. Adams PC, Speechley M, Barton JC, McLaren CE, McLaren GD, Eckfeldt JH. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study. Hepatology. 2012;55(6):1722-1726. 
4. Beaton M, Adams PC. Assessment of silent liver fibrosis in hemochromatosis C282Y homozygotes with normal transaminase levels. Clin Gastroenterol Hepatol. 2008;6(6):713-714. 
5. Bardou-Jacquet E, Morandeau E, Anderson GJ, et al. Regression of fibrosis stage with treatment reduces Long-term Risk of liver cancer in patients with hemochromatosis caused by mutation in HFE. Clin Gastroenterol Hepatol. 2020;18(8):1851-1857. 
6. Adams PC, Reboussin DM, Barton JC, et al. Serial serum ferritin measurements in untreated HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study. Int J Lab Hematol. 2008;30(4):300-305. 
7. Yamashita C, Adams PC. Natural history of the C282Y homozygote for the hemochromatosis gene (HFE) with a normal serum ferritin level. Clin Gastroenterol Hepatol. 2003;1(5):388-391. 
8. Adams PC. The natural history of untreated HFE-related hemochromatosis. Acta Haematol. 2009;122(2-3):134-139. 
9. Adams PC, Kertesz AE, Valberg LS. Rate of iron reaccumulation following iron depletion in hereditary hemochromatosis. Implications for venesection therapy. J Clin Gastroenterol. 1993;16(3):207-210. 
10. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: iron overload progression rate. Blood. 2004;103(8):2914-2919. 
11. McGrath JS, Deugnier Y, Moirand R, Jouanolle AM, Chakrabarti S, Adams PC. A nomogram to predict C282Y hemochromatosis. J Lab Clin Med. 2002;140(1):6-8. 
12. Coutinho MP, Teles MJ, Melo G, et al. Ferritin increase in hemochromatosis subjects after discontinuing their regular maintenance treatment: a longitudinal analysis performed during the COVID-19 imposed hospital lockdown. Hemasphere. 2022;6(9):e770. 
13. European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77(2):479-502. 
14. Le Gac G, Scotet V, Gourlaouen I, et al. Prevalence of HFE-related haemochromatosis and secondary causes of hyperferritinaemia and their association with iron overload in 1059 French patients treated by venesection. Aliment Pharmacol Ther. 2022;55(8):1016-1027. 
15. Ong SY, Gurrin LC, Dolling L, et al. Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial. Lancet Haematol. 2017;4(12):e607-e614. 
16. Katsarou A, Pantopoulos K. Hepcidin Therapeutics. Pharmaceuticals (Basel). 2018;11(4):127. 
17. Buerkli S, Salvioni L, Koller N, et al. The effect of a natural polyphenol supplement on iron absorption in adults with hereditary hemochromatosis. Eur J Nutr. 2022;61(6):2967-2977. 
18. Qian J, Sullivan BP, Peterson SJ, Berkland C. Nonabsorbable iron binding polymers prevent dietary iron absorption for the treatment of iron overload. ACS Macro Lett. 2017;6(4):350-353. 

NEXT MONTH'S CLINICAL DILEMMA

A patient of mine underwent a matched unrelated donor allogeneic hematopoietic cell transplant for B-cell acute lymphoblastic leukemia about 10 years ago and has a long history of chronic graft-versus-host disease (cGVHD) of the lung. His treatment regimen for the past year has been tacrolimus, ruxolitinib, and belumosudil, along with FAM (inhaled fluticasone, azithromycin, and montelukast). At this point, he has end-stage lung cGVHD, is on 3 L of oxygen by nasal cannula, and is homebound.

In the past he was treated with corticosteroids, ibrutinib, and etanercept. He was also treated with extracorporeal photopheresis for a long time, but this was no longer feasible due to insurance coverage and the distance from his home to the clinic. Recently, his lung GVHD has worsened in terms of hypoxia, and he has declined hospice care. My questions are:

• Is there a role of the combined use of ruxolitinib and belumosudil?
• Is there a suggestion for a different treatment regimen for lung cGVHD?
• Is there a role for lung transplant with severe lung cGVHD?

How would you respond? Email us at [email protected].

Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.