Juvenile hemochromatosis: HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

Abstract

Juvenile hemochromatosis (JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation (g.47G>A), treated with phlebotomies and deferasirox. She presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin (SF): 5696 ng/mL, transferrin saturation (TS): 85%]. After sessions of phlebotomies (450 mL every 15 d), the patient presented partial symptomatic improvements and biochemical parameters (SF: 1000 ng/mL, Hb: 11 g/dL). One year later, deferasirox (15 mg/kg per day) was introduced to the treatment, and the patient showed total symptomatic improvement, with significant clearing of the skin, SF: 169 ng/mL, and TS: 50%. Furthermore, after the combined deferasirox-phlebotomy therapy, magnetic resonance imaging measurements revealed normalized level for liver iron (30 μmol/g; reference value < 36 μmol/g). In conclusion, combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

Key Words: Genetic disease; Juvenile hemochromatosis; HAMP gene; Mutation; Iron chelation

Core tip: A 29-year-old Brazilian woman, from a city in the countryside of the State of Bahia, Brazil, was referred to our service in 2015 because of a hepatomegaly clinical condition, detected by imaging exam. This case study reports a patient with juvenile hemochromatosis condition due to HAMP mutation (g.47G>A) treated with phlebotomies and deferasirox, which were able to normalize iron levels and improve symptoms.

INTRODUCTION

Juvenile hemochromatosis (JH), also known as type 2 hemochromatosis, is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage, hypogonadotropic hypogonadism, cardiac diseases and endocrine dysfunctions. JH is subdivided into two groups: Type 2A (associated to HJV - hemojuvelin gene mutation) and type 2B (associated to HAMP - hepcidin gene mutation). Both genes are involved in the production of hepcidin, a peptide that regulates iron homeostasis by adjusting its absorption and storage. HJV and HAMP mutations, therefore, lead to decreased hepcidin levels, and consequently to iron overload in the body[1-3].

CASE REPORT

A 29-year-old Brazilian woman, from a city in the countryside of the State of Bahia, Brazil, was referred to our service in 2015 because of a hepatomegaly clinical condition, detected by imaging exam. In the anamnesis, symptoms such as weakness, skin hyperpigmentation and joint pain in the shoulders and hands were observed. The patient had reported amenorrhea since she was 25 years old, whereas transvaginal ultrasound showed uterus and ovaries were not developed. She also reported that her father died before the age of 50 because of non-alcoholic cirrhosis and diabetes. Furthermore, one of her three brothers, who was 31 years old, died because of the same reported father diseases. The patient’s other two brothers, on the other hand, are healthy.

The patient’s first laboratory tests results were: Serum ferritin (SF) of 5696 ng/mL, transferrin saturation (TS) of 85%, hemoglobin (Hb) of 13.3 g/dL, international normalized ratio of 1.3, aspartate transaminase of 91 U/L, alanine transaminase of 69 U/L, alkaline phosphatase of 288 U/L, gamma-glutamyl transferase of 84 U/L, blood glucose of 72 mg/dL, creatinine of 0.7 mg/dL and albumin of 4.3 g/dL. Her echocardiogram was normal and secondary causes of iron overload (hepatitis, chronic hemolysis, oral or parenteral iron overload, metabolic syndrome and alcohol abuse) were excluded. Genetic analysis for mutations in the HFE gene (p.C282Y, p.H63D and p.S65C) revealed a heterozygous genotype for the p.H63D. Taking in account the patient’s age and the absence of relevant genetic alteration for hereditary hemochromatosis (HH), the HJV (exons 1-4) and HAMP (exons 1-3) genes were sequenced[4], as iron overload in a young individual who presents endocrine dysfunctions is suggestive of a JH diagnosis. The HAMP sequencing revealed the homozygous genotype for the mutation 5′-UTR G>A at position +14 (g.47G>A), confirming the prior suspicious.

In January 2015, the patient started phlebotomies of 450 mL every 15 d. After 12 mo of treatment, there was partial improvement of weakness, skin hyperpigmentation and joint pain symptoms. In addition, the hemoglobin level was never below 11 g/dL and, despite an observed decrease in ferritin level, the values were always above 1000 ng/mL. In January 2016, deferasirox (15 mg/kg per day) was introduced to the treatment, concomitantly with the phlebotomies. No side effects were observed and the serum creatinine values remained normal. In September 2016, the patient showed total symptomatic improvement, with significant clearing of the skin, SF values of 169 ng/mL and TS of 50%. The study protocol was approved by the Ethics Committee of Hospital das Clinicas (HC) of University of Sao Paulo Medical School (FMUSP), Brazil, and consent was obtained from the participants prior to entering the study.

DISCUSSION

When compared with HFE-hemochromatosis, the frequency of the JH condition with HAMP gene mutation is considered very rare. However, some cases were reported[5,6]. Here, we report one case of a Brazilian patient with JH condition due to HAMP mutation (g.47G>A), first identified in a Portuguese family[7]. She presented significant improvement of symptoms through combined treatment with deferasirox and phlebotomies.

Phlebotomy is the choice treatment for hemochromatosis. However, iron chelator has been suggested as an alternative treatment option for iron overload, especially when patients have severe iron overload, did not have tolerance to phlebotomies or where it is contraindicated. The dose used in the present case report was previously evaluated in hemochromatosis patients[8]. Cançado et al[9] (2015) evaluated the efficacy and effectiveness of deferasirox (doses of 5-10 mg/kg per day) for treatment of hemochromatosis patients. They showed that chelation was safe and effective[9].

It is possible to estimate the quantity of liver iron removed using magnetic resonance imaging (MRI) measurements (given as mg of Fe/g of liver). Santos et al[10] (2010) performed a study that measured liver iron concentration before and after combined deferasirox-phlebotomy treatment. They observed that approximately two-thirds (5.55 g) of the iron removed from the liver could be attributed to the action of deferasirox[10]. In the present case, however, we were not able to perform MRI measurements before and after inclusion of the deferasirox as an adjuvant. Nevertheless, we estimated that phlebotomies were able to remove approximately 8.0 g of liver iron (40 phlebotomies and about 200 mg Fe/phlebotomy) in 20 mo. After this period of combined therapy, the MRI showed normal value for liver iron of 30 μmol/g (reference value < 36 μmol/g).

In conclusion, combined deferasirox-phlebotomy treatment was able to promote decrease and normalization of iron levels, besides significant symptomatic improvements.

ACKNOWLEDGMENTS

We mostly thank the participants of the study. We are also thankful for the technical assistance provided by the staff of the Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor).

COMMENTS

Case characteristics

A 29-year-old Brazilian woman, with non-alcoholic cirrhosis and diabetes in the familiar medical history, presented symptoms such as weakness, skin hyperpigmentation, joint pain in the shoulders and hands and amenorrhea.

Clinical diagnosis

HAMP sequencing indicated juvenile hemochromatosis (JH) condition due to g.47G>A mutation.

Differential diagnosis

Patient’s age (29) and absence of relevant genetic alteration for hereditary hemochromatosis (HH) led to sequencing of HJV (exons 1-4) and HAMP (exons 1-3) genes, as iron overload in a young individual who presents endocrine dysfunctions is suggestive of a JH diagnosis.

Laboratory diagnosis

Laboratory tests indicated altered iron biochemical parameters: SF = 5696 ng/mL and TS = 85%.

Treatment

Patient’s treatment was performed with phlebotomies (450 mL every 15 d) for 20 mo, and the iron chelator deferasirox (15 mg/kg per day) was introduced as adjuvant in the last 8 mo of treatment.

Related reports

The dose used in the present case report was previously evaluated in hemochromatosis patients. Cançado et al (2015) evaluated the efficacy and effectiveness of deferasirox (doses of 5-10 mg/kg per day) for treatment of hemochromatosis patients. They showed that chelation was safe and effective. Besides that, Santos et al (2010) performed a study that measured liver iron concentration before and after combined deferasirox-phlebotomy treatment. They observed that approximately two-thirds (5.55 g) of the iron removed from the liver could be attributed to the action of deferasirox.

Experiences and lessons

Phlebotomy is the choice treatment for hemochromatosis. However, iron chelator has been suggested as an alternative treatment option for iron overload, especially when patients have severe iron overload, did not have tolerance to phlebotomies or where it is contraindicated.

Peer-review

In the present case, we have reported a clinical case of a patient with a very rare disorder: juvenile hemochromatosis due to HAMP mutation (g.47G>A). The authors presented a successful combined therapy for the iron overload and symptoms caused by the JH condition, performed with the conventional phlebotomies and the iron chelator deferasirox as an adjuvant.