Hyperammonemia and acute liver failure associated with deferasirox in two adolescents with sickle cell disease.

Chronic red blood cell transfusion therapy (CRTT) prevents strokes and silent cerebral infarcts (SCIs) in children with sickle cell disease (SCD).1 Deferasirox, a once-daily oral iron chelator, is used to manage transfusion-related iron overload. Hyperammonemia and acute liver failure (ALF) have occurred in deferasirox-treated children with transfusion-dependent thalassaemia (TDT).2-5 We report two deferasirox-treated teens with SCD who developed hyperammonemia and ALF. One recovered, while the other died. Patient 1 (P1), a 14-year-old male with haemoglobin (Hb) S-β0 thalassaemia, moyamoya and SCIs, was initiated CRTT in 2012 (age 9 years). Deferasirox (Exjade, 25 mg/kg/day) was started in 2014 (ferritin 2232 ng/mL), held in 2015 (ferritin <500 ng/mL) and restarted in 2016 (ferritin 1050 ng/mL). Disease management was switched to erythrocytapheresis in 2016 (ferritin 694 ng/mL). Deferasirox (Jadenu, 23 mg/kg/day) was continued. At his second erythrocytapheresis, ferritin was 43 ng/mL. Transaminases were normal. Seven days after erythrocytapheresis, he developed vomiting, diarrhoea and confusion. Pupils were reactive and strength was normal. Glasgow coma scale (GCS) was 9, and he was intubated. Deferasirox was discontinued. Initial brain MRI was unremarkable, but MRI 24 hours later demonstrated cortical and deep grey matter diffusion restriction. Lumbar puncture was non-diagnostic. Plasma ammonia was 196 and 299 mcmol/L at 12 and 24 h. Sodium benzoate/sodium phenylacetate, arginine and intravenous 10% dextrose and intralipids were initiated, with a decline to 76 mcmol/L by 36 h. He had ALF and lactic acidosis (Figure 1), which gradually improved along with his mental status. He was extubated on day 7 and discharged on day 20 on sodium phenylbutyrate, arginine and protein restriction. After metabolic and genetic evaluations ruled out urea cycle disorders, these were discontinued. Hyperammonemia has not recurred, and ferritin remains <130 ng/mL on erythrocytapheresis without chelation. Patient 2 (P2), a 15-year-old female with Hb SS, SCIs and acute chest syndrome despite hydroxyurea, was initiated CRTT and stopped hydroxyurea in 2015 (age 12 years). Deferasirox (Jadenu, 19 mg/kg/day) was initiated in 2016 (ferritin 1564 ng/mL) and increased to 24 mg/kg/day (ferritin 2017 ng/mL). Transaminases were normal. In 2017, ferritin was 1155 ng/mL (liver iron content 2.74–3.03 mg/g, Table 1). Liver biopsy (done for bone marrow transplant consideration) showed normal hepatocytes, vessels, bile ducts, reticuloendothelial iron but minimal hepatocellular iron and no fibrosis. Hydroxyurea treatment resumed 2 weeks before presentation. She was admitted with back and chest pain 5 days after the transfusion. Deferasirox and hydroxyurea were continued. Hb fell from 10.1 g/dL on admission to 8.9 g/dL, with a new RBC alloantibody (anti-V), representing delayed haemolytic transfusion reaction (DHTR). Six days after admission (Day 0, Figure 1), she reported nausea and headache, became obtunded (GCS 7), and was intubated. Brain imaging was non-diagnostic. Deferasirox and hydroxyurea were discontinued (ferritin 358 ng/mL). She had hyperammonemia (325 mcmol/L), ALF, lactic acidosis, non-specific organic aciduria and aminoaciduria (Table S1). Viral hepatitis testing was negative. Creatinine was 0.9 mg/dL (baseline 0.6 mg/dL). Ammonia increased to 477 mcmol/L despite sodium benzoate/sodium phenylacetate and lactulose. Haemodialysis was initiated; ammonia improved rapidly (<100 mcmol/L). She developed seizures (Figure S1) and unresponsive pupils. Imaging showed cerebral oedema with tonsillar herniation. Despite coagulopathy treatment with plasma, cerebral haemorrhage and severe anaemia (Hb 5.8 g/dL) followed intracranial pressure (ICP) monitor placement on Day +1. RBC transfusion was deferred until alloantibody identification (Day +8); Hb remained >9 g/dL with Hb S < 30% thereafter. Platelets were transfused on Days +1, 4, 9, and 11 with a goal >100 K/cumm after haemorrhage. Plasma zinc was low, and zinc was supplemented (Table 1). ICP remained elevated despite maximum medical therapy. On Day +25, she developed refractory hypoxemia and cardiopulmonary arrest. The autopsy revealed acute lung injury; cerebral oedema, right frontal lobe haemorrhage, and subacute cerebral, brainstem and cerebellar infarcts; and hepatomegaly without fibrosis, iron in Kupffer cells but no hepatocyte iron, bile stasis and macrophage infiltration. Both teens were adherent to deferasirox with declining ferritin, suggesting a declining total iron burden (Table 1). Both exhibited encephalopathy, hyperammonemia, ALF and lactic acidosis (Figure 1). Neither had pre-existing liver disease. P2 resumed hydroxyurea 2 weeks prior but had previously taken it for years without hepatotoxicity. Plasma deferasirox measurement was not available. Several factors suggest mitochondrial dysfunction contributed to ALF. Both had lactic acidosis, a biomarker for mitochondrial dysfunction, and acute hyperammonemia. Hyperammonemia occurs in primary and secondary mitochondrial disorders.6 Both teens' generalized aminoaciduria and P2's organic aciduria (Table S1) suggested mitochondrial dysfunction.7 Mitochondrial dysfunction may underlie acute deferasirox-associated ALF, aminoaciduria, and organic aciduria in TDT.3 We hypothesize that decreased iron and possibly zinc bioavailability contributed to mitochondrial dysfunction and ALF. Mitochondrial oxidative phosphorylation requires iron.8 If iron chelation is excessive, mitochondrial dysfunction may ensue. When the iron burden is high, deferasirox primarily chelates iron as the most abundant metal cation. However, with a low iron burden, zinc and copper may be chelated.9 P1's ferritin declined precipitously after starting ECP, which decreases iron loading, suggesting a lower iron burden. P2 had elevated iron binding capacity, suggesting excess plasma chelator and low iron bioavailability despite elevated serum iron, lower-than-expected transferrin saturation and low plasma zinc. Zinc deficiency may worsen hyperammonemia and encephalopathy.10 Most reports of deferasirox-related ALF in TDT have lacked iron or zinc measurements, but one child's ferritin declined to <1000 ng/mL preceding ALF.2 Despite similar presentations and treatments, our patients' outcomes diverged. P2's DHTR and intracerebral haemorrhage likely contributed to death. End-organ hypoxic injury may occur during severe anaemia.11, 12 DHTRs can cause multisystem organ injury, including AKI and fatal ALF.13 While deferasirox excretion is primarily faecal, 16% is renally excreted14; AKI may increase deferasirox exposure and dose-dependent adverse effects. Both cases were reported to the United States Food and Drug Administration (https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-program). Deferasirox's package insert was updated, recommending dose reduction for ferritin <1000 ng/mL, cessation for ferritin <500 ng/mL and interrupting when patients are volume-depleted until volume status and renal function normalize.14 Our institution implemented a policy of holding deferasirox during hospitalizations or home-managed acute illnesses. Patients and providers should be educated about deferasirox dose reduction/interruption recommendations. SCD teams should implement processes to identify and manage sudden ferritin decreases. Clinicians should maintain a high index of suspicion for ALF and hyperammonemia in deferasirox-treated children. All authors made substantial contributions to the present research. Drs. Kristin P. Guilliams, Réjean Guerriero, Marwan S. Shinawi and Janis M. Stoll contributed essential elements of case development and analysed the data. Alison S. Towerman and Drs. Daniel N. Willis and Monica L. Hulbert analysed the data and wrote the paper. We thank the patients and their families. Monica L. Hulbert is a member of a scientific advisory board at Global Blood Therapeutics, has research funding from Global Blood Therapeutics and Forma Therapeutics and provides consulting for bluebird bio; her spouse is employed at Pfizer, Inc. All other authors declare no conflicts of interest. Data are available upon request to the corresponding author. Figure S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.