Reversal of end-stage heart failure in juvenile hemochromatosis with iron chelation therapy: a case report

A 31-year-old male was referred to a quaternary intensive care unit (ICU) for consideration for extracorporeal membrane oxygenation (ECMO) due to severe biventricular heart failure refractory to inotropic support (a cardiac index of 1.3 on noradrenaline and dobutamine infusions). He had presented with shortness of breath, extreme lethargy and abdominal pain, and was hypotensive and tachycardic.

Our patient, of Serbian origin, reported no family history of iron overload syndrome, endocrinopathy or cardiomyopathy. There was no history of excess alcohol intake, recreational drug use, or toxic environmental exposures.

A physical examination on admission to the ICU revealed a patent airway. His respiratory rate was 15 breaths/minute, oxygen saturation 98% on 4 liters of oxygen via nasal prongs, and good air entry to bilateral lung fields but slightly reduced at the right base without crackles or wheeze. On a noradrenaline, dobutamine, and amiodarone infusion his blood pressure was 90/64 mmHg with a pulse rate of 105 beats per minute with cardiac monitoring revealing a sinus tachycardia. A cardiovascular examination was significant for a hyperdynamic apex beat with heave, a jugular venous pulse at 2–3 cm and dual heart sounds with nil murmurs. A neurological examination was significant for a Glasgow coma score of 14 (eyes 3 motor 5 verbal 6). His abdomen was soft on palpation with tenderness to the right upper and lower quadrant and no guarding. A peripheral examination was significant for a tanned complexion and the absence of peripheral edema.

Laboratory investigations on admission did not account for the patient’s critical clinical state revealing normal hemoglobin concentration, platelet count, renal function and serum electrolytes. His liver function was mildly deranged with an elevated alanine transaminase (88 units/ L, RR 12–15) and bilirubin (62 umol/L RR, ≤ 23) and decreased albumin (30 g/L, RR 33–46). His C-reactive protein (CRP) and neutrophil count were mildly elevated, 9 mg/L (RR ≤ 5) and 10.27 10⁹/L (RR 1.90–8.00) respectively, with a normal white blood cell count (12.03 10⁹/L, RR 3.90–12.70). Antinuclear antibody and rheumatoid factor test results were negative. A high-sensitivity Troponin I test result was mildly elevated (64 ng/L, RR ≤ 26). Midstream urine and blood culture were negative.

A computed tomography scan demonstrated a dilated heart with associated pleural effusions, ascites, and liver congestion. A transthoracic echocardiogram revealed normal left ventricular (LV) size with severe global systolic dysfunction with an ejection fraction of 5–10%, spontaneous echo contrast, and normal wall thickness. The right ventricular (RV) size was normal with severely reduced function. Mild to moderate mitral and pulmonary regurgitation were noted along with a trivial pericardial effusion.

He had a prolonged ICU stay due to progressive multi-organ dysfunction. He was intubated and ECMO support was initiated on day 2 and biventricular assist devices (BiVAD) were inserted on day 8. An endomyocardial biopsy revealed myocyte intracytoplasmic iron deposition (Fig. 1a and b). This result together with the global nature of the systolic dysfunction was consistent with iron overload as a cause for the cardiomyopathy. There was no echocardiographic or histopathologic evidence to suggest myocarditis and hemodynamic instability precluded coronary angiography.

Serum ferritin (SF) level was 12,361 μg/L and TS was 99% on day 2. Iron chelation therapy was commenced on day 6 with desferrioxamine, initially subcutaneously. Shortly after its commencement, increasing inotropic requirements and bilateral lung infiltrates felt to represent pulmonary edema were noted and desferrioxamine was ceased as a precaution. It was restarted on day 21 once his clinical condition had stabilized and up-titrated to a maximum dose of 4200 mg (60 mg/kg) administered via a 24-hour intravenous infusion and was subsequently well tolerated with rapid removal of iron burden. SF levels peaked on day 13 at 18,676 μg/L and TS was > 99% before decreasing to 1055 μg/L by day 59 with TS also decreasing to 65%.

By the fifth week after presentation, it was considered that he may have developed diabetes insipidus on the basis of a marked unexpected increase in urine output, but because of his parlous clinical state on BiVAD it was not possible to confirm with a water deprivation test at that time. A trial of desmopressin did not result in convincing improvement.

Investigation of his anterior pituitary function revealed isolated hypogonadotropic hypogonadism. Testosterone replacement was commenced with testosterone 1% gel 2.5 g topical daily with subjective improvement in energy levels and sense of wellbeing.

Our patient was listed for heart transplantation and discharged home on day 69 with BiVAD in situ after progressive improvement in his physical capacity with intensive inpatient rehabilitation. Desferrioxamine was continued at home via nightly 10-hour continuous subcutaneous infusions. Our patient was readmitted on day 89 with urosepsis, which was successfully treated with antibiotic therapy. At this time, he was noted to have improved left ventricle function on an echocardiogram, estimated to be only mildly reduced on a technically difficult study. Serial outpatient echocardiograms, both resting and stress, demonstrated myocardial recovery with normal LV size and resting systolic function (visual LV ejection fraction of 55–60%) and normal RV size and low-normal systolic function. With exercise, there was good augmentation of both LV and RV function and a normal hemodynamic response. Successful BiVAD explant occurred, 141 days after initial implant with SF 163 μg/L and TS <1% 12 days prior. Left ventricular biopsy at this time demonstrated less intracytoplasmic iron deposition compared with the initial biopsy (Fig. 1c). Post BiVAD explant, desferrioxamine was ceased as a potential cause of worsening renal tubular acidosis. Cardiac magnetic resonance imaging (cMRI) completed 2 weeks post BiVAD explant demonstrated normal biventricular systolic function but a myocardial T2* time of 12.3 milliseconds (normal > 20 milliseconds) consistent with residual myocardial iron loading. A formal water deprivation test was performed and was normal, therefore desmopressin was ceased.

As the patient’s history was significant for a diagnosis of hemochromatosis, JH was suspected given his age and absence of family history. Targeted gene sequencing was then performed across 39 genes and 11 promoter regions using a custom “AmpliSeq” panel (Life Technologies, Mulgrave, Victoria, Australia) and an Ion Torrent™ Personal Genome Machine™ (Life Technologies) as previously described [2]. Following alignment of the sequencing with the Human Genome version 19 (HG19), our patient’s heterozygosity for the HFE H63D was confirmed, and no other mutation were present in the HFE gene. Variant analysis identified homozygosity for a variant c.G959T (NM_213653) in exon four of the HFE2 gene (aka HJV) resulting in a p.G320V mutation (rs74315323). This DNA change was confirmed by Sanger sequencing. The G320V mutation has previously been reported in multiple cases of juvenile onset hereditary hemochromatosis [3]. No other mutations known to be associated with iron overload were identified in our patient, nor were there any other novel or rare single nucleotide polymorphisms in the coding regions of sequenced genes.

At follow-up 12 months after his presentation with severe biventricular heart failure the patient has made a near-complete recovery and had returned to work. His SF level was 29 μg/L. CMRI, previously contraindicated due to the implanted ventricular assist devices, 20 months after he presented with severe biventricular heart failure, demonstrated T2* time had returned to normal in the myocardium (41 milliseconds) and liver (19 milliseconds). The study also demonstrated normal biventricular function with mild biventricular dilatation and the absence of myocardial fibrosis. He remains on insulin and testosterone replacement and 3-monthly venesections were commenced.