Combined heart–liver transplantation in a case of haemochromatosis

Abstract

Hereditary haemochromatosis results in multiorgan dysfunction secondary to iron overload. Haemojuvelin (HJV)-associated haemochromatosis, is a rapidly progressing form of haemochromatosis caused by mutation in the HJV that frequently results in heart and liver failure. Herein, we describe the successful treatment of a 39-year-old woman with decompensated heart failure and liver cirrhosis requiring extracorporeal membrane oxygenation who was successfully treated with combined heart–liver transplantation. Following her life-saving multiorgan transplantation, she was also noted to have rapid correction of her serum ferritin to normal levels. She remains healthy with excellent allograft function and normal iron and ferratin levels 4 years after the procedure. To our knowledge, this case is the first demonstration that combined heart–liver transplantation is a feasible option for patients with heart and liver failure secondary to HJV-associated haemochromatosis and indeed offers a long-standing corrective solution to treat this condition and restore physiologically normal iron metabolism.

Background

Hereditary haemochromatosis is an genetic disorder in iron metabolism which can lead to a variety of complications, including liver cirrhosis and cardiomyopathy. A severe form of hereditary haemochromatosis, characterised by early onset of disease, results from an inactivating mutation in the haemojuvelin (HJV) gene and is inherited in an autosomic recessive manner.¹ Many patients show symptoms before the age of 30, with manifestations including arthritis, diabetes, cardiomyopathy, liver cirrhosis, hypothyroidism and hypogonadism, all secondary to organ iron deposition.²

Phlebotomy is the standard treatment for hereditary haemochromatosis, although cases of cardiomyopathy and/or liver cirrhosis may progress to irreversible end-organ heart and liver failure.^1–3 Organ transplantation continues to be a treatment option for patients with end-stage organ failure, however, there is limited literature regarding its outcomes in patients with HJV mutations.

Herein, we present a patient with haemochromatosis, secondary to HJV mutation, who exhibited signs of severe iron overload, consisting of severe cardiomyopathy requiring venous-arterial extracorporal membrane oxygenation (V-A ECMO) and advanced liver fibrosis. She underwent successful combined heart–liver transplant.

Case presentation

A 39-year-old female patient diagnosed with haemochromatosis by liver biopsy 12 years earlier. She also had progressive arthritis and hypothalamic hypogonadism with amenorrhea. She was managed with regular phlebotomies but was lost to follow-up. In March 2016, she presented with restrictive cardiomyopathy due to iron deposition and required multiple hospital admissions to treat decompensated heart failure.

Investigations

Genetic analysis at the time of presentation with heart failure was negative for high Fe2+ (HFE) mutation prompting further analysis of HJV mutations. The invitae HH panel, a full-gene sequencing of all five genes associated with haemochromatosis using next-generation sequencing technology, resulted positive for two variants in the HJV gene: a deletion of the entire coding sequence and a G320V mutation (figure 1).

Figure 1.

Sequence, function and expression of haemojuvelin (HJV). BMPR, Bone morphogenic protein receptor; SMAD, S "small" worm phenotype; MAD, "Mothers Against Decapentaplegic" protein; TFR, Transferrin receptor.

In August 2016, she presented again to the emergency room with pleuritic chest pain, shorthness of breath and hypotension. She was started on intravenous diuretic as well as dobutamine for hypotension. Echocardiogram showed systolic and diastolic heart failure and her left ventricle ejection fraction was now 18%. Cardiac MRI showed extensive iron deposition as evidenced by decreased T2* relaxation times (figure 2A–B). Histology of the heart showed cardiomyocyte hypertrophy and haemosiderin deposition (figure 2C–D). Although the patient had preserved liver synthetic function, MELD of 7 and no evidence of portal hypertension, she underwent transjugular liver biopsy which showed profound haemosiderosis with macronodular cirrhosis (figure 2E–F).

Figure 2.

Radiological imaging and histology of haemachomatosis-associated heart and liver lesions.

Treatment

Treatment with phlebotomy was limited by the patient’s severe heart failure and the severely elevated ferritin (approximately 2500 ng/mL) was refractory to desferrioxamine. As a result of the advanced liver and cardiac disease, combined heart–liver transplant was recommended. The patient was independently evaluated by the institution’s liver and cardiac transplant committees and approved for combined heart–liver transplant. Due to deteriorating cardiac function, the patient was listed status 1A for heart transplantation, the highest priority level. While waiting for a suitable donor, the patient’s cardiac status continued to deteriorate requiring increasing doses of dopamine, dobutamine and milrinone. Eventually, she was initiated on V-A ECMO to assist her cardiac output.

A compatible deceased donor offer became available after 48 hours on V-A ECMO. The patient underwent heart–liver transplantation in September 2016. For induction, she received basiliximab and methylprednisolone. The heart transplantation occurred first and, once removed from cardiopulmonary bypass, was followed by liver transplantation. A bicaval technique was required for implantation of the liver due to the quality of the suprahepatic/caval tissue. In addition, the donor liver allograft was significantly larger than the explant requiring delayed abdominal closure.

Postoperatively, the patient showed good cardiac and liver allograft function. As a result of acute kidney injury sustained due to perioperative hypotension, she was initiated on continuous renal replacement therapy and required renal support for 2 weeks. The patient returned to the operating room on postoperative day 2 for closure of her chest and abdomen and was successfully extubated after completion of the procedure. On postoperative day 8, she required a chest re-exploration and mediastinal haematoma evacuation. She was slowly weaned off all pressor support and transferred to the floor on postoperative day 18. The patient was discharged to an inpatient rehabilitation facility on day 23, with discharge to home on day 35 after transplant.

Outcome and follow-up

Following transplantation, ferritin levels progressively decreased and ultimately fell within normal range one and a half months post-transplant (table 1). They remain normal 4 years later. For immunosuppression she is currently maintained on tacrolimus (trough goal 4–6 ng/mL), mycophenolate and everolimus (trough goal 1–4 ng/mL) and has not experienced any rejection events. She remains alive and well with good function of both heart and liver allografts.

Table 1.

Results of iron studies before and after combined heart–liver transplantation

Date	Serum iron (37–145 µg/dL)	TIBC (262–424 µg/dL)	Unsaturated iron binding capacity (112–346 µg/dL)	Ferritin (13–150 ng/mL)
6 August 2016	256	N.C	<30	8978
Transplant
6 September 2016
7 September 2016	214	N.C.	<30	3325
21 September 2016	65	200	106	399
11 December 2016	60	254	194	146
13 June 2017				105
24 August 2018				96
23 September 2019				92

TIBC, total iron binding capacity.

Discussion

Originally described by Starzl⁴ in 1984, combined heart–liver transplants remain uncommon, with only 192 cases reported.^{5 6} Most frequently, combined heart–liver transplants are done to treat amyloidosis or familial hypercholesterolaemia.^{5 6} While heart, liver and combined heart–liver transplants have been described for patients with hereditary haemochromatosis, we report the first documented case of a combined heart–liver transplant for hereditary haemochromatosis due mutation of HJV.

Five genes have been implicated in different subtypes of hereditary haemochromatosis: HFE, hepatic antimicrobial protein, HJV, transferrin receptor 2 and solute carrier family 40 member 1(SLC40A1)(1). HJV is an iron-sensing membrane protein that acts as a coreceptor with bone morphogenic proteins and regulates the expression of hepcidin, the main iron homeostasis hormone via phosphorylation of SMAD-4.³ Dysruption of this gene causes decreased expression of hepcidin and subsequent iron overload. Over 75 mutations in HJV have been identified, the most common one is a G320V mutation, which accounts for two thirds of all patients^{1 7 8} (figure 1). This patient had a Gly320Val mutation. Interestingly, she also had an additional whole gene deletion which has only been reported once previously in the literature⁹ and this compound mutation may account for the severity of her disease.

Combined heart–liver transplantation is used treat metabolic disorders that result in combined cardiac and hepatic failure, such as amyloidosis and haemochromatosis. It has become increasingly used as treatment for secondary cardiac cirrhosis as a result of chronic obstruction of hepatic venous outflow, including post-Fontan procedure.¹⁰ There are multiple variations in the surgical technique for combined heart–liver transplantation. In this case, we proceeded with the most commonly described technique which involves placing the patient on cardiopulmonary bypass, followed by heart transplantation, reperfusion of the heart, reversal of anticoagulation and liver transplantation. In contrast, the ‘en bloc’ technique keeps the heart and liver connected by the inferior cava and the liver is maintained on ice while the heart implant is performed. In the en bloc technique, both organs are reperfused at the same time.^{11 12} En bloc has the advantage of less cold ischaemia time for the liver, potentially improving oxygenation and recovery from ischaemia-reperfusion injury. However, in addition to the technical challenges, there are concerns over how combined reperfusion could affect both organs, by means of hyperkalaemia, hypervolaemia or acidosis.¹³

The patient presented here did have signs of liver fibrosis and early cirrhosis, however, still had adequate liver function, a MELD score of 7 and normal platelet counts. Decompensated heart failure was the main driving factor for the patient’s critical status. However, the decision to proceed with combined transplant vs heart alone was based on the known pathogenesis of JH. As the patient in this case was relatively young at the time of transplantation and she had severe progression of liver disease despite phlebotomy therapy, we concluded that combined heart–liver transplantation would be protective in preventing future development of cardiomyopathy on the new heart. Additionally, studies of combined organ transplant show that patients receiving liver transplants require less immunosuppression than heart alone, suggesting an immunoprotective role of the liver allograft.^14–16 Our patient continues on triple immunosuppression agents, although the concentrations of tacrolimus and everolimus have been successfully reduced without the occurance of rejection.

Most patients with hereditary haemochromatosis can be treated with phlebotomy or chelation therapy, or a combination of both. Liver transplantation for hereditary haemochromatosis is reserved for advanced cirrhosis and is generally considered curative. It is unknown if adherence to these medical treatments could have mitigated completely the development of cardiomyopathy or cirrhosis in this specific patient, however, it is likely that the clinical course would have been improved had the patient not been lost to follow-up for a decade. Data for outcomes from liver transplantation for HJV-associated disease are lacking. Recipient 1-year survival of 72%–81% and 5-year survival of 55%–74%^17–20 for all cause haemochromatosis reflect improved long-term outcomes over the past two decades and refute earlier concerns for worse outcomes in patients with hereditary haemochromatosis when compared with patients transplanted for other causes. The most common causes of death post-transplant remain cardiac complications and infection.^17–20 With regard to transplantation outcomes in patients with documented HJV haemochromatosis only one case of heart transplantation has been reported.²¹

Although the liver contributes only 20% of HJV production, our observation that liver transplant restored normal iron metabolism and resulted in persistent ferritin levels within normal range post-transplant without need for phlebotomy or additional chelation treatments suggest that liver transplantation is sufficient to prevent recurrence of the haemochromatosis phenotype in HJV-associated haemochromatosis.

Learning points.

• Hereditary haemochromatosis, once diagnosed, should be treated with phlebotomy and chelation therapies.

• Genetic testing of the five genes associated with haemochromatosis provides diagnostic and prognostic data.

• Haemojuvelin (HJV)-associated haemochromatosis is a rare and severe form of hereditary haemochromatosis, which can lead to end-stage heart and liver failure.

• Combined heart–liver transplant is a treatment option for patients with dual end-organ failure due to HJV.

• Our follow-up data suggest that heart–liver transplantation restores and maintains normal iron and ferratin levels.