Sudden Onset Iron Overload Cardiomyopathy After Liver Transplantation

Abstract

Iron overload cardiomyopathy has been described in patients who develop acute heart failure after liver transplantation but few reports of this are available. We present a case of a patient with end-stage liver disease who underwent a deceased donor liver transplantation and developed acute onset systolic heart failure with reduced left ventricular ejection fraction. A cardiac magnetic resonance image demonstrated late gadolinium enhancement with diffuse enhancement globally and T1 mapping with severely decreased pre-contrast T1 values suggesting iron overload cardiomyopathy. The patient was treated with iron chelating therapy as well as heart failure guideline-directed medical therapy with subsequent improvement in cardiac function on follow-up magnetic resonance images. Despite our patient’s diagnosis of iron overload cardiomyopathy, her iron studies showed normal serum iron and ferritin levels and no evidence of hepatic iron deposition in the transplanted liver.

Introduction

Liver transplantation (LT) is the treatment option for refractory end-stage liver disease in appropriate candidates. Patients who undergo LT often develop iron overload resulting in hepatic iron deposition. ¹ Iron overload cardiomyopathy (IOC) has also been described in patients who develop acute heart failure after LT ² but few reports of this are available.

Iron overload cardiomyopathy is a major cause of cardiovascular death among patients with varying hematologic diseases requiring chronic blood transfusions. ³ Iron deposits in the myocardium can cause oxidative stress and tissue damage. ³ This subsequently leads to a restrictive cardiomyopathy with diastolic dysfunction which may further progress to dilated cardiomyopathy. These changes may be reversible, making early detection and treatment of vital importance.^1,4 Iron overload cardiomyopathy presentation can vary from asymptomatic cardiac dysfunction in early stages to end-stage heart failure in late presentations. ⁵

We describe a patient with multiple packed red blood cell (pRBC) transfusions, LT, and history of heterozygous HFE mutation who developed acute heart failure due to iron overload which was found to be responsive to iron chelators.

Case Report

A 32-year-old Caucasian female had a past medical history of alcohol use disorder complicated by recurrent episodes of pancreatitis and eventually decompensated cirrhosis with ascites, hepatic encephalopathy, esophageal varices, spontaneous bacterial peritonitis, and hepatic hydrothorax. After she was diagnosed with cirrhosis, she received 13 blood transfusions and 4 iron sucrose (200 mg) infusions along with high doses of oral iron supplementation for refractory iron deficiency anemia.

Despite eventual sobriety, her health deteriorated, and she was evaluated for LT. During her preoperative LT evaluation, labs showed an iron of 173 ug/dL, iron binding capacity 182 ug/dL, and iron saturation 95%. A ferritin 2 years prior was 223 ng/mL. During her initial transplant evaluation, she underwent a dobutamine stress echocardiogram (DSE) which revealed normal baseline left ventricular (LV) systolic function with left ventricular ejection fraction (LVEF) of 55% to 60%. With dobutamine infusion, her LV function augmented to an LVEF 75%. There were no regional wall abnormalities noted at rest or with dobutamine infusion. One month prior to LT, she underwent repeat DSE which confirmed normal LV function at rest with augmentation of LVEF to >70% with dobutamine. The patient subsequently underwent a deceased donor LT (DDLT) at a Model for End Stage Liver Disease (MELD) score of 28. Intraoperatively, estimated blood loss was 7 L and she received 15 units of pRBC, 18 units of fresh frozen plasma, 3 units of platelets, 1 unit of cryoprecipitate, and 1600 mL through autotransfusion. During her procedure, she developed supraventricular tachycardia (SVT) which was treated with cardioversion, esmolol, and amiodarone. She subsequently required use of parenteral vasoactive agents for hypotension. Sections from the explanted liver showed established cirrhosis with micro-regenerative nodules and fibrous septae. Pericellular fibrosis was also focally present (trichrome stain examined), and there was minimal steatosis (<5%) without features of active steatohepatitis (i.e. ballooning degeneration or associated inflammation). Mallory hyaline was not identified. Marked hepatocellular and Kupffer cell hemosiderosis were present (4+ iron on a scale of 0-4). A postoperative transthoracic echocardiogram (TTE) obtained 4 days after transplantation revealed severely reduced LV function with diffuse hypokinesis, an estimated LVEF of 16%, and moderately reduced right ventricular function.

Cardiology was consulted for this finding of new onset heart failure. In the setting of major surgery (LT), SVT, and recent normal DSE, the etiology was initially attributed to stress cardiomyopathy. Repeat TTE 10 days post-LT showed mild improvement in LVEF to 20% to 30%. After inpatient recovery, she was discharged from the hospital with metoprolol succinate, hydralazine, and isosorbide dinitrate as medical management for her new heart failure diagnosis. Angiotensin-converting-enzyme inhibitors were deferred at that time due to hyperkalemia.

Two days after discharge from the hospital, the patient presented to the clinic with palpitations, headaches, and myalgia involving her bilateral upper extremities. Electrocardiogram showed normal sinus rhythm without acute ischemic changes. Routine labs revealed an elevated troponin to 1.1 ug/L, and she was transferred to the emergency department for further evaluation. Additional workup with a repeat TTE showed improvement of her LVEF to 35% to 40% with no wall motion abnormalities. Stress cardiac magnetic resonance imaging (MRI) revealed no evidence of ischemia but demonstrated moderately reduced LV systolic function with LVEF of 38% due to IOC as evidenced by late gadolinium enhancement showing diffuse enhancement globally and T1 mapping with severely decreased pre-contrast T1 values (Figure 1A, B). A T2-star (T2^*) was obtained the following day and resulted in a remarkably short T2^* of 4.75 ms, further supporting the diagnosis of IOC. Evaluation of hemosiderosis with genetic testing revealed the patient to be heterozygous for HFE C282Y mutation and negative for HFE H63D mutation. At that time, her hemoglobin was 7.1 g/dL, white blood cell count 2.1 x 10⁹/L, platelets 87 x 10⁹/L, iron 23 ug/dL, iron binding capacity 195 ug/dL, iron saturation index 12%, ferritin 182 ng/mL, and transferrin 141 mg/dL. Other routine labs including a complete metabolic panel were within normal limits.

Figure 1.

(A) Cardiac MRI showing late gadolinium enhancement. Arrows pointing to focal areas of midmyocardial enhancement in the interventricular septum, lateral ventricular wall, and wall of the right ventricle. The myocardium is diffusely lighter in color despite adequate nulling using an appropriate inversion time. This suggests that there is diffuse iron uptake and that the midmyocardial enhancement and color of the myocardium is not a technical artifact, particularly when taken in the context of T1 images (Figure 1B). (B) Cardiac MRI panel showing severely decreased pre-contrast T1 values. This 4-paneled figure demonstrates the regions of myocardium that were selected for T1 mapping in the left-sided panels before (top left panel) and after (bottom left panel) the injection of contrast. The top right panel demonstrates the numeric values for T1 time, wherein a significant decrease in T1 relaxation time both before (690 ms; reference value ~950 ± 20 ms at our center) and after (400 ms) the injection of contrast compared to what would be expected for normal myocardium is seen. The bottom right panel demonstrates the obtained values in a graphical format. Collectively, this 4-paneled figure corroborates the presence of significant cardiac iron deposition on the T1 mapping sequence. This is also supported by the dramatic increase in extracellular volume (49.4%; reference range 25% ± 4% at our center).

After discharge from the hospital, the patient was followed closely by hematology and cardiology. The initial plan was to treat with dual iron chelation therapy with deferasirox and subcutaneous deferoxamine; however, due to her decreased renal function, she was initiated on single agent with deferasirox. With underlying pancytopenia, deferiprone was not chosen due to risk of neutropenia. Her pancytopenia and low haptoglobin of less than 30 mg/dL were further evaluated with a bone marrow biopsy. The bone marrow morphology and flow cytometry analysis showed no evidence of leukemia, lymphoma, or myelodysplastic syndrome. The Dacie iron stain showed occasional sideroblasts with no definitive ring forms, and the Prussian blue stain on particle crush revealed increased marrow iron stores. Next-generation sequencing resulted in an alteration of RUNX1 R306C, a variant of uncertain clinical significance. The variant was detected at nearly 50% allele frequency suggestive of a possible germline variant; however, further workup for germline testing was not completed. Testing for paroxysmal nocturnal hemoglobinuria was negative.

A cardiac biopsy 6 months post-LT confirmed cardiac myocyte hemosiderosis and associated myocyte hypertrophy (Figure 2A, B). Right heart catheterization was completed and showed the following pressures/measurements: RA 15 mmHg, PA 32/20 (24) mmHg, PCW 19 mmHg, Fick C.O. 2.5 L/min, Fick C.I. 1.52 L/min/m², and PVR 1.96 Wood units. At this time, deferoxamine was added to her chelation therapy regimen. The cardiac MRI at 6 months revealed an LVEF of 17%, decreased from 38% observed previously on her 1-month post-LT cardiac stress MRI. Follow-up cardiac MRIs at 12 months and 18 months post-LT showed improvement in biventricular function with a LVEF of 45% and 63%, respectively; however, despite ongoing iron chelator therapy, her T2* was similar to prior studies at 4.8 ms. Follow-up labs were significant for ferritin 41 ng/mL, iron 76 ug/dL, iron binding capacity of 328 ug/dL, and iron saturation of 23%. These finding were surprising given her MRI T2* results. Surveillance MRI 30 months post-LT continued to show iron overload with T2* 4.9 and LVEF 54% with no symptoms of congestive heart failure 34 months post-LT. Interestingly, her blood iron studies remain stable with iron saturation 15% and ferritin 68 ng/mL with improvement in pancytopenia. She is working full-time, exercising daily, and continues to show no signs of any significant heart failure.

Figure 2.

Cardiac biopsy Prussian blue iron stain highlights hemosiderin deposition. (B) High power view of a hematoxylin and eosin stain showing hypertrophic cardiac myocytes with numerous golden brown pigment granules.

Discussion

LT candidates with end-stage liver disease have a substantial decrease in mortality rate post-transplantation compared to pre-transplant. ⁶ Chronic liver disease has been known to cause altered iron metabolism leading to iron overload involving various organs even in the absence of HFE mutations.^7,8 Hepatic iron deposition can be seen in up to 78% of patients with non-HFE associated cirrhosis. ⁷ A study by O’Glasser et al ⁹ showed that patients with significant hepatic iron deposition had evidence of cardiac iron deposits in 64% of patients who underwent cardiac biopsies prior to LT.

In the current literature, only a few studies describe an acute onset of IOC post-LT in patients without hereditary hemochromatosis. Papadodima et al ² conducted a study in patients who underwent LT to elucidate the frequency and causes of cardiac iron overload after LT and its relationship to cardiac dysfunction in patients without severe hepatic iron deposition. Of the 19 patients included in the study, 7 patients developed acute cardiomyopathy post-LT. Six of those patients were negative for any HFE mutation. One patient was HFE C282Y heterozygous, similar to our patient. A single HFE C282Y mutation does not commonly account for the hemochromatosis phenotype². In addition, 6 of the 7 patients with cardiac iron overload were found to have varying grades of hepatic iron deposition. Our patient underwent a liver biopsy a few months after her LT due to concern for acute rejection; however, an iron stain was not performed on the biopsy. A Ferriscan of her transplanted liver showed a normal average liver iron concentration of 0.6mg/g or 11 mmol/kg dry tissue. It was concluded that cardiac iron overload was associated with cardiac dysfunction following LT and was related to the product of the pre-LT transferrin saturation (TSAT) multiplied by the number of units of pRBC transfused during and following the surgery. ²

Iron overload cardiomyopathy (IOC) is caused by accumulation of iron deposition in the myocardium due to excessive iron stores. This can be a result of several conditions including hereditary hemochromatosis, transfusion of blood products, hepatitis C, alcoholic liver disease, and so on. Excess iron can deposit in various organs and tissues including the liver and heart and subsequently lead to oxidative stress and tissue damage. ³ Patients who require long-term blood transfusion therapy, such as those diagnosed with thalassemia major, are at increased risk of developing myocardial damage leading to a common cause of mortality in this population.^4,10,11 Blood transfusions can increase the level of non-transferrin bound iron or free plasma iron. This form of iron is toxic to organs as it forms free radicals, and its tissue uptake is not regulated by transferrin receptors as compared to the transferrin bound iron. ¹² Fenton et al ¹³ showed that patients with grade 4+ hepatic iron deposition at the time of LT may have some degree of cardiac iron deposition prior to transplant. Other mechanisms for iron overload include increased iron absorption from the gastrointestinal tract as in hereditary hemochromatosis and via exogenous iron excess through dietary intake or parenteral iron infusions. ¹⁴ Interestingly, despite our patient’s diagnosis of iron overload cardiomyopathy, her iron studies showed normal serum iron and ferritin levels and her Ferriscan confirmed no hepatic iron deposition. The donor in this case was hepatitis B virus-positive. Our patient received lamivudine post-LT and has remained seronegative 18 months after transplant.

Echocardiography can be used to detect left ventricular diastolic dysfunction in early stages of IOC and restrictive physiology secondary to myocardial damage; ¹⁵ however, these are nonspecific findings. Cardiac MRI can now identify findings diagnostic for IOC by non-invasively quantifying cardiac iron deposition. Anderson et al ¹⁶ developed a specialized technique, T2^*, which uses cardiac MRI to measure myocardial iron content. In healthy myocardial tissue, the signal omitted by non-iron containing tissue results in a longer lasting tissue relaxation time which appears brighter over time on MRI imaging. The shorter the tissue relaxation time, the higher the myocardial iron content, resulting in a lower T2^* value. A T2^* signal > 20 ms is considered a normal value for a non-iron containing myocardium. Patients with IOC-associated left ventricular dysfunction have a T2^* < 20 ms and a T2^* < 10 ms reflecting heavy myocardial iron load.^16-18

Treatment of the iron overload relies on early detection of the disease and early therapy is a key factor in preventing end-organ damage. In general, iron overload is frequently managed by dietary modification, phlebotomy, and chelating agents. Patients with iron overload or at high-risk for iron overload can be divided into 3 groups based on risk for IOC as follows: ¹⁹

1. T2^* >20 ms: low-risk for congestive heart failure

2. T2^* 10-20 ms: moderate-risk for congestive heart failure

3. T2^* <10 ms: high-risk for decompensated heart failure requiring immediate and intense chelating therapy

In categories 1 and 2, studies have shown that treatment with chelating therapy can delay the development of IOC. In patients with heart failure due to IOC, treatment is typically a combination of chelating agents such as deferoxamine in addition to heart failure guideline-directed medical therapy. Deferoxamine has been used in patients with thalassemia who are on long-term blood transfusion therapy. The subcutaneous form of this treatment has been associated with lower rate of cardiac complications due to iron overload as well as lower mortality.^20,21 Deferoxamine, a hydrophilic chelating agent, binds the free plasma iron molecules and facilitates its excretion in the urine. In patients with IOC, treatment of 12 months duration with intravenous deferoxamine has been shown to reduce myocardial iron deposition as evidenced by an increased MRI T2^* value, recovery of left ventricular function, and improvement in left ventricular ejection fraction. ¹⁷ Deferasirox and deferiprone are lipophilic chelating agents used in iron overload due to transfusion-dependent diseases such as thalassemia and sickle cell anemia. Route of administration is per oral, and it is rapidly absorbed by the gastrointestinal tract and can be found in high concentration in organs such as the liver and kidneys. Deferasirox and deferiprone have the ability to chelate iron deposits in cardiac tissue and excretion is mainly through the liver.^22,23 Lal et al ²⁴ conducted a pilot study evaluating efficacy of combined therapy with deferasirox and deferoxamine in thalassemia patients with iron overload. Combined therapy (deferasirox and deferoxamine) was superior in lowering myocardial iron deposits in comparison with deferoxamine alone. ²⁴ Literature has shown that patients with IOC on adequate medical therapy in early stages of the disease, prior to development of advanced heart failure, can have reversible cardiomyopathy. ¹³ Some studies estimate that patients with advanced cardiac failure due to IOC have a poor prognosis with a survival rate less than 1 year.^11,12 Caines et al ²⁵ showed that patients with IOC have a 10-year survival rate of 41% at 1-year and 81% at 3 and 5-years. These patients had a 30-day mortality rate of 12%, ²⁵ although only one of these studies was in post-LT patients. There are limited studies and data in the literature regarding the benefits of heart transplantation for patients with IOC and whether it improves major outcomes such as mortality is still a topic of discussion. Our patient had multiple risk factors for iron overload including chronic liver disease, multiple pRBC transfusions, and intravenous iron for anemia prior to LT. She was also found to be heterozygous for HFE C282Y mutation. It remains unclear the reason that our patient had the tendency to deposit iron in her heart and spare other organs. While C282Y heterozygosity is associated with subtle changes in iron metabolism, this genotype does not appear to contribute significantly to iron overload.^26,27 The heterozygosity for RUNX1 R306C mutation may play a role in her pancytopenia as RUNX1 is a transcription factor with a differentiation of hematopoietic stem cells into mature blood cells. There was no evidence of myelodysplasia in the bone marrow or leukemia. Heterozygous germline RUNX mutations have been associated with familial platelet disorders and a mild bleeding tendency; however, family history in our patient was negative for leukemia or platelet disorders, and we have no data to suggest that this is a germline mutation. ²⁸ Renal insufficiency limited the ability to optimize iron chelation with dual agents and anemia precluded phlebotomy to remove iron. As mentioned, her congestive heart failure remains compensated. Follow-up MRIs are still indicating evidence of iron deposition on T2*; therefore, she will likely benefit from continued iron chelation therapy.

Conclusion

IOC is an increasingly recognized cardiomyopathy that is reversible in early disease stages but has a poor prognosis in late presentation with refractory advanced heart failure. Imaging modalities, such as cardiac MRI with the T2^* technique, have been helpful in early detection of cardiac iron deposits and guidance of IOC treatment. Several iron chelator treatment regimens have been shown to be effective in treating cardiac complications from iron overload, especially dual hydrophilic and hydrophobic agents. Furthermore, iron chelation when utilized in tandem with heart failure guideline-directed medical therapy, can also be successful in reversing the cardiac dysfunction of IOC. Patients with IOC-associated refractory advanced heart failure may benefit from heart transplantation; however, limited data is available on mortality benefit post-heart transplantation. Iron overload post-LT is common, while IOC post-LT is rare. In a patient with iron overload post-LT, it is important to be on high alert for cardiac dysfunction as early initiation of treatment can improve outcomes. More studies are required to better understand post-LT IOC pathophysiology and increased awareness of this condition is needed to allow early initiation of appropriate treatment to improve patient outcomes.