Iron Overload After Pediatric Liver Transplantation: A Case Report T. Wakiya, Y. Sanada, T. Urahashi, Y. Ihara, N. Yamada, N. Okada, Y. Toyoki, K. Hakamada, and K. Mizuta ABSTRACT Iron is an essential nutrient for living cells; however, an excessive accumulation of iron leads to organ damage and directly affects systemic immunity. Iron overload is clinically classified as hereditary or secondary. Most of secondary iron overload is caused by frequent blood transfusions because there is no active mechanism to excrete iron from the body. As recommended in various guidelines, chelation therapy is effective for reducing iron burden and improving organ function. There have been few reports on iron overload through blood transfusion during the perioperative period of liver transplantation. This report presents a case of iron overload due to repeated transfusions after pediatric liver transplantation managed by chelation therapy. The patient, an 11-month-old female with biliary atresia, underwent living donor liver transplantation. She revealed refractory anemia and required frequent blood transfusion. Both serum ferritin and transferrin saturation tended to increase after repeated transfusions, leading to secondary iron overload. Iron chelation therapy was started to prevent progression to organ failure and infection due to iron overload, and yielded a favorable outcome. It is crucial to consider the possibility of secondary iron overload and to achieve early detection and treatment to avoid progression to irreversible organ damage.

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RON is an essential nutrient for living cells because of its role as a cofactor for enzymes in the mitochondrial respiration chain, in the citric acid cycle or DNA synthesis, as well as being the central molecule for binding and transport of oxygen by hemoglobin and myoglobin. The total amount of body iron is approximately 3 to 4 g, twothirds of which is red blood cell (RBC) iron and recycled iron by RBC destruction; the remainder is stored in ferritin/ hemosiderin, whereas only 1 to 2 mg of iron are absorbed in the intestinal tract and circulated in the blood [1]. Meanwhile, excessive accumulation of iron leads to saturation of transferrin and the circulation of nonetransferrin-bound iron, which produces reactive oxygen species in serum [2]. Iron overload induces organ damage in the liver, heart, pancreas, thyroid, and the central nervous system. The main cause of this organ damage is due to the overproduction of reactive oxygen species in the presence of excess iron [3e7]. There is no active mechanism to excrete iron from the body, thus a progressive accumulation of body iron easily occurs as a result of long-term repeated transfusions in patients with anemia due genetic disorders such as thalassemia, and of bone-marrow failure such as aplastic anemia and myelodysplastic syndrome [8]. Chelation therapy has ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 973e976 (2014)

recently been adopted as a treatment for iron overload after repeated transfusions, yielding favorable outcomes [8]. On the other hand, problems associated iron overload through blood transfusion during the perioperative period are rare because blood transfusions are administered to replace blood loss. However, pediatric liver transplantation (LT) with splenomegaly (especially in proportion to the low body weight) could easily lead to iron overload, even with only perioperative blood transfusion. There have been few reports on iron overload through blood transfusion during the perioperative period of LT. This report presents a case performing chelation therapy for iron overload due to repeated transfusions after pediatric LT. From the Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori (T.W., Y.T., K.H.), and the Department of Transplant Surgery, Jichi Medical University, Shimotsuke, Tochigi (T.W., Y.S., T.U., Y.I., N.Y., N.O., K.M.), Japan. Address reprint requests to Taiichi Wakiya, Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.041 973

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Fig 1. Preoperative abdominal computed tomography (CT). CT scan showed hepatosplenomegaly 1 month after admission; liver volume was 358 mL and spleen volume was 243 mL in CT volumetry.

CASE REPORT The patient, an 11-month-old female with biliary atresia, had undergone portoenterostomy at 2 months of age. Cirrhosis progressed after surgery, at 9 months of age, and she required mechanical ventilation for pneumonia. She was transferred this hospital for LT at 10 months of age. Her body weight at the time of admission was 5.2 kg (3.7 SD). An abdominal examination revealed hepatomegaly and splenomegaly. Her Pediatric End-stage Liver Disease score was 23 at that time. Abdominal computed tomography (CT) showed bilateral atelectasis and hepatosplenomegaly. Liver volume was 280 mL and spleen volume was 165 mL in CT volumetry. The patient was weaned from the ventilator 5 days after admission. She was given enteral and parenteral nutrition and medication to improve her general condition and promote weight gain. However, there was no improvement of the liver failure, the liver and spleen

Fig 2. Evolution of serum markers and blood transfusion before transplantation. Time course of serum ferritin (C) and C-reactive protein (:) before transplantation. The figure also depicts the frequency of blood transfusion (arrows).

WAKIYA, SANADA, URAHASHI ET AL enlarged. The liver volume was 358 mL and spleen volume was 243 mL in CT volumetry 1 month after admission (Fig 1). She experienced respiratory failure due to abdominal distention caused by hepatosplenomegaly, and mechanical ventilation was again required 47 days after the patient was transferred. LT was immediately required due to the rapid deterioration of her general condition. The patient underwent blood typeeidentical living donor LT at 11 months of age, with her mother serving as the donor. Because of severe adhesions and coagulopathy, the operation time was 15 hours 28 minutes; blood loss was 757 mL. Intraoperative blood transfusion volume was 740 mL. Body weight at LT was 5.2 kg and standard liver volume was 203 mL. The graft was an S2 monosubsegment, weighing 174 g, with the graft volume/standard liver volume ratio being 85.7%. The resected liver weight was 380 g. Primary closure could be performed without reduction in blood supply to the graft, and there were no signs of heart failure. Laparotomy was performed for intra-abdominal bleeding on the second postoperative day. Blood loss during this laparotomy was 280 mL and blood transfusion was 65 mL. Subsequently, the patient showed no vascular complications and biliary complications. She was extubated on postoperative day 20, although she took time to improve her nutritional status and respiratory status, and was discharged from the hospital 109 days after transplantation. The patient is now alive and doing well at 39 months after transplantation. This patient revealed refractory anemia during the preoperative period. There was no bone marrow suppression or gastrointestinal bleeding. The anemia was thought to be due the negative impact of hepcidin in chronic inflammation and extravascular hemolysis with splenomegaly. Transfusion of RBCs was required frequently, and the total amount of preoperative blood transfusion after the patient was transferred to the hospital was 840 mL (Fig 2). Anemia was prolonged after LT, and frequent blood transfusions (total of 765 mL) were required. Although it initially tended to decrease, the level of serum ferritin gradually began to rise again from approximately postoperative day 10 (Fig 3). There were no findings corresponding to elevation of serum ferritin levels (such as liver damage due to obstruction of blood flow) and rejection (such as acute and chronic infection). In addition to the findings from a physical examination and blood tests, Still’s disease, hemophagocytic syndrome, and cancer were negative. Transferrin saturation was also high, and elevation of ferritin was determined to have developed from secondary iron overload due to blood transfusion. Iron chelation therapy using deferoxamine (30 mg/kg/d) was started on postoperative day 58 to prevent progression to organ failure and infection due to iron overload. Both serum ferritin and transferrin

IRON OVERLOAD AFTER TRANSPLANTATION

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Fig 3. Evolution of serum markers and blood transfusion after transplantation. Time course of serum ferritin (C) and C-reactive protein (:) after transplantation. The figure also depicts the frequency of blood transfusion (arrows) and the sequential treatment with deferoxamine (POD, postoperative day).

saturation tended to decrease without any adverse effect of deferoxamine. The administration of chelating agents terminated on postoperative day 72, after the serum ferritin level was persistently below 1000 ng/mL.

DISCUSSION

Despite of the lack of genetic background, iron overload is commonly observed as a secondary condition. The most common condition occurs in patients who require long-term blood transfusions due to severe anemia. Ineffective erythropoiesis in these patients and continuous accumulation of exogenous iron by transfusion are thought to be responsible for the iron overload. In addition to these classic conditions, there are many diseases that show mild iron deposition or dysregulation of body iron distribution. Such conditions include chronic hepatitis C, alcoholic liver disease, and nonalcoholic steatohepatitis [8]. The cause of iron overload in this patient was thought to be secondary to frequent blood transfusions. One of the reasons for frequent blood transfusions has been thought to be due to hypersplenism secondary to splenomegaly. In general, the standard spleen volume (SSV) is calculated with the following formula: SSV (cm3) ¼ 0.7 þ 4.6  weight (kg) [9]. In this case, the patient’s spleen, which should have been approximately 25.0 mL, was 243.0 mL in CT volumetry 1 month after admission, and 230 mL on postoperative day 60. In addition, it was suggested that splenomegaly not only caused the iron overload, but also the abdominal distention that led to the respiratory complications and poor oral intake during the perioperative period. Body iron metabolism is normally a semi-closed system; there is no mechanism to regulate iron loss from the body, which averages about 1e2 mg/d in adult men from sweat, shed skin cells, and gastrointestinal losses. Meanwhile, each unit (in Japan, one RBC unit derives from 200 mL of whole blood) of transfused red cells introduces 100 mg of elemental iron into the body. The excess iron is deposited in macrophages of the reticuloendothelial system as the

amount of the transfusion increases because iron cannot be actively excreted. Excessive accumulation of iron released from aging and damaged erythrocytes by reticuloendothelial macrophages leads to saturation of transferrin and the circulation of nonetransferrin-bound iron in serum [2]. As a result, iron is deposited in the form of ferritin and hemosiderin in the parenchymal cells of the liver, heart, pancreas, brain, and joints [10,11]. Ionic iron-mediated toxicity in these organs such as lysosomal disruption in hepatocytes, collagen formation and fibrogenesis, and lipid peroxidation in heart and spleen cells causes various symptoms of cirrhosis, hepatocellular carcinoma, congestive heart failure, arrhythmias, insulin resistance and diabetes, arthritis, fatigue, growth disorder, and sexual dysfunction [3e7]. Iron overload also directly affects systemic immunity and increases the availability of iron to viruses, bacteria, and cancer cells [12,13]. Chow et al reported that increased serum iron markers were an independent risk factor for infectious complications and 1-year mortality rate in orthotopic LT recipients [14]. Early symptoms of iron toxicity may be nonspecific. Accordingly, iron overload is frequently not considered in the differential diagnosis until organ damage has supervened. Although no apparent organ damage in the graft liver or other organs was found, iron chelation therapy was started to prevent progression to organ failure and infection due to iron toxicity. Furthermore, when liver dysfunction appears after LT, rejection and infection are considered in the differential diagnosis, and treatment is often initiated before the cause is clearly established to prevent any adverse events. In the situation in which iron overload causes liver dysfunction, there is a possibility that discriminating the condition can be difficult. Therefore, we introduced the chelation therapy during the early stage. Chelation therapy with deferoxamine or deferasirox is the only means of removing the toxic accumulation of none transferrin-bound iron because phlebotomy is not an option due to iatrogenic iron overload as sequelae of repeated transfusions. Takatoku et al investigated the relationship

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between iron overload, chelation practices, and morbidity/ mortality in patients with myelodysplastic syndromes and aplastic anemia. Serum ferritin is significantly correlated with the frequency and history of transfusion, and appears useful for monitoring iron overload. Serum ferritin is a useful marker to predict clinical comorbidity resulting from iron overload because more patients died with serum ferritin levels >1000 ng/mL than 1000 ng/mL in 75% of patients is 43.4 units, respectively. Daily/ continuous chelation therapy is effective for reducing iron burden and improving organ function [7]. Iron chelation therapy should start when serum ferritin reaches 1000 ng/mL or after transfusion of 40 units of total RBC units (in children, RBC 100 mL/kg) to avoid the risk of end-organ damage caused by toxic free iron. Moreover, it is recommended in various guidelines that the serum ferritin levels be maintained

Iron overload after pediatric liver transplantation: a case report.

Iron is an essential nutrient for living cells; however, an excessive accumulation of iron leads to organ damage and directly affects systemic immunit...
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