- Email: [email protected]
Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin
Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin Elizabeth B. Rand, MD, Saul J. Karpen, MD, PhD, Susan Kelly, RN, Cara L. Mack, MD, J. Jeffrey Malatack, MD, Ronald J. Sokol, MD, and Peter F. Whitington, MD Objective To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. Study design We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchange transfusion in 13 (ET/IVIG), and compared the outcome with 131 historical controls treated conventionally. Results The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/ IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6 to 90 days after receiving ET/IVIG therapy, and those followed for more than 1 year are within normal measures for growth, development, and liver function. Conclusions Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH. (J Pediatr 2009;155:566-71). here is no effective treatment for neonatal hemochromatosis (NH).1-3 Beginning as a fetal liver disease, it typically presents as liver failure in newborn infants that are often born prematurely and with intrauterine growth restriction caused by prenatal insult. Thus, treatment options are limited, and survival rates with medical therapy are generally recorded as being <20%.4-6 Orthotopic liver transplantation (OLT) has been applied, but with substantial difficulty in this clinical scenario.7 More effective medical therapy is clearly needed for newborns with this devastating disease. We have hypothesized that many cases of NH are due to maternal alloimmunity directed at the fetal liver.8 The principal evidence suggesting an alloimmune mechanism comes from the observation that the risk of occurrence in a gestation subsequent to one ending in an affected baby is as high as 90%.9,10 Further, treatment of women at risk for having an affected baby with high-dose intravenous immunoglobulin (IVIG) reduces the occurrence of having a severely affected baby.10,11 This proof of concept that therapy directed at the immune mechanism of NH can prevent the disease in utero led to the hypothesis that the same approach could alter the course of already established disease postnatally. We therefore treated NH-affected newborn infants with exchange transfusion (ET) and IVIG in an attempt to attenuate immune-mediated liver injury and permit recovery. We retrospectively reviewed the course and outcome of newborn infants receiving this therapy and compared them with historical controls derived from recently published series.4,6,10,12,14
T
Methods The subjects of the study were 16 newborn infants with a clinical diagnosis of NH and liver failure. The Pediatric Acute Liver Failure (PALF; http://www.palfstudy.org) study group defines acute liver failure in young children as severe acute liver dysfunction accompanied by hepatic-based coagulopathy uncorrectable by parenteral vitamin K administration in the absence of sepsis-related disseminated intravascular coagulation.15 To meet the diagnostic criteria for coagulopathy in the absence of encephalopathy, the prothrombin From the Department of Pediatrics (E.B.R.), Children’s time must be $20 seconds or an INR $2. NH was diagnosed by demonstration Hospital of Philadelphia, Philadelphia, PA; the Department of Pediatrics (S.J.K.), Baylor College of of extrahepatic siderosis by MRI16,17 and/or oral mucosal biopsy,18,19 or by a maMedicine, Texas Children’s Hospital, Houston, TX; ternal sibling having been diagnosed with NH by these methods or at autopsy. In Children’s Memorial Hospital (S.K.), Chicago, IL; the Department of Pediatrics (C.L.M., R.J.S.), The Children’s 1 subject, the diagnosis was made at the time of open liver biopsy for evaluation Hospital, University of Colorado Denver, Aurora, CO; the
ET IVIG NH OLT
Exchange transfusion Intravenous immunoglobulin Neonatal hemochromatosis Orthotopic liver transplantation
Department of Pediatrics (J.J.M.), Alfred I DuPont Hospital for Children, Wilmington, DE; the Department of Pediatrics (P.F.W.), Children’s Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, IL The authors declare no conflicts of interest, real or perceived. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.04.012
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Vol. 155, No. 4 October 2009 of cholestasis; the histopathology was considered to be characteristic; thus, given the clinical setting, further evaluation was not performed. None of the subjects’ mothers had received IVIG therapy during the affected pregnancy. Affected neonates received therapy with ET and/or IVIG. ET was performed per local clinical protocol as used for the treatment of hyperbilirubinemia using blood bank components: packed RBCs reconstituted with fresh frozen plasma to a hematocrit of 40% to 50%. The recommended volume of ET was twice the calculated blood volume of the subject. The recommended dose of IVIG was 1 g per kg body weight. Various standard commercial preparations of IVIG were used, depending on local availability. Collection of data was approved by the IRB of Children’s Memorial Hospital (Chicago, Illinois) and submission of data by the local center’s IRB where required. Statistical Analyses The significance of differences of continuous variables measured in the subjects at different times was determined by Student t test for paired samples. Repeated-measures ANOVA was used to determine the significance of change over time for group variables. Fisher exact test was used to determine differences in outcome of the current therapy versus that of conventional therapy as extracted from the literature. Data are presented as mean standard deviation.
Results The 16 subjects were enrolled between 2004 and 2008 in 7 institutions in the United States and 1 each in The Netherlands and Australia. Table I provides basic clinical data including the results of laboratory testing and the clinical evidence of liver failure in the subjects. The gestational ages of the subjects ranged from 25 to 41 (median, 35) weeks and birth weights from 0.57 to 3.73 (median, 2.28) kg. The degree of coagulopathy qualified all subjects for
the diagnosis of liver failure: the initial prothrombin time for 15 subjects was 41.0 16.9 seconds (range, 25 to 79 seconds). One subject (patient 15) was considered to have liver failure on clinical grounds and received IVIG on day 1 and day 8 of life: a prothrombin time was measured on day 13, when it was 23.4 seconds. Seven subjects required prolonged mechanical ventilation. Ten were reported to be hypoglycemic to the degree that they required increased glucose infusion rates to maintain adequate blood glucose concentrations. Six subjects showed significant ascites either clinically or by imaging, two in association with anasarca (hydrops). Conventional Treatment Thirteen subjects received some constituents of the combination of chelating agents and antioxidants that has been used for treating NH4,6: 10 received vitamin E; 10 N-acetylcysteine; 9 deferoxamine; 7 selenium; and 4 PGE-1. Fifteen subjects received some support for coagulation: 13 received continuous or repeated infusions of FFP; 8 received cryoprecipitate; and 3 received recombinant factor VII infusions. Eight subjects received pressors to maintain blood pressure. Five subjects developed severe bacterial infection (sepsis or peritonitis), 3 while the subject was receiving deferoxamine, which can impair neutrophil function.20 No significant improvement in the clinical status of the patients was observed up to the point of ET/IVIG treatment. Although the prothrombin times recorded immediately before this treatment in 15 subjects (30.1 7.5 seconds) were somewhat improved relative to those initially recorded (41.0 16.9 seconds; P = .04), most of the subjects were receiving intravenous support for coagulation. Otherwise, conventional treatment appeared to have had no beneficial effects. ET/IVIG Treatment This therapy was initiated on day of life 1 through 30 (15.1 9.0 days). There was no difference in the day of initiation of
Table I. Subject characteristics and findings defining liver failure associated with NH Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Gestational age (wk)
Birth weight (kg)
NH diagnosis*
Initial PT (s)
Ferritin (ng/mL)
ALT IU/L
Hypoglycemia
Ascites
34 38 35 32 40 38 31 39 28 25 29 34 39 35 41 35
2.70 1.65 2.44 1.93 3.20 2.03 1.49 3.73 0.84 0.57 1.04 2.24 3.50 2.45 2.65 2.33
Sib MRI OMB Sib Sib Sib OMB OLB Sib Sib OMB MRI OMB,MRI OMB,MRI OMB,MRI OMB
50 46 25 79 26 52 > 60 36 46 26 28 73 31 61 ND† 30
2016 3026 807 253 1940 847 860 803 664 5509 1818 3068 1782 5065 1245
36 39 35 <6 182 55 14 35 23 52 46 97 23 55 23
Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes
Yes Yes No No No Yes Yes No No Yes No Yes No No
*NH diagnosis established by history in sibling (Sib), MRI, oral mucosal biopsy (OMB), or open liver biopsy (OLB). Prothrombin time (PT) obtained within the first week of life. ALT and ferritin values obtained when the diagnosis of NH was first considered, all within the first 4 weeks of life. †Received IVIG before the PT was measured, with PT peaking at 23.4 sec on day of life 13.
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therapy between the 12 survivors (14.4 9.8 days) and the 4 nonsurvivors (17.2 7.0 days) (P = .6). ET was performed in 13 subjects (Table II): 7 received full double-volume exchange and 6 received less (1 to 1.6 volumes). No complications of ET were recorded. All subjects received IVIG: 13 received a single dose of 1 g/kg, 1 (patient 10) received 2 doses, and 1 (patient 7) received 3 doses. One subject (patient 15) received 2 partial doses 1 week apart, totaling 875 mg/kg. No complications or side effects of IVIG administration were recorded. Treatment had only modest immediate beneficial effect on liver function as estimated by the coagulation profile (Figure). Prothrombin time measured in 11 survivors immediately before treatment was 30.7 9.1 seconds and fell to 24.8 7.8 seconds 1 day after treatment (P = .04). Thereafter, as compared with 1 day after treatment, survivors showed no significant improvement on days 3 (25.1 6.5 versus 25.0 7.1, P = .9) and 7 (22.6 7.7, P = .3). By day 14, some improvement was observed (19.6 5.7, P = .05), and by day 28 after treatment, prothrombin time fell to 17.1 5.0 seconds without the need for coagulation support (P = .002 versus 1 day after treatment). Analysis by repeated-measures ANOVA showed significant improvement over the 4 weeks after treatment (P < .0002). Treatment appeared to have an immediate effect on glucose homeostasis in survivors. Hypoglycemia resolved within 1 day of treatment in 8 of 10 subjects reported to have hypoglycemia before treatment. Two nonsurvivors (subjects 1 and 11) had persistent or intermittent hypoglycemia throughout the hospital course. Outcomes Twelve subjects had good outcome, defined as survival without OLT (Table II). The age at discharge ranged from 18 to 101 (median, 46) days, 6 to 90 (median, 35) days after initial ET/IVIG therapy. Five subjects have been followed for more than 1 year (Table II). At last follow-up, all were within normal measures for height, weight, and development, and
Table II. Treatment of NH and outcome of subjects Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 568
Age at treatment (d)
ET
IVIG
9 14 13 1 12 7 30 30 11 30 21 22 22 18 1 11
Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Outcome
Age at discharge (d)
Current age (mo)
Death OLT/Death Alive Alive Alive Alive Alive Alive Alive Alive Death OLT/Death Alive Alive Alive Alive
45 34 18 97 90 48 77 90 45 101 30 26
34 15 6 21 5 31 7 5 6 57 3 1
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Figure. The prothrombin times of 11 subjects with good outcome after ET/IVIG therapy are plotted against time expressed as the days after treatment. The zero time point is the value obtained immediately before treatment. Coagulation improved somewhat immediately after treatment, but prothrombin times did show further improvement until 4 weeks after treatment, probably reflecting the need for the liver to recover from severe insult. The central horizontal line = median; box = 25 - 75th percentile range; capped bars = maximum and minimum values. *Denotes significant difference from values recorded on day 0 and day 1 (P <.001 for both). One subject was not included in this analysis because a prothrombin time was not performed before initiating treatment.
none had residual clinical liver disease (ie, no hepatosplenomegaly and no evidence of portal hypertension) or dysfunction (ie, normal bilirubin, coagulation and liver enzymes). Poor outcome was defined as death or receipt of OLT. Two subjects received OLT (2 and 3 days after treatment); both died. Two subjects died without receiving OLT: 1 died of aspergillus infection and pulmonary hemorrhage 20 days after treatment, and 1 of multi-organ failure 17 days after treatment. Comparison with Historical Controls Table III (available at www.jpeds.com) summarizes the published data4-6,10,12-14 used to establish historical controls. The patients included in the analysis of these series were not redundant (ie, did not appear in more than 1 series). The 131 patients included were accrued from 1985 to 2008. Of these, 94 did not undergo OLT, of whom 23 survived (24%), and 37 received OLT, of whom 19 survived (51%). The overall survival was 32%. Good outcome as defined by survival without OLT was 23/131 (17%). Eighty-four of the 131 patients received chelation-antioxidant therapy, 15 (17%) of whom survived without OLT. Survival with or without OLT was no greater in those receiving chelation-antioxidant therapy than in those who did not. In summary, outcome of conventional medical therapy for NH was poor, with only 17% of patients surviving without OLT, and antioxidant-chelation therapy did not appear to affect outcome. Rand et al
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Table IV. Comparison of outcome with ET/IVIG therapy versus conventional therapy in historical controls Outcome / Treatment Y DVET/IVIG Conventional Total
Good
Poor
Total
12 23 35
4 108 112
16 131 147
Fisher exact test, P < .001 for improved outcome with ET/IVIG therapy.
Comparison of the prothrombin times between the current series of patients and the historical controls where available shows no significant difference in the degree of coagulopathy. Therefore, it can be said that the current series of patients and the historical controls are comparable in terms of degree of liver dysfunction, and the medical care they were provided was similar with the exception of the ET/IVIG therapy. The comparison of outcomes with the current ET/IVIG therapy versus that of conventional therapy drawn from published literature is provided in Table IV. Using the Fisher exact test, the current therapy significantly improved outcome (P < .001).
Discussion The approach to treating NH presented herein represents a major change from current care. Historically, NH has been difficult to treat, given the early onset of liver failure and the generally poor condition of affected infants. No medical therapy has proven effective, and data from recently published series suggest that only the application of liver transplantation can improve survival in NH.5,13,14 In the largest of these series, among 19 children with NH treated at King’s College London, the overall survival was 36%: 5 of 10 children receiving liver transplants survived, whereas only 2 of 9 (22%) not receiving liver transplant survived.5 The results from the current series suggest that ET/IVIG therapy can improve the outcome of severe NH without need for liver transplantation. Although not the intent of the study, the data show improved survival with the current therapy (12 of 14 patients not receiving OLT) compared with OLT (19 of 37 historical controls plus 0 of 2 in the current series; Fisher exact test, P < .05). In addition, several of the patients in the current series were too small to receive OLT, further arguing for the use of ET/IVIG therapy in this circumstance. This was not a randomized, controlled trial; however, it is unclear how such a treatment trial could ever be performed in the setting of severe NH. The lack of any effective medical therapy against which to compare a new therapy makes a design in equipoise impossible. Randomization between medical therapy and transplantation is likewise difficult. Even though the severity of liver disease as estimated by the degree of coagulopathy was similar in the current series and historical controls, the latter may have received different neonatal care compared with the study infants. For example, all patients receiving ET/IVIG therapy did so since 2004, making it possible that other improvements in medical care might
have affected outcome. However, the literature contains no evidence that improved general medical care of these infants over time has affected outcome. Thus, the dramatic improvement in clinical outcome demonstrated in this study, not generally observed in NH in the same timeframe, suggests that the ET/IVIG therapy is responsible. A potential confounder in this study stems from the fact that the majority of subjects received part of or the entire chelation-antioxidant combination that has been used to treat NH. Since its original description,21 the chelation-antioxidant combination has been the mainstay of medical therapy for this disease.4,6,22 However, the cumulative information in the literature reporting the use of the chelation-antioxidant combination therapy shows it to be of little benefit.4,6,23 In this study, it remained at the discretion of the clinicians caring for the individual patients to decide whether to apply the standard chelation-antioxidant combination therapy or part of it. The concomitant use of chelation-antioxidant therapy could have affected the outcome of these subjects. We, however, do not believe this is the case, based on comparison with historical controls. Currently, we believe it prudent to retain the elements of the chelation-antioxidant combination that may benefit a patient with NH and have little risk associated with their use. Acetylcysteine and vitamin E are considered safe and easily administered and may have potential benefit in the setting of NH as in other forms of acute liver failure.24,25 In contrast, the use of deferoxamine can be potentially harmful because of its inhibitory effect on neutrophil function.20 PGE-1 and selenium have no proven benefit in a setting of established liver disease such as NH. The ET/IVIG therapeutic strategy seeks to limit any ongoing liver injury mediated by maternally derived IgG. ET is intended to remove maternal alloantibody remaining in the neonate’s circulation. High-dose IVIG has many beneficial effects in IgG mediated injury,26 including displacing specific reactive IgG already bound to target antigen and binding to circulating complement, thus preventing or blunting the complement cascade that may cause cell injury. Furthermore, IVIG can interfere with the mechanisms of cell death that result from the formation of membrane attack complexes, namely caspase-dependent apoptosis and calpain-dependent oncosis (death by swelling).27 The precise mechanisms by which IVIG functions in prevention and treatment of NH are yet to be determined. Three patients in this series received no ET and several received less than full double-volume ET, yet had good outcomes. Thus, one must consider whether ET is an essential component of the treatment paradigm, or whether IVIG alone would be effective. ET, in addition to removing specific reactive antibody, adds nonreactive IgG in the amount normally found in plasma. However, the recommended 1 g/kg dose of IVIG is expected to raise the plasma IgG concentration by about 1400 mg/dL, or 2 to 5 times the normal concentration found in the plasma of normal newborn infants. Whether this level of IgG is required for optimal effect is not known. In most cases of NH, liver disease will be well established at the time of birth. The typical case of NH is characterized by
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severe liver injury with extensive loss of hepatocyte mass and fibrosis.1,28 This is a pattern of injury that typifies subacute hepatic failure in which injury has taken place over a time frame of weeks to months.1,29 One cannot say if a similar degree of pathophysiology was present in all of these cases. However, the severe coagulopathy at onset attests to the severity of the liver injury. As acute hepatic necrosis (hepatocyte death in the absence of fibrosis) has never been recorded in NH, it is highly likely that most of these cases had well-established necro-inflammatory liver disease at birth. Furthermore, 2 of the survivors had liver biopsies showing cirrhosis, and the liver explant pathology of the 2 who underwent transplant showed histopathology typical of severe NH. Thus, to benefit patients with NH, a therapy should limit or eliminate ongoing hepatocyte injury to permit survival and ultimately recovery. Any disease-specific therapy should be applied as soon as the disease is diagnosed. In this case series, the therapy was applied from 1 to 30 days after birth, which was entirely dependent on when NH was diagnosed in the individual cases. The diagnosis of NH is often delayed mainly because of unfamiliarity with the disease and lack of suspicion for it in sick neonates. In this series, there was minimal delay in establishing the diagnosis and initiating ET/IVIG therapy once the patient was transferred to the centers involved. It is not clear if outcome would have been better had treatment been initiated earlier. Survival in this series was not associated with earlier treatment in that the day of life that survivors and nonsurvivors started treatment was not different. It is intuitive that earlier use of a beneficial therapy is likely to lead to better results. In the case of IVIG, it could be used in any infant with liver failure without significant risk and with potential benefit in NH and infectious disease. Perhaps the outcome of NH could be further improved by universally applying such a strategy. The question arises as to whether IVIG might have some negative effect when used to treat NH. The 2 subjects who received liver transplants both died, whereas 51% of the historical controls receiving transplants survived. IVIG is routinely used in transplants involving chronic viral hepatitis with beneficial effect. Indeed, IVIG has been shown to be a powerful immunomodulator and to reduce allograft rejection.30 It seems, therefore, that administering IVIG to an infant who may receive a liver transplant does no harm. Some of the infants in this study received more than 1 dose of IVIG, spaced more than one week apart in every case. This was done entirely on the initiative of the local clinicians to perhaps gain some benefit in an infant slow to improve. The risk of repeat administration of high-dose IVIG appears to be very small in other conditions in which it is used such as autoimmune disease. ET/IVIG therapy resulted in minimal immediate or shortterm improvement in coagulation or other objective measure of liver function. This probably is because these patients had severely injured livers, which must recover before improvement in typical measures of function would occur. The prothrombin time in surviving patients showed only mild improvement for weeks after therapy; however, it may have prevented progressive worsening of hepatic synthetic func570
Vol. 155, No. 4 tion. Importantly, other clinical features improved shortly after IVIG, such as resolution of hypoglycemia. Regardless of the mechanisms involved, it is clear that ET/IVIG treatment had a significant positive impact on the medical status of the patients who recovered. The long-term follow-up in the current series suggests that patients whose initial recovery permits hospital discharge will fully recover in time no matter how sick they were initially. In conclusion, ET/IVIG therapy appears to improve the outcome of NH associated acute liver failure and should be considered as early as possible for treatment of this serious condition. Further studies will be needed to more clearly define the role of ET and/or IVIG for this disease and if some components of the antioxidant/chelation combination provide added benefit. n The authors thank Stokes Houck, MD, Lourens R. Pistorius, MD, Rene Romero, MD, and Shikha S. Sundaram, MD, for assistance in preparing the manuscript. Submitted for publication Nov 25, 2008; last revision received Jan 27, 2009; accepted Apr 8, 2009. Reprint requests: Dr Peter F. Whitington, 2300 N Children’s Plaza, Box 57, Chicago, IL 60614. E-mail: [email protected].
References 1. Knisely AS, Mieli-Vergani G, Whitington PF. Neonatal hemochromatosis. Gastroenterol Clin North Am 2003;32:877-89. 2. Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics 2001; 108:960-4. 3. Whitington PF. Fetal and infantile hemochromatosis. Hepatology 2006; 43:654-60. 4. Flynn DM, Mohan N, McKiernan P, Beath S, Buckels J, Mayer D, et al. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed 2003;88:F124-7. 5. Rodrigues F, Kallas M, Nash R, Cheeseman P, D’Antiga L, Rela M, et al. Neonatal hemochromatosis: medical treatment vs transplantation: the king’s experience. Liver Transpl 2005;11:1417-24. 6. Sigurdsson L, Reyes J, Kocoshis SA, Hansen TW, Rosh J, Knisely AS. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr 1998;26:85-9. 7. Sundaram SS, Alonso EM, Whitington PF. Liver transplantation in neonates. Liver Transpl 2003;9:783-8. 8. Whitington PF. Neonatal hemochromatosis: a congenital alloimmune hepatitis. Semin Liver Dis 2007;27:243-50. 9. Kelly AL, Lunt PW, Rodrigues F, Berry PJ, Flynn DM, McKiernan PJ, et al. Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet 2001;38:599-610. 10. Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics 2008;121:e1615-21. 11. Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 2004;364:1690-8. 12. Durand P, Debray D, Mandel R, Baujard C, Branchereau S, Gauthier F, et al. Acute liver failure in infancy: a 14-year experience of a pediatric liver transplantation center. J Pediatr 2001;139:871-6. 13. Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Neonatal hemochromatosis: long-term experience with favorable outcome. Pediatrics 2006;118:2060-5. 14. Heffron T, Pillen T, Welch D, Asolati M, Smallwood G, Hagedorn P, et al. Medical and surgical treatment of neonatal hemochromatosis: single center experience. Pediatr Transplant 2007;11:374-8.
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October 2009 15. Squires RH Jr., Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006; 148:652-8. 16. Hayes AM, Jaramillo D, Levy HL, Knisely AS. Neonatal hemochromatosis: diagnosis with MR imaging. AJR Am J Roentgenol 1992;159:623-5. 17. Udell IW, Barshes NR, Voloyiannis T, Lee TC, Karpen SJ, Carter BA, et al. Neonatal hemochromatosis: radiographical and histological signs. Liver Transpl 2005;11:998-1000. 18. Knisely AS, O’Shea PA, Stocks JF, Dimmick JE. Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. J Pediatr 1988;113:871-4. 19. Smith SR, Shneider BL, Magid M, Martin G, Rothschild M. Minor salivary gland biopsy in neonatal hemochromatosis. Arch Otolaryngol Head Neck Surg 2004;130:760-3. 20. Varani J, Dame MK, Diaz M, Stoolman L. Deferoxamine interferes with adhesive functions of activated human neutrophils. Shock 1996;5: 395-401. 21. Shamieh I, Kibort PK, Suchy FJ, Freese DK. Antioxidant therapy for neonatal iron storage disease (NISD). Abstract. Pediatr Res 1993;33: 109A. 22. Vohra P, Haller C, Emre S, Magid M, Holzman I, Ye MQ, et al. Neonatal hemochromatosis: the importance of early recognition of liver failure. J Pediatr 2000;136:537-41.
ORIGINAL ARTICLES 23. Leonis MA, Balistreri WF. Neonatal hemochromatosis: it’s OK to say ‘‘NO’’ to antioxidant-chelator therapy. Liver Transpl 2005;11:1323-5. 24. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with nonacetaminophen-induced acute liver failure. Liver Transpl 2008;14:25-30. 25. Lee WY, Lee SM. Protective effects of alpha-tocopherol and ischemic preconditioning on hepatic reperfusion injury. Arch Pharm Res 2005; 28:1392-9. 26. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55. 27. Arredondo J, Chernyavsky AI, Karaouni A, Grando SA. Novel mechanisms of target cell death and survival and of therapeutic action of IVIg in Pemphigus. Am J Pathol 2005;167:1531-44. 28. Silver MM, Valberg LS, Cutz E, Lines LD, Phillips MJ. Hepatic morphology and iron quantitation in perinatal hemochromatosis: comparison with a large perinatal control population, including cases with chronic liver disease. Am J Pathol 1993;143:1312-25. 29. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97-106. 30. Tha-In T, Metselaar HJ, Tilanus HW, Boor PP, Mancham S, Kuipers EJ, et al. Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: comparison to calcineurin inhibitors. Transplantation 2006;81:1725-34.
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Table III. Summary of literature regarding outcome of treatment for NH Author (Reference No.)
Years of accrual
No. of patients
No. receiving antioxidant/chelation therapy
Medical therapy/survivors
OLT/survivors
Prothrombin time (range/mean)
Sigurdsson (6) Rodriguez (5) Heffron (12) Grabhorn (11) Flynn (4) Durand (10) Whitington (9)
1985-1995 1990-2002 1997-2005 1992-2004 1990-1998 1986-2000 1989-2008
14 19 8 16 8 13 53
8 10 8 9 5 8 36
9/2 9/2 5/3 9/5 8/3 12/2 42/6
5/2 10/5 3/2 7/6 0 1/0 11/4
17-40 s 25 8 s 30 – 120 s 75 37 s 22 – 58 s 34 12 s 0-31% 12.5 16% N/A N/A N/A
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T
Methods The subjects of the study were 16 newborn infants with a clinical diagnosis of NH and liver failure. The Pediatric Acute Liver Failure (PALF; http://www.palfstudy.org) study group defines acute liver failure in young children as severe acute liver dysfunction accompanied by hepatic-based coagulopathy uncorrectable by parenteral vitamin K administration in the absence of sepsis-related disseminated intravascular coagulation.15 To meet the diagnostic criteria for coagulopathy in the absence of encephalopathy, the prothrombin From the Department of Pediatrics (E.B.R.), Children’s time must be $20 seconds or an INR $2. NH was diagnosed by demonstration Hospital of Philadelphia, Philadelphia, PA; the Department of Pediatrics (S.J.K.), Baylor College of of extrahepatic siderosis by MRI16,17 and/or oral mucosal biopsy,18,19 or by a maMedicine, Texas Children’s Hospital, Houston, TX; ternal sibling having been diagnosed with NH by these methods or at autopsy. In Children’s Memorial Hospital (S.K.), Chicago, IL; the Department of Pediatrics (C.L.M., R.J.S.), The Children’s 1 subject, the diagnosis was made at the time of open liver biopsy for evaluation Hospital, University of Colorado Denver, Aurora, CO; the
ET IVIG NH OLT
Exchange transfusion Intravenous immunoglobulin Neonatal hemochromatosis Orthotopic liver transplantation
Department of Pediatrics (J.J.M.), Alfred I DuPont Hospital for Children, Wilmington, DE; the Department of Pediatrics (P.F.W.), Children’s Memorial Hospital, Northwestern University, Feinberg School of Medicine, Chicago, IL The authors declare no conflicts of interest, real or perceived. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.04.012
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Vol. 155, No. 4 October 2009 of cholestasis; the histopathology was considered to be characteristic; thus, given the clinical setting, further evaluation was not performed. None of the subjects’ mothers had received IVIG therapy during the affected pregnancy. Affected neonates received therapy with ET and/or IVIG. ET was performed per local clinical protocol as used for the treatment of hyperbilirubinemia using blood bank components: packed RBCs reconstituted with fresh frozen plasma to a hematocrit of 40% to 50%. The recommended volume of ET was twice the calculated blood volume of the subject. The recommended dose of IVIG was 1 g per kg body weight. Various standard commercial preparations of IVIG were used, depending on local availability. Collection of data was approved by the IRB of Children’s Memorial Hospital (Chicago, Illinois) and submission of data by the local center’s IRB where required. Statistical Analyses The significance of differences of continuous variables measured in the subjects at different times was determined by Student t test for paired samples. Repeated-measures ANOVA was used to determine the significance of change over time for group variables. Fisher exact test was used to determine differences in outcome of the current therapy versus that of conventional therapy as extracted from the literature. Data are presented as mean standard deviation.
Results The 16 subjects were enrolled between 2004 and 2008 in 7 institutions in the United States and 1 each in The Netherlands and Australia. Table I provides basic clinical data including the results of laboratory testing and the clinical evidence of liver failure in the subjects. The gestational ages of the subjects ranged from 25 to 41 (median, 35) weeks and birth weights from 0.57 to 3.73 (median, 2.28) kg. The degree of coagulopathy qualified all subjects for
the diagnosis of liver failure: the initial prothrombin time for 15 subjects was 41.0 16.9 seconds (range, 25 to 79 seconds). One subject (patient 15) was considered to have liver failure on clinical grounds and received IVIG on day 1 and day 8 of life: a prothrombin time was measured on day 13, when it was 23.4 seconds. Seven subjects required prolonged mechanical ventilation. Ten were reported to be hypoglycemic to the degree that they required increased glucose infusion rates to maintain adequate blood glucose concentrations. Six subjects showed significant ascites either clinically or by imaging, two in association with anasarca (hydrops). Conventional Treatment Thirteen subjects received some constituents of the combination of chelating agents and antioxidants that has been used for treating NH4,6: 10 received vitamin E; 10 N-acetylcysteine; 9 deferoxamine; 7 selenium; and 4 PGE-1. Fifteen subjects received some support for coagulation: 13 received continuous or repeated infusions of FFP; 8 received cryoprecipitate; and 3 received recombinant factor VII infusions. Eight subjects received pressors to maintain blood pressure. Five subjects developed severe bacterial infection (sepsis or peritonitis), 3 while the subject was receiving deferoxamine, which can impair neutrophil function.20 No significant improvement in the clinical status of the patients was observed up to the point of ET/IVIG treatment. Although the prothrombin times recorded immediately before this treatment in 15 subjects (30.1 7.5 seconds) were somewhat improved relative to those initially recorded (41.0 16.9 seconds; P = .04), most of the subjects were receiving intravenous support for coagulation. Otherwise, conventional treatment appeared to have had no beneficial effects. ET/IVIG Treatment This therapy was initiated on day of life 1 through 30 (15.1 9.0 days). There was no difference in the day of initiation of
Table I. Subject characteristics and findings defining liver failure associated with NH Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Gestational age (wk)
Birth weight (kg)
NH diagnosis*
Initial PT (s)
Ferritin (ng/mL)
ALT IU/L
Hypoglycemia
Ascites
34 38 35 32 40 38 31 39 28 25 29 34 39 35 41 35
2.70 1.65 2.44 1.93 3.20 2.03 1.49 3.73 0.84 0.57 1.04 2.24 3.50 2.45 2.65 2.33
Sib MRI OMB Sib Sib Sib OMB OLB Sib Sib OMB MRI OMB,MRI OMB,MRI OMB,MRI OMB
50 46 25 79 26 52 > 60 36 46 26 28 73 31 61 ND† 30
2016 3026 807 253 1940 847 860 803 664 5509 1818 3068 1782 5065 1245
36 39 35 <6 182 55 14 35 23 52 46 97 23 55 23
Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes Yes
Yes Yes No No No Yes Yes No No Yes No Yes No No
*NH diagnosis established by history in sibling (Sib), MRI, oral mucosal biopsy (OMB), or open liver biopsy (OLB). Prothrombin time (PT) obtained within the first week of life. ALT and ferritin values obtained when the diagnosis of NH was first considered, all within the first 4 weeks of life. †Received IVIG before the PT was measured, with PT peaking at 23.4 sec on day of life 13.
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therapy between the 12 survivors (14.4 9.8 days) and the 4 nonsurvivors (17.2 7.0 days) (P = .6). ET was performed in 13 subjects (Table II): 7 received full double-volume exchange and 6 received less (1 to 1.6 volumes). No complications of ET were recorded. All subjects received IVIG: 13 received a single dose of 1 g/kg, 1 (patient 10) received 2 doses, and 1 (patient 7) received 3 doses. One subject (patient 15) received 2 partial doses 1 week apart, totaling 875 mg/kg. No complications or side effects of IVIG administration were recorded. Treatment had only modest immediate beneficial effect on liver function as estimated by the coagulation profile (Figure). Prothrombin time measured in 11 survivors immediately before treatment was 30.7 9.1 seconds and fell to 24.8 7.8 seconds 1 day after treatment (P = .04). Thereafter, as compared with 1 day after treatment, survivors showed no significant improvement on days 3 (25.1 6.5 versus 25.0 7.1, P = .9) and 7 (22.6 7.7, P = .3). By day 14, some improvement was observed (19.6 5.7, P = .05), and by day 28 after treatment, prothrombin time fell to 17.1 5.0 seconds without the need for coagulation support (P = .002 versus 1 day after treatment). Analysis by repeated-measures ANOVA showed significant improvement over the 4 weeks after treatment (P < .0002). Treatment appeared to have an immediate effect on glucose homeostasis in survivors. Hypoglycemia resolved within 1 day of treatment in 8 of 10 subjects reported to have hypoglycemia before treatment. Two nonsurvivors (subjects 1 and 11) had persistent or intermittent hypoglycemia throughout the hospital course. Outcomes Twelve subjects had good outcome, defined as survival without OLT (Table II). The age at discharge ranged from 18 to 101 (median, 46) days, 6 to 90 (median, 35) days after initial ET/IVIG therapy. Five subjects have been followed for more than 1 year (Table II). At last follow-up, all were within normal measures for height, weight, and development, and
Table II. Treatment of NH and outcome of subjects Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 568
Age at treatment (d)
ET
IVIG
9 14 13 1 12 7 30 30 11 30 21 22 22 18 1 11
Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No No
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Outcome
Age at discharge (d)
Current age (mo)
Death OLT/Death Alive Alive Alive Alive Alive Alive Alive Alive Death OLT/Death Alive Alive Alive Alive
45 34 18 97 90 48 77 90 45 101 30 26
34 15 6 21 5 31 7 5 6 57 3 1
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Figure. The prothrombin times of 11 subjects with good outcome after ET/IVIG therapy are plotted against time expressed as the days after treatment. The zero time point is the value obtained immediately before treatment. Coagulation improved somewhat immediately after treatment, but prothrombin times did show further improvement until 4 weeks after treatment, probably reflecting the need for the liver to recover from severe insult. The central horizontal line = median; box = 25 - 75th percentile range; capped bars = maximum and minimum values. *Denotes significant difference from values recorded on day 0 and day 1 (P <.001 for both). One subject was not included in this analysis because a prothrombin time was not performed before initiating treatment.
none had residual clinical liver disease (ie, no hepatosplenomegaly and no evidence of portal hypertension) or dysfunction (ie, normal bilirubin, coagulation and liver enzymes). Poor outcome was defined as death or receipt of OLT. Two subjects received OLT (2 and 3 days after treatment); both died. Two subjects died without receiving OLT: 1 died of aspergillus infection and pulmonary hemorrhage 20 days after treatment, and 1 of multi-organ failure 17 days after treatment. Comparison with Historical Controls Table III (available at www.jpeds.com) summarizes the published data4-6,10,12-14 used to establish historical controls. The patients included in the analysis of these series were not redundant (ie, did not appear in more than 1 series). The 131 patients included were accrued from 1985 to 2008. Of these, 94 did not undergo OLT, of whom 23 survived (24%), and 37 received OLT, of whom 19 survived (51%). The overall survival was 32%. Good outcome as defined by survival without OLT was 23/131 (17%). Eighty-four of the 131 patients received chelation-antioxidant therapy, 15 (17%) of whom survived without OLT. Survival with or without OLT was no greater in those receiving chelation-antioxidant therapy than in those who did not. In summary, outcome of conventional medical therapy for NH was poor, with only 17% of patients surviving without OLT, and antioxidant-chelation therapy did not appear to affect outcome. Rand et al
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Table IV. Comparison of outcome with ET/IVIG therapy versus conventional therapy in historical controls Outcome / Treatment Y DVET/IVIG Conventional Total
Good
Poor
Total
12 23 35
4 108 112
16 131 147
Fisher exact test, P < .001 for improved outcome with ET/IVIG therapy.
Comparison of the prothrombin times between the current series of patients and the historical controls where available shows no significant difference in the degree of coagulopathy. Therefore, it can be said that the current series of patients and the historical controls are comparable in terms of degree of liver dysfunction, and the medical care they were provided was similar with the exception of the ET/IVIG therapy. The comparison of outcomes with the current ET/IVIG therapy versus that of conventional therapy drawn from published literature is provided in Table IV. Using the Fisher exact test, the current therapy significantly improved outcome (P < .001).
Discussion The approach to treating NH presented herein represents a major change from current care. Historically, NH has been difficult to treat, given the early onset of liver failure and the generally poor condition of affected infants. No medical therapy has proven effective, and data from recently published series suggest that only the application of liver transplantation can improve survival in NH.5,13,14 In the largest of these series, among 19 children with NH treated at King’s College London, the overall survival was 36%: 5 of 10 children receiving liver transplants survived, whereas only 2 of 9 (22%) not receiving liver transplant survived.5 The results from the current series suggest that ET/IVIG therapy can improve the outcome of severe NH without need for liver transplantation. Although not the intent of the study, the data show improved survival with the current therapy (12 of 14 patients not receiving OLT) compared with OLT (19 of 37 historical controls plus 0 of 2 in the current series; Fisher exact test, P < .05). In addition, several of the patients in the current series were too small to receive OLT, further arguing for the use of ET/IVIG therapy in this circumstance. This was not a randomized, controlled trial; however, it is unclear how such a treatment trial could ever be performed in the setting of severe NH. The lack of any effective medical therapy against which to compare a new therapy makes a design in equipoise impossible. Randomization between medical therapy and transplantation is likewise difficult. Even though the severity of liver disease as estimated by the degree of coagulopathy was similar in the current series and historical controls, the latter may have received different neonatal care compared with the study infants. For example, all patients receiving ET/IVIG therapy did so since 2004, making it possible that other improvements in medical care might
have affected outcome. However, the literature contains no evidence that improved general medical care of these infants over time has affected outcome. Thus, the dramatic improvement in clinical outcome demonstrated in this study, not generally observed in NH in the same timeframe, suggests that the ET/IVIG therapy is responsible. A potential confounder in this study stems from the fact that the majority of subjects received part of or the entire chelation-antioxidant combination that has been used to treat NH. Since its original description,21 the chelation-antioxidant combination has been the mainstay of medical therapy for this disease.4,6,22 However, the cumulative information in the literature reporting the use of the chelation-antioxidant combination therapy shows it to be of little benefit.4,6,23 In this study, it remained at the discretion of the clinicians caring for the individual patients to decide whether to apply the standard chelation-antioxidant combination therapy or part of it. The concomitant use of chelation-antioxidant therapy could have affected the outcome of these subjects. We, however, do not believe this is the case, based on comparison with historical controls. Currently, we believe it prudent to retain the elements of the chelation-antioxidant combination that may benefit a patient with NH and have little risk associated with their use. Acetylcysteine and vitamin E are considered safe and easily administered and may have potential benefit in the setting of NH as in other forms of acute liver failure.24,25 In contrast, the use of deferoxamine can be potentially harmful because of its inhibitory effect on neutrophil function.20 PGE-1 and selenium have no proven benefit in a setting of established liver disease such as NH. The ET/IVIG therapeutic strategy seeks to limit any ongoing liver injury mediated by maternally derived IgG. ET is intended to remove maternal alloantibody remaining in the neonate’s circulation. High-dose IVIG has many beneficial effects in IgG mediated injury,26 including displacing specific reactive IgG already bound to target antigen and binding to circulating complement, thus preventing or blunting the complement cascade that may cause cell injury. Furthermore, IVIG can interfere with the mechanisms of cell death that result from the formation of membrane attack complexes, namely caspase-dependent apoptosis and calpain-dependent oncosis (death by swelling).27 The precise mechanisms by which IVIG functions in prevention and treatment of NH are yet to be determined. Three patients in this series received no ET and several received less than full double-volume ET, yet had good outcomes. Thus, one must consider whether ET is an essential component of the treatment paradigm, or whether IVIG alone would be effective. ET, in addition to removing specific reactive antibody, adds nonreactive IgG in the amount normally found in plasma. However, the recommended 1 g/kg dose of IVIG is expected to raise the plasma IgG concentration by about 1400 mg/dL, or 2 to 5 times the normal concentration found in the plasma of normal newborn infants. Whether this level of IgG is required for optimal effect is not known. In most cases of NH, liver disease will be well established at the time of birth. The typical case of NH is characterized by
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severe liver injury with extensive loss of hepatocyte mass and fibrosis.1,28 This is a pattern of injury that typifies subacute hepatic failure in which injury has taken place over a time frame of weeks to months.1,29 One cannot say if a similar degree of pathophysiology was present in all of these cases. However, the severe coagulopathy at onset attests to the severity of the liver injury. As acute hepatic necrosis (hepatocyte death in the absence of fibrosis) has never been recorded in NH, it is highly likely that most of these cases had well-established necro-inflammatory liver disease at birth. Furthermore, 2 of the survivors had liver biopsies showing cirrhosis, and the liver explant pathology of the 2 who underwent transplant showed histopathology typical of severe NH. Thus, to benefit patients with NH, a therapy should limit or eliminate ongoing hepatocyte injury to permit survival and ultimately recovery. Any disease-specific therapy should be applied as soon as the disease is diagnosed. In this case series, the therapy was applied from 1 to 30 days after birth, which was entirely dependent on when NH was diagnosed in the individual cases. The diagnosis of NH is often delayed mainly because of unfamiliarity with the disease and lack of suspicion for it in sick neonates. In this series, there was minimal delay in establishing the diagnosis and initiating ET/IVIG therapy once the patient was transferred to the centers involved. It is not clear if outcome would have been better had treatment been initiated earlier. Survival in this series was not associated with earlier treatment in that the day of life that survivors and nonsurvivors started treatment was not different. It is intuitive that earlier use of a beneficial therapy is likely to lead to better results. In the case of IVIG, it could be used in any infant with liver failure without significant risk and with potential benefit in NH and infectious disease. Perhaps the outcome of NH could be further improved by universally applying such a strategy. The question arises as to whether IVIG might have some negative effect when used to treat NH. The 2 subjects who received liver transplants both died, whereas 51% of the historical controls receiving transplants survived. IVIG is routinely used in transplants involving chronic viral hepatitis with beneficial effect. Indeed, IVIG has been shown to be a powerful immunomodulator and to reduce allograft rejection.30 It seems, therefore, that administering IVIG to an infant who may receive a liver transplant does no harm. Some of the infants in this study received more than 1 dose of IVIG, spaced more than one week apart in every case. This was done entirely on the initiative of the local clinicians to perhaps gain some benefit in an infant slow to improve. The risk of repeat administration of high-dose IVIG appears to be very small in other conditions in which it is used such as autoimmune disease. ET/IVIG therapy resulted in minimal immediate or shortterm improvement in coagulation or other objective measure of liver function. This probably is because these patients had severely injured livers, which must recover before improvement in typical measures of function would occur. The prothrombin time in surviving patients showed only mild improvement for weeks after therapy; however, it may have prevented progressive worsening of hepatic synthetic func570
Vol. 155, No. 4 tion. Importantly, other clinical features improved shortly after IVIG, such as resolution of hypoglycemia. Regardless of the mechanisms involved, it is clear that ET/IVIG treatment had a significant positive impact on the medical status of the patients who recovered. The long-term follow-up in the current series suggests that patients whose initial recovery permits hospital discharge will fully recover in time no matter how sick they were initially. In conclusion, ET/IVIG therapy appears to improve the outcome of NH associated acute liver failure and should be considered as early as possible for treatment of this serious condition. Further studies will be needed to more clearly define the role of ET and/or IVIG for this disease and if some components of the antioxidant/chelation combination provide added benefit. n The authors thank Stokes Houck, MD, Lourens R. Pistorius, MD, Rene Romero, MD, and Shikha S. Sundaram, MD, for assistance in preparing the manuscript. Submitted for publication Nov 25, 2008; last revision received Jan 27, 2009; accepted Apr 8, 2009. Reprint requests: Dr Peter F. Whitington, 2300 N Children’s Plaza, Box 57, Chicago, IL 60614. E-mail: [email protected].
References 1. Knisely AS, Mieli-Vergani G, Whitington PF. Neonatal hemochromatosis. Gastroenterol Clin North Am 2003;32:877-89. 2. Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics 2001; 108:960-4. 3. Whitington PF. Fetal and infantile hemochromatosis. Hepatology 2006; 43:654-60. 4. Flynn DM, Mohan N, McKiernan P, Beath S, Buckels J, Mayer D, et al. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed 2003;88:F124-7. 5. Rodrigues F, Kallas M, Nash R, Cheeseman P, D’Antiga L, Rela M, et al. Neonatal hemochromatosis: medical treatment vs transplantation: the king’s experience. Liver Transpl 2005;11:1417-24. 6. Sigurdsson L, Reyes J, Kocoshis SA, Hansen TW, Rosh J, Knisely AS. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr 1998;26:85-9. 7. Sundaram SS, Alonso EM, Whitington PF. Liver transplantation in neonates. Liver Transpl 2003;9:783-8. 8. Whitington PF. Neonatal hemochromatosis: a congenital alloimmune hepatitis. Semin Liver Dis 2007;27:243-50. 9. Kelly AL, Lunt PW, Rodrigues F, Berry PJ, Flynn DM, McKiernan PJ, et al. Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet 2001;38:599-610. 10. Whitington PF, Kelly S. Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin. Pediatrics 2008;121:e1615-21. 11. Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 2004;364:1690-8. 12. Durand P, Debray D, Mandel R, Baujard C, Branchereau S, Gauthier F, et al. Acute liver failure in infancy: a 14-year experience of a pediatric liver transplantation center. J Pediatr 2001;139:871-6. 13. Grabhorn E, Richter A, Burdelski M, Rogiers X, Ganschow R. Neonatal hemochromatosis: long-term experience with favorable outcome. Pediatrics 2006;118:2060-5. 14. Heffron T, Pillen T, Welch D, Asolati M, Smallwood G, Hagedorn P, et al. Medical and surgical treatment of neonatal hemochromatosis: single center experience. Pediatr Transplant 2007;11:374-8.
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October 2009 15. Squires RH Jr., Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006; 148:652-8. 16. Hayes AM, Jaramillo D, Levy HL, Knisely AS. Neonatal hemochromatosis: diagnosis with MR imaging. AJR Am J Roentgenol 1992;159:623-5. 17. Udell IW, Barshes NR, Voloyiannis T, Lee TC, Karpen SJ, Carter BA, et al. Neonatal hemochromatosis: radiographical and histological signs. Liver Transpl 2005;11:998-1000. 18. Knisely AS, O’Shea PA, Stocks JF, Dimmick JE. Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. J Pediatr 1988;113:871-4. 19. Smith SR, Shneider BL, Magid M, Martin G, Rothschild M. Minor salivary gland biopsy in neonatal hemochromatosis. Arch Otolaryngol Head Neck Surg 2004;130:760-3. 20. Varani J, Dame MK, Diaz M, Stoolman L. Deferoxamine interferes with adhesive functions of activated human neutrophils. Shock 1996;5: 395-401. 21. Shamieh I, Kibort PK, Suchy FJ, Freese DK. Antioxidant therapy for neonatal iron storage disease (NISD). Abstract. Pediatr Res 1993;33: 109A. 22. Vohra P, Haller C, Emre S, Magid M, Holzman I, Ye MQ, et al. Neonatal hemochromatosis: the importance of early recognition of liver failure. J Pediatr 2000;136:537-41.
ORIGINAL ARTICLES 23. Leonis MA, Balistreri WF. Neonatal hemochromatosis: it’s OK to say ‘‘NO’’ to antioxidant-chelator therapy. Liver Transpl 2005;11:1323-5. 24. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with nonacetaminophen-induced acute liver failure. Liver Transpl 2008;14:25-30. 25. Lee WY, Lee SM. Protective effects of alpha-tocopherol and ischemic preconditioning on hepatic reperfusion injury. Arch Pharm Res 2005; 28:1392-9. 26. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55. 27. Arredondo J, Chernyavsky AI, Karaouni A, Grando SA. Novel mechanisms of target cell death and survival and of therapeutic action of IVIg in Pemphigus. Am J Pathol 2005;167:1531-44. 28. Silver MM, Valberg LS, Cutz E, Lines LD, Phillips MJ. Hepatic morphology and iron quantitation in perinatal hemochromatosis: comparison with a large perinatal control population, including cases with chronic liver disease. Am J Pathol 1993;143:1312-25. 29. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986;6:97-106. 30. Tha-In T, Metselaar HJ, Tilanus HW, Boor PP, Mancham S, Kuipers EJ, et al. Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: comparison to calcineurin inhibitors. Transplantation 2006;81:1725-34.
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Table III. Summary of literature regarding outcome of treatment for NH Author (Reference No.)
Years of accrual
No. of patients
No. receiving antioxidant/chelation therapy
Medical therapy/survivors
OLT/survivors
Prothrombin time (range/mean)
Sigurdsson (6) Rodriguez (5) Heffron (12) Grabhorn (11) Flynn (4) Durand (10) Whitington (9)
1985-1995 1990-2002 1997-2005 1992-2004 1990-1998 1986-2000 1989-2008
14 19 8 16 8 13 53
8 10 8 9 5 8 36
9/2 9/2 5/3 9/5 8/3 12/2 42/6
5/2 10/5 3/2 7/6 0 1/0 11/4
17-40 s 25 8 s 30 – 120 s 75 37 s 22 – 58 s 34 12 s 0-31% 12.5 16% N/A N/A N/A
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