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Successful Liver Transplants for Marie-Eve Chartier, MD,​a Lara Hart, MD,b​ Massimiliano Paganelli, MD, PhD,​a NajmaLiver Ahmed, MD, Failureb​ Marc Bilodeau, MD,​c FernandoAssociated Alvarez, MDa With Pyruvate Deficiency abstract

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic , and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and . Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal aDivision of , , and , cholestasis and a young adult with a severe form of PKD and having been Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada; bDivision of transfusion dependent during childhood. After transplant, both patients Gastroenterology, Hepatology, and Nutrition, Montreal have normal liver function test results and have considerably decreased Children’s Hospital, McGill University, Montreal, Quebec, Canada; and cLiver Unit, Department of , Université their need for transfusion despite ongoing, mild . We de Montréal, Montréal, Quebec, Canada suggest that PKD can to severe liver dysfunction and that LT and Dr Chartier wrote the manuscript; Drs Hart, splenectomy can be life-saving procedures in such cases. Paganelli, Alvarez, Ahmed, and Bilodeau reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. deficiency (PKD) is We describe 2 patients with severe DOI: https://​doi.​org/​10.​1542/​peds.​2016-​3896 the most common cause of congenital PKD presenting with cholestasis Accepted for publication Jun 12, 2017 nonspherocytic chronic hemolytic and liver failure who required LT: a Address correspondence to Fernando Alvarez, anemia. Children with PKD can have 5-month-old infant and a 21-year-old MD, Division of Gastroenterology, Hepatology, and a wide range of presentations, from adult. Both underwent splenectomy Nutrition, CHU Sainte-Justine, 3175 Cote Sainte- Catherine, Montreal, QC H3T 1C5, Canada. E-mail: unconjugated hyperbilirubinemia at the time of transplant and have [email protected] with mild asymptomatic anemia maintained normal liver function (ISSN Numbers: Print, 0031-4005; Online, to severe,1 transfusion-dependent test results and a decreased need 1098-4275). anemia. Because PKD is an autosomal- for transfusion. To our knowledge, Copyright © 2018 by the American Academy of recessive disorder, it is clinically silent these are the first patients to have Pediatrics in heterozygous carriers; however, successfully undergone LT for PKD. CASE PATIENT 1 FINANCIAL DISCLOSURE: The authors have serious manifestations can present indicated they have no financial relationships at birth in homozygous or2 compound 3 relevant to this article to disclose. heterozygote phenotypes. Gilsanz et al FUNDING: No external funding. reported that PKD could present as A 3.6 kg, term infant was born POTENTIAL CONFLICT OF INTEREST: The authors stillbirths or early neonatal deaths after an uncomplicated have indicated they have no potential conflicts of because of nonimmune . and delivery. He was the firstborn interest to disclose. The development of liver failure is of nonconsanguineous, French- exceptionally rare, with only 3 cases of Canadian parents. He developed μ To cite: Chartier M-E, Hart L, Paganelli M, et al. severe hepatic dysfunction associated at 18 hours of life (total Successful Liver Transplants for Liver Failure with PKD being reported in the bilirubin 349 mol/L) with significant Associated With Pyruvate Kinase Deficiency. literature; all 3 infants died waiting for , Coombs-negative Pediatrics. 2018;141(s5):e20163896 liver transplant4,5​ (LT) or immediately autoimmune hemolytic anemia, thereafter. indicating the likelihood of hemolysis Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number s5, April 2018:e20163896 CASE REPORT in utero and hepatosplenomegaly. μ Conjugated bilirubin was 106 mol/L, liver enzymes were mildly elevated (aspartate aminotransferase: 101 IU/L; alanine aminotransferase [ALT]: 36 IU/L), but synthetic functions (such as international normalized ratio, albumin, and glucose) were normal. Exchange transfusion was performed at 24 hours of life. Weekly follow-up showed a γ slowly increasing direct bilirubin; however, his -glutamyl transferase (GGT) remained normal, and stools pigmented (Fig 1). An extensive workup following North American Society for Pediatric Gastroenterology, Hepatology, and

Nutrition guidelines ruled out 6other causes of neonatal cholestasis. A liver biopsy at 2 months showed FIGURE 1 cholestasis, giant cell hepatitis Laboratory results pre- and post-LT for case patient 1. Curves showing the weekly progression in with mild pericellular fibrosis, mild cholestasis with a concomitant rise in ALT but normal GGT as the progressed in case patient 1. There was normalization of the liver enzymes after LT. deposition, and extramedullar hematopoiesis (Fig 2 A and B). The initial evaluation revealed low-normal pyruvate kinase (PK) enzyme levels, likely falsely elevated from repeated blood transfusions. Pyruvate kinase liver and red (PKLR) gene sequencing showed 2 pathologic heterozygous mutations (c.1529G>A [p.Arg510Gln] and c.1091G>A [p.Gly364Asp]), which confirmed the diagnosis of PKD. FIGURE 2 Liver biopsy of case patient 1. A, Liver biopsy 1 shows giant cell hepatitis with periportal lymphocytes At 3.5 months old, he developed infiltration. In the parenchyma, there is extramedullary hematopoiesis. There is no ductopenia or progressive liver failure with bile duct proliferation. B, Trichrome coloration of liver biopsy 1 shows mild fibrosis. C, Trichrome new-onset ascites and respiratory coloration of liver biopsy 2 done 1 month later showed increased fibrosis compared with the first μ biopsy. compromise. Total bilirubin μ increased to 850 mol/L, and direct bilirubin increased to 660 mol/L (Fig 1). He required biweekly have remained normal (Fig 1). He is He required exchange transfusion albumin transfusions, abdominal on immunosuppressive with at 8 hours of life for severe paracentesis, and blood transfusions. tacrolimus and is transfusion free hyperbilirubinemia secondary to A repeat liver biopsy (Fig 2C) showed with a level of >85 g/L. Coombs-negative autoimmune a progression of fibrosis (Metavir hemolytic anemia. Thorough etiologic stage 2 of 4) but stable iron levels. CASE PATIENT 2 At 5.5 months old, he had a transplant evaluation for hyperbilirubinemia with a cadaveric, reduced liver, and had a negative result. He was not a splenectomy was performed to A 2.9 kg, term infant was born tested for PK enzyme activity before decrease hemolysis and the need for after an uncomplicated pregnancy the exchange transfusion, but transfusion. Sixteen months after LT, and delivery. The parents were both parents had decreased levels his liver enzymes and direct bilirubin consanguineous at a fifth degree. (heterozygous carriers). Subsequent Downloaded from www.aappublications.org/news by guest on September 23, 2021 S386 CHARTIER et al 11 PKLR gene sequencing showed 2 by PK-R and PK-L, respectively. pathologic heterozygous mutations Persistent PK-M2 isoenzyme in (c.1529G>A [p.Arg510Gln] and mature RBCs and the liver has c.1195del [pAla399Leufs*20]). been reported in few patients with severe PKD and is hypothesized to During the first 3 years of life, he be a compensatory mechanism to required monthly transfusions – decrease hemolysis and prevent to maintain a hemoglobin level FIGURE 3 14 17 liver dysfunction. ‍ ‍ In a recent of >70 g/L, but this decreased Liver biopsy of case patient 2 showing mild 18 article, Diez et al questioned this progressively to biannually. portal fibrosis and ductular proliferation. PK-M2 compensatory expression Because of severe hemolysis, and suggested that a mitochondrial he developed cholelithiasis oxidative phosphorylation remnant and cholecystitis and required and candidal infection. He is now contributed to the RBC energy cholecystectomy at 2.5 years old. 5 years post-LT and has slightly supply. They described a patient However, he continued having elevated, indirect bilirubin from with transfusion-dependent anemia obstructive choledocholithiasis and persistent mild hemolysis, but he because of a PKLR-null mutation and required a hepaticojejunostomy has only required blood transfusions the absence of compensatory PK-M2 at 3 years old. He was maintained during infections or minor . expression in the RBCs. However, on ursodeoxycholic acid (UDCA) PKLR Immunosuppression is maintained PK-M2 was not tested in the liver. thereafter. Liver biopsy, done at 10 with tacrolimus. Therefore, mutations in the years old, results showed moderate gene generally result in clinical parenchymal hemosiderosis (iron dry DISCUSSION – symptoms that are confined to RBC weight of 14.8 mg/g) but no fibrosis 15 20 rather than liver damage. ‍ ‍ (Fig 3). Splenectomy was offered repeatedly but was refused by the There are 3 reported cases of PKD PKD is the most common glycolytic parents. presenting as neonatal conjugated enzyme defect resulting in chronic 7 hyperbilirubinemia and liver failure At 18 years old, he required blood hereditary hemolytic anemia. (Table 1). In all cases, the children transfusions yearly, had persistent It was first described in 1961 by μ 8 presented at birth with severe unconjugated hyperbilirubinemia Valentine et al,​ and its prevalence μ anemia, hepatosplenomegaly, and (total bilirubin 465 mol/L; is estimated at 1 in 20000 in the 9 cholestasis with normal GGT levels. direct bilirubin 24 mol/L), white population. It is an autosomal- Their initial course was comparable normal GGT, and slightly elevated recessive condition caused by a to our first patient. Cholestasis and transaminases (ALT: 43 IU/L; reduction in the PK enzyme liver dysfunction progressed rapidly, aspartate aminotransferase: 81 or the production of an abnormal 10,11​ and all 3 died before 5 months of age IU/L). Liver function was normal. and low-functioning enzyme. from posttransplant complications He was subsequently lost to PK is essential for 4,5​ ë or while awaiting . ‍ It was follow-up and discontinued UDCA. (RBC) energy metabolism because 5 therefore suggested by Rapha l et al He returned at 21 years old with it is involved in the conversion of that liver failure was directly extreme , jaundice, and liver adenosine diphosphate to adenosine μ linked to PKD. Although PK-M2 failure. His hemoglobin was 30 g/L, triphosphate in mature erythrocytes. μ PKLR was not measured, we hypothesize total bilirubin was 1384 mol/L, PKD is caused by a mutation in the that liver failure is related to direct bilirubin was 592 mol/L, gene on chromosome 1q21. In individual differences in metabolic international normalized ratio was humans, PK activity is provided by 4 PKLR and proteolytic activity and a 1.6, and albumin was 26 g/L. No isoenzymes encoded by 2 genes. The compensatory presence or absence of etiology other than PKD was found to gene expresses as both PK-L (in 17,19​ PK-M the PK-M2 isoenzyme. ‍ explain the liver failure. He required the liver) and PK-R (in mature RBCs), and inotropic support for whereas the gene, which is More than 250 different mutations renal insufficiency and hemodynamic found on chromosome 15, expresses have been described in patients with instability pretransplant. He was as PK-M1 (in skeletal muscles, the PKD, and they account for2, the21,​ 22​ variable transplanted at 21.5 years old with , and the brain) and PK-M2 (in severity of presentation. ‍ ‍ a cadaveric liver, and a splenectomy proliferating12, fetal13​ tissues and RBC The most common mutation in1,2​ was performed. Liver precursors). ‍ PK-M2 is expressed white patients is in 1529G>A,​ showed signs of chronic cholestasis early in erythroid precursors and in and both our patients harbored this with extensive hepatolithiasis, immature hepatocytes, but as cells mutation. The 2 other mutations moderate fibrosis, mild , differentiate, PK-M2 is replaced seen in our patients (c.1091G>A and Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number s5, April 2018 S387 TABLE 1 Cases of PKD and Liver Failure Described in the Literature Age at Onset of Mutations Surgery Age of Death Cause of Death Reference Symptoms Birth c.1195del /c.721G>T NA (waiting for 3 mo Sepsis Olivier et al4 2015 splenectomy and LT) Birth c.1529G> A /IVS62A>T Splenectomy at 4 mo 5 mo Irreversible lung Raphaël et al5 2007 hemorrhage Birth c.1529G> A /c.1269G>A LT at 4 mo 4 mo (hours after LT) Progressive circulatory Raphaël et al5 2007 insufficiency Birth c.1529G>A /c.1091G>A LT and splenectomy at Alive and doing well at NA Case 1 5.5 mo 16 mo Birth c.1529G>A/c.1195del LT and splenectomy at 21 y Alive and doing well at 26 y NA Case 2 NA, not applicable.

ABBREVIATIONS c.1195del) have also been described in the pathogenesis of liver failure. to induce severe hemolysis in the Several case patients with PKD have γ 11,23,​ 24​ ALT: alanine aminotransferase homozygous state. ‍ ‍ Van Solinge described increased levels 23 GGT:  -glutamyl transferase et al described a 6-week-old and saturation, and a few LT: liver transplant infant with homozygous c.1091G>A have reported multiorgan failure 27,28​ PK: pyruvate kinase who died of severe hemolysis, secondary to iron overload,​ ‍ with 24 PKD: pyruvate kinase deficiency and Rouger et al described 2 patients responding to iron chelation. PKLR: pyruvate kinase liver and case patients with hydrops fetalis The pathogenesis of iron overload red blood cell and homozygous c.1195del in a is likely multifactorial, with chronic RBC: red blood cell consanguineous family. Likewise, hemolysis, multiple transfusions, UDCA: ursodeoxycholic acid the combination of 1529 and 1091 and ineffective mutations was described in 3 triggering an increase in intestinal REFERENCES – patients and resulted in a severe, iron absorption. However, iron 1. Grace RF, Zanella A, Neufeld EJ, et al. dependent23 accumulation is not expected to occur Erythrocyte pyruvate kinase deficiency: anemia but not liver failure. in the neonatal period. This raises 2015 status report. Am J Hematol. Therefore, liver failure cannot be the possibility that iron accumulation 2015;90(9):825–830 explained solely by the severity of in PKD may be associated with 2. Pissard S, Max-Audit I, Skopinski the mutations. an anomaly in , which L, et al. Pyruvate kinase deficiency is a protein that29 maintains iron in France: a 3-year study reveals Other hypotheses have been . 27 new mutations. 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Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number s5, April 2018 S389 Successful Liver Transplants for Liver Failure Associated With Pyruvate Kinase Deficiency Marie-Eve Chartier, Lara Hart, Massimiliano Paganelli, Najma Ahmed, Marc Bilodeau and Fernando Alvarez Pediatrics 2018;141;S385 DOI: 10.1542/peds.2016-3896

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Downloaded from www.aappublications.org/news by guest on September 23, 2021 Successful Liver Transplants for Liver Failure Associated With Pyruvate Kinase Deficiency Marie-Eve Chartier, Lara Hart, Massimiliano Paganelli, Najma Ahmed, Marc Bilodeau and Fernando Alvarez Pediatrics 2018;141;S385 DOI: 10.1542/peds.2016-3896

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