Pediatric liver transplant following near catastrophic head bleed: Lessons learned

Evaluation for liver transplant candidacy is a multidisciplinary effort that involves all aspects of clinical care including social work, nutrition, and a multitude of medical specialties. The prognosis of a pretransplant clinical condition is integrated into the decision to list a patient. Herein, we report a successful liver transplant and recovery of a 3‐month‐old male following a large right hemispheric subdural hematoma related to acute coagulopathy secondary to undiagnosed end‐stage liver disease. On presentation with jaundice, lethargy, and unequal pupils, a CT scan was obtained which demonstrated a large right subdural hematoma with herniation. Once his coagulopathy was corrected, he went for decompressive craniectomy. He survived with medically controlled seizures and improving L‐sided neglect and extremity weakness. Six weeks later, given his continued neurologic recovery and worsening liver function, the decision was made to list him for liver transplantation. One month later, he underwent orthotopic liver transplant. His post‐operative hospital course was complicated by DVTs and heparin‐induced thrombocytopenia, but no neurologic decline, and he was eventually discharged from the hospital on post‐op day 26. Three years later, he has a well‐functioning allograft and no clinically evident neurologic deficits. The prognosis following pediatric neurologic trauma remains somewhat unclear as recovery and neurologic examinations can be influenced by numerous extrinsic factors. This is one of the first reports of near full neurologic recovery of a pediatric liver transplant recipient following a large subdural hematoma with herniation.     

Orthotopic liver transplant for multifocal lymphangioendotheliomatosis with thrombocytopenia

An eight‐yr‐old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach–Merritt‐like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d ‐dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post‐transplant. Post‐transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation.     

Successful liver transplantation in an infant with stage 4S(M) neuroblastoma

We report a 2.5‐month‐old infant with bilateral adrenal neuroblastoma, stage 4S(M), with liver metastases and chemotherapy‐induced veno‐occlusive disease leading to cirrhosis requiring liver transplantation. Despite unknown tumour histology and MYCN‐amplification status, we proceeded with liver transplant. This decision was based on clinical suspicion that our patient was MYCN‐negative due to significant tumour regression, and was supported by evidence indicating that MYCN‐amplification is rare in infants with favourable‐stage neuroblastoma. This is the second case report of neuroblastoma requiring liver transplantation; however, in the previously reported case, the diagnosis of neuroblastoma was not established until after transplantation. We discuss this unique case to justify the potential use of life‐saving liver transplants in infants with neuroblastoma. Pediatr Blood Cancer 2013; 60: 515–517. © 2012 Wiley Periodicals, Inc.     

Paediatric acute liver failure: a practical approach

Acute liver failure (ALF) in the paediatric patient is a multisystem complex disorder, which occurs in the absence of chronic liver disease. Globally, viruses remain a common cause but drugs, metabolic and autoimmune conditions are important triggers. In up to half of cases no specific cause is identified. The definition entails a coagulopathy with a Prothrombin time (PT) ≥ 15seconds or International Normalized Ratio (INR) ≥ 1.5 not corrected by vitamin K in the presence of hepatic encephalopathy (HE) or a PT ≥ 20 or INR ≥2 or above regardless of HE. HE can be difficult to recognize in children and is defined differently than HE in adults. Timely recognition of ALF improves outcomes and allows time to undertake investigations, provide supportive therapy and arrange transfer to a specialist paediatric liver centre with transplant capacity. The purpose of this article is to review the aetiologies of ALF in children and outline an approach to investigation, management and treatment.     

Pathology teach and tell: fibrinogen storage disease in a child with hypofibrinogenemia and decreased ceruloplasmin

The authors present a clinical case of a patient with mild liver disease and coagulopathy. The diagnosis was reached through careful histologic examination of liver biopsy. Electron microscopy played an important role in confirming the diagnosis.     

A rare case of adenoviral fulminant hepatic necrosis after chemotherapy

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

A RARE CASE OF ADENOVIRAL FULMINANT HEPATIC NECROSIS AFTER CHEMOTHERAPY

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

Domino as a bridge to definitive liver transplantation in a neonate

An interim liver transplant was used to extend survival in a neonate. This was accomplished by the initial transplant of a left-lateral segment of a metabolically abnormal liver obtained from a 7-yr-old patient with primary oxalosis. This bridging strategy was required because our neonatal patient was dying of fulminant hepatic failure caused by hepatic vein thrombosis and a small liver or liver segment could not be found. Although problems with hyperoxaluria were encountered in the neonate post-transplant, the interim liver transplant enabled the baby to survive and grow until the age of 4 months. At that time, a definitive transplant was performed using the left-lateral segment of his mother's liver. This case represents the first reported use of a pediatric domino transplant where a metabolically abnormal liver was used to allow sufficient growth to permit a definitive liver transplantation.     

Tyrosinemia type 1 should be suspected in infants with severe coagulopathy even in the absence of other signs of liver failure

Tyrosinemia type l is an inherited metabolic disorder attributable to deficiency of fumarylacetoacetate hydrolase, a terminal enzyme in the degradation pathway of tyrosine. Affected individuals may present with any of a number of signs and symptoms, including failure to thrive, fever, vomiting, diarrhea, hepatomegaly, ascites, jaundice, renal Fanconi syndrome, or conditions such as rickets and hepatocellular carcinoma.1 If untreated, the patient may die of acute liver failure before the second year of life, or from chronic liver failure or hepatocellular carcinoma before the end of the second decade of life.2 Although overt liver failure with coagulopathy may be part of the presentation of tyrosinemia, a significant coagulopathy in the absence of overt signs of liver disease has not been emphasized as a clue to the diagnosis of this condition. We report two tyrosinemic infants who presented with severe coagulopathies and no other signs of liver failure to stress this diagnostic point.     

Treatment of pediatric plasma cell myeloma type post‐transplant lymphoproliferative disorder with modern risk‐directed therapy

Post‐transplant lymphoproliferative disorder (PTLD) related plasma cell neoplasms are rare in pediatric patients. We report a pediatric liver transplant recipient with plasma cell myeloma type PTLD. Cytogenetics included 1q duplication, associated with poor prognosis in adult multiple myeloma, and t(8;14). High‐risk cytogenetics has not been reported in pediatric plasma cell myeloma type PTLD. The patient was treated with bortezomib, dexamethasone, and lenalidomide with subsequent autologous stem cell transplant. He achieved a 6‐year remission, demonstrating tolerance to and efficacy of this modern myeloma regimen in a pediatric patient. Unfortunately, he subsequently died from complications of repeat liver transplant.     

Multivisceral transplantation using a 2.9 kg neonatal donor

Cauley RP, Suh MY, Kamin DS, Lillehei CW, Jenkins RL, Jonas MM, Vakili K, Kim HB. Multivisceral transplantation using a 2.9 kg neonatal donor. Abstract: Prematurity and very low birthweight have often been considered relative contraindications to neonatal organ donation. Organ procurement from neonatal donors is further complicated by unclear guidelines regarding neonatal brain death. We report a successful case of multivisceral transplantation using a graft from a 10‐day‐old, 2.9 kg, neonatal donor born at 36 6/7 wk in a 3.2 kg, three month old with intestinal and liver failure secondary to midgut volvulus. There was immediate liver graft function with correction of recipient coagulopathy, but delayed normalization of laboratory values and delayed return of bowel function. At six‐yr post‐transplant follow‐up, the patient has normal intestine and liver function. Her last histologically confirmed rejection episode was 30 months prior to last follow‐up. This case suggests that multivisceral grafts from very young or small neonatal donors may be transplanted successfully in selected cases. We propose a re‐examination of the brain death guidelines for premature and young infants to potentially increase the availability of organs for infant recipients.     

Hepatocellular carcinoma in a 10‐month‐old biliary atresia child

Abstract: We present a case of a 10‐month‐old boy with BA who developed HCC and was treated with liver transplantation. A four‐month‐old boy was referred to our institution because of persistent jaundice, hepatomegaly, and coagulopathy. He had been treated for the diagnosis of neonatal hepatitis at an outside hospital. He was evaluated and was accepted as a liver transplant candidate, and was subsequently transplanted with a deceased donor liver allograft at the age of 10 months. His native liver showed established cirrhosis because of BA with one focus of moderately differentiated HCC, measuring 0.7 cm in a diameter with microscopic vascular invasion in pathological study. The postoperative course was uneventful, and he is well without recurrence four months after liver transplantation. The occurrence of HCC in a child under one yr old is extremely rare, and only three cases are reported so far including our case.     

Use of a donor iliac vein graft for reconstruction of the inferior vena cava in liver transplantation for hepatoblastoma with caval extension

Complete microscopic tumor resection is critical for successful treatment of hepatoblastoma, and this may include when liver transplantation is required. For tumors involving the IVC or PV, complete resection should include the involved IVC or PV to ensure full tumor clearance. When this is required, the venous reconstruction at transplant or post‐excision can be challenging. We present the management of an 18‐month‐old girl with PRETEXT Stage IV (P, V, F) hepatoblastoma and IVC involvement, where native caval resection and reconstruction was required. The preoperative staging following neoadjuvant chemotherapy was POSTTEXT Stage IV (P, V, F). An orthotopic liver transplantation was performed using a left lateral segment graft from a deceased adult donor. With native hepatectomy, retrohepatic IVC resection from just above the hepatic venous confluence to just above the entry of the right adrenal vein was performed. For caval reconstruction, a venous graft from a deceased donor was used. The graft included the lower IVC with the right common iliac vein and a short stump of the left common iliac vein. The common iliac was a perfect size match for the IVC, and the three natural ostia matched the upper cava, lower cava, and the outflow from the donor left hepatic vein. The patient had an uneventful postoperative course and remains well and disease‐free 2 years after transplant with continued patency of the reconstructed cava. When indicated, a donor iliac vein graft with its natural ostia should be considered in caval reconstruction for pediatric liver transplantation.     

Development of hepatopulmonary syndrome and portopulmonary hypertension in a paediatric liver transplant patient

BACKGROUND: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are pulmonary vascular disorders which occur in patients with severe liver disease and/or portal hypertension. Although these syndromes are frequently diagnosed in patients undergoing assessment for liver transplantation, they seldom occur in the same patient. METHOD: This report describes a female paediatric patient, born with extra-hepatic biliary atresia, who required liver transplantation, at the age of 15, for secondary biliary cirrhosis. She had severe HPS prior to her first liver transplant, which resolved rapidly following surgery, as well as indirect evidence for PPH. She required a second liver transplant 1 yr later for chronic rejection. Whilst evaluating the patient for a third liver transplant, 4 yr later, severe PPH was discovered. The patient died 3 months later from right heart failure. CONCLUSION: HPS and PPH may coexist however they may show differing responses to liver transplantation with progression of PPH despite the resolution of HPS.     

A fetal case of transient abnormal myelopoiesis with severe liver failure in Down syndrome: prognostic value of serum markers

The authors recently encountered a lethal case of Down syndrome with transient abnormal myelopoiesis (TAM). Although the peripheral white blood cell count and blast cells had improved without specific treatment, the patient died of severe coagulopathy due to liver fibrosis when he was 5 years old. The prognosis of TAM with liver fibrosis was poor. The patient had high levels of N-terminal peptide of III procollagen, type IV collagen, and hyaluronic acid. These serum makers are noninvasive indicators of liver fibrosis and may be useful as prognostic indicators of TAM in Down syndrome.     

Bone marrow engraftment and associated dermatologic sequelae in a three‐yr‐old after liver transplantation

We present a case of a three‐yr‐old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft‐vs.‐host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post‐transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft‐versus‐host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described.     

Liver transplantation in a case of hypoproteinemia and coagulopathy

A female infant with hypoproteinemia and coagulopathy associated with hypertyrosinemia was successfully treated with living-related liver transplantation (LRLT). On the 12th day of life plasma amino acid analysis revealed a marked elevation of tyrosine, so the patient was fed on a low-tyrosine and low-phenylalanine diet. However, hepatosplenomegaly. hypotonia, alopecia, eczema and psychomotor delay did not improve and recurrent episodes of disseminated intravascular coagulation (DIC) caused her condition to deteriorate. Liver biopsy on the 230th day revealed marked fatty change accompanied by mild to moderate cholestasis. Therefore. LRLT from her father was performed on the 286th day resulting in improvement of all the aforementioned signs and symptoms. Despite a thorough examination, no diagnosis of a known disorder could be established. However, her elder brother had also been born with severe hypoproteinemia and coagulopathy, and died of DIC on the second day of life. Thus, the disorder is designated as a new entity, namely ‘congenital hypoproteinemia and coagulopathy associated with hypertyrosinemia’.     

Coagulation Studies in Haemolytic Uraemic Syndrome

Serial coagulation investigations were performed in 4 children with the haemolytic uraemic syndrome treated with heparin by continuous infusion. 2 anuric patients showed consumption of factor V and fibrinogen early in the disease, with thrombocytopenia and raised fibrin degradation products. These changes regressed during heparin therapy and renal function fully recovered in both patients. A third patient with a mild form of the disease, normal urinary output, and only borderline thrombocytopenia did not develop demonstrable depletion of factor V or fibrinogen. In a further patient a secondary `wave'' of consumption of platelets and perhaps fibrinogen was seen late in the course of the disease. These findings confirmed the occurrence of a consumptive coagulopathy in severe cases of haemolytic uraemic syndrome.     

Akutes Leberversagen im Kindesalter

Acute liver failure, defined as the onset of hepatic coagulopathy with an INR ≥1.5 (which is not corrected by vitamin K administration) with encephalopathy or with an INR ≥2.0 without encephalopathy, is a life-threatening disorder. Timely referral of the patient to a transplant center can, when all therapeutic strategies are employed, result in survival rates of approximately 70%. In neonates and infants infectious and metabolic causes as well as neonatal hemochromatosis are predominant. In small children, particularly school-age children, drug-induced or autoimmune causes as well as Wilson’s disease play an increasing role. Almost 50% of cases remain etiologically uncertain. Therapy is based on etiology and is symptomatic in many cases. Since cerebral edema is the primary cause of death, restriction of fluid and sodium chloride is important; in addition, the head should be maintained in an elevated position. Despite unfavorable coagulation values, bleeding is an exception; fresh plasma should therefore be used with restraint.     

Solitary hepatic hemangioma in a newborn infant complicated by cardiac failure,consumption coagulopathy,microangiopathic hemolytic anemia,and obstructive jaundice

A newborn infant with a large hepatic hemangioma developed congestive heart failure, consumption coagulopathy, microangiopathic hemolytic anemia, and obstructive jaundice. The patient was mildly heparinized (250 units per kg and day) and underwent successful resection of the tumor without lobectomy at the age of 3 days. Blood volume increased from 93.9 ml/kg at the age of 5 h to 124.2 ml/kg prior to surgery. Red-cell mass simultaneously decreased from 53.8 to 39.4 ml/kg. The increase of blood volume is explained by congestive heart failure, the decrease of red-cell mass by intravascular coagulation within the tumor resulting in formation of thrombi and microangiopathic hemolytic anemia. A review of the literature on infants with symptoms caused by an intrahepatic hemangioma during the first month of life confirms that surgical intervention is the treatment of choice for infants with giant solitary hemangioma of the liver.Supported by Deutsche Forschungsgemeinschaft (SFB 147)