Pediatric liver booklet withcover 28aug2014 by shirley vidad

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COMPENDIUM Pediatric Liver Transplant Hepatology

1 Introduction Pediatric liver transplantation has come to age. Thousands of patients in the pediatric age group have been transplanted world-wide (1,2). Even in the Middle East, pediatric liver transplant programs have been established and been very successful (3, 4). The aim of this compendium is to give a comprehensive guideline how to manage this complex and demanding procedure. It will focus mainly on the pediatric aspect of liver transplantation.

2 Indications for Pediatric Liver Transplantation In Europe, North-America and Asia the most frequent indication for liver transplantation is extrahepatic biliary atresia. In this disease a chronic end stage secondary biliary cirrhosis develops extremely fast and liver transplantation either after or without Kasai procedure will be inevetible. In Saudi Arabia however, the metabolic disorders play an even greater role (3,4). Due to the fact that in this country more than 60 % of the marriages are consanguinous, the resulting genetic background is responsible for many familial cholestatic and non-cholestatic liver diseases ( Fig. 1). These can cause chronic end stage liver disease or failure of one or several other organs. The presentation of these genetic / metabolic disorders may even be that of an acute liver failure. In these patients the time window for a transplantation in time is very narrow. In some occasions the decision to go ahead with liver transplantation has to be made even before the defect is confirmed by either enzymatic or genetic analysis. A third group of patients is that of so called cryptogenic disorders where a final diagnosis of the underlying disease remains unclear despite any effort (4). In acute liver failure this amounts to more than 50% of patients, whereas in chronic end stage liver disease there are about 20% of patients without definite diagnosis (5, 6).

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Pediatric Liver Transplant Hepatology COMPENDIUM

Fig.1 : Distrubution of different indications in pediatric liver transplantation at KFSH from 2010-2012 ( modified from (4)). Abbreviations : BA = extrahepatic biliary atresis: FC = familial cholestasis; HMD = hepatic metabolic disease; CC = cryptogenic cirrhosis; O = others.

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COMPENDIUM Pediatric Liver Transplant Hepatology

3 Pretransplant assessment Children with end stage liver disease are at risk of several complications which need to be prevented, diagnosed and treated if possible (6). These complications are depicted in table 1:

Cause Portal Hypertension

Complication GI Bleeding Ascites SBP

Liver Dysfunction

Encephalopathy Brain Edema Malnutrition Catabolic State Osteopathy HRS HPS / PPS ACLF

Table 1 : Complications of portal hypertension and liver dysfunction. Abbreviations : GI = gastrointestinal; SBP = spontaneous bacterial peritonitis; HRS = hepato-renal syndrome; HPS / PPS = hepatopulmonary syndrome; PPS = porto-pulmonary syndrome; ACLF = acute on chronic liver failure

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a) Portal Hypertension Portal hypertension induced collaterals are frequent events in liver cirrhosis. The pressure in the portal vein system then is rising from normal 5-10 cm H2O to 40 cm and more. The varices in esophagus, stomach and duodenum are at risk for rupture.

aa) GI Bleeding This is a serious event enhanced by thrombocytopenia and coagulopathy. In most patients, bleeding varices are found, some patients bleed from severe gastropathy. In others, gastric or duodenal ulcers can cause GI bleeding. In extrahepatic biliary atresia the prevalence of variceal bleeding is up to 40% (6). Thus, endoscopy plays the most important role in diagnostic approach of these critical patients. The diagnosis of varices can be assessed by ultrasound examination because collaterals at the splenic hilum are associated with fundal or esophageal varices. Prophylactic sclerotherapy or rubber band ligation is recommended for children with grade 3 varices even before the first bleeding episode (6, 7). In an acute bleeding however, the stabilization of the patient has absolute priority over endoscopy. This patient needs support by medical therapy with somatostatin* or vasopressin analogues* and blood transfusion if necessary before endoscopy can be performed. INR and PTT have to be corrected by FFP*, Cryoprecipitate* or Factor VII a* as well, Platelets have to be substituted to an account of more than 60 mrd/L. In portal hypertension the prophylactic treatment with propranolol* is recommended even before the first bleeding episode.

ab) Ascites Ascites develops in portal hypertension and reduced albumin concentration in serum due to reduced liver synthesis rate (Fig. 2) in almost every patient. If ascites causes compression of vena cava, portal â&#x20AC;&#x201C; or renal vein or if a high diaphragm causes pulmonary insufficiency, tapping of ascites is indicated. The abdominal compartment syndrome is another serious complication indicated by high abdominal pressure. The conservative management with spironolactone* to treat the secondary hyperaldosteronism should be started

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COMPENDIUM Pediatric Liver Transplant Hepatology

as soon as possible. If necessary, loop diuretics may be given as well. The most important means however is a balance between intake and output. A negative balance should not exceed 300ml/day in small children. If necessary, albumin* substitution with 1 g albumin / kg and day with an extra bolus of furosemide* is to be given.

Fig.2 : Development of liver fibrosis and â&#x20AC;&#x201C; cirrhosis. Abbreviations : HPS = hepato-pulmonary syndrome; HRS = hepatorenal syndrome

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ac) Hypersplenic syndrome Hypersplenic syndrome (6) derives from splenomegaly, if consumption of platelets, leucocytes and erythrocytes in the enlarged spleen is greater than the capacity of the bone marrow to replace these losses. Additional effect is caused by low thrombopoetin serum levels (8). Critical leucocyte counts with regard to infection are below 10 mrd/L, critical low platelets below 15 mrd/L which enhance any GI bleeding. With regard to infectious risks, the impaired function of the RES in the liver has also to be taken into account. Children with chronic end stage liver disease normally have a hemoglobin concentration between 7-9 g/dL. Values below 7 g/dL need to be corrected by transfusion in order to allow a sufficient oxygen transport.

ad) Spontaneous bacterial peritonitis (SBP) This life threatening complication is observed in about 10-25% of children with chronic end stage liver disease complicated by ascites (6). In children, gram-positive agents (i.e. Streptococcus pneumonia) and gram-negative bacterial agents ( i.e.enterococci) are found most often (9). Any episode of fever, abdominal distension and -pain in a patient with ascites might be the first symptoms of this complication. Diagnostic tapping should be performed with subsequent immediate antibiotic therapy as soon as possible.

ae) Hepatorenal syndrome (HRS) The hepato-renal syndrome is reported to occur in 11-47% of children with chronic end-stage liver disease (6). The pathophysiology of HRS is explained by splanchnic arterial vasodilatation and impaired cardiac output in advanced cirrhosis, leading to ineffective volume in systemic circulation. This causes an activation of the vasoconstrictor system whith a fast (HRS type 1) or slow (HRS type 2) developing renal insufficiency (Fig.3). In adults, type 1 is said to have a bad, type 2 to have a better prognosis (10). It must be differentiated from iatrogenic renal failure caused by the inappropriate use of diuretics. By means of measuring the electrolyte excretion in urin ( high in iatrogenic, low in HRS) caused renal failure it is possible to discriminate between these two features. The therapy in children is not well established, in adults albumin* and terlipressin* are used with 40-60% success if treated early.

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COMPENDIUM Pediatric Liver Transplant Hepatology

Fig.3 : Development of hepatorenal syndrome in chronic end stage liver disease. Abbreviations : HRS = hepatorenal syndrome

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af) Hepatopulmonary / portopulmonary syndrome (HPS /PPS) The hepatopulmonary syndrome is a relatively rare complication of chronic end stage liver disease and is observed in about 6-9% of pediatric patients with chronic end-stage liver disease (6). It may however be also manifest in children without cirrhosis. In these patients HPS is caused by a porto-systemic shunt for instance in Albernathy malformation. HPS is defined as chronic liver disease + intrapulmonary vascular dilatation + impaired gas exchange leading to hypoxemia on room air (Fig.4) (11). HPS must be differentiated from PPS which is defined as pulmonary arterial hypertension ( > 25 mm Hg) associated with liver cirrhosis or portal hypertension (6). Clinical symptoms are cyanosis, exortional dyspnoe, plathypnoe and orthodeoxia. That means that after diagnosing with a contrast enhanced echocardiography using agitated saline solution indirect measures of pulmonary arterial pressure are necessary. A right-heart catheter should be performed if there is suspicion of pulmonary hypertension. A useful clinical tool is measuring oxygenation in upright and head-down position. Patients with HPS show a significant improvement of oxygen saturation in the head-down position. Epoprostenol* and sildenafil* may be administered, but the best therapy in HPS is liver transplantation even if liver function is not severely impaired. In PPS with a mean pulmonary-arterial pressure > 40 mm Hg liver transplantation is contraindicated.

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COMPENDIUM Pediatric Liver Transplant Hepatology

Fig.4 : Development of hepato-pulmonary syndrome. Abbreviations : NO = nitric oxide; AV-shunts = arterio-venous shunts

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b) Cerebral Complications in Liver Disease The brain may be affected in acute and chronic liver failure (6). In acute liver failure, brain edema and brain herniation may harm the brain leading either to death or severe damage of basal ganglia. In chronic end-stage liver disease, especially in cholestatic ones, brain atrophy is the leading problem.

ba) Brain Defects In chronic liver disease, brain atrophy is caused by malnutrition plus vitamin A and â&#x20AC;&#x201C;E deficiency, hypoglycemia will induce brain edema, copper storage and hyperammonemia may cause even irreversible brain damage (12). In patients with Alagille syndrome vascular abnormalities are responsible for cerebral bleeding which can be observed in severe coagulopathy as well.

bb) Encephalopathy Encephalopathy is difficult to assess objectively the younger the patient is. Disturbed day- and night-rhythm may be the first clinical symptom. The grade of encephalopathy does not correlate with serum ammonia concentration. To measure this parameter, 2 hour postprandial measurements are more suitable than fasting values. Children may be awake and asymptomatic with ammonia concentration of 200, whereas others are in coma with values of 150 Îźmol/L. Tremor in hand writing may be of diagnostic value showing the effect of tremor. In severe stage of chronic liver disease with encephalopathy, protein intake should be restricted to not less than 1.5 g protein / kg / day. Age related dose of lactulose* is recommended in patients with high serum ammonia concentration. The issue of brain edema is discussed in acute liver failure

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COMPENDIUM Pediatric Liver Transplant Hepatology

c) Catabolic State and Osteodystrophy ca) Malnutrition If protein production in the liver does not meet the need of the body, catabolism is started. Itâ&#x20AC;&#x2122; s most significant clinical finding is muscle wasting. Malnutrition indicated by body weight below 3rd percentile for age is met in up to 60% of patients with chronic end stage liver disease. Anorexia, maldigestion and malabsorption especially in cholestatic liver disease leading to reduced energy intake are enhanced even by extended energy expenditure (Fig.5) (6). Replacement of water- and fat soluble vitamins, formula feed containing medium chained triglycerides and trace elements are recommended. This in up to 150% of the daily normal requirements. However, the best way to prevent further deterioration will be to transplant the patient, as soon as the patient starts to cross his percentile downwards.

Fig.5 : Development of malnutrition in chronic end stage liver disease

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cb) Osteodystrophy Severe osteodystrophy, even pathological fractures are serious complications in cholestatic liver disease and are observed in up to 70% of these patients (13) . Osteodystrophy results from 2 different problems: Osteoporosis and osteomalacy. The pathophysiology is complex and most probably related to disturbed IGF-1 and PTH metabolism (14). Catch-up of osteodystrophy after liver transplantation takes place but is impaired by the negative impact of CNI on osteoblasts. This is another argument to indicate liver transplantation as soon as diagnosis and prognosis are settled before osteodystrophy develops.

d) Acute-on-Chronic Liver Failure (ACLF) Acute-on-chronic liver failure results from an acute insult in a patient with either diagnosed or undiagnosed chronic liver disease. Itâ&#x20AC;&#x2122;s symptoms are jaundice and coagulopathy with manifestation of ascites and encephalopathy within 4 weeks. As far as undiagnosed patients aged more than 4 years are concerned, autoimmune hepatitis and Wilsonâ&#x20AC;&#x2122;s disease play an important role and must be ruled out. The hepatic insult in developing countries shows a different pattern compared to western countries. Whereas hepatitis A and E are the leading causes with almost 50% in developing countries (15), septicemia, bleeding and hypoglycemia are the leading causes in western countries. These events may lead to hypovolemia and shock which cause hypoperfusion of the liver with consecutive liver necrosis ( Fig. 6) Without liver transplantation the prognosis of ACLF is poor (16).

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Fig.6 : Causes of acute on chronic liver failure . Abbreviations : GI tract = gastrointestinal tract; SBP = spontaneous bacterial peritonitis; UTI = urinary tract infection

e) Acute Liver Failure (ALF) Acute liver failure is defined as a life-threatening illness in which a previous healthy child rapidly progresses to severe hepatic dysfunction and synthetic liver failure within 8 weeks of onset of symptoms. The etiology may differ from continent to continent. In USA 49% of affected children have to be classified

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as indeterminate despite a complete work-up. 19% suffered from drugtoxicity, 10% from metabolic disease, 6% from autoimmune disease, 6% from infection, and 10% from other diagnosed conditions (17). In Saudi Arabia and Asia, hepatitis A and E, intoxication by herbal medicine and hepatic failure caused by metabolic disorders have to be considered. The management of children with acute liver failure has to be optimized because the time frame in which a liver transplantation may be performed successfully is very narrow. In the first rank there is the fluid therapy, which should be reflecting the risk of initiating or deteriorating brain edema. A 30% reduction of the daily fluid requirement is recommended. Albumin and FFP substitution should be used carefully. The use of 20% albumin rather than 5% and factor 7a rather than FFP is advocated. In the second rank there is the prevention of infection with both bacterial and fungal agents. The management should include repeated determinations of WCB in order to rule out aplastic anemia. This serious complication is observed in up to 30% of affected children. The most important issue however is to monitor the brain pressure by means of non-invasive means such as CT or if possible by orbita ultrasound measuring the optic nerve diameter. If the optic nerve diameter exceeds more than 4.5 mm, the prognosis is very poor (18, 19). The neurological status of the patient is difficult to assess because of the fact that a considerable number of patients will not develop encephalopathy or is under sedation for ventilation. With respect to the narrow therapeutic window, the evaluation of a potential living donor has to be started as soon as a patient with acute fulminant liver failure is admitted in order to save time. Predicting survival in pediatric acute liver failure has been attempted in a large cohort of patients. It was reported that only serum bilirubin and INR were significantly associated with outcome (20).

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Vaccination in children with CLD may be uneffective, because the immune response is impaired. The assessment of specific antibodies therefore is of great importance (6). The same holds true for viral infection with CMV, EBV, HSV. In order to identify risk constellations, the corresponding antibodies in the donor have to be measured. Risk constellations are recipient -, donor + and need specific antiviral prophylaxis. Ultrasound and Doppler ultrasound and other types of imaging play an important role in the evaluation process of children with chronic end-stage or acute liver failure. If the examinator is not used to pediatric liver disorders, a catalogue of specific questions is to be asked in order to have an satisfying information about parenchymal and vascular findings ( Table 2).

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PAEDIATRIC RECIPIENTS CHECKLIST FOR PRE-TRANSPLANT EVALUATION OTC, Paediatric Liver Transplant Program, King Faisal Specialist Hospital & Research Centre, Riyadh

Candidate Name:____________________________________

MRN: ____________ ABO:_______

Diagnosis: __________________________________________

Work-up Start Date:_____________

Coordinator: ________________________________________ Donor Name:______________________________________

Work-up Completed:____________ MRN:__________________________

Height:______ Weight:_______ INR:_____ Albumin:_____ T. Bilirubin:______

INVESTIGATIONS HAEMATOLOGY

COMPLETED

TYPE AND SCREEN SICKLE CELL TEST PTT, PT, INR, FIBRINOGEN FACTOR V FACTOR VII G6PD QUANTITATIVE ALPHA 1 ANTITRYPSIN RETICULOCYTE COUNT HEMOGLOBIN ELECTROPHERESIS (INCLUDE SEPARATE REQ) CBCD HLA RECIPIENT PRA CLASS I AND II NUCLEIC ACID EXTRACTION (FOR DNA BANKING AND GENETIC TESTING)

CHEMISTRY BONE PROFILE RENAL PROFILE HEPATIC PROFILE TOTAL AND DIRECT BILIRUBIN GGT TRIGLYCERIDE CHOLESTEROL AMYLASE LIPASE VITAMIN D 25 VITAMIN E CONCENTRATION PTH TSH T3 AND T4

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Pediatric Liver Transplant Hepatology COMPENDIUM BILE ACID SERUM CORTISOL FERRITIN + IRON PROFILE LDH AFP PYRUVIC ACID LACTIC ACID AMMONIA LKM ANTI NUCLEAR ANTIBODY ANTI SMOOTH MUSCLE ANTIBODY

METABOLIC SPECIFIC (<2 YEAR) AMINO ACID PROFILE (SERUM) ACYLCARNITINE AND AA BY TANDEM MS URINE FOR SUCCINYL ACETONE URINE FOR REDUCING SUBSTANCES URINE AMINO ACID PROFILE URINE FOR ORGANIC ACIDS AND GCMS GALT

BACTERIAL/VIRAL CULTURES THROAT CULTURE URINE CULTURE NPA FOR RESPIRATORY VIRUSES (MULTIPLEX PCR)

DEPARTMENTAL PROCEDURES 2D ECHO EKG SURVEY DYSMORPHIC (<2YRS) MRI (IF REQUESTED) CXR FACIAL PHOTOGRAPHS (CONTACT HOSPITAL PHOTOGRAPHER)

AS INPATIENT PRE AND POST TRANSPLANT

ULTRASOUND ABDO WITH PELVIS DOPPLER US HEPATIC/PORTAL VEIN DUPLEX OPTHAMOLOGY REFERRAL (ON REQUEST) BONE MARROW ASPIRATE AND BIOPSY (ON REQUEST) LIVER BIOPSY

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COMPENDIUM Pediatric Liver Transplant Hepatology

SEROLOGY

COMPLETED

HEPATITIS A HEPATITIS B CARE SET HEPATITIS C HIV CMV IgG IgM CMV DETECTION AND QUANT EBV IgG IgM EBV VIRAL LOAD EBV PCR HSV 1,2 AND 6 IgM HSV 1,2 AND 6 IgG TOXOPLASMOSIS IgG IgM VARICELLA ZOSTER IgG IgM MEASLES IgG IgM RUBELLA IgG IgM IMMUNGLOBULINS QUATITATIVE CS ASPERGILLUS ANTIBODY HTLV 1-2 ANTIBODY PARVOVIRUS B19 IgG IgM ADENOVIRUS ANTIBODY SYPHILIS SCREEN

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IF INDICATED (BY REQUEST) INVESTIGATION

COMPLETED

SERUM COPPER SERUM CERULOPLASMIN IgG SUBCLASSES, IgG SUBCLASS 4 COOMBS TEST SWEAT CHLORIDE TEST

VACCINATIONS UP TO DATE (NO LIVE VACCINES 6 WEEKS PRE TRANSPLANT) VACCINE

DATE RECIEVED

ROTAVIRUS POLIO PNEUMOCOCCAL HEPATITS B DTaP BCG

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5)Technical Variants in Pediatric Liver TransplantationLiver Transplantation Theoretically 5 different variants of liver transplantation may be performed : Full size (FS), split (S), reduced size (RS), living related (LR), and auxiliary partial orthotopic liver transplantation ( APOLT). The choice which type is used in the individual patient depends on the donor organ situation, the size of the recipient and the severity of the underlying disease. FS organs of pediatric donors are very seldomly offered. S organs are only suitable if the donor organ quality of a deceased donor is excellent. This means short ischemic time, no organ damage by steatohepatitis or trauma and donor age beyond 40 years. RS organs should be avoided, since the remaining part of the liver is not used. The quality criteria are the same as in S. LR organs may be left lateral segments if the recipient is below 20 kg body weight. In bigger children either full left or even full right lobes are provided. In full left and full right organs, a liver biopsy of the donor is necessary in order to avoid critical situation in both donor and recipient (22). APOLT may be used in metabolic disorders without liver damage such as Crigler-Najjar syndrome or in acute fulminant liver failure. In these patients a recovery of the diseased liver is to be expected as indicated by histological and immunostaining procedures. The transplantation is performed as resection of the left lateral lobe which will be replaced by the transplant. After regeneration of the remaining original lobe, immunosuppression may be stopped. The transplanted graft then will vanish completely. In metabolic disorders transplanted with an APOLT however the transplanted segment needs ongoing immunosuppression. Monitoring the function of an APOLT organ is difficult because the liver function tests do not reflect the integrity of the transplant. Serial biopsies are needed in order to have safe information about the transplant. The graft-body-weight ratio% should not be less than 0.8, but may exceed up to 8-12. In this special situation of a large for size graft, the need for temporary abdominal closure with a patch may be essential in order to prevent a compression damage of the transplant. The results of this large-for-size

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constellation is as good as in average-for-size constellation. I contrast, a small-for- size graft as indicated by a graft-body-weight ratio of less than 0.8 shows a significantly reduced survival (23).

6) Transplant Protocol routine patients The Pediatric Liver Transplant Program has been developed as guidelines. It is based on personal experience gathered from 1978 until now and modified according to the last publications.

Pediatric Liver Transplant Program Protocol (Routine Indications) Pre-transplant diagnosis________________________________________________

Recipient

Donor

CMV Status

☐Positive

☐Negative

☐Positive

☐Negative

EBV Status

☐Positive

☐Negative

☐Positive

☐Negative

HSV Status

☐Positive

☐Negative

Admission Weight (in Kg)________ Height (in cm)_________ Abdominal Girth in cm_________

Monitoring: 1. Vitals signs on admission and every 4 hours 2. Activity as tolerated 3. Diet: NPO six hours prior to surgery except for medications with sips of water 4. Clean the bowel 5. Intravenous Therapy: IV: D5 0.45% sodium chloride maintenance at ____________ml/hour.

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COMPENDIUM Pediatric Liver Transplant Hepatology

Laboratory Investigations: 1. Blood work: CBC/Differential, PT/PTT, Renal profile, Urea, Hepatic profile, AST, GGT, Bone profile, glucose. 2. Blood bank: Type and cross-match for:

< 10kg

10 â&#x20AC;&#x201C; 40 kg

> 40 kg

300 ml packed red blood cells (CMV negative if recipient CMV neg), Radiated (to prevent GVHD)

Packed red blood cells (60 ml/kg)

5 adult units packed red blood cells

Platelets (10ml/kg)

Platelets 1 pool

FFP (60ml/kg) available to O.R.

FFP 2 to 4 units

Diagnostic Imaging: Chest x-ray PA and Lateral STAT, Ultrasound abdomen

Medications: a. Induction: Basiliximab: 10 mg for patients < 35kg IV to be given 6-8 h after reperfusion 20 mg for patients > 35kg IV to be given 6-8 h after reperfusion Methylprednisolone (10mg/kg) IV to O.R. with the patient; maximum 250 mg to be given in anhepatic phase Ranitidine (1 mg/kg) IV every 8 hours (maximum 150 mg/day) Tazocin (75 mg/kg to maximum 4g) IV to O.R. with the patient For patients with prior abdominal surgery, Metronidazole (7.5mg/kg to maximum of 500 mg) IV to the O.R. with the patient.

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PICU orders: Admit to Pediatric Intensive Care Unit. Ventilator Care: as per Pediatric intensivist Vital signs: as per Pediatric Intensive Care Unit Diet: Keep NPO till further order by transplant team.

Drainage Tubes: a. NG to low intermittent suction, irrigate with 5 â&#x20AC;&#x201C; 10 ml normal saline every 12 hours and PRN. b. Indwelling catheter to straight drainage c. Drain â&#x20AC;&#x201C; empty every 12 hours d. JP drains to bulb suction, empty every 4 hours and whenever suction is compromised. e. Replace drainage fluids with appropriate fluids according to S. albumen and S. sodium 1:1 in the first 24 hrs post operatively. f. In case of large fluid losses (> 400ml/day): Replace only 2/3. Start spironolactone (3mg/kg/day, control potassium) and furosemide. Dose adjusted to individual situation. g. Keep hematocrit below 30%. If > 30% : hemodilution

Medications: DO NOT use non-steroidal anti-inflammatory drugs, macrolide antibiotics, gentamicin, or other aminoglycoside unless approved by Transplant Team. Immunosuppression is to be reassessed daily by Transplant Team. Basiliximab 10mg for patients < 35kg IV on post-op day 4 20mg for patients > 35kg IV on post-op day 4

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Methylprednisolone (Solu-Medrol) Day

Dose/ day

1- 7

Solumedrol 1 mg/kg Prednisolone 1.25 mg/ kg (once PO possible)

8- 14

Prednisolone 0.5 mg/kg

15- 21

Prednisolone 0.25 mg/kg

> 21

Decrease by 5 mg/ week until you reach 1 mg/ day; continue for 1 year

Tacrolimus POD #1 (0.05mg/kg) NG/orally twice daily at 0600 and 1800 hours. Caution in patients with renal impairment. Target troughs:

MONTHS POST TRANSPLANT

TACROLIMUS LEVEL FK+ Steroids

FK+ MMF+ Steroids

Month 1- 3

7–9

6- 8

Month 3 – 12

7–9

5- 7

>12 months

3-5

3- 5

MMF trough 1.5- 3.5 mg/L

Antiproliferative Drugs : Sirolimus, Everolimus, Azathioprine No routine medication, use restricted to special indications: Rescue treatment in chronic rejection, malignant tumor and autoimmune hepatitis

Mycophenylate mofetil To be initiated as a triple regimen (with tacrolimus and steroids) in: 1- Patients with renal impairment (cystatin C > 1.5 mg/L) 2- Patients who develop rejection despite adequate CNI trough levels To be decided by the Transplant Team Start with 200 mg/m2 twice daily, advance to 600 mg/m2 twice daily For triple therapy: Trough level: 1.5-3.5mg/l

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Tazocin (75mg/kg; maximum 4g) _________________mg IV Q8 (till drains out) Ursodiol (Actigal) 5mg/kg/dose PO every 12 hours as soon as patient starts oral feeding

Nystatin 2.5-5cc PO swish and swallow Q6 for 1 month (1cc=100 000iu) Prophylactic anticoagulation: Transplant Team to suggest the initiation of anticoagulant and the PICU team will adjust the therapy according to the following: 1. INR should be < 2.5 2. Platelets count > 50,000 3. 3. No active bleeding 4. special request of transplant surgeon, tiny hepatic artery, repeated vascular thrombosis in OR FFP replacement ordered by transplant team/PICU Heparin 10 units/kg/hr, target PTT to be between 40 â&#x20AC;&#x201C; 60â&#x20AC;&#x2122;s; heparin continued until oral feeding is possible Then switch to Enoxaparin: 1mg/kg daily SC Monitor Factor X a to 0.5-1 unit/ ml for 1 month Then switch to aspirin 5 mg/ kg three times weekly AT3 monitoring should be above 60% If any bleeding, discuss with Transplant Service to re-evaluate

Pain management: paracetamol may be given in age adjusted doses, if not sufficient: morphine order Tramal Fluid balance: intake=output Diagnostic Imaging: Ultrasound of liver with Doppler studies daily for 5 days post transplant or as otherwise ordered.

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Laboratory Studies: a. On admission to PICU: STAT: CBCD, PT INR PTT, Hepatic profile, Renal profile, Urea, Bone profile, AST, GGT, Fractionated bilirubin, Lactate, Lipase, and arterial blood gases with lactate, glucose, b. Then every 6 hours for the first 24 hours post-transplant. c. Then every 12 hours for the next 48 hours d. Daily Tacrolimus trough level after 3 doses of Tacrolimus; aimed trough level 7-9 ug/ml, to be drawn as 12h value e. Then routine daily: CBCD, PT INR PTT, Hepatic profile, Renal profile, Bone profile, Urea, Glucose, AST, GGT, Fractionated bilirubin, Lactate, Lipase, and trough Tacrolimus levels in am f. Daily amylase, lipase and bilirubin from JP drain

Cultures: a. Sputum/ETT, urine, blood and abdominal drains for bacterial and fungal cultures for temperature greater than 38째C once per febrile episode b. Blood culture several times daily for persisting fever before antibiotic treatment. If already under antibiotic therapy : stop antibiotics and take blood culture after 24 hs c. Stool cultures for virology and C. difficile toxin for diarrhea PRN

Infection treatment: a. Tazocin IV ( first choice) or b. Meropenum + Vancomycin (second choice) or c. Therapy change according to sensitivity results.

Complete vaccination protocol starting 6 months after transplantation Antiviral Prophylaxis for CMV and EBV: a. High risk individuals D+/R- should receive universal prophylaxis (to start immediately after surgery): Ganciclovir 5mg/kg IV Q24 hours for 14 weeks; in renal impairment adjust as follows:

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Clcr

Dose

50-69 mL/minute

2.5 mg/kg IV Q 24 hours

25-49 mL/minute

1.25 mg/kg IV Q 24 hours

10-24 mL/minute

0.625 mg/kg IV Q 24 hours

<10 mL/minute

0.625 mg/kg/dose 3 times/week following hemodialysis

Upon discharge to hospital housing : start Valcyte; dose= 7 x CrCl PO Q12) Duration : 100 days

BSA x

b. All other groups D+/R+, D-/R-, D-/R+, should receive preemptive care with ganciclovir (i) Monitoring CMV EBV viremia by qcPCR Weekly for the first month; then fortnightly for the next 3 months; (ii) Treat with anti-virals if viremia develops c. If Recipient HSV positive AND not receiving CMV or EBV prophylaxis start Acyclovir (15mg/kg) orally four times daily for 30 days. To start immediately after positive reading

Anti-PCP prophylaxis: If non-sulfa allergic; give trimethoprim/sulfamethoxazole (Septra®) three times weekly as follows:

Weight (kg)

BSA (m2)

Tablet

Liquid (mL)

<10

<0.5

2.5

11 - 20

0.5 - 0.8

Half Tablet

21 - 28

0.81 - 1

One Tablet

7.5

29 - 40

1.1 - 1.34

One Tablet

41 - 60

1.35 -1.89

One and Half Tablet

≥61

≥1.9

2 or 1 DS

If ClCr 15- 30 ml/hr give 50% of the dose; if ClCr < 15 ml/hr do not use

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In sulfa allergy or G6PD deficiency: - Age < 5 years: use atovaquone as follows (not in the hospital formulary) 1-3 months: 30 mg/kg once daily with food 4-24 months: 45 mg/kg once daily with food >24 months: 30 mg/kg once daily with food - Age > 5 years: use pentamidine inhalation 300 mg Q month. Continue prophylaxis for 6- 12 months post transplant.

Comments :

1) Immunosuppression : The immunosuppression protocol is derived from a multicenter randomized study performed in Germany. The aim of this study was to investigate whether a low dose steroid regimen in combination with a calcineurin inhibitor and interleukin 2 receptor antibody was safe with regard to infection and rejection rate if compared with a standard steroid dose regimen. The study showed that a 50% reduction of cumulative steroid load in the 1st posttransplant year was effective and safe when combined with interleukin 2 receptor antibody and calcineurin inhibitor ( R. Ganschow et al, to be published). The long-term efficacy and safety of interleukin 2 receptor antibody could be demonstrated in a single center study ( Ganschow R et al, Pediatr Transplantation 2005, 9: 741-745) In a prospective international multicenter randomized study the efficacy of tacrolimus vs ciclosporin A microemulsion was tested. Tacrolimus was shown to be more effective than ciclosprin A. This result was confirmed even after extension of the study to a 5 year observation period ( Kelly , Pediatr Transpl 2011, 15: 19-24 ). The analysis of 2291 pediatric liver transplant recipients transplanted between 1994 and 2006 showed that infection and not rejection was the leading cause of death ( 3,1 vs 0,6%) These findings suggest that minimizing steroid and

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Pediatric Liver Transplant Hepatology COMPENDIUM

calcineurin inhibitor therapy are of greatest importance for event-free survival of children after liver transplantation (Shepherd RW et al, Am J Transpl 2008, 8:396-403) Evidence Grade A 2) Antinfectious therapy : Since infections have been shown to the most relevant cause of death after pediatric liver transplantation, antibiotic, antiviral and antifungal therapy is of major importance. Guidelines for antiinfectious therapy have to be based upon local experience. This especially refers to EBV and CMV infection, because there is a high infection rate in adults whereas the infants and young children which represent the major part of pediatric liver transplant recipients are na誰ve with regard to EBV and CMV. Evidence Grade B

3) Intensive care management : Short ventilation time, forced infection monitoring and low dose immunosuppression have been shown to be the most important factor for improving patient and graft survival in a single center study (Ganschow R et al, Pediatr Transplantation 2000, 4:275-279 ).Evidence Grade A

4) Ultrasound examinations : In a large prospective study we could demonstrate that ultrasound Doppler examinations were essential in the intra- and postoperative course after pediatric liver transplantation in order to recognize vascular problems as early as possible. ( Kim JS et al. Transplantation 2005, 79: 1206-1209) Evidence Grade A

5) This protocol has been proved by : PICU, Clinical Pharmacy, Pediatric GI

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COMPENDIUM Pediatric Liver Transplant Hepatology

Interpretation of Monitoring Results : 1) Immediate posttransplant period : Day 0-3 a) Metabolic acidosis: in combination with high serum lactate (>10), high serum enzymes ( > 2000) and impaired coagulation ( INR>4) primary poor- or non-function b) Metabolic alkalosis : over compensation most frequently seen in deceased donor transplantation c) Isolated high serum enzymes : large for size syndrome ? d) Combination of 1) and severe ascites : small for size syndrome ? e) Combination of a) and and vanishing hepatic artery signal in DopplerUS : hepatic artery occlusion : immediate repeat of Doppler-US and if confirmed :contact transplant surgeon, relaparotomy f) Bilirubin concentration in JP drain 3x serum bilirubin : bile leak ? Close follow-up, contact transplant surgeon g) Bilirubin concentration in JP drain plus high amylase : bowel perforation near footpoint anastomosis ? Contact transplant surgeon, relaparotomy h) â&#x20AC;&#x153;Muddyâ&#x20AC;? drain fluid : distal bowel perforation: take cultures, contact transplant surgeon. i) Hematocrit > 30% : risk of hepatic artery thrombosis in children< 10 kg body weight

2) Late post-op follow-up : day 4- 28 a) Sudden rise of enzymes, together with increasing bilirubin, low CNI trough level : acute cellular rejection : in patients with basiliximab therapy : after day 14 : acute cellular rejection. In patients without basiliximab therapy : after day 7 : liver biopsy, remind aspirin- or anti-coagulation therapy! b) Malaise, increasing enzymes bilirubin but high CNI trough level : after day 28 : CMV or EBV or other virus induced hepatitis : CMV-EBV-HSV or other virus PCR, liver biopsy, remind aspirin- or anticoagulation therapy

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Pediatric Liver Transplant Hepatology COMPENDIUM

3) Ultrasound results : a) Hepatic artery : normal findings : flow-velocity > 25 cm/sec RI : 0.5-0.8 to be seen up to peripheral arteries pathological findings : flow velocity < 25 cm/sec, high resistance index > 0.9, negative flow in diastolic phase : stiff liver High velocity at anastomosis plus pre-and post-anastomotic dilatation :arterial stricture at anastomosis

b) Portal vein : normal findings : flow velocity > 20 cm/sec modulating wave pattern

pathological findings : flow velocity < 20 cm/sec, hepatofugal flow, partial occlusion : incomplete portal vein thrombosis, :intensify anticoagulation, PTT between 60-80 sec : no portal vein flow : either compression of portal vein by hematoma or portal vein thrombosis

c) Hepatic veins : normal findings : triphasic flow pattern pathological findings : band like flow pattern, for close followup. In combination with refractory ascites : hepatic vein outflow obstruction, interventional radiology : only after 4-6 weeks

d) Hypo-echoic areas : in combination with high serum enzymes : hepatic necrosis: check for arterial capsule collaterals as indicators of hepatic artery complication

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COMPENDIUM Pediatric Liver Transplant Hepatology

References 1) Ganschow R et al . Safe steroid minimization after pediatric liver transplantation with basiliximab induction therapy : a multicenter, randomized study. In preparation 2) Ganschow R et al. Long-term results of basiliximab induction immunosuppression in pediatric liver transplant recipients. Pediatr Transplantation 2005, 9: 741-745 3) Kelly D Safety and efficacy of tacrolimus in pediatric liver recipients. Pediatr Transplantation 2011, 15: 19-24 4) Shepherd RW et al. Risk factors for rejection and infection in pediatric liver transplantation. Am J Transpl 2008, 8: 396-403 5) Ganschow R et al. Intensive care management after pediatric liver transplantation: A single center experience. Pediatr Transplantation 2000, 4: 273-279 6) Kim JS et al. Pediatric Transplantation : The Hamburg experience. Transplantation 2005, 9: 1206-1209

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Pediatric Liver Transplant Hepatology COMPENDIUM

8) Follow-Up Examinations This protocol has been developed according to the results published by the Atlanta group. It was designed for ABO incompatible transplants but may be used for other patients as well. Especially for those patients with borderline renal function, where the use of tacrolimus has to be postponed until recovery of renal function occurs.

Protocol : ABO incompatible pediatric liver transplantation

Indication : Risk of dying on the waiting list with no ABO compatible living or deceased donor or at risk from irreversible damage of a second organ ( i.e. brain, kidney, lung)

Blood group Isoagglutinin Titer ( IgM)

Donor ABO

Body weight Body length BMI

Recipient ABO 1:4

1:8 1:16 (mark the measured titer) 1:32 >1:32

Diagnosis Indication for Plasmapheresis Immunabsorption Rituximab pre-op

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yes / no yes / no (mark the method used) yes / no

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COMPENDIUM Pediatric Liver Transplant Hepatology Immunosuppression Protocol Interleukin 2 receptor AB

< 35 kg: 10 mg, >35 kg: 20mg

6-8h post reperfusion at day 1,4 and18 Tac

9 p.o. (4,6 ) day 7: 0.1mg/kg BID; trough

level Cellcept

10-12ng/ml (4) day 1 : 200 mg/m2 to be

increased level (modified from 4 ) Steroids ( Solumedrol) ( Solumedrol)

tapered intervals and switch

to 600 mg/m2 BID, trough 1.5 - 3.5 intra-op : 10 mg/kg i.v. (5) Post-op : 60mg/m2 to be down in weekly to oral prednisone ( 6 )

CMV/EBV prophylaxis :

ganciclovir 5 mg/kg i.v. BID for 14-21 days, Then maintenance therapy 5

mg/ kg/day for 3 months Prophylaxis of thrombosis :

i.v. heparin : 100 U/kg/24hs,

dose adjusted to PTT 40-60 sec

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Pediatric Liver Transplant Hepatology COMPENDIUM Monitoring : day for 1 wk, days until end of

Isoagglutinine IgM : daily until 3, then on alternate days then every 5 1 month (6) Liver and renal profile, LD, Bilirubin direct +indirect, Ultrasound liver (daily during stay in ICU, thereafter 1- 2x/week ) (4,6).

Weekly:

CMV, EBV HSV viral load

Liver biopsy :

day 7, 21 or if indicated by hemolysis, rise of liver enzymes, and at 3, 6, 12 months p.o. (6) ( relative indication!)

Indication for specific treatment : a) Rising Isoagglutinines b) + hemolysis c) + Rising enzymes

if at least 2 criteria are fulfilled

Treatment :

step 1 : high steroid bolus ( 10-20 mg solumedrol/ kg i.v). step 2 : high immunoglobulins ( 0.8 mg/kg/day i.v. for 7 days step 3 : tacrolimus trough level increased to 12-14 ng/mL (7) step 4 : plasmapheresis 1,5x plasmavolume (4) step 5 : immunabsorption if step1-4 are without success step 6 : rituximab 375 mg/m2

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COMPENDIUM Pediatric Liver Transplant Hepatology

References : 1). Raut V and Uemoto S. Management of ABO-Incompatible Living Donor Liver Transplantation : Past and Present Trends. Surg Today 2011; 41, 317-322 2). Kawagashi N et al. Long-term outcome of ABO-incompatible livingdonor liver transplantation: a single â&#x20AC;&#x201C; center experience. J Hepatobiliary Pancreat Surg 2009, 16: 468-472 3). Urbani L et al. Treatment of antibody-mediated rejection with highdose immunoglobulins an ABO-incompatible liver transplant recipient. Transplant Intern 2007: 20, 467 4). Tanabe M et al. Current progress in ABO-incompatible liver transplantation. Eur J Clin Invest 20120: 40:943-949 5). Heffron Tet al : Successful ABO-incompatible Pediatric Liver Transplanation Utilizing Standard Immunsosuppression With Selective Postoperative Plasmapheresis. Liver Transpl 2006, 12:972-978 6). Gelas T et al. ABO incompatible pediatric liver transplantation in very small recipients:Birminghamâ&#x20AC;&#x2122;s experience. Pediatr Transplantation 2011: 15:706-711 7). Stewart ZA et al. ABO incompatible deceased donor liver transplantation in the United States: A national registry analysis. Liver Transpl 2009: 15: 883-889 8). Al Meshari K. The kidney transplant program at King Faisal Specialist Hospital and Research Center. Saudi J Kidney Dis Transpl 2005: 16:586597 9.) Sakashita H et al. Significance of C4d staining in ABO-identical/ compatible liver transplantation. Modern Pathology, 2007: 20:676-684

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Pediatric Liver Transplant Hepatology COMPENDIUM

8) Follow -up Examinations 8a) After excellent results of short-term survival after pediatric liver transplantation have been achieved not only in single centers but also in multicenter studies, the main interest today focus on the long-term medical management (24,25). The highest influence on the late outcome of pediatric liver transplantation has the early detection of problems in the early postoperative phase. Follow-up examinations are needed in order to check different items : 1. Compliance of the family 2. Quality of immunosuppression â&#x20AC;&#x201C; to avoid over- and underimmunosuppression 3. Acute- or chronic liver dysfunction 4. De novo autoimmune hepatitis 5. Development of allergies 6. Viral infection either as reactivation or as primary infection 7. Acute bacterial infection 8. Doppler ultrasound to rule out parenchymal or vascular complications 9. Side-effects of immunosuppression : arterial hypertension, renal impairment, PTLD

8aa) Compliance of the family : Non adherence to our medical prescriptions may be caused by different problems. Most often, there is a misunderstanding of our prescriptions, some parents are illiterate, some parents do not understand the need for regular medication, some parents do not worry, if they are running short of immunosuppressive drugs. Repeated instructions of the families - in most cases the mother is responsible for medication - have to be organized. The best prevention is to involve the mother in medication right from the beginning in the ward. The critical age with regard to non-adherence for children after liver transplantation is the transition to adulthood (26). Intensive teaching starting at school age is needed to prevent this emerging risk of graft loss. The

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COMPENDIUM Pediatric Liver Transplant Hepatology time schedule of follow-up examinations after pediatric liver transplantation should be individualized. In the short â&#x20AC;&#x201C; term follow-up, weekly examinations are needed, in the intermediate course the time interval is extended to 2, later to 4 and six weeks. In the long-term follow-up, intervals of 3-6 months may be acceptable if the patient is stable. A good communication between the patientâ&#x20AC;&#x2122;s family and the transplant centre is mandatory as shown in some reports ( 4).

8ab) Quality of immunosuppression : The quality of immunosuppression is difficult to assess, since there are no methods available yet to measure directly the quality of immunosuppression (27). What we can do is to measure the trough level of CNI and antimetabolites and to take care that the time interval for appropriate trough level determination has been chosen correctly. A normal trough level does not exclude under- or over immunosuppression. There are only indirect parameter available like liver- or renal function tests and arterial hypertension under CNI therapy and development of Cushing syndrome in long-term treatment with steroids.

8ac) Acute Liver Dysfunction : Any rise in transaminases needs further diagnostic efforts including liver biopsy (28). Acute viral infections often are responsible for intermediate high transaminases by so called reactive hepatitis. Toxic effects may be caused by CNI inhibitors, herbal medicine or unsafe antibiotics which have to be ruled out. Rejection episodes are observed in Saudi Arabia in less than 20% of patients (4). This is much less than in Western countries, where up to 52% are reported. This might be related to the high HLA-identity in the consanguineous constellation in living related liver transplantation. In most cases, non-adherence to medication prescriptions is the reason for acute cellular rejection in this region. In other patients protracted vomiting with insufficient dosing of CNI may play a role. Diarrhea is associated with high trough levels of tacrolimus due to the fact, that the metabolism of tacrolimus in the small bowel epithelium is impaired thus delivering more tacrolimus to

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Pediatric Liver Transplant Hepatology COMPENDIUM

the liver. In contrast, diarrhea in patients treated with CyA causes low and even insufficient trough levels. In most patients a liver biopsy has to be performed to identify the cause of acute or chronic liver transplant dysfunction. The aspirin treatment should be considered before liver biopsy and suspended at least for 4 days.

8ad) De Novo Autoimmune Hepatitis: 3-5% of transplanted children develop a de novo autoimmune disease, whereas 74% develop positive autoimmune marker without autoimmune hepatitis (30, 31) . Autoimmune marker , high immunoglobulin G and liver biopsy proven plasmacell infiltration are needed to establish this diagnosis. For some reason, the addition of azathioprine* is more effective than the increase of CNI or addition of MMF* (24). De novo AIH must be differentiated from recurrence of autoimmune disease in AIH or sclerosing cholangitis. The risk of disease recurrence is about 20% in these disorders.

8ae) Allergies : Allergies are common under CNI. The reason for this is the interleukin 2 blocking by interleukin2 receptor antibodies and the calcineurin-inhibitor itself. Il 2 is needed to direct the t-cell response to either exogen or endogen antigens. Blocking this t-cell answer is responsible for the development of allergic reaction to inhalative, contact or nutritional antigens (32, 33). Especially nutritional antigens are responsible for serious, even lifethreatening events.

8af) Viral Infections : Up to school age, children have to experience viral infections such as common cold and gastroenteritis in order to produce protecting antibodies. The number of infections in normal children may be as high as 12 infections / year. Immunsosuppression in transplanted children seems not to affect them more often or more severe than their normal siblings. However, there are 3 viral agents which play an important role after liver transplantation: These

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COMPENDIUM Pediatric Liver Transplant Hepatology

are CMV, EBV and HSV. This is due to the fact, that small children normally are naïve with regard to CMV, EBV and HSV, their donor on the contrary are positive. This risk constellation is answered by prophylactic ganciclovir therapy for 3 months after liver transplantation in case of CMV and EBV risk constellation. CMV may be harmful in different ways : 1) Acute ulcerations in the upper and lower GI tract. 2) Generalized “septicemia-like” disease 3) Predisposition to acute rejection and aggravation of EBV infection with the risk of PTLD First and second manifestation are observed 3-4 weeks post transplantation. Monitoring of CMV-PCR on a weekly basis helps to diagnose the infection (34). Positivity of the PCR initiates the prevention-therapy with ganciclovir. In patients with acute GI bleeding however, only biopsies from the gastrointestinal tract can provide diagnostic evidence, the PCR may be negative in these patients. With regard to rejection and development of PTLD there are several possible explanations. Any severe viral infection has an immune-suppressive effect. Therefore, immunosuppression is reduced or even suspended in CMV infection in order to overcome this infection. Timing of restarting immunosuppression is difficult, so rejection may happen if there is a too long time gap. PTLD is certainly facilitated by high immunosuppression (35, 36). Active CMV plus EBV infection therefore are considered as important risk factors for the development of PTLD as well as high dose CNI therapy. Early PTLD may present with GI bleeding, abdominal pain, high LDL and high EBV viral load measured by PCR in combination with non-specific symptoms such as abdominal pain, fatigue, fever and weight loss. A thorough GI endoscopy with multiple biopsies, abdominal ultrasound and MRI, brain and chest CT plus bone marrow biopsy are needed in order to establish the prognosis and diagnosis in these patients. The treatment of this complication should be performed in accordance with international protocols.

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Pediatric Liver Transplant Hepatology COMPENDIUM

8ag) Bacterial Infections : After transplantation any spiking fever needs immediate septic work-up with blood- and urine culture. Gram-negative agents may lead to fulminant septicemia within hours (4). A well-organized cooperation between home clinic and treating hospital is needed to minimize the risk of such an unnecessary event. A prophylactic i.v. antibiotic therapy is indicated until cultures are reported to be negative.

8ah) Side Effects of Immunosuppression Survival rates for the first year after transplantation have reached 95% graft and patient survival. There are different factors contributing to this improvement : Better operation techniques, better intensive care, better anti-infectious therapies and last but not least better immunosuppression. Optimizing immunosuppression thus is reported to contribute to this improvement significantly (26). In pediatric liver transplantation, immunosuppression is based on 3 drugs : Steroids, CNI and Interleukin 2 receptor antibodies. Antiproliferative drugs such as Sirolimus and Everolimus and antimetabolites such as MMF, Myfortic and Azathioprine are only administered in special circumstances. A selection of the important interactions between CNI and other frequently used drugs are shown in Table 3 and 4. The use of antibiotics and other drugs in patients with renal impairment has to be taken into consideration, otherwise unnecessary side effects will damage either kidney or other organs ( Table 5).

8ai) Chronic Allograft Dysfunction (CAD) Chronic allograft dysfunction is defined as dysfunction of the liver either appearing after one year post transplantation or lasting more than one year. CAD is a complex of interacting damages which may finally end up in chronic graft failure (Fig. 7). There are donor organ derived problems such as pre-damaged organ or viral infection, recipient related problems such as non-adherence, rejection or disease recurrence and finally allograft related problems such as allograft hepatitis, biliary tract or vascular complications.

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COMPENDIUM Pediatric Liver Transplant Hepatology

To elucidate such complex interaction, a typical scenario is shown: A patient receives a bad quality organ develops a vascular complication such as hepatic artery thrombosis which is complicated by consecutive biliary stricture. The resulting cholestasis is responsible for drug toxicity initiating rejection complicated by primary or secondary CMV infection. In adolescents, nonadherence to medication is a frequent cause of chronic allograft dysfunction opening the door for entering this vicious circle.

Fig 7 : Multiple factors contributing to chronic organ dysfunction (modified from 39)

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Pediatric Liver Transplant Hepatology COMPENDIUM

8aj) Role of Imaging Ultrasound has shown to be a indispensible tool in pediatric and adult liver transplantation. Starting in the pretransplant evaluation, during the transplantation itself and in the post-transplant follow-up, ultrasound and Doppler ultrasound are used in order to show typical features of acute and chronic liver failure and their complications such as portal vein thrombosis, ascites, collaterals, fatty changes, nodular transformation, vascular abnormalities, bile duct lesions, sludge or stone formation. In addition, all abdominal organs can be visualized showing parenchymal or intraluminal pathology. In order to gain optimized information, a specific questionnaire should be addressed to the radiologist which is shown in Table 2. In the OR, repeated Doppler ultrasound examinations document the patency and quality of the flow pattern in order to identify and treat already at this stage any risk factor responsible for the future development of vascular complications. In the post-transplant followâ&#x20AC;&#x201C;up complications of the vascular or biliary system and lymphoma have to be identified. In recent years new ultrasound methods have been developed: Fibroscan helps to identify patients with fibrosis by means of a non-invasive technique to diagnose this phenomenon in the course after liver transplantation. Transcapsular arterial neovascularization after liver transplantation may indicate transplant failure.

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COMPENDIUM Pediatric Liver Transplant Hepatology

Liver

Size

Normal / Increased / shrunken

Echogenicity

Normal / increased

Focal Lesions

Number / Size

Hepatic Artery

Open / Size / Pattern

Portal Vein

Open / Thrombosed/ Flow Direction / Pattern

S.Mesenteric V.

Open / Thrombosed / Pattern

Hepatic Veins

Open / Pattern

Bilary System

Bile duct

Normal / dilated / sludge / stones

Spleen

Size

Number / Position

Vascular System

Kidneys

Splenic Artery

Size / Flow

Splenic Vein

Open / Tortuous

Shunts

Left Kidney / Thorax

Size

Normal /Small / Large

Perfusion

Regular / Pathological

Calcifications

Diffuse / Localized

Uropathy

Stones / Obstruction

Ascites

Amount

Content / Septated

Lymphnodes

Number

Size / Localization

Table 2 : Questions to the radiologist for ultrasound / Doppler ultrasound examination in liver disease

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Pediatric Liver Transplant Hepatology COMPENDIUM

9b) Long-Term Follow-Up In the long-term follow-up pediatric liver transplant recipients are at risk of having chronic viral infection, biliary complications by vascular complications and by arterial hypertension and renal insufficiency due to side effects of CNI. These complications are seen in 5-15% of transplanted children if a low immunosuppression protocol is used. In patients with high dose CNI treatment, these complications are even higher. In children with arterial hypertension or renal insufficiency reduction of CNI therapy is the first step and if necessary, antiproliferative drugs without nephrotoxicity are needed to prevent rejection. There is increasing concern about chronic allograft dysfunction in patients with normal liver function tests. Interface hepatitis seems to be associated with late graft fibrosis (37, 38). Interface hepatitis is said to represent a form of chronic rejection. Protocol biopsies are therefore recommended in order to diagnose this complication. But since liver biopsy is an invasive procedure with the need of general anesthesia in most children the indication for liver biopsy has to be set by increasing splenomegaly or other signs of portal hypertension.

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COMPENDIUM Pediatric Liver Transplant Hepatology

10) Guidelines for home care Immunosuppression does not equal severe immunodeficiency. In general, wearing of face masks is not necessary. However, in case of infection within the family, strict hand disinfection and wearing of masks is recommended. Kindergarden and scool should be informed that the child is under immunosuppression. Infections such as infectious vomiting or diarrhea, scarlet, measles, chickenpox and rubella should be reported to the family. The family should then contact the transplant centre for further advice.

Sport: sport is allowed and even promoted. Children with splenomegaly however should not play football or doe gymnastics. Pets are allowed if they are under veterinarian control

Travelling : travels to countries with increased risk of malaria, yellow fever or other tropical diseases should be avoided. If unevetible, parents should get clearance from transplant centre. Never allow a transplanted child to direct intensive sun exposure. Sun protectors > factor 30 are recommended, wearing a sun hat and t-shirt as well.

Nutrition : there is no need for dietary restriction after successful liver transplantation. Soft ice and open drinks should be avoided. Infections : most infections are caused by viral agents. A prophylactic antibiotic therapy therefore is unnecessary. In case of superinfection ( greenish or yellow secretions) or infections lasting longer than 5 days however should be treated. The choice of antibiotics should be discussed with the transplant centre. High grade fever however without clinical signs of infection should be taken serious. An immediate contact with the transplant center is needed and a guided diagnostic septic work-up and prophylactic antibiotic therapy is needed.

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Pediatric Liver Transplant Hepatology COMPENDIUM

Angina tonsillaris and otitis are to be treated with antibiotics. Urinary tract infections have to be diagnosed by urine culture. In case of unexplained high fever, septic work-up is needed immediately and antibiotic therapy should be started thereafter until results of blood and urine culture are negative. Acute diarrhea may lead to dehydration and disturbed metabolism of tacrolimus. Therapy has to be coordinated with the transplant centre.

Vaccination : Children with chronic end stage liver disease do not respond properly to vaccinations. The vaccination program has to be started or restarted 6 months after transplantation avoiding the hot season. Vaccinations include attenuated and life vaccines.

11) Outlook More than 30 years after the first successful liver transplantation in a child, the chance to yield a good quality of life and a solid perspective for longterm survival has been achieved. The essential predisposition for this achievement is an optimized interdisciplinary cooperation between surgeons, pediatric hepatologists, pathologists, radiologists, infectiologists, social and psychosocial team and last but not least with research teams. The actual published 10 year patient and graft survival rates are based on the data from late eighties and early nineties (1, 2). Since then, the initial loss of patients and grafts has been almost completely abolished. The 10 year survival rate based on the actual achievements will be much better. However, the longterm course after pediatric liver transplantation shows a complex interaction between donor organ, recipient, immunosuppression and environment (39) that future research needs to elucidate (40).

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COMPENDIUM Pediatric Liver Transplant Hepatology

12) Immunosuppressive drugs 12 a) Drug Pharmacology : Side effects Drug

Steroids

CNI

Tac<CyA

Ac A.Hyper

MMF/MPA

Sir/Ever +

Tac>CyA +

Ren Insuff

+ +

GI Tract Neurol

Pancreati-

Diarrhea

Bone MarTox

Aza

Skin

CyA : HT

Mucosa

CyA : GH

Tab. 3 Overview on most important side effects of transplant immunosuppressive drugs. Abbreviations : CNI : calcineurin inhibitors; MMF Mycophenolate Moftil; MPA : Mycophenolate-sodium; Sir : sirolimus; ever : everolimus; Tac : Tacrolimus; CyA : Cyclosporin A; Aza : azathioprine; D.M: Diabtes mellitus; HC : Hypercholesterolemia; A.hyper: arterial hypertension; Ren Insuff. : renal insufficiency; GI Tract : Gastrointestinal tract; Neurol : Neurological complications; Bone-Marrow: Bone-marrow depression; Tox : Toxic liver damage; HT : Hypertrichosis GH : Gingiva hyperplasia

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Pediatric Liver Transplant Hepatology COMPENDIUM

Steroids

CyA

Tac

Aza

MMF / MM EC

m TOR Inhib. Sirol. / Everol

Absorption

30-100 min

60120 min

60 min

60-120 min

40 min / 120-150 min

1-2 h, 0,5-2h

Oral Bio Availability

80-100%

50%

56%

88 %

90%

Ca 20% ca 16%

yes

Stool 12%, Urine Urine : 93% :1%, Me- Liver : 6% tabolites 50-70%

Enterohep. no Circulation

Glucuronyl conjugates

94% Stool

98% Stool

Binding

CBG

LDL : 90% Ery 4158% Plasma 3347%

Albumin Albumin : 98% :30%

Halflife

12-36 h

Metabolism

Glucuronisation

Exkretion

/ > 90%

no Stool :91% / 80% Urine : 2% / 5%

Albumin :97 % / 83%

Albumin :92 % / 74 %

6,316-40 h short 20,4 h

Prolonged by enterohep. Recirculation

62 h / 31,5 h

CYP 3A4

Glucuronisation CYP3A4

CYP3A4

TPMT

Tab. 4 Pharmacokinetic data of immunosuppreesive drugs . Abbreviations : LDL : low density lipoproteins; Ery : erythocytes; CBG : cortisol binding globulin; CYP 3A4 : Cytochrome P450 3A4; TPMT : Thiopurine methyltransferase

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COMPENDIUM Pediatric Liver Transplant Hepatology

12b) Drug Interaction Trough Level

CyA

Allopurinol

Amoxycillin

Ampicillin

Azithromycin

Tac

Azathioprin

Clarithromycin

Ceftriaxon

Ciprofoxazin

Colchizin

Diltiazem

Doxyciclin

Erythromycin

Fluconazol

HIV Protease bl

Trough Level

CyA

Tac

Trough Level

Isoniazid

Ketokonazol

Metoclopramid

Metronidazol

Nifedipin

Omeprazol

+ ++

Phenobarbital

Phenytoin

Rifampin

+ ++

Tobramycin

Carbamazipin

Itraconazol

Propafenon

Trough Level

+ +

Trimethoprim

+ Verapamil

Valproat +

Table 5 :Interaction of frequent used drugs with Tacrolimus and CiclosporinA + = increase or decrease of trough level, ++ = strong increase or decrease of trough level ( modified fromDaschner M : Tabellarum Nephrologicum. Shaker , Aachen ( FR Germany), 2009)

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12c) Drug doses in renal insufficiency Drugs needing dose

Adaptation in

Renal insufficiency

Spironolactone

)+( Cefixim

)+( Ciprofloxacin

)+( Pethidin

)+( Cefotaxim

Ofloxacin

)+( Tramadol

Ceftazidim

Teicoplanin

Aspirin

)+( Cefuroxim

Vancomycin

)+( Amoxicillin

Imipinem + Cilastin

Colistin

)+( Ampicillin

Meropenem

Fluconazol

Benzylpenicillin

Amikacin

Flucytosin

)+( Flucoxacillin

Gentamycin

Aciclovir

)+( Mezlocillin

Certomycin

Foscarnet

Sultamicillin

Tobramycin

Ganciclovir

Cefazolin

)+( Clarythromycin

Lamivudin

)+( Erythromycin

Valganciclovir

Table 6 : Drug dose adaption in renal insufficiency : (+) = if GFR below 40mL/min /1.73 m2BSA; + = if GFR is , 20 mL/min/ 1.73 m2 BSA; without mark : normal dose ( modified fromDaschner M : Tabellarum Nephrologicum. Shaker , Aachen ( FR Germany), 2009)

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12c) Drug doses in renal insufficiency Drugs needing dose

Adaptation in

Renal insufficiency

Spironolactone

)+( Cefixim

)+( Ciprofloxacin

)+( Pethidin

)+( Cefotaxim

Ofloxacin

)+( Tramadol

Ceftazidim

Teicoplanin

Aspirin

)+( Cefuroxim

Vancomycin

)+( Amoxicillin

Imipinem + Cilastin

Colistin

)+( Ampicillin

Meropenem

Fluconazol

Benzylpenicillin

Amikacin

Flucytosin

)+( Flucoxacillin

Gentamycin

Aciclovir

)+( Mezlocillin

Certomycin

Foscarnet

Sultamicillin

Tobramycin

Ganciclovir

Cefazolin

)+( Clarythromycin

Lamivudin

)+( Erythromycin

Valganciclovir

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Drug

Recommended dose

Trough level

Comment

Albumin

1g/kg/dose

Prefer 20% solution

Azathioprine

1-2 mg/kg/day

Pancreatitis, leucopenia

Basiliximab

10 – 20 mg

20 mg :weight > 35kg

Cryoprecipitate

10 mL/kg

Cyclosporine A

14 mg/kg BID oral

Epoprostenol

2ng/kg/min i.v.

Factor VIIa

20-30 mcg/kg

Half life : 6 hrs

FFP

10 mL/kg

Beware of fluid overload

Furosemide

i.v.: 1 mg/kg/dose

Beware of nephrocalcinosis

Ganciclovir

i.v. : 5 mg/kg BID

Treatment of CMV infection

Lactulose

p.o. 2,5-90 mL/day

Adjust dose to 3 stools/day

Mycophenolate

p.o. 200-600 mg/ kg BID

Slow increase of dose

Propanolol

p.o.0.5-1 mg

Heart rate – 25%

Beware of drowsiness, fatigue

Sildenafil

0.88-2.5 mg/kg/dose i.v.

Sirolimus

3-1 mg/m2

Spironolactone

60 mg/m2 in 2-3 doses

Tacrolimus

0.05-0.1 mg/kg BID

Valganciclovir

700 mg/m

Vasopressin

0.5 mU/kg/hr

Adapt to trough level

Use after 4 weeks after tx Monitor K+

Fast metabolizers!?

Myfortic

Patient gets pale! Not available in SA

Terlipressin

Not available in SA

Everolimus

1.53mg/m2/day

Not available in SA

Octreotide

1-2µgxkg xh

Not available in SA

-1

Table 7 : List of * marked drugs in the text with dose recommendations

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14) References 1). European Liver Registry 2012, ELTR Paul Brousse Hospital, 14 Av Paul Vaillant-Couturier, BP 200-94804 Villejuif CEDEX 2). McDiarmid SV et al. A multivariate analysis of pre-, peri- and posttransplant factors affecting outcome after pediatric liver transplantation. Ann Surg 2011, 254: 145-154 3). Khan I et al. One hundred and thirty-seven living donor pediatric liver transplants at Military Hospital. Results and outlook for future. Saudi Med J 2009; 303: 403-408 4). Al Goufi T et al. Pediatric Liver Transplantation : A preliminary report of KFSH&RC Organ Transplant Center Experience. Ann Saudi Med J Suppl. 2013, 33: 3-7 5). Rajnayagam J et al. Pediatric acute liver failure : etiology, outcomes and the role of serial pediatric end-stage liver disease scores. Pediatr Transplant 2013; 17:362-368 6). Leonis MA, Balistreri WF. Evaluation and Management of End-Stage Liver Disease in Children. Gastroenterology 2008; 134:1741-1751 7). Shneider B et al. Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant 2012; 16: 426-437 8). El Sayed R et al. Relation of serum levels of thrombopoetin to thrombocytopenia in extrahepatic portel vein obstruction versus cirrhotic children. J Pediatr Hematol Oncol 2011; 33: e267-270 9). Preto-Zamperlini M et al. Elevated C-reactive protein and spontaneous bacterial peritonitis in children with chronic liver disease and ascites. J Pediatr Gastroenterol Nutr 2013. Epub ahead of print 10).Hasper D, Joerres A. New insights into the management of hepato-renal syndrome. Liver International 2011; 31 (suppl 3) 27-30 11). Grace J, Angus PW. Hepatopulmonary syndrome: Update on recent advances in pathophysiology, investigation and treatment. J Gastroenterology and Hepatology 2013; 28:213-219

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12). Mardini H, Record C. Pathoigenesis of hepatic encephalopathy : lessons from nitrogen challenges in man. Metabol Brain Dis 2013; 28: 201-207 13). Taveira ATA et al. Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease. Braz J Med Biol Res 2010; 1127-1134 14). Kryskiewicz E et al. Bone metabolism in cholestatic children before and after living-related liver transplantation-a long-term prospective study. J Clin Densitrometry 2012; 233-240 15). Jagadisan B et al. Acute on chronic liver disease in children from the developing worlsd: Recognition and prognosis. JPGN 2012; 54: 77-82 16). Lal J et al. Predictors of outcome in acute-on-chronic liver failure in children. Hepatol Int 2011; 5:693-697 17). Squires RH et al. Acute liver falure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006; 148: 652-658 18). Helmke K, Hansen HC. Fundamentals of transorbital sonographic evaluation of optic nerve sheath expansion under intracranial hypertension II. Patient study. Pediatr Radiol 1996; 26: 706-710 19). Helmke K et al. Detection and monitoring of intracranial pressure dysregulation 0n liver failure by ultrasound. Transplantation 2000; 70: 392-395 20). Brandy R Lu et al. Evaulation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure. J Pediatr 2013; 162: 1010-1016 21). Madan N et al. Evaluation of cardiac manifestations in pediatric liver transplant candidates. Pediatr Transplant 2012; 16:318-328 22). Kim JS et al. Pediatric transplantation : the Hamburg experience. Transplantation 2005; 15: 1206-1209 23). Herden U etal. A formula to calculate the standard liver volume in children and its application in pediatric liver transplantation. Transpl Int 2013; doi:10.1111/tri 12198 [Epub ahead of print]

Compendium Pediatric Liver Transplant 28 Aug 2014.indd 57

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24).NG VL et al. Health status of children alive 10 years after pdiatric liver transplantation performed in the US and Canada: Report of the studies of pediatric liver transplantation experience. J Pediatr 2012; 160: 820826 25). Kelly DA et al. Long-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. 2013; 19: 798-825 26). Dhawan A. Immunosuppression in pediatric transplantation : Are little people different? Liver Transplantation 2011 17: S13-S19 27). Israeli M et al. Confronting the challenge: individualized immune monitoring after organ transplantation using the cellular immune function assay. Clin Chim Acta 2012; 413: 1374-1368 28). Abraham SC et al. Significance of central perivenulitis in pediatric liver transplantation. Am J Surg Pathol 2008; 32: 1479-1488 29).Kelly D. Safety and efficacy of tacrolimus in pediatric liver recipients. Pediatr Transplant 2011: 15:19-24 30).Richter A et al. Clinical relevance of autoantibodies after pediatric liver transplantation. Clin Transplant 2007; 21:427-432 31).Pongpalbut A et al. Histopathology of den novo autoimmune hepatitis. Liver Transpl 2012; 18: 811-818 32).Shroff P et al. Presentation of atopic disease in a large cohort of pediatric liver transplant recipients. Pediatr Transpl 2012; 16: 379-384 33).Lee Y et al. Long-term follow-up of den novo allergy in pediatric liver transplantation â&#x20AC;&#x201C; 10 yr experience of a single center. Pediatr Transplant 2013; 17:251-255 34).Kowalsky S et al. Prevention of cytomegalovirus following solid organ transplantation: A literature review. Pediat Transplant 2013; 17: 499-509 35).Narkewicz MR et al. Decreasing incidence of symptomatic EpsteinBarr virus disease and posttransplant lymphoproliferative disorder in pediatric liver transplant recipients: report of the studies of pediatric liver transplantation experience. Liver Transpl 2013; 19: 730-740

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36). Smets F, Sokal EM. Epstein â&#x20AC;&#x201C; Barr virus-related lympgoproliferation in children after liver transplant : role of immunity, diagnosis and management. Pediatr Transplant 2002; 6: 280-287 37). Herzog D et al. Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic transplant recipients. Liver Transpl 2008; 14: 946-955 38).Briem-Richter A et al. Liver allograft pathology in healthy pediatric liver transplant recipients. Pediatr Transplant 2013; 17: 543-549 39).Burdelski M et al. Chronic organ dysfunction in pediatric liver transplantation. Saudi Med J.2013 Suppl 33, 27-29 40).Alonso EM et al. The SPLIT Research Agenda 2013. Pediatr Transplant 2013; 17: 412-422

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