The Adolescent Liver Tran s p lan t P ati en t Deirdre Kelly,
FRCPCH, FRCP, FRCPI, MD
a,b,
*, Jo Wray,
PhD, C Psychol
c
KEYWORDS Pediatric Liver transplantation Adolescent Adherence KEY POINTS Advances in medical and surgical therapy mean that significant numbers of children with previously fatal liver disease survive into adolescence and adult life with or without transplantation. Eighty percent of transplant recipients, irrespective of time of transplant, are expected to survive for more than 20 years. Survivors of childhood liver disease require a different approach than other young adults. Physicians need to consider their emotional, social, and sexual health and be aware of the high rate of nonadherence both for clinic appointments and medication and the implications for graft loss/progress of liver disease. Physicians need to be familiar with the long-term consequences of liver transplantation in childhood and adolescence (eg, renal failure, recurrent disease, osteoporosis, and posttransplant malignancies, especially post-transplant lymphoproliferative disease). Developing adequate transitional care for these young people is based on effective collaboration at the pediatric–adult interface and is a major challenge for pediatric and adult providers alike in the 21st century.
INTRODUCTION
Over the last 25 years, there have been significant advances in medical technology and therapy, improving diagnosis and management of pediatric liver disease. Children with previously fatal diseases now survive into adult life in increasing numbers, but some require transplantation in adolescence. Improvements in operative techniques, preoperative and postoperative management, organ preservation, donor management, and the availability of more potent and less toxic immunosuppressive drugs have contributed to better outcome in
Disclosure: None. a The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK; b University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; c Critical Care and Cardiorespiratory Division, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom * Corresponding author. The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. E-mail address: [email protected] Clin Liver Dis 18 (2014) 613–632 http://dx.doi.org/10.1016/j.cld.2014.05.006 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
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pediatric and adolescent liver transplantation (LT). These improvements have led to 1-year survival rates of more than 90% and 5- and 10-year survival rates of 80%.1–3 The success of liver transplantation means that the long-term survival rate for child and adolescent recipients of LT is 80% over 20 years; thus most children with liver disease can expect to become adults. DEFINITION OF ADOLESCENCE
The World Health Organization defines adolescence as the period of growth and development occurring between childhood and adulthood, from 10 to 19 years of age.4 Adolescents are developmentally, psychologically, and medically distinct from both adults and children.5 Adolescence is a challenging time for any young person as adolescents need to Achieve autonomy and independence while maintaining supportive links with their family Develop a sense of identity, particularly through social relationships Chronic illness and transplantation in adolescence exaggerate these challenges and place the young person at risk of social isolation, delayed development of peer support networks, and enforced dependency on family members. SPECIFIC ISSUES IN ADOLESCENCE
Adolescence is a time of egocentrism, a change from concrete to more abstract thinking, and a time for experimenting with risk taking, which is the same for all adolescents including those with liver disease. Although the brain continues to develop through adolescence, it does not do so evenly; the areas controlling physical coordination, emotion, and motivation develop first, and the prefrontal cortex, which is responsible for executive functioning (eg, planning, problem solving, impulse control), does not mature until about 25 years old. The result is a young person who is likely to seek high excitement and indulge in risky behaviors (drugs, alcohol, sex), demonstrating poor planning and judgment without considering negative consequences. Assuming responsibility for managing treatment protocols and adhering to medications can therefore be genuinely challenging for the adolescent with liver disease. INDICATIONS FOR TRANSPLANTATION
LT is standard therapy for acute or chronic liver failure at any age (Box 1). Chronic Liver Failure
The main reasons for transplantation for chronic liver failure are
Decompensated cirrhosis Portal hypertension unresponsive to therapy Intractable variceal bleeding Ascites Encephalopathy Malnutrition
In adolescents, growth failure and delayed puberty with amenorrhea in girls are additional issues.
The Adolescent Liver Transplant Patient
Box 1 Indications for LT in adolescents Chronic liver failure Biliary atresia Autoimmune hepatitis I and II Fibropolycystic liver disease 1/– Caroli syndrome Immunodeficiency Inborn errors of metabolism Alagille syndrome Progressive familial intrahepatic cholestasis (PFIC-3) a1-Antitrypsin deficiency Cystic fibrosis Glycogen storage type IV Tyrosinemia type I Wilson disease Acute liver failure Acetaminophen poisoning Autoimmune hepatitis I and II Viral hepatitis (A, B, C, E, or indeterminate) Wilson disease Inborn errors of metabolism with extrahepatic disease Crigler–Najjar type I Primary oxalosis Liver tumors Benign tumors Unresectable malignant tumors
Biliary Atresia
Extrahepatic biliary atresia (EHBA) is a disease of unknown etiology in which there is obstruction or destruction of the extrahepatic biliary tree. It occurs in approximately 1 out of every 15,000 live births.6 Initial management is based on early diagnosis and palliative surgery, the Kasai portoenterostomy in which the biliary tree is excised to expose biliary channels, and a Roux loop is created for drainage. The operation is successful if there is restoration of biliary flow within 6 months, but is dependent on the age of surgery, the expertise of the surgeon, and the extent of fibrosis at operation.7 Biliary atresia is the main indication for LT worldwide and accounts for 76% transplants in children younger than 2 years; 80% of children who have a successful operation do not require transplantation before adolescence.7 Inherited Metabolic Liver Disease a1-Antitrypsin deficiency
a1-Antitrypsin deficiency is the most common form of inherited metabolic liver disease in childhood in Europe. Although 50% to 70% of children develop persistent liver
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disease progressing to cirrhosis, only 20% to 30% require transplantation in childhood or adolescence.8,9 Alagille syndrome
This autosomal dominant condition has an incidence of 1 case per 100,000 live births.10 It is a multisystem disorder with cardiac, facial, renal, ocular, and skeletal abnormalities. The condition is caused by mutations in the Jagged 1 gene (JAG1), which encodes a ligand of Notch 1.11 The main clinical issues are cholestasis, malnutrition, and cardiac or renal disease. The development of liver failure is unusual, and with adequate support, about 50% of children regain normal liver function without significant cholestasis by adolescence, while approximately 30% require liver transplantation.12 Progressive Familial Intrahepatic Cholestasis
This group of inherited cholestatic diseases is caused by mutations in the hepatocellular transport system genes involved in bile synthesis. They are rare, with an incidence of 1 case per 50,000 population to 1 case per 100,000 population worldwide occurrence and equal sex distribution. Progressive familial intrahepatic cholestasis 1 (PFIC1) is caused by mutations in ATP8B113 and presents in the first months of life with episodes of jaundice and severe pruritus and very high serum bile acid levels. Due to the extrahepatic expression of ATP8B1, other clinical features include pancreatitis, diarrhea (loss of the ileal transporter), sensorineural deafness, and short stature. PFIC2 is caused by mutations in ABCB1114 and presents with persistent cholestasis from birth, coagulopathy secondary to fat-soluble vitamin K deficiency, and pruritus. Hepatocellular carcinoma has been reported in infancy. PFIC3 is caused by mutations in ABCB415 and presents anytime during childhood or adult life with complications of chronic liver disease or liver failure. Pruritus is often mild. PFIC1 and PFIC2 both have low-normal gamma glutamyl transferase (GGT) despite marked cholestasis in contrast to the elevated GGT in PFIC3. Cholesterol tends to be low. Synthetic function is maintained until liver failure develops. Most patients require LT in childhood, although those with a milder phenotype require transplantation in adolescence for biliary cirrhosis and portal hypertension. Tyrosinemia Type I
Tyrosinemia type I is an autosomal recessive disorder caused by a defect of fumaryl acetoacetase (FAA).16 There is a lifetime risk of developing hepatocellular carcinoma (HCC).17 Clinical features are heterogeneous, even within the same family. Acute liver failure is a common presentation in infants, while older children or adolescents present with chronic liver disease, rickets, a hypertrophic cardiomyopathy, renal failure or a porphyria-like syndrome with self-mutilation. Renal tubular dysfunction and hypophosphatemic rickets may occur at any age. Management is with a phenylalanine and tyrosine-restricted diet and nitisone, which prevents the formation of toxic metabolites and allows normal growth and development.18 The long-term outcome has significantly improved with nitisone therapy and transplantation is now only indicated in those adolescents who do not respond to nitisone, or develop HCC19 delaying. Cystic Fibrosis
Cystic fibrosis (CF) occurs in 1 in every 3000 live births worldwide.20 The gene defect is an abnormality in the cystic fibrosis transmembrane conductance regulator (CFTR) located on chromosome 7 q31. It is a multiorgan disease mainly affecting the lungs
The Adolescent Liver Transplant Patient
and pancreas. Cystic fibrosis associated liver disease (CFLD) occurs in 27% to 35% of patients and usually presents before the age of 18 years.21 Approximately 5% to 10 % of patients develop cirrhosis and portal hypertension during the first decade of life and present with complications in adolescence or early adult life.22 The indications for LT include malnutrition unresponsive to nutritional support, intractable portal hypertension, and hepatic dysfunction. It is essential that transplantation is carried out before pulmonary disease becomes irreversible,23 especially as there is stabilization of pulmonary function and nutrition, but deaths from respiratory failure in adult life should be anticipated.24 Wilson Disease
Wilson disease is an autosomal recessive disorder with an incidence of 1 case per 30,000 live births. The defective gene is on chromosome 13 and encodes a copper transporting P-type adenosinetriphosphatase (ATPase) (ATP7B).25 Clinical features in adolescence include hepatic dysfunction (40%) fulminant hepatitis, chronic hepatitis or cirrhosis, and psychiatric symptoms (35%). Neurologic symptoms may be nonspecific, but deteriorating school performance, abnormal behavior, lack of coordination, and dysarthria are common. Renal tubular abnormalities, renal calculi, and hemolytic anemia are associated features. LT is indicated for those with advanced liver disease (Wilson score >6), fulminant liver failure or progressive hepatic disease despite therapy.26,27 Autoimmune liver disease types I and II
Most adolescents with autoimmune liver disease types I or II respond to immunosuppression with prednisolone or azathioprine. LT is indicated for those who present with fulminant hepatic failure, advanced portal hypertension, or in patients who do not respond to immunosuppression despite the use of second-line drugs such as cyclosporine A, tacrolimus, and mycophenalate mofetil.28 Fibropolycystic Liver Disease
Fibropolycystic liver disease is a rare indication for LT in adolescence, as liver function remains normal for many years even with severe portal hypertension. Liver replacement is only indicated if hepatic decompensation develops or hepatic enlargement interferes with quality of life. The disease may be associated with polycystic kidney disease, and both liver and kidney replacement may be required at the time of renal replacement.29 Primary Immunodeficiency
Young people with CD40 ligand deficiency (hyper IgM syndrome) have recurrent cryptosporidial infection of the gut and biliary tree leading to sclerosing cholangitis. It is important to carry out bone marrow transplantation before the development of significant liver disease or to consider combined liver and bone marrow transplantation.30 Timing of Transplantation for Adolescents with Chronic Liver Failure
As many adolescents with cirrhosis and portal hypertension have well-compensated liver function, the timing of LT may be difficult to predict and is based on Deterioration in hepatic function Failure of nutrition and growth Difficulty in maintaining normal life and education In practice, the need for liver transplantation is indicated by Persistent rise in total bilirubin greater than 150 mmol/L
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Prolongation of prothrombin ratio (international normalized ratio [INR] >1.4) Fall in serum albumin less than 35 g/L.1 These parameters are used in the pediatric end-stage liver disease score (PELD) in order to predict death and provide prioritization on the waiting list.31,32 There is a modified formula for children older than 12 years.32 It is important to consider psychosocial development. Children with chronic liver disease have lower IQ scores33,34 and significantly impaired motor skills,33 but some of these impairments, particularly the delay in motor skills, may be reversed following LT if it is performed early enough.3,31 Thus, any significant delay in developmental or educational parameters is an indication for LT. ACUTE LIVER FAILURE
The main indications for LT for acute liver failure in adolescence are drug induced, infectious hepatitis, or metabolic disease (eg, Wilson disease).35,36 Drug-Induced Liver Failure
Many different drugs cause acute liver failure including antibiotics, antituberculosis therapy, antiepileptic therapy, and Acetaminophen poisoning.37 Adolescents have a lower incidence of liver failure with acetaminophen overdose than adults, possibly because of the effect of hepatic maturation and glutathione production.38 Transplantation is more likely to be required if the overdose was taken with another drug (eg, lysergic acid diethylamide [LSD], Ecstasy) or with alcohol.39 Transplantation is required if there is a persistent coagulopathy (INR>4), metabolic acidosis (pH300 mmol/l) or rapid progression to hepatic coma grade III. Cerebral edema may persist despite evidence of hepatic regeneration and recovery, and influence postoperative recovery. Viral hepatitis
Hepatitis A and B are the most common causes of acute liver failure in the developing world.40,41 However, in the United Kingdom and United States, indeterminate hepatitis is the most common cause (Box 2) and has the worst prognosis for spontaneous recovery.36 Hepatitis C virus (HCV) is a rare cause for acute liver failure.35 Hepatitis E infection occurs in travelers and is associated with acute liver failure in pregnant women.42 MANAGEMENT OF ADOLESCENTS WITH ACUTE LIVER FAILURE
Management includes Assessment of prognosis for recovery or liver transplantation Prevention and treatment of hepatic complications while awaiting a donor organ/ regeneration of native liver Provision of psychosocial support and information for patients and parents Poor prognostic factors for spontaneous recovery are
Indeterminate hepatitis Rapid onset of coma with progression to grade III or IV hepatic coma Diminishing liver size Falling transaminases Increasing bilirubin (>300 mmol/L) Persistent coagulopathy (PT >40 seconds; INR >4) Hypoglycemia (
FRCPCH, FRCP, FRCPI, MD
a,b,
*, Jo Wray,
PhD, C Psychol
c
KEYWORDS Pediatric Liver transplantation Adolescent Adherence KEY POINTS Advances in medical and surgical therapy mean that significant numbers of children with previously fatal liver disease survive into adolescence and adult life with or without transplantation. Eighty percent of transplant recipients, irrespective of time of transplant, are expected to survive for more than 20 years. Survivors of childhood liver disease require a different approach than other young adults. Physicians need to consider their emotional, social, and sexual health and be aware of the high rate of nonadherence both for clinic appointments and medication and the implications for graft loss/progress of liver disease. Physicians need to be familiar with the long-term consequences of liver transplantation in childhood and adolescence (eg, renal failure, recurrent disease, osteoporosis, and posttransplant malignancies, especially post-transplant lymphoproliferative disease). Developing adequate transitional care for these young people is based on effective collaboration at the pediatric–adult interface and is a major challenge for pediatric and adult providers alike in the 21st century.
INTRODUCTION
Over the last 25 years, there have been significant advances in medical technology and therapy, improving diagnosis and management of pediatric liver disease. Children with previously fatal diseases now survive into adult life in increasing numbers, but some require transplantation in adolescence. Improvements in operative techniques, preoperative and postoperative management, organ preservation, donor management, and the availability of more potent and less toxic immunosuppressive drugs have contributed to better outcome in
Disclosure: None. a The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK; b University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; c Critical Care and Cardiorespiratory Division, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom * Corresponding author. The Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. E-mail address: [email protected] Clin Liver Dis 18 (2014) 613–632 http://dx.doi.org/10.1016/j.cld.2014.05.006 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
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pediatric and adolescent liver transplantation (LT). These improvements have led to 1-year survival rates of more than 90% and 5- and 10-year survival rates of 80%.1–3 The success of liver transplantation means that the long-term survival rate for child and adolescent recipients of LT is 80% over 20 years; thus most children with liver disease can expect to become adults. DEFINITION OF ADOLESCENCE
The World Health Organization defines adolescence as the period of growth and development occurring between childhood and adulthood, from 10 to 19 years of age.4 Adolescents are developmentally, psychologically, and medically distinct from both adults and children.5 Adolescence is a challenging time for any young person as adolescents need to Achieve autonomy and independence while maintaining supportive links with their family Develop a sense of identity, particularly through social relationships Chronic illness and transplantation in adolescence exaggerate these challenges and place the young person at risk of social isolation, delayed development of peer support networks, and enforced dependency on family members. SPECIFIC ISSUES IN ADOLESCENCE
Adolescence is a time of egocentrism, a change from concrete to more abstract thinking, and a time for experimenting with risk taking, which is the same for all adolescents including those with liver disease. Although the brain continues to develop through adolescence, it does not do so evenly; the areas controlling physical coordination, emotion, and motivation develop first, and the prefrontal cortex, which is responsible for executive functioning (eg, planning, problem solving, impulse control), does not mature until about 25 years old. The result is a young person who is likely to seek high excitement and indulge in risky behaviors (drugs, alcohol, sex), demonstrating poor planning and judgment without considering negative consequences. Assuming responsibility for managing treatment protocols and adhering to medications can therefore be genuinely challenging for the adolescent with liver disease. INDICATIONS FOR TRANSPLANTATION
LT is standard therapy for acute or chronic liver failure at any age (Box 1). Chronic Liver Failure
The main reasons for transplantation for chronic liver failure are
Decompensated cirrhosis Portal hypertension unresponsive to therapy Intractable variceal bleeding Ascites Encephalopathy Malnutrition
In adolescents, growth failure and delayed puberty with amenorrhea in girls are additional issues.
The Adolescent Liver Transplant Patient
Box 1 Indications for LT in adolescents Chronic liver failure Biliary atresia Autoimmune hepatitis I and II Fibropolycystic liver disease 1/– Caroli syndrome Immunodeficiency Inborn errors of metabolism Alagille syndrome Progressive familial intrahepatic cholestasis (PFIC-3) a1-Antitrypsin deficiency Cystic fibrosis Glycogen storage type IV Tyrosinemia type I Wilson disease Acute liver failure Acetaminophen poisoning Autoimmune hepatitis I and II Viral hepatitis (A, B, C, E, or indeterminate) Wilson disease Inborn errors of metabolism with extrahepatic disease Crigler–Najjar type I Primary oxalosis Liver tumors Benign tumors Unresectable malignant tumors
Biliary Atresia
Extrahepatic biliary atresia (EHBA) is a disease of unknown etiology in which there is obstruction or destruction of the extrahepatic biliary tree. It occurs in approximately 1 out of every 15,000 live births.6 Initial management is based on early diagnosis and palliative surgery, the Kasai portoenterostomy in which the biliary tree is excised to expose biliary channels, and a Roux loop is created for drainage. The operation is successful if there is restoration of biliary flow within 6 months, but is dependent on the age of surgery, the expertise of the surgeon, and the extent of fibrosis at operation.7 Biliary atresia is the main indication for LT worldwide and accounts for 76% transplants in children younger than 2 years; 80% of children who have a successful operation do not require transplantation before adolescence.7 Inherited Metabolic Liver Disease a1-Antitrypsin deficiency
a1-Antitrypsin deficiency is the most common form of inherited metabolic liver disease in childhood in Europe. Although 50% to 70% of children develop persistent liver
615
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disease progressing to cirrhosis, only 20% to 30% require transplantation in childhood or adolescence.8,9 Alagille syndrome
This autosomal dominant condition has an incidence of 1 case per 100,000 live births.10 It is a multisystem disorder with cardiac, facial, renal, ocular, and skeletal abnormalities. The condition is caused by mutations in the Jagged 1 gene (JAG1), which encodes a ligand of Notch 1.11 The main clinical issues are cholestasis, malnutrition, and cardiac or renal disease. The development of liver failure is unusual, and with adequate support, about 50% of children regain normal liver function without significant cholestasis by adolescence, while approximately 30% require liver transplantation.12 Progressive Familial Intrahepatic Cholestasis
This group of inherited cholestatic diseases is caused by mutations in the hepatocellular transport system genes involved in bile synthesis. They are rare, with an incidence of 1 case per 50,000 population to 1 case per 100,000 population worldwide occurrence and equal sex distribution. Progressive familial intrahepatic cholestasis 1 (PFIC1) is caused by mutations in ATP8B113 and presents in the first months of life with episodes of jaundice and severe pruritus and very high serum bile acid levels. Due to the extrahepatic expression of ATP8B1, other clinical features include pancreatitis, diarrhea (loss of the ileal transporter), sensorineural deafness, and short stature. PFIC2 is caused by mutations in ABCB1114 and presents with persistent cholestasis from birth, coagulopathy secondary to fat-soluble vitamin K deficiency, and pruritus. Hepatocellular carcinoma has been reported in infancy. PFIC3 is caused by mutations in ABCB415 and presents anytime during childhood or adult life with complications of chronic liver disease or liver failure. Pruritus is often mild. PFIC1 and PFIC2 both have low-normal gamma glutamyl transferase (GGT) despite marked cholestasis in contrast to the elevated GGT in PFIC3. Cholesterol tends to be low. Synthetic function is maintained until liver failure develops. Most patients require LT in childhood, although those with a milder phenotype require transplantation in adolescence for biliary cirrhosis and portal hypertension. Tyrosinemia Type I
Tyrosinemia type I is an autosomal recessive disorder caused by a defect of fumaryl acetoacetase (FAA).16 There is a lifetime risk of developing hepatocellular carcinoma (HCC).17 Clinical features are heterogeneous, even within the same family. Acute liver failure is a common presentation in infants, while older children or adolescents present with chronic liver disease, rickets, a hypertrophic cardiomyopathy, renal failure or a porphyria-like syndrome with self-mutilation. Renal tubular dysfunction and hypophosphatemic rickets may occur at any age. Management is with a phenylalanine and tyrosine-restricted diet and nitisone, which prevents the formation of toxic metabolites and allows normal growth and development.18 The long-term outcome has significantly improved with nitisone therapy and transplantation is now only indicated in those adolescents who do not respond to nitisone, or develop HCC19 delaying. Cystic Fibrosis
Cystic fibrosis (CF) occurs in 1 in every 3000 live births worldwide.20 The gene defect is an abnormality in the cystic fibrosis transmembrane conductance regulator (CFTR) located on chromosome 7 q31. It is a multiorgan disease mainly affecting the lungs
The Adolescent Liver Transplant Patient
and pancreas. Cystic fibrosis associated liver disease (CFLD) occurs in 27% to 35% of patients and usually presents before the age of 18 years.21 Approximately 5% to 10 % of patients develop cirrhosis and portal hypertension during the first decade of life and present with complications in adolescence or early adult life.22 The indications for LT include malnutrition unresponsive to nutritional support, intractable portal hypertension, and hepatic dysfunction. It is essential that transplantation is carried out before pulmonary disease becomes irreversible,23 especially as there is stabilization of pulmonary function and nutrition, but deaths from respiratory failure in adult life should be anticipated.24 Wilson Disease
Wilson disease is an autosomal recessive disorder with an incidence of 1 case per 30,000 live births. The defective gene is on chromosome 13 and encodes a copper transporting P-type adenosinetriphosphatase (ATPase) (ATP7B).25 Clinical features in adolescence include hepatic dysfunction (40%) fulminant hepatitis, chronic hepatitis or cirrhosis, and psychiatric symptoms (35%). Neurologic symptoms may be nonspecific, but deteriorating school performance, abnormal behavior, lack of coordination, and dysarthria are common. Renal tubular abnormalities, renal calculi, and hemolytic anemia are associated features. LT is indicated for those with advanced liver disease (Wilson score >6), fulminant liver failure or progressive hepatic disease despite therapy.26,27 Autoimmune liver disease types I and II
Most adolescents with autoimmune liver disease types I or II respond to immunosuppression with prednisolone or azathioprine. LT is indicated for those who present with fulminant hepatic failure, advanced portal hypertension, or in patients who do not respond to immunosuppression despite the use of second-line drugs such as cyclosporine A, tacrolimus, and mycophenalate mofetil.28 Fibropolycystic Liver Disease
Fibropolycystic liver disease is a rare indication for LT in adolescence, as liver function remains normal for many years even with severe portal hypertension. Liver replacement is only indicated if hepatic decompensation develops or hepatic enlargement interferes with quality of life. The disease may be associated with polycystic kidney disease, and both liver and kidney replacement may be required at the time of renal replacement.29 Primary Immunodeficiency
Young people with CD40 ligand deficiency (hyper IgM syndrome) have recurrent cryptosporidial infection of the gut and biliary tree leading to sclerosing cholangitis. It is important to carry out bone marrow transplantation before the development of significant liver disease or to consider combined liver and bone marrow transplantation.30 Timing of Transplantation for Adolescents with Chronic Liver Failure
As many adolescents with cirrhosis and portal hypertension have well-compensated liver function, the timing of LT may be difficult to predict and is based on Deterioration in hepatic function Failure of nutrition and growth Difficulty in maintaining normal life and education In practice, the need for liver transplantation is indicated by Persistent rise in total bilirubin greater than 150 mmol/L
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Prolongation of prothrombin ratio (international normalized ratio [INR] >1.4) Fall in serum albumin less than 35 g/L.1 These parameters are used in the pediatric end-stage liver disease score (PELD) in order to predict death and provide prioritization on the waiting list.31,32 There is a modified formula for children older than 12 years.32 It is important to consider psychosocial development. Children with chronic liver disease have lower IQ scores33,34 and significantly impaired motor skills,33 but some of these impairments, particularly the delay in motor skills, may be reversed following LT if it is performed early enough.3,31 Thus, any significant delay in developmental or educational parameters is an indication for LT. ACUTE LIVER FAILURE
The main indications for LT for acute liver failure in adolescence are drug induced, infectious hepatitis, or metabolic disease (eg, Wilson disease).35,36 Drug-Induced Liver Failure
Many different drugs cause acute liver failure including antibiotics, antituberculosis therapy, antiepileptic therapy, and Acetaminophen poisoning.37 Adolescents have a lower incidence of liver failure with acetaminophen overdose than adults, possibly because of the effect of hepatic maturation and glutathione production.38 Transplantation is more likely to be required if the overdose was taken with another drug (eg, lysergic acid diethylamide [LSD], Ecstasy) or with alcohol.39 Transplantation is required if there is a persistent coagulopathy (INR>4), metabolic acidosis (pH300 mmol/l) or rapid progression to hepatic coma grade III. Cerebral edema may persist despite evidence of hepatic regeneration and recovery, and influence postoperative recovery. Viral hepatitis
Hepatitis A and B are the most common causes of acute liver failure in the developing world.40,41 However, in the United Kingdom and United States, indeterminate hepatitis is the most common cause (Box 2) and has the worst prognosis for spontaneous recovery.36 Hepatitis C virus (HCV) is a rare cause for acute liver failure.35 Hepatitis E infection occurs in travelers and is associated with acute liver failure in pregnant women.42 MANAGEMENT OF ADOLESCENTS WITH ACUTE LIVER FAILURE
Management includes Assessment of prognosis for recovery or liver transplantation Prevention and treatment of hepatic complications while awaiting a donor organ/ regeneration of native liver Provision of psychosocial support and information for patients and parents Poor prognostic factors for spontaneous recovery are
Indeterminate hepatitis Rapid onset of coma with progression to grade III or IV hepatic coma Diminishing liver size Falling transaminases Increasing bilirubin (>300 mmol/L) Persistent coagulopathy (PT >40 seconds; INR >4) Hypoglycemia (
