+Model CLINRE-565; No. of Pages 4
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
A practical approach to the child with abnormal liver tests Thierry Lamireau a,∗, Valérie McLin b, Valério Nobili c, Pietro Vajro d a
Pediatric Gastroenterology Unit, Children’s Hospital, place Amélie-Raba-Léon, 33076 Bordeaux, France Pediatric Gastroenterology Unit and Swiss Center for Liver Disease in Children, University Hospitals Geneva, 6, rue Willy Donze, 1211 Geneva 14, Switzerland c Hepatometabolic Unit, Bambino Gesu’ Children Hospital, IRCCS, Rome, Italy d Department of Medicine and Surgery, Pediatric Section, University of Salerno, 84081 Baronissi (SA), Italy b
Summary The presence of elevated aminotransferases on routine blood tests can reveal liver diseases of various severities. In children, etiologies are more numerous and complex than those usually considered in adults. Information derived from family and personal history, physical examination and basic laboratory data are necessary to reach a timely and correct diagnosis. A stepwise approach is proposed to guide the timing of more specific investigations that are often required. © 2014 Published by Elsevier Masson SAS.
A few liver tests, i.e. aminotransferases, bilirubin, gammaglutamyl transferase (GGT) and alkaline phosphatases (ALP), are used to follow the evolution of known chronic liver diseases. They are also part of the routine biochemical evaluation for the suspicion of acute hepatitis (nausea, fever, icterus, hepatomegaly, ascites) or chronic hepatobiliary disease (asthenia, pruritus, hepatomegaly, splenomegaly). In addition, they have become part of the standard work-up for growth failure, chronic diarrhea, and chronic abdominal
∗
Corresponding author. Tel.: +33 5 56 79 98 24; fax: +33 5 56 79 56 58. E-mail address: [email protected] (T. Lamireau).
pain. On the other hand, liver tests are not recommended in cases of benign viral, systemic diseases which are known to be often associated with a moderate increase of aminotransferases, as any abnormal test will need follow-up leading to unnecessary stress and cost. Aminotransferases are the main test used to assess liver cell injury. Aspartate aminotransferase (AST) is present in hepatocytes, cardiac and skeletal muscle, kidneys, brain, pancreas, lungs and erythrocytes. Alanine aminotransferase (ALT) is more specific to hepatocyte injury, although this enzyme is also expressed at a lower level in muscle and kidneys. In clinical practice, normal values are within 2 standard deviations of the mean obtained in healthy individuals. England et al. [1] recently proposed ALT centiles stratified by sex and age in a healthy European population: they
http://dx.doi.org/10.1016/j.clinre.2014.02.010 2210-7401/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
+Model
ARTICLE IN PRESS
CLINRE-565; No. of Pages 4
2
T. Lamireau et al. Table 1 Proposed upper limit of normal (ULN) for alanine aminotransferase (ALT) levels in children. ALT ULN (IU/L)
Boys
Girls
Infants Children Adolescents
60 40 26
55 35 22
Adapted from [1,2].
Second step If the patient is seronegative for hepatitis A, the second step should be to look for other viruses: HBV, HEV, Epstein-Barr virus (EBV), HHV6, cytomegalovirus (CMV). An ultrasound examination of the liver and biliary tree should also be performed to rule out acute obstruction of the common bile duct with biliary lithiasis. The underlying cause of biliary stones should be further investigated with appropriate tests.
Third step proposed an ALT upper limit of normal (ULN) of 60 IU/L in boys and 55 IU/L in girls during the first 18 months of age, and an ALT ULN of 40 IU/L for boys and 35 IU/L for girls after the age of 18 months. Some studies in adolescents show that the ULN used by most laboratories is too high to detect chronic liver disease, and that an ALT ULN of 25.8 IU/L for boys and 22.1 IU/L in girls improves test sensitivity [2] (Table 1). Investigating unexpected elevated aminotransferases is important for differentiating between muscular and hepatic disease, to initiate treatment for treatable diseases (e.g. Wilson’s disease, autoimmune hepatitis [AIH], metabolic disorders), to recommend genetic counseling for hereditary disorders, and to setup appropriate preventive measures (for example, HAV and HBV vaccination). Therefore, persistently elevated aminotransferases in a child should alert the physician to the possibility of an underlying liver or multisystem disorder and prompt a referral to a specialized center for diagnostic evaluation and management.
Rapid and high (>10 N) increase of aminotransferases The degree of emergency is indicated by the association with increased prothrombin time indicating impending liver failure, and not by the level of increased aminotransferases which is not directly correlated to disease severity. The main causes of acute hepatitis are viruses (A, B, E), Wilson’s disease, AIH, and acute obstruction of common bile duct. Important hepatocyte destruction may also be due to ischemia during hemodynamic shock, acute cardiac failure, or secondary to toxics (mushroom) or drugs (acetaminophen). In case of muscular pain, coma or hypoglycemia, serum level of creatine phosphokinase (CPK) should be measured to exclude rhabdomyolysis of infectious, toxic, traumatic or metabolic origin. The etiology should be investigated in a stepwise approach, but it is recommended to urgently rule out treatable diseases in case of liver failure.
First step In the absence of informative history, a practical approach is to first assess anti-hepatitis A virus IgM (HAV) and start symptomatic treatment if positive. This attitude is advised because HAV infection is frequent, even in Europe where the prevalence is not as high as in developing countries.
The third step should look for autoimmune hepatitis, Wilson’s disease, and metabolic disorders. If the entire work-up is negative and aminotransferases decrease, a follow-up is required to document complete normalization over the next 3 months. If the enzymes normalize the reasonable diagnosis is unexplained acute hepatitis [1]. If aminotransferases remain elevated, the work-up should continue, including liver biopsy.
Persistent and moderate ( ALT, it is mandatory to exclude an extra-hepatic disorder, such as myopathies (Duchenne and Becker dystrophies, drug- or toxin-induced muscle disorders, caveolinopathies, hypothyroidism), cardiomyopathies, hemolytic disorders, endocrine
Table 3
3 (hyperthyroidism, adrenal insufficiency, hypopituitarism) or metabolic disorders (mitochondrial cytopathies, disorder of fatty acid beta-oxidation). Collaboration with the corresponding specialists is essential. If the patient’s history or physical examination suggests a particular disease, diseasespecific labs should of course already be part of the retesting panel.
Second step Second line investigations (Table 2) of persistently elevated aminotransferases should include tests for viral infections (Epstein-Barr virus, CMV, HBV, HCV), autoimmune hepatitis, Wilson’s disease, celiac disease, ␣1-anti-trypsin deficiency, endocrine diseases (hypothyroidism, hypocorticism), and cystic fibrosis. In case of cholestasis (elevated serum GGT and/or total serum bile acids), an ultrasound examination and/or magnetic resonance imaging of the liver and biliary tree is mandatory to exclude chole- or choledocho-lithiasis, congenital dilatation of common bile duct, or sclerosing cholangitis. Alagille syndrome, progressive familial intrahepatic cholestasis, and cystic fibrosis should also be sought. Non-alcoholic fatty liver disease (NAFLD) is usually suspected in case of fatty liver on ultrasound examination in an obese child [9,10]. An elevated AST/ALT ratio may be indicative of non-alcoholic steatohepatitis (NASH), a progressive and more serious condition [11]. Nevertheless, NAFLD and NASH are diagnoses of exclusion even in obese children with elevated liver function tests, and a number of other diseases causing fatty liver (Table 3) should be excluded on the basis of patient age [4]. Family history or extra-hepatic signs can direct the clinician toward various genetic or metabolic diseases, such as Schwachmann syndrome, Gaucher disease, NiemannPick disease, lysosomal acid lipase deficiency, glycogen storage disease (type I, VI and IX), hereditary fructose intolerance, urea cycle defects, mitochondrial diseases, organic acidosis, citrin deficiency, congenital disorders of glycosylation, Turner syndrome, and congenital hepatic fibrosis.
Main causes of fatty liver disease.
General or systemic
Genetic-metabolic
Drugs/chemicals
Obesity Metabolic syndrome Diabetes mellitus type 1 Thyroid disorders Protein malnutrition Anorexia nervosa
Wilson’s disease Cystic fibrosis Schwachmann syndrome ␣1-anti-trypsin deficiency Lipase acid deficiency Disorders of FA-beta-oxidation Hereditary fructose intolerance Glycogen storage disease Mitochondrial cytopathies Peroxisomal disorders a/hypolipoproteinemias
Ethanol Ectasy, cocaine, solvents Nifedipin, diltiazem Estrogens, corticosteroids Methotrexate Sodium valproate HIV disease and treatments
FA: fatty acid; HIV: human immunodeficiency virus.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
+Model CLINRE-565; No. of Pages 4
ARTICLE IN PRESS
4
T. Lamireau et al.
In case of protracted isolated AST elevation, the possibility of macro-AST should be investigated by polyethylene glycol and/or electrophoresis testing. This condition is benign and should be recognized to avoid useless, invasive, expensive and time-consuming testing [12].
Third step If aminotransferase elevation persists without any explanation, a liver biopsy can be useful for diagnosis. The histologic features relevant for the diagnosis include the following: fatty liver (Table 3), presence of virus (CMV, HBV), copper load revealed by rhodanin stain (Wilson’s disease), interface hepatitis (autoimmune hepatitis), abnormalities of ductal plate, PAS positive glycogen (glycogen storage disease) or hyaline globules (␣1-anti-trypsin deficiency), spumous Kupffer cells (Nieman-Pick disease, Gaucher disease), nodular regenerative hyperplasia (areas of architectural collapse on Gomorri staining).
Conclusion The presence of elevated aminotransferases on routine blood tests can reveal liver diseases of various severities. In children, etiologies are more numerous and complex than those usually considered in adults. Information derived from family and personal history, physical examination and basic laboratory data are necessary to reach a timely and correct diagnosis. A stepwise approach is proposed to guide the timing of more specific investigations that are often required.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] England K, Thorne C, Pembrey L, Tovo PA, Newell ML. Ageand sex-related reference ranges of alanine aminotransferase levels in children: European paediatric HCV network. J Pediatr Gastroenterol Nutr 2009;49:71—7. [2] Schwimmer JB, Dunn W, Norman GJ, Pardee PE, Middelton MS, Kerkar N, et al. SAFETY study: alanine aminotransferase cutoff values are too high for reliable detection of pediatric chronic liver disease. Gastroenterology 2010;138:1357—64. [3] Iorio R, Sepe A, Giannattasio A, Cirillo F, Vegnente A. Hypertransaminasemia in childhood as a marker of genetic liver disorders. J Gastroenterol 2005;40:820—6. [4] Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: a stepwise approach. World J Gastroenterol 2013;19:2740—51. [5] Gianini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172:367—79. [6] Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002;123:1367—84. [7] Bugeac N, Pacht A, Mandel H, Iancu T, Tamir A, Srugo I, et al. The significance of isolated elevation of serum aminotransferases in infants and young children. Arch Dis Child 2007;92:1109—12. [8] Senadhi V. A paradigm shift in the outpatient approach to liver function tests. South Med J 2011;104:521—5. [9] Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013;58:1218—29. [10] Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012;54:700—13. [11] Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 2008;135:1961—72. [12] Caropreso M, Fortunato G, Lenta S, Palmieri D, Esposito M, Vitale DF, et al. Prevalence and long-term course of macro-aspartate aminotransferase in children. J Pediatr 2009;154:744—8.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
ARTICLE IN PRESS
Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
MINI REVIEW
A practical approach to the child with abnormal liver tests Thierry Lamireau a,∗, Valérie McLin b, Valério Nobili c, Pietro Vajro d a
Pediatric Gastroenterology Unit, Children’s Hospital, place Amélie-Raba-Léon, 33076 Bordeaux, France Pediatric Gastroenterology Unit and Swiss Center for Liver Disease in Children, University Hospitals Geneva, 6, rue Willy Donze, 1211 Geneva 14, Switzerland c Hepatometabolic Unit, Bambino Gesu’ Children Hospital, IRCCS, Rome, Italy d Department of Medicine and Surgery, Pediatric Section, University of Salerno, 84081 Baronissi (SA), Italy b
Summary The presence of elevated aminotransferases on routine blood tests can reveal liver diseases of various severities. In children, etiologies are more numerous and complex than those usually considered in adults. Information derived from family and personal history, physical examination and basic laboratory data are necessary to reach a timely and correct diagnosis. A stepwise approach is proposed to guide the timing of more specific investigations that are often required. © 2014 Published by Elsevier Masson SAS.
A few liver tests, i.e. aminotransferases, bilirubin, gammaglutamyl transferase (GGT) and alkaline phosphatases (ALP), are used to follow the evolution of known chronic liver diseases. They are also part of the routine biochemical evaluation for the suspicion of acute hepatitis (nausea, fever, icterus, hepatomegaly, ascites) or chronic hepatobiliary disease (asthenia, pruritus, hepatomegaly, splenomegaly). In addition, they have become part of the standard work-up for growth failure, chronic diarrhea, and chronic abdominal
∗
Corresponding author. Tel.: +33 5 56 79 98 24; fax: +33 5 56 79 56 58. E-mail address: [email protected] (T. Lamireau).
pain. On the other hand, liver tests are not recommended in cases of benign viral, systemic diseases which are known to be often associated with a moderate increase of aminotransferases, as any abnormal test will need follow-up leading to unnecessary stress and cost. Aminotransferases are the main test used to assess liver cell injury. Aspartate aminotransferase (AST) is present in hepatocytes, cardiac and skeletal muscle, kidneys, brain, pancreas, lungs and erythrocytes. Alanine aminotransferase (ALT) is more specific to hepatocyte injury, although this enzyme is also expressed at a lower level in muscle and kidneys. In clinical practice, normal values are within 2 standard deviations of the mean obtained in healthy individuals. England et al. [1] recently proposed ALT centiles stratified by sex and age in a healthy European population: they
http://dx.doi.org/10.1016/j.clinre.2014.02.010 2210-7401/© 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
+Model
ARTICLE IN PRESS
CLINRE-565; No. of Pages 4
2
T. Lamireau et al. Table 1 Proposed upper limit of normal (ULN) for alanine aminotransferase (ALT) levels in children. ALT ULN (IU/L)
Boys
Girls
Infants Children Adolescents
60 40 26
55 35 22
Adapted from [1,2].
Second step If the patient is seronegative for hepatitis A, the second step should be to look for other viruses: HBV, HEV, Epstein-Barr virus (EBV), HHV6, cytomegalovirus (CMV). An ultrasound examination of the liver and biliary tree should also be performed to rule out acute obstruction of the common bile duct with biliary lithiasis. The underlying cause of biliary stones should be further investigated with appropriate tests.
Third step proposed an ALT upper limit of normal (ULN) of 60 IU/L in boys and 55 IU/L in girls during the first 18 months of age, and an ALT ULN of 40 IU/L for boys and 35 IU/L for girls after the age of 18 months. Some studies in adolescents show that the ULN used by most laboratories is too high to detect chronic liver disease, and that an ALT ULN of 25.8 IU/L for boys and 22.1 IU/L in girls improves test sensitivity [2] (Table 1). Investigating unexpected elevated aminotransferases is important for differentiating between muscular and hepatic disease, to initiate treatment for treatable diseases (e.g. Wilson’s disease, autoimmune hepatitis [AIH], metabolic disorders), to recommend genetic counseling for hereditary disorders, and to setup appropriate preventive measures (for example, HAV and HBV vaccination). Therefore, persistently elevated aminotransferases in a child should alert the physician to the possibility of an underlying liver or multisystem disorder and prompt a referral to a specialized center for diagnostic evaluation and management.
Rapid and high (>10 N) increase of aminotransferases The degree of emergency is indicated by the association with increased prothrombin time indicating impending liver failure, and not by the level of increased aminotransferases which is not directly correlated to disease severity. The main causes of acute hepatitis are viruses (A, B, E), Wilson’s disease, AIH, and acute obstruction of common bile duct. Important hepatocyte destruction may also be due to ischemia during hemodynamic shock, acute cardiac failure, or secondary to toxics (mushroom) or drugs (acetaminophen). In case of muscular pain, coma or hypoglycemia, serum level of creatine phosphokinase (CPK) should be measured to exclude rhabdomyolysis of infectious, toxic, traumatic or metabolic origin. The etiology should be investigated in a stepwise approach, but it is recommended to urgently rule out treatable diseases in case of liver failure.
First step In the absence of informative history, a practical approach is to first assess anti-hepatitis A virus IgM (HAV) and start symptomatic treatment if positive. This attitude is advised because HAV infection is frequent, even in Europe where the prevalence is not as high as in developing countries.
The third step should look for autoimmune hepatitis, Wilson’s disease, and metabolic disorders. If the entire work-up is negative and aminotransferases decrease, a follow-up is required to document complete normalization over the next 3 months. If the enzymes normalize the reasonable diagnosis is unexplained acute hepatitis [1]. If aminotransferases remain elevated, the work-up should continue, including liver biopsy.
Persistent and moderate ( ALT, it is mandatory to exclude an extra-hepatic disorder, such as myopathies (Duchenne and Becker dystrophies, drug- or toxin-induced muscle disorders, caveolinopathies, hypothyroidism), cardiomyopathies, hemolytic disorders, endocrine
Table 3
3 (hyperthyroidism, adrenal insufficiency, hypopituitarism) or metabolic disorders (mitochondrial cytopathies, disorder of fatty acid beta-oxidation). Collaboration with the corresponding specialists is essential. If the patient’s history or physical examination suggests a particular disease, diseasespecific labs should of course already be part of the retesting panel.
Second step Second line investigations (Table 2) of persistently elevated aminotransferases should include tests for viral infections (Epstein-Barr virus, CMV, HBV, HCV), autoimmune hepatitis, Wilson’s disease, celiac disease, ␣1-anti-trypsin deficiency, endocrine diseases (hypothyroidism, hypocorticism), and cystic fibrosis. In case of cholestasis (elevated serum GGT and/or total serum bile acids), an ultrasound examination and/or magnetic resonance imaging of the liver and biliary tree is mandatory to exclude chole- or choledocho-lithiasis, congenital dilatation of common bile duct, or sclerosing cholangitis. Alagille syndrome, progressive familial intrahepatic cholestasis, and cystic fibrosis should also be sought. Non-alcoholic fatty liver disease (NAFLD) is usually suspected in case of fatty liver on ultrasound examination in an obese child [9,10]. An elevated AST/ALT ratio may be indicative of non-alcoholic steatohepatitis (NASH), a progressive and more serious condition [11]. Nevertheless, NAFLD and NASH are diagnoses of exclusion even in obese children with elevated liver function tests, and a number of other diseases causing fatty liver (Table 3) should be excluded on the basis of patient age [4]. Family history or extra-hepatic signs can direct the clinician toward various genetic or metabolic diseases, such as Schwachmann syndrome, Gaucher disease, NiemannPick disease, lysosomal acid lipase deficiency, glycogen storage disease (type I, VI and IX), hereditary fructose intolerance, urea cycle defects, mitochondrial diseases, organic acidosis, citrin deficiency, congenital disorders of glycosylation, Turner syndrome, and congenital hepatic fibrosis.
Main causes of fatty liver disease.
General or systemic
Genetic-metabolic
Drugs/chemicals
Obesity Metabolic syndrome Diabetes mellitus type 1 Thyroid disorders Protein malnutrition Anorexia nervosa
Wilson’s disease Cystic fibrosis Schwachmann syndrome ␣1-anti-trypsin deficiency Lipase acid deficiency Disorders of FA-beta-oxidation Hereditary fructose intolerance Glycogen storage disease Mitochondrial cytopathies Peroxisomal disorders a/hypolipoproteinemias
Ethanol Ectasy, cocaine, solvents Nifedipin, diltiazem Estrogens, corticosteroids Methotrexate Sodium valproate HIV disease and treatments
FA: fatty acid; HIV: human immunodeficiency virus.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
+Model CLINRE-565; No. of Pages 4
ARTICLE IN PRESS
4
T. Lamireau et al.
In case of protracted isolated AST elevation, the possibility of macro-AST should be investigated by polyethylene glycol and/or electrophoresis testing. This condition is benign and should be recognized to avoid useless, invasive, expensive and time-consuming testing [12].
Third step If aminotransferase elevation persists without any explanation, a liver biopsy can be useful for diagnosis. The histologic features relevant for the diagnosis include the following: fatty liver (Table 3), presence of virus (CMV, HBV), copper load revealed by rhodanin stain (Wilson’s disease), interface hepatitis (autoimmune hepatitis), abnormalities of ductal plate, PAS positive glycogen (glycogen storage disease) or hyaline globules (␣1-anti-trypsin deficiency), spumous Kupffer cells (Nieman-Pick disease, Gaucher disease), nodular regenerative hyperplasia (areas of architectural collapse on Gomorri staining).
Conclusion The presence of elevated aminotransferases on routine blood tests can reveal liver diseases of various severities. In children, etiologies are more numerous and complex than those usually considered in adults. Information derived from family and personal history, physical examination and basic laboratory data are necessary to reach a timely and correct diagnosis. A stepwise approach is proposed to guide the timing of more specific investigations that are often required.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] England K, Thorne C, Pembrey L, Tovo PA, Newell ML. Ageand sex-related reference ranges of alanine aminotransferase levels in children: European paediatric HCV network. J Pediatr Gastroenterol Nutr 2009;49:71—7. [2] Schwimmer JB, Dunn W, Norman GJ, Pardee PE, Middelton MS, Kerkar N, et al. SAFETY study: alanine aminotransferase cutoff values are too high for reliable detection of pediatric chronic liver disease. Gastroenterology 2010;138:1357—64. [3] Iorio R, Sepe A, Giannattasio A, Cirillo F, Vegnente A. Hypertransaminasemia in childhood as a marker of genetic liver disorders. J Gastroenterol 2005;40:820—6. [4] Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: a stepwise approach. World J Gastroenterol 2013;19:2740—51. [5] Gianini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172:367—79. [6] Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology 2002;123:1367—84. [7] Bugeac N, Pacht A, Mandel H, Iancu T, Tamir A, Srugo I, et al. The significance of isolated elevation of serum aminotransferases in infants and young children. Arch Dis Child 2007;92:1109—12. [8] Senadhi V. A paradigm shift in the outpatient approach to liver function tests. South Med J 2011;104:521—5. [9] Nobili V, Svegliati-Baroni G, Alisi A, Miele L, Valenti L, Vajro P. A 360-degree overview of paediatric NAFLD: recent insights. J Hepatol 2013;58:1218—29. [10] Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, et al. Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr 2012;54:700—13. [11] Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 2008;135:1961—72. [12] Caropreso M, Fortunato G, Lenta S, Palmieri D, Esposito M, Vitale DF, et al. Prevalence and long-term course of macro-aspartate aminotransferase in children. J Pediatr 2009;154:744—8.
Please cite this article in press as: Lamireau T, et al. A practical approach to the child with abnormal liver tests. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.02.010
