Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: A stepwise approach. World J Gastroenterol 2013; 19(18): 2740-2751 [PMID: 23687411 DOI: 10.3748/wjg.v19.i18.2740]
Corresponding Author of This Article
Pietro Vajro, Professor, Department of Medicine and Surgery, Pediatrics, University of Salerno, Via Allende, 84081 Baronissi, Italy. pvajro@unisa.it
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Gastroenterology & Hepatology
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Review
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Pietro Vajro, Department of Medicine and Surgery, Pediatrics, University of Salerno, 84081 Baronissi, Italy
Pietro Vajro, European Laboratory for Food Induced Disease, 84081 Baronissi, Italy
Sergio Maddaluno, Claudio Veropalumbo, Department of Translational Medical Sciences, Pediatrics, Medical School of the University of Naples “Federico II”, 80131 Naples, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: Vajro P, Maddaluno S and Veropalumbo C contributed equally to this work.
Correspondence to: Pietro Vajro, Professor, Department of Medicine and Surgery, Pediatrics, University of Salerno, Via Allende, 84081 Baronissi, Italy. pvajro@unisa.it
Telephone: +39-89-965016 Fax: +39-89-672409
Received: November 12, 2012 Revised: December 20, 2012 Accepted: January 17, 2013 Published online: May 14, 2013 Processing time: 184 Days and 19.6 Hours
Abstract
We aimed to examine the major causes of isolated chronic hypertransaminasemia in asymptomatic children and develop a comprehensive diagnostic flow diagram. A MEDLINE search inclusive of publications throughout August 2012 was performed. We found only a small number of publications that had comprehensively investigated this topic. Consequently, it was difficult to construct a diagnostic flowchart similar to those already available for adults. In children, a “retesting panel” prescription, including gamma-glutamyl transpeptidase and creatine kinase in addition to aminotransferases, is considered a reasonable approach for proficiently confirming the persistence of the abnormality, ruling out cholestatic hepatopathies and myopathies, and guiding the subsequent diagnostic steps. If re-evaluation of physical and historical findings suggests specific etiologies, then these should be evaluated in the initial enzyme retesting panel. A simple multi-step diagnostic algorithm incorporating a large number of possible pediatric scenarios, in addition to the few common to adults, is available. Accurately classifying a child with asymptomatic persistent hypertransaminasemia may be a difficult task, but the results are critical for preventing the progression of an underlying, possibly occult, condition later in childhood or during transition. Given the high benefit/cost ratio of preventing hepatic deterioration, no effort should be spared in diagnosing and properly treating each case of persistent hypertransaminasemia in pediatric patients.
The measurement of serum transaminase levels has become part of the routine biochemical evaluation that takes place before surgery or for the investigation of pathologies not necessarily related to liver injury in many countries. An investigation of unexpected hypertransaminasemia is important for differentiating muscular and hepatic disease; to institute timely and specific treatment for progressive, but still asymptomatic, treatable liver conditions [e.g., Wilson’s disease, autoimmune hepatitis (AIH), and non-alcoholic fatty liver disease (NAFLD)]; to furnish genetic counseling for hereditary disorders; and/or to setup appropriate preventive measures (e.g., avoidance of viral hepatitis transmission). Moreover, prevention of possible hepatic deterioration has a high benefit/cost ratio by avoiding the need for eventual liver transplantation[1].
Currently, the most frequent cause of hypertransaminasemia in both adults and children is obesity, although obesity-related liver disease is still sometimes erroneously considered cryptogenic because of a poor perception of obesity among medical practitioners[2-4]. In adults, the causes of isolated hypertransaminasemia other than obesity-related liver disease are limited to viral hepatitis, toxic damage, autoimmune hepatobiliary diseases, celiac disease, Wilson’s disease, and hereditary hemochromatosis[5,6], whose diagnostic work-up is well established[4,6-11]. The problem is more complex in children, in whom individually rare genetic/metabolic conditions collectively constitute 20%-30% of liver diseases[12,13]. Therefore, persistent hypertransaminasemia in a child should alert the physician to the possibility of an underlying hepatic or multisystem metabolic disorder and prompt a referral to a specialized center for diagnostic evaluation. However, despite extensive investigation, the etiology of some cases may have to be defined as truly unknown (cryptogenic)[12,14].
There are only a few reports examining the possible causes of isolated chronic hypertransaminasemia in asymptomatic pediatric populations[12,14-16], and often these studies are biased by flawed inclusion and exclusion criteria, and/or an inadequate diagnostic work-up. Consequently, there is no diagnostic algorithm for the differential diagnosis of unexpected chronic hypertransaminasemia in pediatric patients.
The aim of this report is to develop a comprehensive diagnostic algorithm that includes many of the frequent causes of isolated asymptomatic hypertransaminasemia in children and adolescents. We examined current adult guidelines and expert opinions, and then performed a MEDLINE search inclusive of publications throughout August 2012 using the key words: transaminase, aminotransferase, hypertransaminasemia, liver disease, and children. We also evaluated reports from specialized tertiary pediatric hepatology centers. A secondary aim was to provide a basis for future studies on the cost/benefit ratio of diagnostic assessment procedures.
TRANSAMINASES: BACKGROUND ON ORIGINS, LEVELS, AND THRESHOLD LEVELS
Aminotransferases are normally present in circulation at low levels. They are intracellular enzymes produced principally by hepatocytes, and their increase in serum is therefore indicative of liver cell injury. However, aspartate aminotransferase (AST) is also found in cardiac and skeletal muscles, the kidneys, brain, pancreas, and lungs, and in erythrocytes, in decreasing order of concentration. Additionally, alanine aminotransferase (ALT) is present in skeletal muscle and kidneys, but at low concentrations, and its increase in the circulation is more specific for liver damage than AST. Aminotransferase serum levels depend not only on the tissue of origin, but also on the enzyme half-life, which is longer for ALT than AST. Thus, in diseases such as muscular dystrophy, patients can have AST and ALT serum values that are elevated to the same degree, instead of the expected prevalent elevation of AST[17].
In clinical practice, normal parameter values are within 2 standard deviations of the mean value obtained in healthy individuals. This implies that 5% of the results of healthy subjects fall outside this range. While transaminase reference intervals for adults have recently been revised[18,19], this has not occurred for children. England et al[20] recently proposed ALT centiles stratified by sex and age in a healthy European population. They propose an ALT upper limit of normal of 60 IU/L in boys and 55 IU/L in girls during the first 18 mo of life. The range changes to 40 IU/L in boys and 35 IU/L in girls after the age of 18 mo. The Screening ALT for Elevation in Today’s Youth (SAFETY) study conducted on a population of North American patients aged between 12 and 17 years shows that the upper limit of normal used by most laboratories for ALT is too high to detect chronic liver disease and that less than half of North American hospitals utilize gender-specific values. In that study, the ALT thresholds in use had a low sensitivity for the detection of chronic liver damage (30%-40%). Using the National Health and Nutrition Examination Survey (NHANES) ALT threshold of 25.8 IU/L for boys and 22.1 IU/L for girls, the sensitivity improved to 70%-80%, while the specificity was only reduced from approximately 90% to approximately 80%[21].
Clinical recommendation
In the pediatric population, there is no established reference range of ALT and AST. ALT thresholds currently in use have a low sensitivity for the detection of chronic liver damage. In teenagers, the biologically-determined and gender-specific ALT threshold of 25.8 U/L for boys and 22.1 U/L for girls established by NHANES increases this sensitivity, with only a modest specificity reduction.
APPROACH TO ASYMPTOMATIC HYPERTRANSAMINASEMIA
Table 1 summarizes the most frequent causes of persistently-elevated transaminase levels in asymptomatic children, schematically classified under the categories of viral, autoimmune, metabolic, and other types of hepatobiliary diseases or extrahepatic causes of hypertransaminasemia.
Table 1 Main causes of asymptomatic hypertransaminasemia in children.
A detailed evaluation of medical and family history and an accurate clinical examination are crucial in determining the likely etiology of hypertransaminasemia, as they may indicate towards possible muscle or liver conditions.
Initial step: The retesting panel
A stepwise approach contemplates repeating the tests to confirm the results[5,9,10]. In adults, timing of retesting is not firmly established because it has usually been empirically guided by the degree of transaminase alterations found {mild [< 5 times upper limit of normal (× ULN)]; moderate (5-10 × ULN); marked (> 10 × ULN)}.
In pediatric patients, information about gamma-glutamyl transferase (GGT) rather than alkaline phosphatase values might help to determine whether the liver injury is predominantly hepatocellular or cholestatic[5]. Creatine phosphokinase (CPK) should also be evaluated to rule out occult muscle disease[22].
As in adults[5,10,23], in many asymptomatic children, abnormal values can show normal values when retested[12,14-16,23]. The reported percentage of patients who normalize aminotransferase serum values within 6 mo from the first detection of abnormality ranges from 26% to 73.6%[12,14-16]. A fluctuating pattern (transient/self-limiting or intermittent) is frequently observed at all ages, and more than one retesting may be warranted even for a mild increase of transaminases. In areas with a high prevalence of hepatitis B (HBV) and C (HCV) virus infection and in high-risk populations, it is advisable to request viral markers at the time of repeat testing to accelerate the screening protocol[9,10]. Recently, Senadhi[24] recommended that HBV and HCV screening is warranted in all asymptomatic patients with mild transaminase elevations.
In selected patients who participate in strenuous sports, liver tests should be repeated after at least one week without exercise, especially if hypertransaminasemia was associated with high CPK or with elevation of other enzymes of muscle origin[25]. If high CPK and hypertransaminasemia are confirmed, it is mandatory to exclude muscular diseases, which are often clinically asymptomatic during the first 5-6 years of life and can be recognized only after a detailed and oriented neurologic examination[22]. In addition to the well-known muscular dystrophies, myocyte injury, necrosis induced by drugs or toxins, and increased exercise are possible causes of high CPK and hypertransaminasemia. Additionally, some mitochondrial, endocrine and metabolic myopathies, and gluten enteropathy are also causes of high CPK and hypertransaminasemia. A serum elevation of CPK ranging from 450 to 5000 U/L (normal upper limit: 150 U/L) accompanying isolated asymptomatic hypertransaminasemia can also be a marker of a caveolinopathy, a group of newly described and still poorly understood muscle diseases that affect the limb-girdle, distal muscles, and heart. A diagnosis may be particularly challenging in pediatric patients that are only mildly symptomatic[26].
First, second, and third line investigations
The evaluation of patients with confirmed hypertransaminasemia should include first (and eventually second and third) line investigations (Table 2). If the patient’s history or physical examination suggests a particular disease, selected first-line investigations should already be part of the retesting panel. However, some authors suggest that first-line exams for hepatocellular causes of liver disease should be performed without the need to confirm hypertransaminasemia in patients with increased serum levels of ALT > 3-5 × ULN[27]. Historically, a hypertransaminasemia duration of approximately 6 mo has been arbitrarily used to determine chronic liver disease. However, it is unwise to wait for 6 mo before investigating a possible cause of liver damage, as some hepatopathies, such as autoimmune liver disease or Wilson’s disease, can become rapidly life-threatening without appropriate treatment[28].
Table 2 Retesting panel; first, second, and third line investigations in children with asymptomatic mild hypertransaminasemia.
Conjugated and unconjugated bilirubin Protein electrophoresis Serum albumin Prothrombin time and partial thromboplastin time Blood cell count Hepatic ultrasonography If only AST elevation is confirmed: PEG test and electrophoresis for macro-AST
Viral markers (HAV, HBV, HCV) Minor hepatotropic viruses serology (e.g., EBV, CMV) Ceruloplasmin, serum copper ANA, SMA, LKM, LC1, anti-SLA, total IgG Serum α1 antitrypsin EMA, tTgasi IgA, deamidated AGA IgA (< 2 yr), total IgA
Urinary copper, molecular ATP B7 analysis HCV RNA, HBV DNA Genetic and metabolic enlarged screening2 (“non-alcoholic fatty liver disease bin”) Sweat test Fecal elastase, steatocrit Other hepatic imaging techniques (MRI, ERCP, CT, etc.) Liver biopsy3 Jejunal biopsy (after celiac disease serology)
In the case of protracted isolated AST elevation, the possibility of macro-AST should be investigated by polyethylene glycol and/or electrophoresis testing. Macro-AST is a condition characterized by the presence in serum of a macromolecular complex formed by association with other plasma components [e.g., immunoglobulin G (IgG)] or by self-polymerization. Due to their large size, macro-AST components cannot be filtered by renal glomeruli and are retained in the plasma. The condition is benign, but may cause diagnostic uncertainty and lead to useless, invasive, expensive, and time-consuming testing[29].
Clinical recommendation
Aminotransferase levels should be retested upon finding hypertransaminasemia in asymptomatic patients. At this time, the levels of CPK (for muscular disease) and GGT (for biliary involvement) should also be evaluated. An accurate clinical history and physical examination are of paramount importance for guiding an appropriate investigation and avoiding expensive and unnecessary tests.
MOST COMMON LIVER DISEASES
Non-alcoholic fatty liver disease
NAFLD is the most common cause of hypertransaminasemia in children and adolescents[12,14,16,21]. In clinical practice, NAFLD is usually suspected by the finding of hypertransaminasemia and ultrasonographic fatty liver in an obese child[30,31]. Although the ALT serum level is a useful diagnostic tool, it is not a sensitive marker of NAFLD. It is common to observe the entire histological spectrum of NAFLD in patients with normal ALT levels[22,32]. The evaluation of both AST and ALT values is important because an increased AST/ALT ratio has been reported to reflect a progressive and more serious condition [fibrotic non-alcoholic steatohepatitis (NASH)][33].
Due to the worldwide obesity epidemic, obesity may be erroneously accepted as a normal condition even in the presence of abnormal liver function tests[2]. Conversely, in the presence of obesity, all other conditions associated with abnormal transaminase levels, such as celiac disease[34,35], Wilson’s disease[36], autoimmune hepatitis[37], or muscular diseases[22], must be investigated and excluded. In many of these diseases, prompt treatment will avoid irreversible disease progression[38] (Table 3).
Table 3 Fatty liver disease; possible causes in likely asymptomatic children and adolescents.
General or systemic
Genetic-metabolic causes
Drugs/chemicals
Obesity
Cystic fibrosis
Ethanol
Metabolic syndrome
Shwachman syndrome
Ecstasy, cocaine, solvents
Obstructive sleep apnea
Wilson’s disease
Nifedipine
Polycystic ovary syndrome
Alpha 1-antitrypsin deficiency
Diltiazem
Diabetes mellitus type 1
Fructosemia
Estrogens
Thyroid disorders
Cholesterol ester storage disease
Corticosteroids
Hypothalamic-pituitary disorders
Glycogen storage disease (type I, VI and IX)
Methotrexate
Inflammatory bowel disease
Mitochondrial and peroxisomal defects
Prednisolone
Celiac disease
α- and β-oxidation defects
Valproate
Protein calorie malnutrition
Organic acidosis
Vitamin
Rapid weight loss
Abeta or hypobetalipoproteinemia
Zidovudine and HIV treatments
Anorexia nervosa
Porphyria cutanea tarda
Solvents
Small intestinal bacterial overgrowth
Homocystinuria
Pesticides
Hepatitis C
Familial hyperlipoproteinemias
Bile acids synthesis defects
Congenital disorders of glycosylation
Citrin deficiency
Turner syndrome
Abdominal ultrasound and liver function tests should be performed as a first step in the diagnosis of possible NAFLD in children[39]. Ultrasonography, however, detects fat levels above 30% only. Waist circumference is a valid surrogate marker of central obesity, which is closely correlated with liver involvement[40]. When pediatric NAFLD is suspected, other liver diseases should be excluded based on an age-driven algorithm[39]. In obese children and adolescents with disordered breathing during sleep, sleep apnea syndrome should be viewed as a risk factor for NAFLD. Interestingly, weight loss, avoidance of a sedentary life, and effective treatment of sleep apnea syndromes resulted in a significant improvement of liver enzyme levels[41,42].
Clinical recommendation: NAFLD and NASH are diagnoses of exclusion even in obese children with hypertransaminasemia. Other fatty liver causing diseases should be investigated based on the patient’s age and clinical features.
Viral infections
Serological markers of hepatitis viruses are part of the first-line etiology investigation panel (Table 2). A positive history of blood or blood-derivative transfusion, tattooing, ingestion of potentially-contaminated food, and the ethno-geographic origin of the patients give a clue as to a possible infectious etiology. Although immigration and international adoption from endemic areas are well-recognized risk factors, hepatitis B shows an emerging presentation of subclinical chronic hepatitis B in children[43].
In countries where universal vaccination against HBV has been introduced, a significantly-reduced rate of HBV infection in children and mother-to-infant transmission has been observed. However, international adoption and immigration maintain an ample reservoir of HBV infection. Although significantly less infectious than HBV, HCV infection remains a widespread problem in the absence of an effective vaccine. In Western countries, perinatal transmission is currently the primary mode of HCV spread in children, which accounts for approximately 65% of cases[44]. Although hypertransaminasemia may suggest HCV infection, adult[45] and pediatric HCV carriers[46] may have normal or fluctuating aminotransferase levels even in the presence of serious liver damage.
Among the conditions falling within the category of adult cryptogenic hypertransaminasemia is a new entity called “occult” HCV infection. Said entity is characterized by fluctuating serum levels of HCV RNA, while the virus genome and its replicative intermediate RNA-negative strand are detectable in the liver and in peripheral blood mononuclear cells with or without antibodies to HCV[47]. Similarly, “occult” HBV infection has been recognized in patients with cryptogenic hepatitis B surface antigen (HBsAg)-negative chronic liver disease[48]. Intrahepatic replicative activity (HBV covalently closed circular DNA and pregenomic RNA) has recently been described in adults with occult hepatitis B infection. HBV occult infection seems to be relatively frequent in immunized children born to HBsAg-positive mothers. HBsAg negativity is not sufficient for excluding the presence of HBV DNA. These findings emphasize the importance of considering occult HBV infection in hypo-endemic areas[49].
In pediatric patients, hepatitis A virus infection may be followed by up to 1 year intermittent hypertransaminasemia due to relapsing viremia, which does not evolve to chronic liver damage[50]. Other hepatotropic viruses are a frequent cause of liver disease. Epstein-Barr virus and/or cytomegalovirus should be excluded in patients with a history of fever, lymphadenopathy (mainly latero-cervical), pharyngitis, asthenia, and/or hepatosplenomegaly. In patients with paucisymptomatic immunodeficiency, coxsackievirus and adenovirus may be the cause of liver enzyme alteration. Gastrointestinal infection by rotavirus can be accompanied by self-limiting hepatic and non-hepatic transaminase elevation in 20% of infected patients[51].
Currently minor, rather than major, hepatotropic viruses are a common cause of hypertransaminasemia in children in developed countries[12,15,16].
Clinical recommendation: Viral serological markers are part of the first-line investigation panel.
Toxic causes
An accurate medical history is crucial in determining the possible role of toxin-induced hepatotoxicity in children with hypertransaminasemia[52]. In adults, diagnostic scores have been proposed and evaluated to define the association between drugs and liver disease[53,54]. Alcohol abuse can induce liver disease and hypertransaminasemia even in childhood, especially in adolescents[6]. It has been suggested that elevated serum GGT levels, and/or an AST/ALT ratio > 1, and/or an increase in mean corpuscular volume may help in identifying excessive drinking[55]. Carbohydrate deficient transferrin is another tool for identifying unhealthy occult drinking[56]. If medication or alcohol are suspected causes of hypertransaminasemia in an adolescent, aminotransferases should be retested after 6-8 wk of controlled or monitored abstinence[57]. In addition to prescribed or over-the-counter medications and herbal remedies, illegal drugs or substances of abuse should be considered in differential diagnoses and be carefully investigated[58,59].
Autoimmune liver disease
AIH is a progressive inflammatory liver disease without a known etiology, and is characterized histologically by interface hepatitis and serologically by high levels of transaminases, IgG, and positive autoantibodies[60]. The exact prevalence of autoimmune hepatitis is unknown, but it is approximately one in 200000 in the general population of the United States[61]. Sometimes, the histology of autoimmune hepatitis is associated with bile duct injury-determining overlap syndrome or autoimmune sclerosing cholangitis (ASC); this condition is different from primary sclerosing cholangitis, which is characterized by inflammation and fibrosis in the intrahepatic and/or extra-hepatic bile load in the absence of interface hepatitis[62,63]. It is important to perform a cholangiography in all children with the histological features of autoimmune hepatitis, as ASC is as prevalent as AIH in childhood, and thus only cholangiography can differentiate between these conditions[64]. There are two types of AIH classified according to antibody profile: type 1 [anti-nuclear antibodies and anti-smooth muscle antibodies (SMA)] and type 2 [anti-liver kidney microsomal antibody (LKM1); and/or antibodies to liver cytosol type 1 (anti-LC1)][65]. Anti-soluble liver antigen (anti-SLA) antibodies can be positive in otherwise autoAb-negative patients. These antibodies cannot be detected by immunofluorescence, and require enzyme-linked immunosorbent assay and immunoassays for identification. Type 2 may tend to be more severe and prevalent in children, adolescents, and young adults than in the older population[60]. The absence of autoantibodies in a child with hypertransaminasemia does not exclude the diagnosis of autoimmune hepatitis. In fact, seronegative but empirically steroid-responsive autoimmune hepatitis has been reported[66-68]. Conversely, the increase in serum gamma-globulins is not universal in AIH. As for Wilson’s disease, the diagnosis of autoimmune hepatitis may be difficult because it is not based on specific markers. Consequently, a scoring system has been devised[69,70] that gives positive predictive values for females, the presence of other autoimmune diseases, hypergammaglobulinemia, and positivity for ANA, SMA, LKM1, LC1 and ASLA. It also gives negative scores for viral markers and a positive history for drugs and alcohol use. A simpler score based on only four items[71] has not yet been fully validated in children. Primary biliary cirrhosis is not observed during childhood, although very rare cases of anti-mitochondrial autoantibody positivity have been reported[72].
AIH (and ASC) may present with only hypertransaminasemia, which can occur in children with apparent good health. It should therefore be investigated with appropriate examinations; if left untreated, cirrhosis may develop.
Clinical recommendation: Autoimmune hepatitis should be rapidly identified in order to administer prompt therapy and avoid cirrhotic evolution. Hypertransaminasemia and hypergammaglobulinemia may be the only findings of seronegative autoimmune hepatitis. It is important to perform a cholangiography in all children with the histological features of autoimmune hepatitis because, in childhood, autoimmune sclerosing cholangitis is as prevalent as autoimmune hepatitis.
Celiac disease and hypertransaminasemia
Celiac disease may be associated with liver involvement in both adults and children. Isolated hypertransaminasemia may be the first manifestation of clinically silent celiac disease[73,74]. It is currently controversial[75] as to whether, in children less than 2 years old, AGA-IgA and IgG should be tested, because of a diagnostic sensitivity higher than that of anti-endomysium antibodies and anti-transglutaminase antibodies at that age. Selective non-responsiveness to HBV immunization in a hypertransaminasemic child may be a clue to undiagnosed celiac disease[76].
So-called “celiac hepatitis” is the most common hepatopathy in celiac patients and is characterized by a moderate increase of transaminase levels usually associated with minimal and non-specific liver lesions of the lobule and portal tracts. A gluten-free diet generally results in normalization of the liver enzymes and repair of histological damage. Due to high disease prevalence, patients with a known diagnosis of celiac disease and persistent hypertransaminasemia should be tested for other possible causes of liver damage before ascribing liver function test abnormalities to celiac disease. Co-existing causes of hepatopathy have been reported[77]. Celiac disease may present as hepatic steatosis in obese children with hypertransaminasemia resistant to weight loss. In such cases, the addition of a gluten-free diet is necessary to resolve their liver abnormalities[34].
Celiac disease can be associated with a variety of autoimmune liver diseases, including AIH, autoimmune cholangitis, and overlap syndromes, with a frequency of AIH peaking at 2.9% in celiac disease children less than 10 years old[74]. Autoimmune hepatic involvement can either precede or follow the diagnosis of celiac disease. It is necessary to diagnose AIH associated with celiac disease promptly, because it is not responsive to a gluten-free diet alone and requires long-term associated immunosuppressive therapy[78].
Wilson’s disease and hypertransaminasemia
The prevalence of Wilson’s disease is estimated at one in 30000 in most populations (Table 4). The prevalence is as high as one in 10000 in China, Japan, and Sardinia[79]. It may present at any age. Usually, the onset of symptomatic liver disease is at approximately 12 years of age[80]. It is only during adolescence or early adult life that patients usually present with complicating neurological and psychiatric manifestations. The most important laboratory diagnostic clues are hypoceruloplasminemia (< 20 mg/dL in 85%-95% cases), increased free serum copper, increased intrahepatic copper (> 250 μg/g dry weight), and increased basal and post-penicillamine challenge urinary copper excretion[81,82]. These findings are not specific if considered individually, and several conditions may be responsible for false negative and false positive results. Therefore, a score (the “Ferenci score”), which takes into account the Kayser-Fleischer ring, neuropsychiatric symptoms, the occurrence of Coombs negative hemolytic anemia, increased urinary copper, decreased serum ceruloplasmin, increased copper content of hepatocytes, and the presence of causative mutations, has been devised to distinguish between an unlikely/probable/highly-likely diagnosis of Wilson’s disease[81]. More recently, a new cut-off value for urinary copper excretion in asymptomatic children with Wilson’s disease has been suggested. The new value of 40 μg/24 h replaces the previously-used 100 μg/24 h[83,84]. The post-penicillamine challenge urinary copper estimation has been reported to be poorly sensitive in asymptomatic children[84]. A molecular diagnosis and/or haplotype analysis of the region surrounding ATP7B on chromosome 13 should be considered in children with enigmatic liver disease, especially those with features of NAFLD[84,85]. Wilson’s disease-like hypoceruloplasminemic liver disease has been recently described in congenital disorders of glycosylation (CDG) type X[84,86,87]. Non-Wilsonian high urinary copper excretion has been reported in pediatric nodular regenerative hyperplasia[84].
Table 4 Clinical and laboratory findings for orienting diagnosis of some genetic metabolic liver diseases.
Chubby face, fatty liver, specific serum amino acids pattern
Citrin deficiency
1:20000 in East Asia
++
Failure to thrive, lactic acidosis
Mitochondrial diseases
1:8500 (all disorders)
+
Failure to thrive, ketoacidosis, hypoglycemia
Organic acidosis
1:1000 (all disorders)
+
Mild coagulopathy, clinical phenotype
Congenital disorders of glycosylation
From 1:10000 to 1:100000
+
Short stature, female gender, karyotype
Turner syndrome
1:2000
+
Failure to thrive, positive sweat test
Cystic fibrosis
1:2500
+
Clinical recommendation: The criteria adopted for the diagnosis of Wilson’s disease are non-specific if considered individually. The Ferenci score will distinguish between unlikely, probable, and highly-likely diagnoses of Wilson’s disease. New pediatric cut-off values and the real value of post-penicillamine urinary test in asymptomatic cases need careful consideration.
OTHER DISEASES
Disorders, such as inborn errors of metabolism and/or congenital conditions affecting the liver, are much more common in pediatric patients than in adults (Table 3). These diseases are rare when considered individually, but represent a large group if considered collectively. It is difficult to establish their incidences; in most cases, they are relatively asymptomatic and may therefore remain undiagnosed[88]. Although many etiologies present in the neonatal period with cholestasis or acute illness, several may become manifest only later in infancy or childhood. Extreme care is required to avoid misdiagnosing these cases. This is particularly true if the patients have NAFLD-like symptoms that risk being considered part of the NASH syndrome[38]. Laboratory investigations for genetic metabolic diseases that may often be responsible for a NAFLD-like fatty liver picture should be guided by age and clinical/family history (Table 4). We will comment only on the most relevant metabolic liver diseases and refer the reader to a series of comprehensive reviews for specific information regarding the less common ones[89,90].
Hepatic derangement with severe, but self-limiting, hypertransaminasemia and variable histological patterns may be the sole initial evident manifestation of Shwachman-Diamond syndrome (incidence: 1:50000 worldwide). The mechanisms that can contribute to liver damage in these patients are not known[91]. Citrin deficiency (incidence: 1:20000 in East Asia), a condition now also recognized in Western countries, may present with a pattern of neonatal cholestasis and increased levels of blood citrulline, or NAFLD in children and adolescents[92]. Hereditary fructose intolerance (incidence: 1:20000 worldwide) typically occurs with a pattern of early-onset cholestasis during weaning. However, it may present later in patients who spontaneously follow a low fructose diet because of instinctive fructose refusal/dislike or avoidance. In these cases, medical observation may be dictated by the incidental finding of hypertransaminasemia, hepatomegaly, and/or bright liver by ultrasound observation. Feeding history is crucial for the diagnosis, which is confirmed by molecular analysis of gene mutations[93]. Mitochondrial diseases are often multisystem, but some cases may present with exclusive or prevalent mild liver involvement [e.g., mitochondrial DNA depletion syndrome due to deoxyguanosine kinase (DGUOK, OMIM 251880)]. Some congenital disorders of glycosylation (incidence: 1:50000-1:100000) may present as chronic isolated hypertransaminasemia. Children with clinically asymptomatic, cryptogenic hypertransaminasemia with liver steatosis-fibrosis and mild coagulopathy should be screened for CDG[86,87]. Congenital hepatic fibrosis (CHF, incidence: unknown) is a developmental disorder of the porto-biliary system. It is one of the fibropolycystic diseases, which include Caroli disease, autosomal dominant polycystic kidney disease, and autosomal recessive polycystic kidney disease. Clinically, it is characterized by non- cirrhotic portal hypertension, and rarely complicated by (porto-) pulmonary hypertension and hepatopulmonary syndrome. Hepatocellular function is relatively well-preserved, unless cholangitic episodes are present. Hereditary familial hemochromatosis (incidence: 1:20000 worldwide) most often presents after the transition to maturity, and is well-discussed in studies on adult patients and outside the scope of this article. Alpha 1-antitrypsin deficiency (incidence: 1:7000) presents clinical symptoms only in a minority of affected people. In infancy, the most common presentation is cholestasis. During childhood, it may present with minimally symptomatic disease that becomes significant liver disease only in 10%-15% of patients, often after several years of a near-normal quality of life, and may progress to decompensated liver disease[94]. Glycogenosis types VI and IX may be associated with elevated ALT and a soft hepatomegaly that is often not discernible at clinical examination, but without the gross metabolic abnormalities that are typically observed in the other types of glycogenosis. Cystic fibrosis rarely has a prevalent or exclusive hepatic presentation[95]. Nodular regenerative hyperplasia is an infrequently-identified liver disease characterized by non-fibrotic nodular hepatocyte regeneration, secondary portal hypertension, and mild stable abnormalities of liver function tests. In adults, it is usually associated with malignant prothrombotic or rheumatological conditions. These associations are rarely encountered in pediatric practice. The diagnosis is sometimes suggested by minimal histological changes (e.g., sinusoidal dilation)[96].
TRANSAMINITIS AND CRYPTOGENIC HEPATITIS
The term “transaminitis” was coined to describe overall liver enzyme leakage without hepatotoxic consequences in adult patients receiving drug therapy of any type. Hypertransaminasemia is due to an unknown effect of the drug (e.g., changes in hepatocellular membranes due to lipid lowering) or underlying conditions (i.e., fatty liver)[97]. Childhood “cryptogenic” hepatitis appears to be a symptomless disease characterized by isolated hypertransaminasemia that onsets during the first 4 years of life, and mild to moderate histologic liver lesions. Although the frequency of spontaneous remissions is low, childhood chronic cryptogenic hepatitis appears, in the short-term, to be a non-progressive disease. This diagnosis can only be attempted once all other known causes of liver disease are excluded[14,15].
DISCUSSION AND CONCLUSION
Given the large number of pediatric conditions that may be responsible for isolated persistent hypertransaminasemia, one can conclude that even asymptomatic children should undergo an intensive liver work-up. Based on the possibility of a fluctuating pattern, it seems reasonable to repeat ALT and AST testing to confirm hypertransaminasemia, rather than embarking on expensive investigations that may prove to be useless. An enzyme panel costs approximately $30, whereas tests to identify only some of the most common causes of elevated liver enzymes (such as serology for hepatitis B and C infection and ultrasonography for NAFLD) cost approximately $400[10]. However, the cost-benefit considerations of a stepwise diagnostic approach vs a simultaneous (and timesaving) testing approach in children should not deter from the need to avoid repeated vein punctures, which is often a traumatic experience. As seen in patients with a fever of unknown origin, in asymptomatic children with cryptogenic hypertransaminasemia, ordering investigations as screening procedures in the hope that something abnormal will be identified might have a number of disadvantages. These disadvantages include: possible adverse reactions or complications, loss of the patient’s faith in the medical staff, high testing costs, and a soporific effect on the doctor’s diagnostic mental activities[98].
The prescription of a “retesting panel”, which includes the determination of GGT and CPK in addition to aminotransferase levels, has the advantage of confirming the persistence of the abnormality, helping to rule out, at least in part, cholestatic hepatopathies and myopathies, and guiding the subsequent diagnostic steps that are shown in Figure 1. Testing serum bile acids and cholangiography are other means to better assess cholestasis. If reassessment of physical and anamnestic findings suggests specific etiologies, these should be checked in the initial enzyme retesting panel (e.g., viral serologies or hepatorenal ultrasonography for viral hepatitis and NAFLD, respectively). In the presence of even subtle symptoms or signs (e.g., jaundice, ascites, pruritus, hepatomegaly, and/or splenomegaly), complete testing to identify the possible cause of liver disease should be included in the initial retesting.
Figure 1 Diagnostic algorithm for the diagnosis of pediatric mild chronic asymptomatic hypertransaminasemia.
Modified from the reference of 28. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CB: Conjugated bilirubin; UB: Unconjugated bilirubin; CPK: Creatine kinase; GGT: Gamma-glutamyl transferase; PE: Pulmonary embolism; PEG: Polyethylene glycol; PT: Prothrombin time; PTT: Partial thromboplastin time; US: Ultrasound; MRI: Magnetic resonance imaging; ERCP: Endoscopic retrograde cholangiopancreatography; pANCA: Perinuclear anti-neutrophil cytoplasmic antibodies; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AIH: Autoimmune hepatitis; α1 ATD: α1-antitrypsin deficiency.
The first line panel in asymptomatic hypertransaminasemic patients should consist of liver ultrasonography, liver function tests, and a number of investigations for the most frequent etiologies. Second and third line investigations are justified either by the inconclusive first line panel or to explore specific plausible conditions. Liver biopsy is part of these panels, but its exact timing and role remains a controversial issue[28,39,99-101]. It has been shown that in those patients with negative etiological investigations, a liver biopsy will most likely not add further useful information[10,15], and considering that a percutaneous liver biopsy samples only 1:50000 of the liver, sampling error is an obvious limitation which can lead to misdiagnosis and staging inaccuracies[102]. The competence of the pediatric liver disease pathologist is paramount. Steatosis of the liver in a non-obese individual may suggest a metabolic/genetic hepatopathy[14,38].
In conclusion, here we provide an overview of pediatric persistent hypertransaminasemia and list a series of metabolic, genetic, gastrointestinal, and extrahepatic causes that should be taken into account in clinical practice. The number of these etiologies constitutes a wider field of what one usually considers in adulthood. Importantly, information derived from the combination of the patient’s history, physical examination, and basic laboratory data are necessary to reach a timely and correct diagnosis. We also provide a stepwise approach that should always be guided by clinical scenarios.
ACKNOWLEDGMENTS
We are grateful to Professor Giorgina Mieli Vergani (London) for thoughtful discussion and suggestions.
Footnotes
P- Reviewer Yu DZ S- Editor Song XX L- Editor Rutherford A E- Editor Li JY
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