Topics on Continuous Training

M.J. Quiles Blanco, L. Fernández Tomé

Consultant. Pediatric Hepatology and Liver Transplant Service. La Paz University Hospital. Madrid

Abstract Liver diseases in childhood encompass a wide range of conditions, including cholestasis, metabolic, autoimmune, fibro-cystic diseases, tumors, and infections. Diagnosis begins with a thorough medical history and complementary tests, allowing for disease identification, prognosis evaluation, and treatment response monitoring. Laboratory tests are essential to detect liver damage, liver failure, or cholestasis. Key markers include transaminases AST (aspartate aminotransferase), ALT (alanine aminotransferase), bilirubin, GGT (gamma-glutamyl transferase) and clotting. Additionally, imaging techniques and genetic studies complement the diagnostic approach, enabling comprehensive management. Primary care pediatricians play a vital role in the early detection and follow-up of these conditions, such as prolonged jaundice or persistent hypertransaminasemia.

 

Resumen Las enfermedades hepáticas en la infancia abarcan una amplia gama de patologías, que incluyen: colestasis, enfermedades metabólicas, autoinmunes, fibroquísticas, tumores e infecciones. El diagnóstico se basa en una anamnesis detallada y pruebas complementarias que permiten identificar la enfermedad, evaluar su pronóstico y respuesta al tratamiento. Las pruebas de laboratorio son fundamentales para detectar daño hepático, insuficiencia hepática o estudiar un paciente con colestasis. Los marcadores utilizados principalmente incluyen transaminasas AST (aspartato aminotransferasa), ALT (alanina aminotransferasa), bilirrubina, GGT (gamma-glutamil transferasa) y la coagulación como marcador de función hepática. Además, las técnicas de imagen y los estudios genéticos complementan el diagnóstico, permitiendo un manejo integral. El pediatra en Atención Primaria juega un papel crucial en la detección temprana y seguimiento de estas patologías, como en la ictericia prolongada o hipertransaminasemia persistente.

 

Key words: Liver disease; Cholestasis; Portal hypertension; Liver damage; Infections.

Palabras clave: Enfermedad hepática; Colestasis; Hipertensión portal; Daño hepático; Infecciones.

 

 

Pediatr Integral 2025; XXIX (1): 16 – 24

 

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Diagnosis in liver disease

https://doi.org/10.63149/j.pedint.4

 

Introduction

Liver diseases in childhood are very diverse. They can be divided into large groups: cholestasis, metabolic diseases, autoimmune diseases, fibrocystic diseases, tumors or infections(1). Diagnosis always begins with the clinical history, followed by the addition of the relevant complementary tests. These diagnostic tests allow us to screen for liver disease, assess its prognosis and its response to treatment once it has been started.

Medical history

A complete and detailed history is essential to guide the diagnosis in patients with suspected liver disease, including personal, family and pregnancy history. Physical examination looks for clinical signs, such as hepatosplenomegaly or stigmata of liver disease.

A detailed history is essential to guide the necessary tests in a patient with suspected liver disease: complete clinical history with personal and family history, pregnancy history, ultrasounds and prenatal tests, type of delivery, need for resuscitation, birth weight, metabolic and hearing screening, weight-height curve, aversions to dietary diversification and psychomotor development. In addition, it is important to know if there is a history of pharmacological treatment or herbal or homeopathic products.

Regarding family history, the presence of autoimmunity in the family, obstetric history (gestational pruritus), history of malformations or fetal deaths, consanguinity, stones or cysts in the family, among others, will be assessed. Questions should be directed according to the suspicion.

Regarding the physical examination, it should be noted that in chronic liver disease the clinical signs appear late and are not specific to a particular disease. Jaundice is observed in hyperbilirubinemia; when concentrations exceed 3 mg/dL it becomes evident in the sclerae. The causes are diverse and are not always related to liver disease (Table I).

Palmar erythrosis or hepatic palms is a dotted erythema on the fingertips and in the thenar and hypothenar region due to vasodilation (Fig. 1).

Spider veins can be located on the face, abdomen or back of the hands (Fig. 2).

Data indicating the development of portal hypertension, as a complication of the disease, are: the detection of collateral circulation (distended and marked blood vessels in the hypochondrium and abdomen) and hepato- or splenomegaly (Fig. 3).

Some patients, in the course of advanced liver disease, may present ascites and clubbing due to the existence of intrapulmonary arteriovenous shunts. Xanthomas are lipid deposits on the face and in extension areas, seen in severe cholestasis together with itchy scratching lesions(2). Some diseases may present a specific phenotype (Alagille syndrome, TORCH infections, hypopituitarism, Zellweger syndrome, glycosylation disorders) or the presence of a heart murmur. 10% of patients with biliary atresia may have situs inversus (“syndromic” forms), which may modify auscultation. Acanthosis nigricans is a frequent finding in children with non-alcoholic fatty liver disease (NAFLD). Hepatic encephalopathy is difficult to assess, especially in younger children; Initially, it consists of subtle changes in behavior, but as it progresses, drowsiness becomes more evident and, in the final stages, unresponsive coma. It occurs in situations of acute liver failure in previously healthy children or in chronic liver patients who suffer a decompensation, such as an episode of digestive bleeding or infection.

Hepatomegaly may be present in hepatic and extrahepatic diseases. The etiopathogenic mechanisms involved are: inflammation (infection, autoimmunity), storage (glycogenosis, obesity), infiltration, vascular congestion and biliary obstruction.

Splenomegaly is detected in diseases that have developed portal hypertension, such as autoimmune hepatitis, extrahepatic obstruction to portal flow (cavernoma) or in storage diseases (glycogenosis and lysosomal diseases).

Laboratory

The liver performs key functions in synthesis, storage and clearance, and its assessment often begins with analyses that may be nonspecific. In Pediatrics, it is important to interpret values based on age.

The liver is an organ involved in important functions in the body: synthesis, storage, excretion and purification of numerous substances. The diagnosis of liver diseases often begins with an analytical extraction where all of them can be assessed. Any altered analytical parameter must be analyzed in the specific context of the patient. In general, they are nonspecific and do not determine the type of liver disease; even a patient with chronic liver disease may present with normal transaminases. Another possibility is the detection of a systemic disease without liver involvement, although there may be an alteration in liver biochemistry, as occurs in situations of shock or systemic hypoperfusion or in respiratory infections so common in childhood.

It is essential in Pediatrics to have correct references by age for all the parameters analyzed, for example: a newborn can have GGT up to five times higher than the normal value limit(3).

Classically, the parameters that can be analyzed are classified according to the information they provide about the state of the liver: whether there is liver damage, liver failure, or cholestasis.

Liver damage

AST and ALT are key liver enzymes for assessing liver damage; AST is also found in other tissues, so its elevation is not specific for liver damage. ALT is more specific to the liver, and the joint analysis of both helps to identify the cause and severity of the damage.

Transaminases

Transaminases are intracellular enzymes that catalyze the transfer of the alpha-amino group (NH2) of amino acids (AST: aspartic acid, ALT: alanine) to the alpha-keto group of ketoglutaric acid.

AST is found in more cells than just the liver: muscle, heart, kidney, pancreas, brain, leukocytes and erythrocytes. Elevated AST is therefore not specific and the differential diagnosis should include creatine phosphokinase (CPK) to determine whether the AST elevation is of muscular origin (if CPK is elevated, we will suspect excessive physical effort or muscular dystrophy, among others), or haptoglobin and LDH (lactate dehydrogenase) in case it is of erythrocyte origin.

The ALT enzyme is more specific, being found in the cytosol of the hepatocyte. Both must be studied together, since the ratio between the two can provide information on the underlying cause. AST is present not only in the cytosol but also in the mitochondria of the hepatocyte; its elevation may imply more serious necrosis. An “inverted” transaminase ratio (AST greater than ALT) indicates more profound liver damage.

There are tables with percentiles and variability by sex, but in the clinical practice a cut-off point of 45 IU/L is usually used. However, there is no direct relationship between the transaminase level and the severity of the underlying disease. Transaminases are released into the blood after damage to the hepatocyte membrane and there is a poor relationship between the degree of necrosis in liver biopsies and the elevation of transaminases obtained.

The differential diagnosis of asymptomatic hypertransaminasemia will include: non-alcoholic fatty liver disease (NAFLD), Wilson’s disease, alpha-1 antitrypsin deficiency, viral hepatitis, toxins, autoimmune disease and fructosemia (Table II).

Non-alcoholic fatty liver disease is the most common cause of liver disease in children in the USA, given the rise in childhood obesity: its early diagnosis and monitoring are important due to its high prevalence and good outcome with appropriate treatment. The association with metabolic syndrome, cirrhosis and hepatocellular carcinoma has made it a major cause of transplant indication in adults(4,5) (Table III).

In the case of any hypertransaminasemia, it is important to monitor the patient until the analytical resolution or diagnosis is ensured. Although most cases resolve spontaneously, this does not eliminate the need for study and monitoring.

Associated signs of severity are: higher values (ten times the normal value), associated alteration of GGT and/or bilirubin, presenting data of liver failure (coagulopathy or bleeding such as epistaxis) or signs of portal hypertension (splenomegaly or thrombocytopenia)(6).

LDH

The enzyme lactate dehydrogenase (LDH) is present in cardiac and skeletal muscle, erythrocytes, kidney and brain. It is elevated in ischemia and hemolysis. In the case of a sustained elevation of LDH and alkaline phosphatase, malignant infiltration of the liver must be ruled out.

Synthesis function

Albumin, the main blood protein synthesized in the liver, and coagulation factors are key indicators of liver function. Lipoproteins and cholinesterase also help to assess the severity and progression of liver disease.

Albumin

Albumin is the main protein in blood, it is synthesized only in the liver and has a half-life of 20 days; therefore, low levels are usually indicative of chronic pathology. The differential diagnosis of hypoalbuminemia will include protein-losing enteropathy, nephrotic syndrome or severe malnutrition. Its functions not only include regulating oncotic pressure, it has immunomodulatory and antioxidant effects, it stabilizes the endothelium and transports various molecules (including drugs and toxins).

Clotting

The liver synthesizes many proteins of the coagulation cascade (procoagulants and anticoagulants): factors V, VII, IX, X, XI, prothrombin and fibrinogen. Vitamin K is necessary in several of the reactions and the liver’s storage capacity is limited; therefore, in deficiency situations (cholestasis or diarrhea) prothrombin time and INR (international normalized ratio) are prolonged, but this will be resolved after the intramuscular or intravenous administration of vitamin K.

Acute liver failure is defined by an elevated INR (or prolonged prothrombin time and low prothrombin activity), but there is a balance between pro- and anticoagulant factors and, therefore, it does not reflect the risk of bleeding or the need for transfusion of blood products. It is a critical situation that requires management in pediatric liver transplant units. In the case of a decreased prothrombin activity value or increased INR, vitamin K should be administered to assess the reversibility of the condition and, if not, referral to a specialized center(7,8).

Low fibrinogen levels can be seen in cases of disseminated intravascular coagulation or in advanced liver disease. There are genetic diseases with specific mutations that affect its synthesis: afibrinogenemia (autosomal recessive inheritance), dysfibrinogenemia or hypofibrinogenemia (autosomal dominant inheritance). Fibrinogen levels can be elevated as an acute phase reactant.

Factor VIII is not synthesized in the liver, therefore, it is used to differentiate coagulation disorders due to liver disease (normal factor VIII) from those due to disseminated intravascular coagulation (decreased factor VIII).

Lipoproteins

The liver synthesizes and metabolizes many lipoproteins. In cholestasis, there is an increase in cholesterol synthesis induced by the regurgitation of phospholipids into the plasma circulation. In addition, lipoprotein X is formed, which is an abnormal form of LDL (low-density lipoprotein).

In non-cholestatic liver disease, a decrease in cholesterol and lipoproteins indicates worsening dysfunction and a worse prognosis.

In acute liver damage there is hypertriglyceridemia and increased LDL due to decreased activity of LCAT (lecithin cholesterol acetyl transferase) and triglyceride lipase.

On the other hand, the alteration in lipoprotein levels is nonspecific and does not allow the cause of the liver disease to be determined. Xanthomas appear in pathologies that greatly increase cholesterol levels, as in Alagille syndrome.

Cholinesterase

Cholinesterase (CHE) catalyzes the hydrolysis of choline esters. It is synthesized in the liver, pancreas and small intestine and is therefore indicative of liver disease or its progression, because it indicates an inability to synthesize proteins. There is great interindividual variability, but it is useful to see the progression in successive analyses in the same patient.

It may also be decreased in malnutrition, congestive heart failure and congenital cholinesterase deficiency (occurs in 4% of the population).

Detoxifying function

The liver detoxifies ammonia through the urea cycle. In cases of liver damage, ammonia accumulates in the blood and affects the brain, causing encephalopathy in acute liver failure or decompensated cirrhosis.

Ammonium

Ammonium is synthesized in the colon by urease from intestinal bacteria that break down dietary proteins and is metabolized in the liver through the urea cycle, converting it into urea and glutamine.

Liver damage involves the release of ammonia into the blood, which has a deleterious effect on brain tissue. Hepatic encephalopathy in children has a poor correlation with ammonia levels. It may occur in cases of acute liver failure or in episodes of decompensation on cirrhosis; for example, in an episode of intestinal bleeding (acute decompensation on chronic disease: acute-on-chronic).

Another cause of hyperammonemia is the presence of portosystemic shunts that may be congenital or appear in a cirrhotic liver with obstruction to the entry of blood through the portal vein or in portosinusoidal disease.

In addition, some ammonia is synthesized in the small intestine and kidney, and can be induced by certain drugs, such as valproic acid.

Damage to bile flow

Cholestasis is a decrease in bile flow that accumulates bilirubin and other compounds in the blood. Its diagnosis involves evaluating bilirubin, alkaline phosphatase (ALP), GGT and bile acids, among others. Elevated conjugated bilirubin always indicates liver damage.

Cholestasis is the condition in which bile flow is reduced, leading to the accumulation of bile acids, cholesterol and bilirubin in plasma. In liver biopsy, it is defined by the presence of bile pigment in hepatocytes and bile ducts(9).

Cholestasis is associated with complex transcriptional alterations in bile salt transporters and enzymes involved in bile synthesis. This is a growing field of research, in which new genes involved are being described that help to understand the molecular mechanism of familial intrahepatic cholestasis and offer new therapeutic targets.

Bilirubin

Bilirubin is a pigment derived from the metabolism of the heme group of hemoglobin from erythrocytes destroyed in the spleen, bone marrow and liver, and a small fraction originates from the destruction of proteins containing heme: myoglobin, cytochromes and peroxidases. Unconjugated bilirubin will be introduced into the hepatocyte, where it will be conjugated with the enzyme UDP (uridine diphosphate) glucuronyltransferase, being soluble and able to be excreted into bile through the bile canaliculus to later give color to the feces.

The bilirubin level will be altered in pathologies with cholestasis or in those pathologies with an insufficient liver, in which the metabolism of the same will also be affected.

Conjugated bilirubin binds to albumin and has a longer half-life, up to 14 days; this explains why, in reversible obstructive processes, it remains elevated once the process has been resolved.

Indirect or unconjugated (lipid-soluble) hyperbilirubinemia can be detected in: hemolysis (see LDH); Crigler-Najjar syndrome (congenital UDP glucuronyltransferase deficiency); Gilbert syndrome (present in 5% of the healthy population, hyperbilirubinemia in the context of an infectious or stress condition without involving chronic liver disease); or in physiological hyperbilirubinemia in the newborn, which has a multifactorial origin related to neonatal hepatic immaturity(10). When the transport capacity bound to albumin is exceeded, the free fraction crosses the blood-brain barrier, causing brain injury (kernicterus).

Conjugated hyperbilirubinemia is defined by a direct bilirubin value greater than 20% of total bilirubin or greater than 1 mg/dL if total bilirubin is <5 mg/dL. It always indicates hepatobiliary damage and is always pathological. It can be detected in urine with a dipstick quickly and cheaply, but it is not usually used because external factors, such as pH or tubular alteration, can modify it. Studies should not be delayed in these patients, since it may have prognostic implications; for example, early detection and treatment in galactosemia, panhypopituitarism or sepsis, in the case of a newborn with cholestasis before sequelae appear, or biliary atresia or choledochal cyst before the damage is irreversible. The bilirubin level does not differentiate whether the disease is intra- or extrahepatic(11) (Table IV).

 

Alkaline phosphatase

Alkaline phosphatase (ALP) is a group of enzymes involved in metabolizing phosphate esters to inorganic phosphate. It is found in numerous cells: the canalicular membrane of the hepatocyte, osteoblast, brush border of the enterocyte, renal proximal tubule, leukocytes and placenta. Its function in the liver is not clear. An isolated elevation in ALP in a growing child (precisely because of its involvement in bone synthesis) without other abnormal liver tests does not indicate liver disease. There are tables of percentiles with normal values by age of ALP(12) (Table V).

There is a condition called benign hyperphosphatasemia of infancy, in which the level remains elevated for weeks without any other apparent cause (up to 10 times the normal value). It can also be elevated in diarrhea. A subsequent analytical control will have to be carried out to verify normality and rule out other data that imply different pathologies (LDH in tumors, GGT in biliary obstructive processes).

GGT

Gamma glutamyltransferase is an enzyme that catalyzes the transfer of glutamyl groups from peptides, such as glutathione, to other amino acids. It is also present in many cells: kidney, pancreas, liver, spleen, brain and small intestine; therefore, in isolation it is nonspecific. It helps to discriminate the hepatic origin of an elevated ALP. Neonates have higher values, which normalize around 6-9 months of age (Table V).

It is a drug-inducible enzyme and will also be elevated in obstructive processes of the biliary tract: biliary atresia, sclerosing cholangitis and Alagille syndrome, among others. It does not differentiate between intra- or extrahepatic obstructive processes. In familial intrahepatic cholestasis, the classification used considers elevated or normal GGT. There is an entity called benign recurrent cholestasis (autosomal recessive) that has an intermittent presentation, with episodes of cholestasis and pruritus lasting up to weeks or months. The locus is the same as that of familial intrahepatic cholestasis due to FIC1 defect. Sometimes, it is triggered by pregnancy or the use of oral contraceptives (Table VI).

 

Bile acids

Bile acids are synthesized in the hepatocyte and are conjugated with glycine or taurine and excreted into the bile to participate in the digestion of dietary fat. In addition, they activate nuclear receptors that participate in various functions: they control the homeostasis of the synthesis of bile acids themselves and in the metabolism of drugs, lipids and glucose. It is an expanding field as a pharmacological target for various diseases.

In liver disease, bile acid metabolism is altered by destruction of cell mass, decreased excretion and the appearance of portosystemic shunts. Congenital defect of bile acid synthesis is a disease with low prevalence that is diagnosed by measuring the level of bile acids in urine. It cannot be measured if the patient receives ursodeoxycholic acid.

Miscellany

Serum globulins

Serum globulins are classified according to their migration in electrophoresis:

• Alpha-1 which mainly includes alpha-1antitrypsin, ceruloplasmin and orosomucoid; all of them acting as acute phase reactants.

In alpha-1 antitrypsin deficiency, in addition to lung disease in adults (early emphysema), liver disease develops in children due to the accumulation of misfolded protein. It is related to the genotype, so that not all mutations cause disease. Ceruloplasmin participates in the transport of copper in blood and is low in Wilson’s disease.

• Alpha-2: it includes haptoglobin, which can also behave as an acute phase reactant.

• Beta: the main ones are transferrin and betalipoprotein.

• Gamma: gamma globulins are IgG, IgM and IgA. In autoimmune hepatitis there is hypergammaglobulinemia at the expense of IgG. They are synthesized by B lymphocytes, so they are not exactly an indicator of liver function.

Amino acids

Measurement of amino acids in blood and urine is used to diagnose congenital metabolic defects, such as urea cycle defects, tyrosinemia, or organic acidemias (methylmalonic, propionic).

Autoantibodies

Although they are not synthesized in the liver, in the differential diagnosis of liver disease it is common to screen for autoimmune diseases: anti-transglutaminase IgA, anti-LKM (microsomal type 1 antibodies of the liver and kidney), anti-hepatic cytosol (LC1), antinuclear (ANA) and anti-smooth muscle(13).

Alpha-fetoprotein

Tumor marker, with special relevance in hepatocellular carcinoma, although not always elevated. It can be used, in addition to diagnosis, to evaluate recurrence after treatment.

Microbiology

Diagnosis of liver disease is often directed towards viral infection in healthy children or children of mothers with hepatitis B or C virus infection. Therefore, the diagnostic tests include: TORCH serologies, cytomegalovirus, Epstein Barr virus (EBV), hepatitis A, B, C and E. Acute viral hepatitis is associated with a high level of cytolysis, may be asymptomatic or present as a nonspecific picture of abdominal pain, vomiting and diarrhea, not always associated with jaundice. It is important to monitor the clinical course. A serious complication of viral hepatitis is lymphohistiocytotic hemophagocytosis secondary to EBV and, occasionally, acute liver failure.

Genetics

Nowadays, thanks to advances in research, genetic testing is included in advanced stages of the diagnostic process. The study of a gene in a suspected disease allows us to avoid more invasive techniques, such as liver, skin or muscle biopsy. They are also very important tests for the study of relatives (siblings, parents), for example, in alpha-1 antitrypsin deficiency or Wilson’s disease.

In cases where it is not easy to determine the origin of the liver disease, specific genetic panels for liver disease or those involving alterations in the liver are used: bile acid transport, recurrent acute liver failure, hepatic fibrosis due to ciliopathies, congenital errors of metabolism or familial intrahepatic cholestasis, among others.

Imaging techniques

• Ultrasound: it identifies malformations of the bile duct or lithiasis and tumors, or detects signs of chronicity, such as ascites, alteration in hepatic echogenicity, splenomegaly, presence of varicose veins or alteration in arterial or venous flow in the Doppler study.

• Cholangioresonance: It should be performed to rule out biliary tract involvement (isolated sclerosing cholangitis or overlap syndrome) in autoimmune liver pathology.

• Elastography: a technique that provides information on the degree of fibrosis in the liver and the proportion of fat. The speed of propagation of the elastic wave is proportional to the stiffness. It has a good correlation with the results obtained by liver biopsy(14).

Invasive techniques

• Liver biopsy: pathological anatomy can help differentiate certain pathologies: autoimmune hepatitis, where interface hepatitis of the liver will be detected as well as plasma cell infiltrate; Wilson’s disease, with copper quantification in tissue; alpha-1 antitrypsin defect, with positive PAS granules; or biliary atresia, with cholestasis and ductal proliferation. Immunohistochemical techniques can detect the presence or absence of bile canaliculus transporters and membrane proteins, allowing the diagnosis of familial intrahepatic cholestasis (BSEP, MDR3).

• Endoscopy: in children with advanced portal hypertension with marked thrombocytopenia, a primary bleeding prophylaxis program is carried out with endoscopy and treatment in case of finding varices (placement of bands).

• Intraoperative cholangiography: the gold standard in the diagnosis of biliary atresia, it consists of injecting contrast into the biliary tract, allowing its anatomy to be delineated. Cholangiography can also serve as a therapeutic measure in cases of obstructive cholestasis or infants with thick bile syndrome or lithiasis.

• Transparietohepatic cholangiography: ultrasound-guided puncture of the liver parenchyma performed by interventional radiologists to inject contrast through a peripheral biliary radical and reach the main biliary tract. It allows the treatment of complications, mainly in transplant patients: balloon dilation and/or stent placement.

Role of the Primary Care pediatrician

The primary care pediatrician will often be the one who, maintaining a high degree of suspicion, is able to diagnose a patient with liver disease, as is the case of prolonged jaundice in an infant. At one month of age, up to 1/5 of newborns will be jaundiced due to indirect hyperbilirubinemia related to breastfeeding, but it is important to rule out liver disease. From 15 days of life, an analysis should be requested, distinguishing between direct and indirect bilirubin for early referral and the stools should be seen in person to ensure the absence of acholia or hypocolia, since the description by the family may be erroneous (see Algorithm 1 at the end of the article).

Patients with hypertransaminasemia will also be monitored until the analysis is normal; if this does not resolve, further study should be carried out and, if necessary, referral to a specialist in pediatric gastroenterology or hepatology (see Algorithm 2 at the end of the article).

Warning signs that should be kept in mind are: encephalopathy, coagulopathy that is not reversed with vitamin K, other signs of liver failure, such as hypoalbuminemia or hypoglycemia, or development of portal hypertension (splenomegaly or thrombocytopenia).

Conflict of interest

There is no conflict of interest in the preparation of this manuscript nor source of funding.

Bibliography

The asterisks indicate the interest of the article in the opinion of the authors.

1.* Jara P. Liver disease in children. Enfermedad hepática en el niño. Tile Von Spain. S.L. 2013.

2.* Lledín Barbancho D, Vecino López R. Clinical, biochemical and imaging examinations in the assessment of digestive and hepatobiliary pathology. Exploraciones clínicas, bioquímicas y técnicas de imagen en la valoración de la patología digestiva y hepatobiliar. Pediatr Integral. 2015; XIX: 66.e1-e18. Available at: https://www.pediatriaintegral.es/publicacion-2015-01/exploraciones-clinicas-bioquimicas-y-tecnicas-de-imagen-en-la-valoracion-de-la-patologia-digestiva-y-hepatobiliar/.

3. Lee Ng V. Laboratory Assessment of Liver Function and Injury in Children. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. Cambridge University Press; 2007. p. 163-76.

4. Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017; 64: 319-34.

5. Johansen L, BSPGHAN Liver Steering Group. UK Fatty Liver Disease Guideline. 2020.

6.* Hegarty R, Dhawan A. Fifteen-minute consultation: The child with an incidental finding of elevated aminotransferases. Arch Dis Child Educ Pract Ed. 2018; 103: 228-30.

7.* Squires JE, McKiernan P, Squires RH. Acute Liver Failure: An Update. Clin Liver Dis. 2018; 22: 773-805.

8. Baker A, BSPGHAN. Investigation and treatment of liver disease with acute onset. Local hospital protocol. 2013.

9. Fernández Tomé L, Frauca Remacha E. Cholestasis in infants. Colestasis en el lactante. Protoc diagn ter pediatrics. 2023; 1: 341-60.

10. Maisels MJ, Clune S, Coleman K, Gendelman B, Kendall A, McManus S, et al. The natural history of jaundice in predominantly breastfed infants. Pediatrics. 2014; 134: e340-5.

11. Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, et al. Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. JPGN. 2017; 64: 154-68.

12. Heiduk M, Päge I, Kliem C, Abicht K, Klein G. Pediatric reference intervals determined in ambulatory and hospitalized children and juveniles. Clin Chim Minutes. 2009; 406: 156-61.

13. Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, et al. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr. 2018; 66: 345-60.

14. Levitte S, Lee LW, Isaacson J, Zucker EJ, Milla C, Barth RA, et al. Clinical use of shear-wave elastography for detecting liver fibrosis in children and adolescents with cystic fibrosis. Pediatr Radiol. 2021; 51: 1369-77.

15. Ros Arnala I, Reyes Andrade J, Mercadal Hally M, Blesa Baviera LC, García Tirado D, Campuzano Martín SH, et al. Diagnostic management of hypertransaminasemia in pediatrics: consensus document of the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP), the Spanish Association of Primary Care Pediatrics (AEPap), and the Spanish Society of Primary Care Pediatrics (SEPEAP). Actuación diagnóstica ante hipertransaminasemia en pediatría: documento de consenso de Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP), Asociación Española de Pediatría de Atención Primaria (AEPap) y Sociedad Española de Pediatría de Atención Primaria (SEPEAP). Anales de Pediatría. 2022; 96: 448.e1-e11.

Recommended bibliography

– Jara P. Liver disease in children. Enfermedad hepática en el niño. Tile Von Spain. S.L. 2013.

An easy-to-read manual that summarizes pediatric liver pathology and the indications and complications of liver transplantation. Some therapeutic advances, given the year of publication, are not included, but it features great authors.

– Lledín Barbancho D, Vecino López R. Clinical, biochemical and imaging examinations in the assessment of digestive and hepatobiliary pathology. Exploraciones clínicas, bioquímicas y técnicas de imagen en la valoración de la patología digestiva y hepatobiliar. Pediatr Integral. 2015; XIX: 66.e1-e18. Available at: https://www.pediatriaintegral.es/publicacion-2015-01/exploraciones-clinicas-bioquimicas-y-tecnicas-de-imagen-en-la-valoracion-de-la-patologia-digestiva-y-hepatobiliar/.

A comprehensive and clarifying article on the diagnostic approach to a child with suspected liver disease.

– Hegarty R, Dhawan A. Fifteen-minute consultation: The child with an incidental finding of elevated aminotransferases. Arch Dis Child Educ Pract Ed. 2018; 103: 22830.

Brief and concise article from the British reference center King’s College Hospital on the management in Primary Care of a child with possible liver disease, summarizing the alarming data.

– Squires JE, McKiernan P, Squires RH. Acute Liver Failure: An Update. Clin Liver Dis. 2018; 22: 773-805.

Summary of the largest registry of acute liver failure in children collected, updating diagnostic protocols with recommendations to optimize management and early referral to a transplant center.

Clinical case

A 10-year-old boy attended the clinic after a 5-day history of fever, mild abdominal pain complaint and feeling asthenia. The physical examination revealed spider veins on the hands and three centimeter splenomegaly. His auxology was: weight: 35 kg (45th centile), height: 140 cm (51st centile); BMI: 17.8 kg/m2. He has recently had several episodes of epistaxis and has requested an appointment with a private ENT specialist, but has not yet had the consultation. Emergency Room Laboratory results: AST: 259 IU/L; ALT: 122 IU/L; GGT: 44 IU/L; total bilirubin: 1.2 mg/dL; prothrombin activity: 55%; platelets: 40 x 10 e3/µL. Highlights in the examination: abdominal distension, splenomegaly, collateral circulation and spider veins. Personal history: Parents report that 2 years ago he had a first analysis in the Emergency Room with the following findings: AST: 313 IU/L; ALT: 602 IU/L; GGT: 71 IU/L; total bilirubin: 0.6 mg/dL; direct bilirubin: 0.2 mg/dL; platelets: 300 x 10 e3/µL. No clotting test was extracted. Upon repeating the blood test 10 days later at the health care center: AST: 199 IU/L; ALT: 229 IU/L; GGT: 49 IU/L; total bilirubin: 0.7 mg/dL; direct bilirubin: 0.2 mg/dL; prothrombin activity: 90%; platelets: 280 x 10 e3/µL and positive parvovirus IgM serology was found, but no further controls were done. Family history: maternal grandfather with rheumatoid arthritis and paternal grandmother with type 2 diabetes mellitus, the rest are of no interest to the case.