The main organ of human metabolism, liver, is involved in many biochemical synthesis and transformation. Parenchymal cells (hepatocytes), which form the main structure of this organ, regulate protein, carbohydrate, lipid, food-borne amino acids, processing of fats and vitamins, hormones, drugs and bilirubin metabolism. Albumin performs the synthesis of proteins and enzymes such as clotting factors. Bile production, regulation and secretion and detoxification of drugs and chemicals are performed in hepatocytes. Conversion of ammonia to urea, detoxification of endogenous and exogenous toxins, phagocytosis of certain substances from blood and excretion of residual products in bile are among the tasks [1,2].

Liver function tests are used in the diagnosis and follow-up of liver diseases. Disorders of these tests are common in liver diseases, but the degree of enzymatic disorders varies from one disease to another. The evaluation of these tests, which are widely used in patient follow-up, requires a certain knowledge and experience. Accurate evaluation of liver function tests in children is very important. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) indicate hepatocellular damage. Prothrombin time (PT), partial thromboplastin time, INR (International Normalized Ratio) and albumin factors 5 and 7 show synthesis functions. Gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and 5’nucleotidase show bile flow and cholestasis. Bilirubin and serum bile acids give information about hepatic excretion functions (Figure 1) [3].

Figure 1: Laboratory findings in liver disease.

AST and ALT are intracellular enzymes commonly found in many organs and tissues. ALT is a cytosolic enzyme and is more specific to the liver. Since AST is both cytosolic and mitochondrial isoenzyme, it is found in the liver, brain, striated muscles, pancreas and blood cells. In serum, both aminotransferases are normally present at low concentrations (30-40 IU / ml). AST levels in the liver are 7000 times higher than serum and ALT levels are 3000 times higher than serum. In liver diseases, as a result of increased permeability due to increased hepatocyte destruction, these enzymes move out of the cell membrane and serum levels rise. Eliminations of aminotransferases occur in the reticuloendothelial system. AST has a half-life of 17 ± 5 hours and ALT has a half-life of 47 ± 10 hours [1,4,5]. Although the reference ranges for aminotransferases are generally valid for adults, values for children are mostly at the study level. If we look at these studies Kelishadi et al. 'S study conducted in 4078 children aged 10-18 years, the upper limit for ALT was 40 U / L [6]. England et al. In their study on the total ALT value of 5011 obtained from 1293 healthy children, the upper limit value was 60 U / L for boys younger than 18 months and 55 U / L for girls; Found 40 U / L in boys aged between 18 months and 5 years and 35 U / L in girls [7]. The NHANES (National Health and Nutrition Survey) reported that the ALT threshold was 25.8 IU / L in boys and 22.1 IU / L in girls [8]. Aminotransferase heights can be divided into three groups. Values up to 3 times higher than normal levels are considered as light degrees, values between 3-10 times as moderate degrees and values higher than 10 times as heavy degrees [9]. Let's examine the tests to be taken when aminotransferase elevation is seen in pediatric patients and what should be considered in the differential diagnosis;

When elevated aminotransferase levels are detected, serological panel including hepatitis viruses and hepatobiliary ultrasonography (USG) are among the first step tests. With the information we provide from these examinations, chronic viral hepatitis (Hepatitis B and Hepatitis C), liver fats and possible toxic hepatitis will be investigated. Acute Hepatitis A infection should be considered when a previously healthy child patient has more than 10-fold increase in aminotransferase levels with complaints of fatigue, nausea, vomiting, diarrhea [3,10]. 

Other viral hepatitis agents (CMV, EBV, HSV, etc.) and viruses that cause systemic febrile infection often cause hepatitis, causing different levels of elevation in aminotransferases. However, aminotransferases are also affected during the course of bacterial, parasitic and fungal infections. Infectious diseases leading to elevation of aminotransferase are seen in Table 1 [11]. In the second step, viral markers are examined according to the patient's clinic.

Occur due to enzyme defects. It leads to pathologies in the synthesis or catabolism of proteins, carbohydrates and fats. It constitutes 20-30% of all liver diseases. Metabolic diseases should be kept in mind when the causative factor for elevation of aminotransferase is not detected and at continuing elevations [12]. Metabolic diseases that may lead to elevated aminotransferase are shown in Table 2.

Paracetamol, nonsteroidal anti-inflammatory drugs, antibiotics, antituberculosis drugs, anticonvulsants, chemotherapeutics, herbal teas, high-dose vitamins and fungi may cause elevated aminotransferases [13]. Drug history should be questioned in the patient's medical history.

It is necessary for the growth, development and functions of organs. These hormones regulate the basal metabolic rate in all cells. Liver functions are also affected in disorders related to these hormones [14].

May be the first finding of isolated aminotransferase elevation in children. In their study, Wright et al. Reported the mean time between ALT / AST elevation and creatine kinase (CK) elevation in children diagnosed with muscular dystrophy as 7 months and recommended that CK level be considered as the first step test [15].

Hepatic dysfunction due to hepatic congestion develops especially in right heart failure. A sudden and severe increase in aminotransferase levels is observed in cardiogenic ischemic hepatitis developing in acute heart failure. After correcting the cardiac cause, aminotransferase levels return to normal [16].

Usually affects the liver. In the presence of hemolysis, the AST level increases after the destruction of erythrocytes. In sickle cell anemia, increased AST, LDH and indirect bilirubin are seen as a result of hemolysis and ineffective erythropoiesis [17].

Aminotransferase height may be encountered. Approximately 26-57% of pediatric patients with celiac disease have been reported to have elevated aminotransferase at diagnosis [18].

It is one of the rare conditions that cause elevation of serum AST. The AST enzyme is composed of macro-AST by forming complexes with immunoglobulin G. Macro-AST should be considered after excluding other causes at AST height alone [19].

The alkaline phosphatase enzyme is of liver, intestinal and bone origin. It is found in high amounts in the liver, bone, placenta, kidney and ileal mucosa. High levels of growth and adolescence are normal. Its half-life is 3 days. Elevated ALP levels during clinical follow-up are often liver or bone-induced elevations. Increased presence of 5’nucleotidase and ALP indicates biliary obstruction. If other liver function tests are normal, elevated ALP is not a sign of liver and biliary system disease. It may be found to be high when full, so it should be checked again in hunger. Cofactor is zinc. Liver diseases with elevated ALP are viral hepatitis, infiltrative liver diseases, intrahepatic and extrahepatic cholestasis. Non-liver diseases with elevated ALP include osteomalacia, hyperparathyroidism, hyperthyroidism, cystic fibrosis, rickets and paget's disease [20-24].

Gamma glutamyl transpeptidase is found in the epithelial cells of hepatocytes and small bile ducts. It is also found in the pancreas, spleen, kidney tubules, brain, breast and small intestine. GGT levels vary with age and are 6-8 times higher in adults than in adults. Postnatal 6-9. returns to normal levels per month. Its half-life is 28 days. It is a slightly more sensitive indicator of cholestasis than ALP. GGT activity is consistent with ALP in hepatobiliary diseases. High GGT levels are mostly seen in biliary obstructions, especially in biliary obstructions, biliary atresia, sclerosing cholangitis and Alagille syndrome. In addition, drugs that activate the microsomal enzyme system, such as barbiturate, phenytoin, rifampin and warfarin, increase GGT levels. When normal or low GGT and cholesterol levels are detected with hyperbilirubinemia, progressive familial intrahepatic cholestasis should be considered [25-27].

Bilirubin, the final breakdown product of hemoglobin, is present in conjugated (direct) and non-conjugated (indirect) form in serum. Bilirubin increases due to hepatocellular damage and cholestatic liver diseases (Table 3). If an increase in indirect bilirubin is seen, it is important to exclude diseases that initially present with hemolysis. Indirect hyperbilirubinemia is also detected in physiologic and hypothyroid cases in the newborn (1).

Albumin is a protein synthesized in the liver. Low albumin gives an idea of the liver's synthesis task and overall capacity. The serum albumin level is the most commonly used test to investigate the synthesis power of the liver and the normal serum level is 3.5-4.5 g / dL. Because it has a half-life of up to 20 days, it is not used to reflect sudden liver disorders. Malabsorption, protein and energy malnutrition, protein-losing enteropathy and nephrotic syndrome can also be seen in low levels of albumin [28-29].

Prothrombin time is dependent on factors I (fibrinogen), II (prothrombin), V, VII, IX and X coagulation factors synthesized in the liver. Because of the short half-life of these factors, it is more useful than albumin in the follow-up of acute liver failure. Prothrombin time prolongation is an important test in the evaluation of liver synthesis function. Therefore, it is a useful prognostic indicator in acute or chronic liver diseases. It is the most sensitive test that gives information about the progression of acute liver failure and is among the criteria used in the timing of transplantation [30-32].

Liver function tests seen in newborns, infants, older children and adolescents have different approaches according to age groups. Metabolic diseases are common in neonates and infants, whereas acute infectious hepatitis causes higher enzyme levels in school-age children. Along with these, cholestatic liver diseases such as biliary tract abnormalities, biliary atresia, and idiopathic giant cell hepatitis are also observed in neonatal and early infancy [32-34]. The following factors should be questioned when taking the patient's medical history;
• Viral infection, presence of another disease,
• Whether there is a previous liver function test height,
• Diarrhea, weight loss, growth pause,
• Fatigue, loss of appetite, fatigue,
• Nutritional problems, abdominal pain, vomiting, amenorrhea,
• Drug use, toxin,
• Jaundice, acolic defecation, urine color,
• Developmental stages,
• Intramuscular injection, excessive exercise, forced blood collection,
• Question whether there is consanguineous marriage, family liver disease, muscle disease and metabolic disease.
The following findings should be considered when performing physical examination;
• Patient's height, weight, body mass index,Growth retardation, hepatomegaly, splenomegaly,
• Jaundice, pruritus, acid, spider angioma, telangiectasia,
• Clubbing, palmar erythema, sign of gowers
• Gastroknemius hypertrophy, upper extremity muscle weakness,
• It is necessary to check for coarse motor skills delay

Transaminase height when compared to the normal increase in how many times guiding. Although there is no clear rule, aminotransferase levels that exceed 10 times the reference limits are mostly seen in viral, toxic, or ischemic hepatitis, whereas values above or below this limit can be measured in non-alcoholic hepatitis and autoimmune hepatitis.
ALT and AST heights can be classified into 3 groups;

1) Mild high transaminase value: <5-fold increase

2) Moderately high transaminase value: 5-10 fold increase

3) Very high transaminase value:> 10-fold increase

Mild and moderately high transaminase values can be caused by many diseases. It may be related to liver or non-liver diseases. If transaminase levels in asymptomatic patients are found to be less than 3 times the upper limit of normal, it is recommended to repeat the test in the form of ALT, AST, CPK, GGT panel at least one week after the condition that they do not exercise. In studies, it was found that transaminase values were within normal limits. ALT and AST elevation, GGT, total and direct bilirubin elevation; cholestatic liver disease, high CPK level; muscular dystrophy. Serum albumin level, complete blood count, prothrombin time, protein electrophoresis and hepatobiliary ultrasonography are the second-line tests. [35].
If we look at the examinations in the differential diagnosis;
• HAV, HBV, HCV, EBV, CMV and other viral markers for viral hepatitis,
• Ceruloplasmin and serum copper levels for Wilson's disease,
• Serum α-1antitrypsin for deficiency of α-1antitrypsin,
• ANA (antinuclear antibody), SMA (smooth muscle antibody), LKM (antimicrosomal antibody) and anti-SLA (solubleliverantigen) for autoimmune hepatitis,
• Tissue transglutaminase antibody and total IgG for celiac disease,
• Thyroid function tests should be checked for hypo-hyperthyroidism.
If the cause cannot be determined with these tests, urine copper level, molecular ATPB7 analysis, HCV RNA, HBV DNA, metabolic and genetic screening tests for fatty liver disease, sweat test and fecal elastase can be evaluated as third step tests. Liver biopsy should be performed in terms of etiology and histological diagnosis in chronic hepatitis and acute hepatitis with unknown cause [36-41].

When very high transaminase values (AST / ALT> 1000 IU / L) are seen, the causes of acute hepatitis should be considered first. Hepatitis A, Hepatitis B and Hepatitis C virus serology are the first laboratory tests that should be requested. After exclusion of viral hepatitis (A, B, C, D, E, G, CMV, EBV), hepatic damage caused by drug or toxic causes caused by enzyme induction or toxic effects should be considered. Ischemic hepatitis (hypotension, heart failure, sepsis, Budd-Chiari), acute bile duct obstruction, other causes of fulminant hepatitis (Wilson's disease, autoimmune hepatitis) may also lead to very high transaminase values [41-43]. In addition, ALT, AST and LDH levels in the newborn after hypoxic delivery reach peaks in 1-3 days and return to normal after 7-10 days [44].

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Table 1:  Infectious diseases leading to aminotransferase elevation.

Table 2: Metabolic diseases leading to elevated aminotransferase.

Table 3: Causes of Hyperbilirubinemia.