Elevated Transaminases – Where to Start?

Abstract

Pediatricians in clinical practice relatively often find elevated levels of "liver" enzymes— - alanyin aminotransferase (ALT) and aspartate aminotransferase (AST) as indicators of hepatocellular damage, as well as gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP), which indicate biliary tract involvement. When assessing possible liver disease, it is important to assess synthetic liver function — albumin, prothrombin time (PT) and INR (International Normalized Ratio) - as well as excretory function — total and conjugated bilirubin. It should be emphasized that an INR >2 that is not corrected by the administration of vitamin K is indicative of liver failure. (1) The degree of elevation of liver enzymes is not always a reliable indicator of disease severity or prognosis, just as normal values do not necessarily rule out the presence of liver disease. (1) However, to facilitate further assessment, liver enzyme levels are categorized as mildly elevated (2–5 times above the upper reference limit (normal, N) for age and sex), moderately elevated (5–10 × N), and markedly elevated (>10 × N). (2)

Children with elevated liver enzymes may be completely asymptomatic or present with various symptoms, and the differential diagnosis is very broad, ranging from acute and chronic liver diseases to various systemic diseases and extrahepatic causes (Table 1). One of the most common causes of elevated liver enzymes in children of all ages is an infection, usually a viral one. (2) Other possible causes of elevated liver enzymes in both younger and older children include alpha-1-antitrypsin deficiency, drug-induced liver damage and choledochal cysts. (1) In younger children, there are also various cholestatic diseases (biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, etc.) and numerous metabolic diseases which, although extremely rare individually, together account for a significant proportion of liver diseases in infants and young children (3). Tumors, such as hepatoblastoma, are also a possible cause. In older children in industrialized countries, the most common cause of elevated liver enzymes is liver disease associated with metabolic syndrome. (4) Due to the high prevalence of this disease, the latest guidelines (4) recommend screening for liver disease in overweight and obese children who have additional risk factors. However, even in children with metabolic syndrome, other possible liver diseases must always be excluded. In older pediatric patients, other possible causes include autoimmune hepatitis, sclerosing cholangitis and Wilson’s disease. (1)

As with any patient assessment, a detailed history and physical examination are essential. The physical examination should focus on warning signs such as poor somatic growth, jaundice, signs of pruritus, spider nevi, xanthomas, precordial murmurs, ascites, hepatosplenomegaly, lumpiness, muscle weakness, or other neurologic abnormalities. The medical history should particularly include symptoms of infection, weight loss, stool consistency, medication intake, a family history of liver or systemic diseases and possible consanguinity. If elevated liver enzyme levels are associated with warning signs, the child should be referred immediately to a pediatric gastroenterologist. (2)

If a child has mildly elevated liver enzymes without warning signs, it is recommended to repeat the laboratory tests in 1–2 weeks with additional parameters (ESR, CRP, CBC, AST, ALT, GGT, ALP, bilirubin, uric acid, urea, creatinine, glucose, CK, LDH, albumin, PT, INR). (2) If repeated tests show signs of liver dysfunction, referral to a gastroenterologist is required. If liver enzymes are moderately to markedly elevated with clear signs of infection, it is recommended to repeat extended tests within 24–72 hours +/- microbiological clarification. If drug-induced liver injury is suspected, the drug should be discontinued and the expanded tests should be repeated in 2 days. In case of deterioration or persistence of elevated values in follow-up tests, signs of impaired synthetic function or an unclear cause, immediate referral for further investigation is recommended. (2) Further investigations are also required if slightly elevated values persist. (5) If testing by a gastroenterologist is not considered necessary, liver enzyme levels should be monitored until fully normalized, ideally with a follow-up test in 1–2 months to rule out fluctuating enzyme elevations. (5)