We demonstrated that non‐cholestatic isolated elevation of serum aminotransferases in apparently healthy, thriving infants and young children is mostly a benign condition that usually resolves within a year. Since most healthy infants and children are not examined routinely for liver enzymes, we believe this may be the tip of the iceberg and probably this finding is much more common.
The most frequent viral infections causing hepatitis are hepatitis A, B, C, E, non‐A–E hepatitis, EBV and CMV. We studied serological markers for hepatitis A, B, C, EBV and CMV and also CMV antigen in the urine. None of the children screened had evidence of these infections. We did not investigate for hepatitis E serology. Nevertheless, although hepatitis E is endemic in Israel,15
it is rarely found in children and resolves within 4 weeks.15,16
The aetiology is unclear but may be related to some unknown viral aetiology, especially in febrile subjects. In the subgroup in which we did demonstrate an aetiology (not included in this study), urine CMV antigen was the most informative test. The results of other investigations in this group with non‐cholestatic abnormality were nearly all negative.
Several papers have attempted to determine normal values for serum aminotransferases in children. Infants under 1 year of age show higher serum aminotransferases than older subjects, mainly higher ALT levels.17
Landaas et al18
studied a group of 291 children and found that ALT levels were 14–84 U/l between 3 weeks and 4.5 months, and 11–46 U/l between 4.5 months and 1½ years. On the other hand, Gomez et al19
examined 2099 child outpatients and found only slightly higher ALT levels in the first year. Jorgensen et al20
found significantly higher AST levels at 2 and 6 months in infants who were exclusively breastfed compared to formula‐fed infants. We found that the group who normalised their serum aminotransferases was older, consumed more breast milk and had significantly lower initial and maximal ALT levels.
Iorio et al
evaluated the prevalence of different causes of elevated aminotransferase levels in a large series of asymptomatic children referred for hypertransaminasaemia not due to major hepatotropic viruses.21
A total of 425 consecutive children with isolated hypertransaminasaemia were retrospectively evaluated. Of these, 61% normalised their liver enzymes during the first 6 months of observation, and 43.6% of these had no overt cause of hypertransaminasaemia. Of the 39% who had hypertransaminasaemia for more than 6 months, 75 had obesity‐related liver disease and 51 (12%) were found to have genetic disorders. No aetiology was found in only 22 children in this group. Liver biopsy, performed in 18 of the 22 patients, showed minimal chronic hepatitis in 12, mild chronic hepatitis in four and moderate chronic hepatitis in two children. Unlike our study, their study population was significantly older. In addition, they also evaluated patients with cholestasis and did not limit their patients to those who had negative findings at physical examination.
The decision whether or not to perform a biopsy in these children is controversial. Biopsy of the liver may be indicated following evaluation of abnormal biochemical liver tests in association with a serologic workup which is negative or inconclusive.22
The results of the liver biopsies including electron microscopy were not helpful and did not contribute much to the diagnosis, as also found in the study by Iorio et al
Liver biopsy is probably unnecessary in the majority of cases and should be reserved only for selected patients. Liver biopsy should probably be considered after 14–16 months of elevated aminotransferases. In those selected for a liver biopsy, it is recommended that besides regular light and electron microscopy, an additional sample should be taken and frozen at −70°C for further metabolic or GSD enzymatic assays if needed.
The liver biopsy electron microscopy findings were compatible with GSD in three of these children. Iorio et al21
demonstrated GSD type IX in three of their children. None of the children in our study had clinical or biochemical findings suggestive of GSD and in two, the liver enzyme abnormality spontaneously resolved. The reason for these findings has not been elucidated; they may be the result of a mild, possibly transient, metabolic abnormality or a mild form of GSD for which an enzyme has yet to be identified. Therefore, biochemical screening for GSD, including fasting glucose, lactate, urate, lipids and oligosaccharides, should be part of the investigation.
The main limitations of the study are its mostly retrospective nature. In addition, not all of the patients underwent complete workup since it was dependent on duration of abnormality. Nevertheless, this is the first report of a relatively large group of infants and young children with isolated elevation of serum aminotransferases that shows its mostly benign nature.