Sažetak Hepatotoksičnost Antituberkulotika U Majke I Djeteta S Tuberkulozom Pluća – Prikaz Slučaja Hepatotoxicity of Antituberculosis Drugs in a Mother and a Child Aff Ected by Pulmonary Tuberculosis -a Case Report Prikaz Slučaja Case Report

Cilj: Prikazati rezultate praćenja hepatotoksičnosti antituberkulotika u majke i djeteta primljenih na bolničko liječenje zbog tuberkuloze pluća. Ispitanici i metode: Majka (23 godine) i dijete (2 godine i 4 mjeseca) lije-čeni su izonijazidom, rifampicinom, pirazinamidom, etambutolom, odnosno streptomicinom. U svrhu praćenja hepatotoksičnosti antituberkulotika odre-đivana je katalitička aktivnost aspartat-aminotransferaze (AST), alanin-ami-notransferaze (ALT), alkalne fosfataze (ALP), gamaglutamiltrasferaze (GGT), laktat-dehidrogenaze (LD) i bilirubina. Abstract Aim: To present results of monitoring hepatotoxicity of antituberculosis drugs in a mother and a child admitted for hospital treatment due to pulmonary tuberculosis. Patients and methods: A mother (23 yrs) and a child (2 yrs and 4 months) were on isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin therapy. To monitor the hepatotoxicity of these antituberculosis drugs, catalytic activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), lactate dehydrogenase (LD) and bilirubin were determined. Results: The highest increase in enzyme activity in the mother was recorded two weeks since the institution of therapy: AST, ALT, ALP, GGT and LD activities were 34-fold, 43-fold, 1.2-fold, 5.5-fold and 1.7-fold higher, respectively, than the upper normal values. In the child, the highest rise in enzyme activity occurred during the 1 st week since the application of therapy; compared to the upper reference range values, AST, ALT, GGT and LD were 28.1-, 29.2-, 2.5-and 3.3-fold higher, respectively. After temporary discontinuation of therapy, the catalytic activity levels returned within the reference range limits, and the therapy was gradually reintroduced until full dose was achieved. During the subsequent period until recovery, both the mother and the child tolerated the antituberculosis drug therapy well, i.e. without elevation of enzyme activity. Conclusion: Markedly elevated catalytic activities of AST and ALT in the mother and the child during antituberculosis drug therapy indicate the occurrence of a possible predisposition for severe hepatotoxicity. During initial weeks of antituberculosis drug administration, it is necessary to monitor the activity of liver enzymes every week in order to detect their possible hepatotoxicity and carry out prompt therapy evaluation. kao posljedice antituberkulotske terapije.

In this report, we present the results of monitoring hepatotoxicity of antituberculosis drugs in a mother and a child treated for pulmonary tuberculosis.According to  1); other results were within reference ranges.A week after therapy initiation, the levels of liver enzymes increased, showing further rising tendency (Table 1, Fig. 1).Index of maximum increase in enzyme activities was recorded during the 2 nd week since therapy institution (Fig. 2), and AST, ALT, ALP, GGT and LD levels were 34-, 43-, 1.2-, 5.5-and 1.7-fold those of the upper normal limits, respectively.At the same time, total bilirubin concentration was 56.8 μmol/L (2.8-fold increase compared to the upper normal limit).Upon discontinuation of therapy, decreased values for the investigated biomarkers were observed so that the drugs were gradually reintroduced in a reduced dose until reaching the full dose.The drugs were well tolerated during continued treatment, and Mycobacterium tuberculosis was successfully eliminated.
The child MK, a child at the age of 2 years and 4 months, the son of the patient IK, had not been ill before.He was vaccinated and had a BCG scar.1); other results were within age-adjusted reference ranges.AST, ALT, GGT and LD activities were increasing a week since the commencement of therapy (Table 1, Fig. 1).The index of maximum elevation of enzyme activities was recorded during the 1 st week since therapy initiation (Fig. 2), while elevations of AST, ALT, GGT, and LD were 28.1-, 29.2-, 2.5-, and 3.3-fold those of the age-adjusted upper normal limits, respec-SLIKA 1. Usporedba promjena enzimskih aktivnosti u serumu majke (A) i djeteta (B).U serumu majke maksimalno povećanje očitovalo se drugog tjedna, a u serumu djeteta prvog tjedna od početka terapije.

Discussion
We report of a mother and a child with pulmonary tuberculosis in whom antituberculosis drug administration at the very beginning of treatment resulted in liver damage.
Severe degree of hepatotoxicity in the mother and the child indicate the presence of a possible predisposition for such response during antituberculosis drug therapy, yet we found no related information in the available literature.According to the criteria of the American Thoracic Society, both the mother and the child suff ered from severe hepatotoxicity (2).After a temporary discontinuation of therapy, reintroduction of lowered and then increasing drug doses until full dose, the values of the analyzed biomarkers remained during the entire course of treatment within the reference range.Asymptomatic elevation of the catalytic activity of AST occurs in approximately 16%-20% of individuals administered standard four-drug antituberculosis therapy (12,13).
The incidence of hepatotoxicity is more frequent in elderly persons and women, particularly if they suff er from a more severe type of tuberculosis (12).In a previous report of hepatotoxicity of antituberculosis drugs in children, a rise in catalytic activity of liver enzymes was established in half of the children on INH, RIF and PZA therapy, with enzyme activity increase on average lower than twofold (14), which indicates a mild degree of hepatotoxicity.In most patients, asymptomatic elevation of aminotransferase activity resolves spontaneously.Still, if the increase in values is higher than 5-fold (with symptoms or without them), or higher than 3-fold (with symptoms), the therapy should be discontinued.An increase in ALP activity or bilirubin concentration requires immediate therapy evaluation (2).The therapy continues after AST levels return to the values that are lower than 2-fold upper normal limit.RIF therapy is reintroduced fi rst (13), and then, after a week, AST activity is checked.If AST activity has not risen, INH is introduced in the therapy.Provided that there is no rise in AST activity after a week, PZA can also be included in the therapy.According to this protocol, the levels of liver enzymes and bilirubin did not increase any more in our patients, and the therapy could be administered until complete recovery.16) described maximum twofold elevation of liver enzymes during the second week of antituberculosis drug therapy.These authors believe that the therapy should be temporarily discontinued only if jaundice occurs, and that -in case of asymptomatic elevation of enzyme activity -enzyme levels will spontaneously return to baseline values even without therapy discontinuation.
It may be assumed that hepatotoxicity in the mother and the child was caused by INH or its metabolites.We found no information in the available literature on such severe hepatotoxicity.Literature search commonly resulted in records of mild (14,16) or moderate ( 17) degree of hepatotoxicity.In children with moderate liver damage, INH fast acetylators demonstrated on average 3-fold increase in AST activity and 6-fold increase in ALT activity, while in INH slow acetylators AST activity was 7-fold and ALT activity was 18-fold that of the initial levels (17).
The shortcoming of this report on hepatotoxicity is the fact that NAT polymorphism and GST and CYP2E1 were not investigated, which should be done in a future study.
The results demonstrated that the activity of liver enzymes should be monitored every week during initial weeks of antituberculosis drug administration in order to detect their possible hepatotoxicity and perform prompt therapy evaluation.

FIGURE 1 .
FIGURE 1.Comparison of changes in enzyme activities in the sera of the mother (A) and the child (B).Maximum increase in the mother's serum manifested during the second week, and in the child's serum during the fi rst week since therapy initiation.

FIGURE 2 .
FIGURE 2. Index of the maximum increase in catalytic activity of AST, ALT, ALP, GGT and LD in the mother and son's sera.The highest activity increase in the mother's serum was observed for ALT (43-fold that of the upper normal limit), and in the child's serum for AST (28.1-fold that of the age-adjusted upper normal limit) this is the fi rst overview of hepatotoxicity of antituberculosis drugs in a Croatian family.

TABLE 1 .
Catalytic activities of AST, ALT, ALP, GGT and LD during fi rst 5 drugs in a 5-month-old infant in whom hepatotoxicity occurred already on day 5 after INH, RIF and PZA administration.In children with the average age of 7.6 years, Corrigan et al. ( Pereira et al. (15)described the occurrence of hepatic lesions during administration of antituberculosis