Therapeutic Management of Idiosyncratic Drug-Induced Liver Injury and Acetaminophen Hepatotoxicity in the Paediatric Population: A Systematic Review

Literature Search and Study Characteristics

A total of 3,877 records were identified through the search strategy, of which 2,645 duplicates were excluded. After screening the title and abstract, 1,141 records failed to meet the inclusion criteria and were removed. A total of 91 full-text records were assessed for inclusion. Of them, 38 records were excluded as they were considered irrelevant for the study, 20 had no data on treatment, 16 were not original articles (reviews, letters or commentaries), and four were conducted in adult populations. One full-text article could not be retrieved. Therefore, 12 studies met the inclusion criteria. After reviewing the references of these studies, reviews, and meta-analyses identified in the literature search, 13 additional records were retrieved. Thus, 25 articles were finally included in this review (Fig.1).

Fig. 1figure 1

Flow chart of the literature review process

Fifteen case reports, six case series, and four retrospective cohort studies, published between 1984 and 2022, with a total of 140 patients, from preterm newborn neonates to adolescents, were included (Table 1) [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. Most of the studies were conducted in infants (n = 6) [20,21,22,23,24,25,26] and children (n = 13) [27,28,29,30,31,32,33,34,35,36,37,38,39]. In addition, one study reported findings from either preterm newborn neonates [18] or term or post-term neonates [19], and four studies included adolescents [36, 38, 40, 41] (of note, Novelli et al. [36] and Scheffner et al. [38] reported findings from both children and adolescents). In one study, the patient’s age was not reported [42]. Overall, 11 studies included patients with idiosyncratic DILI (n = 97) [25, 30,31,32,33,34,35, 37,38,39, 41], and 14 with APAP (n = 24) [18,19,20,21,22,23,24, 26,27,28,29, 36, 37, 40] (one study included both idiosyncratic and APAP cases [37]), whereas in one study, type of DILI could not be ascertained (n = 19) [42]. Therapeutical approaches used to manage DILI and DILI-related ALF were NAC (12 studies), ursodeoxycholic acid (UDCA) (three studies), corticosteroids (three studies), molecular adsorbent recirculating system (MARS) (three studies), continuous renal replacement therapy (CRRT, two studies), carnitine (one study), and the combination of glycyrrhizin, reduced glutathione (GSH), polyene phosphatidylcholine (PPC) and S-adenosylmethionine (one study). Ten studies provided heterogeneous DILI definitions [25, 27, 28, 34,35,36,37,38,39, 42]. Two studies [34, 35] adhered to the criteria set by the RegiSCAR group [43]. Karaarslan et al. [25] defined liver injury as an elevation of transaminases six times the upper limit of normal (ULN). Rumack [27] defined hepatotoxicity due to APAP as aspartate aminotransferase (AST) levels > 1,000 IU/L. Two studies defined idiosyncratic DILI as liver transaminases > 50 IU/L and bilirubin > 1.2 mg/dL, with abnormal coagulation parameters [38], or as a score > 5 in the Digestive Disease Week–Japan 2004 (DDW-J) scale [39]. For DILI-related ALF, two studies [28, 42] used the definition provided by the PALF study group [8], whilst another two studies [37, 41] used either the King’s College or the Clichy-Villejuif criteria [44, 45]. An additional study defined ALF cases as those who presented with bilirubin > 15 mg/dL, creatinine > 2 mg/dL, encephalopathy grade above II and International Normalized Ratio (INR) > 2.5, and elevations in alanine aminotransferase (ALT), AST and lactate [36]. The use of causality scales (Naranjo, DDW-J) was limited to only two studies [39, 41]. In most of the studies, pattern of liver injury was not described or could not be calculated. Most of the interventions did not show other related adverse effects. Severity of DILI episode was reported in 56 cases (40% of all), of whom nearly 60% presented with ALF or DILI progressed to ALF. Of the whole sample, 19 cases died (14%), four underwent liver transplantation (2.9%), and 117 recovered (84%). Therapeutic options for the management of DILI across the paediatric age groups are depicted in Fig. 2. Characteristics and outcome of DILI in the paediatric population are summarized in Table S1 (see the electronic supplementary material [ESM]).

Table 1 Characteristics of included studies in the systematic reviewFig. 2figure 2

Therapeutical options for the management of idiosyncratic drug-induced liver injury and acetaminophen hepatotoxicity in paediatric patients. ALF acute liver failure, CVVH continuous venovenous hemofiltration, GSH reduced glutathione, LTx liver transplantation, MARS molecular adsorbent recirculating system, NA not available, NAC N-acetylcysteine, PPC polyene phosphatidylcholine, SAM S-adenosylmethionine, TMP-SMZ sulfamethoxazole-trimethoprim, UDCA ursodeoxycholic acid

Preterm Newborn Neonates N-acetylcysteine

One study described the case of a male preterm neonate who was started on intravenous paracetamol to promote ductal closure. After 5 days of therapeutic paracetamol dosing, the newborn developed acute transaminitis with coagulopathy (AST 994 µ/L, ALT 663 µ/L, alkaline phosphatase [ALP] 1,175 µ/L, INR of 4.2). Blood paracetamol levels were elevated, and NAC was started (200 mg/kg over 4 h, followed by 100 mg/kg over 16 h) along with supportive treatment, while paracetamol was withdrawn. Liver function tests improved, and the newborn recovered uneventfully [18].

Term and Post-term Neonates N-acetylcysteine

One study reported the use of NAC in a 4-day-old boy with severe hepatocellular liver injury with coagulopathy (ALT 978 IU/L; AST 718 IU/L; total serum bilirubin 9 mg/dL and INR of 5.4), with clinical manifestations compatible with acetaminophen toxicity. The newborn received supportive treatment and intravenous NAC (150 mg/kg over 15 min, 50 mg/kg over 4 h and 100 mg/kg over 16 h), and recovered spontaneously without any adverse effects related to the treatment administered [

留言 (0)

沒有登入
gif