Table 1.
Characteristics of included studies in the systematic review
| Intervention | Study | Location | Study design | n | Age | Sex | Culprit drug (n) | DILI type (n) | DILI/ALF diagnosis definition | Severity of DILI at recognition (n) | DILI pattern (n) | Treatment regime (route) (n) | Outcome (n) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| M | F | |||||||||||||
| Preterm newborn neonates (from day of birth through the expected date of delivery plus 27 days) | ||||||||||||||
| N-acetylcysteine (NAC) | Raghu and Berry (2022) [18] | New Zealand | Case report | 1 | 35 days | 1 | Acetaminophen | APAP | NA | Severe | Hepatocellular | NAC (IV), 200 mg/kg over 4 h, 100 mg/kg over 16 h | Recovery | |
| Term and post-term neonates (from day of birth plus 27 days) | ||||||||||||||
| N-acetylcysteine (NAC) | Walls et al. (2007) [19] | United States | Case report | 1 | 4 days | 1 | Acetaminophen | APAP | NA | Severe | NA | NAC (IV), 150 mg/kg bolus over 15 min, 50 mg/kg dose over 4 h, 100 mg/kg over 16 h | Recovery | |
| Infants (or toddlers) (from 1 month [28 days] to 23 months) | ||||||||||||||
| N-acetylcysteine (NAC) | Muñiz et al. (2004) [20] | United States | Case report | 1 | 58 days | 1 | Acetaminophen | APAP | NA | NA | NA | NAC (unspecified route), 140 mg/kg loading dose, 70 mg/kg every 4 h (17 doses) | Recovery | |
| Ebenezer et al. (2008) [21] | India | Case report | 1 | 7 months | 1 | Acetaminophen | APAP | NA | Severeg | NA | NAC (IV), dose unspecified | Death | ||
| Hon and Leung (2009) [22] | China | Case report | 1 | 5 months | 1 | Acetaminophen | APAP | NA | NA | NA | NAC (oral), 18 doses (1 g initially, 570 mg every 4 h) | Recovery | ||
| Beringer et al. (2011) [23] | United Kingdom | Case series | 2 |
5 months 6 months |
1 | 1 | Acetaminophen (2) | APAP | NA |
Severe (1) NA (1) |
Hepatocellular (1) NA (1) |
NAC (IV), dose unspecified | Recovery (2) | |
| Savino et al. (2011) [24] | Italy | Case report | 1 | 11 months | 1 | Acetaminophen | APAP | NA | ALF | Hepatocellular | NAC (IV), 150 mg/kg over 90 min, 300 mg/kg/day over 5 days | Recovery | ||
| Karaarslan et al. (2022) [25] | Turkey | Retrospective cohort study | 14 | 11 months (median) | 6 | 8 | Valproic acid (4), carbamazepine (4), methotrexate (2), isoniazid (1), baclofen (1), itraconazole (1), herbals (1) | Idiosyncratic | ALT/AST > 6 × ULN | Non-ALF | NA |
NAC (IV), 5 mg/kg/h over 5 days (7) SoC (7) |
Recovery (14) | |
| Continuous renal replacement therapy (CRRT) | Awasthi et al. (2021) [26] | India | Case report | 1 | 18 months | 1 | Acetaminophen | APAP | NA | ALF | NA | CVVH | Recovery | |
| Children (from 2 to 11 years) | ||||||||||||||
| N-acetylcysteine (NAC) | Rumack (1984) [27] | United States | Case series | 3a | ≤ 5 years | NA | NA | Acetaminophen | APAP | AST levels > 1,000 IU/L |
Mild (1) Moderate (2) |
NA | NAC (oral), 140 mg/kg loading dose, 70 mg/kg every 4 h (17 doses) | Recovery (3) |
| Di Giorgio et al. (2017) [28] | Italy | Case series | 6 | 2.2 years (median) | 4 | 2 | Acetaminophen (6) | APAP | PALF Study Groupc | ALF | NA | NAC (IV), 100 mg/kg/day | Recovery (6) | |
| Brenner et al. (2019) [29] | United States | Case report | 1 | 2 years | 1 | Acetaminophen | APAP | NA | ALF | NA | NAC (IV), 150 mg/kg bolus, 12.5 mg/kg/h until recovery | Recovery | ||
| Ursodeoxycholic acid (UDCA) | Simma et al. (1995) [30] | Austria | Case report | 1 | 5 years | 1 | TMP-SMZ | Idiosyncratic | NA | Severef | Hepatocellular | UDCA, 16 mg/kg/day | LTx | |
| Chawla et al. (2000) [31] | United States | Case report | 1 | 2 years 9 months | 1 | Amox/clav | Idiosyncratic | NA | NA | Cholestatic | UDCA, 30 mg/kg/day | LTx | ||
| Cho et al. (2013) [32] | South Korea | Case report | 1 | 7 years | 1 | TMP-SMZ | Idiosyncratic | NA | NA | Cholestatic | UDCA, 20 mg/kg/day, after confirmation of VBDS 30 mg/kg/day | Recovery | ||
| Corticosteroids | Hubiche et al. (2011) [33] | France | Case report | 1 | 2 years | 1 | TMP-SMZ | Idiosyncratic (DIHS) | NA | NA | NA | Prednisone 1 mg/kg/day (2 weeks) | Recovery | |
| Ahluwalia et al. (2015) [34] | United States | Retrospective cohort study | 29 | 11 years (median) | 16 | 13 |
Antibiotics (20) Antiepileptics (9) |
Idiosyncratic (DRESS) | RegiSCARd | NA | NA |
Corticosteroids (oral, IV), negative for HHV6 (n = 20, median total dose 5 mg/kg)h; positive for HHV6 (n = 4, median total dose 6.5 mg/kg) |
Recovery (29) | |
| Maarouf et al. (2018) [35] | United States | Case report | 1 | 8 years | 1 | TMP-SMZ | Idiosyncratic (DRESS) | RegiSCARd | NA | NA | Methylprednisolone (IV), 1 mg/kg/day | Recovery | ||
| Molecular Adsorbent Recirculating System (MARS) | Novelli et al. (2008) [36] | Italy | Case series | 1 | 9 years | 1 | Acetaminophen | APAP |
Bilirubin > 15 mg/dL Creatinine > 2 mg/dL Encephalopathy grade > II INR > 2.5 Elevated AST and ALT serum levels and lactate |
ALF | NA | MARS, number of cycles unspecified | Recovery | |
| Lexmond et al. (2015) [37] | The Netherlands | Retrospective cohort study | 3 | 4–6 years | 1 | 2 |
Valproic acid (1) Acetaminophen (2) |
Idiosyncratic (1) APAP (2) |
King´s college criteriae Clichy-Villejuif criteriaf |
ALF | NA |
MARS (1), number of cycles unspecified No MARS (2) |
LTx (1) Recovery (2) |
|
| Carnitine | Scheffner et al. (1988) [38] | Germany | Case series | 14 | 5 years (median) | 10 | 4 | Valproic acid (14) | Idiosyncratic |
ALT/AST > 50 IU/L Bilirubin > 1.2 mg/dL Abnormal coagulation parameters |
NA | Hepatocellular (14) |
Carnitine (5), 10–120 mg/kg No treatment (9) |
Death (14) |
| Glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine | Wang et al. (2012) [39] | China | Case series | 31 | 8.8 ± 3.9 years (mean ± SD) | 20 | 11 |
Antimicrobials (13) TCM (9) Antipyretics (6) Chemotherapy (4) Immunosuppressants (2) Other drugs (7)b |
Idiosyncratic | DDW-J >5 | NA |
Hepatocellular (8) Cholestatic (8) Mixed (15) |
Glycyrrhizin, GSH, PPC, S-adenosylmethionine (31), doses unspecified |
Recovery (30) Death (1) |
| Adolescents (from 12 to < 18 years) | ||||||||||||||
| N-acetylcysteine (NAC) | Epperson et al. (2021) [40] | United States | Case report | 1 | 17 years | 1 | Acetaminophen | APAP | NA | NA | NA |
NAC (IV), 150 mg/kg loading dose, 12.5 mg/kg/h over 4 h, 6.25 mg/kg/h over 16 h NAC (IV), 12.5 mg/kg/hi |
Recovery | |
| Molecular Adsorbent Recirculating System (MARS) | Novelli et al. (2008) [36] | Italy | Case series | 1 | 14 years | 1 | Acetaminophen | APAP |
Bilirubin > 15 mg/dL Creatinine > 2 mg/dL Encephalopathy grade > II INR > 2.5 Elevated AST and ALT serum levels and lactate |
ALF | NA | MARS, number of cycles unspecified | LTx | |
| Ng et al. (2013) [41] | Singapore | Case report | 1 | 17 years | 1 | TMP-SMZ | Idiosyncratic (DRESS) | King´s college criteriae | Moderateg | Hepatocellular | MARS, two cycles | Recovery | ||
| Carnitine | Scheffner et al. (1988) [38] | Germany | Case series | 2 | 15 years (median) | 1 | 1 | Valproic acid | Idiosyncratic |
ALT/AST > 50 IU/L Bilirubin > 1.2 mg/dL Abnormal coagulation parameters |
NA | Hepatocellular (2) |
Carnitine (1), 30 mg/kg No treatment (1) |
Death (2) |
| Unspecified age | ||||||||||||||
| Continuous Renal Replacement Therapy (CRRT) | Deep et al. (2016) [42] | United Kingdom | Retrospective cohort study | 19 | NA | NA | NA | Unspecified | Unclear | PALF Study Groupc | ALF | NA |
CRRT (6) No CRRT (13) |
Recovery (6/6) Recovery (12/13); Death (1/13) |
ALF acute liver failure, ALT alanine aminotransferase, Amox/clav amoxicillin-clavulanate, APAP acetaminophen overdose, AST aspartate aminotransferase, CRRT continuous renal replacement therapy, CVVH continuous venovenous hemofiltration, DDW-J Digestive Disease Week–Japan 2004, DIHS drug-induced hypersensitivity syndrome, DILI drug-induced liver injury, DRESS drug reaction with eosinophilia and systemic symptoms, F female, GSH reduced glutathione, INR international normalized ratio, IV intravenous, LTx liver transplantation, M male, MARS molecular adsorbent recirculating system, NA not available, NAC N-acetylcysteine, PALF pediatric acute liver failure, PPC polyene phosphatidylcholine, SD standard deviation, SoC standard of care, TCM traditional Chinese medicines, TMP-SMZ trimethoprim-sulfamethoxazole, UDCA ursodeoxycholic acid, ULN upper limit of normal, VBDS vanishing bile duct syndrome
aOnly patients who had hepatotoxicity due to acetaminophen overdose
bNine children took one single medication, seven were treated with two drugs at the same time, and 15 were treated with three or more drugs at the same time. Other drugs included albendazole, isoniazid and rifampicin
cPediatric Acute Liver Failure Study Group criteria [8]: (1) no known evidence of chronic liver disease; (2) biochemical evidence of acute liver injury; (3) hepatic-based coagulopathy defined as a prothrombin time (PT) ≥ 15 s or INR ≥ 1.5 not corrected by vitamin K in the presence of clinical hepatic encephalopathy or a PT ≥ 20 s or INR ≥ 2.0 regardless of the presence or absence of clinical hepatic encephalopathy
dRegiSCAR criteria [43]: hospitalization; reaction suspected to be drug related; and at least three of the following features: acute skin rash, fever above 38 ºC, enlarged lymph nodes in at least two sites, involvement of at least one internal organ, blood count abnormalities (lymphocytes above or below the laboratory limits, eosinophils above the laboratory limits in percentage or absolute count, platelets below the laboratory limits)
eKing’s College criteria [44]: in patients with acetaminophen-induced fulminant hepatic failure: arterial pH < 7.3; or prothrombin time >100 s combined with serum creatinine >300 µmol/L in patients with at least grade III encephalopathy. In patients with non-acetaminophen-induced fulminant hepatic failure: prothrombin time > 100 s, or age < 11 and > 40 years, jaundice for > 7 days before encephalopathy, prothrombin time > 50 s, and serum bilirubin >300 µmol/L
fClichy-Villejuif criteria [45]: grade III or IV of hepatic encephalopathy and factor V levels < 20% in patients aged < 30 years, and < 30% in patients aged ≥ 30 years
gDILI progressed to acute liver failure
hThe remaining five children (negative for HHV6) were managed with supportive therapy alone
iTreatment was restarted along with scheduled steroids and antihistamines