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Examples of the most common pathological injury patterns. (A) Acute hepatitis due to herbal decoction with Ephedra sinica for respiratory infection. Biopsy shows confluent and bridging necrosis around the central vein and significant lobular inflammation. (B) Chronic hepatitis due to the combination of cephalosporin antibiotics and antipyretic analgesics for fever of unknown origin. Liver biopsy shows fibrous septa formation and moderate interface hepatitis. (C) Acute cholestasis due to azithromycin. Biopsy showed hepatocellular and canalicular cholestasis with bile plugs. (D, E) Cholestatic hepatitis due to herbal decoction with Polygonum multiflorum for vitiligo. Biopsy showed prominent canalicular cholestasis, confluent necrosis, and neutrophilic infiltration (H&E stain, ×200; for orientation, V indicates the central vein, P indicates the portal area, and arrows indicate cholestasis).
Source publication
Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited.
All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied.
A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns w...
Context in source publication
Context 1
... biopsies were performed in 59 children (85.5%) and the pathological patterns of injury in 55 children were listed in Table 1, whereas four of the cases could not be classified into any pattern because of mild histological changes. Liver cell de- generation, necrosis, and lobular inflammation were common findings, with typical confluent necrosis in 11 cases (18.6%), bridging necrosis in five cases (8.5%), and submassive necrosis in one case who did not present with clinical features of liver failure. Twenty-nine biopsies (49.2%) showed various degrees of interface hepatitis. Hepatocellular and/or canalicular cho- lestasis were observed in 16 cases (27.1%). Twenty-nine biop- sies (49.2%) demonstrated eosinophil infiltration and none had duct sclerosis or loss. Typical examples of pathological patterns were described in Fig. 2. In 15 cases (25.4%), the liver biopsy after the normalization of liver biochemistry still showed the histologic features of chronic hepatitis, such as moderate portal inflammation, interface hepatitis, fibroplastic proliferation, and fibrous septa formation. All three cases with ALF showed the pathological characteristics of cholestatic hepatitis involving confluent and bridging necrosis, cholestasis, interface hepatitis, and fibrous septa formation, but none demonstrated submassive ...
Citations
... Besides, we found that there was a difference in the clinical phenotype of CILI between children and adults, with hepatocellular injury predominating in children and cholestatic injury predominating in adults. Previous studies have shown that DILI in children is mainly hepatocellular injury, and the incidence of cholestatic injury has an increasing trend with age, and the proportion is higher in elderly patients [12,28,29]. Biliary excretion and bile salt export pump inhibited [30], and the aging-related decrement in biliary function may contribute to the higher rate of cholestatic injury in the elderly [31]. ...
Purpose
To summarize the clinical and biochemical characteristics of patients with ceftriaxone-induced liver injury and guide the selection of safe medication.
Methods
Retrieved domestic and foreign databases from inception to October 2023, collected case data conforming to ceftriaxone-induced liver injury, and statistically analyzed the data.
Results
A total of 617 articles were retrieved, and 16 articles with 33 cases (10 children, 23 adults) were included. Males represented 60% (18/30), with a male-to-female ratio of 1.5:1. The age of onset ranged from 2 days to 96 years, with 15 of 23 adults (65%) over 55 years old. The time from ceftriaxone use to liver injury fluctuated between 0.5 and 47 days. Only 9 patients (27.3%, 9/33) had clinical symptoms, and the clinical classification was dominated by cholestatic injury (46.2%, 12/26). There was a significant difference in the clinical classification of ceftriaxone-induced liver injury between children and adults (P = 0.0126), with hepatocellular injury predominating in children and cholestatic injury predominating in adults. The severity of liver injury was mainly mild (66.7%, 12/18). Peak values of alanine aminotransferase ranging from 228.5 to 8098 U/L, aspartate aminotransferase ranging from 86.7 to 21575 U/L, alkaline phosphatase ranging from 143 to 2434 U/L, and total bilirubin ranging from 3.35 to 66.1 mg/dL. There was a significant difference in peak values of alkaline phosphatase between children and adults (P = 0.027), with a higher peak value of alkaline phosphatase in adults (1039 ± 716.4 U/L vs. 257 ± 134.9 U/L). Patients with normal imaging examinations accounted for the majority (61.5%, 7/13). The prognosis of 32 patients (97%, 32/33) was good, and one child with sickle cell anemia who developed immune hemolysis, progressive renal failure, and acute liver injury after using ceftriaxone died in the end.
Conclusion
Ceftriaxone-induced liver injury can occur at any age, with a higher risk in the elderly, and age may be related to the clinical classification. Although the clinical manifestations are not specific, close monitoring of liver biochemical indicators during the use can detect liver injury early. Most cases have a good prognosis, but for people with concomitant sickle cell anemia, it is necessary to be vigilant about the occurrence of severe hemolytic anemia.
... Therefore, the administration of EEEA for 21 days made an increase in ALT, AST, and LDH which may be an indicator of liver toxicity, particularly at high doses. This hepatotoxicity may be caused by ephedrine, the major active component of Ephedra species since many previous studies have demonstrated its potential to induce liver toxicity (Reuben et al., 2010;Zhu et al., 2015). A recent study performed by Wen and Lia (2020) indicated that ephedrine administration enhanced the apoptosis of hepatocellular cells and negatively affected liver function. ...
ABSTRACTAnindigenousSaharanspeciescalledEphedraalatacanbefoundinAlgeria,NorthAfrica,andotherplaces.Ithasawiderangeofapplicationsinconventionalmedicineallaroundtheworld.So,theobjectiveofthecur-rentinvestigationwastoevaluatethesafetyofEphedraalata’sethanolicextract(EEEA)throughsubacuteoraltoxicityinSwissfemalemice.MicereceiveddailyoraldosesoftheEEEArangingfrom(250,500,1000,2000,4000,and5000mg/kgbodyweight)for21days.Toassessthetoxicity,theblood,aswellastheprimaryorgans(kidney,liver,brain,andheart),werecollectedandexamined.Nomortalityoranyclinicalsignsofintoxicationwereobservedintreatedmice.Therewerealsonosignificantdifferences(p>0.05)inbody,kid-ney,brain,andheartweights,themajorityofhematologicalparameters(HB,HT,RBC,WBC..),andbiochemi-calparameters(PROT,CRE,URE,andTC).Furthermore,asignificant(p>0.05)decreaseinliverweight,anincreaseinALT,AST,LDH,andsomehistologicalalterations(withnohepatocytenecrosis)wereobservedinmiceadministratedrelativelyhighdosesofEEEA.ThisfindingsuggestsapossiblehepatotoxiceffectoftheEEEAparticularlyathighdoses.Fromthestudy,EEEAcanbeusedasacomplementarytreatmentthathelpstoraisetheantioxidants,asastagethatisusedinthetreatmentofcancerousdiseases.©2023SAAB.PublishedbyElsevierB.V.Allrightsreserved.
... Studies showed that Forsythia Fruit exhibits anti-inflammatory effects that prevent fulminant hepatitis while displaying several potential therapeutic effects [27,28]; however, no reports showed an association with liver injury. In contrast, Schizonepeta Spike was cited as a potential cause of hepatotoxicity, and the (+)-menthofuran in Schizonepeta Spike was reported to be involved in hepatotoxicity [29][30][31]. Reports on Saposhnikovia Root and Rhizome in traditional Chinese medicine suggested their involvement in DILI [32][33][34][35]. The present results support the previous findings on Schizonepeta Spike and Saposhnikovia Root and Rhizome but contradict those on Forsythia Fruit. ...
The current study aimed to identify the crude drugs associated with drug-induced liver injury (DILI) in 148 Kampo medicines prescribed throughout Japan using the Japanese Adverse Drug Event Report (JADER) database, a large-scale spontaneous reporting system in Japan. First, we tabulated the number of DILI reports from the report-based dataset and the background information from the patient-based dataset. Thereafter, we combined the 126 crude drugs into 104 crude drug groups to examine multicollinearity. Finally, the reporting odds ratios (RORs), 95% confidence intervals, p values for Fisher’s exact test, and number of reports were calculated for each crude group to identify those associated with DILI. Notably, the number of adverse event reports for DILI (63,955) exceeded that for interstitial lung disease (51,347), the most common adverse event. In total, 78 crude drug groups (90 crude drugs) were reported to have an ROR > 1, a p < 0.05, and ≥10 reported cases. Our results highlight DILI as an essential issue, given that it was among the most frequently reported adverse drug reactions. We were able to clearly identify the crude drugs associated with DILI, which could help manage adverse drug reactions attributed to Kampo medicines and crude drugs.
... Analgésico, Antipirético, Antiinflamatório não esteroidal Acetaminofeno (Kumar et al., 2018;Hedeland et al., 2014), Ibuprofeno (Hita, 2013) Tuberculostático Etambutol (LiverTox, 2012), Isoniazida (Kumar et al., 2018;Hita et al., 2013;Gil et al., 2007;Ruslami et al., 2022;Le Roux et al., 2013), Rifampicina (Kumar et al., 2018;Hita et al., 2013;Gil et al., 2007;Ruslami et al., 2022) e Pirazinamida (Kumar et al., 2018;Ruslami et al., 2022) Outros Ácido Ascórbico (Zhu et al., 2015), Quanto ao quadro clínico observado nos pacientes que apresentaram DILI, nota-se que dentre os observados, foram descritos sinais e sintomas hepáticos e gastrintestinais, como anorexia (Hita et al., 2012), diarreia (Hita et al., 2012), dor abdominal (Hita et al., 2012;Gil et al., 2007), hepatoesplenomegalia (Hita et al., 2012;Gil et al., 2007), icterícia (Hita et al., 2012;DiPaola et al., 2019;Ruslami et al., 2022;Le Roux et al., 2013) e vômitos (Hita et al., 2012;Le Roux et al., 2013). ...
... No que diz respeito aos exames de imagem, foi realizado ultrassonografia abdominal em apenas um paciente, que mostrou hepatoesplenomegalia com líquido livre intra-abdominal (Hita et al., 2012). Zhu et al., 2015;Kumar et al., 2018;Hita et al., 2013). Casos com sinais e sintomas clínicos autolimitados voltaram ao estado de normalidade entre 4 a 36 semanas do início do quadro, com média de 14 semanas, sem que houvesse alguma forma de insuficiência hepática aguda (Hita et al., 2012). ...
... Houve relato de pacientes que precisaram ser admitidos no Serviço de Saúde local devido a presença de vômitos incoercíveis (Hita et al., 2012). Considerando a evolução dos pacientes a médio e longo prazo, foi citada a ocorrência de DILI com caráter crônico (Zhu et al., 2015;Kumar et al., 2018) em alguns pacientes, bem como a resolução do quadro após a suspensão do fármaco suspeito envolvido, sem que houvesse retorno da DILI após reintrodução gradual dos medicamentos (Ruslami et al., 2022;Asgarshizari et al., 2015). ...
A injúria hepática induzida por medicamentos (DILI – que vem do inglês Drug Induced Liverr Injury) consiste numa lesão ocasionada por medicamentos, ervas e xenobióticos, que levam a alterações hepáticas. A incidência de DILI na pediatria é desconhecida, pois casos são subclínicos ou subnotificados. O objetivo deste trabalho foi realizar uma revisão da literatura para identificar os principais medicamentos envolvidos em DILI na pediatria. Foram identificados 339 artigos nas bases de dados, sendo que 48 foram selecionados para leitura na íntegra e após seleção e elegibilidade totalizou-se 13 artigos. A DILI na pediatria é um desafio pela vasta clínica, diagnóstico difícil e tratamento inespecífico. Foi verificada elevada e heterogênea possibilidade de fármacos que causam dano hepático em crianças. É importante que estudos sejam realizados para garantir melhores resultados quanto ao diagnóstico, prevenção e tratamento, assim como a organização de bancos de dados com informações sobre eventos adversos hepáticos envolvendo o uso de medicamentos na pediatria.
... In addition, hepatocelular injury was the most common pattern (56%), and only one case died after undergoing liver transplantation [47]. In contrast, findings from a single center in India reported a much higher mortality rate, nearly 30%, in 39 paediatric DILI cases, mainly caused by anti-tuberculosis drugs [48], whilst in another single-center Chinese study including 69 paediatric DILI patients, mostly due to Chinese medicines (13%), the mortality rate was similar to western DILI cohorts (2.9%) [49] (Table S2, see ESM). ...
IntroductionDrug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce.Objective
We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population.Methods
We included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents).ResultsOverall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy.Conclusions
This systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population.PROSPERO registration number CRD42021214702.
... In literature, few case reports or case series of DILI are described in childhood, mostly associated with antipyretics, anti-inflammatories and antibiotics but also antiepileptics, antituberculosis, antineoplastics and unconventional drugs [14]. According to adult studies, DILI is often due to a combination of drugs in children and antibiotics are the most commonly implicated drug class [15]. Moreover, the class of the offending drug is largely dependent upon regional distribution. ...
... Conversely, complementary/alternative drugs and anti-tubercular agents have been reported as prevalent groups of drug implicated in DILI in India (39% and 33%, respectively) [17]. Furthermore, chinese herbal medicine represents the main etiological agent of pediatric DILI in China [15]. ...
... In most cases, a complete recovery of DILI is achieved after the discontinuation of the medication over a period ranging from days to months. A progression towards chronic DILI may reach 20% of cases [15]. Since ALF accounts about 20% of DILI complications in paediatrics, any children with suspected drug-induced liver damage presenting coagulopathy, encephalopathy and/or hypoglycemia should be immediately referred to a pediatric liver transplant center. ...
Drug-induced liver injury (DILI) is an under-recognized cause of paediatric liver disease. Although DILI in children accounts for about 1% of all reported adverse drug reactions throughout all age groups and less than 10% of all clinical DILI cases, it is responsible for about 20% of acute liver failure (ALF) cases. A wide range of drugs, herbal products and nutritional supplements have been associated with the development of DILI through dose-dependent, idiosyncratic or indirect mechanism. Limited literature is available in pediatric population, making DILI a still challenging diagnosis. An accurate medical history is of pivotal importance and should investigate about drug consumption, clinical and laboratory findings, individual and family risk factors for drug-related side effects or comorbidities, the timing of the injury onset after the implicated agent has been started (latency). Clinical presentation of DILI varies from asymptomatic or very mild to serious and sometimes fatal conditions; laboratory tests may be helpful in ruling out other causes of liver injury but, with few exceptions, they are aspecific. Early suspicion and prompt withdrawal of the offending drug play a key role for a successful management of most cases. Rarely a specific therapy is available, as for acetaminophen toxicity, treated with N-acetylcysteine, and sodium valproate toxicity, where carnitine may be beneficial. Although controlled trials are not available yet, corticosteroids and ursodeoxycholic acid can be considered if no improvement is proven after discontinuation of drug. The present short review is not intended to deal with all aspects concerning DILI but to focus on epidemiology, pathogenesis, clinical features, practical management and current challenges in paediatric age.
... Chinese patent medicines are traditional Chinese medicine products, some of which contain Western medicine ingredients such as acetaminophen, chlorpheniramine maleate, and other Western medicines. In a retrospective study of pediatric DILI in China, Chinese herbal medicine and combined drugs each accounted for 21.7% of cases, while Western medicines accounted for 56% of cases (Zhu et al., 2015). Acetaminophen-related ALF and idiosyncratic druginduced liver injury-related ALF account for more than 50% of all acute liver failure cases in the United States and may progress rapidly to death within 72 h (Chayanupatkul and Schiano, 2020). ...
Background: Drug-induced liver injury (DILI) caused by Chinese patent medicines is increasing in China. The incidence of invasive fungal infections (IFIs) is increasing due to the suppression of the immune function in greater numbers of patients. Invasive procedures such as deep vein catheterization and the use of glucocorticoids are also predisposing factors to IFIs. The clinical presentation of IFI in teenagers is often atypical, challenging to diagnose, difficult to treat, and associated with a high fatality rate.
Case presentation: Herein, we report 2 teenagers with liver failure after receiving oral Chinese patent medicines. Case 1 was a 14-year-old boy who presented with subacute liver failure who had been administered a Chinese patent medicine that included acetaminophen. Administration of glucocorticoids and non-bioartificial liver treatment improved his condition. Subsequently, invasive pulmonary Aspergillus (IPA) was diagnosed and was successfully treated with voriconazole for 85 days. Case 2 was a 17-year-old girl who presented with acute liver failure after taking the Chinese patent medicine QubaiBabuqi tablets for vitiligo. Chest computed tomography (CT) revealed multiple pulmonary nodules with an intermittent low-grade fever, and she was diagnosed with IPA. She was initially treated with caspofungin (23 days) and then voriconazole (406 days) for 429 days. Her liver function returned to normal, and lung lesions were absorbed in 2 patients. At the same time, two to three histopathological examinations of the liver biopsy showed that the drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.
Conclusion: To the best of our knowledge, this is the first report of the successful treatment of 2 cases of liver failure (Child–Pugh class C) caused by Chinese patent medicines complicated with IPA in teenagers. Drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.
... [3] In children diagnosing of DILI is challenging, because of the absence of specific markers. [4] The symptoms of liver injury are always nonspecific such as fatigue, nausea, vomiting or jaundice or it includes biochemical dysfunction such as elevation in Alanine transaminase (ALT), Alkaline phosphatase (ALP), or Total Bilirubin (TB). [4] Compared to adults the children's have different characteristics of DILI due to their changes in drug metabolism and their special requirements of medication. ...
... [4] The symptoms of liver injury are always nonspecific such as fatigue, nausea, vomiting or jaundice or it includes biochemical dysfunction such as elevation in Alanine transaminase (ALT), Alkaline phosphatase (ALP), or Total Bilirubin (TB). [4] Compared to adults the children's have different characteristics of DILI due to their changes in drug metabolism and their special requirements of medication. [4] The main cause of death of several patients is the presence of infection and irrational use of antibiotics. ...
... [4] Compared to adults the children's have different characteristics of DILI due to their changes in drug metabolism and their special requirements of medication. [4] The main cause of death of several patients is the presence of infection and irrational use of antibiotics. Irrational use of antibiotics is the leading cause for emergence of multidrug resistant strains of bacteria. ...
... The aetiology is unclear however, activity of beta-glucuronidase has been linked as one of the possible mechanisms leading to jaundice in breastfed infants (30,34). CHMs-associated hepatotoxicity has also been reported by researchers in China who reported incidence of jaundice among children ingesting CHMs that are used to treat diseases such as upper respiratory tract infection or vitiligo (35). In addition, heavy metals such as As could also lead to liver toxicity which leads to development of jaundice (36). ...
Introduction: In Malaysia, herbal medicines are used for variety of reasons including health promotion and home remedies during pregnancy and postpartum with Manjakani (Quercus infectoria) as one of the most commonly consumed herbs. Herbal medicines consumption had been linked to heavy metals contamination and transfer from mother to infant and may affect infant's growth and development. This study aims to (i) determine Manjakani consumption among postpartum mothers, (ii) quantify its heavy metals level, namely lead, cadmium, arsenic and chromium , and (iii) determine health risk associated with its consumption. Methods: A cross-sectional study involving 106 postpartum mothers was carried out in Kuala Lumpur. Six samples of Manjakani were sampled and extracted using microwave digester and analysed using Inductively coupled plasma mass spectrometry (ICP-MS). Non-carcinogenic health risks for herbal medicine consumption were calculated using Hazard Quotient (HQ). Results: Manjakani was consumed by 16% of mothers (n=17). Highest level of the metals was shown by chromium with mean concentration of 4210 ± 1910 ug/kg, followed by lead (170.8 ± 193.2), arsenic (39.3 ± 27.1) and cadmium (7.7 ± 0.76). There were no significant non-carcinogenic health risks with lead, arsenic, chromium and cadmium contamination (HQ < 1). Conclusion: Manjakani is consumed by mothers during confinement period. Heavy metals were quantified in Man-jakani although no significant association was observed with socio-demographic characteristics and birth outcomes.
... * p < 0.001 versus negative control control group and groups treated with chlorpheniramine maleate and cetirizine hydrochloride alone. In the same context, Zhu et al. (2015) declared that acetaminophen, chlorpheniramine maleate, vitamin C, and other Chinese herbs caused drug-induced cholestatic liver injury with various degrees in children after chronic treatment. Albumin is the main protein synthesized by the liver (Edoardo et al. 2005) and measuring its serum level is one of the liver function tests that reflect hepatic function. ...
H1 antihistamines are the most widely used drugs for relieving symptoms of histamine-mediated disease. Although chlorpheniramine maleate and cetirizine hydrochloride have tolerable side effects, they induce severe side effects on chronic use such as hepatitis and cholestatic jaundice. Oxidative stress has been implicated as a mechanism of drug-induced hepatotoxicity. l-Carnitine is an effective biological active compound that is involved in oxidation of fatty acids in the liver through transportation of fatty acids into the mitochondria for energy production from fat. l-Carnitine has well-known antioxidant properties, improves hepatic function, and improves mitochondrial function in hepatic cells. In the present study, we evaluated the possible role of oxidative stress and the therapeutic and hepatoprotective effect of l-carnitine on chlorpheniramine maleate– and cetirizine hydrochloride–induced liver damage during chronic use. Methods are measurement of ALT, AST, ALP and albumin serum levels and measurement of hepatic oxidative stress biomarkers MDA and GSH in groups with and without combination with l-carnitine. Histopathological examination of changes in hepatic tissue and scoring of the induced hepatic damage was conducted in all treatment groups. Co-treatment of l-carnitine with chlorpheniramine maleate and cetirizine hydrochloride significantly improved the deteriorated hepatic function as indicated by reduction in the serum levels of ALT, AST, ALP, and elevation in serum albumin levels compared with control and untreated groups. Moreover, co-administration of l-carnitine with chlorpheniramine maleate and cetirizine hydrochloride decreased hepatic MDA and elevated hepatic GSH levels compared with control and untreated groups. Ultrastructure examination of hepatic tissue found that co-treatment with l-carnitine decreased hepatic necrosis and damage. In conclusion, oxidative stress can be a possible explanation of hepatic damage induced by chronic therapy with chlorpheniramine maleate and cetirizine hydrochloride. l-Carnitine has prominent hepatoprotective effects on chlorpheniramine maleate– and cetirizine hydrochloride–induced hepatic damage possibly through improvement of hepatic function and decreasing oxidative stress.
