Toxic hepatitis,

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It is one of the most frequent causes of acute liver injury in children, sometimes with evolution to acute liver failure ALF or death. The most common drug used that has liver toxicity is acetaminophen, with easy access, being released toxic hepatitis medical prescription.

Fortunately, the antidote used in acetaminophen intoxication acetylcysteine makes mortality to remain low among these cases. Toxic hepatitis drugs that cause toxic hepatitis are albendazole, valproic acid, anaesthetics and antituberculosis agents. In paediatrics, the early recognition of the possible cause that led to liver injury may be the key for the correct management and for a favourable outcome.

If there is a toxic cause, the emergency referral to a specialized centre is vital in these patients. Keywords toxic hepatitis, toxic, hepatitis, acute liver failure ALFacetaminophen, children, teenagers Rezumat Toxicitatea secundară ingestiei de medicamente reprezintă o problemă în întreaga lume, fiind o cauză importantă de toxic hepatitis şi mortalitate la copii şi adolescenţi.

Este una dintre toxic hepatitis mai frecvente cauze de injurie hepatică acută la copil, cu po­ten­ţial de evoluţie către insuficienţă hepatică acută IHA sau de­ces. Paracetamolul este medicamentul implicat cel mai frecvent în hepatitele de cauză toxică din cauza faptului că în ţara noastră se eliberează fără prescripţie medicală, fiind uşor accesibil în special adolescenţilor cu gânduri suicidare.

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Din fericire, utilizarea N-acetilcisteinei ca antidot determină o mortalitate redusă în aceste cazuri. Alte medicamente im­pli­ca­te în declanşarea fenomenelor de hepatotoxicitate sunt al­ben­da­zo­lul, acidul valproic, anestezicele, medicaţia an­ti­tu­ber­cu­lo­sta­ti­că etc. Recunoaşterea timpurie de către medicul pediatru a cause of laryngeal papillomas posibile etiologii hepatotoxice poate reprezenta cheia către un diagnostic rapid, un tratament precoce şi un prognostic fa­vo­ra­bil.

Etiologia toxică a hepatitelor acute impune transferul de urgenţă al pacientului către un centru specializat, acest lucru având importanţă vitală, cu predilecţie în cazurile severe care evo­luea­ză cu IHA. Cuvinte cheie medicamente toxice hepatită insuficienţă hepatică acută paracetamol copii adolescenţi Introduction Hepatotoxicity is defined as an increase of the serum levels of aminotransferases or conjugated bilirubin or cholestasis enzymes secondary to the action of an agent with hepatotoxic potential 1,2.

Now, the term used for hepatotoxicity determined by drugs is drug-induced liver injury DILI. Almost all the drugs can cause DILI, but most of the times the phenomena of hepatotoxicity are mild. Only in several cases, there is an evolution with severe liver injury. Drugs can determine hepatotoxicity by two mecha­nisms: toxicity dependent on the doses acetaminophen, halothane and idiosyncratic reactions antibiotics, nonsteroidal anti-inflammatory drugs.

The clinical manifestations of drugs hepatotoxicity are gastrointestinal symptoms, jaundice, neurologic manifestations, bleeding, acute renal injury or ascites We present some of the drugs most frequently incriminated in hepatotoxicity in children, following their mechanism of action. The main drugs that cause liver injury in children are presented in Table 1. Table 1 Mechanism of drugs toxicity Intrinsic hepatotoxicity occurs as a result of large quantities of a hepatotoxic compound or its rela­ted metabolites.

Based on the way they act upon the he­patic structure, intrinsic hepatotoxicity is classified in direct or indirect hepatotoxicity. In direct hepatoto­xi­city, the lesions are produced through the direct action of toxic hepatitis upon the hepatocyte cyto­toxic effect and the result is represented by the hepatic steatosis or areas of necrosis.

Indirect hepatotoxicity consists of the alteration of certain intracellular synthesis me­ta­bolic processes or transport processes which de­ter­mine the toxic hepatitis of the cellular function and, sub­sequently, its death. The intrinsic hepatotoxicity depends simptome cancer ovarian stadiul 4 the dose, independent of the genetic background.

The symptoms occur after a short time hours, days from ingestion. A toxic hepatitis for toxic hepatitis direct intrinsic hepatotoxicity is the carbon tetrachloride, while acetaminophen in large doses could determine cellular lesions both through direct, as well as through indirect mechanism Acetaminophen Acetaminophen is the prototype toxic hepatitis intrinsic hepatotoxicity.

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Fortunately, the administration of acetylcysteine N-ACCas an antidote in the acetaminophen intoxication, condiloame și planificare to a toxic hepatitis rate of mortality in these cases. When large doses are administered, these routes become oversaturated and the metabolization of acetaminophen shall be performed mainly on the P cytochrome route Figure 1.

The toxic metabolites resulted, such as N-acetyl-p-benzoquinoneimine NAPQIwill determine mitochondrial disfunction and cellular death cytotoxicity and necrosis. NAPQI depletes the glutathione reserves.

As glutathione is the natural antioxidant of the liver, the result will be apoptosis, cellular lysis, and central-lobular necrosis Figure 1.

Acetaminophen metabolism pathway adapted after Byeong JC, et al. Although the liver injury starts after hours following the ingestion, the clinical symptoms usually occur in a late stage after hours from toxic hepatitis — Table 2. These symptoms are represented by jaundice, convulsions or coma, liver failure and death Table 2 Clinical manifestations in acetaminophen intoxication The level of acetaminophen in the blood is used for the assessment of the severity of the acetaminophen overdose and the risk of liver toxicity.

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The idiosyncratic hepatotoxicity occurs in people with a genetic predisposition, independent of the dose, and involves immune-mediated phenomenon. The hepatotoxicity phenomena appear after weeks from the exposure, being secondary to a metabolic or an immune mechanism.

The idiosyncratic hepatotoxicity develops as a result of certain genetic mutations that increase toxic hepatitis susceptibility to the action of the toxic agent, the best example being isoniazid. The immune mechanism is a hypersensitivity reaction after the interaction between the toxic and immune system.

Due to this reason, cutaneous rash, fever, arthralgia, eosinophilia or other autoimmune features such as an increase of immunoglobulins G IgG or the presence of serum antinuclear antibodies ANA could be associated in this type of hepatotoxicity It can determine hepatotoxicity through idiosyncratic reaction.

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These metabolites, together with the one produced by the INH bioactivation itself, are responsible for the liver injury Figure 2. In case of overdosage of INH, the clinical manifestations are predominantly neurological coma, convulsions, ataxia, psychotic reactions, death Figure 2. Metabolization route for isoniazid adapted after Wang P, et al.

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The slow acetylators display a higher risk of hepatotoxicity after the therapy with INH because of the prolonged exposure to the toxic element by increasing the half-life time. Certain authors sustain the hypothesis that the fast acetylators are also predisposed to toxicity because of the fast formation of large quantities of toxic metabolites Figure 2.

Valproic acid Valproate is a fat organic acid usually used in the treatment of convulsions. Frequently, it can determine liver injury, with a slight increase of transaminases.

If large doses are used, it could cause severe liver disease, such as ALF, Reye syndrome or hyperammonaemia. The mechanism of liver toxicity is the mitochondrial destruction that generates subsequently the death of hepatocytes. Hyperammonaemia is usually present in diseases that alter the metabolism of the fatty acids or in urea cycle disorders.

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toxic hepatitis The antidote in the overdosage of valproic acid is the parenteral administration of car­ni­tine. The severe forms that evolve with hyperam­mo­nae­mia or neurological manifestations could benefit from extracorporeal epuration methods 23, Albendazole The administration of albendazole even in therapeutic doses could be associated with liver injuries, steatosis or periportal necrosis. Albendazole has an antiparasite effect by the increased avidity of the drug itself, as well as of its metabolites for tubulin, inhibiting the polymerisation of microtubules.

Microtubules are an important component of the body of the toxic hepatitis, but also represent important constituents of eukaryote cells cytoskeleton, being part of the internal structure of chilli and flagella, also involved in the intracellular movement of the secretor vesicles, organelle, chromosomes. Linking to the tubulin, albendazole delays the formation of microtubules and, in this way, it could amplify the hepatocyte destruction.

Often, albendazole is prescribed for the treatment of intestinal parasitosis, some proven, other only suspected. In a liver injury after albendazole, there is no antidote. The administration of corticoids proved its utility in the forms that associate elements of autoimmunity.

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The use of this drug only hpv oropharyngeal cancer nejm very well documented cases of digestive toxic hepatitis hydatic cyst, aspergillosis, or severe parasite infections could reduce the number of cases with liver injury Nonsteroidal anti-inflammatory drugs NSAIDs NSAIDs represent one of the most frequently prescribed drugs around the world, being used in children as anti-inflammatory, analgesic or toxic hepatitis drugs.

Aspirin induces hepatotoxicity through a dose-mediated mechanism, by direct damage to the hepatocyte, or impaired mitochondrial function. In some children, aspirin can cause Reye syndrome, a severe condition characterized by metabolic toxic hepatitis, fulminant liver failure with hepatic encephalopathy, hypoglycemia and coagulopathy.

This is the reason why, at present, the aspirin use in children is limited only to exceptional cases. In adults, an important cause of hepatotoxicity occurs secondary to diclofenac use, which is less prescribed in the pediatric population. Ibuprofen is the most frequently used drug in children, being known for its safe properties and a very low level of hepatotoxicity.

In the rare cases of hepatotoxicity that have been described, it was secondary to both mechanisms: dose-dependent hepatotoxicity or immune-mediated toxicity.

Hepatotoxicity secondary to ibuprofen may range from mild transaminases to severe forms of cholestatic hepatitis with impaired liver function 29, Antibiotics Another important cause of toxic hepatitis may be the use of antibiotics, such as penicillins, cephalo­sporins, clavulanic acid or macrolides.

Their admi­nis­tration can frequently lead to cholestatic liver injury, the mechanism being both direct toxicity and hypersensitivity.

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The outcome of these cases is often favourable, with the remission of manifestations after stopping the administration Amoxicillin-clavulanate is the most frequent drug that causes idiosyncratic DILI in adults in developed countries, as cholestatic hepatitis.

The combination of amoxicillin with clavulanic acid is significantly associated with a risk of DILI compared to amoxicillin alone. Once the administration is stopped, the clinical manifestations improve Cephalosporins have low hepatotoxicity potential, being described only a few cases of liver injury in children. They can cause liver damage through the direct toxic effect or by idiosyncratic reaction.

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More particular is ceftriaxone, which is known for its potential to cause biliary sludge with symptoms of cholecystitis and cholestatic toxic hepatitis Hepatotoxicity is secondary to both mechanisms: direct toxicity triggered by the accumulation of toxic metabolites and allergic response, in this case accompanied by hypersensitivity reaction manifestations.

The clinical manifestations of hepatotoxicity can vary from asymptomatic forms to severe disease, with ALF. Also, in children, the vanishing bile duct syndrome was described in a few cases 36, In children, there are described only a few cases, including some with cholestatic hepatitis or vanishing bile duct syndrome According to some authors, the risk of hepatotoxicity in children is higher after clarithromycin administration compared to azithromycin Anaesthetics Among the anaesthetics, halothane is commonly implicated in liver injury.

Hepatotoxicity after halothane is due to an idiosyncratic mechanism, appearing after repeated exposures to this substance that determines the stimulation of the immune system. The autoantibodies are produced anti-CYP2E1 and will cause hepatocytes destruction, with fever, rash, arthralgias, or eosinophilia 40, Regarding the hepatotoxicity after inhaled anaesthetics, it is proved that their effect is inferior to systemic anaesthetics.

Of all, sevoflurane has the least hepatotoxic potential; for this reason, it is one of the most commonly used volatile anaesthetics agents in children. In the few cases that cause hepatotoxicity, sevoflurane is similar to halothane.

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It is degraded in the liver to intermediate metabolites that bind toxic hepatitis cytoplasmic proteins, resulting in complexes that stimulate autoantibodies production Conclusions In pediatrics, the early recognition of the possible cause of liver injuries may be the key for a favorable outcome of such cases that can have also a severe evolution.

These cases require significant resources and sometimes expensive treatments, from hepatic dialysis to emergency liver transplantation in severe forms. For these reasons, an early diagnosis, a specific therapy depending on the etiology or sometimes the emergency referral to a toxicology specialized centre and also the consideration of liver transplantation could be vital for these patients.

Doi matematicieni poeți: Ion Barbu și Florentin Smarandache

Conflicts of interests: The authors declare no conflict of interests. Bibliografie Calnot A, Perret C. Liver zonation. In: Monga S. Molecular Pathology of Liver Diseases.

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