2. Drug-induced hepatotoxicity: an overview

identify and to prevent the cause of the problem. In addition, we present the key results obtained by a structured review made in PubMed/Medline using the terms such as "liver disease" and "drug-induced liver Injury", until December 2015, and articles available in English, Spanish and French that recognized any drug as a possible trigger of hepatotoxicity were selected. The information obtained in this structured review was analyzed and compiled

Thereby, use of drugs had generated some noxious effects on patient's health; one of the organs that may be affected is the liver, because substances or its formed metabolites in the biotransformation process; drugs can induce liver injury. Hepatotoxicity is the injury or liver damage caused by exposure to drugs or other nonpharmacological agents [1]. It is an adverse drug reaction that may be uncommon but serious, and is the most common cause of drug withdrawal from the pharmaceutical market [2]. Hepatic toxicity incidence by drugs is vari-

There are two types of hepatotoxicity: intrinsic reaction which is dose-dependent and predictable (less common) and idiosyncratic reaction which is not dose-dependent and not predictable (more common). Besides, the hepatic injury can be classified into hepatocellular, cholestatic and mixed, caused by increase in alanine aminotransferase (ALT), that is, >2–3 times and/or increase in alkaline phosphatase (ALP), that is, >2 times the upper limit of normal [4, 5]. The risk factors include: idiosyncrasy, age, gender, alcohol consumption, smoking, concomitant use of other drugs, previous or underlying liver disease and genetic and environmental factors [6, 7]. Clinical and pathological manifestations of hepatotoxicity include acute and chronic hepatitis, fulminant hepatitis, cholestasis, ductopenia, granulomatous hepatitis and steatosis (steatohepatitis, macrovesicular or microvesicular steatosis) [6], generally accompanied by nonspecific symptoms such as abdominal pain, jaundice, fever, nausea, vomiting,

It is estimated that approximately 1100 drugs, excluding substances of abuse and natural products, are associated with hepatotoxicity reactions [9]. Although most lipophilic drugs may cause hepatic disorders, the most commonly associated pharmacological groups are antibiotics (amoxicillin-clavulanic acid and rifampicin), nonsteroidal anti-inflammatory analgesics (NSAIDs) (diclofenac and ibuprofen), antidepressants (paroxetine) and anticonvulsants (phenytoin, carbamazepine and valproic acid) [1, 10]. Identification of hepatotoxicity is a complex process to perform; therefore, in practice, this is based on considering the presence of such alteration, conducting a thorough investigation related to the use of any substance and ruling out other causes of liver disease [11]. In order to solve the difficulty of identification and to try to estimate the probability that a therapeutic agent is associated with a hepatic disease, clinical scales have been developed; there are scales such as the Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) and the Clinical Diagnostic Scale (M & V CDS) that assess factors such as absence or presence of confounding factors, temporal relation of hepatotoxicity with drug consumption, coexistence of risk factors, previous description in the literature, exclusion of other causes and effects of readministration of the drug [12]. In general, there is no specific treatment for hepatic toxicity by drugs, which is based on suspending the suspected drug, treating symptoms, avoiding other possible hepatotoxic agents and monitoring laboratory tests [13, 14].

able, because several retrospective and prospective studies were reported [3].

to give a better understanding about hepatotoxicity.

78 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

diarrhea, pruritus and rash [8].

Hepatotoxicity is defined as injury or liver damage caused by exposure to drugs or other nonpharmacological agents [1]. It is an adverse drug reaction that may be uncommon but serious, and therefore, have a considerable impact on health [2]. Hepatotoxicity generates between 1/600 and 1/3500 of all hospital admissions, 2–3% of hospitalizations for jaundice, 10% of acute jaundice hepatitis (being more than 40% in people over 50 years of age) and between 15 and 30% of cases of fulminant hepatic failure [15, 16]. In the United States, a multicenter prospective study showed that drugs, including acetaminophen, are the most common cause of acute liver failure, explaining 39% of cases and overcoming viral hepatitis A and B, which represent 12% [17]. On the other hand, in France, an incidence of 13.9 (2.4) cases per 100,000 inhabitants is estimated, corresponding to an annual global frequency of 8.1 (1.5) cases [18]. In Switzerland, the estimated incidence is 2.2 per 100,000 inhabitants over 15 years of age; while in Spain, the annual incidence of severe liver disease is estimated as 7.4 per 1,000,000 population (95% confidence interval between 6.0 and 8.8) [10]. There are some countries in which evidence about incidence of liver injury by drugs is limited [19], generally, published information is based on clinical case reports.

Although hepatotoxicity is less frequent than other adverse drug effects, due to its severity and is the most common cause of drug withdrawal in the pharmaceutical market, it is assessed as a major adverse event [20], so, it is a frequent impediment to the development of drugs by pharmaceutical companies. In the past 20 years, in Europe and the United States medications such as troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran, lumiracoxib, pemoline and tolcapone have been withdrawn from the market [10, 21–23]; currently, some of them are retired worldwide.

The identification of hepatotoxicity is a complex process to perform; therefore, in clinical practice, it is based on considering the presence of such alteration, investigate about the use of any substance and ruling out other causes of liver disease [19]. It is necessary to identify all drugs used (prescription and over-the-counter), natural products, food, exposure to industrial toxics or substance abuse; moreover, try to identify the offending agent and to search for a description in literature may help. Besides, the chronological relationship between exposure to the suspected agent and the hepatotoxic reaction is a key to define causality; the drugs used in the last 3 months should be considered as suspects. The presence of hypersensitivity manifestations (rash, fever and eosinophilia) improves identification process as well as histological analysis through liver biopsy [24]. When a re-exposure to the suspected agent appears, it becomes a very conclusive indicator of causality.

There is no specific treatment for hepatic toxicity by drugs, which is based on suspending the suspected drug, treating symptoms (use of corticosteroids for hypersensitivity reactions), avoiding other possible hepatotoxic agents and continuous monitoring of laboratory tests [13, 14]. There are some exceptions of antidotes for treating liver toxicity by certain drugs such as the use of N-acetyl cysteine as an antidote for acetaminophen toxicity, or N-acetyl cysteine itself for the treatment of hepatotoxicity by phenytoin and carbamazepine, or carnitine for valproic acid toxicity [25]. With the suspension of the offending drug, in most cases, the health of the patients tends to improve; however, in other cases, the damage continues to progress and hospitalization is necessary, when irreversible liver failure occurs, liver transplantation is required and if the liver tissue damage is severe, patients can die in a few hours.

• Immune response: is attributed to the formation of new antigens, this give origin to the idiosyncratic hepatotoxicity. Moreover, it can be accompanied by presence of inflamma-

Hepatotoxicity by Drugs

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http://dx.doi.org/10.5772/intechopen.72005

• Oxidative stress: is produced by ATP depletion accompanied by increase in intracellular

• Lipid peroxidation: is generated by the interaction between free radicals and fatty acids in membrane, the subsequent reaction may produce electrophilic metabolites generating

Liver histology is the ideal tool to define the pattern of hepatic toxicity; however, in clinical practice, most hepatotoxic lesions are classified according to biochemical tests [16]. In this way, according to Council for International Organizations of Medical Sciences (CIOMS), liver injury is considered, if at least one of the main hepatic enzymes, such as alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase and total bilirubin (TB), increases by two times, the upper limit of normal (ULN) [33]. Besides, liver injury is classified into the

• Hepatocellular lesion is characterized by damage in hepatocytes, which is manifested by elevation in ALT is more than two times the ULN or a ratio (R) of ALT/ALP greater than

• Cholestatic lesion is presented in cholangiocytes when ALP increases more than two times

• Mixed lesion is showed when ALT and ALP increases more than two times the ULN or R

On the other hand, Hy's rule defines liver damage when ALT level increases more than or equal to three times the ULN accompanied by bilirubin elevation [5, 35] and with or without

The influence of sensibility or idiosyncrasy of each person is recognized as an important risk factor. In addition, there are some factors that increase the probability of occurrence of hepato-

• Age: the elderly population is mostly affected by toxicity of drugs because of physiological changes and polymedication [10]; however, with valproic acid, young population is

• Gender: female patients are the most susceptible for toxicity of drugs because of biological differences and pharmacokinetics; moreover, sex-specific factors such as menopause,

• Alcohol consumption: may increase the toxic potential of pharmacological agents [37].

tory cells such as neutrophils and lymphocytes.

DNA damage [32].

following three types of lesions:

the ULN or R greater than two.

is between two and five [4, 34].

or equal to five.

rise of APL levels.

3.4. Risk factors

toxicity [36]:

the most affected.

pregnancy and menstruation may have influence.

3.3. Type of injury

calcium concentration, it can generate necrosis [28].
