1. Introduction

The objective of this chapter is to explain hepatotoxicity by drugs and provide relevance to a health problem that can lead to death if neglected; even though there is published information about it, it is still limited in some parts of the world. On the other hand, it is intended to disclose some activities developed by a pharmacist in a case of one patient with hepatotoxicity by drugs, which can contribute to the improvement of a patient's health status by helping to

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited.

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 to give a better understanding about hepatotoxicity.

The liver injury generated by hepatotoxic medicines has been an adverse event, hard to identify and prevent, because of the sensibility of each patient. There is no specific treatment, except with a few drugs, hence, it is not possible to guarantee the recovery of symptoms in all cases. In such a way, it is necessary to search strategies that allow optimization of the health care process of patients with hepatic toxicity. Thereby, the pharmacist intervention can contribute to the diminu-

Hepatotoxicity by Drugs

79

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

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,

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]; cur-

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

tion of the deleterious effects in patient health, promoting the proper use of the drugs.

2. Drug-induced hepatotoxicity: an overview

published information is based on clinical case reports.

rently, some of them are retired worldwide.

becomes a very conclusive indicator of causality.

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

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, diarrhea, pruritus and rash [8].

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].

The liver injury generated by hepatotoxic medicines has been an adverse event, hard to identify and prevent, because of the sensibility of each patient. There is no specific treatment, except with a few drugs, hence, it is not possible to guarantee the recovery of symptoms in all cases. In such a way, it is necessary to search strategies that allow optimization of the health care process of patients with hepatic toxicity. Thereby, the pharmacist intervention can contribute to the diminution of the deleterious effects in patient health, promoting the proper use of the drugs.
