Hepatotoxicity Induced by Drugs

#### **Chapter 1**

## Drug-Induced Hepatotoxicity

*Godwin Okwudiri Ihegboro and Chimaobi James Ononamadu*

#### **Abstract**

This chapter aims at discussing the consequential effects of drug-induced hepatotoxicity on man. The liver carries out drug detoxification among other roles, but sometimes, drug toxicity can occur caused by either medication overdose or imbalance drug metabolic reactions (Phase 1 & 2), resulting in the formation of reactive (toxic) metabolites (electrophilic compounds or free radicals) that binds covalently to hepatocytes, leading to liver injury/diseases like acute and chronic hepatitis, cholestasis, steatosis among others. Mitochondrial dysfunction, oxidative stress and lipid peroxidation are some of the mechanisms of liver injury. Furthermore, drug hepatotoxicity results in hepatocellular, gastroenterological, cholestatic as well as immunological disorders. The clinical manifestations of drug toxicity arise from the abnormalities observed in liver's biochemical and molecular indicators. Our findings, revealed that in the event of liver injury, liver function indices like aspartate and alanine aminotransferases, ALP (alkaline phosphatase) and gamma glutamyl transferase (GGT) activities, intracellular calcium (Ca2+) and lipid peroxidation increases whereas indices of oxidative stress such as glutathione and its allies, catalase and superoxide dismutase activity deplete. At molecular level, the gene expression levels of Bcl-2 mRNA and microRNA genes (miR-122, 192 and 194) reduces while mitochondrial genes (MMP-2 and MMP-9) overexpresses. Since drug abuse is deleterious to human health, therefore, adherence to doctors' prescription guidelines should be followed.

**Keywords:** liver, hepatotoxic agents, hepatotoxicity, liver indicators, gene expression

#### **1. Introduction**

The liver is a reddish-brown multifunctional organ that lies beneath the diaphragm in the abdomen's right upper quadrant and overlies the gallbladder. It performs varieties of biological and metabolic functions, but one significant of them is xenobiotic metabolism/ detoxification, in which exogeneous lipophilic xenobiotics (drugs and herbal supplements) are converted to hydrophilic compounds via biochemical processes catalysed by cytochrome P450 enzyme systems. The metabolic products obtained are then actively transported by hepatocyte transporter proteins into the plasma or bile for excretion by the kidney or gastrointestinal tract [1, 2]. However, sometimes, these xenobiotics produce reactive (or toxic) metabolites or electrophiles that bind covalently to hepatocytes, resulting to changes in protein conformation, DNA mutation or induce lipid peroxidation respectively, thereby leading to hypersensitivity reaction or liver necrosis. This is known

as drug-induced injury (or hepatogenous poisoning, toxic-liver disease, chemical-driven injury). This situation often leads to hospitalisation and/or liver transplantation, depending on the magnitude of the liver injury [3]. There are over 1000 hepatotoxic agents available, however, drugs account for about 20–40% of the cases associated with liver failure/ injury [4]. Notably, there are two categories of drug-induced liver injury (DILI) namely: intrinsic (or pharmacological) and idiosyncratic DILI respectively. Intrinsic DILI, refer to a form of liver toxicity caused by a drug in a projectable and dose-dependent manner (e.g. acetaminophen). In this circumstance, liver injury sets-in after an elevated concentration of the drug is attained. On the other hand, idiosyncratic DILI (which occurs relatively), is a non-projectable, non-dose-dependent response to drug and differs in the period of latency (e.g. Trovafloxacin and Troglitazone). It is worthy of note, that approximately 75–80% cases of idiosyncratic reactions end up in death or liver transplantation and as such precautionary measures should be observed in the use of drugs [5, 6]. The dreadful incidences of DILI can be checked by creating drug pharmacovigilant awareness, in which cases of adverse side effects after drug administration should be withdrawn or stopped abruptly to avoid further harm to the body. Besides the harmful effects of acetaminophen (APAP) overdose that has been well documented, studies provide us with wide spectrum of drug inducible agents like, Atypical antipsychotic (AAP), D-galactosamine ((D-GalN)), N-nitrosodiethylamine (NDEA), thioacetamide, Anti- Tuberculosis Drugs (ATD), Anti- Retroviral Drugs (ARDs), Antimalarial Drugs, NSAIDs (Non-Steroidal Anti-inflammatory Drugs), azacytidine, to mention but a few [3]. Therefore, this chapter focuses on discussing the mechanism of action and toxicological implications of druginduced hepatotoxicity of the aforementioned drugs to human health.

#### **2. Drugs and their role in hepatotoxicity**

#### **2.1 Paracetamol**

As much as there are several analgesic drugs consumed by man as pain killer agents, paracetamol seems to be the commonly used and contains acetaminophen the active ingredient, which has been shown to be well-tolerated in prescribed dose but in the event of overdose, liver damage occurs. This is because, acetaminophen metabolism catalysed by cytochrome P450 enzymes in the liver produces N-acetyl-pbenzoquineimine (NAPBQI) – a highly reactive (toxic) intermediate metabolite [7]. In the normal sense, this metabolite gets detoxified by glutathione conjugation in phase II reaction. Nevertheless, during acetaminophen's overdose, a high concentration of the toxic metabolite is produced, and thus overwhelms the detoxification process, leading to hepatocellular necrosis. Reports have shown that liver injury caused by this metabolite can be reduced by the administration of acetylcysteine - a precursor of glutathione, by scavenging the toxic metabolite from the system [8].

#### **2.2 Atypical antipsychotic (AAP)**

Antipsychotic drugs are detoxified via the cytochrome-P450 system in the phase 1 and phase 11 reactions. In its metabolism, the enzyme known as mono-oxygenase converts the drugs into less toxic metabolites through hydrolysis, oxido-reduction and dealkylation processes. However, sometimes, the phase products may display high level of toxicity, hence, phase 11 reaction becomes inevitable. The phase II reaction mainly involves a biochemical process called conjugation reaction which makes use

#### *Drug-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.103766*

of glucuronic acid, sulphate, acetate, amino acids and glutathione to convert phase 1 products to a more body friendly form and subsequently for excretion. Many antipsychotic drugs beside antisulpride, risperidone, and paliperidone are catabolised primarily via the CYP2D6 and CYP3A4 systems while clozapine and olanzapine use the CYP1A2 system for its drug metabolism. Experimentation shows that antipsychotic drugs potentially damages liver cells through three mechanisms (i) By increasing bile secretion and excretion leading to cholestasis which relates to immune-mediated hypersensitivity (a typical mechanism of chlorpromazine) (ii) Accumulation of toxic or reactive intermediates (or metabolites) that eventually attacks liver cells (iii) By Increasing the risk of metabolic idiosyncratic syndrome leading to high risk of non-alcoholic fatty liver diseases which is typical of olanzapine and clozapine. Indiscriminate consumption of antipsychotic drugs presents some clinical manifestations (or side effects) and this can be encapsulated into four categories namely:


#### **2.3 D-galactosamine (D-GalN)**

Galactosamine, one of the commonly used experimental model for hepatotoxicity study in animals, is an amino sugar derivative found majorly as glycoprotein in living cells. In addition, it forms a component of some hormonal systems like Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) respectively. Biochemical investigation into the hepatotoxic effect of D-galactosamine revealed that it induces liver damage by interfering with the products of galactosamine metabolism via Leloir pathway of galactose metabolism. Firstly, galactosamine is transformed to galactosamine-1-phosphate (Gal-1-P) catalysed by galactokinase while the second phase involves the conversion of galactosaminr-1-phosphate to Uridine diphosphategalactosamine (UDPG) by galactose uridyltransferase. At low substrate specificity, UDPG inhibits the activity of UDP-galactose-41 -epimerase, thereby causing a significant accumulation in the hepatic cells and others like UDP-N-acetylglucosamine and UDP-N-acetyl galactosamine with corresponding depletions of uridine triphosphate (UTP), uridine diphosphate (UDP), uridine monophosphate (UMP) as well as uridine diphosphate-glucose (UDP-Glu) and uridine diphosphate-galactose (UDP-Gal), respectively. The outcome of this process then causes the loss of intracellular Ca2+ homeostasis, inhibits hepatocyte ATP metabolism and hepatitis which invariably affects cell membrane, inhibits mRNA, protein and nucleic acid biosynthesis. These effects increase protein gene (p53) expression and decreases Bcl-2 mRNA levels in the liver. It is noteworthy, that the hepatoxic action of galactosamine is effective when in combination with lipopolysaccharide (GalN/LPS). This combination

induces the Kupffer cells to secrete pro-inflammatory mediators that leads to liver cell apoptosis [11]. Experimental design that involves the treatment of animals with D-GalN alters albumin mRNA, glucose-6-phosphatase, histone-3 mRNA, alpha fetoprotein mRNA (αFP mRNA), gamma-glutamyl transpeptidase (GGTP) expressions. Furthermore, it also upregulates expression of tumour nuclear factor (TNF-α mRNA) that has activity of necrotic factor-kappa B (NF- κB10) and alter membrane cofactor protein (MCP-1) level in serum. Also, serum ALT and AST activities increases substantially [12, 13].

#### **2.4 N-nitrosodiethylamine (NDEA)**

N-nitrosodiethylamine (NDEA), is a member of the nitrosamine family and are found in various foodstuff and underground water with high nitrate level. It has hepatocarcinogenic property by yielding adducts of DNA carcinogen in the liver and induces hepatic cancer. NDEA's mechanism of hepatic damage is such that after treatment, it stimulates increase in liver mitochondrial transitional permeability (MTP), leading to increase hydrogen peroxide (H2O2) production, resulting in peroxidative stress [14, 15]. Alternatively, cytochrome P450 activates NDEA, generating reactive electrophilic molecules capable of increasing oxidative stress and liver cytotoxicity and carcinogenicity [16].

#### **2.5 Thioacetamide**

Thioacetamide (TAA), is a white crystalline, organosulfur compound with high affinity for water and alcohol. It is chemically designated as C2H5NS and generally classified as class 2B human carcinogenic agent. NDEA exhibits wide range of relevance such as serve as sulphide source in the synthesis of compounds (organic and inorganic), controls the deterioration of orange fruits (fungicidal role), precipitates cadmium sulphide from acidic solutions, drug development, pesticide production, serve as cross-linking agent but to mention a few. However, scientific reports documented that long-term oral consumption of TAA causes liver cell adenomas, cholangiomas and hepatocarcinomas as well as affects protein, nuclei acid synthesis and GGTP activity. The bio-transformation of TAA via oxidative bioactivation in the liver microsomes catalysed by flavin-containing mono-oxygenases (FMOs) and cytochrome P450 systems produce two toxic metabolites. Firstly, TAA is catalysed by thioacetamide-S-oxygenase to form a reactive intermediate, thioacetamide-S-oxide (TAASO) adduct through oxidation process, which then induces hepatocytic oxidative stress, resulting to increase in nucleoli and Ca2+ concentrations as well as inhibit mitochondrial activity, thereby leading to hepatotoxicity with a resultant effect of centrilobular necrosis. However, the action of CYP2E1 inhibitors (such as 4-methylpyrazole and diallyl sulphide) and TAA, block TAASO toxicity in a relative and absolute manner respectively. The second phase of metabolism involves the conversion of TAASO to thioacetamide-S-S-dioxide (TAASO2 - a reactive species) by the action of thioacetamide-S-oxide-S-oxygenase and then covalently binds with protein and nucleic acid causing hepatotoxicity with consequential effect of liver damage/ injury [17, 18]. The characteristic validation of the hepatotoxic effect of TAA includes decrease in microRNA gene expression (miR-122, miR-192 and miR-194) and increase in AST and ALT activities, mitochondrial membrane protein gene expression (MMP-9 and MMP-2) as well as myeloperoxidase, interleukin-10 (IL-10) and tumour nuclear factor (TNFα) respectively [19–21].

#### **2.6 Acetylaminofluorene (AAF)/DEN**

This is a fluorine derivative compound with carcinogenic tenacity. Its incorporation in diet and subsequent administration induces increased incidences of liver and urinary bladder carcinomas in animal model. Acetylaminofluorene, a by-product of diethyl nitrosamine (DEN) initiates carcinogenesis by increasing reactive oxygen species (ROS) production and facilitate hyperproliferation [22]. Acetylaminofluorene metabolism by cytochrome P450 produces metabolites like 2-aminofluorene (AF), 2-glycoloylaminofluorene (2-GAF), N-hydroxy-2-acetylaminofluorene (NH-2-AAF), 2-acetylaminofluoren-3-,-7-,-9-ol (3-, 7-, 9-hydroxy-AAF) and 2-acetylaminofluoren-9-one (AAF-9-one) respectively and exhibits different toxicity pathway. For instance, N-hydroxy-2 acetylaminofluorene and AAF binds covalently at Carbon - 8th positions in guanine; causing single strand breaks in DNA with resultant effect of severe apoptosis. Sometimes, AAF exposure increases expression of genes implicated in p53-signalling pathway, mRNA genes [encode mitochondria drug resistance proteins (Mdr1b, Mrp1 and Mrp3)] and microRNA genes respectively, thereby resulting in apoptosis [23–25]. Studies showed that at small dose of 2-AAF for long (2.24 or 22.4 mg/kg, 3 times/week for 31 days) or high dose (448 mg/kg BW, i.g., 5 days/week for 8 weeks) produces maximum hepatocellular carcinogenesis through AAF- DNA adducts [26, 27]. Interestingly, lower dose of 2-AAF (50 mg/kg BW, i.p.) was reported to increase lipid peroxidation, deplete GSH level while the activities of glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and glutathione-S-transferase (GST) were significantly reduced [28].

#### **2.7 Anti- tuberculosis drugs (ATD)**

Anti-tubercular drugs are the most auspicious prescription medication used for the treatment of cases of tuberculosis - an infectious disease with high mortality rate [29]. However, long- term administration of anti-tubercular drugs like rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (first line anti-tubercular drugs), significantly increase hepatotoxicity and induces liver injury in mammals [30]. The mechanism that precipitates anti-tubercular drug's liver damage maybe unclear, nevertheless, studies show significant increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities. Furthermore, lipid peroxidation, intracellular calcium (Ca2+) level and CYP4502EI activity also increases while GSH level, GPx and catalase activities decreases [31]. Recently, research shows that acetylators generate high level of acetylated drug which undergo further metabolism to yield other toxic intermediates which causes liver disruption, for instance, Isoniazid acetylation by N-acetyltransferase (NTA2) enzyme produces mono-acetyl hydrazine (MAH) that increases liver toxicity [32]. Notably, polymorphism at gene loci of NTA2, CYP2E1 and GST (detoxifying enzymes) modulate the activities of these enzymes and hence increases the risk of hepatotoxicity [33]. Studies have shown some administrable dose regimen of anti-tubercular drugs that can be used for biochemical evaluation, for example, intraperitoneal administration of 50 mg/kg BW of isoniazid, 100 mg/kg BW of rifampicin and intragastric administration of 350 mg/kg BW of pyrazinamide respectively. Also, when they are in combined form such as INH and RIF as well as INH, RIF and PZA induces hepatotoxicity. This observation was in agreement with previous work as reported by [34] that daily oral administration of isoniazid (15 mg/kg BW), rifampicin (20 mg/kg BW) and pyrazinamide (35 mg/kg BW) in combined form for 45 days, increases malondialdehyde level (MDA).

#### **2.8 Anti- retroviral drugs (ARDs)**

The therapeutic action of highly active antiretroviral drugs (HAART) like Protease inhibitors (PI), non-Nucleoside reverse transcriptase inhibitors (nNRTI) and Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI) used in the management of human immunodeficiency virus (HIV) undergo various pathways, nonetheless, their adverse effects are targeted/localised at the hepatic cells [35, 36]. Take for example, all anti-retroviral therapy-native (ART-naïve) like atazanavir or ritonavir and NRTIs (such as zidovudine or didanosine) alongside N-Apostolova Efavirenz (nNRTI) causes hepatic mitochondrial dysfunction and acute mitotoxic effect and oxidative stress respectively [37, 38]. Furthermore, administration of 50 μM of Efavirenz (EFV) can activate the activities of caspase-3 and caspase −9, trigger apoptotic mitochondrial intrinsic pathway and directly inhibit mitochondrial complex 1 subunit (MC1s) expression [39, 40]. The therapeutic efficacy of antiretroviral drugs is seen when used in combinations such as nNRTI and NRTIs but reports have documented that this combination produces deleterious effects on the mitochondria and also cause hepatic steatosis [41]. Another typical mechanism of action of some antiretroviral drug like stavudine (NRTI) is its ability to arrest cell cycle in growth phase (G1 phase) through upregulation of cyclic-dependent kinase inhibitor (CDKN2A) as well as p21 genes and inhibiting mitochondrial DNA replication [42].

#### **2.9 Anti-malarial drugs**

Amodiaquine (an anti-malarial drug) hepatotoxic effect is achieved in humans when it is being oxidised by liver microsomes and peroxidases, produces iminoquinone, (a reactive metabolite) which binds to proteins irreversibly, causing direct liver toxicity by disrupting the hepatocyte function [43].

#### **2.10 Anti-hyperlipidemic drugs**

This class of drugs act mainly by hepatocellular or mixed reactions and rarely by cholestatic reaction. The Niacin and Statin are the commonly used drugs in the treatment of hyperlipidemic conditions, however, they have potential to induce liver injury. Studies revealed that the administration of Lovastatin and Simvastatin in animal model (rabbits or Guinea pig) resulted in hepatocellular necrosis while Atorvastatin produced a mixed pattern of liver injury. It is noteworthy, that Simvastatin in combination with other drugs like flutamide, troglitazone and diltiazem gives a more pronounced hepatic effect and this has been attributed to the drug–drug interaction mechanism [1].

#### **2.11 Non-steroidal anti-inflammatory drugs (NSAIDs)**

The liver damaging effects of NSAIDs like acetylsalicylic acid ranges from elevated ALT, AST and ALP activities to acute cytolytic, cholestatic or mixed hepatitis as well as increases in bilirubin and prothrombin time. The mechanistic action of NSAIDinduced hepatotoxicity is unclear but both intrinsic (Aspirin and phenylbutazone) and idiosyncratic (Ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin) reactions have been documented [44]. Suggestively, hypersensitivity and metabolic aberrations are thought to responsible for liver injury. Unlike

*Drug-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.103766*

hypersensitivity reactions that are characterised by considerable anti-nuclear factor or anti-smooth muscle antibody titres as well as lymphadenopathy and eosinophilia, metabolic aberrations are caused by genetic polymorphisms, altering susceptibility to variety of drugs [45]. Diclofenac hepatotoxicity in humans and rats, for example, is linked to mitochondrial ATP synthesis impairment and the production of N-5 dihydroxydiclofenac (active metabolites), which causes cytotoxicity. Also, diclofenacinduced liver injury results in mitochondrial transition permeability (MTP), causing ROS formation, protein thiols production, mitochondrial swelling and oxidation of NADP+ (Nicotinamide adenine dinucleotide phosphate) respectively [45].

#### **2.12 Anti-hypertensive drug**

This anti-hypertensive drug called methyl dopa metabolises in the liver by Cytochrome P450, however, the oxidative reaction of methyl dopa by CYP450 produces superoxide anions (free radicals) to a reactive quinone or semi-quinone that binds tightly to the hepatic cells causing liver injury such as acute/chronic hepatitis and cholestasis with clinical evidence of elevated activities of ALT, AST and ALP respectively in the blood system [1].

#### **2.13 Azacytidine drug**

Azacytidine (or Azacitidine), is a pyrimidine nucleoside analogue of cytidine which is metabolised to a triphosphate molecule in the intracellular domain and then introduced into the RNA and DNA molecule firmly held together covalently by DNA methyltransferase 1(DNMT 1) - an enzyme that adds methyl to DNA molecule at the carbon 5 position of cytosine. Azacitidine has an anticancer effect but at low doses, it inhibits DNA methylation resulting in its deactivation leading to DNA hypomethylation shortly after cell division in the absence of DNMT1. The antineoplastic activity of this drug comes from its hypomethylation, leading to tumour suppressor gene (TSG) reactivation which is rapidly lost in myelodysplastic syndrome (MDS) – a disorder associated with clonal haematopoietic stem cell, caused mainly due to ineffective cellular maturation with side effects as peripheral blood cytopenia and abnormalities in functional blood cell. The cytotoxic effect of azacytidine is achieved when the product of its phosphorylation is incorporated into RNA molecule, thereby leading to an elevated level of CDKN2B - a gene that encodes the protein p15 (a cell growth inhibitor responsible for myeloid differentiation as well as tumour suppression) in their bone marrow [46, 47].

#### **2.14 Acetylcholinesterase inhibitors**

Administration of tacrine (a reversible cholinesterase inhibitor) in the treatment of Alzheimer disease, gives rise to an elevated ALT activity in the bloodstream, inferring that there is disruption in the integrity of the hepatocytes. Tacrine's mechanism of liver toxicity may be probably due to the inhibition of cholinesterase activity, resulting in the stimulation of cholinergic coeliac ganglion sensory (or afferent) sympathetic pathway, in which blood constricts, leading to impaired perfusion of the sinusoids and reperfusion injury-mediated by ROS [1].

Despite the basic biochemical indicators discussed above that are associated with drug-induced hepatotoxicity, recent studies have further identified other indicators and these are represented in **Table 1** as shown below:


**Abbreviations:** *IL (Interleukin), HO 1 (Heme oxygenase 1), TNFα (Alpha tumour nuclear factor), MT (Mitochondrial transition), MMP12 (Mitochondrial membrane permeability 12), NLRP3 (NOD-like receptor protein 3), MDA (Malondialdehyde), iNOS (Inducible nitric oxide synthase), COX 2 (Cyclo-oxygenase 2), NTA2 (N-acetyltransferase 2), HAT (Histone acetyltransferase), CYP (Cytochrome), ABCB1 (ATP binding cassette B1), NAD (Nicotinamide adenine dinucleotide), HLA (Human leucocyte antigen), CK (Creatinine kinase), HMG-CoA (Hydroxylmethylglutaryl Coenzyme A), anti-PLT (anti-platelet), SOD (Superoxide dismutase), CAT (Catalase), GST (Glutathione-Stransferase), GR (Glutathione reductase), GPx (Glutathione peroxidase), ALP (Alkaline phosphatase), HMGB1 (High mobility group box protein 1), SREBP2 (Sterol regulatory element binding protein 2).*

#### **Table 1.**

*Some recent findings on drug-induced liver toxicity.*

#### **3. Conclusions**

Drugs primarily serve as therapeutic agents in the treatment and management of various diseases, but over dependent or illicit consumption of drugs, results in hepatotoxicity which confers a detrimental effect on the liver's architecture and functions respectively. Our findings showed that drug-induced hepatotoxicity can cause liver inflammation (associated with excruciating pains), liver transplantation (economically burdensome) as well as death. As a result of these frightening effects outlined above, we hereby conclude that doctor's prescription guideline should be adhered to strictly, indiscriminate use of illicit drugs should be discouraged while regulatory bodies and law enforcement agencies should be empowered to prosecute drug offenders promptly.

#### **Acknowledgement**

The expertise of Professor Iheanacho Kizito, Department of Biochemistry, Federal University of Technology, Owerri is well appreciated.

*Drug-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.103766*

#### **Conflict of interest**

The authors declare no conflict of interest in this work.

### **Author details**

Godwin Okwudiri Ihegboro\* and Chimaobi James Ononamadu Department of Biochemistry and Forensic Science, Nigeria Police Academy, Wudil, Kano, Nigeria

\*Address all correspondence to: goihegboro@npa.edu.ng

© 2022 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.

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#### *Drug-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.103766*

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#### **Chapter 2**

## Oncological-Therapy-Associated Liver Injuries

*Victor-Mihai Sacerdoțianu, Costin-Teodor Streba, Ion Rogoveanu, Liliana Streba and Cristin Constantin Vere*

#### **Abstract**

Drug-induced liver injury (DILI) represents a large group of hepatic disease caused by various treatments, including oncological agents. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated. The most common liver disease patterns induced by oncologic therapy are steatosis and steatohepatitis, focal nodular hyperplasia, pseudocirrhosis, acute hepatitis, hepatic necrosis, immune-mediated hepatitis, cholestasis, fibrosis and cirrhosis, sinusal obstructive syndrome. In rare cases, chemotherapy treatment is associated with a high-risk hepatic adenoma or hepatocellular carcinoma development. It was demonstrated that the majority of chemotherapy classes can induce these effects on the liver, for example, alkylating agents, antimetabolites, and antitumor antibiotics, but also immunotherapy agents can be involved. The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/ or blood test abnormalities. Imaging techniques may be helpful in the diagnosis of oncological-therapy-associated liver injuries, for example, focal nodular hyperplasia, pseudocirrhosis, and sinusal obstructive syndrome. If liver disease occurs as an adverse effect of these agents, the recommendation to stop or continue the administration of oncologic treatment with close monitoring relies upon the risk and benefits of this medication.

**Keywords:** oncological therapy, immunotherapy, hepatic toxicity, adverse effects, chemotherapy-induced liver injuries

#### **1. Introduction**

Drug-induced liver injury (DILI) represents a large group of hepatic diseases caused by various therapeutical agents.

There are two types of DILI, with differences in pharmacologic mechanism and clinical onset patterns. The first type, the predictable one, named *intrinsic* or direct, is typically dose-related and affects a large proportion of exposed individuals if the safe amount is exceeded. It produces distinctive liver lesions, and the onset of clinical and laboratory abnormalities is usually after a short time after drug consumption, hours to days. The effects can be also reproduced using routine animal testing [1].

#### *Hepatotoxicity*

The second type of DILI, the unpredictable one, named *idiosyncratic*, affects only a small proportion of susceptible individuals exposed to various doses (not doserelated). It produces variable liver injuries, and the onset of clinical and laboratory abnormalities may begin from days to weeks after drug consumption. Usually, the effects cannot be reproduced using routine animal testing [2].

Even the acetaminophen consumption is the cause of the majority of DILI in the USA, in this chapter, our focus will be on injuries induced by oncologic treatment [3]. Despite the chemotherapy possibility of decreasing tumor size and stage, fighting against micrometastatic disease, and prolonging overall survival, it is associated with side effects. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated.

Several risk factors are associated with a higher incidence of adverse drug reactions, including DILI induced by chemotherapy. Host-related risk factors such as the old age, female sex, HLA class I allele A\*33:01, chronic liver disease, and drugrelated risk factors such as dose, site of metabolization, and lipophilicity, appear to influence the frequency of occurrence of oncologic treatment hepatic adverse effects. Identifying the risk factors for the development of liver injury after chemotherapy initiation can influence the treatment decision and also improve the patient outcome.

The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Elevation of alanine transaminase (ALT), aspartate transaminase (AST), conjugated and total bilirubin (TB), and international normalized ratio (INR) with low values of albumin is frequently revealed in these patients. Symptoms may be absent or nonspecific, or patients can present jaundice, encephalopathy, or coagulopathy manifestation.

DILI, which includes the liver injuries produced by oncological agents, is defined if one of the following criteria is present: (a) more than 5× upper limit of normal ALT value, (b) more than 2× upper limit of normal ALP value (often with the elevation of gamma-glutamyltransferase (GGT)), or (c) more than 3× upper limit of normal ALT value accompanied by more than 2× upper limit of normal TB level value. In practice, there are situations when patients presented with elevated values of the aforementioned blood tests before starting the potential liver harmful treatment, and in this case, the mean of these values replaces the upper limit of normal.


#### **Table 1.**

*DILI pattern with his associated biochemical blood tests and histological abnormalities, adapted after EASL clinical practice guidelines, 2019: drug-induced liver injury [2].*

The most recent guidelines of EASL (European Association For The Study Of The Liver) classified DILI in "hepatocellular," "cholestatic," or "mixed" types due to the pattern of changes in liver enzymes (**Table 1**) [2].

#### **2. Patterns of oncological-therapy-related liver injury**

The most common liver disease patterns induced by oncologic therapy are discussed below, and the agents frequently involved are listed in **Tables 2** and **3**.

#### **2.1 Steatosis and steatohepatitis**

NAFLD affects 10–39% of the global population, and only 2% of these patients are caused by drugs. A common effect of chemotherapy is to increase the amount of hepatocellular fat content. Two entities are described, steatosis and steatohepatitis, often known as chemotherapy-induced acute steatohepatitis, "CASH." Steatosis is defined by the accumulation of lipids within hepatocytes without inflammatory foci. Steatohepatitis is the lipid accumulation with concurrent inflammation of liver parenchyma on hepatocytes that appear enlarged (ballooning phenomes) and can lead to degeneration [4–6].



#### **Table 2.**

*Commonly used agents in chemotherapy and their associated liver-related side effects.*

Various therapeutic agents used in oncology can induce steatosis or steatohepatitis. Regimens that contain antitumoral molecules such as 5-fluorouracil, methotrexate, tamoxifen, irinotecan, L-asparaginase, oxaliplatin, mitomycin C, bleomycin sulfate, and dactinomycin were linked with fatty liver transformation [7, 8]. Usually, specific changes are detected after a period of 3–12 months of chemotherapy.

Treatments recommended for patients diagnosed with cancer contain not only antitumoral agents. Associated medication used in oncology can also induce nonalcoholic fatty liver disease. Glucocorticoids used for induction treatment of acute leukemia may cause macrovesicular steatosis [9].

A high number, up to 85%, of patients treated with regimens mentioned above develop CASH due to altered lipoprotein synthesis and therefore abnormal lipid metabolism. The development of steatohepatitis is based on an abnormal function of hepatocyte mitochondria and peroxisomes, inside which the process of oxidation of fatty acids (FAO) takes place. Several chemotherapy agents inhibit free fatty acids (FFA) β-oxidation, which promotes the accumulation of reactive oxygen species (ROS) and lipid peroxidation and increases oxidative stress in hepatocytes. All these processes lead to CASH. At the same time, lipid peroxidation stimulates stellate cell activation, fibrosis, and necrosis of hepatocytes.

#### *Oncological-Therapy-Associated Liver Injuries DOI: http://dx.doi.org/10.5772/intechopen.106214*


#### **Table 3.**

*Immunomodulatory agents in chemotherapy and their associated liver-related side effects.*

The intramitochondrial accumulation of tamoxifen leads to the inhibition of FFA β-oxidation, ATP synthesis, and cellular respiration. Another mechanism of steatosis and steatohepatitis is explained by the alteration of lysosomal phospholipid metabolism, which promotes the activation of the adenosine pathway and therefore increases FFA synthesis and also coenzyme A sequestration. This mechanism was observed in patients undergoing treatment with irinotecan and methotrexate. For methotrexate, the increased level of homocysteine due to impaired methylenetetrahydrofolate reductase leads to increased pro-inflammatory cytokines and hepatic stellate cell activation, which promote liver fibrosis. Increased expression of acyl-coenzyme A oxidase 1 (ACOX1) was observed for patients treated with 5-fluorouracil and irinotecan. Inhibition of mitochondrial FFA β -oxidation and

reduced expression of carnitine palmitoyl-transferase and ACOX1 induction were observed for irinotecan [10].

ACOX1 is the first limiting enzyme of peroxisomal FAO and may be increased as a response to decreased mitochondrial FFA β-oxidation. A high level of ACOX1 leads to increased expression of pro-inflammatory genes and a high amount of ROS, processes associated with immune cell infiltration. A hepatic steatosis liver can progress to steatohepatitis if contained hepatocytes own altered mitochondrial FFA β-oxidation and high amounts of ROS and inflammation. Mitochondria can be a direct target of every chemotherapy agent via cytotoxicity effect, and every agent can also have multiple pathways to induce steatosis or steatohepatitis [11].

Histologically, there are no marked differences between metabolic steatohepatitis and CASH. Even actually is rare recommended, if liver biopsy is performed on this patient, microvesicular steatosis is usually described. Distribution can be focal, multifocal, or diffuse. Macroscopic, fatty liver has a yellowish appearance and may be enlarged.

Recognition of this liver disease is important for adequate management that improves the prognosis. Usually, clinical manifestations of patients with chemotherapy-induced steatosis and steatohepatitis are subtle. Transaminase levels show elevation of ALT/AST. Steatosis and steatohepatitis liver is characterized by hyperechogenicity with posterior beam attenuation on transabdominal ultrasound examination. On computed tomography, a reduction in liver parenchymal attenuation can be observed when compared with the spleen. With high accuracy, magnetic resonance imaging can quantify the number of lipids in the liver due to spectroscopy and elastography available modes. A reduction in liver signal intensity is described in out-of-phase imaging for patients with steatohepatitis [12–14]. Delayed regeneration and prolonged liver disfunction were observed in oncologic patients with steatosis and more obvious with steatohepatitis, which was associated with a higher risk of postoperative hepatic failure, infections, and longer period of the intensive-care-unit stay [4, 15]. Repeated chemotherapy cycles are responsible for more severe inflammation, fact that worsens hepatocellular damage and leads to the development of fibrosis, cirrhosis, and liver failure [16, 17]. A limited CASH risk with the best oncologic treatment effects was observed for chemotherapy regimens with a maximum duration of 4 months [18].

For patients diagnosed with cancer, blood lipid and transaminase levels should be performed before initiation and regularly during oncologic treatment. Steatosis and steatohepatitis are in most cases reversible even though they can persist for a few weeks or months after treatment completion [7, 19]. Once the diagnosis was confirmed, the recommendation to stop or continue the administration of oncologic agents with close monitoring relies upon the risk and benefits of this medication. Healthy eating habits and limited high-fat alimentation are recommended to prevent increased blood lipid levels and worsening steatosis or steatohepatitis. Hepatoprotective drug administration, to prevent the worsening damage to the liver, is indicated [20].

Risk factors for CASH occurrence can be patient-related (metabolic syndromes, obesity, diabetes, dyslipidemia, alcohol abuse, preexisting chronic liver disease or hepatic location of the tumor, genetic polymorphism, gut microbiota, and chemotherapy history) or drug-related (cumulative or maximum dose of treatment or combination of more agents) [4]. Special attention is required for women with breast cancer with the A2 allele of CYP17A1 due to the associated increased risk of developing steatosis when treated with tamoxifen [21, 22].

#### **2.2 Focal nodular hyperplasia**

Focal nodular hyperplasia is the second most common benign hepatic lesion with unclear pathogenesis. Some explanations for this lesion may include a similar mechanism to focal sinusoidal obstruction syndrome [23].

Some agents used in oncology such as 6-thioguanine and oxaliplatin have an increased risk of inducing nodular hyperplasia and early fibrosis [24, 25]. Focal nodular hyperplasia is characterized by solitary or multiple lesions in liver parenchyma, which usually appear on CT as homogeneous, isodense, or mildly hypodense images. Contrast-enhanced CT shows arterial hyperenhancement, and late enhancement can be seen when a central scar is visible. These lesions may be incorrectly labeled as hypervascular liver metastasis. Characteristic MRI features for focal nodular hyperplasia are nonspherical shape lesions with imprecise margins and particularly hyperenhanced zones in the hepatobiliary phase for specific contrast agents. Signal isointensity on T1- and T2-weighted images, the absence of halo enhancement, and the absence of restriction to water diffusion in the echo-planar sequence are other characteristics that support the diagnosis of focal nodular hyperplasia [23, 26].

#### **2.3 Pseudocirrhosis**

Pseudocirrhosis is an imagistic term characterized by hepatic nodularity due to diffuse regenerative nodular hyperplasia but with insignificant fibrosis, different from the classic histopathological attributes of cirrhosis, features that appear after oncologic treatment initiation [27]. Pseudocirrhosis is associated with antineoplastic drugs used for the treatment of metastatic breast, colon, and pancreatic cancers. These agents are oxaliplatin, 5-fluorouracil, gemcitabine, capecitabine, irinotecan, methotrexate, and tamoxifen [28]. It can also appear in patients with carcinoid tumors and Hodgkin lymphoma.

Pseudocirrhosis can represent a cause of portal hypertension and even liver failure, but it lacks the typical clinical and paraclinical features of cirrhosis. The synthetic function of the liver is usually preserved.

On CT examination, pseudocirrhosis looks like macronodular cirrhosis with capsular retraction, diffuse nodularity, lower liver volume, and hypertrophy of the caudate lobe. For up to 9% of cases, signs of portal hypertension, including portosystemic shunts, can appear on imaging evaluation. The severe capsular retraction has been described in some cases of liver metastasis from breast cancer, and those must be excluded due to different treatments and prognoses that are associated with this stage [6, 23].

#### **2.4 Acute hepatitis**

Multiple oncological agents are involved in acute hepatitis occurrence, with highfrequency vinblastine, rituximab, etoposide, anastrozole, 6-mercaptopurine, 5-fluorouracil, lapatinib [6, 29, 30]. Even though not routinely indicated, if liver biopsy is performed on patients that underwent treatment with anastrozole, the histopathology report revealed necrosis of hepatocytes limited in acinar zone 3. This zone is related to P450 isoenzymes that are involved in drug metabolism. Histopathological report of liver biopsy of patients treated with lapatinib revealed portal-to-portal and portalto-central bridging necrosis and hepatocellular necrosis in acinar zone 1 [31, 32]. Etoposide-induced acute hepatitis is described as a viral hepatitis pattern [29].

Clinical manifestation of acute hepatitis can range from mild symptoms to illappearing patients. Usually, AST and ALT are markedly increased. Imaging findings are nonspecific and may include hepatomegaly with decreased attenuation, splenomegaly, wall thickening of gallbladder, ascites, and periportal edema. Severe forms of acute hepatitis appear in patients with prior chronic hepatitis B or C due to reactivation when treated with rituximab. Patients with MHC class II alleles HLA-DQA1∗02:01, DQB1∗02:02, or DRB1∗07:01 are at high risk of liver injury if receiving regimens with lapatinib [6, 33].

Acute hepatitis induced by anticancer treatment rapidly improved after drug withdrawal. Liver enzymes and bilirubin return to normal values after a few months of treatment discontinuation [5].

#### **2.5 Hepatic necrosis**

Acute liver failure due to hepatic necrosis is a major and worrisome complication of chemotherapy-induced liver injury. Oncologic agents that produce acute hepatitis are more likely to cause hepatic necrosis. Mithramycin, etoposide, and dacarbazine are some of these offending drugs. Mithramycin also known as plicamycin is an antineoplastic antibiotic that has been reported as the most hepatotoxic chemotherapeutic drug capable of causing liver necrosis. Histopathologic reports of the hepatic biopsy reveal centrilobular necrosis.

Clinically, patients with hepatic necrosis develop acute encephalopathy with deterioration of liver synthetic function. Almost all patients receiving plicamycin have increased levels of LDH, aminotransferases, and alkaline phosphatase with normal values of bilirubin. These modifications occur on the first day of treatment, reach the maximum level the next day, and then decrease to normal 3 weeks after treatment cessation. When severe necrosis develops, a computer tomography scan reveals a substantial decrease in the enhancement of liver parenchyma and cystic appearance [6, 34, 35].

#### **2.6 Immune-mediated hepatitis**

Metastatic melanoma, non-small-cell lung cancer hepatocellular carcinoma, and urothelial carcinoma are types of cancer that benefit from immunotherapy agents' efficacy. Side effects are not rare for this class of treatment and are named immunerelated adverse effects, including the liver with immune-mediated hepatitis [36].

Immune checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Monoclonal antibodies against these targets are ipilimumab against CTLA-4, pembrolizumab, nivolumab against PD-1 and atezolizumab, avelumab, and durvalumab against PD-L1. From this list, the higher hepatotoxicity was found for CTLA-4 inhibitors, ipilimumab. Patients diagnosed with metastatic melanoma develop immune-mediated hepatitis in 2–9% of cases if they are treated with ipilimumab, and if dacarbazine is associated, the percentage rises up to 31.6% [37, 38].

Immunotherapy contains agents that increase the host's immune system to fight against tumors, but the subsequent uncontrolled T cell activation is responsible for hepatotoxicity and liver disease. Liver biopsy revealed diffuse T-cell infiltrate, eosinophil infiltration, portal, and periportal inflammation, and spotty or confluent necrosis [39–41]. Usually, patients are asymptomatic and, in rare cases, fevers, malaise, or symptoms related to fulminant liver failure can be present. Elevation in serum of ALT, AST, and bilirubin occurs especially after ipilimumab. Anti-nuclear, anti-smooth muscle, or other autoimmune hepatitis antibodies are negative. These clinical and paraclinical abnormalities occur from 6 to 14 weeks after immunotherapy initiation or after three doses of this regimen [42, 43]. Some risk factors contribute to a higher chance of liver injury development: a higher dose of treatment, multiple agents association, preexisting liver disease, or autoimmune diathesis [44].

Treatment with corticosteroids or mycophenolate mofetil is indicated for patients with important hepatotoxicity after immunotherapy for cancer [39]. HLA-DRB1\*07:01 allele is associated with an increased risk for lapatinib liver injury. Infliximab should not be indicated due to the risk of hepatotoxicity [45, 46].

#### **2.7 Cholestasis**

Chemotherapeutic regimens include kinase inhibitors (e.g., erlotinib, sorafenib, nilotinib), thiopurines (6-mercaptopurine and azathioprine), estrogens, 5-fluorouracil, cytarabine, interleukin-2, alkylating agents (chlorambucil, cyclophosphamide, cisplatin), and mitomycin are associated with cholestatic liver injury [29, 35].

Thiopurines cause a variety of DILI phenotypes that can be intrinsic or idiosyncratic with a mixed or cholestatic form of hepatic injury [47]. Intrahepatic cholestasis is the most frequent type of injury in patients undergoing treatment with 6-mercaptopurine (frequently when the daily dose exceeds 2 mg/kg). Azathioprine may produce hepatic injury, but less frequently than 6-mercaptopurine, and this one has been related to a mild form of liver toxicity; however, long-term use can cause cholestatic liver disease [35].

Significant hepatotoxicity has been linked to fluorodeoxyuridine, a metabolite of fluorouracil that was previously administered through the hepatic artery to patients with hepatic metastases from colorectal cancer. In several cases, the treatment has been linked to irreversible intrahepatic and extrahepatic biliary strictures. Monitoring of aminotransferases helps with identifying the right time for drug discontinuation when the liver is suffering [29].

Interleukin-2 therapy is used in melanoma and renal cell cancers, and a lot of patients undergoing this treatment can develop a deep and reversible intrahepatic cholestasis with increased serum levels of biochemical markers of cholestasis. Some potential physiopathological mechanisms may include chemical hepatitis and biliary sclerosis. Allopurinol can block xanthine oxidase involved in drug metabolism, which rises hepatotoxicity. Histologically features of this hepatic injury appear as cholestasis with variable hepatocellular necrosis. Laboratory tests show elevated levels of bilirubin, alkaline phosphatase, and aminotransferases. Jaundice is the clinical feature that is associated with this type of hepatotoxicity [6]. In conclusion, cholestasis is induced by a multitude of antineoplastic drugs and withdrawal usually leads to recovery of the liver and jaundice disappearance [29].

#### **2.8 Fibrosis and cirrhosis**

Liver fibrosis and cirrhosis induced by chemotherapy are usually associated with alkylating agents, 6-thioguanine, and methotrexate.

Methotrexate is a folic acid antagonist that inhibits the proliferation of certain body cells, particularly those that are multiplying rapidly such as tumor cells, bone marrow cells, and skin cells. Long-term methotrexate treatment, commonly used to treat severe psoriasis or rheumatoid arthritis, can induce hepatic fibrosis, which leads to cirrhosis without producing significant symptoms [48]. The use of methotrexate as maintenance therapy in children with acute leukemia was related to fibrosis and cirrhosis development in multiple cases [49, 50]. Furthermore, cirrhosis induced by methotrexate has led to the transplantation of the liver in an important number of patients. Hepatic stellate cells have a central role in the physiopathological mechanism. The hepatic test may be normal or ALT can be temporarily increased. In rare cases, a liver biopsy may be necessary to confirm the diagnosis [29].

Patients who receive treatment with methotrexate need rigorous monitoring, especially those who have both obesity and diabetes [51]. It has been demonstrated that folic acid may reduce hepatic injury [29].

#### **2.9 Sinusal obstructive syndrome**

Previously named veno-occlusive disease, sinusoidal obstruction syndrome is the last step of hepatic sinusoidal injury evolution. The most exposed are patients who receive cytoreductive chemotherapy combined with radiotherapy or are in the setting of bone marrow transplantation [52].

Cyclophosphamide, oxaliplatin, irinotecan, 5-fluorouracil, 6-mercaptopurine, dacarbazine, vincristine, mitomycin-C, cytarabine, busulfan are chemotherapy agents involved in hepatic sinusoidal injury [53–58]. Usually, sinusoidal obstruction syndrome occurs 5 weeks or later after administration of the aforementioned agents [23].

Direct injury of endothelial cells that lined the hepatic sinusoids is the mechanism of this type of disease. Endothelial injury promotes erythrocyte extravasation and aggregation into space of Disse, which impairs venous outflow. This leads to sinusoidal congestion. The next step is a fibrotic reaction due to hepatic stellate cell activation, which leads to presinusoidal collagen deposit and central venules obstruction with sinusoidal obstruction syndrome development and centrilobular necrosis. Increased activity of matrix metalloproteinase 2 and 9 may facilitate this process [59, 60].

No direct hepatocellular function alteration was observed for this entity [61, 62]. Histological findings vary from hepatic sinusoidal dilatation to subendothelial fibrin deposits associated with centrilobular necrosis of hepatocytes and low grades of nodular regenerative changes. The macroscopic liver had a bluish marbled appearance. Due to the area affected, sinusoidal obstruction syndrome can be classified into mild, moderate, or severe if less than 1/3, 1/3–2/3, or more than 2/3 of the lobule was affected [7, 63]. There are three phases of sinusoidal obstruction syndrome: acute, subacute, and chronic. Patients may present painful hepatomegaly, short periods of jaundice, weight gain, and encephalopathy. Some patients have splenomegaly and ascites due to portal hypertension. Transient elevation of transaminases and bilirubin can be revealed on blood tests [64, 65].

Transabdominal ultrasound revealed hepatosplenomegaly, decreased flow in portal vein on Doppler mode, ascites, and gallbladder wall thickening. In the hepatobiliary phase of gadoxetic-acid-enhanced MRI, sinusoidal obstruction syndrome can present a diffuse heterogenous reticular pattern. CT and MRI findings also include narrowing of main hepatic veins [66, 67].

Viral hepatitis, Budd-Chiari syndrome, or other forms of DILI must be excluded before sinusoidal obstruction syndrome diagnosis. The evolution of persistent sinusoidal obstruction syndrome is represented by progression to regenerative nodular hyperplasia followed by fibrosis and cirrhosis development. Also, sinusoidal obstruction syndrome can impair chemotherapy response and liver regeneration after resection, which worsens prognosis. Patients with hepatitis C infection, stem cell

*Oncological-Therapy-Associated Liver Injuries DOI: http://dx.doi.org/10.5772/intechopen.106214*

transplant recipients, and those treated for Hodgkin lymphoma are more susceptible to developing sinusoidal obstruction syndrome after specific chemotherapeutic regimens. In addition, patients with colorectal cancer with hepatic metastasis are more susceptible to sinusoidal obstruction syndrome development if the oxaliplatin or irinotecan treatment is combined with 5-fluorouracil [57, 58, 68].

Sinusoidal obstruction syndrome changes can be reversible after cessation of chemotherapy. Supportive therapy and administration of bevacizumab or defibrotide sodium can reduce liver injury and may improve the efficacy of systemic treatment. Delaying surgery for patients with suspected sinusoidal obstruction syndrome can be an option [69].

Except for the patterns discussed above, other chemotherapy-induced liver disease exists, with a low frequency. For example, estrogens, which are used for advanced prostate cancer, are associated with a high risk of peliosis hepatitis, hepatic adenoma, or hepatocellular carcinoma development [70].

Despite the pattern of liver disease induced by oncologic agents administration, a correct diagnosis and management may reduce the hepatic damage and improve the prognosis of these patients.

#### **Acknowledgements**

This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS—UEFISCDI, project number PN-III-P1-1.1-TE-2019-1474, within PNCDI III.

#### **Author details**

Victor-Mihai Sacerdoțianu1 , Costin-Teodor Streba1,2\*, Ion Rogoveanu1 , Liliana Streba<sup>3</sup> and Cristin Constantin Vere1

1 Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania

2 Department of Pulmonology, University of Medicine and Pharmacy of Craiova, Romania

3 Department of Oncology, University of Medicine and Pharmacy of Craiova, Romania

\*Address all correspondence to: costinstreba@gmail.com

© 2022 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.

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## **Chapter 3** Paracetamol-Induced Hepatotoxicity

### *Nida Mirza*

#### **Abstract**

Drug-induced hepatotoxicity is common in clinical settings, one of the commonly used drugs leading to liver injury is paracetamol. It is a commonly used analgesic and antipyretic drug. The toxicity of paracetamol has been described in accidental, iatrogenic, and intentional ingestion; also, the extent of liver injury varies from person to person depending on host factors, nutritional status, age, etc. The toxicity of paracetamol is not usually recognized by clinicians as initially, the symptoms are subtle. There is a specific antidote available for paracetamol-induced liver injury to prevent acute liver failure; however, it needs to be given time for proper action, therefore a strong clinical suspicion is to be taken when there is no proper history of ingestion.

**Keywords:** paracetamol, N-acetyl cysteine, drug-induced liver injury

#### **1. Introduction**

The liver contributes significantly to the metabolism and removal of drugs from the human body [1]. Metabolization of drugs and xenobiotics to nontoxic substances in the liver by enzymes is important for the proper function of the body, alteration in these statuses leads to a shift of metabolism toward the production of oxidants, which coheres to lipids or nuclear proteins which results in mutations, membrane damage, and alteration of enzyme activity respectively which further leads to organ malfunction. The production of oxidants is the most common action in the pathogenesis of liver damage by pharmaceutical drugs and herbal products [2]. Liver damage may occur due to environmental toxicants, drugs, and microbial metabolites. There are two sets of enzymes, phase I and phase II enzymes which play a very important role in the metabolism and detoxification of various drugs and other toxins. Paracetamol is one of the most commonly used drugs as an analgesic and antipyretic, it is a structural analog of phenacetin, which was withdrawn due to concerns for nephrotoxicity. Paracetamol is relatively safe compared with other NSAIDS; however, overdose can cause a spectrum of liver injuries from mild elevation in liver enzymes to acute liver failure and encephalopathy [3]. A lot of research has been conducted to know the pathogenesis of paracetamol-induced liver toxicity. N-acetyl cysteine (NAC) is used as an antidote for paracetamol-overdosed patients; however, it should be administered as early as possible [4]. It has now been recognized that paracetamol toxicity consists of multiple pathways, including paracetamol metabolism, oxidative stress, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and compensatory liver repair and regeneration. Some patients with liver

failure require liver transplantation for survival [5]. In this chapter, we have discussed the paracetamol-induced hepatotoxicity, pathophysiology, and factors that increase the risk of its toxicity, prevention, treatment, and patient outcome.

### **2. Epidemiology and pathogenesis**

#### **2.1 Incidence of hepatotoxicity**

Paracetamol overdose is among one of the commonest causes of acute liver failure in some countries. The common settings for paracetamol-induced liver injury are suicidal overdose, unintentionally or accidentally in alcoholics, and with therapeutic use [6]. Studies done in the adult population have shown the most common etiology of acute liver failure (40%) was paracetamol overdose, more with unintentional intake rather than taken for suicide [7, 8]. However, a multicenter prospective study of pediatric patients reported that only 14% of acute liver failure is attributed to paracetamol overdose [9]. In a study on patients with an unintentional overdose of narcotic users, around 30% of patients were also taking over-the-counter paracetamol along with narcotic drugs. Patients sometimes are not knowing that their pain-reliving medicines advised by a physician are in combination with paracetamol and thus may take these medications along with oral over-the-counter paracetamol resulting in overdose. Due to delayed presentation and treatment, risk of mortality is comparatively more with unintentional overdose rather than intentional overdosage [10]. In 19% and 12.5% of indeterminate ALF, paracetamol-protein adducts were identified [11, 12]. In chronic alcoholics, paracetamol-induced hepatotoxicity has been well recognized and reported to occur at lower doses compared with non-alcoholics [13, 14]. In a study on chronic alcoholics with paracetamol hepatotoxicity, the average toxic dose of paracetamol was 7 g per day; however, a lower dose of 2.5 g per day has also found to cause toxicity [15]. Paracetamol hepatotoxicity had been found with ingestion of therapeutic doses in individuals with malnutrition, advanced age, chronic pulmonary diseases, cardiac dysfunction, and chronic liver disease [16]. Drug interactions of paracetamol with other drugs (e.g., anticonvulsants, antitubercular) also result in hepatotoxicity at lower doses [17, 18].

#### **2.2 Toxic dose in adults and children**

In single oral ingestion, the toxic dose for children is more than 200 mg/kg of body weight, whereas in adults and adolescents, it is more than 7.5 g. In children younger than 6 years of age, toxicity occurs after ingestion of more than 75 mg/kg body weight per day. Acute toxic dose is in a single dose in repeated dosing [19], However, toxic dose also varies in different ethical groups like in Japanese lower doses may cause intoxication [20]. Children are found to be less sensitive to acute intoxication than adults, and this may be due to larger glutathione stores and comparatively larger liver [21].

#### **2.3 Pathophysiology**

Paracetamol enters the enterohepatic circulation after absorption in the gut and the liver by glucuronidation and sulfation 95% of its metabolized, and only a small amount of the drug is removed by the kidneys. In therapeutic doses, 2.7 hours is the mean elimination half-life of paracetamol ingestion [22]. N-acetyl-p-benzoquinone

#### *Paracetamol-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.104729*

imine (NAPQI) is formed by oxidation reaction in approximately 5% fraction of the drug, and this further binds to cysteine, DNA, and lipids. Antioxidant glutathione (GSH) detoxifies NAPQI by forming a mercapturic metabolite, which is removed by the kidneys (**Figure 1**). On ingestion of a higher dose of paracetamol, intracellular GSH is depleted and there is a relative shunting of the metabolism of paracetamol toward oxidation, thus forming increased amounts of NAPQI. CYP2E1 has a primary role in the oxidation of paracetamol; however, some other CYP isoforms have been identified, including CYP3A4 and CYP1A2. A major portion of CYP2E1 is distributed in the centrilobular regions of the hepatic lobule, leading to centrilobular necrosis as seen on biopsy [23]. The greatest intrinsic activity toward paracetamol is of CYP2E1 and CYP3A among all known CYPs. Studies conducted in the mouse model of paracetamol overdose showed paracetamol adduct formation occurs in centrilobular hepatocytes [24] liver biopsy if done, the histopathology of liver tissue shows centrizonal necrosis and mild inflammation [25]. The main autopsy finding in those who died due to liver failure is centrizonal hemorrhagic necrosis with no or little inflammatory reaction and normal histologic appearance of portal tracts [26].

### **3. Clinical manifestations and laboratory findings**

Paracetamol overdose identification is of significant value as an early start of treatment can prevent morbidity and mortality significantly. Many a times, patients may not tell the information about paracetamol ingestion and exact dosage. The most common symptoms are malaise, nausea with/without vomiting, and abdominal pain, as these symptoms are not peculiar leading to difficulty in making the diagnosis in absence of a history of overdose. The clinical course of paracetamol hepatotoxicity has four established sequential phases [27]. Each phase usually occurs following a fixed time interval after the paracetamol over-ingestion; however, these may be modified by factors like the formulation (mixed with opiate preparations, sustained release, etc.), co-ingestion (alcohol, herbal supplements, or other pharmaceutical drugs), and presence of chronic liver disease. The first phase starts within the first

24 hours of intake of the drug and usually has symptoms such as nausea, vomiting, muscle aches, dullness, and perspiration. However, some patients may remain asymptomatic in this phase, which leads to a delay in the diagnosis in patients who are unaware of their overdose. Biochemically liver transaminase values are usually normal in this phase. In the second phase that occurs 24 hours to 72 hours after intake, transaminases and bilirubin begin to rise and prothrombin time may be prolonged [28, 29]. Liver transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] may rise to several thousand IU [30]. There are lesser increases in alkaline phosphatase and bilirubin. In phase III that occurs 72 hours to 96 hours after ingestion, liver injury occurs maximally in this phase and is characterized by continued progression of hepatotoxicity, possibly fulminant hepatic failure, and the onset of multiorgan system failure and hypoglycemia, jaundice, oliguria, acute tubular necrosis, encephalopathy, coagulopathy and lactic acidosis, central nervous system symptoms including confusion, somnolence, or coma. The risk of mortality is maximum in the third phase, mostly due to multi-organ dysfunction. There is a "two-hit" mechanism in the development of lactic acidosis one is that NAPQI in excess causes mitochondrial dysregulation, which is further followed subsequently by tissue hypoxia and decreased hepatic metabolism and clearance of lactate [8, 31]. Phase IV occurs after approximately 96 hours after the recovery from the third phase, the patient may either die from liver failure and its complications or start to recover. Those who improve liver functions usually return to normal within three weeks, with the histological improvement of the liver within 3 months. Usually, the fourth phase lasts for 1 to 2 weeks, but its duration varies from patient to patient. Aminotransferase elevations usually resolve within two weeks duration. An early signal of severe toxicity is prolonged prothrombin time within 30-hour of paracetamol ingestion [32]. Usually, bilirubin levels do not go higher as compared with liver failure due to other etiology [33]. Acute renal failure may occur in association with hepatotoxicity and also can occur as the liver injury is improving and some may even need dialysis [34–36]. A distinguished feature of paracetamol overdose in chronic alcoholics is seen in which laboratory abnormalities may include extremely high serum aminotransferase levels (AST > ALT) and prolonged prothrombin time within a small time frame of ingestion [37].

#### **3.1 Kings college criteria**

King's College criteria are used for mortality prediction in ALF caused by paracetamol. The criteria include the presence of metabolic acidosis (arterial pH < 7.30) alone OR the presence of these three: Grade III or IV hepatic encephalopathy (HE), prothrombin time (PT) > 100 sec, and creatinine level > 3.4 mg/dL [38].

#### **4. Treatment**

#### **4.1 General management**

On assessment of paracetamol overdose, a detailed history should be taken, which should include ingested dose, co-intake of other pharmaceutical drugs or herbal medications, alcohol intake (acute and chronic), presence of any liver disease or disorder, and any other co-morbidity. Biochemical parameters including serum AST,

#### *Paracetamol-Induced Hepatotoxicity DOI: http://dx.doi.org/10.5772/intechopen.104729*

ALT, bilirubin, prothrombin time, blood urea nitrogen (BUN), creatinine, electrolytes, complete blood count, and urinalysis should be done. The plasma paracetamol levels should be sent for measurement ideally 4 hours after ingestion or as early as 24 hours, but not before 4 hours because continuous absorption of paracetamol leads to falsely low levels. The test should be repeated after 4 hours of the first test and then at 16, 24, and 32 hours after ingestion. Management for paracetamol overdose includes prevention of absorption from the gut, elimination of absorbed paracetamol from the blood, inhibition of formation of toxic metabolite NAPQI, and detoxification of NAPQI. The timing of presentation and the degree of hepatic decompensation guide the choice of therapy. Gastric lavage, administration of activated charcoal, and ipecacuanha (induces emesis) can prevent or decrease gut absorption within the first few hours after ingestion [39, 40]. NAC is used as an antidote in paracetamol overdose, and if initiated within the first 8 hours from the time of ingestion or overdose, a good response is seen. Methionine and cysteamine also cause detoxification of NAPQI, but have shown severe adverse central nervous system effects so not used commonly [41]. It has been found that starting NAC therapy as late as 36 hours after overdose leads to a significantly better outcome in paracetamol hepatotoxicity [42]. NAC acts by restoring glutathione levels (hydrolyzed to cysteine, which restores glutathione), attaching to NAPQI and by increasing conjugation reaction in hepatocytes leading to the formation of non-toxic products [43]. Mortality from paracetamol overdose had declined from 5% without the use of antidote to 0.7% with the use of NAC. Cimetidine was used initially to prevent the formation of NAPQI as it inhibits cytochrome P450 but was not effective in many trials [44, 45]. Liver transplantation should be considered to prevent mortality in selected cases.

#### **4.2 N-acetylcysteine**

The standard dosage of oral NAC is a single dose of 140 mg per kg and after that 17 doses of 70 mg per kg over 72 hours. The total dose thus will be 1330 mg/kg. The standard dosage of intravenous NAC is typically three weight-based doses; the first dose is 150 mg per kg in the first 1 hour, the second dose is 50 mg per kg to be given over 4 hours, and lastly, third dose is 100 mg per kg to be given over 16 hours [46]. Higher hepatic concentrations can be achieved by oral NAC therapy, and the only issue is that it is unpalatable, also difficult for children to consume so many doses, and may cause vomiting. Intravenous N-acetylcysteine therapy results in higher plasma concentrations and is more convenient for those who are vomiting; side effects of parentally given NAC can be an allergic reaction, which is mostly mild and treated by antihistaminics and by temporarily stopping intravenous NAC [47].

#### **4.3 The Rumack: Matthew nomogram**

The Rumack–Matthew nomogram is the semilogarithmic plot of plasma paracetamol levels with time and is used to assess potential hepatotoxicity. This nomogram was developed retrospectively based on data from patients who has single paracetamol overdose and acute ingestions of paracetamol and had not received treatment with the antidote. The nomogram forecasts potential toxicity from 4 hours to 24 hours following ingestion. The upper line of the nomogram is the "probable" line, also known as the Rumack–Matthew line (**Figure 2**). Around two-third of a patient with paracetamol levels above this line will have a liver injury. The lower line is the

#### **Figure 2.**

*Rumack–Matthew nomogram: Serum paracetamol concentration vs. time post ingestion. Taken from Rumack and Matthew [48].*

"possible" line and includes a 25% margin of error in level estimation discrepancy or unreliable ingestion time. Using the Rumack–Matthew nomogram patients treated with supportive care only who had paracetamol levels above the probable hepatic toxicity line had a 14–89% incidence of hepatotoxicity and a mortality of 5–24% [49, 50]. Poor prognostic signs identified are age group >50 years a plasma factor V concentration < 10% of normal [51].

#### **4.4 N-acetylcysteine dosing and Rumack–Matthew nomogram**

In a case of single ingestion of paracetamol overdose, obtain paracetamol concentration at as early as possible but not before 4 hours. If the paracetamol concentration on the Rumack–Matthew nomogram is above the "treatment line" (the line connecting 150 μg/mL [993 μmol/L] at 4 hours and 4.7 μg/mL [31 μmol/L] at 24 hours), administration of NAC is indicated. If time of ingestion is not known exactly, then it is less than 24 hours post-ingestion NAC should be started, if plotted above treatment line. In a case where patient has ingested extended-release formulations or co-ingested with other drugs like opioids, anticholinergics, or other medications that slows gut motility, if the initial 4-hour concentration plots above the treatment line, NAC should be initiated within 8 hours post-ingestion [52].

#### **4.5 Management for acute liver failure**

Acute liver failure is defined as severe acute liver injury for fewer than 26-week duration with encephalopathy and impaired synthetic function (INR >1.5 or higher) in a patient without pre-existing liver disease. ALF can lead to multiorgan dysfunction, which can present as hypotension, acute renal failure, coagulopathy, encephalopathy, sepsis, and cerebral edema. Intensive care is needed for patient with acute liver failure as they may deteriorate rapidly. A proper centra venous line and arterial line for hemodynamic monitoring and, as well as a urinary catheter for urine output monitoring. Coagulation parameters, blood counts, metabolic panels, blood sugar, and arterial blood gases are to be measured with proper time intervals. The neurological status should be evaluated regularly, for cerebral edema and intracranial pressure monitoring when intracranial hypertension is identified [53, 54]. Patient should be admitted in intensive care unit in presence of encephalopathy and coagulopathy. Due to risk of rapid deterioration, a proper communication with liver transplant centers should be done and transfer decisions should be considered for those who had rising INR, rising creatinine or decreasing urine output, metabolic acidosis, hypotension, or/and encephalopathy [55]. Retrospective study showed treatment after 10–36 hours with NAC was associated with a mortality of 37% when compared with 58% in patients given supportive treatment only, while prospective study with 50 patients with established liver failure showed mortality was 20% in the treated group versus 48% *(P* < 0.05) in the controls [56, 57]. Liver transplantation is another therapeutic option for patients with paracetamol-induced fulminant hepatic failure. Early recognition of poor prognostic factors can be useful in determining need for transplant and providing time to obtain a donor. Many factors affect survival, and the development of ALF after paracetamol overdose ALF in pediatric patients had 100% survival with grade II, but only 18% with grade III, also the development of cerebral edema reduced survival to 22% [58]. Significantly better survival is reported for patients who sought medical care within 24 hours of ingestion compared with later presentation. The overall mortality is as high as 28% for patients who develop ALF from paracetamol overdose, which is better than rates for ALF due to other causes. Reported survival rates for paracetamol-induced ALF vary from 65–73% without liver transplantation. Requirement of inotropic support is a poor survival factor and survival rate is below 10% in patients with metabolic acidosis that failed to respond to adequate fluid resuscitation [59]. Serum creatinine concentrations and PT are closely correlated with survival. Survival rate of 80% patients for peak PT below 90 seconds, which reduces to 8% around for PT beyond 180 seconds [60]. Survival rate is around 65% for patients with serum creatinine below 100 mmol/L, which reduces to 23% if above 300 mmol/L. Requirement of liver transplantation was less in paracetamolinduced ALF than ALF due to other causes [61]. In a recent study, overall survival rate after liver transplantation was about 70%, with 1-year survival of 73% after 1 year and 67% at the end of 5 years. Multiorgan failure and neurologic complications are attributed for most of the deaths after liver transplantation [62].

#### **5. Conclusion**

The morbidity and mortality from paracetamol overdose vary from patient to patient, and also depend on underlying comorbidities, nutritional status, history of alcoholism and co ingestion of other drugs. Overdose nay result in mild liver injury, clinically significant hepatotoxicity, or death, and timely administration of antidote directs prognosis. Death from paracetamol overdose in developed countries has decreased to 1–2% after the use of N-Acetyl cysteine, which was previously much higher (6–25%).

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Nida Mirza Sri Aurbindo Institute of Medical Science, Indore, India

\*Address all correspondence to: nydamirza.1@gmail.com

© 2022 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.

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