3.5. Clinical manifestations

The mechanisms of drug-induced liver injury are related with the clinical manifestations. The main clinical-pathological manifestations of hepatotoxicity and its histological findings include [6, 24, 26, 39]


appetite, besides, signs like hepatic encephalopathy or increase in hepatic enzyme levels,

Acute hepatitis Acetaminophen, allopurinol, carbamazepine, diclofenac, phenytoin, ibuprofen,

Cholestatic hepatitis Phenytoin, amoxicillin-clavulanate [39], carbamazepine, chlorpromazine [6, 15]

Granulomatous hepatitis Allopurinol, aspirin, carbamazepine, chlorpromazine, diltiazem, hydralazine,

Macrovesicular steatosis glucocorticoids and methotrexate [26], steroids, nitrofurantoin, gold, methotrexate, ibuprofen, indomethacin, sulindac, metoprolol [6]

Cholestasis Anabolic steroids [6, 39], estrogens, contraceptive steroids [2, 26]

atorvastatin [26] Fulminant hepatitis Lamotrigine, nimesulide, isoniazid, clarithromycin [40]

Vanishing bile duct syndrome Sulfonamides, beta-lactams [39], carbamazepine [2]

sulfasalazine [6, 26, 40]

Microvesicular steatosis tetracycline, valproic acid, zidovudine, minocycline [6, 9, 26]

Chronic hepatitis Methyldopa, isoniazid, phenytoin [40], amoxicillin-clavulanic acid, bentazepam and

isoniazid, naproxen, metoprolol, piroxicam, pyrazinamide, valproic acid [2, 39, 40]

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nitrofurantoin, penicillin, phenylbutazone, phenytoin, pyrazinamide, quinidine,

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 impairment, 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) [8, 10, 18, 19]. In addition, a recent study shows that among intravenous drugs, antibiotics and antineoplastic are the pharmacological groups

A structured review in PubMed/Medline was made using the terms: "liver disease" and/or "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; this review excluded articles reporting hepatotoxicity related with other agents different to drugs, any liver disease, reports of clinical trials about predictive patterns of injury or studies of stem cells. Then, some information was extracted regarding: expression of hepatotoxicity, type of injury, mechanisms of hepatotoxicity, risk factors and clinical manifestations. To assess the probability of occurrence of hepatotoxicity and the type of injury, three categories were established: definite, probable and possible probability, according to evidence [42]. To report

making the identification of liver toxicity difficult.

Steatohepatitis Amiodarone, tamoxifen [6, 9, 36]

Table 1. Clinical patterns caused by drugs.

most associated with hepatic toxicity [41].

3.6. Hepatotoxic drugs

Clinical pattern Drugs


Many drugs have a specific pattern of injury in the liver but in some cases, the same drug can generate different patterns in the patients, the patterns and the drugs that cause them are presented in Table 1.

Many of these manifestations are accompanied by unspecific symptoms like discomfort, fever, nausea, vomiting, abdominal pain, jaundice, dark urine, pale stools, pruritus, loss of weight or


Table 1. Clinical patterns caused by drugs.

appetite, besides, signs like hepatic encephalopathy or increase in hepatic enzyme levels, making the identification of liver toxicity difficult.

### 3.6. Hepatotoxic drugs

• Concomitant administration of drugs or herbal remedies: becomes a risk factor because it

• Previous or underlying hepatic diseases: may increase the risk of hepatotoxic agents [38]. • Genetic factors: related with genetic polymorphism in cytochrome P450 can unchain a

The mechanisms of drug-induced liver injury are related with the clinical manifestations. The main clinical-pathological manifestations of hepatotoxicity and its histological findings include

• Acute hepatitis: caused by a wide variety of drugs and characterized by parenchymal inflammation, necrosis and Kupffer cells in sinusoids, which include symptoms like

• Chronic hepatitis: characterized by persistent biochemical abnormalities beyond 6 months;

• Fulminant hepatitis: also called acute liver failure may cause death and its manifestations

• Cholestatic hepatitis: manifested by mixed hepatocellular and cholestatic injury accompa-

• Cholestasis: caused by bile plugs; include symptoms like jaundice and pruritus is charac-

• Vanishing bile duct syndrome: presented by a paucity of bile ducts; inflammation and

• Granulomatous hepatitis: presence of granulomas in portal tracts or parenchymal, accom-

• Steatohepatitis: is the presence of fat in hepatocytes accompanied by inflammation and

• Macrovesicular steatosis: characterized by the presence of medium- or large-sized fat

• Microvesicular steatosis: characterized by the presence of small-sized fat droplets in the

Many drugs have a specific pattern of injury in the liver but in some cases, the same drug can generate different patterns in the patients, the patterns and the drugs that cause them are

Many of these manifestations are accompanied by unspecific symptoms like discomfort, fever, nausea, vomiting, abdominal pain, jaundice, dark urine, pale stools, pruritus, loss of weight or

malaise, asthenia, anorexia, jaundice can be present but not always [15].

increases the probability of drug interactions.

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

hepatic lesion.

[6, 24, 26, 39]

3.5. Clinical manifestations

fibrosis or cirrhosis may be present.

terized by minimal inflammation.

nied by inflammation.

cholestasis may appear.

fibrosis.

presented in Table 1.

panied with inflammation.

cytoplasm of hepatocytes.

are necrosis and microvesicular steatosis.

droplets in the cytoplasm of hepatocytes.

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 impairment, 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) [8, 10, 18, 19]. In addition, a recent study shows that among intravenous drugs, antibiotics and antineoplastic are the pharmacological groups most associated with hepatic toxicity [41].

A structured review in PubMed/Medline was made using the terms: "liver disease" and/or "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; this review excluded articles reporting hepatotoxicity related with other agents different to drugs, any liver disease, reports of clinical trials about predictive patterns of injury or studies of stem cells. Then, some information was extracted regarding: expression of hepatotoxicity, type of injury, mechanisms of hepatotoxicity, risk factors and clinical manifestations. To assess the probability of occurrence of hepatotoxicity and the type of injury, three categories were established: definite, probable and possible probability, according to evidence [42]. To report the results, a list was made with 181 drugs and 17 combined pharmaceutical forms or therapeutic regimen; these were selected as substances likely to develop hepatotoxicity. Eight drugs had definite probability: methotrexate, minocycline, vancomycin, everolimus, isoniazid, rifampicin, pyrazinamide and tamoxifen (Table 2). The drugs assessed as probable were 61 (Table 3) and as possible were 119 (Table 4) [43].

Drugs assesses as probable

Table 3. Drugs assessed as probable.

Drugs assessed as possible

Thioctic acid nilutamide Actinomycine D Busulfan Donepezil Indicine N-oxide Loratadine Octreoctide Ibuprofen Oxaprozin Indomethacin Terbinafine Ajmaline Quinidine Hydralazine Candesartan Irbesartan

Table 4. Drugs assessed as possible.

Ranitidine Glibenclamide Gliclazide Glimepiride Metformin Pioglitazone Rosiglitazone Mesalamine Mesalazine Sulfasalazine Oxymetholone Esomeprazole Orlistat

Propylthiouracil Methylprednisolone Doxapram hydrochloride

> Carmustine Cyclophosphamide Cytarabine Dacarbazine Mitoxantrone Trabectedin Leflunomide Sirolimus Thalidomide Tocilizumab Alfuzosin Tamsulosine Cyclofenil Raloxifene Testosterone Disulfiram Simvastatin Pravastatin Naftidrofuryl Piroxicam Rofecoxib Aurothioglucose Glucosamine Nicotinic acid Labetalol Nicardipine Diltiazem Tienilic acid Ferrous fumarate Ticlopidine

Diclofenac Lumiracoxib Nimesulide

Allopurinol Dantrolene Cyproterone acetate Halothane Isoflurane Bentazepam Lamotrigine Valproic acid Tolcapone

Sodium aurothiomalate

Flutamide Etopóside Imatinib Ipilimumab Oxaliplatin Temozolomide Tioguanine Glatiramer Azathioprine Infliximab Buprenorphine Clometiazol Carbamazepine

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Amphotericin B Clindamycin Dapsone Fosfomycin Sulfadimethoxine Amoxicillin Nafcillin Oxacillin Cefdinir Erythromycin Spiramycin Doxycicline Levofloxacin Daptomycin Brivudin Didanosine Zidovudine Atomoxetine Spironolactone Fosinopril Lisinopril Bromfenac Acetylsalicylic acid Pazopanib Nafamostat Dipirone Mebendazole Metronidazole

Dextropropoxyphene

Zolmitriptan Enflurane Methoxyflurane Propofol Sevoflurane Thiopental Imipramine Mirtazapine Nefazodone Nomifensine Sertraline Felbamate Phenytoin Phenobarbital Clozapine Quetiapine Risperidone Methylphenidate Amodiaquiea Mefloquine Quinine Etretinate Alendronate Methimazole Dabigatran Clopidogrel Dalteparin Phenprocoumon Bosentan Sitaxentan

Benzarone Fluconazole Itraconazole Ketoconazole Rifampicin Efavirenz Nevirapine Paracetamol Telithromycin Ciprofloxacin Trovafloxacin

Acarbose Troglitazone Papaverine Vitamin A Amiodarone Propafenone Metildopa Perhexiline Enalapril Atorvastatin Ezetimibe Flupirtine Nitrofurantoin Ornidazole Flucloxacillin


Table 2. Drugs assessed as definite.


### Drugs assesses as probable

the results, a list was made with 181 drugs and 17 combined pharmaceutical forms or therapeutic regimen; these were selected as substances likely to develop hepatotoxicity. Eight drugs had definite probability: methotrexate, minocycline, vancomycin, everolimus, isoniazid, rifampicin, pyrazinamide and tamoxifen (Table 2). The drugs assessed as probable were 61 (Table 3)

> Hepatic toxcity mechanism

Direct toxicity or immune adverse reactions

Lipid peroxidation (necrosis)

Lipid peroxidation (necrosis). Formation of hepatotoxic metabolites

Disrupt of βoxidation of lipids. Steatohepatitis

Possible direct toxicity or hepatotoxic metabolites

Direct toxicity. Lipid peroxidation (necrosis). Dysfunction mitochondrial

Risk factors Clinical and pathological

Adult population Increase of

Women from 16 to 57 years

Genetic polymorphisms. Female, old age, VIH co-infection

Women from 50 to 70 years. Overweight, hyperlipidemia, hypertension, diabetes,

osteoporosis, alcohol consumption <20 g/

Neoplasms, liver transplantation

Previous hepatic disease. Alcoholism, obesity, diabetes. Cumulative dose. Use of steroids. Previous exposure to hepatotoxins

day

manifestations

aminotransferases. Rash, fever, eosinophilia

Autoimmune hepatitis. Steatosis. Periportal inflammation, swelling and collapse hepatocytes, antinuclear antibody, eosinophilia. Increase of aminotransferases. Jaundice, fever, abdominal pain, rash, anorexia, nausea, arthralgia,

fatigue, pruritus

Hepatic encephalopathy. Steatosis. Granulomatous inflammation, central necrosis. Increase of liver enzymes. Jaundice, abdominal pain, anorexia, nausea, dark urine, vomiting, asthenia

Steatohepatitis. Fibrosis. Micronodular cirrhosis. Necrosis. Inflammatory infiltrate. Hepatomegaly, peliosis hepatis, increase in aminotransferases. Nausea, vomiting, malaise, right upper quadrant pain

aminotransferases, fatigue

Steatohepatitis. Fibrosis, cirrhosis. Inflammatory infiltrate. Necrosis. Increase of liver enzymes

Increase of

and as possible were 119 (Table 4) [43].

Hepatic toxcity expression

Idiosyncratic (immunoallergic) Lesion type (probability of occurrence)

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

Hepatocellular (definite)

(definite)

(probable)

(definite)

information

(possible)

Idiosyncratic Hepatocellular

Idiosyncratic Hepatocellular

Idiosyncratic Hepatocellular

No information Hepatocellular

No information No

Table 2. Drugs assessed as definite.

Drugs assessed as definite

Drug [code ATC]

Vancomycin [J01XA01]

Minocycline [J01AA08]

Isoniazid, rifampicin, pyrazinamide [J04 AM05]

Tamoxifen [L02BA01]

Everolimus [L01XE10]

Methotrexate [L04AX03]

Table 3. Drugs assessed as probable.

### Drugs assessed as possible


Table 4. Drugs assessed as possible.
