SciELO - Scientific Electronic Library Online

 
vol.103 issue9Diagnostic accuracy and therapeutic impact of endoscopic ultrasonography in patients with intermediate suspicion of choledocholithiasis and absence of findings in magnetic resonance cholangiographyIntraductal papillary mucinous neoplasm author indexsubject indexarticles search
Home Pagealphabetic serial listing  

My SciELO

Services on Demand

Journal

Article

Indicators

Related links

  • On index processCited by Google
  • Have no similar articlesSimilars in SciELO
  • On index processSimilars in Google

Share


Revista Española de Enfermedades Digestivas

Print version ISSN 1130-0108

Rev. esp. enferm. dig. vol.103 n.9 Madrid Sep. 2011

https://dx.doi.org/10.4321/S1130-01082011000900006 

POINT OF VIEW

 

Hepatotoxicity in 2011 - advancing resolutely

Hepatotoxicidad en 2011: progresando decididamente

 

 

Marta Lozano-Lanagrán1, Mercedes-Robles1, María Isabel-Lucena2 and Raúl J.-Andrade1

1Unit of Hepatology. Department of Digestive Diseases. 2Department of Clinical Pharmacology. Hospital Universitario "Virgen de la Victoria". School of Medicine. Málaga. Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd). Barcelona, Spain

Correspondence

 

 

Introduction

Liver toxicity from drugs, and also from alternative medicine products such as herbalist's remedies and dietary supplements, is currently an increasingly relevant health issue. A great majority of hepatic adverse reactions seen in clinical practice are unpredictable (unrelated to a drug's pharmacological characteristics) and basically result from an interaction of three circumstances: a drug with potential to generate hepatotoxic radicals in a genetically susceptible individual under certain environmental factors. This type of reaction, which occurs only rarely, goes undetected during a drug's development process, and hence typically manifests when dozens of thousands of patients are exposed to it post-marketing; this still represents the first cause for a drug's market withdrawal. On the other hand, the absence of objective diagnostic tests and variable clinical presentation commonly entail a delayed diagnosis of liver toxicity. In the present article, we review recent advances in this area and new consensus as result of investigators from different countries.

 

Epidemiology

The actual incidence of liver toxicity in clinical practice is little known. Only one prospective population study in France established the crude annual incidence of hepatic drug reactions to be 14 cases per 100,000 population (16 times higher than reported to regulatory agencies via the yellow card system) (1). In practice the risk for idiosyncratic hepatotoxicity associated with the use of most drug agents is thought to oscillate between 1/10,000 and 1/100,000 exposed individuals. The diagnosis of drug-related hepatotoxicity is substantially less common than that of other causes of liver disease. Toxicity is believed to represent 4-10% of jaundice cases admitted to general hospitals (2). Among inpatients the incidence of idiosyncratic hepatotoxicity has been estimated between 0.7% and 1.4% (3). Antibacterials, nonsteroidal anti-inflammatory drugs, and anticonvulsants rank at the top of the list of drug classes involved in hepatotoxicity (4,5), and amoxicillin/clavulanic acid is in absolute figures the most commonly involved molecule (4,5). Geographical variability is high regarding agents responsible for liver damage (Table I). Most cases in western countries are associated with antibiotics, anticonvulsants, and psychotropic drugs; less than 10% correspond to herbal remedies and dietary supplements, but this proportion has been increasing in the last few years (1,4-8). In Asia herbal remedies are a relevant cause of hepatotoxicity (9). A recent study showed that idiosyncratic hepatotoxicity and fulminant liver failure occur more commonly with drugs administered at a daily dose ≥ 50 mg/day, as compared to those administered at lower doses (10).

 

Risk factors

Literature references on hepatotoxicity risk factors such as age, sex, alcohol ingestion, smoking, concomitant drugs, underlying liver disease, and genetic factors are abundant. However, the fact that liver toxicity is no isolated disorder but includes a wide variety of liver responses to numerous chemicals should be considered, hence risk factors do not usually apply to many causal agents. Advanced age represents an important risk factor for isoniazide-related hepatotoxicity (11), while valproate-induced liver damage (12) and Reye's syndrome from aspirin ingestion are more common in children (13). It has been suggested that women might be more susceptible to liver toxicity (9), perhaps because they use a greater number of drugs. However, extensive population studies could not find a higher frequency of hepatotoxicity among females (1,4,5). The black race is more susceptible to anticonvulsant hypersentivity syndrome (14), whereas Caucasian whites seem to have an increased risk for liver toxicity in association with flucoxacillin (15).

Genetic factors play a significant role in drug-induced liver damage. Recently, candidate gene studies and genome-wide analyses have identified several genetic markers associated with increased hepatotoxicity risk. Thus, flucoxacillin-induced hepatotoxicity is closely linked to HLAB5701 (15), the same allele responsible for susceptibility reactions to abacavir, which is present in at least 4% of Caucasian Europeans (16). Estrogen-induced cholestasis is associated with mutations in gene ABC B11, which codes for the bile salt export pump (17), and valproate-related liver toxicity is linked to mutations in the gene encoding mitochondrial DNA polymerase gamma, POL G1 (18). On the other hand, a double null genotype for cytosolic glutathione transferase (GST M1 T1) -a key enzyme in the defense against oxidative stress- entails an increased risk for liver toxicity with various drugs, particularly non-steroidal anti-inflammatory drugs and antibacterials (19). No single risk factor to date has proven sufficiently predictive of hepatotoxicity in a given individual.

 

Case definition, phenotypes, and prognostic determinants

Liver toxicity may present with clinical and pathological manifestations that are virtually reminiscent of every known liver condition, and whose severity may oscillate from asymptomatic liver enzyme elevations to fulminant liver failure. The most common presentation form is a clinical picture that mimics acute viral hepatitis, nut other forms may occur, including chronic hepatitis, liver cirrhosis, primary biliary cirrhosis-like disease, veno-occlusive disease, and even neoplasms (20).

However, patients very often manifest only mild changes in liver tests and no histological data are available. Hence, in searching for homogeneity in the definition of hepatotoxicity an international consensus group established that liver toxic damage would be present when in the presence of drug exposure an elevation in serum alanine-aminotransferase (ALT), conjugated bilirubin, or combined bilirubin, ALT and alkaline phosphatase (AP) levels > 2 times the upper limit of normal (ULN) is identified (21). Recently a new group of experts redefined the case concept according to said biochemical criteria because of their perception that, given the increasing number of patients with high ALT secondary to non-alcoholic fatty liver, ALT threshold levels should be increased to > 5 times the ULN to minimize false negative results, whereas AP could keep its previously established threshold (> 2 x ULN). A new case category would be the combination of increased ALT > 3 x ULN and total bilirubin > 2 x ULN (22) (Table II).

In line with this method, toxic liver injury is characterized, based on serum ALT and AP levels (when separately elevated), and on the relationship (R) between both (when concurrently elevated), as hepatocellular (R ≥ 5), cholestatic (R ≤ 2) and mixed (R = 2-5) (21). R must be estimated from an initial blood sample since pattern may change (from hepatocellular to cholestatic or mixed) in later stages because of the varying resolution times of different liver enzymes (faster for ALT versus AP) (23), and its value is critical for the CIOMS/RUCAM scale. In situations where ALT or AP are elevated before drug administration, baseline values will be used as ULN. The categorization of liver lesions according to this criterion exhibits a good overall correlation with underlying injuries and is excellent for prognostic purposes (4,24). Age and sex influence the hepatocellular and cholestatic expression of hepatotoxicity. The former is more common in women younger than 60 years, and the latter is more common in males above 60. In contrast, mixed expression has no relation to these variables (25).

Liver toxicity symptoms are nonspecific, similar to those in any acute liver condition, and include asthenia, anorexia, nausea, abdominal pain, fever, jaundice, choluria, and pruritus. Early pruritus is typical of cholestatic forms and only develops late -if ever- in hepatocellular patterns. Hypersensitivity symptoms may help in the diagnosis of hepatotoxicity. Symptoms such as rash, fever, and facial edema, associated with eosinophilia and atypical lymphocytosis are helpful for the diagnosis, and are characteristic of liver toxicity from selected drugs, including aromatic anticonvulsants, sulfamides, and allopurinol (23).

Acute hepatocellular expression is the most common presentation of toxic liver disease, and may be caused by a wide variety of drugs. Acute toxic hepatocellular damage with jaundice entails death or a need for liver transplantation in 10% of patients on average (26), a fact known as "Hy's rule". An analysis of Registro Español de Hepatotoxicidad and the Swedish SADRAC database has validated this, and using a multivariate analysis also found that other variables such as advanced age, female gender, and AST levels were independently associated with poor prognosis (4,24). In contrast, an analysis of the prospective cohort in the collaborative DILIN group in the USA failed to validate Hy's rule but identified diabetes as a risk factor for serious disease progression (5).

While in most cases hepatotoxicity resolution is complete with no apparent sequels, a subgroup oscillating between 5.7% in the Spanish Registry (4) and 14% in the US Registry show biochemical evidence of chronicity. In the Spanish Registry study acute cholestatic/mixed patterns had a greater tendency toward chronicity when compared to the hepatocellular type (9 vs. 4%, respectively; p < 0.031) (27), although residual lesion severity was greater in the latter (30% of cirrhosis and 20% of chronic hepatitis). Cardiovascular and CNS drug classes are more prone to chronic hepatotoxicity induction (27). Very recent analyses suggest that, regardless of the lesion's hepatocellular, cholestatic, or mixed pattern, most liver profile normalizations occur within one year, hence this cutoff could be most suitable to tell prolonged resolution from true chronic progression (28).

 

Causality assessment

The availability of molecular markers for liver toxicity that could be used in clinical practice still seems far removed. Therefore, the diagnosis of hepatotoxicity remains a challenge for clinicians. Only seldom may a conclusive diagnosis with hepatotoxicity be reached. This includes the measuring of plasma levels for some intrinsic liver toxins such as acetaminophen or aspirin.

Under usual clinical conditions the causality attribution process is based on the suspicion of liver toxicity together with an appropriate exclusion of specific causes (Table III). A key element to maximize diagnostic yield is a high degree of suspicion that any liver disease may be related to drug exposure, followed by an attentive research of toxic exposure, a consistent time sequence, an analysis of the hepatotoxic potential of identified agents, and a cautious exclusion of specific causes of liver disease (29) (Fig. 1).

Liver damage latency is defined as the time from the first day with drug exposure to symptom development. This period is variable since liver toxicity may develop even following the discontinuation of its causal agent (typical in hepatotoxicity from amoxicillin-clavulanate) (30). In 80% cases, symptoms occur in the first three months from the beginning of treatment (9). Causality attribution resides in the availability of detailed information on drug exposure in advance of liver damage, as well as an appropriate exclusion of alternative causes (31). An exclusion of other liver disease causes is necessary, including acute hepatitis A, B or C; autoimmune hepatitis; Wilson's disease; primary sclerosing cholangitis; hepatitis E; graft-versus-host disease; and a pancreato-biliary origin. Ruling out hepatitis E is presently vital because of its increasing incidence in the last few years, particularly in eastern European countries. Detailed history taking is important with a focus on alcohol abuse, heart failure, hypotension, hyperthermia, and hypoxia before symptom onset, as these may cause liver ischemia. Sepsis and parenteral nutrition must be ruled out in inpatients, as these may result in cholestatic liver damage. Criteria favoring a diagnosis with hepatotoxicity include identifying hypersensitivity manifestations and rapid clinical and biological improvement following drug discontinuation (dechallenge). The gold standard for the diagnosis of hepatotoxicity is a recrudescence of clinical and biological changes after rechallenge. However, because of ethical reasons this is unjustifiable except under exceptional circumstances. Most re-exposures occur unintentionally (6% in the Spanish hepatotoxicity registry) and may entail an increased risk of undesirable outcomes (32). Notwithstanding, careful questioning may on occasion unveil subtle evidence of accidental re-exposure, which will significantly help during diagnosis. In such cases the first episode following drug exposure surely lacked jaundice and symptoms were nonspecific (abdominal discomfort, fever, asthenia), which made its identification challenging to a doctor not familiar with liver toxicity (33).

The role of liver biopsy in the diagnosis of hepatotoxicity is uncertain (5,10). While the presence of eosinophils, granulomata, necrosis, and cholestasis adds to the suspicion of liver toxicity, no specific features may confirm the diagnosis (34-36). Figure 1 shows a diagnostic algorithm for hepatoxicity.

Special situations in causality assessment

Hepatotoxicity causality attribution exhibits relevant differences in children as compared to adults. Drug prescription is lower in children versus adults, and the former seem to be less susceptible to hepatotoxicity. Exceptions exist, including Reye's syndrome and hepatotoxicity from aspirin and valproate. These age-related differences in susceptibility may result from cytochrome P-450's genetic expression (37).

Individuals with chronic viral (B or C) liver disease have an increased risk for idiosyncratic liver toxicity, at least with some drugs, owing to pharmacokinetic changes, disregulated cytokine expression, and altered drug metabolism pathways (38-43). Non-alcoholic steatohepatitis and obesity have shown no greater risk for liver toxicity but in cases induced by methotrexate and tamoxifen (43-46). Multiple studies have shown an increased risk of elevated ALT in patients coinfected with HIV and HBV or HCV as compared to HIV infection alone during antiretroviral therapy, but telling hepatotoxicity from an underlying liver disease exacerbation is sometimes challenging (41-43). The role of alcohol as susceptibility factor and its potential influence in the course of toxic liver disease is controversial. In the CIOMS/RUCAM scale (see below) for the assessment of suspected hepatotoxicity, alcohol consumption is worth one point, and thus increases diagnostic probabilities, but no scientific evidence supports this. On the other hand, in the multivariate analysis of factors with a potential impact on serious hepatotoxicity outcomes in DILIN, alcohol use during the previous 12 months behaved as a protective factor (OR = 0.33) (5). Autoimmune hepatitis represents a particularly difficult issue when it comes to differentiate it from idiosyncratic hepatotoxicity, since both conditions lack specific markers and some drugs induce autoimmune hepatitis-like syndromes (minocycline, nitrofurantoin, and methyldopa) (47-59). Other drugs such as interferon alfa or anti-TNF-alfa antibodies may unmask latent autoimmune hepatitis. In fact, the development of hepatitis with autoimmunity phenomena during drug therapy poses the dilemma of whether it is a true autoimmune hepatitis, and onset coincided with the taking of an unrelated drug, or the drug gave rise, either directly or through low-grade liver injury, to autoimmune hepatitis in a genetically predisposed patients (50). Selected drugs, even in the absence of liver damage, may favor the development of antibodies.

Diagnostic scales

Causality attribution scales for hepatotoxicity attempt to semi-quantitatively estimate the likeliness that a pharmacological agent may be responsible for liver injury. These tools have both strengths and weaknesses (51), but their main drawback is maybe that they cannot be compared to an objective diagnostic parameter. Two diagnostic scales or algorithms are currently used to assess causality in hepatotoxicity: the CIOMS/RUCAM scale (52), and the María & Victorino scale (53), also known as Clinical Diagnostic Scale (CDS). Both scales provide a scoring system for 6 items in the decision-making strategy. Responses correspond to weighted values that add up to provide a total score. These ratings are translated into suspicion categories. The former scale showed in a study a higher consistency with clinical judgment (54), but its reproducibility among experts has also been questioned by a recent study (55). The primary disadvantage of the CIOMS/RUCAM scale is its complexity, which renders its use in daily practice difficult. The María & Victorino scale adds an assessment of immuno-allergic phenomena such as fever, rash, or cytopenias, and excludes factors such as pregnancy and alcohol ingestion. This scale obtained an excellent kappa when 50 hepatotoxicity cases were compared to expert opinions (56). Despite this, in a wide independent series the María & Victorino scale showed inferior results as compared to the RUCAM scale (54). Other diagnostic tools are less applicable. Thus, Naranjo's Adverse Reaction Probability Scale provides a scoring system to attribute drug-related adverse reactions using simple questions, and is user-friendly; however, it is of little use for hepatotoxicity (57). Japanese researchers added the results of lymphocyte stimulation tests and eosinophilia tests to the RUCAM scale (58). No comparison of the Japanese RUCAM scale to expert opinions has been carried out to date.

 

Treatment

The primary therapeutic measure is immediate discontinuation of any non-essential drugs since the ongoing presence of a drug responsible for hepatotoxicity may result in higher probabilities of fulminant or chronic outcome (26,27). Drug discontinuation must lead to clinical improvement, albeit a worsening of liver function may be on occasion detected for several days or even weeks. The way to restored liver function is variable. Clinical improvement is slower for the cholestatic versus the hepatocellular pattern. N-acetylcysteine has shown some effectiveness in reducing the need for transplantation in acute liver failure unrelated to acetaminophen intoxication (including idiosyncratic toxic hepatitis) provided it is administered early during encephalopathy (59). N-acetylcysteine may probably be also effective to prevent hepatotoxicity progression toward fulminant forms. Corticoids have not been effective for serious cases (60) but may be used for some patients with hypersensibility manifestations. In non-controlled studies ursodeoxycholic acid seems effective for prolonged ductopenia and toxic cholestasis (61). Novel therapy targets may include cytoprotective Keap1-Nrf2 signaling, which is started in liver inflammation by Nrf2 translocation into the nucleus, where it activates the transcription of a number of antioxidant genes such as NQ01, HO-1, and yGCS. Nrf2-knockout mice exhibit greater liver toxicity in experimental studies. Thus, in a post-injury liver regeneration model serum total bilirubin levels increased 5-fold in these mice (p < 0.001), which proves a reduced liver functional capacity in the absence of Nrf2 activity (62). Nrf2 activators might thus have liver protective properties in cases of toxic liver injury. Another potential target would be nuclear receptors, which are involved in multiple physiological liver functions. Of late, the famesoid X receptor agonist obeticholic acid, which showed choleretic and antifibrotic properties in experimental models, has been successfully tried to improve cytolysis and cholestasis indices in patients with primary biliary cirrhosis and deficient response to ursodeoxycholic acid (63), and might theoretically be also effective in patients with prolonged toxic cholestasis.

 

References

1. Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002;36:451-5.         [ Links ]

2. Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol 2007;102:558-62.         [ Links ]

3. Meier Y, Cavallaro M, Roos M, Pauli-Magnus C, Folkers G, Meier PJ, et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 2005;61:135-43.         [ Links ]

4. Andrade RJ, Lucena MI, Fernández MC, Peláez G, Pachkoria K, García-Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period. Gastroenterology 2005;129:512-21.         [ Links ]

5. Chalasani N, Fontana R, Bonkovsky MD, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924-34.         [ Links ]

6. De Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004;58:71-80.         [ Links ]

7. Hussaini SH, O'Brien CS, Despott EJ, Dalton JR. Antibiotic therapy: a major cause of drug-induced juandice in southwest England. Eur J Gastroenterol Hepatol 2007;19:15-20.         [ Links ]

8. Friis H, Andreasen PB. Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992;232:133-8.         [ Links ]

9. Takikawa H, Murata Y, Horiike N, Fukui H, Onji M. Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006. Hepatology Res 2009;39:427-31.         [ Links ]

10. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 2008; 47:2003-9.         [ Links ]

11. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996;51:132-6.         [ Links ]

12. Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987;37:379-85.         [ Links ]

13. Heubi JE, Partin JC, Partin JS, Schubert WK. Reye's syndrome: current concepts. Hepatology 1987;7:155-64.         [ Links ]

14. Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Clev Clin J Med 1999;66:239-45.         [ Links ]

15. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816-9.         [ Links ]

16. Hughes CA, Foisy MM, Dewhurst N, Higgins N, Robinson L, Kelly DV, et al. Abacavir hypersensitivity reaction: an update. Ann Pharmacother 2008;42:387-96.         [ Links ]

17. Meier Y, Zodan T, Lang C, Zimmermann R, Kullak-Ublick GA, Meier PJ, et al. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump. World J Gastroenterol 2008;14:38-45.         [ Links ]

18. Stewart JD, Horvath R, Baruffini E, Ferrero I, Bulst S, Watkins PB, et al. Polymerase gamma gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology. 2010;52(5):1791-6.         [ Links ]

19. Lucena MI, Andrade RJ, Martinez C, Ulzurrun E, García-Martín E, Borraz Y, et al. Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology 2008;48:588-96.         [ Links ]

20. Andrade RJ, Salmerón J, Lucena MI. Drug hepatotoxicity. In: Reddy KJ, Faust T, editors. The Clinician's Guide to Liver Disease. New Jersey: SLACK Inc.; 2006. p. 321-43.         [ Links ]

21. Bénichou C. Report of an International Consensus Meeting. Criteria of drug-induced liver disorders. J Hepatol 1990;11:272-6.         [ Links ]

22. Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury (DILI). Clin Pharmacol Ther 2011; (in press).         [ Links ]

23. Fontana R, Seef L, Andrade RJ, Björnsson E, Day CP, Serrano J, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 2010;52:730-42.         [ Links ]

24. Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005;42:481-9.         [ Links ]

25. Lucena MI, Andrade RJ, Kaplowitz N, García-Cortes M, Fernández MC, Romero-Gomez M, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology 2009;49:2001-9.         [ Links ]

26. Zimmerman HJ: Hepatotoxicity. The adverse effects of Drugs and Other Chemicals on the River. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.         [ Links ]

27. Andrade RJ, Lucena MI, Kaplowitz N, García-Muñoz B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006;44:1581-8.         [ Links ]

28. Borraz Y, Fernández MC, García-Muñoz B, Romero-Gómez M, Robles M, Durán JA, et al. Would it be desirable to modify the cut-off point for definition of chronicity in drug-induced liver injury (DILI)? Hepatology 2010;52(Supl.):457A.         [ Links ]

29. Andrade RJ, Camargo R, Lucena MI, González-Grande R. Causality assessment in drug-induced hepatotoxicity. Expert Opin Drug Saf 2004;3:329-44.         [ Links ]

30. Lucena MI, Andrade RJ, Fernández MC, Pachkoria K, Peláez G, Durán JA, et al. Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain. Hepatology 2006;44:850-6.         [ Links ]

31. Agarwal VK, McHutchison JG, Hoofnagle JH. Important elements for the diagnosis of drug-induced liver injury. Clin Gastroenterol Hepatol 2010;463-70.         [ Links ]

32. Fernández-Castañer A, García-Cortés M, Lucena MI, Borraz Y, Peláez G, Costa J, et al. An analysis of the causes, characteristics, and consequences of reexposure to a drug or compound responsible for a hepatotoxicity event. Rev Esp Enferm Dig 2008;100:278-84.         [ Links ]

33. Andrade RJ, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega MC, Lucena MI. Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists World J Gastroenterol 2007;13:329-40.         [ Links ]

34. Goodman ZD. Drug hepatotoxicity. Clin Liver Dis 2002;6:381-97.         [ Links ]

35. Kleiner DE. The pathology of drug-induced liver disease. Semin Liv Dis 2009;29:364-72.         [ Links ]

36. Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Path 2009;62:481-92.         [ Links ]

37. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology- drug disposition, action and therapy in infants and children. N Engl J Med 2003; 349:1157-67.         [ Links ]

38. Wong WM, Wu PC, Yuen MF, Cheng CC, Yew WW, Wong PC, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000;31:201-6.         [ Links ]

39. Wu JC, Lee SD, Yeh PF, Chan CY, Wang YJ, Huang YS, et al. Isoniazidrifampin-induced hepatitis in hepatitis B carriers. Gastroenterology 1990;98:502-4.         [ Links ]

40. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000;283:74-80.         [ Links ]

41. Cicconi P, Cozzi-Lepri A, Phillips A, Puoti M, Antonucci G, Manconi PE, et al. Is the increased risk of liver enzyme elevation in patients co-infected with HIV and hepatitis virus greater in those taking antiretroviral therapy? AIDS 2007;21:599-606.         [ Links ]

42. Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007;196:670-6.         [ Links ]

43. Maida I, Babudieri S, Selva C, D'Offizi G, Fenu L, Solinas G, et al. Liver enzyme elevation in hepatitis C virus (HCV): HIV co-infected patients prior and after initiation of HAART: role of HCV genotypes. AIDS Res Hum Retroviruses 2006;22:139-43.         [ Links ]

44. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;128:1287-92.         [ Links ]

45. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005;329:62-5.         [ Links ]

46. Whiting-O'Keefe QE, Fyfe KH, Sack KD. Methotrexate and histologic hepatic abnormalities: A meta-analysis. Am J Med 1991;90: 711.         [ Links ]

47. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996;20:312(7024):169-72.         [ Links ]

48. Peedikayil MC, Dahhan TI, Al Ashgar HI. Nitrofurantoin-induced fulminant hepatitis mimicking autoimmune hepatitis. Ann Pharmacother 2006;40(10):1888-9.         [ Links ]

49. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002;6(3):755-74.         [ Links ]

50. Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, et al. Recurrent drug-Induced Liver Injury (DILI) with different drugs in the Spanish Registry. The dilemma of the relationship to autoimmune hepatitis. J Hepatol 2011;53(3):683-91.         [ Links ]

51. García-Cortés M, Stephens C, Fernández-Castañer A, Lucena MI, Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol 2011;55(3):683-91.         [ Links ]

52. Danan G, Bénichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323-30.         [ Links ]

53. Maria V, Victorino R. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26:664-9.         [ Links ]

54. Lucena MI, Camargo R, Andrade RJ, Pérez-Sánchez C, Sánchez de la Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001;33:123-30.         [ Links ]

55. Rochon J, Protiva P, Seeff LB, Fontana RJ, Liangpunsakul S, Watkins PB, et al. Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology 2008; 48:1175-83.         [ Links ]

56. Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol 2000;33:949-52.         [ Links ]

57. García-Cortes M, Lucena MI, Pachkoria K, Borraz Y, Hidalgo R, Andrade RJ. Evaluation of Naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008;27:780-9.         [ Links ]

58. Takikawa H, Takamori Y, Kumagi T, Onji M, Watanabe M, Shibuya A, et al. Assessment of 387 Japanese cases of drug induced liver injury by the diagnostic scale of the International Consensus Meeting. Hepatol Res 2003;27:192-5.         [ Links ]

59. Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137(3):856-64.         [ Links ]

60. Rakela J, Mosley JW, Edwards VM, Govindarajan S, Alpert E. A double-blinded, randomized trial of hydrocortisone in acute hepatic failure. The Acute Hepatic Failure Study Group. Dig Dis Sci 1991; 36:1223-8.         [ Links ]

61. Spagnuolo MI, Iorio R, Vegnente A, Guarino A. Ursodeoxycholic acid for treatment of cholestasis in children on long-term total parenteral nutrition: a pilot study. Gastroenterology 1996;111:716-9.         [ Links ]

62. Beyer TA, Xu W, Teupser D, Keller UAD, Bugnon P, Hildt E, et al. Impaired liver regeneration in Nrf2 knockout mice. EMBO J 2008; 27:212-23.         [ Links ]

63. Mason AL, Luketic V, Lindor K, Hirschfield GM, Gordon SC, Mayo MJ, et al. Farnesoid-X receptor agonists: a new class of drugs for the treatment of PBC? An international study evalulating the addition of obeticholic acid (INT-747) to ursodeoxycholic acid. Hepatology 2010;52(Supl.):357A.         [ Links ]

 

 

Correspondence:
Raúl J. Andrade.
Unit of Hepatology.
School of Medicine.
Boulevard Louis Pasteur, n.o 32.
29071 Málaga, Spain.
e-mail: andrade@uma.es

Received: 07-03-11.
Accepted: 10-03-11.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License