Raúl J. Andrade
Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Madrid. Spain; andrade@uma.es

Q. HOW FREQUENT IS DILI AMONG THE GENERAL POPULATION?

Idiosyncratic drug-induced liver injury (DILI) is a rare diagnosis in clinical practice by far less common than other liver diseases such as viral hepatitis. However, data on DILI incidence in the general population are very limited. A main barrier to undertake these studies is the lack of a standard for DILI diagnosis so suspected cases should undergo a formal causality assessment process, which always result in some degree of uncertainty. There have been 2 population-based studies published so far. In a prospective study of a population of 80,000 inhabitants of northern France, conducted during a 3 year-period, the incidence of DILI encountered was 13.9 cases per 100,000 inhabitants-years, a rate 16 times higher than that reported to the French National Agency of pharmacovigilance 1. More recently a population-based study in Iceland including all inhabitants (over 250.0000), reported an incidence of DILI of 19.1 cases per 10.000 inhabitants-years. Such as incidence for instance is higher than those of autoimmune hepatitis or primary biliary cholangitis and could be in the range of new cases of hepatitis C. The Icelandic study also reported cases of hepatotoxicity associated with herbal and dietary supplements and was able to evaluate the quantitative risk of DILI associated with hepatotoxic drugs, estimating the risk of amoxicillin-clavulanic acid hepatotoxicity in 1 per 2350 exposed individuals 2. Of note, a high proportion of cases in these studies went unnoticed and was detected by routine biochemistry. Hence, no question the true incidence of DILI is very likely underestimated in clinical practice.

Q. HOW ACCURATE IS THE CLINICAL DIAGNOSIS OF DILI AND WHO ARE THE RELEVANT PATIENTS AT RISKS?

Idiosyncratic hepatotoxicity can present with a broad a clinical spectrum, although most often does it as an acute viral hepatitis-like syndrome, symptoms not providing any particular clues for diagnosis unless eosinophilia or rash reinforces suspicion of drug allergy. New emerging biomarkers, which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122 are still under evaluation and are not available in routine clinical practice. Indeed, the absence of specific biomarkers makes DILI a diagnostic of exclusion so the causality assessment of a patient having a DILI suspicion case still relies on a temporal relationship between the initiation of a drug and the onset of liver damage along the judicious use and interpretation of serum liver biochemistry and other routine laboratory and imaging tests to careful rule-out alternative explanations of liver disease 3. A consensus group recently proposed strict criteria to define liver damage based on a threshold for liver enzyme elevation as a prerequisite to adjudicate a DILI case 4. At present time, there is a general consensus upon the use of these criteria in prospective Registry studies 5, 6. Besides, pathological findings in DILI are not specific resembling those of many other liver disorders, thus limiting the value of liver biopsy in DILI diagnosis, the exception being when worsening of a pre-existing liver disorder (i.e. alcoholic hepatitis, autoimmune hepatitis) is an alternative diagnosis to consider.

With regard to the relevant patients at DILI risk, we are just starting to identify the risk factors for hepatotoxicity. Genetic factors are important determinants in DILI as recently showed by genome-wide association studies (GWASs), which have discover a number of novel associations between hepatotoxicity with human leucocyte antigen (HLA) class I and II alleles. Interestingly, these associations, in contrast to GWASs focused on other complex traits, have substantially higher risk ratios for susceptibility to DILI 3. Interestingly, there is substantial overlap among the risk alleles associated with clinically varied phenotypes of toxicities due to structurally dissimilar compounds. Actually, a GWASs recently published from a joint international collaboration demonstrated HLA-A*33:01 as a risk factor for a cholestatic or mixed pattern of DILI when these are considered as a single phenotype irrespective of the causative drugs 7. Overall, the strength of association between HLA genotypes and DILI yet remarkable for some drugs (eg. HLA-B57*01 increases by 80 folds the risk of developing DILI when exposed to flucoxacilin) has raised controversy regarding the use of pre-prescription genotyping as the incidence of DILI is so low that this strategy is not cost-effective. In contrast, the majority of HLA alleles associated with DILI have a very high negative predictive value of >0.95. Therefore, genotyping can be used to rule out adverse hepatic reactions due to particular drugs so that alternative diagnoses are considered.

Other non-genetic risk factors of DILI such as age, gender or associated diseases are more elusive. Older patients and woman are generally believed to be more prone to DILI but this long-standing conception is not supported by evidence since these host factors have not yet been identified in large prospective Registries as a risk for all-cause DILI 5, 6. However, prescription patterns rather than a biological basis could account for the increase of risk reported in some studies. For instance, in the population based study from Iceland there was a trend of higher incidence of DILI with increasing ages that paralleled the number of prescription drugs 2. Nevertheless, age appears to have an influence on the DILI phenotype: cholestatic damage is more common in the elderly, whereas younger individuals more commonly exhibit hepatocellular injury 5.

Q. IS THERE ANY LINK BETWEEN DILI AND AUTOIMMUNE LIVER DISEASES?

Yes, there is. For instance, recurrent DILI by a different drug tends to present with an AIH phenotype 8. Besides, DILI particularly induced for some drugs such as minocycline typically present with an autoimmune phenotype with antinuclear antibodies (ANAs), smooth muscle antibodies (SMAs) and elevated IgG levels as well as histological features of AIH. This situation is hard to differentiate from “idiopathic” AIH. AIH-induced by drugs typically resolves after stopping the causative drug. If treated with corticosteroids, a lack of recurrence following corticosteroid cessation supports a diagnosis of drug-induced AIH rather than idiopathic AIH. As yet there are no diagnostic tests to differentiate idiopathic from drug-related AIH, although histological findings can help in the differential diagnosis 9. The HLA-B*35:02 genotype, which is associated with minocycline-induced DILI, is a useful diagnostic test in the setting in distinguishing it from idiopathic AIH 3.

Q. CAN WE PREDICT PROGNOSIS OF DILI AND HOW DO WE TREAT IT?

Several studies have identified risk factors of severity in DILI. Hepatocellular injury, female sex and jaundice 5, as well as pre-existing liver disease 6 are associated with higher mortality, fulminant liver failure and liver transplantation. Nowadays, the large amount of information in liver biochemistry at DILI onset in order to predict a serious outcome. Thus, a marked increase of AST and an AST/ALT ratio >1.5 at DILI recognition predict a worse prognosis. In consequence, a new “Hys’law” meaning the use of AST or ALT, whichever was higher also showed a better balance between sensitivity and specificity as compared with the standard Hy´s law in predicting acute liver failure/liver transplantation 10.

Unfortunately, we do not have still specific therapy for DILI. Prompt withdrawal of any non-essential drug is paramount. Recent multicenter efforts could enable in a near future to undertake clinical trials in DILI.

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.
  2. Bjornsson ES, Bergmann OM, Bjornsson HK, Kvaran RB, Olafsson S. Incidence, Presentation and Outcomes in Patients with Drug-Induced Liver Injury in the General Population of Iceland. Incidence, Presentation and Outcomes in Patients with Drug-Induced Liver Injury in the General Population of Iceland. Gastroenterology 2013; 144: 1419
  3. Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 2017;66:1154-1164.
  4. Aithal GP, Watkins P B, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, Wilke R A, Avigan M, Kaplowitz N, Bjornsson E, Daly AK. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther.: 2011 ; 89 : 806-815.
  5. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M et al. Drug- induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129:512-521.
  6. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015;148: 1340-52.
  7. Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. Association of liver injury from specific drugs or group of drugs with polymorphism in HLA and in other genes in a genome wide association study. Gastroenterology. 2017;152:1078-1089.
  8. 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; 55:
  9. Foureau DM, Walling TL, Maddukuri V, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol 2015; 180(1): 40-51.
  10. Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hys law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology 2014; 147: 109-118.