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European Review for Medical and Pharmacological Sciences 2017; 21 (1 Suppl): 122-134

Drug-induced liver injury 2017:


the diagnosis is not easy but always
to keep in mind
G. MARRONE1, F.G. VACCARO1, M. BIOLATO1, L. MIELE1, A. LIGUORI1,
C. ARANEO1, F.R. PONZIANI1, N. MORES2, A. GASBARRINI1, A. GRIECO1
1
Gastroenterology Area, Fondazione Policlinico Universitario A. Gemelli, Catholic University
of the Sacred Heart, Rome, Italy
2
Pharmacology Institute, Fondazione Policlinico Universitario A. Gemelli, Catholic University
of the Sacred Heart, Rome, Italy

Abstract. – A drug-induced liver injury (DI- in the total bilirubin (TB), decrease in the plas-
LI) is defined as a liver injury caused by expo- matic protein and albumin levels and appearance
sure to a drug or a non-infectious toxic agent of coagulopathy (increase in prothrombin time
with a variable degree of organ dysfunction. A
better understanding of DILI epidemiology has
and International Normalized Ratio), are indic-
been obtained in recent years with the insti- ative of liver dysfunction. If hepatic adaptive
tution of international registries in the United capacity has not exceeded and liver function is
States and Europe. Despite the advances in the not compromised, then the damage may be as-
understanding and characterization of the phe- ymptomatic. On the contrary, the appearance of
nomenon, DILI remains an exclusion diagnosis signs and symptoms such as fatigue, anorexia,
so, probability scores and the analysis of liter- nausea, pain in right upper quadrant, dark urine,
ature reports are useful tools in dealing with a
suspected DILI. Idiosyncratic DILI can be con- light stool, and jaundice are certainly indicative
sidered a relatively rare event but it is one of of liver dysfunction4.
the leading causes of acute liver failure. Thus, For the above-mentioned reasons, biochemical
proper management is essential to avoid seri- cut-offs for significant liver damage have been
ous consequences. Here, we present an updat- proposed in the literature. The first definition
ed review of diagnostic and classification crite- of clinically significant liver damage was pro-
ria of DILI. Prognostic tools, and principles of
management and therapy have also been brief-
posed by a consensus-conference in 1990: ALT
ly discussed. or conjugated bilirubin levels elevation, more
than two-fold the upper limit of normality (ULN)
or the coexistence of aspartate-amino-transferase
Key Words
Drug-induced liver injury, DILI, Drug hepatitis,
(AST), ALP and TB elevation, with at least one
Herbal. of them being higher than two times the ULN2.
In 2001, a consensus conference organized by
the American Association for the Study of Liver
Diseases (AASLD), in collaboration with the
Food and Drug Administration (FDA) and the
Introduction American pharmaceutics manufacturers and re-
searchers (CDER-PhRMA) defined clinically sig-
Liver often plays a critical role in the me- nificant liver damage as the combined elevation
tabolism of drugs and xenobiotics, leading to a of transaminases ≥ 3 x ULN and TB values ≥ 2
peculiar risk of toxic effects1. Drug-induced liver x ULN5. This statement is consistent with Hyman
injury (DILI) is defined as a liver injury caused Zimmerman’s observations made in the ‘70s6.
by exposure to a drug or non-infectious toxic Zimmerman noted that the combination of hepa-
agent, and it is associated with different levels of tocellular damage (characterized by a predomi-
organ dysfunction2. nant elevation of transaminases) and jaundice,
A rise in the alanine-amino-transferase (ALT) without biliary obstruction and ALP elevation,
and alkaline phosphatase (ALP) level represents was a particularly severe event, with a mortality
a reliable marker of tissue damage3 while a rise range between 10% and 50%. This observation,

122 Corresponding Author: Giuseppe Marrone, MD; e-mail: giusmarrone@gmail.com


DILI 2017

referred to by Dr Robert Temple as “Hy’s Law,” of acute liver failure (ALF) and ALF-related liver
showed validity over the years and is currently transplantation in the US16,17. Under this scenario,
used by the FDA in the evaluation of potential the direct toxicity of acetaminophen overdose is
drug-related liver damage7. overarching. In a prospective US study of 308
Recently, in an attempt to provide a more ALF cases, idiosyncratic hepatotoxicity was con-
uniform criteria for the diagnosis of clinical firmed only in 40 cases (13% of the total), while
picture and reporting in the scientific literature, acetaminophen overdose accounted for 120 cases
an international DILI Expert Working Group (39% of the total)18.
proposed a new definition for drug-induced liver Excluding acetaminophen overdose, DILI is
damage: isolated increase of ALT ≥ 5 x ULN or responsible for 7-15% of ALF not only in the
increase of ALT values ≥ 3 x ULN and concomi- US but also in Europe19,20,21. Moreover, DILI
tant increase of TB values ≥ 2 x ULN or increase represents the leading cause of drug withdraw-
of ALP values ≥ 2 x ULN and concomitant in- al or prevention of drug marketing5. Among
crease of gamma-glutamyl-transferase (γ-GT) in hospitalized patients, the reported incidence of
the absence of any bone disease. In some peculiar drug-induced liver injury is nearly 1%, with the
cases, such as valproate mitochondrial damage or risk being higher when anti-cancer and anti-TBC
chronic damages, clinically significant threshold drugs are involved. But even in this setting of
for transaminases and ALP can be lower8. patients, an under-reporting or missed diagnosis
From a pharmacological point of view, it is could result in a misleading information stating
possible to identify two types of DILI: dose-de- low incidence of DILI22.
pendent and dose independent or idiosyncratic. Given the relative rarity of the DILI event,
Dose-dependent DILI, also known as direct tox- the better understanding of the problem requires
icity, is predictable, reproducible and develops the analysis of a high number of cases. For this
with short latency after the consumption of a reason, many epidemiological registers have been
dose exceeding a known toxic threshold. Dam- created all over the world.
age entity is proportional to administered dose9. The Drug-Induced Liver Injury Network (DI-
Idiosyncratic DILI, instead, is unpredictable and LIN), founded in the US by the National Institute
usually develops at therapeutic doses. The dam- of Diabetes and Digestive and Kidney Diseases
age amount is not always proportional to admin- (NIDDK), is probably the most trustworthy DILI
istered dose and the time to damage’s onset can registries in the world23.
vary widely6,10. In Europe, the broader DILI register is the
Spanish one, founded in 1994 at Malaga University
with actually more than 800 recorded cases24,25,26.
Epidemiology Both major European registries and USA DI-
LIN agree in reporting the antibiotics as the first
The proper definition of DILI epidemiology is class of involved drugs in adverse reactions, with
hard to assess because of difficult diagnosis and amoxicillin/clavulanic acid the most frequent in-
signaling issues, with subsequent underestima- dividual agent14,23,24,27. In the above-cited regis-
tion of the problem. tries, the age of subjects who experimented DILI
Retrospective studies in the United King- ranged between 49-53 years (the median age was
dom and Sweden reported an estimated inci- 55 years in Iceland cohort). In DILIN, LatinDILI,
dence of 2-3/100,000 per year in the general and Iceland cohort, the female sex is predominant
population11,12. Prospective studies in France and (59%, 59%, and 56% respectively) while in the
Iceland reported an incidence ranging between Spanish Registry, there is only a slight prevalence
13.9-19.1/100,000 per year13,14. of the male sex (51%).
In these studies, acetaminophen overdose-in- Interestingly, in the south-east Asian regis-
duced DILI were excluded or represented a min- tries, there is a high prevalence of herbs-related
imum percentage, while they are more relevant DILI, which, in some cases, exceeds 70% of the
in the United States9. On the other hand, the in- total cases28. This seems to be a different feature
cidence of idiosyncratic hepatotoxicity seems to compared to Western registers, but in recent
be coincident among US and European cohorts15. years, an increase in herbal and dietary supple-
Overall DILI is a rare event even if it is ments (HDS) hepatotoxicity has been observed
responsible for a high percentage of hospital ad- in the DILIN prospective network (second most
mission for jaundice, and remains the first cause involved class, 16% of the total)23 (Table I).

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G. Marrone, F.G. Vaccaro, M. Biolato, L. Miele, A. Liguori, et al

Table I. Principal DILI registries and epidemiological records around the world.
Setting Time Country Number of
period (or countries) recorded Comments
DILI-cases
DILIN23 2004-2013 USA 899 Only idiosyncratic reactions.
Most involved classes of drugs:
antimicrobial (45%) and HDS (16%).
Main single agents involved: amoxicillin/
clavulanic acid (10%) and isoniazid (5%).
Fatal cases: 10%.
Main biochemical pattern of damage
at presentation: hepatocellular (54%).
Spanish 1994-2007 Spain 603 Most involved class of drugs:
Registry of anti-infectious (33%).
Hepato- Most involved single agent: amoxicillin/
toxicity24,26 clavulanic acid (17%).
Fatality rates significantly higher among
female population (p<0.01).
Main biochemical pattern of damage
at presentation: hepatocellular (55%).
LatinDILIN27 2011-2015 Argentina, Uruguay, 206 Most involved classes of drugs: anti-infective,
Chile, Mexico, musculoskeletal agents and sex hormones.
Paraguay, Venezuela, Most involved single agents: amoxicillin/
Ecuador, Brazil, clavulanic acid (10%) and diclofenac (6%).
and Peru Fatal cases: 4,6%.
Main biochemical pattern of damage at
presentation: hepatocellular (54%).
Population- 2010-2012 Iceland 96 Crude annual incidence of idiosyncratic DILI
based study among the population of Iceland: 19.1/100,000.
of DILI in Most involved classes of drugs: antibiotics
Iceland14 (37%) and immunosuppressant (10%).
Most involved single agents: amoxicillin/
clavulanic acid (22%) and diclofenac (6%).
Fatal cases: 1%.
Korean 2005-2007 South-Korea 371 Most involved class of drugs: HDS (73%).
prospective Main biochemical pattern of damage at
nationwide presentation: hepatocellular (78%).
study of Fatal cases: 1.5%.
DILI28

Drug Induced Liver Injury (DILI), Drug Induced Liver Injury Network (DILIN).

Pattern of damage ALP values should be acquired on the same day


or no later than 48 hours apart from each other30.
The identification of damage pattern is useful When ALT or ALP are unavailable, AST
not only for classification but also for diagnostic, and γ-GT could be used with good agreement in
prognostic and reporting aspects, with the pur- the hepatocellular pattern of damage (94-96%)31,
pose of data homogenization for Drug regulatory even if their reliability is not completely defined.
agencies and scientific communication. When an alteration in liver enzymes pre-ex-
The biochemical pattern of liver damage is de- ists to DILI, it is possible to use as pre-damage
fined by the ratio ALT/ULN / ALP/ULN at presen- reference value the previous mean levels of ALT
tation, the so-called “R ratio”. An R ≥ 5 identifies and ALP32.
the hepatocellular pattern of injury; R ≤ 2 identi- In addition to the above biochemical pat-
fies the cholestatic pattern, while an R between 2 terns of liver injury, some clinical-laboratory
and 5 defines the mixed pattern. If ALT>2 ULN phenotypes have been proposed to better define
and ALP is normal, the damage pattern is consid- the disease. They include acute hepatic necrosis,
ered as hepatocellular29. Conventionally, ALT and acute hepatitis, cholestatic hepatitis, mixed hep-

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atitis, enzyme elevations without jaundice, bland Diagnosis


cholestasis, hepatic steatosis and lactic acidosis,
non-alcoholic fatty liver, chronic hepatitis, the si- The diagnosis of DILI is a diagnosis of exclu-
nusoidal obstruction syndrome (or vein-occlusive sion. Clinical history, time of drug exposure and
disease), nodular regenerative hyperplasia and the course of liver damage are crucial points in the
development of hepatic neoplasia-like adenomas evaluation of subjects with suspected drug-in-
and hepato-carcinomas33. duced liver injury. Usually, DILI manifestations
In addition to the biochemical pattern, a his- are highlighted in the six months following the
tological pattern of damage may be identified. start of the involved drug29, although there are
Recently, the DILIN reported a series of possible some exceptions24. The key aspect in the assess-
histological patterns in a prospective systematic ment of a suspected DILI is the exclusion of other
analysis of 249 biopsies performed on patients with causes of DILI, and the biochemical pattern of
suspected DILI: 1) acute hepatitis; 2) chronic hep- presentation could help in the diagnostic pro-
atitis; 3) acute cholestasis; 4) chronic cholestasis; cess36 (Table III).
5) cholestatic hepatitis; 6) granulomatous changes; According to the American College of Gastro-
7) steatosis; 8) steatohepatitis; 9) coagulative/con- enterology (AGA) guidelines29, in hepatocellular
fluent necrosis; 10) massive/sub-massive necrosis; liver injury, the first condition to be excluded is
11) vascular injury; 12) hepatocellular alteration; acute viral hepatitis (HAV, HBV, HCV, HEV,
13) nodular regenerative hyperplasia; 14) mixed CMV, EBV, and HSV), autoimmune hepatitis
injury; 15) unclassifiable injury; 16) minimal non- (AIH), vascular liver diseases (Budd-Chiari syn-
specific changes; 17) normality (Table II). drome, ischemic liver injury) and Wilson’s dis-
Nevertheless, 206 of the analyzed biopsies ease37. Regarding AIH, it should be noted that
(83% of the total), had just one of the five domi- some drugs, such as minocycline and nitrofuran-
nant histological patterns: acute hepatitis, chronic toin, can induce a peculiar form of DILI, very
hepatitis, acute cholestasis, chronic cholestasis similar to that of idiopathic AIH38; therefore, a
and cholestatic hepatitis. The observed histo- differential diagnosis can be difficult. According
logical patterns were strictly connected with the to AASLD guidelines, these difficult cases re-
involved drugs, strengthening the concept of main an indication for liver biopsy39.
“histological signature”: a specific drug causes In the cholestatic pattern, the first condition
specific tissue modifications34. to be excluded is a biliary obstruction. Oth-
The concept of “drug signature” has also been er conditions to take into account include total
strongly validated for other features of DILI such parental nutrition40 and sepsis41. Biliary autoim-
as severity, latency, and biochemical pattern35. mune diseases such as primary biliary cholangitis
(PBC) and primary sclerosing cholangitis (PSC)
can be investigated by searching for specific
Table II. Histological patterns of liver damage34. autoantibodies (AMA and p-ANCA respectively)
Dominant pattern of damage Prevalence and with liver biopsy in PBC or proper imaging
techniques in the case of PSC42,43.
Acute cholestasis High
Acute hepatitis High
Liver imaging can also reveal infiltrative he-
Cholestatic hepatitis High patic diseases44 and fatty liver diseases (NAFLD/
Chronic cholestasis High NASH)45.
Chronic hepatitis High Differential diagnosis also includes hemochro-
Coagulative/confluent necrosis Low matosis and α-1-antitrypsin deficiency, which can
Fibrosis/Cirrhosis Low be excluded assessing iron metabolism parame-
Granulomatous changes Low ters and serum enzymatic activity, respectively29.
Hepatocellular alteration Low
Massive/sub-massive necrosis Low
Once the other possible causes of damage are
Minimal nonspecific changes Low excluded, it is necessary to define the causal link
Mixed injury Low between the involved drug and the observed liver
Nodular regenerative hyperplasia Low injury.
Normality Low Among the parameters considered in causality
Steatohepatitis Low assessment, particular attention should be paid in
Steatosis Low defining the time criterion (drug administration
Unclassifiable injury Low
Vascular injury Low
must precede the development of liver injury),
the de-challenge (improvement of liver damage

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Table III. Biochemical pattern of liver damage and related drugs according to major registries4,48.
Hepatocellular Cholestatic Mixed
Acetaminophen Amoxicillin-clavulanic acid Allopurinol
Allopurinol Anabolic steroids Azathioprine
Clindamycin Captopril Carbamazepine
Clopidogrel Cefazolin Chlorpromazine
Disulfiram Chlorpromazine Clindamycin
Fluoxetine Cyproheptadine Cyproheptadine
Flutamide Enalapril Doxycycline
Herbals Estrogens Methimazole
Imatinib Griseofulvin Mycophenolate mofetil
Interferon alpha and beta Macrolides Phenobarbital
Irbesartan Methimazole Phenytoin
Isoniazid Oral contraceptives Sulfonamides
Ketoconazole Sulfonylureas Trimethoprim-sulfamethoxazole
Lamotrigine Terbinafine Verapamil
Levofloxacin Ticlopidine
Lisinopril Trimethoprim-sulfamethoxazole
Losartan Verapamil
Methotrexate
Methyldopa
Minocycline
Mycophenolate mofetil
Nitrofurantoin
NSAIDs
Omeprazole
Pyrazinamide
Propylthiouracil
Rifampin
Valproic acid

after drug discontinuation) and the re-challenge46 literature data about hepatotoxicity of the sus-
(new presentation of the damage, usually with pected drug and the effect of the “re-challenge”
short latency and greater magnitude, at drug when applied30,49.
re-administration). M&V was developed in order to improve RU-
As the time-to-onset of DILI after drug ad- CAM performance. When compared to RUCAM,
ministration can vary widely, from few days to it appears to be easier, even if less accurate50.
even more than one year, detecting the implicated Naranjo scale is not specific to hepatic adverse
drug can be very difficult, especially in polyphar- reactions but is the most rapid to use in the as-
macotherapy4. In these cases, the research of the sessment of adverse drug reactions51,52.
scientific literature of cases reports or similar The above-mentioned scores have been pro-
clinical experiences can help to make the correct posed with the aim of guaranteeing an objective
diagnosis47. LiverTox48, a free online database of assessment of causality in the case of adverse
more than 650 potentially hepato-toxic drugs, drug reactions, but the most used method re-
may be consulted for free. mains “expert opinion”. In DILIN registry, three
Many scores systems have been proposed experts independently review suspected DILI
for causality assessment of DILI. Among oth- cases and the probability category is accepted
ers, Roussel Uclaf Causality Assessment Method if there is a full matching of assessments, oth-
(RUCAM), Maria and Victorino scale (M&V) erwise experts meet to define the most appro-
and the Naranjo probability scale are the most priate probability. The DILIN prospective study
used and widely accepted. compared RUCAM score and expert opinion
RUCAM is probably the most accurate and assessment. Expert evaluations demonstrated
reproducible one. It considers the biochemical higher agreement rates than RUCAM score but
pattern of damage, the onset time and the course both showed a considerable inter-observer vari-
of damage, risk factors, polypharmacotherapy, ability53 (Table IV).

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Table IV. Causality assessment methods to support the diagnosis of DILI.


Hepatocellular Cholestatic Mixed
Roussel Uclaf Causality 7 analyzed aspects: 5 probability levels:
Assessment Method -Time to damage onset -Highly probable
(RUCAM)30 -Effect of drug discontinuation -Probable
-Risk factors -Possible
-Concomitant medications -Not likely
-Potential other causes of liver injury -Excluded
-Known hepatotoxicity of the implicated drug
-Effect of rechallenge
Maria and Victorino 5 analyzed aspects: 5 probability levels:
scale (M&V)50 -Time to damage onset -Definite
-Potential other causes of liver injury -Probable
-Extrahepatic manifestations -Possible
-Known hepatotoxicity of the implicated drug -Not likely
-Effect of rechallenge -Excluded
Naranjo scale51 10 questions answered as either Yes/No/Don’t know: 4 probability levels:
-Previous conclusive reports of the reaction? -Definite
-Adverse reaction onset after drug administration? -Probable
-Adverse reaction improvement after drug discontinuation -Possible
or antagonist administration? -Doubtful
-Adverse reaction reappearance upon drug re-administration?
-Are there other possible cause for the reaction?
-Adverse reaction reappearance after placebo administration?
-Drug detected in blood at toxic concentrations?
-Worsening of the reaction at increasing doses
or improvement upon decreasing doses?
-Previous reactions to the drug or related agents?
-Adverse reaction confirmed by any other evidence?

Drug Induced Liver Case evaluation by three independent experts based on history, 5 probability levels:
Injury Network clinical and laboratory findings. -Definite
(DILIN) causality Assessment accepted if there is a complete agreement -Highly likely
assessment method53 among the three expert reviewers. In case of -Probable
disagreement, reviewers meet to reconcile the -Possible
differences and reach a final single score. -Unlikely
Expert opinion Subjective judgement of the association between the
involved drug and the adverse event by one or more experts

Recently, Bjornsson and Hoofnagle proposed Therefore, it is clear that new and more reli-
to add to the causality assessment the analysis of able tools are needed to improve the final DILI
the number of literature reports for the suspected diagnosis. Experimental studies on the use of
drug. They classified drugs in the LiverTox data- new markers of liver injury, such as high-mo-
base in five categories according to the number bility group box 1 protein, the keratine-18 and
of published case-reports. Of 671 investigated the miRNA-122, are ongoing3. Several studies
drugs, 318 (47%) had no convincing reports of have been conducted with the aim to identify
hepatotoxicity. They found that pharmacological genetic polymorphism predisposing to DILI, but
agents with the higher number of published re- at present, robust data are lacking, with the ex-
ports had at least one instance of a fatal outcome ception of flucloxacillin-induced liver injury54,55.
or a re-challenge. These authors have proposed HLA-B*5701 allele is associated with an 80.6
a new causality assessment method based on fold increase (p=9x10-19) of risk of flucloxacillin
RUCAM score that would be able to give a dif- hepatotoxicity. This polymorphism has a low
ferent probability weight based on the number of positive predictive value (0.12%) and a high neg-
cases-reports47. ative predictive value (99.99%). For these reasons,

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HLA-B*5701 polymorphism could be useful in confounding factors, such as drug interactions,


the differential diagnosis of cholestasis in sub- presence of contaminants, pre-existing diseas-
jects exposed to flucloxacillin but a positive test es and inadequate product preparation, must be
should not influence drug prescription56. considered60.
Reports of HDSILI are heterogeneous and of
extremely variable quality mainly because of the
Liver toxicity induced by herbal and difficulties in case definition and characteriza-
dietary supplements (HDS) tion. A lot of herbs from Chinese, Indian and Ko-
rean traditional medicine such as ephedra sinica
In 1998, the World Health Organization esti- (ma huang)65, larrea tridentata (chaparral)66, ger-
mated that 80% of the world population preferen- mander67, black cohosh68, European mistletoe69,
tially used herbs for therapeutic purposes57. This pennyroyal oil70, some flower plants containing
is traditionally a feature of some regions of the pyrrolizidine alkaloids71, green tea extract72, kra-
world, mainly in the east or Africa, but in recent tom (mitragyna speciosa), roman absinthe (arte-
years, the use of such products has significantly misia herba alba), aegelina (aegle marmelos), and
increased in the Western countries as well58,59. garcinia cambogia, have been reported to cause
Herbal products can have pharmacological prop- liver injury73,74.
erties even if they’re not clearly recognized as Diagnostic and therapeutic approach to HDSI-
medicines so, they can have beneficial but also LI is not different from conventional DILI but
toxic and adverse effects. As for drugs, the herb- expert opinion can assure better results than
al liver toxicity can be direct or idiosyncratic. RUCAM in causality assessment29.
Herb-herb, herb-drug interactions and toxic ef-
fects from contaminants are also to be taken into
account. In fact, adulteration of herbal products Prognosis
with traditional drugs, heavy metals, microbes or
pesticides has been reported in literature60. DILI outcome is generally favorable, with
The English expression “herbal and dietary 90% of recoveries in case of drug discontin-
supplements” (HDS), refers not only to herbal uation29, but a not so negligible percentage of
products, but also to dietary supplements contain- subjects can experience adverse outcomes such
ing vitamins, minerals, amino-acids, proteins, as ALF or chronic liver disease.
enzymes, gland or organic tissues, chemically Female sex, older age, pre-existing liver disease,
synthetized molecules and even illicit anabolyz- alcohol abuse, hepatocellular biochemical pattern
ing steroids61. and some genetic determinants are associated with
In many countries, the regulation about com- a more severe course of DILI and adverse outcome
position, dosage, and quality of HDS is often (death or transplantation)75,76, but risk factors can
lacking or incomplete so manufacturers are not vary according to the involved agents. In subjects
always obliged to declare an exhaustive analyt- who experiment a re-challenge, in any case unin-
ical description of the marketed products. For tentional, the outcome can be worse46.
these reasons, safety and effectiveness of HDS is ALF is defined by the presence of coagu-
not always ensured, and occurrence of toxicity is, lopathy and encephalopathy in subjects without
therefore, not a rare event62,63,64. liver cirrhosis and with an illness of <26 weeks’
Based on the DILIN registry, HDS are respon- duration. It is associated with a mortality rate
sible for 16% of the observed DILI. In 76% of of 60-80% without liver transplantation77,78,79.
these DILI (otherwise referenced as HDSILI) was Among drug-induced ALF, acetaminophen over-
attributed to a mix of different active principles dose appears to have a better prognosis than
so it is hard to identify the single active substance idiosyncratic reactions36. In DILIN and Spanish
responsible for the toxic event60. Registry, fatal outcome (death out of need for
The approach to HDSILI should include liver transplantation) accounted for 10% and 7%
a detailed patient medical history focused on respectively23,24. In severely adverse reaction, the
identifying the assumed product, the purchasing major challenge is the early identification of the
methods, preparation, storage, and intake. When subject whose condition will progress to ALF and
possible, the visual analysis of the product and who will require orthotopic liver transplantation,
the laboratory analysis should be obtained. Af- which is the best therapeutic choice in subjects
ter proper analysis of the implicated product, who don’t have spontaneous recovery80.

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In acetaminophen overdose, the Rumack-Mat- The combination of MELD score and serum
thew monogram, combining plasmatic drug lev- apoptotic markers, such as caspase-cleaved CK-
els and time passed since assumption, could be 18 or intact product, by means of M-30 or M-65
a valid instrument in patients’ monitoring81. Fur- ELISAs88 or the combination of such apoptotic
thermore, the Model for Acetaminophen-induced products with clinical parameters (coma grade,
Liver Damage, that considers ALT, AST, INR, INR, bilirubin and phosphorus levels)89 appears
and creatinine, showed a 100% sensitivity and a to predict the ALF outcome better than classical
91% specificity in predicting mortality82. scores such as Kings College Criteria and MELD.
Prognostic assessment in idiosyncratic DILI These methods represent an attractive prospec-
can be more difficult. The MELD (Model for tive but their use is limited by the difficulty of
End-Stage Liver Disease) score and plasmat- obtaining such determinations routinely.
ic hemoglobin could be used as predictors of Robles-Diaz et al90, recently proposed a new
short-term outcome and is therefore needed for index to predict ALF in DILI. They integrated
OLT21,83. the Hy’s rule with the “new R ratio” (nR), ob-
King’s College Criteria (KCC) were construct- tained by the ratio of the higher among AST and
ed in 1989 from the retrospective analysis of a co- ALT/ALP, both normalized for ULN. A positive
hort of 588 patients with acute liver failure. In ac- Hy’s rule and an nR≥ 5 at presentation showed
etaminophen-induced ALF, arterial pH, prothrom- a sensitivity of 90% and a specificity of 63% in
bin time and creatinine significantly correlated predicting the risk of ALF.
with prognosis while in non-acetaminophen-in- In some cases, DILI may progress to chronic
duced ALF, static variables such as etiology (non injury. In DILIN, chronic liver injury is intended
A, non B hepatitis or DILI), age and duration of as a persistent increase in liver enzymes or histo-
jaundice before the onset of encephalopathy and logical and radiological evidence of liver damage,
two dynamic variables, such as bilirubin and pro- lasting six months or more91. Using this cut-off,
thrombin time, correlated with prognosis84. the prevalence of chronic damage is 15-20% and
In a prospective study conducted in the US, cholestatic DILI seems to have a higher risk of
KCC were tested in 275 patients with acetamin- chronicity92. Recently, a period of 12 months has
ophen-induced toxic ALF. KCC were fulfilled in been proposed for the definition of chronic dam-
only 40 subjects, of whom 19 died and 6 underwent age. With this longer cut-off, the prevalence of
transplantation. This study confirmed a good spec- chronic liver damage is 10% and cholestatic DILI
ificity of the criteria in predicting a fatal outcome does not show an increased risk of chronicity but
(92%) but adverse outcome was also high among only a slower resolution25. Risk factors for devel-
patients who did not meet the KCC, resulting in opment of chronic DILI are advanced age, female
a low sensitivity (26%). In the same study, the sex, and severity of the acute DILI93. Biochemical
Acute Physiologic and Chronic Health Assessment predictors of chronic damage development are
II (APACHE II) appeared to be more sensitive ALP > 1.1 x ULN and a TB > 2.8 x ULN at the
(68%) but slightly less specific (87%) than KCC in second month damage onset25.
predicting patients’ transplant-free survival85. Chronic DILI can present an anatomo-patho-
McPhail et al86 in a recent meta-analysis eval- logic evaluation with different patterns such as
uated the performance of KCC and MELD score cirrhosis, steatosis94, steatohepatitis95, nodular re-
in both acetaminophen and non-acetaminophen generative hyperplasia96, peliosis97 and vanishing
induced ALF. The overall diagnostic accuracies bile duct syndrome98,99.
of KCC and MELD were substantially comparable
even if KCC appeared to be less sensitive while
MELD score was less specific. Neither of these Damage monitoring
scores appeared to be optimal but KCC are proba- and therapy
bly more reliable in acetaminophen-induced ALF
while MELD score could be useful in prognostic Routine monitoring of liver enzymes has not
evaluation of non-acetaminophen-induced ALF. shown favorable costs/benefits ratio in preventing
In acetaminophen overdose, the Sequential the liver from severe adverse events15. Serum
Organ Failure Assessment (SOFA score) has determination of the involved drug and its me-
shown to perform better than MELD, APACHE tabolites, instead, can be useful in the prevention
II and KCC in selecting liver transplant candi- and management of some kinds of direct hepato-
dates87. toxicity9,100.

129
G. Marrone, F.G. Vaccaro, M. Biolato, L. Miele, A. Liguori, et al

The development of signs and symptoms of Conclusions


liver damage always deserve a comprehensive
hepatological evaluation. In some cases, patient DILI is a relatively rare event, but it can have
education can be useful in the early recognition serious consequences in some cases. The actual
of signs and symptoms of DILI101,102. epidemiological dimension of DILI is still affected
The main treatment for DILI is discontinu- by the absence of general registers in most coun-
ation of the involved drug. This can determi- tries and an under-reporting attitude. Nevertheless,
nate clinical and biochemical improvement and the presence of a few national registries such as
prevent severe liver damage. To avoid useless the Swedish, French and the Spanish registry
discontinuation of needed therapies, clinically may help in the understanding of the problem.
significant DILI should be distinguished from Collaborative prospective studies on large series
tolerance phenomenon and adaptive response103. with molecular and genetic analysis will allow a
The transient mild increase of liver enzymes, in better understanding of the pathogenic factors and
fact, does not necessarily imply liver damage. To mechanisms of injury in the future.
distinguish real DILI from adaptive response and The future challenge is the identification of
tolerance, FDA in 2009 suggested to perform a individual predisposing factors that could allow
laboratory monitoring if ALT or AST > 3 x ULN. a better customization of drug therapy in order to
Suspected drug must be discontinued when ALT reduce the incidence of severe DILI.
or AST > 8 x ULN, ALT or AST > 5 x ULN The creation of international consortia for the
for more than two weeks, and ALT or AST > 3 registry and the study of individual predisposi-
x ULN with TB > 2 x ULN or INR > 1.5 and tions to DILI is desirable and, today, thanks to
ALT or AST > 3 x ULN with hypersensitivity the organizational efforts of some pilot countries,
symptoms and signs104. a European consortium with these purposes is
Specific treatments for DILI are scarce. N-ace- emerging117.
tylcysteine (NAC) is the consolidated antidote in
case of acetaminophen overdose9,105. NAC ad-
ministration can also increase the probability of Conflict-of-interest statement
transplant-free survival in adults diagnosed with Marrone M, Vaccaro FG, Biolato M, Miele L, Liguori A,
idiosyncratic DILI due to other causes106,107. Araneo C, Ponziani FR, Mores N, Gasbarrini A and Grieco
Corticosteroids can be used in DILI with clin- A declare no conflict of interest related to this publication.
ical and laboratory manifestations of hyper-sen-
sitivity and in DILI-induced autoimmune hepati-
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