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416

Age

The capacity to metabolize medications may be impaired with age, and hence,

may predispose individuals to DILI.However, in an observational study of 899

patients considered to have DILI, the age of at least 65years was not associated

with increased mortality or liver transplantation [30]. A similar distribution in

gender and age was documented in a study from Spain that included 603 cases of

DILI, with a peak distribution in the 40 to 49 and 60 to 69 age groups, with no

reported cases in the 20 to 29 years aged group. Patients at least 60 years old

accounted for 46% of cases, with a signicant majority being men; however, ful-

minant liver failure and liver transplantation were more common in women than

in men. The proportion of cholestatic liver injury increased with age [31], a nd-

ing similar to the study from the United States [30]. In contrast, a prospective

study from Iceland that included 96 patients with DILI, excluding acetaminophen

induced toxicity, documented the highest incidence in the group 80 to 106years of

age, i.e. 41 per 100,000 inhabitants. The mean prescription rate increased with

age, and it was the highest for this group [32]. These ndings have suggested that

an increase in the number of medications in the elderly may be implicated in DILI

risk [32, 33].

Isoniazid hepatotoxicity from a sample of 3377 patients was studied from a data-

base of patients treated from 1996 to 2003in a public health department clinic in the

United States. Classied per 1000 individuals and according to age group, 4.40

events were reported in the 25 to 34years group, 8.54 in the 35 to 49 years, and

20.83 for those at least 50years old [34]. In contrast, the use of valproic acid as part

of antiseizure therapy was associated with a marked increase, 1:600, in fatal hepa-

totoxicity in patients younger than 2 years of age [35]. Other risk factors included

developmental delay and metabolic disorders [35].

In regards to isoniazid, a predominance of cholestatic liver injury occurs in the

elderly, which differs from the typical hepatocellular injury associated with this

drug, which happens more frequently in people over the age of 35, and that dramati-

cally increases after age 50 [34].

Gender

The studies from Spain, Iceland, and the United States did not support an increase

in the incidence of DILI in women versus men [30–32]; however, it is noted that

women tend to be more susceptible than men to DILI of the autoimmune type,

which may be a reection of the increased risk of some autoimmune liver diseases

in this gender, including autoimmune hepatitis and primary biliary cholangitis

[36, 37].

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Race andEthnicity

The daily use of four grams of acetaminophen in a controlled study documented that

Hispanic American subjects had a 1.9 relative risk (RR) (95% condence interval

(CI), 1.1–3.33) versus non-Hispanic subjects of exhibiting an increase in serum

activity of ALT.There was no difference in the peak and trough or area under the

drug curve levels between the subjects who exhibited versus those who did not

exhibit an increase in serum ALT activity. The ndings suggested that drug metabo-

lism alone may not have been related to ALT activity increases, and perhaps, the

ethnicity determined the increase in ALT activity. Racial characteristics of the

Hispanic subjects were not reported; thus, it is unclear whether the ALT phenome-

non was related to ethnicity, race, or both [38].

Idiosyncratic DILI was reported in association with increased morbidity and

mortality in a study that included 144 African American versus 841 non-Hispanic

white patients. Trimethoprim/sulfamethoxazole, methyldopa, and phenytoin were

more injurious in African American than in non-Hispanic white subjects. The sever-

ity of DILI was worse in African American patients, who had more skin reactions,

were hospitalized more often, underwent more liver transplantations, and had more

liver related deaths 6 months post DILI than the non-Hispanic white subjects [39].

A meta-analysis of pharmacogenetic studies of drug-metabolizing enzyme poly-

morphisms that included 2225 patients and 4906 control subjects revealed an asso-

ciation between drug-induced liver injury from anti-tuberculosis drugs and

CYP2E1*1A in East Asians when the data were stratied by ethnicity [40].

Alcohol

The effect of alcohol on toxicity has been documented for substances that include

acetaminophen, cocaine, halothane, and isoniazid, on which it has a marked

enhancement, with a moderate enhancement for others, including vitamin A and

methotrexate [41].

Pregnancy

Pregnancy is included as a variable in causality assessment scales; however, there is

no evidence that pregnancy per se increases the risk of DILI; however, some drugs

used in pregnancy, including methyldopa, hydralazine, and propylthiouracil used to

treat specic comorbidities can cause DILI; thus the clinician must be aware of their

association with liver injury.

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Comorbidities

Risk factors for nonalcoholic fatty liver disease may be associated with steatosis

and steatohepatitis from medications. In this regard, tamoxifen was associated with

an increased risk for nonalcoholic steatohepatitis in patients with high serum tri-

glyceride and fasting blood sugar concentrations, and low high density lipoprotein.

Tamoxifen related injury was not associated with hypertension, obesity, and over-

weight state in a study from Iran [42]. These results contrast with those from a

prospective randomized, double blind, placebo controlled trial from Italy in which

tamoxifen was associated with an increased risk to develop nonalcoholic steato-

hepatitis only in overweight and obese women with characteristics of the metabolic

syndrome [43].

Methotrexate is another drug that has received much attention regarding its ther-

apeutic benets and its risk for hepatotoxicity. In this regard, a record review from

patients listed from 1987 to 2011 for liver transplantation with the Organ Procurement

and Transplantation Network because of liver disease from methotrexate was con-

ducted [44]. The study reported a low (0.07%) proportion of adult patients listed or

transplanted for methotrexate induced liver disease, with Caucasian, middle-aged

women with diabetes being signicantly present in the group. These characteristics

did not differ from the group listed for nonalcoholic steatohepatitis except for the

race [44]. The results also indicated that a common pathway might underlie the

pathogenesis of nonalcoholic steatohepatitis and methotrexate induced liver injury

when it happens. However, the results cannot be interpreted to suggest that metho-

trexate increases the risk of toxicity in patients at risk for nonalcoholic steatohepa-

titis [44]. Although a slight deviation from the discussion of comorbidities as risk

factors for DILI, it is worth noting that the authors cite a request for additional data

regarding methotrexate induced hepatotoxicity [44], which might have been exag-

gerated for a drug that has important benecial effects [45]. The authors add that

their work fullls that request and conclude that methotrexate induced hepatotoxic-

ity is rare [44]. However, the EASLD (European Association for the Study of Liver

Diseases) Clinical Practice Guidelines: Drug-induced liver injury state “compo-

nents of the metabolic syndrome should be considered risk factors for the occur-

rence and the degree of DAFL [drug-induced fatty liver disease] in patients treated

with tamoxifen and methotrexate” [33].

Chronic Liver Disease

Baseline increased activity of aminotransferases and coinfection with the hepatitis

C virus were identied as risk factors for DILI in association with antiretroviral

drugs, from a retrospective review of data from 8851 patients enrolled in 16 Adult

AIDS Clinical Trial Group studies from 1989 to 1999 [46].

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In a study that included 371 patients with HIV infection, 24.5% of the patients

diagnosed with tuberculosis had underlying liver disease, comprised of acute and

chronic viral hepatitis, alcoholic hepatitis, “other hepatitis,” and chronic liver dis-

ease, which was diagnosed at baseline or during anti-tuberculosis treatment.

Increased serum AST and ALT activities occurred in 31.2% of the episodes of posi-

tive tuberculosis diagnosis during the rst month of treatment, with the most com-

mon increases being twice the upper limits of normal (ULN) in half of the patients.

However, ve and ten times the ULN values were also documented. This study’s

relevance is that patients with HIV and tuberculosis may also have chronic liver

disease, suggesting that liver prole monitoring during treatment is important [47].

Hepatitis C was also identied as a risk factor for DILI in association with anti-

tuberculosis drugs, as documented from a retrospective study of 128 patients.

Coinfection with hepatitis B and C was also identied as a risk factor for DILI as

were increased age and baseline abnormality of the liver panel [48].

From a prospective study that examined the outcomes of 899 patients with DILI,

it was reported that the severity of the liver injury was greater in patients with liver

disease and that DILI was associated with a signicant increase in mortality of

10.8% over those without preexisting liver disease. The most common drug associ-

ated with DILI in patients with preexisting liver disease was azithromycin [30].

Drug Dependent Risk Factors

Medication dose contributes to liver injury, with greater than 50mg per dose associ-

ated with an increased risk for DILI.For example, acetaminophen at a single dose

greater than 7.5g is related to acute liver toxicity. However, idiosyncratic DILI is

characterized by a lack of clear dose dependency [49]; nevertheless, it is now con-

sidered that idiosyncratic DILI may also be related to dosage.

Among prescription medicines from pharmacy databases in the United States, a

statistically signicant relationship was observed between daily doses of oral medi-

cations and liver failure reports, liver transplantation, and death from DILI [50].

Recorded by the Swedish Adverse Drug Reactions Advisory Committee, 9% of all

DILI cases were in the category of less than 10mg per day, 14.2% in the 11–49mg

per day, and 77% in the at least 50mg per day group, with an associated death or

liver transplantation in 2%, 9.4%, and 13.2%, respective to the categories [50].

Drug Metabolism

Drug metabolism can generate metabolites that react with intracellular substances

that alter cellular function and provoke injury [51]. Some of the drugs documented

to cause reactive metabolites include acetaminophen, tamoxifen, isoniazid, and car-

bamazepine [52].

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Hepatic metabolism greater than 50% was dened as high for a study that

explored the relationship between metabolism and DILI [53]. It was reported that

drugs with high hepatic metabolism were associated with a signicant increased

frequency of high ALT activity, liver failure, and DILI associated with death [53].

Lipophilicity

Lipophilicity is a chemical compound’s ability to dissolve in fats, oils, lipids, and

non-polar solvents. Highly lipophilic drugs have an increased ability to cause toxic-

ity. The combination of lipophilicity and daily dose, known as the rule-of-two, is

considered an indication of a drug’s hepatotoxic potential [54]. In this regard, high

lipophilicity may facilitate an increase in the drug uptake by the hepatocyte [54].

The Ro2 analysis is a model that may identify the hepatotoxicity potential of drugs

in the development process [55, 56].

Drug Interactions

It is not infrequent for patients with DILI to be taking multiple medications. The

exercise of reviewing each medication’s start date and the rst day of documented

abnormalities, clinical or laboratory, is fundamental, and it may take more than the

20 to 30minutes allowed to see patients in many clinics. The identication of DILI

culprits has been greatly facilitated by the creation of the LiverToxNIH.gov website

[2]. The readers of this book must learn that unless a vigorous medication reconcili-

ation, which may involve reviewing the medication bottles, calls to the pharmacy,

and communication with other members of the health care team is done, the drug

involved will not be identied, and the opportunity to discontinue it will be missed.

The mechanism of hepatotoxicity in drug interactions may be related to the abil-

ity of some agents to induce the cytochrome p450 family of enzymes, such as rifam-

picin, which, when coadministered with isoniazid, increases the odds of DILI [57],

and carbamazepine and phenytoin, with valproic acid [58].

Mitochondrial Toxicity

Drugs that decrease mitochondrial number and function are associated with fatty

liver, including liver failure. The mechanism of this type of liver injury may result

from increased production of reactive oxygen species, impaired mitochondrial per-

meability transition, altered mitochondrial respiration, mitochondrial DNA dam-

age, or inhibition of beta-oxidation of fatty acids [59].

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This category of hepatotoxic drugs includes aluridine, a nucleoside analogue

[60], thiazolidinediones, brates, cholesterol lowering drugs, antidepressants of the

serotonin reuptake inhibitors type, serotonin antagonists used for nausea treatment,

pain medications (NSAIDs), some antibiotics including uoroquinolones and mac-

rolides, kinase inhibitors and anthracyclins, anticancer drugs [61], and most of the

reverse transcriptase inhibitors used in the treatment of HIV, which act by the inhi-

bition of human DNA polymerase gamma [62].

Inhibition ofHepatobiliary Transporters

Hepatobiliary transporters regulate the uptake of substances into the hepatocyte and

the export of endobiotic and xenobiotics to prevent their intracellular accumulation,

which can be toxic. The bile salt export protein (BSEP) is located on the hepato-

cyte’s canalicular domain and removes monovalent, conjugated bile salts from those

cells. An association between the pharmacological interference with BSEP function

and DILI has been hypothesized [63].

The role of BSEP in DILI has been described for several drugs, including gli-

tazones [64], some antiretrovirals agents [65], and endothelin antagonists [66]. In

vitro models that test the function of BSEP have been suggested for inclusion in the

development of drugs to identify potential toxic agents prior to the human testing

phase [63].

Epidemiology

Four hundred and sixty-one DILI cases were conrmed from 1994 to 2004 in

Spain’s cooperative network [67]. Antimicrobials were the most common type of

drugs, with amoxicillin-clavulanate comprising 12.8% of the cases [67].

A prospective study conducted in Iceland from 2010 to 2011 included 96 sub-

jects with DILI.The crude annual incidence was reported as 19.1 (95% condence

interval [CI], 15.4–23.3) cases per 100,000 inhabitants, 56% being women, with a

median age of 55years. Seventy-ve percent was caused by prescription medica-

tions and 16% by dietary supplements. Again, the most common drug involved in

DILI was amoxicillin-clavulanate, in 22% of the cases, with diclofenac in 6%, and

azathioprine, iniximab, and nitrofurantoin in 4% [32].

The Drug-Induced Liver Injury Network from the United States provided a sub-

group analysis of its prospectively collected data on DILI beginning in 2004 with

patients followed for 6 months. From 1257, causality was assessed in 1091, with

899 being conrmed as denite, highly likely, or probable DILI.Azithromycin was

signicantly more common in patients with liver disease, 6.7%, versus those with-

out liver disease, 1.5% [30].

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It is essential to identify vitamins, minerals, dietary elements, food components,

natural herbs, herbal preparations, and synthetic compounds taken to supplement

the diet as possible culprits in the approach to a patient with liver injury. A report

including these substances documented the DILI cases proportion from 7% in 2004

to 2005 to 20% in 2013–2014, with bodybuilding supplements as a cause of liver

injury from 2% to 6% over the same period [68].

Approach toaPatient withSuspected Drug-Induced

Liver Injury

DILI is part of the differential diagnosis of a patient with an abnormal liver prole.

It is a diagnosis of exclusion; thus, other causes of liver disease must be excluded

before attributing liver disease to a drug, without the workup being an impediment

to a rapid diagnosis [2].

A detailed medication history including those prescribed, over the counter and

herbal supplements, and illicit drugs and alcohol is very important. In addition,

serology for acute or chronic viral hepatitis A, B, C, and E [69], autoimmune mark-

ers, and serum concentration of immunoglobulins, ceruloplasmin, and alpha 1 anti-

trypsin, and iron studies comprise the laboratory investigation in a patient with liver

disease, including DILI [70]. Ischemic hepatitis is a complication not infrequently

identied in hospitalized patients [71]. In addition, hepatic manifestation of extra-

hepatic diseases has to be considered in the differential diagnosis [72, 73].

The information required from the history in the approach to a patient with liver

disease from DILI is: (1) time to onset or latency, i.e., challenge, which is the time

from the rst dose of the agent to the onset of liver injury, (2) time to recovery, i.e.,

dechallenge, (3) injury pattern and clinical phenotype, (4) exclusion of other causes

of liver disease, (5) known information about a drug being the cause of liver injury,

i.e., likelihood, and (6) response to reexposure, accidental or intentional, i.e., rechal-

lenge, which is not done intentionally.

The time to onset can be established from the time the drug was prescribed to the

time the rst symptom or sign of liver injury is experienced or exhibited, e.g.,

fatigue, jaundice, or choluria, because the time to the rst abnormal liver test cannot

be identied unless the patient is being monitored with blood work [2, 74, 75].

The time to recovery is when the medication is stopped to the time the liver

injury is resolved. In general, the resolution starts on discontinuation of the drug

with notable decreases in liver associated enzyme activity within a week of discon-

tinuing the agent; however, prolonged DILI can occur, which requires continuity of

care to document resolution [2, 74, 75].

The pattern of liver injury, i.e., the pattern of the liver prole, or the clinical phe-

notype, may be typical and consistent with what has been reported in the literature,

hence the importance of search databases, e.g., LiverToxNIH.gov and communica-

tion with pharmacists [2, 74, 75].

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The exercise through which efforts are made to identify the DILI agent is called

causality assessment. The instruments used in the causality assessment process for

hepatotoxicity are the Roussel Uclaf Causality Assessment Method (RUCAM) [76]

and its modication, Maria and Victorino (M & V) system [77]. Expert opinion is

the best method to arrive at a diagnosis of DILI [78]; however, as it requires the

participation of several clinicians, it may not be practical in some settings if an

immediate opinion is necessary, but it is undoubtedly worthwhile to seek it as soon

as possible.

In the context of clinical trials, and clinical work, possible hepatotoxicity by

laboratory criteria is dened as [79]:

1. minimally abnormal serum test results, which signify a warning:

(a) AST or ALT above the ULN and up to three times the ULN, o r.

(b) alkaline phosphatase up to 1.5 the ULN, or,

2. markedly abnormal serum test results, which are an indication for immediate

action, i.e., discontinuation of the drug and clinical follow up:

(a) AST or ALT more than three times the ULN, o r.

(b) alkaline phosphatase more than 1.5 the ULN, or,

Causes of liver disease must be excluded as the drug is discontinued, as

already stated.

Mortality can be high when DILI is associated with hepatocellular injury and

jaundice [1]. The early identication of the high potential for a bad outcome with

this type of DILI phenotype is fundamental in clinical trials and clinical medicine.

This observation is known as Hy’s rule, after the master of hepatotoxicity, Dr.

Hyman J. Zimmerman, who recorded it [1, 80]. Severe hepatocellular injury,

reected by increased activity of serum transaminases, can overwhelm the liver’s

capacity to function, e.g., to handle bilirubin, which is reected by hyperbilirubine-

mia and is associated with a ten to 50 percent mortality from ALF from DILI [1].

The Food and Drug Administration has incorporated Hy’s rule in their drug approval

process, and it modied the term Hy’s rule to Hy’s Law [80, 81].

Hy’s Law has been reexamined. The R value is a number that predicts the devel-

opment of ALF from DILI [80, 81]. The development of the new R value, i.e., nR,

has been published. Data recorded between 1994 and 2012 from 777 subjects with

805 episodes of DILI were examined regarding the peak in serum ALT activity and

bilirubin concentration. Thirty-two of the 771 patients developed ALF.The inde-

pendent high risk factors to develop ALF were female gender, high serum bilirubin

concentration, and serum AST to ALT activities ratio (AST: ALT). Comparative

analyses with total bilirubin greater than two times the ULN, and either serum ALT

activity greater than three times the ULN, an R value of ALT times the ULN divided

by SA of alkaline phosphatase times the ULN of at least ve were included as vari-

ables versus an nR, which was calculated by the inclusion of whichever transami-

nase activity was the highest, ALT or AST, divided by SA of alkaline phosphatase

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times the ULN of at least ve. At diagnosis, the R and the nR identied patients who

developed ALF, with 67% and 63% specicity. The serum ALT activity and the nR

model provided a 90% specicity for the development of ALF versus the R model,

the sensitivity of which was 83%. The height of the serum alkaline phosphatase

activity was similar between the group of patients who developed and those who did

not develop ALF.An algorithm comprised of SA of AST greater than 17.3 times the

upper limit of normal, a serum total bilirubin concentration of 6.6 times the ULN,

and an AST: ALT activity ratio greater than 1.5 identied patients who developed

ALF with a specicity and sensitivity of 82% and 80%, respectively. The use of this

relatively new paradigm further facilitates the identication of patients who are at

risk for ALF.It alerts the clinician to provide support measures to patients and vigi-

lant follow up for timely evaluation for liver transplantation [82].

A study that included 250 patients with suspected DILI evaluated the causality

assessment by the use of a structured expert opinion process versus the Roussel

Uclaf causality assessment method. Detailed clinical and laboratory data from

patients with suspected DILI were distributed to expert committee members who

reviewed, adjudicated, and completed a RUCAM scale. For 187 cases associated

with a single agent, there was an initial complete agreement for 50 cases (27%)

within the expert opinion process, and for 34 (19%) with a ve-category RUCAM

scale, which was not signicantly different. The two methods exhibited a modest

correlation with each other. It was noted that the RUCAM method decreased the

causality towards less probable than the expert opinion. Importantly, the RUCAM

approach substantially shifted the causality likelihood towards lower probabilities

than the DILI expert opinion process. The results were interpreted to suggest that

the expert opinion process produced higher agreement rates and likelihood scores

than the RUCAM scale. However, the authors noted a substantial interobserver vari-

ability in both methods [78].

The availability of the LiverTox.NIH.gov website has revolutionized and

improved the approach to a patient with suspected DILI [2]. We access it in our

clinic sessions to identify the likely agent in possible DILI cases and generate a

discussion between at least two clinicians to develop an expert opinion.

Clinical Manifestations

Patients with DILI may be asymptomatic or have fatigue, pruritus, or both, depend-

ing on the pattern of liver injury [2, 74, 75].

Physical examination may be normal and may reveal scleral icterus and spider

angiomata, especially in chronic DILI cases. If chronic, patients may have hepato-

megaly, splenomegaly, and ascites, as a sign of decompensation. In sinusoidal

obstruction syndrome (SOS), tender hepatomegaly and ascites are typical, and jaun-

dice can be present. Liver masses are usually identied by radiographic studies,

especially adenomata, which tend not to be palpable. Malignant tumors can present

with palpable liver masses and their complications (Table14.2).

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Table 14.2 Clinical phenotypes of drug-induced liver injury [2]

Clinical

Phenotype

Typical

agents Latency Clinical manifestations Type of liver prole

Liver

histology

Duration of liver

injury/

prognosis

Acute hepatic

necrosis

acetaminophen

aspirin

niacin

intravenous

amiodarone

terbutaline

One to fourteen

days

Nausea, vomiting,

abdominal pain, and

altered mental status,

somnolence and coma

jaundice

systemic involvement

(e.g., renal, bone

marrow, lung)

Hepatocellular Centrilobular necrosis, little

lobular lymphocytic

inltration, minimal or no

brosis or cholestasis

It can be fatal or

associated with

rapid recovery

Acute hepatitis isoniazid,

pyrazinamide,

disulram,

fenobrate, ephedra

greater celandine,

green tea

Two to

24weeks

Prodrome:

inappetence fatigue

nausea,

jaundice,

choluria

Hepatocellular Hepatocellular necrosis,

lobular disarray, lymphocytic

inltration, minimal or no

brosis

Two to four weeks

1) Cholestatic

2) mixed

hepatitis

1) amoxicillin/

clavulanate,

sulfonylureas

rifampin, penicillins,

cephalosporins,

methimazole

2) phenytoin,

carbamapezine,

iamotrigine

sulfonamide,

macrolide antibiotics,

enalapril

1) 2 to

24weeks

2) 4–24weeks

Pruritus and jaundice 1) Cholestatic with

modest

hepatocellular

features and

bilirubin >2mg/dl

2) Cholestatic and

hepatocellular

1) intrahepatic cholestasis

with some inammatory cells

but mild to moderate focal

hepatocellular necrosis

2) intrahepatic cholestasis

with inammatory cells and

moderate to severe

hepatocellular necrosis.

Short or prolonged.

Liver associated

enzymes may

decrease by 50%

over four to twelve

weeks

(continued)

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10.10.20268 Мб0Книга_4704_Библиотеки_им_академика_М_И_Перельмана.pdf
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10.10.20268 Мб0Книга_4706_Библиотеки_им_академика_М_И_Перельмана.djvu