EASL Liver Disease Colombo M

Clinical Practice Guidelines JOURNAL
OF HEPATOLOGY
EASL Clinical Practice Guideline: Occupational liver diseasesq

European Association for the Study of the Liver⇑
Summary remains challenging in clinical practice due to the lack of

A variety of chemicals have been linked to occupational liver pathognomonic signs and sensitive biomarkers of liver injury.
diseases, including several solvents and mixtures thereof, pesti- Whilst acknowledging that viral infections in hospital workers
cides, and metals. Workplace exposures have been associated are recognised as OLDs, herein, attention will only be paid to
with virtually the entire spectrum of acute and chronic liver dis- chemically induced liver injuries.
eases. However, their prevalence is inadequately quantified and These recommendations are intended to provide standardis-
their epidemiology limited. Occupational liver diseases may ation of nomenclature, definitions and classification of the type
result from high accidental or from prolonged lower level expo- of liver injuries, based in part on the criteria for drug-induced
sures. Whereas the former is uncommon and easily recognised, liver injury (DILI), which attempt to grade their severity.4,5
the latter are relatively more frequent but often overlooked The main focus will be to increase awareness of OLDs within
because they may display normal values of conventional mark- the medical community and to improve recognition and man-
ers, have an insidious onset and be asymptomatic or be obfus- agement of affected patients in a consistent manner.
cated and confounded by concurrent conditions. In addition, Due to the absence of data on observational studies and
specific tests of toxicity are not available, histopathology may meta-analyses or systematic reviews, the evidence and recom-
not be revealing and the assessment of internal dose of chemi- mendations in these guidelines have been graded according to
cals is usually not decisive. Given these circumstances, the diag- the Oxford Centre for Evidence-based Medicine, which assesses
nosis of these liver disorders is challenging, one of exclusion and evidence according to diagnostic, prevalence, aetiological, prog-
often requires an interdisciplinary approach. These recommen- nostic or preventive categories,6 and – even when the evidence
dations offer a classification of the type of liver injuries associ- is inconclusive – can still generate grades of recommendation.
ated with occupational exposures – based in part on the This follows the recent recommendations for European Associa-
criteria for drug-induced liver injury – a grading of their sever- tion for the Study of the Liver (EASL) Clinical Practice Guidelines
ity, and the diagnostic and preventive criteria for chemically (CPGs).7
induced occupational liver disease. This CPG has been developed along a 2 year mandate by a
Ó 2019 European Association for the Study of the Liver. Published by panel of experts chosen by the EASL Governing Board who
Elsevier B.V. All rights reserved. had 3 face to face meetings. This included experts in hepatology,
toxicology, pharmacology, pathology, occupational medicine
and epidemiology. Conflicts of interest were declared as
Introduction requested, and consensus was reached by discussion, whenever
Occupational exposures can induce liver injury in a similar way required. The recommendations were peer-reviewed by exter-
to prescription drugs, herbal and dietary supplements, and nal expert reviewers and approved by the EASL Governing
workplace exposure has been implicated in the full spectrum Board. The CPG was developed using data collected from
of liver disease. However, the awareness of hepatologists for PubMed and Cochrane database searches up to December
this specific aetiology of liver injury is limited and the incidence 2018. The searches were conducted using the terms ‘‘liver dis-
and prevalence of occupational liver diseases (OLDs) remains eases, occupational”, ‘‘hepatotoxicity”, ‘‘drug-induced liver
unknown. Acute liver injury is likely to decrease, at least in high injury”, and ‘‘chemicals”, ‘‘toxicants”, ‘‘vinyl chloride”, ‘‘TASH”,
income countries, given the improvement in health and safety ‘‘NAFLD”. Papers were searched for additional references. No
in workplaces achieved over the recent years. Unpredictable other restrictions were applied. This CPG is based, as far as pos-
routes of exposure such as breakdown, cleaning and mainte- sible, on evidence from existing publications and, when unavail-
nance of machinery, and accidental leakage still occur though able, the authors provided personal experiences and opinions
and new causes of OLD will potentially come to light, such as and reached a unanimous expert consensus.
liver silicosis, particulate matter air pollution and increasing
use of nanomaterials.1–3 Moreover, the diagnosis of OLD
Epidemiology
Despite the well-documented presence of multiple potentially
Received 12 August 2019; accepted 12 August 2019
q
Clinical Practice Guideline Panel: Chair: Massimo Colombo; Panel members: Carlo
hepatotoxic chemicals at a variety of workplaces (e.g., agricul-
La Vecchia, Marcello Lotti, M. Isabel Lucena, Christophe Stove, Valérie Paradis; EASL tural, hospitals, dry cleaning shops, chemical factories covering
Governing Board representative: Philip Newsome. polymer synthesis, resins, leather and printing) the prevalence
⇑ Corresponding author. Address: European Association for the Study of the Liver
of OLD is unknown. We will address the role of occupational risk
(EASL), The EASL Building – Home of Hepatology, 7 rue Daubin, CH 1203 Geneva,
Switzerland. Tel.: +41 (0) 22 807 03 60; fax: +41 (0) 22 328 07 24. factors as they contribute to non-malignant and malignant liver
Journal of Hepatology 2019 vol. xxx j xxx–xxx

Please cite this article in press as: European Association for the Study of the Liver. J Hepatol (2019), https://doi.org/10.1016/j.jhep.2019.08.008
Clinical Practice Guidelines
Box 1. Summary of epidemiological studies on occupational liver disease.
a. Non-malignant liver diseases

Data are insufficient to provide recommendations, due to difficulties in adjusting for covariates and confounding factors.
b. Liver neoplasms
i. Vinyl chloride monomer and angiosarcoma of the liver and hepatocellular carcinoma
Following the control of occupational exposure to VCM in the mid-1970s, few additional cases of VCM-related angiosarcoma of the liver are anticipated in the
future. By inference, this applies to other liver cancers, too.
Surveillance with ultrasounds for development of emergent liver neoplasms should be discussed for workers exposed to high levels of VCM in the past, i.e. until
the mid-1970s, as defined by their job title (reactor cleaners).
ii. Controversial associations with liver cancers

The available evidence does not support recommendations for screening for liver cancers in trichloroethylene and other chlorinated solvent-exposed workers,
workers exposed to polychlorinated biphenyl and workers exposed to pesticides.
conditions. A summary of the main conclusions and recommen- VCM and cirrhosis,15 which is in agreement with experimental
dations is shown in Box 1. studies of VCM-exposed rodents and pathology reports of
VCM-exposed workers and patients with VCM-related liver
Non-malignant liver diseases angiosarcoma. These studies did not observe evidence of cirrho-
In a population survey of over 13,700 workers from Taiwan, sis, only periportal fibrosis.16–19
higher prevalence rates of self-reported unspecified ‘‘liver dis- In another example, despite prior experimental data associ-
ease” were observed among blue-collar or unskilled workers, ating shift work with non-alcoholic fatty liver disease
although notably they also reported more frequent tobacco (NAFLD),20,21 a cross-sectional study based on multiple cycles
and alcohol use,8 raising uncertainty about causation. Substan- of the National Health and Nutrition Examination Survey
tially higher mortality rates from non-neoplastic diseases of the (NHANES) cohort found no evidence of an association when
liver were also reported in low versus high social class occupa- comparing 1,019 shift-workers with 8,159 other adults (odds
tions in a Korean cohort of workers enrolled in the national ratio 1.11, 95% CI 0.87–1.43.)22 Circadian disruption (jet lag)
employment insurance program between 1995 and 2000.9 Sim- has been related to hepatocellular carcinoma (HCC) in rodents,
ilarly, using 1979–1981 data, the California Occupational Mor- possibly through induction of NAFLD.21 Data on shift work
tality Study (COMS) reported a high mortality from cirrhosis and liver neoplasms in humans, however, are inconclusive.
among selected low social class occupations, including bar- Data are insufficient to provide recommendations due to dif-
tenders, loggers, laborers, roofers, construction workers, farm ficulties in adjusting for covariates and confounding factors.
workers, ironworkers and painters for men, and waitresses,
telephone operators, cosmetologists, dress makers, hospital Liver malignancies
orderlies, textile workers and laborers for women. Conversely, Vinyl chloride monomer and angiosarcoma of the liver and
a low mortality from cirrhosis was observed among high social hepatocellular carcinoma
class occupations.10 An elevated mortality from cirrhosis was Since the first 3 reported cases of liver angiosarcoma amongst
observed among publicans and bar staff of both sexes, and male VCM reactor cleaners in a US facility,23 subsequent evidence
seafarers, caterers, cooks and kitchen porters in an analysis of has confirmed the causative link between high occupational
national English and Welsh death data.11 Overall, these findings exposure to VCM (among autoclave workers) and angiosarcoma
point to unfavourable lifestyle factors linked to lower social of the liver.12,13 In the most recent update, a collaborative re-
class, in particular alcohol abuse and tobacco smoking, which analysis of nearly 10,000 US workers exposed to VCM reported
may coexist with exposure to other occupational toxins. 63 deaths from angiosarcoma of the liver, occurring after an
However, one of the challenges can be the presence of con- average of 40 years of follow-up.13 With reference to HCC, the
founding factors. As an example, an excess risk of cirrhosis fol- International Agency for Research on Cancer (IARC) concluded
lowing high cumulative exposure to vinyl chloride monomer in 1987 that VCM exposure causes HCC,24,25 in part based on
(VCM) in the workplace was suggested by a re-analysis of Euro- data from 2 large collaborative re-analyses of VCM-exposed
pean workers, albeit in the absence of a linear trend in risk or of European12 and US workers.13 A meta-analysis of data from
an excess mortality from cirrhosis.12 However, incorrect associ- these 2 large cohorts estimated a summary RR of 1.35 for liver
ations can often be made when conclusions are drawn from sin- cancers other than angiosarcomas, which was of borderline sig-
gle studies. A systematic review and meta-analysis including nificance (95% CI 1.04–1.77). This estimate was based on 60
data from the aforementioned European multicentre study,12 deaths mainly from HCC but also from liver cancer of unspeci-
along with a large multicentre collaborative re-analysis from fied or undefined histology, and hence possibly angiosarco-
North America13 and 5 smaller independent cohort studies, of mas.26,27 It is therefore unclear if the excess risk was real or
over 40,000 VCM-exposed workers with 203 deaths from cir- due to misclassification of HCC.12,15 In any case, in 2012, the
rhosis,14 did not find any increased mortality from cirrhosis in IARC confirmed its earlier conclusion on VCM exposure as a cau-
VCM-exposed workers overall. The pooled relative risk (RR) sal factor for HCC.24,25 In 2017, a US collaborative re-analysis
was 0.73 (95% CI 0.61–0.83), with no evidence of heterogeneity provided results updated up to 2013 and, based on 32 deaths
or publication bias. Thus, the available epidemiological data do from the disease, found that the increased risk of HCC was
not support a relationship between occupational exposure to restricted to workers with very high estimated cumulative
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exposures, i.e. over 1,000 ppm-years – approximately 25 times a presser as a surrogate of tetrachloroethylene exposure), did
working lifetime (40 years) at the exposure limit of 1.0 ppm.13 not find a consistent association, even among studies with a
More recently, an ecologic investigation from Texas found a large number of observed events/exposed cases or a strong
positive association between the incidence of HCC and VCM exposure-assessment approach.36
concentrations in air28 – in this case the exposure was environ-
mental though and not occupational. In conclusion, whilst high Polychlorinated biphenyl exposure. A meta-analysis of occupa-
VCM exposure has a clear causative association with angiosar- tional exposure to polychlorinated biphenyls (PCBs) found no
coma of the liver, its link with HCC is not as well- significant association with liver cancer (pooled standardized
established.15 Following the control of occupational exposure mortality ratio [SMR] = 126, 95% CI 65–220), although this was
to VCM in the mid-1970 s, few additional cases of VCM- based on only 12 events from 4 investigations.37 An excess mor-
related angiosarcoma of the liver are anticipated in the future. tality from liver, gallbladder and biliary tract cancers was
By inference, this applies to other liver cancers too. detected in a cohort of US PCB-exposed workers, based on 5
deaths among men and 9 among women,38 but this was only
significant in women. Similarly, no increase in mortality from
Recommendation liver cancer was reported in an updated analysis of 2 Italian
occupational cohorts.39 A combined analysis of the 3 largest
US capacitor manufacturing cohorts, including overall 24,865
Surveillance with ultrasound for development of emer- workers exposed to PCBs from 1938 to 1977 at plants in Indi-
gent liver neoplasms should be discussed for workers ana,40 Massachusetts, and New York,41 with 63 deaths from
exposed to high levels of VCM in the past, i.e. until the liver, biliary tract and gallbladder cancer also found no excess
mid-1970s, as defined by their job title (reactor clean- liver cancer mortality overall (SMR 0.98, 95% CI 0.76–1.26), irre-
ers). Grade D spective of longer (≥90 days of employment) or higher cumula-
Evidence: Extrapolation from level 2 studies (historic tive PCB exposure (≥600,000 unit-days).42 Thus, epidemiologic
cohort studies) evidence does not support an association between occupational
exposure to PCBs and liver cancer risk. Yet, PCBs are currently
classified as Group 1 ‘‘Carcinogenic to humans” by IARC,43 lar-
Controversial associations with liver cancers gely based on evidence of melanoma risk in humans.
Trichloroethylene. Trichloroethylene (TCE), which has been
widely used for decades to degrease metal parts and for dry Pesticides. In the Agricultural Health Study cohort44 there was
cleaning,29 when given at very high doses to certain strains of an excess HCC risk in metolachlor (a widely used herbicide)
rats and mice can induce a variety of cancers, including liver/ users, but there were only 23 exposed cases, and the RR for
kidney tumours, and lymphomas.30 The evidence from epidemi- the highest intensity-weighted lifetime days exposure category
ologic studies is less clear. A meta-analysis combining results was significant only when non-exposed applicators were used
from 9 cohort studies (generally based on fewer than 10 events) for comparison (RR = 3.18, 95% CI 1.10–9.22). Other herbicides
found a modest association for overall TCE exposure and cancer and pesticides were occasionally associated with slight changes
of the liver or gallbladder/biliary tract (pooled RR 1.29, 95% CI in liver function and enzymes,45,46 and also to HCC risk, but the
1.07–1.56). However, there was no consistent dose-risk rela- evidence was inconsistent.47 In a systematic review from 2015,
tionship as the estimate for the highest TCE exposure category including 15 studies on pesticide exposure and liver cancer
(RR 1.28, 95% CI, 0.93–1.77) was similar to that of the overall (mainly HCC), most studies, particularly those relying on self-
analysis.31 The pooled RR from the 3 studies providing informa- reported exposure and occupation, job-exposure matrices, and
tion on liver cancer alone fell short of finding an association rural residence, found no association.48 In addition, a Canadian
(pooled RR 1.25, 95% CI 0.99–1.57).32 A nested case-control cohort of over 2 million agricultural workers found, if anything,
study from the Nordic record-linkage study did not find an a reduced liver cancer occurrence.49 However, biomarker-based
increased liver cancer risk among dry cleaners when TCE was studies conducted on Chinese populations suggested that cer-
the dominant solvent,33 in agreement with a US cohort of over tain organochlorine serum levels, mainly of dichlorodiphenyl
5,000 dry cleaning workers.34 trichloroethane (DDT), may be associated with an increased
liver cancer risk.50–52
Tetrachloroethylene (or perchloroethylene). A record-linkage Various jobs. In a cohort of over 8 million Koreans followed for
study from 4 Nordic countries based on census occupation an average of 11 years, higher mortality rates from liver and
information (i.e. the Nordic Country Occupational Cancer, intrahepatic bile duct cancers were observed in both male and
NOCCA, study) suggested an association between occupational female of lower social class groups.9 Similarly, male cooks and
exposure to TCE or perchloroethylene (also named tetra- kitchen porters, caterers, publicans and bar staff, and seafarers
chloroethylene), a chlorinated solvent mainly used in dry clean- had a higher mortality from liver cancer in an analysis of
ing, and HCC.35 national mortality data from England and Wales, which has
A systematic review by the U.S. Environmental Protection been attributed to higher levels of alcohol consumption in those
Agency that included 18 studies which used different occupations compared to the general population.11 A record-
exposure-assessment approaches (e.g. individual exposure linkage study of 15 million adults from 5 Nordic countries iden-
assigned using a job-exposure matrix; individuals employed tified 17,730 HCC cases in men and 10,973 in women in the
only in facilities using tetrachloroethylene as the primary sol- 1960–90 censuses that were followed-up until 2005.53 Of note,
vent exposure; occupational title as dry cleaner, launderer or the highest standardised incidence ratios (SIR) in men were
Journal of Hepatology 2019 vol. xxx j xxx–xxx 3

observed among waiters (4.22, 95% CI 3.47–5.13), cooks and female beverage manufacture workers.59 Two case-control
stewards (SIR = 2.6, 95% CI 1.9–3.3) and beverage workers studies, 1 in Italy and 1 in France, also found associations
(SIR = 2.5, 95% CI 1.85–3.31).53 Other significant high-risk job between HCC and employment in repair of motor vehicles.60
categories included journalists, seamen, administrators, sale/ and metal machining jobs.61 A Japanese study on 51 offset col-
shop workers, plumbers and economically inactive subsets. In our proof-printing workers exposed to 1,2-dichloropropane
women, excess risks were seen amongst smelting workers and/or dichloromethane reported 11 cases of cholangiocarci-
(SIR = 2.11, 95% CI 1.09–3.68), tobacco workers (SIR = 2.04, noma. Despite this cluster, no further reports are available on
95% CI 1.08–3.48), waitresses (SIR = 1.36), launderers and dry 1,2-dichloropropane and/or dichloromethane.62
cleaners (SIR 1.27) and building caretakers (SIR 1.21). Whilst A narrative review reported associations between polycyclic
the pattern of high-risk occupations in men largely reflects aromatic hydrocarbons and liver cancer, besides solvents and
the high frequency of alcohol consumption and other known asbestos, with however inconsistent findings across original
lifestyle risk factors for HCC (e.g. tobacco and hepatitis), chem- reports, and unsatisfactory mechanistic justification for asbes-
ical factors may at least in part contribute to the highest SIR tos. There were also scattered reports of an association between
observed in women.53 Based on Finnish data, Lindbohm et al. heavy metals and NAFLD.63
reported excess risks of liver cancer among workers highly We should call for raised attention on unexpected clusters of
exposed to chlorinated hydrocarbons and other solvents, OLD and new work-related health risks in general, as the only
though based on a limited number of exposed individuals.54 way to establish epidemiological links is to have such reports
Similarly, an excess of liver cancer was observed in a Danish made publicly available.
cohort of 15,534 men and 3,593 women working in the printing The available evidence does not support recommendations
industry in 1970.55 A US case-control study conducted in 1975– for screening for liver cancers in trichloroethylene and other
1980 and including 265 HCC cases, found an excess liver cancer chlorinated solvent-exposed workers, workers exposed to poly-
risk for male farm labourers and males employed in winemak- chlorinated biphenyl and workers exposed to pesticides.
ing, gasoline service stations, laundering, bartenders and other
eating and drinking places.56 Another US retrospective study
with over 1,700 deaths from liver cancer found an increased risk The occupational setting
for oil refinery workers, plumbers and pipe fitters, textile work- A wide variety of chemicals, encountered at the workplace, have
ers, butchers and meat cutters and cooks.57 Similarly a Danish been linked to liver injury. Table 1 provides a list of compounds,
nested case-control study with almost 1,000 liver cancer cases with the associated liver pathologies, which are further elabo-
found an excess risk in a large number of industries, including rated on in Section 6. Table 2 links these compounds to (typical)
the printing industries and among employees with easy access usages, which may be further linked to professions in which
to alcoholic drinks.58 A follow-up study based on the Swedish these compounds are (or can be) encountered. The latter is par-
Family-Cancer Database found increased liver cancer risks for ticularly relevant to allow a suspicion to be raised between
male sales agents, journalists, seamen, waiters, cooks and workplace-related exposure to a liver toxicant (even when
Table 1. Pathological patterns and morphological features of liver disease associated with workplace-related toxicants.
Pathological patterns Morphological features Toxicants
Acute damage
Hepatocellular Hepatocellular necrosis ± lobular CCl4, chloroform, toluene, TNT, PCBs, chloronaphthalene,
inflammation DMF, hydrazine, 2-nitropropane, phosphorus, DMA,
halothane, TCE, tetrachloroethane, 1,4-dichlorobenzene
Microvesicular steatosis DMF
Cholestatic/mixed Cholestasis, cholangitis Methylenedianiline
Combined features Nitrobenzene, paraquat, methylenedianiline
TAFLD Steatosis (macro/microvesicular) Chloroalkenes (PCE, TCE), VCM, chloroform, CCl4, volatile
Steato-hepatitis (steatosis + lobular organic compounds (benzene, toluene, styrene, xylene),
inflammation + hepatocellular ballooning) dioxins, chlordecone, DMF, hydrazine, arsenic, mercury, POPs,
pesticides, and some nitro-organic compounds
Vascular Sinusoidal obstruction syndrome VCM, dioxin, pyrrolizidine alkaloids, arsenic, copper sulfate
Peliosis VCM
Chronic damage
Fibrosis Periportal fibrosis VCM, PCBs, chloronaphthalene, Tetrachloroethane
Extensive fibrosis/cirrhosis VCM
Vascular Porto-sinusoidal vascular disease VCM, sprays containing copper sulfate and lime
(previously hepatoportal sclerosis)
Tumors
Epithelial
Hepatocellular carcinoma Arsenic, dimethylnitrosamine
Cholangiocarcinoma 1,2-Dichloropropane, dichloromethane
Vascular
Angiosarcoma VCM, Arsenic
Epithelioid hemangioendothelioma VCM
DMF, dimethylformamide; PCBs, polychlorinated biphenyls; POPs, persistent organic pollutants; VCM, vinyl chloride monomer.

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historical – possibly a decade or more ago) and an observed Drug-chemical interactions
disease. Liver cytochrome P450 isozymes are responsible for the oxida-
tive metabolism of most drugs and workplace-related xenobi-
otics. The concurrent administration of drugs and exposure to
Recommendation chemicals could either induce or inhibit microsomal activity,
either directly or via the generation of reactive metabolites,
thereby modifying the effect of either drug or chemical expo-
It is advisable that workers with potential exposure to sure. For instance, first-generation anti-epileptics are known
hepatotoxic chemicals receive a document listing the for their enzyme inducing capacities. Hence, enzyme induction
chemicals used in the factory. Such a document may be by carbamazepine, a known hepatotoxin in itself, favours chem-
made available to the workers without request. Grade D ically reactive metabolite formation from other chemicals,
Evidence: Level 5 (Expert opinion) thereby increasing their risk of liver toxicity. This is exemplified
by a carbamazepine-treated patient presenting with acute hep-
atitis resulting from the use of paints, paint thinner, carbon
The National Institute for Occupational Safety and Health has tetrachloride (CCl4) and organic solvents in enclosed areas with-
published a pocket guide to hazardous chemicals.64 This guide out ventilation, in whom the hepatotoxicity was mistakenly
can help clinicians to know if the chemicals to which the patient ascribed to carbamazepine.69 The predisposition to severe liver
has been exposed are known causes of the observed liver and renal injury in a worker using CCl4 to clean paintings, prob-
disease. ably due to microsomal induction by concomitant treatment
with phenobarbital, underscores the importance of not over-
looking the potential for drug/xenobiotic interactions at the
workplace.70 In addition, we should also keep in mind the
Host risk factors for occupational liver disease potential of xenobiotic interactions in industry workers exposed
Understanding what makes one particular worker susceptible to multiple chemicals at once. Thus, a mixed exposure to chlo-
to develop liver injury after exposure to industrial chemicals rinated organic solvents, including dichloromethane, 1,2-
as opposed to other co-workers who do not manifest any hep- dichloropropane, and trichloroethylene, may induce a synergis-
atic dysfunction is key. The answer to this question is complex. tic effect towards the development of severe acute hepatitis.71
Many industrial chemicals belong to the group of so called ‘‘in- Furthermore, in an experimental model, thinner pretreatment
trinsic” hepatotoxins. These are substances with predictable (methanol or toluene are the major constituents) via inhalation
toxicity, which dose-dependently and directly (or through acti- potentiated the hepatotoxicity induced by CCl4 through an
vation of chemicals to toxic metabolites) produce liver damage. induction of microsome oxidases to increase the formation of
In practical terms, the dichotomy between intrinsic and idiosyn- free radicals and membrane lipid peroxidation.72
cratic hepatotoxins is an overly simplified concept because the
potential for toxic injury extends along a spectrum, modified
by the toxin and host factors, involving different biochemical
Recommendation
and immunological responses.65 Elaborating on this concept,
the hepatotoxic potential of some chemicals, such as phospho-
rus or pyrrolizidine alkaloids, is closely linked to the extent of Caregivers, as well as workers exposed to liver enzyme
exposure and rarely to host vulnerability. On the other hand, inducers and/or using enzyme inducing drugs should
individual susceptibility is critical in determining the probabil- be informed of the possibility of interactions with anti-
ity of developing liver injury from compounds such as convulsant drugs. Grade C
halothane or paracetamol. Therefore, risk assessments should Evidence: Level 4 (case series)
also take into account host-environmental interactions that will
likely modulate the severity of liver injury and add complexity
to the diagnosis of OLD. Genetic variations in metabolic pathways
Genetic polymorphisms in genes encoding enzymes involved in
Age and gender xenobiotic metabolism (oxidation and detoxification) result in
Age plays an important role for drug disposition and sensitivity different drug levels, which can then result in variable drug
to xenobiotics. As body composition changes with age, particu- effects, thus exemplifying another element that may determine
larly in women, exhibiting a higher percentage of adipose tissue, an individual’s susceptibility to chemical-induced liver disease.
lipophilic chemicals could enhance the risk of liver injury.66 Hence, patients exhibiting a poor metaboliser genotype may
However, the net effect of age as a risk modifier for OLDs is show higher serum toxin concentrations and associated risk of
unknown. toxicity. Hsiech et al.73 showed in a longitudinal study of 320
In an experimental model, female rats exhibited a more sev- workers exposed to VCM that 13 developed liver fibrosis with
ere phenotype of mercuric chloride-induced hepatotoxicity, as those that were homozygotes for CYP2E1 variant alleles (low
evidenced by higher increases in aminotransferases and activity) being overrepresented in this group. However, liver
histopathological findings.67 Interestingly, in patients with DILI, injury from drugs and chemicals is a complex process, reflecting
despite an equal sex distribution, females are at a higher risk of the interplay between the toxin’s physicochemical properties
developing acute liver failure.68 Female sex might be a risk fac- and host factors that modulate the final response to hazardous
tor for chemical-induced liver injury, although robust evidence exposures.74 Consequently, knowledge of genetic variability has
from human data is still lacking. not yet proven useful for discriminating high-risk populations.75

Table 2. Overview of workplace-related toxicants and typical uses.

Toxicant Uses (selection)
Arsenic Pesticide; impurity in smelting processes
Carbon tetrachloride Chemical manufacturing; cleaning fluid; dry cleaning; degreasing agent; refrigerant; pesticide
Chlordecone Pesticide
Chlorinated hydrocarbons Degreasers and cleaning solvent; refrigeration
Chloroform Pharmaceutical industry; dyes and pesticides; reagent
1,4-Dichlorobenzene Insecticide
Dimethylacetamide Industrial solvent; production of acrylic fibers
Dimethylformamide Industrial solvent, chemical manufacturing (acrylic fibers and plastic); paints
Dimethylnitrosamine Waste product of rocket fuel manufacturing
Dioxin Pesticide
Halothane Anesthesiology
Hexachlorobenzene Fungicide
Hydrazine Rocket fuel; preparation of gas precursors in airbags; oxygen scavenger
Methylene dianiline Production workers; intermediate for polyurethane foam insulation
2-Nitropropane Paint; adhesive; coatings
Paraquat Insecticide
Phosphorus Munition
Polychlorinated biphenyls Production; electrical utility (coolants, insulating fluids)
1,1,2,2-Tetrachloroethane Aircraft manufacturing; formerly in paints and pesticides; dry cleaning; leather treatment
Toluene Paints; coatings; adhesives; inks; cleaning agents; dyes
Trichloroethylene Glue and cleaning solvent; grease remover; decaffeination of coffee
Trinitrotoluene Munition
Vinyl chloride Plastic (PVC) and rubber manufacturing
Xylene Resins; gums; paints; adhesives; inks; gasoline
PVC, polyvinylchloride.
Indeed, according to the code of ethics issued by the Interna- Pre-existing liver diseases
tional Commission on Occupational Health the selection of As exposure to some occupational toxins may induce acute or
high-risk populations upon genetic testing should be considered chronic liver injury, it is important to assess the functional sta-
unethical. Instead, improving working environments is tus of patients’ livers, as toxin exposure may be worsened by
recommended.76 underlying liver disease. However, this remains quite a contro-
versial issue, with minimal clinical data to support the view that
Alcohol underlying liver disease may increase susceptibility to occupa-
There is agreement that social habits, such as alcohol consump- tional chemicals.82
tion, can worsen or potentiate the toxicity associated with occu-
pational exposure to chemical substances, thus acting as a Non-alcoholic fatty liver disease
confounding factor when making a diagnosis of the role of occu- NAFLD, the most prevalent liver disease worldwide, is consid-
pational exposure (e.g. fatty liver). Notably, the prevalence of ered the clinic-pathological hepatic manifestation of obesity
alcohol use amongst industrial workers is inferred to be high, and metabolic syndrome. It is recognised that in patients with
with reports of male workers having higher consumption than NAFLD, CYP2E1 is upregulated (like in obese patients), favouring
females.77 the metabolism of toxins (like VCM) into reactive metabolites,
It is well recognised that alcohol consumption can increase which could ultimately increase the susceptibility to toxicant-
the hepatotoxic effects of other compounds taken simultane- associated steatohepatitis (TASH) development. There is exper-
ously through its inducing effect on the cytochrome P450 sys- imental evidence that exposure to low doses of VCM may also
tem (CYP), particularly the isoform CYP2E1.78 Indeed, high sensitise the liver to other metabolic stresses and potentiate
alcohol intake had a severe potentiating effect on occupational liver injury.83 Similarly, there is evidence that pre-existing
exposure to CCl479 and other chemicals that are activated by NAFLD increases the risk of acetaminophen overdose-induced
the same cytochrome P450 enzymes.80 Alcohol drives the gen- acute liver injury.84 Notably, patients with NAFLD were not at
eration of toxic free radical intermediates and therefore a higher risk of statin hepatotoxicity.85 However, a recent study
enhances the likelihood of severe CCl4-induced liver injury.81 in the US, using electronic medical records, showed that
patients with surrogate markers of NAFLD (i.e. consistently ele-
vated alanine aminotransferases [ALT] levels and high preva-
Recommendation lence of hypertension, type II diabetes mellitus and obesity)
had a greater incidence of suspected DILI related to the drugs
most frequently involved in hepatotoxicity.86 Interestingly,
Caregivers and workers should be informed by the drugs inducing mitochondrial dysfunction such as tamoxifen,
attending physician that alcohol can be toxic to the liver methotrexate and irinotecan can worsen steatohepatitis in
and potentiates liver toxicities due to occupational expo- patients with metabolic syndrome and obesity.84,87 Thus, we
sure. Grade C could extrapolate from existing data that underlying NAFLD
Evidence: Extrapolation from 2c studies (outcome could increase susceptibility to TASH from industrial chemical
research and mechanistic studies) exposure.88

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Table 3. Thresholds of liver enzymes used to define acute liver injury and
pattern of damage according to Ratio (R) [4,5].
Recommendation a. Any one of the following CRITERIA TO DEFINE LIVER INJURY*:
1) Alanine aminotransferase (ALT) level ≥5x upper limit of normality
(ULN)
Occupational workers with classical risk factors of fatty 2) Alkaline phosphatase (ALP) level ≥2 ULN (particularly if
liver may be advised by the attending physician to have concomitantly elevated gamma-glutamyl transpeptidase (GGT) in the
a baseline screen for NAFLD/ non-alcoholic steatohepati- absence of bone disease)
3) ALT level ≥3 ULN and simultaneous total bilirubin (TB) level >2
tis (NASH), alcohol-related fatty liver disease (AFLD)/
ULN
alcohol-related steatohepatitis (ASH), and a close
follow-up. Grade D b. PATTERN OF LIVER INJURY according to R value:
R value is defined as: (ALT/ULN)/(ALP/ULN)***
Evidence: Level 5 (Expert opinion)
Hepatocellular pattern: R ≥5
Cholestatic pattern: R ≤2
Mixed pattern: R value is >2 and <5
Viral hepatitis *In patients with abnormal baseline liver blood tests, ULN is replaced by the mean
Nowadays, there are effective therapies for curing hepatitis C baseline values obtained prior to the exposure to the suspect chemical, and the
increases in ALT, ALP and TB should be proportionate to this modified baseline.
and for suppression of viraemia in patients with chronic hepati- ***AST can replace ALT when this one is unavailable.
tis B. Hence, except in developing countries with limited access ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate amino-
to these new therapies, chronic hepatitis B and C are not a con- transferase; TB, total bilirubin; ULN, upper limit of normal.
cern for workers exposed to occupational chemicals. However,
in patients with eradicated or controlled liver infection, residual
lesions (fibrosis, steatosis) can persist. It is known that hepatitis
1) ALT level ≥5x the upper limit of normal (ULN)
C virus can be associated with a greater risk of diabetes, insulin
resistance and consequently NAFLD. There is also a complex
2) Alkaline phosphatase (ALP) level ≥2 ULN (particularly if
interplay between hepatitis B infection and NAFLD.89 Further-
concomitantly elevated gamma-glutamyltransferase (GGT)
more, regression of fibrosis with long-term viraemia suppres-
in the absence of bone disease) or
sion in patients with chronic hepatitis B undergoing tenofovir
therapy has been documented, with underlying NAFLD being
3) ALT level ≥3 ULN and simultaneous total bilirubin (TB) level
suggested as an explanation for those who did not experience
>2 ULN.
fibrosis regression.90 Likewise, in patients exposed to occupa-
tional chemicals, regular alcohol intake above predefined
In patients with abnormal baseline liver blood tests, ULN is
thresholds (>20 g/day [women], >30 g/day [men]) should be
replaced by the mean baseline value obtained prior to exposure
investigated because it increases the risk of AFLD or ASH.91
to the suspect chemical, and increases in ALT, ALP and TB should
be proportionate to this modified baseline.
Isolated increases in GGT activity are not a marker of cellular
Recommendation damage, rather indicating enzyme induction. It is important to
assess whether this liver parameter could be used in occupa-
A screen for the concurrent presence of NAFLD/NASH, tional medicine as a sensitive early indicator of biological
AFLD/ASH and/or residual fibrosis is suggested in work- change after exposure to toxicants, once alcohol consumption
ers with cured hepatitis C or controlled chronic hepatitis has been discarded as a causative factor.
B virus infection and clinical data suggestive of NAFLD/ The definitions used here refer to an acute hepatic reaction in
NASH, AFLD/ASH in order to better delineate their risk people exposed to hepatotoxins; the difficulty remains how to
profile when exposed to chemicals. Grade D define chronic liver disease induced by (transient exposure) to
Evidence: Level 5 (Expert opinion) occupational chemicals.
Biochemical classification of drug-induced liver injury

The pattern of liver damage is classified according to Interna-
Definition of liver injury in occupational liver diseases
tional Consensus Meeting criteria,4,5 which used ALT and ALP
Biochemical definition of acute liver injury activity, expressed as a multiples of the ULN, to determine the
Hepatic injury in a working population exposed to potential ratio (R) of ALT/ALP. Aspartate aminotransferase (AST) can
hepatotoxins is generally detected by standard liver biochem- replace ALT when this one is unavailable.94 Liver injury is ter-
istry that reflects necro-inflammatory processes in the liver.92 med hepatocellular when R ≥5, cholestatic when R ≤2, and
These biomarkers are not specific for any form of toxic liver dis- mixed when R is >2 and <5. (Table 3). The values used for the
ease, lack mechanistic insight and may not confer prognostic classification of liver damage should be those available from
significance.93 The similar clinical and histopathological fea- blood tests when liver injury is first recognised. Due to the dif-
tures of hepatic injury observed as a consequence of the expo- ferences in the clearance kinetics of ALT and ALP, there is a ten-
sure to occupational chemicals and drugs, makes it dency for the liver injury pattern to shift to a cholestatic/mixed
appropriate to adopt the consensus criteria used for DILI.4,5 biochemical signature.68
Using these criteria and by common convention, the thresholds Alternatively, acute liver damage associated with occupa-
of liver enzymes used to define acute liver injury are as follows tional hepatotoxins can be classified based on liver biopsy find-
(Table 3): ings, which can confirm the biochemical classification and also
contribute to diagnostic accuracy. While in DILI the correlation

between biochemical categorisation and the histological fea- for a few selected chemicals does hepatotoxicity dominate the
tures is fair,95 for OLDs, data on biochemical and histological clinical picture. These include VCM,13 methylene dianiline,98
correlation are lacking. Toxic exposure to drugs or chemicals and dimethylformamide (DMF), the universal solvent.99 Taking
can mimic virtually the entire spectrum of liver diseases, which into account these limitations, the severity of chemical liver
applies especially for OLDs that can often present insidiously injury may be evaluated using the adapted severity index scale
with atypical phenotypes of toxic liver injury, including steato- for DILI (Table 4) (adapted from [4] and [5)]).
sis, TASH, fibrosis, cirrhosis, vascular liver disorders and liver
cancer.88 In this context, the liver enzyme threshold values
mentioned above are not applicable, because there is a poor Recommendation
relationship between the level of aminotransferases (that can
even be normal) and the severity of the liver injury. Therefore,
the definition of damage in the setting of a prolonged low- Severity of acute chemical liver injury can be evaluated
level exposure to occupational toxicants necessarily relies on using the adapted severity index scale designed for DILI.
imaging techniques and histopathological findings. Thus, the Grade D
criteria adopted to define liver injury developed for DILI (mostly Evidence: Level 5 (expert opinion)
in an acute setting) may have a low sensitivity to detect chronic
liver damage related to occupational exposure, which nonethe-
less can lead to significant liver disease in the long term. Clinical-pathological presentations
OLD may present with a wide spectrum of histological lesions
ranging from hepatocellular, mixed hepatocellular/cholestatic,
Definition vascular, TASH, fibrosis, and malignancy, some of which may
coexist in the same patient. Importantly, there are no morpho-
Acute liver injury in occupational workers should be logical features that are pathognomonic of toxic injury.
classified as hepatocellular, cholestatic and mixed, accord- OLD results from high accidental exposure or from prolonged
ing to liver biochemistry during the first laboratory assess- low-level exposures. The former is relatively uncommon and is
ment at recognition. easily recognised clinically, whereas the latter is more frequent
Evidence: Level 5 (expert opinion) but often overlooked because of the insidious onset, asymp-
tomatic nature, confounding by concurrent conditions and
because liver biochemistry may be unremarkable. In addition,
Grading severity of chemical-induced liver disease
specific tests of toxicity are not available, histopathology may
An attempt to grade the severity of OLDs in a comprehensive
not be revealing and the assessment of internal dosing of chem-
and systematic way has not proven possible due to the lack of
icals is almost always not decisive. Consequently, the long-term
robust evidence. The standard classification used to grade
effects of low-level exposure on chronic liver disease and liver
idiosyncratic drug-induced acute liver failure may not apply
cancer remain a concern.
when considering occupational liver injury because of the
On the other hand, whereas there is no evidence to suggest
direct, massive and rapid liver damage induced by the chemical
that a transient exposure to occupational chemical hepatotoxins
alongside the often simultaneous involvement of other
may lead to a chronic liver disease, it might occur, as has been
organs.96 Hence, the characteristic delay of 26 weeks between
the case for very specific drugs. Indeed, short term use of ebro-
the onset of jaundice and the appearance of encephalopathy,
tidine, an H2 receptor antagonist withdrawn from the market in
which is typical for idiosyncratic drug-induced acute liver fail-
Spain because of hepatotoxicity, led to cirrhosis rapidly after
ure, will likely not occur. On the contrary, fulminant liver failure
initial presentation with acute hepatocellular injury.100 Inter-
with symptoms appearing 24–48 h after exposure to the chem-
estingly, ebrotidine has in its chemical structure a bromo-
ical, as observed with CCl4 poisoning, may be the standard for
benzene ring101 and the brominated benzenes have been
acute exposure to occupational toxicants.97
related to hepatotoxicity in experimental studies.102
In OLD, other organ failures may be the consequence of the
Given these circumstances a classification according to clin-
direct effect of the chemical but may also arise from multi-
ical presentation is more appropriate.
organ failure in the setting of severe liver damage. Indeed, only
Table 4. Category severity description#.

1. Grade mild: Elevated alanine aminotransferase/ alkaline phosphatase (ALT/ALP) concentration reaching criteria for liver injury* but
bilirubin concentration <2 upper limit of normality (ULN)
2. Grade moderate: Elevated ALT/ALP concentration reaching criteria* for liver injury and bilirubin concentration ≥2 ULN, or symptomatic
hepatitis
3. Grade severe: Elevated ALT/ALP concentration reaching criteria for liver injury, bilirubin concentration ≥2 ULN, and one of the following:
International normalized ratio ≥1.5
Ascites and/or encephalopathy, and absence of underlying cirrhosis
Other organ failure considered to be due to occupational liver injury or to the toxic exposure
4. Grade fatal or liver Death or transplantation due to liver injury
transplantation:
#
Category adapted from references 4 and 5.
*Criteria for liver injury are defined in Table 3.
The international normalized ratio (INR) or standardized prothrombin time.

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Acute liver injury had a distinctive profile: they were younger men and more fre-
Acute hepatitis due to extensive exposure to a toxic agent may quently developed steatosis, fibrosis and cholestasis in liver
result from inhalation (the most important portal of entry), per- biopsies.115
cutaneous absorption or accidental ingestion.
Fibrosis
Hepatocellular necrosis Fibrosis may accumulate in the liver because of chronic insults
Almost all forms of acute environmental hepatic injury in induced by various toxicants through the development of
humans involve the hepatic parenchyma and produce hepato- chronic hepatitis, subacute necrosis or steatohepatitis injury.
cellular jaundice. Hepatocyte cytotoxicity and the resulting hep- While periportal fibrosis has been clearly associated with
atocellular necrosis characterise most of these acute effects, long-term exposure to VCM, progression to cirrhosis has been
though in some cases histopathological findings show peculiar discussed much more.116,117 An excess of deaths from non-
features (Table 1). In some instances, hepatocellular damage alcohol related cirrhosis has been observed among female rub-
may present with accompanying hypersensitivity features. ber workers, suggested to be associated with occupational expo-
Indeed, hepatitis associated with generalised skin disorders sure to nitrosamines.118
has been reported in workers from China and Asia who have
been exposed to TCE.103 Inclusions of copper in lungs and liver Vascular disorders
were detected in vineyard sprayers104 and liver histology A number of vascular lesions may be produced by toxicants.
showed diffuse proliferation of Kupffer cells, sarcoid-like granu- These include:
lomas and atypical proliferation of sinusoidal lining cells. How-
ever, it should be noted that acute hepatic injury in the setting Sinusoidal obstruction syndrome. Sinusoidal obstruction syn-
of systemic toxicity can be overlooked, as the liver injury may drome (SOS) is associated with endothelial injury in the sinu-
be less significant, in comparison to prominent extrahepatic soids, predominantly in the centrolobular areas, resulting in
clinical manifestations of toxicity such as renal failure, skin or sinusoidal dilatation, congestion with hepatocyte atrophy, and
pulmonary toxicity.105 potentially obliterative oedema to fibrotic changes of small hep-
atic veins (so called veno-occlusive disease).119 Clinical presen-
Acute cholestasis/mixed injury tation may depend on the extent of liver injury from mild liver
Hepatocellular necrosis with cholestatic lesions is produced by test abnormalities to abdominal swelling and pain, ascites, hep-
methylenedianiline98 and the toxic herbicide paraquat.106 atomegaly and splenomegaly.120
Microvesicular steatosis Peliosis. Peliosis, defined by large blood-filled cavities not lined
Microvacuolar steatosis, characterised by the presence of foamy by endothelial cells, results from damage to sinusoidal cells.
changes in the hepatocyte cytoplasm which is composed of tiny Marked sinusoidal dilatation is often concomitantly
fat droplets with a preserved centrally located nucleus, has been observed.121
reported upon exposure to dimethylformamide.107
Porto-sinusoidal vascular disease (previously known as hepatopor-
Chronic liver injury tal sclerosis). Porto-sinusoidal vascular disease, a cause of
Toxicant-associated steatohepatitis ‘‘idiopathic/non-cirrhotic portal hypertension”, is characterised
Fatty liver has been related to the occupational exposure to by portal vein obliteration associated with progressive peripor-
organic solvents.108,109 TASH has been described in highly tal fibrosis.122 It can result from long exposure to VCM and in
exposed VCM workers.110 It is a severe form of fatty liver char- vineyards to sprays containing copper sulphate and lime.123 It
acterised by steatosis, inflammatory infiltrates, ballooning hep- seems to be a precursor lesion of angiosarcoma.124
atocytes and in some cases fibrosis and cirrhosis, and then is
pathologically indistinguishable from NASH even occurring in Liver malignancies
lean individuals.111 Some patients exposed to industrial chemi- Primary liver malignancies may develop from epithelial (HCC or
cals do not have the traditional risk factors of NASH and the biliary/cholangiocarcinoma) or mesenchymal (endothelial/
conventional markers of liver damage may be normal.88 Indeed, angiosarcoma, vascular/leiomyosarcoma) cells). The most
fibrosis was reported in as many as 55% of highly exposed VCM recognised association between toxicants and primary liver
workers showing TASH, while serum aminotransferases were malignancies is VCM and angiosarcoma.
within normal ranges in most cases.110
Brazilian petrochemical workers were more likely to develop Angiosarcoma. Angiosarcomas are high grade tumours that grow
abnormal aminotransferases and GGT values than those in the rapidly and may lead to hepatomegaly and jaundice. Indeed,
administrative part of the industry, even after controlling for angiosarcoma has a very poor prognosis as it is diagnosed at a
alcohol consumption, obesity and history of hepatitis.112 Inter- symptomatic phase, advanced and not resectable or trans-
estingly, 72% of the petrochemical workers with a diagnosis of plantable. At macroscopy, angiosarcomas are often large haem-
NAFLD did not have insulin resistance suggesting that exposure orrhagic nodules, ill-defined, with variably solid and cystic
to these volatile substances can itself induce accumulation of fat areas. Histologically, the tumour is highly cellular and com-
in the liver.113 Indeed, abnormal liver enzymes and histology posed of atypical endothelial cells, elongated or with epithelioid
typically subsided in these patients when they were moved appearance. Different growth patterns may be observed: sinu-
away from the industrial area.114 Furthermore, individuals soidal, solid, papillary, cavernous and anastomosing types. Inva-
exposed to volatile chemicals (benzene, xylene, VCM, and sion of hepatic or portal veins is frequent. Specific genomic
others) with abnormal liver tests and without evidence of obe- alterations are observed, including amplification of genes MYC
sity or other features of metabolic syndrome at presentation and FLT4.125,126

Epithelioid haemangioendothelioma. Epithelioid haemangioen- Overt liver injury/abnormal liver test profile
dothelioma (EHE) of the liver is a recently recognised and
uncommon neoplasm of vascular origin. Gelin et al., described
the first case occurring after close contact with VCM. The Suspicion of
occupation liver disease
patient developed serious portal hypertension with bleeding
• Acute liver injury
varices, which required liver transplantation. The patient died • TASH
20 months later from variceal haemorrhage and encephalopa- Define specific phenotype • Fibrosis/cirrhosis
thy due to local tumour recurrence with portal thrombosis.127 • Vascular disease
• Neoplasm
Hepatocellular carcinoma. HCC developed in the setting of OLD

does not present any specific morphological features. A distinct
case of sequential occurrences of HCC and angiosarcoma of the Occupational Known chemical Exposure
liver was recently reported in a VCM-exposed worker without history hepatotoxin intensity/length
cirrhosis and any known risk factor for chronic liver disease.128
Besides, a KRAS G12D point mutation, which is considered to be
characteristic of VCM-induced angiosarcoma, was present. Back Etiological assessment according to clinical context
in 1983, Evans et al. also identified concurrent and sequential
angiosarcoma and HCC in 5 VCM workers.129
Rule out: Search for:
• Viral/infectious hepatitis • Presence of other organ
• Biliary obstruction involvement
Diagnosis
• Alcoholic hepatitis • Hypersensitivity/autoimmune
Diagnosis relies on a high level of suspicion. A stepwise algo- manifestations
• Autoimmune hepatitis
rithm approach to OLD diagnosis is depicted in Fig. 1. Thus, in • Ischaemic injury
order to establish causality, a coherent synthesis is required • Drug-induced liver injury Confounding factors:
between the characteristics of the patient’s disease (phenotype), • NAFLD
the exclusion of more common liver disorders, the collection of • Alcohol abuse
Liver biopsy: • Pre-existing chronic liver disease
a thorough occupational history, the presence of hepatotoxic Usually required to characterise • Drug therapy: tamoxifen,
chemicals within an industrial process and their known capabil- the phenotype amiodarone, methotrexate
ity to cause that disease along with the intensity and length of
exposures experienced by the workers.
The report of 3 different recurrent acute liver injury episodes,
Diagnosis of
occurring after inadvertent re-exposure to organic solvents at occupational liver disease
work, highlights the importance of considering OLDs despite
their rarity in the differential diagnosis of toxic hepatitis, in
order to reach an accurate diagnosis.130 Management
In the EU, the diagnosis of OLD, as well as any other occupa- Follow-up assessment
tional disease, relies heavily upon the expertise of certified
occupational physicians, those professionals who are responsi- Fig. 1. Schematic approach to the assessment and diagnosis of occupa-
tional liver disease. OLD, occupational liver diseases; TASH, toxicant-
ble for the health surveillance of workers. All workers exposed
associated steatohepatitis.
to (hepatotoxic) chemicals in the EU should follow preventive
measures and undergo periodical medical surveillance by a des-
ignated occupational physician. His/her tasks include the
assessment of chemical exposure by environmental and/or bio- Collecting the occupational history
logical monitoring, workplace visits, information to the workers OLDs very rarely display pathognomonic signs and, because of
and other preventive measures. Therefore, the occupational the multifactorial causality of disease, the physician should try
physician has a key role (and responsibility) in putting together to assess the relevance of occupational components in an all-
the specific clinical and exposure information available to other encompassing approach. Taking an occupational history repre-
professionals involved in the prevention, detection and manage- sents a key step in the clinical assessment of suspected OLD.
ment of OLD and interpreting the evidence provided by the rest Thus, in addition to focusing on the patient’s symptoms, the
of the team. work environment must be explored, bearing in mind that occu-
pational exposure occurs most commonly by inhalation and
through the skin. The list of information to be obtained from
Recommendation the patient/worker is detailed in Box 2.
In conclusion, collecting all relevant information about the
occupation and associated environment is challenging and often
The diagnosis of OLD should rely on the judgment of an
requires a multidisciplinary approach that involves occupa-
expert occupational physician. The assessment of OLD
tional medicine physicians and industrial hygienists. The exper-
may be improved, on a case by case basis, by input from
tise of toxicologists and epidemiologists may also be needed,
a multidisciplinary team including hepatologists, pathol-
given the discrepancy between a large number of chemicals that
ogists, toxicologists, and epidemiologists. Grade D
cause liver toxicity experimentally, with little or no evidence in
Evidence: Level 5 (expert opinion)
humans131 (Box 3).

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Box 2. Critical information to be obtained from the patient with a (OSHA), the National Institute of Safety and Health (NIOSH) or
suspicion of occupational liver disease. the American Conference of Governmental Industrial Hygien-
ists (ACGIH). Also, data from biomonitoring may be available.
1. A chronological summary of all work activities and their duration.
Such data are superior to those obtained from workplace
2. A detailed description of the work place, of the job and of a typical working
monitoring systems, as they allow a personalised view of
day.
the exposure. Moreover, in instances where the exposure is
3. An inventory of all chemicals that are present and how are used.
Sometimes this information can be obtained from the managment.
relatively recent (during the past months) or still ongoing,
biomonitoring could be applied to objectively document the
4. Details of any measures to limit chemical exposure such as: work place
ventilation and the nature protective measures that are taken (require- exposure and, based upon quantitative assessments, even
ment to wear special clothing and gloves, the use of masks, goggles and make statements about the extent of exposure.
other devices). Urine and blood are the most commonly used biological
5. Enquiring if programs of industrial hygiene, biological monitoring and matrices for biomonitoring. However, for both matrices, the
medical surveillance are or have been in place and retrive the result, if window of detection of the toxicants themselves or their
necessary, keeping in mind however that compliance with occupational
metabolites is quite limited (typically maximally in the range
exposure limits do not necessarily protect all workers from adverse
effects. of days). For a more extended historical window, segmental
6. Enquire as to whether coworkers have similar symptoms and signs to
hair analysis could be used or, alternatively, adducts in blood
those of a patient with suspected occupational liver disease. This may could be monitored.134,135 Many of the toxicants listed in
involve questioning and even examining coworkers. If several cases Table 1 will be converted to reactive intermediates in the
come to light, it may be possible to demonstrate an exposure-response liver, which will form covalent adducts with macromolecules
relationship.
such as DNA and proteins. As both haemoglobin and albumin
7. Enquire if compensation procedures have been undertaken and results are highly abundant proteins, many groups have focused on
are available.
adducts with these proteins to document exposure to toxi-
8. Exposures to chemicals other than those present at work places,
cants, even when these toxicants or their metabolites are no
associated for instance with environmental air pollution, hobbies,
recreational habits and others should be ruled out. longer detectable in blood or urine. Adducts with haemoglo-
bin are detectable up to >100 days following exposure, as
their disappearance is linked to the lifespan of red blood cells,
which is about 4 months. When the timing of the exposure is
Box 3. The assessment of occupational liver disease may be improved, on known, it is even possible to perform a back-calculation to
a case by case basis, by input from a multidisciplinary team derive the adduct concentration right after the exposure took
encompassing.
place (in case of acute exposure). This gives an idea about the
extent of exposure, compared to the background exposure,
• Occupational physicians
typically assessed in a reference population.136 Yet, it should
• Hepatologists
be remarked that there is not necessarily a link between
• Pathologists
the level of exposure and the extent of damage, as this will
• Toxicologists
• Epidemiologists
be compound dependent. Although the markers that can be
assessed this way are highly selective, there are still con-
founding factors. For example, smoking results in elevated
Assessment of exposure levels of several albumin and haemoglobin adducts, rendering
An inherent difficulty when assessing exposure to chemicals it impossible to distinguish moderate exposure to certain tox-
is the unequivocal demonstration of this exposure. As out- icants from the contribution by smoking.137,138 Although
lined before, liver injury markers such as ALT, AST and GGT adduct monitoring has already successfully been applied for
or, more recently, miRNAs, merely represent liver damage a number of compounds listed in Table 1, this approach has
and, although they may be used for classification of the type not yet been widely applied for assessing (the absence or
of liver damage, they do not offer any insight into the aetiol- extent of) occupational exposure.135,137,139,140 The occupa-
ogy underlying this damage.132 In essence, there are no long- tional history and, when available, the result of workplace
term biomarkers that can lead to identification of historical monitoring and biomonitoring, are crucial for formulating a
exposure (i.e. exposure that took place (many) years ago) to presumptive diagnosis. It is occasionally necessary to remove
a potential hazardous chemical. Exposure data may, however, the patient from exposure to the suspected workplace toxic
be available and be consulted retrospectively. Monitoring sys- substance to establish the workplace relationship.
tems at the workplace is one way to deduce exposure data.
These data could be used to consult workplace exposure limit Workup for alternative aetiologies
databases, such as those from National lists of occupational Laboratory tests
limit values (OEL) from EU member states, including Germany A comprehensive liver aetiology screen should be undertaken,
(DFG-MAK Commission), The Netherlands (DECOS), and including evaluation of viral serology (hepatitis A-E), liver
France (ANSES), and also from other sources such as the Sci- autoantibodies and serum immunoglobulins, ferritin and trans-
entific Committee on Occupational Exposure Limits ferrin saturation, alpha-1-anti-trypsin levels and ceruloplasmin
(SCOEL),133 the Occupational Safety and Health Administration (depending on age).

Imaging
Imaging investigations will be determined by the clinical
Recommendations
presentation and nature of likely toxin exposure. In many
instances, patients will have an initial abdominal ultrasound
but may require additional computed tomography (CT) or mag- Liver biopsy may be performed in patients with persis-
netic resonance imaging (MRI) scanning to delineate the nature tently abnormal non-invasive liver tests, depending on
of lesions and examine the biliary system in more detail. Indeed, the clinical context and the magnitude of the liver
routine abdominal ultrasound along with evaluation of liver abnormalities. Grade D
fibrosis using transient elastography are advisable in all cases. Evidence: Level 5 (Expert Opinion)
When performing a liver biopsy to diagnose a liver mass,
Non-invasive diagnosis of liver disease sampling of non-tumoral liver is suggested. Grade D
Non-invasive markers like transient elastography, Fib-4 (Fibro-
Evidence: Level 5 (Expert Opinion)
sis 4) and albumin to platelet ratio index (APRI) have been
applied to identify and stage liver diseases across multiple aeti-
ologies.141 In the setting of liver injury associated with occupa-
Follow-up
tional exposure, these tests might help i) Identify sub-clinical
For episodes of acute liver injury with no evidence of liver fibro-
hepatic injury not accompanied by symptoms and/or abnormal-
sis, patients should be followed-up until there is complete res-
ities of serum liver blood tests, ii) Stage the severity of overt
olution of any abnormal liver parameters.
chronic liver disease and, iii) Evaluate resolution of acute liver
For patients with persistent alterations in liver tests after
injury, chronicity suspected after 12 months of persistent alter-
removal from exposure, one should search for confounding fac-
ation (as in DILI4). Whilst the majority of non-invasive tests
tors or alternative aetiologies and stratify follow-up accordingly
were conceived as markers of liver fibrosis, increasingly there
to the presence of these coexisting disorders.
are data to suggest they may provide information on necro-
infammation and degeneration of liver cells.141
While workers exposed to toxicants may develop a variety of
histopathological lesions in the liver, TASH mimics histopatho- Management
logical changes observed in NASH. This is a major challenge, Patient management will largely be determined by the nature
as NASH is emerging as an epidemic across all age strata world- and severity of the OLD. In acute injury cases the priority is to
wide, therefore making the characterisation of TASH extremely remove the patient from further exposure whilst establishing
difficult.110,115 Indeed, an individual with liver disease must be the level of liver dysfunction. In the event that the acute liver
removed from exposure, however this does not necessarily pro- dysfunction is severe and ongoing, consideration should be
vide evidence of a relationship with work environment. given to the appropriate setting within the hospital and need
for liver transplantation. This will be determined by the magni-
tude of liver dysfunction using internationally accepted
criteria.142
Recommendation
In the setting of chronic disease, the degree of liver fibrosis
will determine management. Advanced fibrosis/cirrhosis will
Staging of OLD can require dynamic evaluation with prompt evaluation for the complications of chronic liver disease
repeat measurements of liver tests and liver stiffness and also transplantation if there is evidence of significant
by transient elastography or serum predictors of fibrosis decompensation.142
like Fib-4 and APRI after patient removal from occupa- There is a need to inform the competent health authority/-
tional exposure to suspected toxicants. Grade D compensation agency.
Recommendation
Liver biopsy
Liver biopsy is currently the most reliable approach for diagno-
sis and staging of liver disease of any aetiology, but it is limited The relevant health authority and/or compensation
by cost, sampling error and procedure-related morbidity and agency can be informed of the documented or suspected
mortality. In patients with more than 1 risk factor, liver biopsy OLD case. Grade D
remains the most robust diagnostic approach to define the
cause of underlying liver abnormalities. Workers exposed to
potentially hepatotoxic agents may in fact present with comor-
bidities like overweight, diabetes, arterial hypertension, alcohol Prevention
abuse, viral hepatitis and medications that cause persistence of Successful prevention has markedly reduced the risk of liver
liver abnormalities after withdrawal from occupational expo- diseases to workers, although areas of high risk still exist,
sure and may require histological examination of the liver for particularly in developing countries. Two broad approaches
a definite diagnosis. to prevent workers from being affected by liver toxicants
When performing a liver biopsy to diagnose a liver mass, are used; primary prevention involves either elimination or
sampling of non-tumoral liver is advisable to assess the status control of exposures through interventions in the working
of the background liver. environments and secondary prevention is aimed at the

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identification of excessive exposure and early clinical effects Conflict of interest
in individuals. Thus, prevention is achieved with industrial Please refer to the accompanying ICMJE disclosure forms for
hygiene techniques, mainly with adherence to exposure lim- further details.
its, and programmes of medical surveillance of exposed work-
ers, aimed at avoiding further damage by removing workers Acknowledgements
from additional exposure. The decision to temporally or per- We would like to thank the reviewers of this Clinical Practice
manently remove the affected workers from the workplace Guideline for their time and critical reviewing: EASL Governing
depends on the severity of OLD, working environment and Board, Jordi Bruix and Maurizio Manno.
social factors. We thank Professor Laurent Castera, Hospital Beaujon, Cli-
As mentioned earlier (section 7.b), the occupational risk is chy, France for his thoughtful insights in non-invasive diagnosis
assessed by comparing the measurement of a given environ- of liver damage and Professor Raul J Andrade, Hospital Univer-
mental exposure with an appropriate exposure limit. These lim- sitario Virgen de la Victoria, IBIMA, UMA, Malaga, Spain, CIBER-
its may refer to the risk of inhalation or dermal exposures, or ehd, for his suggestions and recommendations in chemical-
both, depending on the chemicals and their uses, and are induced liver injury definition, severity, risk factors and assess-
intended to protect the majority of exposed workers. However, ment. We acknowledge the support from European Cooperation
a number of variables influence the exposure of a single worker in Science & Technology (COST) Action CA17112 Prospective
in addition to a given environmental concentration, including European Drug-Induced Liver Injury Network. MIL and RJA are
the way materials are handled, the size and ventilation of a members of COST Action CA17112.
specific workplace and the amount of time spent doing specific
tasks. Thus, in order to have a reliable assessment of exposure,
several environmental measurements are usually needed. While Supplementary data
most countries have their own exposure limits, these are Supplementary data to this article can be found online at
broadly comparable with the American ACGIH-derived thresh- https://doi.org/10.1016/j.jhep.2019.08.008.
old limit values,143 which are revised on a regular basis, being
the most influential worldwide.
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Clinical Practice Guidelines JOURNAL

EASL Clinical Practice Guideline: Occupational liver diseasesq

Summary remains challenging in clinical practice due to the lack of

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a. Non-malignant liver diseases

ii. Controversial associations with liver cancers

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Table 2. Overview of workplace-related toxicants and typical uses.

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Biochemical classification of drug-induced liver injury

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Table 4. Category severity description#.

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Hepatocellular carcinoma. HCC developed in the setting of OLD

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