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Keywords:

  • drug rash with eosinophilia and systemic symptoms;
  • drug-induced hypersensitivity syndrome;
  • human herpesvirus 6;
  • hypersensitivity syndrome;
  • trichloroethylene

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

The number of patients suffering from trichloroethylene (TCE)-related severe skin disorders with liver dysfunction has been increasing in developing countries in Asia, especially since the mid-1990s. In Japan, five cases of this disease have been reported, but none since the 1990s. However, two additional cases were recently observed in Tokyo. The published work and our investigation indicated that oxidative metabolites of TCE, which might include trichloroacetylated-protein adducts, could induce a generalized skin eruption. Furthermore, human leukocyte antigen (HLA)-B*1301 and HLA-B*44 were identified as markers of individual susceptibility to TCE-induced hypersensitivity syndrome (HS). Moreover, polymorphism of aldehyde dehydrogenase (ALDH), the major enzyme in TCE metabolism, appeared to be associated with TCE-induced HS. Interestingly, this disorder is quite similar to drug-induced hypersensitivity syndrome (DIHS), also referred to as drug rash with eosinophilia and systemic symptoms (DRESS), from the perspective of the onset of the reaction after exposure to TCE/drugs, clinical manifestations, blood examination and period of virus reactivation. This article reviews the similarity between TCE-related HS and DIHS/DRESS.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Trichloroethylene (TCE) is a ubiquitous solvent used worldwide, mostly for degreasing metals, and it was used extensively until the mid-1980s, when its possible carcinogenicity in humans became hotly debated after the publication of rodent study results. TCE was replaced by chlorofluorocarbons and 1,1,1-trichloroethane. In 1996, however, these two solvents were banned internationally because of their ozone-depleting potential. Thus, the use of TCE has actually increased again, especially in industrializing countries.1

Generalized skin disorders due to TCE, which were originally described in a US textbook published before the 1950s,2 began to increase after the mid-1990s in Asia, where more than 300 cases were reported, along with five cases from the USA, four from Canada and one from Spain.3–6 In Japan, five cases of generalized skin disorders caused by TCE have been reported, although none since the 1990s.1 Recently, two additional patients were observed in Tokyo, including one recently reported by our department.7 The disorder is classified into two types according to the skin manifestations: Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and hypersensitivity syndrome (HS).3,7 When we analyzed TCE-induced skin disorders in the published work, many patients have the latter manifestation, characterized by an onset of the reaction, clinical features and laboratory data that are quite similar to those of drug-induced hypersensitivity syndrome (DIHS),8,9 also referred to as drug rash with eosinophilia and systemic symptoms (DRESS).10 In fact, Dai et al.11 recently observed that only three of 111 TCE-related generalized skin reaction patients had SJS/TEN, and the remainder had HS; the authors categorized the other patients as 75 with exfoliative dermatitis and 33 with erythema multiforme, but these are included in HS, as described below. Thus, this review of TCE-induced skin disorders discusses primarily the hypersensitivity syndrome type, and reviews similarities between TCE-induced HS and DIHS.

Reaction onset

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Huang et al.1 found that the interval from exposure until the onset of the first symptom of TCE-induced skin disorders was 27.9 ± 9.8 days in an analysis of 59 patients. This is consistent with the findings in the two recent Japanese patients; the first symptoms were observed 3 weeks after exposure to TCE.7,12

Drug-induced hypersensitivity syndrome is characterized by a severe skin eruption, high fever, liver dysfunction, leukocytosis with eosinophilia and atypical lymphocytes, lymphadenopathy and hypogammaglobulinemia that develop 2–6 weeks after administrating the causative drug.8,9,13 Thus, the onset of reaction is similar in DIHS and TCE-induced HS and longer than in other delayed allergic diseases, such as maculopapular drug eruptions.

Clinical manifestations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

The clinical manifestations of TCE-induced HS and DIHS are quite similar, and are typically characterized by the following features (Table 1). Facial manifestations include edema of the face, scales, and crusts, especially on the wings of the nose and around the lips (Fig. 1a), and diffuse erythematous lesions, except around the eyes. The rash often becomes a severe generalized exfoliative dermatitis or erythroderma (Fig. 1b), although erythema multiforme, which usually includes target lesions, is also found in these two disorders (Fig. 1c). Blisters sometimes develop, especially on the forearms (Fig. 1d). Sterile follicle-centered pustules may form. The face, upper trunk and upper extremities are the first body parts to be affected and the lower extremities become involved later. The eruption can become purpuric, primarily on the legs, and desquamation occurs with resolution. There is ocular and oral involvement in a few cases, but it is not as severe as in SJS/TEN, which helps distinguish HS from SJS/TEN.7,13 There is a high fever in 73–86% of TCE-induced HS and 100% of DIHS.1,7 Lymphadenopathy is seen in 81% of TCE-related HS and 75% of DIHS.1,7 Eosinophilia has been reported in 25% of TCE-induced HS and 70% of DIHS,1,7 although remarkable eosinophilia was seen in the two recent Japanese cases and has been reported in other cases of TCE-induced HS.5,7 Perhaps if physicians examined the differential count more closely during the course of the disease in reported cases the percentage of eosinophilia in TCE-induced HS may be higher. More than 90% of the patients with TCE-induced HS and DIHS have liver dysfunction.7,13

Table 1.   Findings in hypersensitivity syndrome caused by trichloroethylene and DIHS
 TrichloroethyleneDrugs
  1. Drugs: facial edema, severe exanthematous rash, exfoliative dermatitis, erythroderma, targetoid erythematous lesions pustules, blisters, no necrosis in the epidermis. There are many findings common to these two syndromes. The onset of the reaction is approximately 1 month after trichloroethylene or drug exposure. The period of reactivation of HHV-6 after the onset is similar in these two diseases. CMV, cytomegalovirus; DIHS, drug-induced hypersensitivity syndrome; HHV, human herpesvirus. (Reproduced from Watanabe et al.,7 with permission.)

Onset of the reaction2–6 weeks2–6 weeks
Fever (%)73–86100
Lymphadenopathy (%)38–8175
Eosinophilia (%)2370
Liver dysfunction (%)46–9496.8
Mortality rate (%)910–20
Virus reactivationHHV-6, CMVHHV-6, 7, CMV, Epstein–Barr virus
image

Figure 1.  Clinical findings on admission. (a) The patient’s face shows edema and erythema with scaling. Crusts were seen on the wings of the nose and around the lips. (b) Confluent erythematous rash from the upper back to the waist. (c) Targetoid erythematous lesions on the forearm and dorsum of the hand. (d) A diffuse erythematous rash and blisters are seen on the forearm. (Reproduced from Watanabe et al.,7 with permission.)

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Liver dysfunction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Trichloroethylene can induce two pathophysiologically different types of hepatitis: (i) acute or subacute hepatitis, induced in a dose-dependent manner after exposure; and (ii) immune-mediated hepatitis, which occurs in TCE-induced HS. Regarding hepatitis due to HS, it was found that TCE had a strong sensitization potential related to delayed-type hypersensitivity in the guinea pig maximization test, and the sensitization rate was approximately 70%.14 The plasma aspartate aminotransferase and alanine aminotransferase levels were significantly higher in sensitized animals than in non-sensitized ones, suggesting that TCE causes immune-mediated hepatic damage. Interestingly, the hepatocytes showed diffuse ballooning, without lymphocyte infiltration or necrotic cells, which was quite different from what is seen in TCE-induced acute hepatic damage in the guinea pig, but very similar to the hepatic damage seen in CYP2E1-induced rats exposed to TCE.15 Unfortunately, the guinea pig maximization test study failed to determine what antigen played a key role in causing hepatitis (i.e. TCE itself, its metabolites, or CYP2E1 adducts, as suggested as the cause of halothane hepatitis)16 or whether CYP2E1 was involved in the pathogenesis.

Shiohara et al.13 demonstrated that liver dysfunction is a typical finding in DIHS and that there can be other organ involvement, such as renal involvement, coronary artery thrombosis and diabetes mellitus. Patients with TCE-related HS also have other organ involvement in addition to liver dysfunction.1,4

Course of hs due to tce

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

When Bauer placed his patients on systemic steroid therapy, their dermatitis resolved in 3–4 days.4 Nevertheless, in most reports, liver function takes 6 weeks to normalize.4 In fact, the two recent Japanese patients required hospitalization for 1 month because of relapsing rash and liver dysfunction.7,12 In DIHS, the severe hepatitis has a prolonged course, characterized by multiple exacerbations and remissions of both the rash and liver disease.13

Metabolism of trichloroethylene

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Inhaled trichloroethylene is metabolized by cytochrome P450 (CYP) to choral hydrate, which is further metabolized to trichloroethanol and trichloroacetic acid. The urinary excretion of trichloroethanol and trichloroacetic acid in cyp 2e1−/− mice exposed to a relatively high dose of trichloroethylene (1000–2000 ppm) was one-half to one-fifth that in wild-type (cyp 2e1+/+) mice, suggesting that the major form of CYP involved in trichloroethylene metabolism is CYP2E1.17 The metabolic pathway of trichloroethylene is shown in Figure 2.

image

Figure 2.  Metabolic pathway of trichloroethylene (TCE). The oxidative metabolites of TCE, which might include trichloroacetylated-protein adducts, could induce the generalized skin eruption. Aldehyde dehydrogenase (ALDH) is the major enzyme in TCE metabolism. ADH, alcohol dehydrogenase.

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Results of patch testing

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Previous investigations have indicated that the generalized rash caused by TCE is mediated by a delayed-type hypersensitivity mechanism.7,18 Not all patients showed a positive reaction for TCE on patch testing. In fact, we found that patch testing was negative for TCE itself, but positive for trichloroethanol, trichloroacetic acid and chloral hydrate in our patient.7 Similarly, Phoon et al.19 observed a negative reaction for TCE itself. Conversely, three reported cases were positive for TCE on patch testing, and one of these patients was also positive for the metabolite trichloroethanol, but not for trichloroacetic acid (Table 2).6,18,20 Together, the oxidative metabolites of TCE, which may include trichloroacetylated-protein adducts, could induce the generalized skin eruption.7

Table 2.   Results of patch testing for trichloroethylene (TCE) and its metabolites
 TrichloroethyleneTrichloroethanolTrichloroacetic acidChloral hydrate
  1. The patch tests were negative for trichloroethylene (TCE) itself in Watanabe et al. and Phoon et al., while in another three reported cases, patch testing was positive for TCE. (Reproduced from Watanabe et al.,7 with permission.)

Conde-Salazar et al.6(+)   
Chae et al.20(+)   
Nakayama et al.18(+)(+)(−) 
Phoon et al.19(−)   
Watanabe et al.7(−)(+)(+)(+)

Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Huang et al.1 checked the immunoglobulin (Ig)G antibody titers against HHV-6 in 57 patients who were hospitalized with TCE-induced HS in Guangdong Province, China, using blood samples collected on the 21st day of hospitalization. They observed marked increases in the anti-HHV-6 IgG titer (≥256) in 14 of 57 (27%) patients, but not in the tolerant workers. Cytomegalovirus (CMV) did not differ significantly between the cases and controls. In general, when HHV-6 is reactivated in patients with DIHS, HHV-6 DNA is detected in the serum approximately 3–5 weeks after the onset, and this is followed by a dramatic rise in the anti-HHV-6 IgG titers.13,21 In the two recent Japanese patients with TCE-induced HS, the anti-HHV-6 antibody was elevated 6 weeks after the onset.7,12 Thus, if Huang et al.1 had examined the HHV-6 titer approximately 6 weeks after hospitalization, perhaps a higher percentage of patients would have had significantly higher anti-HHV-6 IgG titers. Moreover, Huang et al.1 might have found that a higher percentage of patients had reactivated CMV, because the CMV IgG antibody titer is generally elevated 10–21 days after elevation of the HHV-6 antibody titer.21

Genetic factors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Following epidemiological surveys conducted in Guangdong Province, China, more than 200 cases of HS were diagnosed, with a prevalence rate of less than 1% among TCE-exposed workers.1Table 3 shows the prevalence of TCE-induced skin disorders and the airborne TCE concentrations in the workplace. These data indicate that not all people who are exposed TCE develop HS, and no dose–response relationship was observed in patients. In fact, Phoon et al.19 found that twin sisters developed TCE-induced skin disorders, while another 14 workers in the same sections were asymptomatic. This suggests that some genetic susceptibility exists. Recently, human leukocyte antigen (HLA)-B*1301 was identified as a marker of individual susceptibility to TCE-induced HS, with an odds ratio of 27.5 in a patient group in China.28 This finding is analogous to that in carbamazepine-induced Stevens–Johnson syndrome and allopurinol-induced severe cutaneous adverse reactions, including DIHS, which have strong associations with HLA-B*1502 and HLA-B*5801, respectively.29,30 In China, the allele frequency of HLA-B*1301 is higher in the southern population (∼10%) than in the northern population (3–4%), and this is may be a major factor explaining the mass outbreak of TCE-induced hypersensitivity dermatitis in the southern population.28 The allele frequency in Japan is 1.3%,31 which is even lower than in the Han population in northern China and may partly explain why there have been fewer cases in Japan than in China.7 Additionally, HLA-B*44 was demonstrated to be related to TCE-induced HS. Li reported that HLA-B*44 was present 6.2% of 113 patients, but was not observed in any of the 142 TCE-tolerant workers.28 They found that HLA-B*1301 and HLA-B*44 have similar amino acid residues (I94I95 R97), which may be involved in susceptibility to TCE-induced HS. A previous study that included 15 white patients demonstrated that HLA-B*44 was associated with the risk of Stevens–Johnson syndrome with ocular involvement;32 thus, it is possible that the weak association of HLA-B*44 with HS in TCE-exposed workers is not a chance finding.28 Interestingly, HLA-B*1301 was present in one recent Japanese patient7 and the other had both HLA-B*1502 and HLA-B*44 (unpubl. data, T. Fukasawa et al., 2010). These findings suggest that checking for HLA prospectively in TCE workers before employing them could decrease the risk of this disease.

Table 3.   Prevalence of trichloroethylene (TCE)-induced skin disorders and airborne TCE concentration in the workplace
 Patients/workers (%)Airborne concentration of TCE (mg/m3)
  1. Not all people who are exposed TCE develop hypersensitivity syndrome, and no dose–response relationship was observed in the patients.

Conde-Salazar et al.61/400 (0.25)Unknown
Huang et al.1<1%373–4266
Shi and Ma225/550 (0.9)71–756
Pantucharoensri et al.232/130 (1.5)81–216
Estrella-Gust et al.247/171 (4.1)491–1220
Phoon et al.191/23 (4.3)518–912
Joson et al.2546/945 (4.9)Unknown
Phoon et al.191/18 (5.6)<50
Nakayama et al.181/8 (12.5)113
Phoon et al.192/16 (12.5)Unknown
Kubota26Unknown54–270
Goon et al.27UnknownUnknown

Aldehyde dehydrogenase polymorphism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

Polymorphism in aldehyde dehydrogenase (ALDH), the major enzyme in TCE metabolism (Fig. 2), was reported to be associated with TCE-induced HS.33 The frequency of heterozygous ALDH2 *1/*2 plus homozygous ALDH2 *2/*2 in patients with this disease was significantly lower than in exposed controls. The two recent Japanese TCE-induced HS patients were both homozygous ALDH2 *1/*1 (unpubl. data, T. Fukasawa et al., 2010). Based on these findings, it will be useful to examine ALDH2 polymorphism as well as the HLA typing described above.

Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

The polymorphism of TNF-α was investigated using a control study consisting of 111 patients with TCE-induced HS and 152 tolerant workers.34 The frequency of the TNF-α-308 wild-type allele in cases was significantly higher than in controls. Individuals heterozygous for TNF-α-308 had a decreased risk of TCE-induced skin disorders, relative to the homozygous genotype.

N-acetyltransferase is an important metabolic enzyme in the conjugation pathway of TCE metabolism.11 NAT includes two isoenzymes, NAT1 and NAT2, which are encoded by two separate genes and exhibit multiple genetic polymorphisms. A previous investigation indicated that slow or intermediate NAT2 acetylators are at increased risk of HS-induced skin disorders, compared with tolerant TCE workers. Furthermore, possession of the slow acetylator phenotypes of both NAT1 and NAT2 further increases the risk.11

Mortality

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

The mortality from DIHS is approximately 10–20% and is correlated with the degree of hepatic or renal involvement.1,13 According to the latest data for Japan, the mortality rate of SJS/TEN was 10.1%.35 The mortality of TCE-related HS was 9% and that of TCE-related SJS/TEN was 13%.1

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

As described above, there are many findings common to TCE-related HS and DIHS. Drugs that frequently cause DIHS include carbamazepine, phenytoin, phenobarbital, mexiletine, dapsone, salazosulfapyridine, allopurinol and minocycline.13 Thus, if we see DIHS patients who have not taken these drugs, we should examine whether they have been exposed to TCE. Additionally, we should remember that TCE can cause SJS/TEN.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References

We thank Michihiro Kamijima and Tomotaka Sato for their excellent technical assistance. This work was partly supported by Health and Labor Sciences Research Grants (Research on Intractable Diseases) from the Ministry of Health, Labor and Welfare of Japan.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Reaction onset
  5. Clinical manifestations
  6. Liver dysfunction
  7. Course of hs due to tce
  8. Metabolism of trichloroethylene
  9. Results of patch testing
  10. Human herpesvirus (hhv)-6 reactivation in tce-induced hs patients
  11. Genetic factors
  12. Aldehyde dehydrogenase polymorphism
  13. Polymorphisms in tumor necrosis factor (TNF)-α and n-acetyltransferase (NAT)
  14. Mortality
  15. Conclusions
  16. Acknowledgments
  17. References
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    Shiohara T, Inaoka M, Kano Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpesvirus and antiviral and antidrug immune responses. Allergol Int 2006; 55: 18.
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    Tang X, Que B, Song X et al. Characterization of liver injury associated with hypersensitive skin reactions induced by trichloroethylene in the guinea pig maximization test. J Occup Health 2008; 50: 114121.
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    Okino T, Nakajima T, Nakano M. Morphological and biochemical analyses of trichloroethylene hepatotoxicity: differences in ethanol- and phenobarbital-pretreated rats. Toxicol Appl Pharmacol 1991; 108: 379389.
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    Kenna JG. Immunoallergic drug-induced hepatitis: lessons from halothane. J Hepatol 1997; 26 (Suppl 1): 512.
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