2015 Volume 57 Issue 1 Pages 87-90
Objectives: It has been reported that chlorinated organic solvent is a cause of hepatitis. Methods: we investigate clinical and pathological findings of a patient with severe acute hepatitis who was exposed to chlorinated organic solvents. Results: A 34-year-old man who was exposed to chlorinated organic solvents including dichloromethane, 1,2-dichloropropane, and trichloroethylene, presented with general fatigue, vomiting, and diarrhea. At admission, his laboratory test results showed extremely elevated aspartate aminotransferase (4,872 IU/l), alanine aminotransferase (3,000 IU/l), and lactate dehydrogenase (11,600 IU/l) levels and a prothrombin level below normal (41%). No encephalopathy was noted. These findings were indicative of severe acute hepatitis. Viral hepatitis, autoimmune hepatitis, alcoholic disease, bile duct disease, and viral infection were excluded as causes of hepatitis by clinical, laboratory, and imaging findings. After diagnosis, the patient was administered fresh frozen plasma and glucagon-insulin therapy. Liver function recovered within a few weeks, and a liver biopsy performed 25 days after admission showed the recovery phase after acute liver damage. Conclusions: These clinical and pathological findings indicate that exposure to chlorinated organic solvents may have induced severe acute hepatitis in this patient.
(J Occup Health 2015; 57: 87–90)
The toxicities of various chemicals, including organic solvents, have been reported, and methods for protection and occupational exposure limits have been established. Most organic solvents are mainly absorbed into the body via inhalation, ingestion, and the skin, and they often directly affect the eyes, skin, and respiratory tract. Absorbed organic solvents are toxic to the nervous system, liver, kidney, and heart1, 2). Hepatic damage after exposure to certain organic solvents has been described3–9). Here, we report a case of severe acute hepatitis in a printing company worker who was exposed to various chemicals, including organic solvents such as 1,2-dichloropropane (DCP), dichloromethane (DCM), and trichloroethylene (TCE). This study was performed according to the Declaration of Helsinki (2008), and the patient provided written informed consent.
The patient started work in an offset color proof-printing department of a company in 1986. The present building was constructed in 1991. The printing room was located in the first basement floor of the building, with a front room adjacent to the printing room. The ventilation rates of these rooms were very low because of the basement location and the low capacity of the installed ventilation equipment. The patient made printing plates in the front room. In the process, he used high-purity TCE to remove stains from glass plates for about one year just before developing severe acute hepatitis. The amount of TCE he used per day was estimated to be 1-2 l based on his memory. Because no respiratory protection was provided, he have been exposed to high levels of TCE.
In the printing room, proof-printing workers used large amount of organic solvent cleaner to remove ink residue from a rubber transcription roller. The cleaners was a mixture of gasoline (50% by weight) and 1,1,1-trichloroethane (50%) before 1989; it was a mixture of DCP (50–60%), DCM (15–25%), and 1,1,1-trichloroethane (15–25%) from approximately 1985 to 1992–1993; and it was a mixture of DCP (40–50%), DCM (40–50%) and petroleum hydrocarbons (1–10%) from 1992–1993 to March 1996; and it was nearly pure DCP solvent (98%) from April 1996 to October 2006. Airborne solvent concentrations in the printing room were estimated to be extremely high, which was confirmed in an experiment conducted by the Japanese National Institute of Occupational Safety and Health10).
Furthermore, because the contaminated air of the printing room flowed into the front room due to positive pressure in the printing room, the airborne solvent concentrations were also estimated to have been high in the front room. Consequently, the patient was also exposed to these chemicals when working in the front room. In addition to making printing plates, he also supervised the progress of printing mainly in the front room but frequently went into the printing room to provide guidance and occasionally to conduct proof-printing. When working in the printing room, he was exposed to high levels of the abovementioned chlorinated organic solvents. Other chemicals such as kerosene and inks were also used in the department.
The patient (at 34 years of age) experienced general fatigue, vomiting, and diarrhea and visited a hospital in December 1996. According to the period of solvent use, he had been exposed to DCP and TCE just before the onset of symptoms and to DCM within 1 year before onset. He had drank 350 ml of beer per day during previous 10 years (<80 g of ethanol daily, which is the lower limit for alcoholic liver disease11)) and smoked 20 cigarettes/day during the previous 14 years. He had no history of blood transfusion, sometimes took vitamins and aspirin for headaches, and had a body mass index of 18.3.
At admission, the patient was lucid with no abnormal neurological system or respiratory tract findings. The liver was palpable in the right infracostal region at a two finger widths. No dermatitis was noted. The laboratory test results at admission are shown in Table 1. The aspartate aminotransferase (AST, 4,872 IU/l), alanine aminotransferase (ALT, 3,000 IU/l); and lactate dehydrogenase (LDH, 11,160 IU/l) levels were markedly elevated, and the prothrombin test value was 41%. The concentrations of total bilirubin and direct bilirubin were 1.2 mg/dl and 0.2 mg/dl, respectively. The serum alkaline phosphatase and γ-glutamyl transpeptidase (γ-GTP) levels were within the reference range. Eosinophilia was not detected. The results for hepatitis viral markers (IgM-HA antibody, hepatitis B e antigen and antibody, hepatitis B surface antigen and antibody, hepatitis B core antibody, hepatitis B virus DNA polymerase, hepatitis C virus [HCV] antibody, HCV RNA, hepatitis D virus antibody, and GBV-C RNA) were negative. The patient was positive for cytomegalovirus IgG and Epstein-Barr (EB) virus IgG antibody, but negative for cytomegalovirus IgM antibody and EB virus IgM antibody, indicating previous infections with cytomegalovirus and EB virus. Serum anti-nuclear antibody and lupus erythematosus (LE) test results were negative. Serum complement (CH50; 50% hemolytic unit of complement), carcinoembryonic antigen, and carbohydrate antigen 19-9 levels were within the reference ranges. Ultrasonography and computed tomography showed mild hepatomegaly but no abnormal findings in the biliary system. From these findings, severe acute hepatitis was diagnosed, and the patient was treated with fresh frozen plasma and glucagon-insulin therapy. Liver function recovered within a few weeks (Fig. 1). A liver biopsy performed 25 days after admission showed size inequality of hepatocytes and multinuclear hepatocytes (Fig. 2). Many phagocytes were present in the hepatic lobules, and mild lymphocytes infiltration and fatty droplets in a few hepatocytes were seen. Fibrous expansion of portal areas and cholestasis were not observed. These findings are indicative of the recovery phase after acute liver damage. The clinical course and pathological findings indicate that the patient's severe acute hepatitis was not caused by viral hepatitis, autoimmune hepatitis, alcoholic disease, bile duct disease, or viral infection (cytomegalovirus and EB virus) but instead was caused by exposure to chlorinated organic solvents.
| Red blood cell (×104/mm3) | 448 |
| Hemoglobin (g/dl) | 13.6 |
| White blood cell (/mm3) | 6,800 |
| Prothrombin test (%) | 41 |
| Aspartate aminotransferase (U/l) | 4,872 |
| Alanine aminotransferase (U/l) | 3,000 |
| Alkaline phosphatase (U/l) | 140 |
| Total bilirubin (mg/dl) | 1.2 |
| Direct bilirubin (mg/dl) | 0.2 |
| Lactate dehydrogenase (U/l) | 11,160 |
| γ-Glutamyl transpeptidasea (U/l) | 45 |
| BUNa (mg/dl) | 18 |
| Creatinea (mg/dl) | 0.6 |
| Naa (mEq/ml) | 137 |
| Ka (mEq/ml) | 3.6 |
| Cla (mEq/ml) | 105 |
| CRP (mg/dl) | 1.9 |
Changes in alanine and aspartate aminotransferase levels after admission.
Pathological findings of liver biopsy (hematoxylin and eosin, 20×, and inset, 40×).
Use of TCE was stopped at the printing company after this event. Since his discharge from the hospital, he has not been exposed to high concentrations of chlorinated organic solvents. The patient is now in good health.
Severe acute hepatitis developed in a worker in an offset color proof-printing department of a company. The three criteria for the diagnosis of toxic hepatitis include the following: (1) liver damage after occupational exposure to a substance, considering the patient's work history and current workplace; (2) elevated liver enzyme activity to at least double the upper limit of the reference range; and (3) exclusion of tertiary conditions such as other causes of liver damage12, 13). The patient in this study was exposed to various solvents, including DCP, DCM, and TCE. His serum AST, ALT and LDH levels were remarkably elevated at the time of admission to the hospital and improved rapidly after admission (stopping exposure) and treatment. The patient did not have any known cause of severe acute hepatitis, such as viral hepatitis, autoimmune hepatitis, alcoholic liver disease, viral infection (adenovirus, cytomegalovirus, or EB virus), or biliary tract disease.
Acute toxicity cause by DCP, DCM and TCE has been reported by several investigators3–9). The International Chemical Safety Cards produced of the International Labour Organization2) warn that long-term or repeated exposure to DCM or DCP may affect the liver and kidneys. Repeated or prolonged contact of skin with TCE may cause dermatitis. This solvent may affect the central nervous system, liver, and kidneys. Recently, Chang et al.14) reported that exposure to both lead and organic solvents is dangerous, even if exposure to each of the individual components is within the respective permissible limit. In the present case, the patient developed symptoms during exposure to DCP and TCE and within 1 year of exposure to DCM. There were few workers exposed to both DCP and TCE. Therefore, DCP and TCE were suspected to be the causative agents of the severe acute hepatitis in the patient. DCM also might have contributed to the development of hepatitis. In addition, mixed exposure to such organic solvents might synergize towards the development of the hepatitis.
Toxic hepatitis after exposure to chemicals can be divided into three types: hepatocellular, cholestatic, and mixed type15). Laboratory test results in this patient showed elevated AST, ALT, and LDH levels and a decreased prothrombin value, whereas the serum alkaline phosphatase and γ-GTP levels were within the reference ranges. These results indicate that the hepatitis in this patient should be classified into as a hepatocellular type. Recently, an outbreak of cholangiocarcinoma occurred in this same company, and chlorinated organic solvents, particularly DCM and DCP, were suspected to play a causative role16, 17). In patients with occupational cholangiocarcinoma, laboratory test results showed elevated γ-GTP levels (with or without elevated AST and/or ALT levels), and pathological findings demonstrated chronic bile duct injury and non-injured hepatocytes17). In addition, the patients with occupational cholangiocarcinoma were not exposed to TCE. Therefore, the mechanism causing severe acute hepatitis in the present patient seemed to be different from that causing occupational cholangiocarcinoma.
Although this patient's liver function improved rapidly after restricting further exposure and administering fresh frozen plasma and glucagon-insulin therapy, death due to acute liver failure was reported in a patient with suspected TCE exposure9). Thus, regular assessment of liver function in workers exposed to such chlorinated organic solvents is important because excessive exposure may induce lethal acute hepatitis.
