Clin J Gastroenterol (2008) 1:64–68 DOI 10.1007/s12328-008-0009-0

CASE REPORT

A fatal case of acute hepatitis B developed in a toluene abuser Hideaki Kato Æ Jun Monma-Ohtaki Æ Makoto Nakamura Æ Yuji Nishi Æ Makoto Ohyama Æ Yoshitaka Maeno Æ Yoshimi Seko-Nakamura Æ Saeko Nagao Æ Masataka Nagao

Received: 11 January 2008 / Accepted: 31 March 2008 / Published online: 16 May 2008 Ó Springer 2008

Abstract Liver dysfunction involving toluene intoxicity includes elevation of transaminase level and delayed complications of liver failure, but its effect on hepatitis B virus (HBV) infection is as yet unknown. Here, we report a case of fulminant hepatitis B developed in a toluene abuser. A 23-year-old female toluene abuser was admitted to a local clinic because of nausea, vomiting, and dizziness, and a mild elevation of serum transaminase level was identified. She was treated as an outpatient, but continued toluene inhalation during follow-up. Five days later, she was found in a drowsy state of consciousness and taken to the emergency unit of our institution. Laboratory findings showed an alanine aminotransferase level of 4,659 IU, a remarkably prolonged prothrombin time, and she was diagnosed with fulminant hepatitis B. Intensive care was carried out, but she died the next day. Molecular analysis revealed that the HBV isolate was classified as genotype C, and nucleotide positions that are prone to fulminant hepatitis were A at 1,762 and G at 1,764 in the core promoter region, and G at 1,896 in codon 28 in the precore region. The long-term toluene inhalation could have contributed to drastic clinical course of acute hepatitis B in this patient.

H. Kato (&)  M. Nakamura  Y. Nishi  M. Ohyama Department of Gastroenterology, Toyokawa City Hospital, Kohmei-cho 1-19, Toyokawa 442-8561, Japan e-mail: [email protected] H. Kato  J. Monma-Ohtaki  Y. Maeno  Y. Seko-Nakamura  M. Nagao Department of Forensic Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan S. Nagao Department of Pulmonary Medicine, Hiroshima University Hospital, Hiroshima, Japan

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Keywords Fulminant hepatitis  Genotypes  Hepatitis B  Intoxication  Toluene

Introduction Hepatitis B virus (HBV) infects approximately 350 million people worldwide [1] and causes a wide spectrum of diseases ranging from subclinical liver dysfunction to lifethreatening fulminant hepatitis [2]. Fulminant hepatitis caused by HBV has been shown to be associated with viral factors, such as viral genotypes, the core promoter and the precore sequence [3], and the administration of glucocorticoid and anticancer drugs [4–6]. Host conditions such as an immuno-suppressed condition are also considered to be associated with disease severity and, for example, posttransplant fulminant hepatitis B has occurred in some recipients of bone marrow or liver transplantation [7, 8]. In addition, a causal relationship between occupational exposure to aromatic organic agents such as toluene, xylene, and styrene and liver injury has been suggested [9–11]. The inhalation of toluene-containing substances such as paint or glue is carried out for its euphoric effects, and toluene abuse has been identified as a problem in the USA since the 1960s [12]. In Japan also, toluene abuse is a social problem especially in younger age groups, and based on the Justice Ministry’s white paper on crime, approximately 5,000 persons are arrested due to toluene abuse annually in Japan. To date, data on the relationship between acute hepatitis B and toluene abuse are extremely limited. In this report, we describe a fatal case of fulminant hepatitis B developed in a patient that was a known toluene abuser. Molecular analysis of HBV isolates recovered from the patient was carried out. We also discuss the possible attribution of

Clin J Gastroenterol (2008) 1:64–68

toluene to the clinical course of the patient with fatal liver dysfunction.

65 Table 1 Laboratory findings on admission Component

Results

Serum

Case report On October 12th, a 23-year-old female was referred to a local clinic because of nausea, vomiting, and dizziness. She had been a habitual toluene abuser since the age of 14 and had been receiving medication for the treatment of psychological disorders due to toluene abuse. Physical examination revealed tenderness in the epigastric region of the abdomen, and laboratory investigation showed that serum asparate aminotransferase (AST) was 131 IU/l (normal 5–40 IU) and alanine transaminase level (ALT) was 137 IU/l (normal 0–40 IU). Her serum was positive for hepatitis B surface antigen (HBsAg), but negative for antibodies to hepatitis C. She was diagnosed with hepatitis B, and further laboratory evaluation was planned to determine whether it was an acute or chronic infection. Since the laboratory data showed only mild liver dysfunction, she was followed as an outpatient. As the symptoms continued, she was referred to the hospital twice in 5 days, but deterioration of the symptoms was not noted on physical examination. On October 17, she was found to be in a drowsy state of consciousness by her father and was taken to the emergency unit in our hospital. At the time of referral, her consciousness was highly disturbed. Physical examination revealed that her body temperature was 37.7°C, pulse rate was 108 beats per minute, and blood pressure was 114/69 mmHg. Laboratory findings showed AST, 3,650 IU; ALT, 4,659 IU; total bilirubin, 10.3 IU (normal 0–2.0 IU); direct bilirubin 8.9 IU (normal 0–1.2 IU); prothrombin time 14% (normal 80–120%); hepaplastin test, 9% (normal 70–120%); HBV DNA, 5.4 LEG/ml; IgM-HBcAb 14.6 s/co (normal \1); C-reacting protein, 1.56 mg/dl (normal \0.5 mg/dl); white blood cells, 7,100/mm3; red blood cells, 462 9 104/mm3; hemoglobin, 14.8 g/dl; and platelets, 26 9 104/mm3 (Table 1). She was diagnosed with fulminant hepatitis B. Intensive treatment for liver failure was immediately commenced, and preparation for liver transplantation was intended. However, after admission, her condition worsened drastically, and she was died of acute liver dysfunction the next day. Autopsy was proposed, but her family refused it. Her father indicated that during the follow-up as an outpatient, she continued inhalation of toluene and inhaled an increased dose compared to October 16. Her acquaintances were not aware of the change in her condition because she was sometimes in a daze due to regular toluene inhalation. After written informed consent was obtained from her family, molecular analysis of the HBV strain isolated from

Component

Results

Viral markers

AST

3,656 IU

HBsAg (CLIA)

[2,000 IU/ml

ALT

4,569 IU

HBsAb (CLIA)

Negative

LDH

1,943 IU

HBeAg (CLIA)

51.7 s/co

ALP

768 IU

HBeAb (CLIA)

Negative

c-GTP

613 IU

IgM HBcAb (CLIA)

14.6 s/co

Total birilubin 10.3 mg/dl Direct birilubin 8.9 mg/dl

HBV DNA (TMA) 5.4 LGE/ml ANA Negative

Total protein

7.0 mg/dl

AMA

Negative

Albumin

4.0 mg/dl

IgM HAAb

Negative

BUN

20.6 mg/dl

HCVAb

Negative

Creatinin

1.0 mg/dl

IgM HEVAb

Negative

C-reacting protein

1.56 mg/dl

IgG HEVAb

Negative

Ammonia

[400 mg/dl

IgM CMVAb

Negative

IgM EB-VCAAb

Negative

HDV RNA(RTPCR)

Negative

Complete blood cell count WBC

7,100/ll

RBC

462 9 104/ll Thyroid hormones

Ht

43.2%

TSH

Hb

14.8 g/dl

fT3

2.7 pg/ml

Plt

26 9 104/ll

fT4

1.66 ng/dl

0.093 lIU/ml

Coagulation PT

48.9 s 14%

HPT

9%

ALP Alkaline phosphatase, ALT alanine aminotransferase, AMA antimitochondrial antibody, ANA antinuclear antibody, AST aspartate aminotransferase, BUN blood urea nitrogen, CLIA chemiluminescent immunoassay, CMV cytomegalovirus, EB-VCA Ebstein-Barr viral capsid antigen, fT3 free triiodothyronine, fT4 thyroxine, c-GTP c-glutamyltranspeptidase, HPT hepaplastin test, HA hepatitis A, HB hepatitis B, Hb hemoglobin, HDV hepatitis D virus, HEV hepatitis E virus, Ht hematocrit, LDH lactate dehydrogenase, LGE logarithm genome equivalent, Plt platelet cell count, PT prothrombin time, RBC red blood cell count, RT-PCR reverse transcription polymerase chain reaction, s/co sample/cut off index, TMA transcription mediated amplification, TSH thyroid stimulating hormone, WBC white blood cell count

the patient was carried out and also the serum concentration of toluene was measured. The complete genome of the HBV isolate was determined by the method described previously [13]. The genome length of the isolate was 3,215 base pairs, and deduced amino acid lengths were 220, 183, 843, and 154 in the S, core, polymerase, and X protein, respectively. Deduced amino acid sequences at positions 122 and 160 in the S region were lysine and arginine, respectively, thus the HBsAg subtype was adr. Nucleotides in the core promoter region were A at 1,762

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Clin J Gastroenterol (2008) 1:64–68

and G at 1,764, and in the precore region G at 1,896 in codon 28 (Table 2). Nucleotide substitutions that are reported to be associated with fulminant hepatitis were also investigated. Two mutations, A at 996 and G at 3,109, were observed in this patient. The concentration of toluene in the serum was analyzed using gas chromatography-mass spectrometry [14], but toluene was not detected.

Discussion It is estimated that there are approximately 350,000 cases annually of acute hepatitis B in Japan, and 13% of the hospitalized patients develop fulminant hepatitis [3]. Despite the remarkable progress in the treatment of fulminant hepatitis, such as liver transplantation, the disease still has a high mortality rate of more than 50% [15]. A close association between the core promoter and the precore sequence and fulminant hepatitis has been reported. Sato et al. investigated the HBV isolates recovered from 43 patients with fulminant hepatitis B in Japan, and all the HBV strains harbored either a nucleotide mutation from G to A at nucleotide 1,896 in the precore region or two point mutations in the core promoter region, from A to T at nucleotide 1,762 and from G to A at nucleotide 1,764 [16]. Petrosillo et al. also investigated HBV isolates recovered from patients with

fulminant hepatitis B during an outbreak in a hospital and reported that all the HBV strains from the 11 patients harbored a nucleotide mutation from G to A at nucleotide 1,896 in the precore region as well as from A to T at nucleotide 1,762 and from G to A at nucleotide 1,764 [17]. In in vitro studies, these mutations observed in the precore and core promoter regions were revealed to be associated with an increase in viral replication [13], and to result in severe liver damage. In this case, neither the G to A mutation at nucleotide position 1,896 nor the two point mutations in the core promoter region were observed, thus virus factors were less likely to have contributed to the development of fulminant hepatitis. Nucleotide substitutions that render a patient more prone to fulminant hepatitis other than 1,762/1,764 in the core promoter region and 1,896 in the precore region were also investigated. These mutations were derived from comparing the sequences of fulminant hepatitis to those of acute hepatitis. Among these mutations, two mutations were observed in this patient that were reported by Chen et al., who analyzed 8 patients with fulminant hepatitis and 26 patients with acute hepatitis and found 6 mutations that might be associated with fulminant hepatitis [18]. However, in contrast to the fact that the HBV strain detected in this study was genotype C, these mutations were found among patients infected with HBV genotype D. At this time, it is unknown whether the two mutations observed in

Table 2 Nucleotide changes associated with fulminant hepatitis B and nucleotide sequences in this case Region

Nucleotide position

Mutation

This case

Reference

S

491a

T

A

Chen et al. [18]

Polymerase

996a

A

A

Chen et al.

Polymerase

1,171a

A

C

Chen et al.

BCP

1,766

T

C

Baumert et al. [26]

BCP

1,768

A

T

Baumert et al.

BCP

1,753

Vb

T

Imamura et al. [27]

BCP

1,754

V

T

Imamura et al.

BCP BCP

1,762/1,764 Between 1,774 and 1,775

T/A GTTAATCATTA insertion

A/G None

Sato et al. [16] Pult et al. [28]

BCP

1,862

T

G

Hou et al. [29]

Precore

1,896

A

G

Omata et al. [30]

Core

2,339

G

A

Sugiyama et al. [31]

PreS1

2,959a

C

T

Chen et al.

PreS1

3,098a

A

T

Chen et al.

PreS1

a

3,109

G

G

Chen et al.

PreS2

3,206/3,207

C/A

T/G

Pollicino et al. [32]

Nucleotide sequences corresponding to mutations associated with fulminant hepatitis are shown in bold Full-nucleotide sequence of HBV strain in this study has been deposited with the DNA data bank of Japan (accession no. AB426467) BCP Basic core promoter a Nucleotide positions are renumbered according to a representative sequence of genotype C (accession no. D50517) b

V means nucleotides C, G or A

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Clin J Gastroenterol (2008) 1:64–68

the HBV isolate in this study were associated with the fulminant course of this patient. Toluene belongs to a family of aromatic hydrocarbons characterized by a benzene ring and is ubiquitously used as an industrial and domestic solvent. Deliberate inhalation of fumes given off by volatile substances containing toluene results in intoxication, and long-term use leads to psychological dependence. Manifestation of toluene intoxication includes euphoria, disinhibition, dizziness, lethargy, stupor, nausea, and vomiting, and chronic misuse symptoms include cerebellar syndrome, ataxia, nystagmus, tremor, fatigue, difficulty in concentration, and also Parkinsonism. Liver disorders caused by chronic exposure to toluene include hepatomegaly and mild elevation of serum transaminase levels, and histopathologically marked microvesicular and macrovesicular fatty change preferentially localized in the pericentral area [19]. Most acute direct toluene abuse-related deaths result from cardiac arrhythmia owing to ‘‘sensitization’’ of myocardium to adrenaline, and deaths may also occur from delayed effects such as liver failure, renal failure, and bone marrow depression. Pharmacokinetically, toluene eliminates from the serum within 4–6 h after the cessation of exposure [20], and therefore, it is preferred to use adipose tissue or brain, as they contain lipid-bound toluene, for detecting its presence. This may explain why toluene was not detected in this patient, although misuse of the solvent was confirmed by her family. Toluene abuse may be a factor in the deterioration of the clinical course of this patient, however, it might not be enough to explain the cause of death of this patient as a solely acute or chronic toluene effect. The mechanism of hepatoxicity by toluene has not been well defined. The pathological investigation revealed marked microvesicular and macrovesicular fatty change as well as necrosis and hemorrhage preferentially localized in the pericentral area [19] and also showed infiltration of lymphocytes and inflammatory changes in the periportal area. From these findings, liver damage induced by toluene is considered to be the result of a direct cytotoxic effect [21]. One experimental animal study showed that exposure to toluene at concentrations of 533–800 ppm for 7 days increased liver weights, and electron microscopical examination revealed ultrastructural changes that were compatible with changes in cytochrome P-450 concentrations [22]. It was also reported that the hepatotoxicity of toluene resulted in reduced levels of proteins being synthesized in the liver, including those concerned with blood clotting [23]. Therefore, severe liver damage in this patient was speculated to be caused by synergism between toluene and HBV infection. It is likely that HBV infection of the patient with deterioration of liver function, including reduced P-450 activity and the levels of proteins concerned with blood clotting due to toluene inhalation, resulted in fulminant hepatitis.

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It is sometimes problematic for clinicians to differentiate between acute hepatitis B infection and exacerbation of chronic hepatitis B infection. The most reliable finding indicating an acute HBV infection is the confirmation of HBsAg-negative status at the previous testing. If previous data are not available, it is sometimes difficult to distinguish by only serological testing. During the symptomatic phase of infection, both patients with acute and chronic HBV are likely to show similar serologies as determined by the available commercial assays. Antibody production of HBcAg occurs early in the course of the acute phase of HBV infection and can persist for many years, and chronically infected patients produce a high titer of antibody to hepatitis B core antigen. In contrast to most viral infections, patients with acute and chronic HBV infection often produce both immunoglobulin (Ig) M class and IgG class anti-HBc antibodies; therefore, the mere presence of IgM anti-HBc can not distinguish acute from chronic infection. Higher levels of IgM antiHBc are generally produced during the acute phase as compared with chronic infection, and this quantitative difference has become the only serological means of differentiating acute HBV infection from acute exacerbation of chronic infection [24]. Based on the finding of a high titer of IgM HBcAb (14.6 s/co), the patient in this study was diagnosed with acute HBV infection. With regard to the infectious route of HBV in this case, it was impossible to identify the transmission route because of her severe condition. Sugauchi et al. investigated 485 patients with acute hepatitis B in Japan [25]. In the report, HBV was determined to have been transmitted through sexual contact in 45%, medical practice in 3%, and blood transfusion in 1%. It was striking that the transmission route was not clear in 51% of the patients in the study. Sugauchi et al. indicated that intravenous drug abusers were included in the group whose transmission route was unclear. Since it is likely that toluene abusers also tend to abuse other types of drugs, it is possible that this patient was in this group. So far, a relationship between acute hepatitis B and toluene toxicity has not been reported. In this patient, whether toluene had a direct effect on HBV replication or if the condition of hepatocytes latently exhausted by toluene inhalation resulted in liver failure concominant with infection of HBV is unclear. However, it is possible that the drastic clinical course of acute hepatitis B in this patient was affected by toluene inhalation. It is well-known that drug abusers are at high-risk for obtaining bloodborne viruses such as HBV, hepatitis C virus, and human immunodeficiency viruses because of their high-risk behaviors. Therefore, cases of acute hepatitis B among toluene abusers might occur more frequently than previously thought. Accumulation of data on the relationship

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between acute or chronic hepatitis B and toluene inhalation is required, and clinicians should pay careful attention to patients with acute hepatitis who abuse toluene.

Clin J Gastroenterol (2008) 1:64–68

17.

18.

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A fatal case of acute hepatitis B developed in a toluene abuser.

Liver dysfunction involving toluene intoxicity includes elevation of transaminase level and delayed complications of liver failure, but its effect on ...
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