研究目的

Investigate the association between chronic viral hepatitis with the incidence of liver function impairment and the onset time of DIH.

第二章研究方法 2.1 研究材料

We retrospectively enrolled patients diagnosed with TB who were receiving anti-TB agents at the Changhua Christian Hospital, a tertiary referral hospital in central Taiwan, from January 2002 to December 2009.

2.2 研究設計

2.2.1 資料收集

Information was collected by a computer-assisted search of medical records of patients diagnosed with TB. The following data were collected: age, sex, underlying diseases, concurrent use of other hepatotoxic agents, dates of prescribing and stopping anti-TB agents, regimens and doses of anti-TB agents, serology testing for hepatitis B virus surface antigen (HBsAg) and hepatitis C virus (HCV) antibodies, serial liver function tests at baseline and during anti-TB treatment (including levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total and direct bilirubin), associated symptoms of hepatitis (including poor appetite, nausea, vomiting, fatigue, lower leg edema, abdominal discomfort, and jaundice), and treatment outcomes.

Patients with abnormal baseline liver function tests, HIV infection, those who were lost to follow-up, transferred to other institutions, had stopped anti-TB treatment because an alternative diagnosis was made,

and whose death was not attributable to drug induced hepatitis were excluded. We excluded patients with abnormal baseline liver function tests or human immunodeficiency virus (HIV) infection from the present study. These patients were excluded because: (1) it is difficult to define patients with an abnormal baseline liver function test who develop liver function impairment after therapy; (2) patients with HIV infection may experience abnormal liver function secondary to antiretroviral agents or opportunistic infection; (3) if patients with HIV infection developed liver function impairment during anti-TB treatment, it would be difficult to determine its cause.

2.2.2 定義

The criteria used to define transient liver function impairment (TLI) and DIH were based on previous study recommendations [2, 8, 11, 12]. TLI was defined under 2 sets of conditions: (1) if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels increased at any level, but resolved spontaneously despite continued anti-TB medications; (2) if the drug was first discontinued and the patient was successfully re-challenged with the drug after the liver function test results were normal. For example, if the liver enzyme level was elevated to 150 IU/L, and this abnormality resolved spontaneously during continuation of anti-TB treatment, we defined this condition as TLI. DIH was confirmed in a patient if the liver transaminase level exceeded 120 IU/L with symptoms of acute hepatitis or exceeded 200 IU/L with or without symptoms while the anti-TB drug treatment was stopped, and the liver transaminase level increased to >120 IU/L when the patient was re-challenged with the drug. Resolution of liver toxicity manifestations after drug withdrawal is evidence of DIH [13]. Mild DIH was defined as 120

IU/L< AST/ALT levels <= 200 IU/L, moderate DIH as 200 IU/L <

AST/ALT levels <= 500 IU/L, and severe DIH as AST/ALT levels

>500 IU/L.

2.2.3 治療和監測

Most patients initially received daily isoniazid, rifampicin, ethambutol, and pyrazinamide in the first 2 months followed by isoniazid, rifampicin, and ethambutol in the subsequent 4 months.

Liver function tests were performed once per 2 weeks in the first month after the initiation of treatment and on a monthly basis thereafter. If any liver chemistry abnormalities were detected, monitoring was performed more frequently. Patients developing increased liver transaminase levels but without clinical symptoms were carefully observed without discontinuation of any anti-TB agents. If the patient had symptoms of hepatitis, all drugs that could possibly be hepatotoxic were stopped. After liver transaminase normalization, hepatotoxic drugs were serially restarted. If liver transaminase levels increased during a rechallenge of the therapy, the specific drug was discontinued. A drug was considered responsible for adverse effects if symptoms appeared with the start of the drug, resolved with withdrawal, and reappeared with a challenge of the same drug.

2.3 統計方法

Values are expressed as mean ± standard deviation or as number (percentage) in the text and tables. Differences with regard to numerical values between different groups were analyzed using the Student t test or the Mann–Whitney U test depending on the distribution of the data. Nominal variables were assessed using the chi-square test or the Fisher exact test. Baseline characteristics among the HBV, HCV, and control groups were analyzed by 1-way ANOVA and post hoc analysis. A P value of <0.05 was considered statistically significant.

第三章研究結果 3.1 描述性統計分析

3.1.1 病人背景資料

A total of 553 patients were enrolled. All patients were screened for HBV and HCV before anti-TB treatment. Of these, 392 were negative for HBsAg and HCV antibody (control group), 75 were positive for HBsAg and negative for HCV antibody (HBV group), and 71 were positive for HCV antibody and negative for HBsAg (HCV group).

Fifteen patients were positive for both HBsAg and HCV antibody (HBV + HCV group). Baseline characteristics of the HBV, HCV, HBV + HCV, and control group patients are shown in Table 1. Age, sex, baseline renal function test results, and the initial treatment regimen were almost identical in the 3 groups; most patients (> 90%) started their anti-TB regimen with a standard 4-drug combination, including isoniazid, rifampicin, ethambutol, and pyrazinamide.

3.1.2 排除病人描述

One hundred and thirty-seven patients were excluded because of the following reasons: 37 had abnormal baseline liver function tests, 3 were alcohol-dependent, 7 had HIV infection, 8 were lost to follow-up, 25 were transferred to other institutions, 43 stopped anti-TB treatment because an alternative diagnosis was made, and 22 died during anti-TB treatment but their death was not attributable to DIH.

3.2 推論性統計分析

3.2.1 肝功能異常發生的機率

Seventy-two (13%) patients developed liver function impairment during anti-TB therapy. The incidence of any liver function impairment was higher in patients with HBV or HBV than in those without; incidences of elevated liver function enzyme levels during anti-TB therapy in HBV, HCV, and control groups were 19% (14/75), 21% (15/71), and 11% (41/392), respectively (Table 2). Patients in the HCV or HBV groups had a significantly higher incidence of TLI during treatment than controls (all P < 0.001). However, the incidence of DIH showed no significant differences among the 3 groups (7% [5/75], 9% [6/71], and 8% [32/392], all P > 0.05). The major contribution to the differences in liver function impairment during anti-TB treatment between the HBV, HCV, and control groups was only because of TLI. These results are shown in detail in Table 2.

3.2.2 黃膽發生的機率

The incidence of jaundice was higher in patients with DIH than in those with TLI (Table 3). Jaundice developed in 25 patients with DIH, but only in 5 patients with TLI (odds ratio [OR] 5.2, 95% confidence interval [CI] 2.0–13.7; P < 0.001). In the control group, 3 patients with TLI and 16 patients with DIH developed jaundice (OR 5.5, 95%

CI 1.6–19.1; P = 0.004). Among the patients in the HBV and HCV groups, those with DIH had higher incidences of jaundice than those with in TLI, although the differences were not statistically significant.

In patients with chronic viral hepatitis, 8 patients with DIH and 2 patients with TLI developed jaundice (OR 4.7, 95% CI 1.0–22.1; P = 0.061). The incidence of jaundice was similar in HBV, HCV and control group at the range from 5 to 8 percent (Table 4).

3.2.3 藥物引起肝炎的嚴重程度

There were no significant differences in the severity of liver function impairment in patients in the HBV, HCV, and control groups.

Among the patients without chronic hepatitis B or C, mild hepatotoxicity developed in 10 patients (2.6%), moderate hepatotoxicity in 10 (2.6%), and severe toxicity in 11 (2.8%). Among the 5 HBV patients with drug-induced hepatotoxicity, 2 (2.7%) had mild hepatotoxicity, no patient had moderate hepatotoxicity, and 3 (4%) had severe hepatotoxicity. Among the 6 HCV patients with DIH, 2 (2.8%) had mild hepatotoxicity, 2 (2.8%) had moderate hepatotoxicity, and 2 (2.8%) had severe hepatotoxicity.

3.2.4 肝功能異常出現的時間

The mean onset times of liver function impairment in patients with TLI and those with DIH were 46 ± 33 days and 47 ± 29 days, respectively (P > 0.05). The mean onset times of TLI in controls, HBV, and HCV were significantly different (23 days, 48 days, and 68 days, respectively, all P < 0.05; Table 5). We did not find any significant effect of the type of anti-TB medication on the time of DIH onset. In the control group, TLI developed within 1 month in 6 patients (6/9 [67%]). In contrast, less than half of the patients developed TLI during the first month of treatment in the HCV and HBV groups.

The onset times of DIH are also shown in detail in Table 4. The mean onset times of DIH in controls, HBV, and HCV groups were not significantly different (40 days, 39 days, and 67 days, respectively, all

P > 0.05). Eighty percent of HBV patients and 90% of controls

developed DIH within 2 months. Nevertheless, 50% of the HCV patients developed DIH after 2 months (P < 0.05).

In patients with chronic viral hepatitis who developed liver function

impairment, approximately 40% developed DIH either <2 months or

>2 months after initiation of anti-TB therapy. Conversely, among patients without chronic viral hepatitis, 76% developed liver dysfunction within 2 months due to DIH, and no patient developed TLI after 2 months.

3.2.5 不同種類的抗結核病藥物引起肝功能異常的出現時間

The onset time of DIH in isoniazid-, rifampicin-, and pyrazinamide-related hepatotoxicity were 47 ± 41 days (range, 3–120 days), 48 ± 33 days (range, 3–128 days), and 36 ± 31 days (range, 3–115 days), respectively (Table 7). We did not find any significant effect of different types of anti-TB medication on the onset of DIH with all P value larger than 0.05 (Table 8).

第四章討論 4.1 結果討論

In clinical practice it is difficult to decide whether anti-TB treatment should be continued because TLI is relatively common in patients with anti-TB treatment. A newly acquired viral hepatitis or acute exacerbation of chronic hepatitis is of particular concern in areas where the disease is endemic [2, 14, 15]. Inability to recognize other causes of hepatotoxicity and unnecessary discontinuation of anti-TB medication may prolong the course of treatment, increase the possibility of treatment failure, and increase the rate of drug resistance. On the other hand, failure to find true DIH and discontinuation of medication promptly may be fatal [16, 17].Recent reports on large series of patients with anti-TB DIH demonstrate that fatality is not uncommon occurring in over 20% of patients with anti-TB DIH particularly in those who exhibit jaundice. In fact the mortality with the occurrence of acute liver failure is still higher over 67% [18 - 20].

In our study, we found that TLI had a significantly higher incidence in the HBsAg- or HCV antibody-positive patients (14.3%) than in controls (2.3%). Moreover, TLI was observed more often (14.3%) than DIH (7.1%) in patients with chronic viral hepatitis. Conversely, the incidences of DIH and TLI were 8.7% and 2.3%, respectively, in patients without chronic viral hepatitis. The incidence of DIH was about the same in patients with or without chronic hepatitis (7.1% vs.

8.7%). These results are valuable and are worthy of further consideration in anti-TB treatment.

4.2 其他相關性討論

The severity of DIH in HBV carriers and control groups has been discussed by Lee et al [8]. They found that HBsAg-positive carriers had a higher proportion of moderate-to-severe DIH compared with HBsAg-negative subjects. However, our results found that the severity of DIH was not significantly different between the HBV, HCV, and control groups. The findings may be different because we included 30 DIH patients in our control group whereas Lee et al.

included only 4 in their study.

The effect of chronic hepatitis on the onset of liver function impairment during anti-TB chemotherapy has been mentioned in a few studies. Previous studies have reported that DIH usually occurred within the initial 2 months of therapy [21, 22]. We found that TLI occurred later in patients with chronic hepatitis. One possible explanation is a flare-up of the chronic hepatitis virus. A future study with detailed follow-up of hepatitis viral load in patients with viral hepatitis taking anti-TB medication would help to find out if this

assumption is valid. We observed that the HCV group had a tendency towards a later onset of DIH than the HBV and control groups, although the difference was not statically significant. However, we still found that DIH developed more frequently in the HCV group than in the control group, more than 2 months after initiating anti-TB therapy. Therefore, we suggest that patients with HCV should have liver function tests routinely during the later period of anti-TB treatment even when DIH does not occur within first 2 months. Chien

et al. also studied the onset of DIH [23]. They found that the onset of

DIH in patients without chronic hepatitis was approximately 40 days, and our study had a similar finding. One anomaly in their study was that co-infection with HBV was associated with a later onset at a mean of 102 days in 3 patients. Wang et al. investigated the impact of baseline HBV and HCV viral load on hepatitis during anti-TB treatment [24]. They found a high baseline hepatitis viral load is associated with higher odds of getting DIH and flare up of viral hepatitis whereas in chronic viral hepatitis patients carrying low or undetectable baseline viral loads the odds is not different from

patients without chronic hepatitis. In our study, the incidence of DIH is not increased in patients with chronic HBV or HCV may be contributed to our strict inclusion criteria. We excluded patients with abnormal baseline liver function. Based on the results of our study and Wang’s study, we infer that the chances of DIH will not increase in chronic viral hepatitis with baseline normal liver biochemistry test.

Another interesting finding is with regard to jaundice. We did not find that chronic hepatitis had a significant effect on the incidence and onset of jaundice. Patients with DIH had a higher incidence of jaundice than those with TLI. This reflects true organ toxicity in patients with DIH. If jaundice develops during anti-TB treatment, DIH should be considered first regardless of previous hepatitis status.

Discontinuation of the hepatotoxic drug and close observation are necessary even in patients with chronic hepatitis. On the contrary, TLI reflects flare up of chronic viral hepatitis or hepatic adaption to anti-tuberculosis chemotherapy [25]. Patients may develop some sort of tolerance to the drug in question and therefore may never develop hepatitis the second time the drug is administered.

4.3 研究限制

Because this was a retrospective study, it has some limitations. First, precise information on concurrent use of other herbal medicines or so-called health foods that are commonly consumed by Taiwanese patients was not available from medical chart review. Second, the measurement of liver function in most patients was performed on a regular biweekly or monthly basis. Therefore, the exact day of the onset of liver function impairment may be earlier than the day recorded in this study. Third, most patients who developed liver function impairment were not routinely checked for HBV and HCV viral load, hepatitis A virus IgM, and hepatitis E virus IgM, which are endemic in Taiwan [26]. Occasionally, definite causes of hepatitis were not determined.

第五章結論與建議 5.1 結論

In conclusion, we found that liver function impairment during anti-TB therapy was mostly because of TLI in patients with chronic viral hepatitis, and because of DIH in patients without chronic viral hepatitis. Chronic hepatitis had no significant effect on the onset of DIH, but TLI occurred later in patients with chronic hepatitis. Our study can help clinicians to proper management of liver function impairment in patients receiving anti-TB treatment.

5.2 建議

We emphasize that the present study found some important clinical effects. First, physicians shall not worry about a higher likelihood of DIH in their chronic viral hepatitis patients during anti-TB therapy whose baseline liver biochemistry tests are normal. Second, physicians should take the onset of liver function impairment and whether the patient had chronic hepatitis into consideration to decide whether the potential hepatotoxic drug should be stopped. In patients with chronic viral hepatitis developing abnormal liver function test during anti-TB therapy, continue anti-tuberculosis medication is a rational approach unless hepatitis symptoms occur. Because the chance of TLI is approximately twice of DIH regardless of the onset time of abnormal liver function test according to our observation. In patients without chronic hepatitis who experienced liver function, the onset time is an important factor for clinical decision. If liver function impairment occurred after 2 months, we suggested hepatotoxic agents shall be stopped instantly and rechallenge the drug separately to

determine the culprit medication. Third, in patients with chronic hepatitis, we suggested follow up liver biochemistry test intensely even after 2 months of initializing anti-TB therapy owing to half of HCV patients developed DIH during this period.

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在文檔中中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/50308 (頁 16-0)

第二章 研究方法 2.1 研究材料