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Abstract

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  2. Abstract
  3. References

We report 13 patients (10 with chronic hepatitis C, 1 with chronic hepatitis B, 2 with nonalcoholic steatohepatitis) with persistently elevated alanine aminotransferase (ALT) levels who were treated with dimethyl-4,4′-dimethoxy-5,6,5′,6-dimethylenedioxybiphenyl-2,2′ dicarboxylate (DDB). ALT rapidly normalized in 12/13 patients and remained normal during treatment. Unlike ALT levels, aspartate aminotransferase, gamma-glutamyl transferase and glutamate dehydrogenase levels were not affected. Furthermore, there was no beneficial effect on the histological grade and stage of liver disease. In vitro experiments with hepatocytes resulted in a significant decrease of hepatocellular ALT levels in the DDB treated cells, suggesting, that DDB affects the synthesis and/or degradation of ALT in liver cells. In conclusion, the normalization of ALT during DDB treatment does not indicate therapeutic efficacy. In view of the wide use of DDB in patients with chronic liver diseases who participate in clinical studies DDB use should be excluded. (HEPATOLOGY 2004;39:1732–1733.)

Dimethyl-4,4′-dimethoxy-5,6,5′,6-dimethylene- dioxybiphenyl-2,2′dicarboxylate (DDB, BeijingUnion Factory, Beijing, China) is registered as “liver support” medication in China and Egypt and is widely used for the treatment of chronic liver diseases of different etiologies in these countries. The costs are about $4 per month. Beneficial effects of DDB have been observed in liver cell injury models1–3 and in about 80% of 222 patients with chronic hepatitis of different etiologies.4 In recent years DDB use has also increased in Western countries.

We report a retrospective analysis of 13 patients (10 with chronic hepatitis C, 1 with chronic hepatitis B, 2 with nonalcoholic steatohepatitis) who were treated with DDB (12 mg, 3 times per day) in our outpatient clinic between 2000 and 2003. The blood samples were obtained during regular patient follow-up visits. The analyses were performed in our quality controlled clinical laboratory. All patients had persistently elevated alanine aminotransferase (ALT) levels for more than 6 months before treatment and no other treatments for their liver diseases during DDB treatment. The 10 patients with chronic hepatitis C (7 males, 3 females; mean age, 57 ± 10 years; 9 with genotype 1, 1 with genotype 4, 2 with liver cirrhosis) had a mean duration of their disease of more than 10 years; most of them were nonresponders to combination therapy with interferon alpha and ribavirin. The patient with chronic hepatitis B was previously treated with lamivudine and had developed lamivudine resistance. Nonalcoholic steatohepatitis was diagnosed by exclusion of other causes and by liver histology.

ALT normalized in 12/13 patients within 2–12 weeks of DDB treatment, irrespective of the baseline level and the etiology of the disease, and remained normal during treatment. After DDB treatment, ALT relapsed in all patients within 2–6 weeks (Table 1). Interestingly, DDB does not affect ALT levels in healthy individuals. Side effects did not occur in our patients and have not been described previously.

Table 1. ALT, AST, GGT, and GLDH Levels of DDB-Treated Patients
DDBHCV Infection (n = 10)HBV Infection (n = 1)NASH (n = 2)
BeforeDuringAfterBeforeDuringAfterBeforeDuringAfter
  • NOTE. Values expressed as mean ± SD.

  • Abbreviations: AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; GLDH, glutamate dehydrogenase; HCV, hepatitis C virus; HBV, hepatitis B virus; NASH, nonalcoholic steatohepatitis; nd, not done.

  • *

    Normal <23 U/L.

  • Normal <18 U/L.

  • Normal <28 U/L.

  • §

    Normal <4 U/L.

ALT*81 ± 3418 ± 761 ± 3082154857 ± 3314 ± 041 ± 3
AST40 ± 1429 ± 1237 ± 1680436719 ± 416 ± 126 ± 13
GGT39 ± 1834 ± 1636 ± 13312827127 ± 117148 ± 15287 ± 30
GLDH§8 ± 38 ± 49 ± 6ndndndndndnd

Unlike gamma-glutamyl transferase ALT levels, aspartate aminotransferase levels did not change significantly. and glutamate dehydrogenase did not change at all. Also, there was no significant effect on the hepatitis B virus DNA level in the 1 patient with chronic hepatitis B (before DDB treatment, 66 × 106copies/mL; during DDB treatment, 44 × 106 copies/mL) or the hepatitis C virus RNA level in 6 patients with chronic hepatitis C (before DDB treatment, 7.8 ± 16 × 106 copies/mL; during DDB treatment, 11.5 ± 15 × 106 copies/mL). Furthermore, 5 patients with chronic hepatitis C had, for reasons not related to DDB treatment (planned participation in a clinical study, medical reasons), liver biopsies after 1 year of treatment that could be compared with biopsies obtained 3–20 months before treatment. The grade of inflammation was unchanged in 2, worse in 2, and better in 1 patient; the stage of fibrosis was worse in 3 and stable in 2 patients.5 All 5 patients had responded to DDB treatment with a persistent ALT normalization (Table 2).

Table 2. ALT Levels and Liver Histologies Before and After 1 Year DDB Treatment of 5 Patients With Chronic Hepatitis C
DDBALT (normal <23 U/L)Grade*Stage*
  • NOTE. Values expressed as mean ± SD.

  • *

    Grading and staging according to reference 5: 5 = none; 1 = mild; 2 = moderate; 3 = severe; 4 (for stage only) = cirrhosis.

Before treatment65 ± 171, 2, 2, 1, 1*3, 3, 2–3, 1, 3*
3 months20 ± 10  
6 months17 ± 3  
9 months18 ± 7  
12 months15 ± 22, 2, 2, 0, 24, 3, 4, 1, 3–4

To further analyze the effect of DDB on ALT levels, in vitro experiments were performed. DDB dissolved in dimethylsulfoxide (DMSO) was added at different concentrations to patient sera with elevated ALT levels. In a second experiment, serum with elevated ALT levels from a patient with chronic hepatitis C not treated with DDB was added at different concentrations to sera of patients who had responded to DDB and to sera of healthy controls. In both experiments, DDB had no effect on ALT levels in vitro and, therefore, did not interfere with the ALT assay or affect the degradation of ALT in serum. In a further experiment primary Tupaia hepatocytes were incubated for 5 days with 10 μg DDB/mL in DMSO and compared to DMSO alone and to medium without addition; culture medium was changed daily. ALT levels in the culture medium were below the detection limit in all 3 groups. In the cell lysates, however, ALT levels were significantly lower in the DDB treated cells (113 U/L compared to 500 U/L in the DMSO and 530 U/L in the control group). By comparison, AST levels (DDB, 1,700 U/L; DMSO, 1,900 U/L; control, 2,100 U/L) and lactate dehydrogenase levels (DDB, 3,000 U/L; DMSO, 2,650 U/L; control, 3,000 U/L) were similar in all 3 groups. These results suggest that DDB affects the synthesis and/or the degradation of ALT in hepatocytes.

In summary, DDB effectively normalizes elevated ALT levels in patients with chronic liver diseases of different etiologies, while aspartate aminotransferase, gamma-glutamyl transferase,and glutamate dehydrogenase levels are not affected. Despite the small number of patients studied, ALT normalization in our view does not indicate a therapeutic benefit, because there was no beneficial effect on the histological grade and stage of the liver diseases. Rather, preliminary in vitro experiments suggest that DDB affects the synthesis and/or degradation of ALT in hepatocytes by an as yet unknown mechanism. In view of the wide use of DDB in patients who participate in clinical studies in which ALT levels are an important outcome parameter, the use of DDB should be excluded.

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    Fu T, Liu G. Protective effects of dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate on damages of isolated rat hepatocytes induced by carbon tetrachloride and D-galactosamine. Biomed Environ Sci 1992; 5: 185194.
  • 2
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  • 3
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  • 4
    Zhang Y, Yu H, Shi J, Qi H, Dong Z, Xu H. The therapeutic effect of bipheny-dimethy-dicarboxylate (DDB) on certain abnormal laboratory parameters in chronic hepatitis. J Tradit Chin Med 1987; 7: 137138.
  • 5
    Hytiroglou P, Thung SN, Gerber MA. Histological classification and quantitation of the severity of chronic hepatitis: keep it simple! Semin Liver Dis 1995; 15: 414421.