blood cells without concomitant liver infectionâThe liver trans- plantation ... contains a glucocorticoid-responsive element. ... tation. CDT values were determined by a double-anti- body radioimmunoassay. Results: In the 241 alcohol-abstinent subjects, CDT levels ... vival rates similar to those for patients who undergo.
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blood cells without concomitant liver infection—The liver transplantation model. Transplantation 1990;49:1155-1158. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus contains a glucocorticoid-responsive element. Proc Natl Acad Sci U S A 1986;83:1627-1631. McMillan JS, Shaw T, Angus PW, Locarnini SA. Effect of immunosuppressive and antiviral agents on hepatitis B virus replication in vitro. Hepatology 1995;22:36-43. Wong PY, Marinos G, Peakman M, Tredger JM, Lau JY, Vergani D, et al. FK 506 in liver transplantation for chronic hepatitis B: In vitro studies on lymphocyte activation and virus replication. Liver Transpl Surg 1995;1:362-370. Wilde MI, Goa KL. Muromonab CD3: A reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection. Drugs 1996;51:865-894. Bonnefoy-Berard N, Revillard JP. Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3. J Heart Lung Transplant 1996;15:435-442. Wong JT, Eylath AA, Ghobrial I, Colvin RB. The mechanism of anti-CD3 monoclonal antibodies. Mediation of cytolysis by inter-T cell bridging. Transplantation 1990;50:683-689. Janssen O, Wesselborg S, Kabelitz D. Immunosuppression by OKT3. Induction of programmed cell death (apoptosis) as a possible mechanism of action. Transplantation 1992;53:233234. Sheiner PA, Schwartz ME, Mor E, Schluger LK, Theise N, Kishikawa K, et al. Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation. Hepatology 1995;21:30-34. Rosen HR, Shackleton CR, Higa L, Gralnek IM, Farmer DA, McDiarmid SV, et al. Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation. Am J Gastroenterol 1997;92:1453-1457. Gonzalez RA, de la Mata M, de la Torre J, Min˜oG, Pera C, Pen˜a J, et al. Levels of HBV-DNA and HBsAg after acute liver allograft rejection treatment by corticosteroids and OKT3. Clin Transplant 2000;14:208-211. Guilhot S, Miller T, Cornman G, Isom HC. Apoptosis induced by tumor necrosis factor-alpha in rat hepatocyte cell lines expressing hepatitis B virus. Am J Pathol 1996;148:801-814. Guidotti LG, Ando K, Hobbs MV, Ishikawa R, Runkel L, Schreiber RD, Chisari FV. Cytotoxic T lymphocytes inhibit hepatitis B virus gene expression by a noncytolytic mechanism in transgenic mice. Proc Natl Acad Sci U S A 1994;91:3764-3768. Stoll-Becker S, Repp R, Glebe D, Schaffer S, Kreuder J, Kann M, et al. Transcription of hepatitis B virus in peripheral blood mononuclear cells from persistent infected patients. J Virol 1997;71:5399-5407. Ko¨ck J, Theilmann L, Galle P, Schlicht HJ. Hepatitis B virus nucleic acids associated with human peripheral blood mononuclear cells do not originate from replicating virus. Hepatology 1996;23:405-413. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, Bismuth H. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993; 329:1842-1847. Markowitz JS, Martin P, Conrad AJ, Markmann JF, Seu P, Yersiz H, et al. Prophylaxis against hepatitis B recurrence following liver transplantation using combination lamivudine and hepatitis B immune globulin. Hepatology 1998;28:585-589.
Detecting Alcoholic Relapse Posttransplant Carbohydrate-deficient transferrin is not a useful marker for the detection of chronic alcohol abuse. Schmitt VM, Stieber P, Jungst D, Blizer M, Wachtler M, Heberger S. Eur J Clin Invest 1998; 28:615-621. (Reprinted with permission.) Abstract Background: The role of carbohydrate-deficient transferrin (CDT) as a reliable marker for the detection of chronic alcohol abuse has been discussed controversially. Methods: Therefore, we investigated CDT in the sera from 405 subjects with different alcohol intake. Besides healthy control subjects (n ⴝ 42), inpatients and outpatients in a department of gastroenterology (n ⴝ 325) and patients admitted to a department of otorhinolarynology (n ⴝ 38) were studied. A total of 213 patients suffered from various forms of liver diseases, and 89 patients had liver transplantation. CDT values were determined by a double-antibody radioimmunoassay. Results: In the 241 alcohol-abstinent subjects, CDT levels ranged from 3 to 90 units L-1 (median ⴝ 12); the 92 moderate drinkers (20-60 g of alcohol per day) showed values from 3 to 40 units L-1 (median ⴝ 12), and the 72 subjects with chronic alcohol abuse (> 60 g per day) revealed CDT levels from 3 to 100 units L-1 (median ⴝ 16). The diagnostic specificity for alcohol abuse was 86.8% for men (sensitivity 36.9%) and 95% for women (sensitivity 0%). Conclusion: Our data indicate that measurement of CDT does not reach clinical use in the detection of chronic alcohol abuse in an unselected population because of its insufficient specificity and sensitivity.
Comments Alcohol-related liver disease accounts for up to 50% of the patients who die of end-stage liver disease.1 Patients with alcoholic cirrhosis have posttransplantation survival rates similar to those for patients who undergo transplantation for non–alcohol-related liver disease.2-4 However, relapse has been a significant concern in this population. Most studies report relapse rates after transplantation of 0% to 30%.5 These studies used various definitions of relapse. Campbell et al6 reported a small minority of patients who returned to problematic drinking, leading to rehospitalization and, in some cases, death. The search for a way to detect alcohol use after transplantation has included developing biochemical markers that reliably detect relapse. Abnormalities in transferrin levels, later named carbohydrate-deficient transferrin (CDT), were found in the cerebrospinal fluid of patients with alcohol cerebellar degeneration in 1976,7 and later, in the serum of alcohol abusers.8 Since then, CDT has been studied as a marker of excessive
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alcohol consumption and thus is of interest as a possible indicator of alcohol use in patients post–liver transplantation. In a review from 1991, Stibler9 summarized the results from studies including 2,500 individuals and estimated the clinical sensitivity of CDT to be 82% and the specificity to be 97%. She noted that CDT measures the accumulated effect of alcohol consumption of 50 to 80 g/d for at least 1 week and then normalizes with abstinence over 15 days. Thus, this test appears attractive to monitor patients for recurrent alcohol use posttransplantation. Schmitt et al,10 in the blind prospective study of CDT discussed here, reported on 405 subjects, 89 of whom had received a liver transplant. Three hundred thirty-three subjects from the entire patient group had alcohol consumption less than 60 g/d, and 72 patients had chronic alcohol intake greater than 60 g/d. Fortytwo subjects served as healthy controls. The history of alcohol use was obtained by careful patient interviews, with chronic alcohol abuse defined as alcohol intake greater than 60 g/d for more than 2 weeks. CDT levels were determined by double-antibody radioimmunoassay. The investigators reported CDT concentrations ranging from 3 to 100 units L⫺1. Of note, a CDT level of 90 units L⫺1 was found in an abstinent liver transplant recipient. In women, there was no significant difference in CDT values between abstinent patients and alcohol abusers. In men, the difference between abstinent patients and chronic drinkers was not significant. For patients with liver disease, the sensitivity and specificity of CDT was less than that of the total study group. Other investigators have explored the use of CDT in transplant recipients. Heinemann et al11 examined the validity of CDT in a group of patients with end-stage liver disease before and after transplantation. They found elevated CDT levels pretransplantation in patients abstaining from alcohol, although they noted that this was a small number of patients. Posttransplantation, CDT levels decreased significantly, as did ␥-glutamyltransaminase and aspartate aminotransferase levels. Four patients had elevated CDT levels, and 2 of these patients acknowledged the resumption of alcohol use. Berlakovich et al12 prospectively studied 97 patients who survived at least 3 months posttransplantation, with a mean follow-up of 1 to 3 years. In this study, the alcohol relapse rate at 1 year was 6% and at 3 years was 9%. Thirteen patients were excluded because a stable relationship with a psychologist could not be established. CDT levels were measured by double-antibody
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radioimmunoassay. Twelve patients returned to drinking; alcohol use was detected by CDT level in 11 patients and not detected by CDT level in 1 patient. Eighty-three patients had true-negative results, and there were 2 false-positive results, resulting in a sensitivity of 92% and a specificity of 98%. In this study, CDT level elevations did not correlate with morphological or biochemical parameters suggestive of liver disease. Compared with other markers for heavy drinking, Salaspuro13 noted in a review article that in men, CDT level is slightly more sensitive than ␥-glutamyltransferase level for moderate alcohol use and slightly, but not significantly, better than aspartate aminotransferase, alanine aminotransferase, and -hexosaminidase levels to identify men drinking more than 400 g/d of alcohol. Rommelspacher et al14 studied the alcogens, -carboline and tetrahydroisoquinolone, which are natural substances that are innocuous until a promoter mechanism is triggered in predisposed individuals, resulting in transformation of the normal function of the brain leading to addictive drinking. He found elevated levels of unsubstituted and substituted -carbolines in alcoholic and nonalcoholic patients before liver transplantation, possibly because of reduced breakdown in the liver. Alcogen levels normalized in patients posttransplantation, although this occurred slowly in nonalcoholic patients. The investigators speculated that lower alcogen levels may explain decreased rates of alcohol use after transplantation. It is possible that alcogen levels could also be used to monitor alcohol relapse posttransplantation. Most transplant centers require a psychological or psychiatric evaluation as part of the assessment of the transplant candidate.15 Unfortunately, no single pretransplantation variable predicts posttransplantation relapse.16 Six months of abstinence before transplantation, a generally required exclusion criterion, does not predict survival. However, in 1 study, motivation and compliance were predictive.17 At this time, few studies used CDT levels to screen for alcohol relapse posttransplantation, and 2 studies, including the study discussed here, suggested that CDT level lacks adequate specificity and sensitivity to predict relapse posttransplantation. As noted by DiMartini and Beresford,18 multivariate models, including pretransplantation and posttransplantation variables with sufficient follow-up, may yield important information about how best to identify the patients at greatest risk for relapse in the future. Further refinements in detecting biochemical abnormalities in recidivists may also
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lead to improved detection of relapse. Ultimately, multicenter studies using standardized instruments to diagnose alcoholism and common definitions of alcohol relapse will greatly enhance the assessment of biochemical markers for alcohol relapse.
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Acknowledgment The author thanks Julie Stamschror for help with manuscript preparation.
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Sheila G. Jowsey, MD Mayo Clinic Mayo Bldg West 11A 200 First St SW Rochester, MN 55905
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References 1. Grant BF, DeBakey S, Zobeck TS. Liver cirrhosis mortality in the United States, 1973-1988. In: US Alcohol Epidemiologic Data Reference Manual, Alcohol Epidemiologic Data System. Rockville, MD: US Department of Health and Human Services, Public Health Service, Drug Abuse and Mental Health Administration, National Institute on Alcohol Abuse and Alcoholism, 1991. 2. Bird LAG, O’Grady JG, Harvey FAH, Calne RY, Williams R. Liver transplantation in patients with alcoholic cirrhosis: Selection criteria and rates of survival and relapse. BMJ 1990;130:1517. 3. McCurry KR, Baliga P, Merion RM, Ham JM, Lucey MR, Beresford TP, et al. Resource utilization and outcome of liver transplantation for alcoholic cirrhosis. Arch Surg 1992;127:776777. 4. Pageaux G-P, Michel J, Coste V, Perney P, Possoz P, Perrigault P-F, et al. Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism. Gut 1999;45:421-426. 5. DiMartini AF, Trzepacz PT. Alcoholism and organ transplantation. In: Trzepacz PT, DiMartini AF (eds). The transplant patient. Cambridge: Cambridge University Press, 2000:222-223. 6. Campbell DS, Beresford TP, Merion RN, Punch JD, Ham JM,
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Lucey MR, et al. Alcohol use relapse following liver transplantation for alcoholic cirrhosis: Long-term follow-up [abstract]. Proceedings of the American Society of Transplant Surgeons, Houston, TX, May 20-22, 1993:131. Stibler H, Kjellin KG. Isoelectric focusing and electrophoresis of the CSF proteins in tremor of different origin. J Neurol Sci 1976;30:269-285. Stibler H, Allgulander C, Borg S, Kjellin KG. Abnormal microheterogeneity of transferrin in serum and cerebrospinal fluid in alcoholism. Acta Med Scand 1978;204:49-56. Stibler H. Carbohydrate-deficient transferrin in serum: A new marker of potential alcohol consumption reviewed. Clin Chem 1991;37:2029-2037. Schmitt VM, Stieber P, Jungst D, Blizer M, Wachtler M, Heberger S. Carbohydrate-deficient transferrin is not a useful marker for the detection of chronic alcohol abuse. Eur J Clin Invest 1998;28:615-621. Heinemann A, Sterneck M, Kuhlencordt R, Rogiers X, Schulz KH, Queen B, et al. Carbohydrate-deficient transferrin: Diagnostic efficiency among patients with end-stage liver disease before and after liver transplantation. Alcohol Clin Exp Res 1998; 22:1806-1812. Berlakovich GA, Windhager T, Freundorfer E, Lesch OM, Steininger R, Muhlbacher F. Carbohydrate-deficient transferrin for detection of alcohol relapse after orthotopic liver transplantation for alcoholic cirrhosis. Transplantation 1999;67:1231-1235. Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: A systematic review. Alcohol 1999; 19:261-271. Rommelspacher H, Wiest M, Neuhaus R, Platzgummer W, Schmidt LG, Neuhaus P. Long-term changes of markers of alcoholism after orthotopic liver transplantation. Transplantation 1996;62:1451-1455. Everhart JE, Beresford TP. Liver transplantation for alcoholic liver disease: A survey of transplantation programs in the United States. Liver Transpl Surg 1997;3:220-226. Osorio RW, Ascher NL, Avery M, Bachetti P, Roberts JP, Blake JR. Predicting recidivism after orthotopic liver transplantation for alcoholic liver disease. Hepatology 1994;20:105-110. Roggla H, Roggla G, Muhlbacher F. Psychiatric prognostic factors in patients with alcohol-related end-stage liver disease before liver transplantation. Wien Klin Wochenschr 1996;108:272275. DiMartini A, Beresford TP. Alcoholism and liver transplantation. Curr Opin Organ Transplant 1999;4:177-181.
