- Email: [email protected]
Yes, there is (quality of) life after liver transplantation
HEPATOLOGY Elsewhere T. JAKE LIANG, EDITOR
ADVISORY COMMITTEE BRUCE R. BACON, St. Louis, MO HENRY C. BODENHEIMER, New York, NY JAMES M. CRAWFORD, Boston, MA NORMAN D. GRACE, Boston, MA SANJEEV GUPTA, Bronx, NY JOEL LAVINE, San Diego, CA RICHARD H. MOSELEY, Ann Arbor, MI
Gastrointestinal Unit GRJ-724 Massachusetts General Hospital 32 Fruit St Boston, MA 02114
YES, THERE IS (QUALITY OF) LIFE AFTER LIVER TRANSPLANTATION!
Levy MF, Jennings L, Abouljoud MS, Mulligan DC, Goldstein RM, Husberg BS, Gonwa TA, et al. Quality of life improvements at one, two, and five years after liver transplantation. Transplantation 1995;59:515-518. ABSTRACT
We prospectively studied adult liver transplant (OLTX) recipients to evaluate the effect of OLTX on quality of life (QOL). Over an 8-year period, all adult patients undergoing OLTX at our institution were asked to complete a psychological questionnaire that probed broad facets of QOL. Patients seen for their 1, 2, and 5 or moreyear post-OLTX visits were also asked to complete the form. Questions were then grouped by categories broadly highlighting self-image (SI), health perception (HP), ability to function (F), and ability to work (W). Questions ranged from demographic and occupational topics to symptom distress/frequency, activities of daily living, and the impact of health on daily life. Numerical scores were assigned to each question, and added to derive scores on SI, HP, and F. Higher scores reflect better QOL. Employment data (W) were also compared, though not amenable to scoring. A total of 573 forms were completed (210 pretransplant, 150 at 1 year, 131 at 2 years, 79 at 5 years). All posttransplant scores were significantly higher than pretransplant ones (P ° .0001, ANOVA). Scores at posttransplant time points were not significantly different from each other. Subscores of SI and HP revealed less symptom frequency and distress following OLTX (P ° .0003) continuing to beyond 5 years. Health limitations on activities decreased both at 1 year postOLTX and again at 2 years (P ° .0001) and were sustained to beyond 5 years. Fewer people were working for pay at 1 year post-compared with pre-OLTX, but preOLTX levels of employment had been regained by the second year, continuing to increase to beyond 5 years. OLTX leads to improved QOL by the end of the first posttransplant year, sustained through the 5th posttransplant year and beyond. Self-image, functioning ability, and perception of health status were significantly improved. Ill health interference in daily life continues to decrease as OLTX becomes more remote. Employment suffers early after OLTX, but recovers by the second post-OLTX year and continues to increase long-term. COMMENTS
Liver transplantation has become the treatment of choice for end-stage liver disease of various etiologies.
Overall, 1-year survival is 79%,1 and many centers are reporting 1-year survivals approaching 90%. Longterm results, estimated to be 75%, are also quite good. However, liver transplantation places a heavy burden on limited health care resources. The average cost per transplantation is approximately $250,000.2 This figure does not take into account the cost of follow-up medical care or life-long immunosuppressive medications. In this era of health care reform, growing cost consciousness, and oversight by third-party payers, the concept of value for your health care dollar has been introduced. The relative worth of a resource intensive treatment, such as liver transplantation, may depend not only on the rate of survival but also on the resources required and the resultant quality of life. Today there is no doubt that transplantation is life saving, nor is there any question that it consumes significant health care dollars. However, there is a paucity of information on the quality of life in patients with chronic liver disease and even less information regarding the effect of transplantation on quality of life in patients with chronic liver disease. Quality of life is a multifaceted concept that seeks to measure functional behavior, cognitive abilities, emotional well-being, and psychosocial adjustment. Most studies evaluating quality of life in liver transplant recipients have used several different instruments to measure this complex entity. Investigation has typically been conducted at a single center with small numbers of patients using these various quality of life instruments. Posttransplantation quality of life has often been the only time point evaluated. Some of the earliest studies were generated by investigators at the University of Pittsburgh Health Science Center, Pittsburgh, PA. The impact of chronic liver disease itself on quality of life has not been extensively studied. Two studies have addressed the issue of quality of life in patients with chronic liver disease. Tarter et al3 undertook the first large scale study of the impact of chronic liver disease on quality of life in adults. They reported a moderate degree of impairment of life quality in adult patients with chronic liver disease of various origins. Psychosocial functioning was affected more than physical ability. In a second study, Price et al4 prospectively studied 109 individuals with chronic liver disease over a 2-year period; 27 patients underwent transplantation, 71 patients did not undergo transplantation, and 11 patients were rejected for trans-
182
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WBS: Hepatology
HEPATOLOGY Vol. 23, No. 1, 1996
HEPATOLOGY Elsewhere
plantation. Improvement in quality of life was evident at 6 months in liver graft recipients, and 2 years after transplantation, the quality of life was similar to the general population. Quality of life in patients who did not undergo transplantation showed no improvement. Studies from several different centers confirm most orthotopic liver transplant candidates have an improvement in quality of life when compared with their pretransplantation status.5-8 Despite improvement in quality of life, patients do not recover to the same functional level as normal individuals.6 Liver transplantation seems to effect a better recovery of daily physical activities than psychosocial function. This observation raised concern about full rehabilitation after liver transplantation. Commander et al19 helped to allay these concerns showing that the prevalence of psychiatric morbidity in 32 liver transplant recipients surviving at least 6 months was 18.8%, a figure not significantly different from that in the general population. Many studies measuring quality of life after liver transplantation show a significant improvement but are difficult to critically evaluate. Often the number of patients used is too small to provide statistical significance or adequate long-term follow-up. Additionally, very few studies have looked at quality of life both before and after transplantation. In this article, Levy et al10 attempted to address these shortcomings. They use a revised questionnaire composed of questions from several well-known standardized quality of life questionnaires. The questions were grouped by categories involving self-image, health perception, ability to function, and ability to work. A numerical score was given to each question and then added to obtain a global score in each category except for the ability to work. Higher scores reflected better quality of life. There were significant improvements in all categories at 1, 2, and 5 years after transplantation when compared with the pretransplantation state. The ability to work was highly gender dependent, with male patients being more likely to work. Although the level of employment at year 1 was less than pretransplantation employment, these levels were regained by the end of the second posttransplantation year and sustained to 5 years after transplantation. Nearly 70% of the patients were working for pay at 5-years after their transplantation, 80% of those on a fulltime basis. Self-image, perception of health status, and functional ability were improved 1 year after transplantation, and this improvement continued for the 5-year follow-up period. Thus, this longterm prospective study by Levy et al confirms that liver transplantation not only improves survival but also quality of life. Most importantly, this enhanced function is sustained at least 5 years postoperatively. Despite attempts to address limitations of prior studies on quality of life after transplantation, this study has several drawbacks well recognized by the authors. First, patients were left on their own to complete data forms voluntarily, leading to a potential selection bias, because nonresponders may have provided very different answers. Family members were allowed to help fill
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183
out questionnaires, therefore responses may have been biased by the family’s experience in the care-taking of these patients. Finally, the study did not allow for matched data, that is, answers were not obtained from the same recipient at each time point. Although the study is subject to the above limitations, it is an important investigation that provides reassurance that despite the cost of liver transplantation, patients recover to a productive life of sustained good quality. Interim results of an ongoing multicenter study from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database on quality of life in liver transplant recipients were published the same month by Belle et al.11 Pretransplantation or baseline quality of life forms were completed for 391 of a possible 602 pretransplant recipients. One hundred ninety-one recipients completed a baseline and a follow-up instrument. Follow-up data were obtained between 8 to 14 months after transplantation. In general, marked improvement was observed in all aspects of quality of life examined for 1-year survivors. Domains studied were measures of disease, personal functioning, psychological distress and well-being, social and role functioning, and general health perceptions. Greatest levels of improvement were observed in the measures of disease and general health perception. Together, these two large scale studies10,11 document the personal and social value accrued after liver transplantation. Although liver transplantation is a resource-intensive and costly treatment, this therapy gives value for money spent in terms of survival and quality of life sustained for at least up to 5 years after transplantation.10 SONIA H. UCHMAN, MD ROSE CESAR, MD Rhode Island Hospital Division of Gastroenterology Brown University School of Medicine Providence, RI REFERENCES 1. United Network for Organ Sharing Scientific Registry, July 1994. U.S. Transplants, October 1, 1986 - December 31, 1992. One, two, and three year graft and patient survival rates by organ. 2. Nicholas JJ, Oleske D, Robinson LR, Switala J, Tarter R. The quality of life after orthotopic liver transplantation: an analysis of 166 cases. Arch Phys Med Rehabil 1994;75:431-435. 3. Tarter RE, Switala J, Arria A, Van Thiel DH. Impact of liver disease on daily living in transplantation candidates. J Clin Epidemiol 1991;44:1079-1083. 4. Price CE, Lowe D, Cohen AT, Reid FDA, Forbes GM, McEwen J, Williams R. Prospective study of the quality of life in patients assessed for liver transplantation: outcome in transplanted and not transplanted groups. J R Soc Med 1995;88:130-135. 5. Tarter RE, Siegfried E, Biller PA, Switala J, Van Thiel DH. The quality of life following liver transplantation: a preliminary report. Gastroenterol Clin North Am 1988;17:207-217. 6. Tarter RE, Switala J, Arria A, Plail J, Van Thiel D. Quality of life before and after orthotopic hepatic transplantation. Arch Intern Med 1991;151:1521-1526. 7. Bonsel GJ, Essink-Bot ML, Klompmaker IJ, Slooff MJH. Assess-
WBS: Hepatology
184 HEPATOLOGY Elsewhere
8.
9. 10.
11.
HEPATOLOGY January 1996
ment of the quality of life before and following liver transplantation. Transplantation 1992;53:796-800. Riether AM, Smith SL, Lewison BJ, Cotsonis GA, Epstein CM. Quality of life changes and psychiatric and neurocognitive outcome after heart and liver transplantation. Transplantation 1992;54:444-450. Commander M, Neuberger J, Dean C. Psychiatric and social consequences of liver transplantation. Transplantation 1992; 53:1038-1040. Levy MF, Jennings L, Abouljoud M, Mulligan D, Goldstein R, Husberg B, Gonwa T, et al. Quality of life improvements at one, two, and five years after liver transplantation. Transplantation 1995;59:515-518. Belle SH, Porayko MK, NIDDK Liver Transplantation Database. Improvement in quality of life after transplantation for recipients in the NIDDK liver transplantation database. Transplant Proc 1995;27:1230-1232.
PRECORE MUTANTS REVISITED
Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, et al. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995; 122:241-248. ABSTRACT
Objective: Fulminant hepatitis B can be induced by hepatitis B virus (HBV) strains with mutations in the precore region that cannot encode hepatitis B e antigen (HBeAg). Such mutations are rarely seen in HBV DNA clones from patients with fulminant hepatitis B in the United States and France. Thus, the other mutations in HBV strains causing fulminant hepatitis B need to be identified. Design: Retrospective clinical, serologic, and molecular biological studies of patients with fulminant hepatitis B. Setting: University and city hospitals in Japan. Patients: 43 patients with fulminant hepatitis B. Measurements: The precore region coding for a part of the HBeAg precursor and the core promoter regulating the transcription of precore messenger RNA (mRNA) were sequenced in HBV DNA clones. Results: A point mutation from G to A at nucleotide 1896 in the precore region was detected in 519 (98%) of 529 HBV DNA clones from 38 patients. Two point mutations in the core promoter, from A to T at nucleotide 1762 and from G to A at nucleotide 1764, were detected in all 130 clones from the remaining 5 patients, who did not have mutations in the precore region, and in 20 (63%) of 32 clones from a patient with chronic hepatitis B who had transmitted HBV to 1 of these other 5 patients. Mutations in the core promoter were also detected in clones from 26 (68%) of the 38 patients with the precore mutation at nucleotide 1896. Neither HBeAg nor antibody to HBeAg was detected in 37 (90%) of the 41 patients tested. Conclusions: In Japan, fulminant hepatitis B is closely associated with HBV strains that do not produce HBeAg because of mutations in the precore region, which affect translation of HBeAg, or because of mutations in the core promoter, which affect transcription of the HBeAg coding region. COMMENTS
Infection with HBV leads to a wide spectrum of liver injury ranging from acute self-limited infection and ful-
m4533$0035
12-16-95 01:35:43
hepa
minant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Both viral factors as well as host immune response(s) may be important in determining the course of HBV infection. There is accumulating evidence that certain mutations in HBV may influence the course of infection and clinical manifestations of disease. In fulminant hepatitis B, mutations inactivating the precore reading frame have been described.1,2 Inactivation of the precore reading frame abolishes the synthesis of HBeAg. Whether the precore or other viral mutations are important for the pathogenesis of fulminant hepatic failure or are simply the effect of immune selection pressure is still unclear. In favor of the first is the following hypothesis: during the early stage of infection, mutant-infected hepatocytes are not eliminated efficiently by the host immune responses because HBeAg may play an important role in early viral clearance. Viral spread is dependent on the efficiency of viral replication and reinfection, as well as the vigor of host immune responses against the virus. Therefore, virus not expressing HBeAg may spread more efficiently to uninfected hepatocytes, causing widespread infection of hepatocytes. In the latter stage of infection, subsequent host immune responses triggered by viral components other than HBeAg are activated and lead to fulminant necrosis of hepatocytes. HBV DNA levels at this stage could again be low because of massive destruction of hepatocytes. Furthermore, functional studies of an HBeAg-negative HBV strain associated with an epidemic of fulminant hepatitis revealed a strongly enhanced replication compared with the wildtype strains in transfected human hepatoma cells. Such an observation is consistent with the above hypothesis. However, this study has shown that enhanced replication was not caused by the precore stop codon mutation at position 1896.3 Several questions remain unresolved: Why does the precore mutant in an animal model (woodchuck) have no fulminant phenotype?4 Why do asymptomatic carriers with low levels of HBV DNA or patients with chronic active hepatitis and high levels of HBV DNA harbor the HBeAg-negative strain as well? And, even more strikingly, why are many patients with fulminant hepatitis B not associated with mutations in the precore region? Recent studies have shown that only 10% to 50% of patients with fulminant HBV infection in the United States are infected by viruses containing precore mutations.5,6 One possible interpretation of all these data is that the HBeAg-negative mutants may be important but not sufficient for enhanced pathogenicity. It seems possible that either additional or other mutations are present outside the precore region and alter the biological behavior of the virus. Furthermore, different host immune responses may contribute to the development of fulminant hepatitis in certain individuals. A similar concept has been documented recently in a paper describing major histocompatibility complex alleleic-specific protection against HBV infection in Africa.7
WBS: Hepatology
ADVISORY COMMITTEE BRUCE R. BACON, St. Louis, MO HENRY C. BODENHEIMER, New York, NY JAMES M. CRAWFORD, Boston, MA NORMAN D. GRACE, Boston, MA SANJEEV GUPTA, Bronx, NY JOEL LAVINE, San Diego, CA RICHARD H. MOSELEY, Ann Arbor, MI
Gastrointestinal Unit GRJ-724 Massachusetts General Hospital 32 Fruit St Boston, MA 02114
YES, THERE IS (QUALITY OF) LIFE AFTER LIVER TRANSPLANTATION!
Levy MF, Jennings L, Abouljoud MS, Mulligan DC, Goldstein RM, Husberg BS, Gonwa TA, et al. Quality of life improvements at one, two, and five years after liver transplantation. Transplantation 1995;59:515-518. ABSTRACT
We prospectively studied adult liver transplant (OLTX) recipients to evaluate the effect of OLTX on quality of life (QOL). Over an 8-year period, all adult patients undergoing OLTX at our institution were asked to complete a psychological questionnaire that probed broad facets of QOL. Patients seen for their 1, 2, and 5 or moreyear post-OLTX visits were also asked to complete the form. Questions were then grouped by categories broadly highlighting self-image (SI), health perception (HP), ability to function (F), and ability to work (W). Questions ranged from demographic and occupational topics to symptom distress/frequency, activities of daily living, and the impact of health on daily life. Numerical scores were assigned to each question, and added to derive scores on SI, HP, and F. Higher scores reflect better QOL. Employment data (W) were also compared, though not amenable to scoring. A total of 573 forms were completed (210 pretransplant, 150 at 1 year, 131 at 2 years, 79 at 5 years). All posttransplant scores were significantly higher than pretransplant ones (P ° .0001, ANOVA). Scores at posttransplant time points were not significantly different from each other. Subscores of SI and HP revealed less symptom frequency and distress following OLTX (P ° .0003) continuing to beyond 5 years. Health limitations on activities decreased both at 1 year postOLTX and again at 2 years (P ° .0001) and were sustained to beyond 5 years. Fewer people were working for pay at 1 year post-compared with pre-OLTX, but preOLTX levels of employment had been regained by the second year, continuing to increase to beyond 5 years. OLTX leads to improved QOL by the end of the first posttransplant year, sustained through the 5th posttransplant year and beyond. Self-image, functioning ability, and perception of health status were significantly improved. Ill health interference in daily life continues to decrease as OLTX becomes more remote. Employment suffers early after OLTX, but recovers by the second post-OLTX year and continues to increase long-term. COMMENTS
Liver transplantation has become the treatment of choice for end-stage liver disease of various etiologies.
Overall, 1-year survival is 79%,1 and many centers are reporting 1-year survivals approaching 90%. Longterm results, estimated to be 75%, are also quite good. However, liver transplantation places a heavy burden on limited health care resources. The average cost per transplantation is approximately $250,000.2 This figure does not take into account the cost of follow-up medical care or life-long immunosuppressive medications. In this era of health care reform, growing cost consciousness, and oversight by third-party payers, the concept of value for your health care dollar has been introduced. The relative worth of a resource intensive treatment, such as liver transplantation, may depend not only on the rate of survival but also on the resources required and the resultant quality of life. Today there is no doubt that transplantation is life saving, nor is there any question that it consumes significant health care dollars. However, there is a paucity of information on the quality of life in patients with chronic liver disease and even less information regarding the effect of transplantation on quality of life in patients with chronic liver disease. Quality of life is a multifaceted concept that seeks to measure functional behavior, cognitive abilities, emotional well-being, and psychosocial adjustment. Most studies evaluating quality of life in liver transplant recipients have used several different instruments to measure this complex entity. Investigation has typically been conducted at a single center with small numbers of patients using these various quality of life instruments. Posttransplantation quality of life has often been the only time point evaluated. Some of the earliest studies were generated by investigators at the University of Pittsburgh Health Science Center, Pittsburgh, PA. The impact of chronic liver disease itself on quality of life has not been extensively studied. Two studies have addressed the issue of quality of life in patients with chronic liver disease. Tarter et al3 undertook the first large scale study of the impact of chronic liver disease on quality of life in adults. They reported a moderate degree of impairment of life quality in adult patients with chronic liver disease of various origins. Psychosocial functioning was affected more than physical ability. In a second study, Price et al4 prospectively studied 109 individuals with chronic liver disease over a 2-year period; 27 patients underwent transplantation, 71 patients did not undergo transplantation, and 11 patients were rejected for trans-
182
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WBS: Hepatology
HEPATOLOGY Vol. 23, No. 1, 1996
HEPATOLOGY Elsewhere
plantation. Improvement in quality of life was evident at 6 months in liver graft recipients, and 2 years after transplantation, the quality of life was similar to the general population. Quality of life in patients who did not undergo transplantation showed no improvement. Studies from several different centers confirm most orthotopic liver transplant candidates have an improvement in quality of life when compared with their pretransplantation status.5-8 Despite improvement in quality of life, patients do not recover to the same functional level as normal individuals.6 Liver transplantation seems to effect a better recovery of daily physical activities than psychosocial function. This observation raised concern about full rehabilitation after liver transplantation. Commander et al19 helped to allay these concerns showing that the prevalence of psychiatric morbidity in 32 liver transplant recipients surviving at least 6 months was 18.8%, a figure not significantly different from that in the general population. Many studies measuring quality of life after liver transplantation show a significant improvement but are difficult to critically evaluate. Often the number of patients used is too small to provide statistical significance or adequate long-term follow-up. Additionally, very few studies have looked at quality of life both before and after transplantation. In this article, Levy et al10 attempted to address these shortcomings. They use a revised questionnaire composed of questions from several well-known standardized quality of life questionnaires. The questions were grouped by categories involving self-image, health perception, ability to function, and ability to work. A numerical score was given to each question and then added to obtain a global score in each category except for the ability to work. Higher scores reflected better quality of life. There were significant improvements in all categories at 1, 2, and 5 years after transplantation when compared with the pretransplantation state. The ability to work was highly gender dependent, with male patients being more likely to work. Although the level of employment at year 1 was less than pretransplantation employment, these levels were regained by the end of the second posttransplantation year and sustained to 5 years after transplantation. Nearly 70% of the patients were working for pay at 5-years after their transplantation, 80% of those on a fulltime basis. Self-image, perception of health status, and functional ability were improved 1 year after transplantation, and this improvement continued for the 5-year follow-up period. Thus, this longterm prospective study by Levy et al confirms that liver transplantation not only improves survival but also quality of life. Most importantly, this enhanced function is sustained at least 5 years postoperatively. Despite attempts to address limitations of prior studies on quality of life after transplantation, this study has several drawbacks well recognized by the authors. First, patients were left on their own to complete data forms voluntarily, leading to a potential selection bias, because nonresponders may have provided very different answers. Family members were allowed to help fill
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hepa
183
out questionnaires, therefore responses may have been biased by the family’s experience in the care-taking of these patients. Finally, the study did not allow for matched data, that is, answers were not obtained from the same recipient at each time point. Although the study is subject to the above limitations, it is an important investigation that provides reassurance that despite the cost of liver transplantation, patients recover to a productive life of sustained good quality. Interim results of an ongoing multicenter study from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database on quality of life in liver transplant recipients were published the same month by Belle et al.11 Pretransplantation or baseline quality of life forms were completed for 391 of a possible 602 pretransplant recipients. One hundred ninety-one recipients completed a baseline and a follow-up instrument. Follow-up data were obtained between 8 to 14 months after transplantation. In general, marked improvement was observed in all aspects of quality of life examined for 1-year survivors. Domains studied were measures of disease, personal functioning, psychological distress and well-being, social and role functioning, and general health perceptions. Greatest levels of improvement were observed in the measures of disease and general health perception. Together, these two large scale studies10,11 document the personal and social value accrued after liver transplantation. Although liver transplantation is a resource-intensive and costly treatment, this therapy gives value for money spent in terms of survival and quality of life sustained for at least up to 5 years after transplantation.10 SONIA H. UCHMAN, MD ROSE CESAR, MD Rhode Island Hospital Division of Gastroenterology Brown University School of Medicine Providence, RI REFERENCES 1. United Network for Organ Sharing Scientific Registry, July 1994. U.S. Transplants, October 1, 1986 - December 31, 1992. One, two, and three year graft and patient survival rates by organ. 2. Nicholas JJ, Oleske D, Robinson LR, Switala J, Tarter R. The quality of life after orthotopic liver transplantation: an analysis of 166 cases. Arch Phys Med Rehabil 1994;75:431-435. 3. Tarter RE, Switala J, Arria A, Van Thiel DH. Impact of liver disease on daily living in transplantation candidates. J Clin Epidemiol 1991;44:1079-1083. 4. Price CE, Lowe D, Cohen AT, Reid FDA, Forbes GM, McEwen J, Williams R. Prospective study of the quality of life in patients assessed for liver transplantation: outcome in transplanted and not transplanted groups. J R Soc Med 1995;88:130-135. 5. Tarter RE, Siegfried E, Biller PA, Switala J, Van Thiel DH. The quality of life following liver transplantation: a preliminary report. Gastroenterol Clin North Am 1988;17:207-217. 6. Tarter RE, Switala J, Arria A, Plail J, Van Thiel D. Quality of life before and after orthotopic hepatic transplantation. Arch Intern Med 1991;151:1521-1526. 7. Bonsel GJ, Essink-Bot ML, Klompmaker IJ, Slooff MJH. Assess-
WBS: Hepatology
184 HEPATOLOGY Elsewhere
8.
9. 10.
11.
HEPATOLOGY January 1996
ment of the quality of life before and following liver transplantation. Transplantation 1992;53:796-800. Riether AM, Smith SL, Lewison BJ, Cotsonis GA, Epstein CM. Quality of life changes and psychiatric and neurocognitive outcome after heart and liver transplantation. Transplantation 1992;54:444-450. Commander M, Neuberger J, Dean C. Psychiatric and social consequences of liver transplantation. Transplantation 1992; 53:1038-1040. Levy MF, Jennings L, Abouljoud M, Mulligan D, Goldstein R, Husberg B, Gonwa T, et al. Quality of life improvements at one, two, and five years after liver transplantation. Transplantation 1995;59:515-518. Belle SH, Porayko MK, NIDDK Liver Transplantation Database. Improvement in quality of life after transplantation for recipients in the NIDDK liver transplantation database. Transplant Proc 1995;27:1230-1232.
PRECORE MUTANTS REVISITED
Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, et al. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med 1995; 122:241-248. ABSTRACT
Objective: Fulminant hepatitis B can be induced by hepatitis B virus (HBV) strains with mutations in the precore region that cannot encode hepatitis B e antigen (HBeAg). Such mutations are rarely seen in HBV DNA clones from patients with fulminant hepatitis B in the United States and France. Thus, the other mutations in HBV strains causing fulminant hepatitis B need to be identified. Design: Retrospective clinical, serologic, and molecular biological studies of patients with fulminant hepatitis B. Setting: University and city hospitals in Japan. Patients: 43 patients with fulminant hepatitis B. Measurements: The precore region coding for a part of the HBeAg precursor and the core promoter regulating the transcription of precore messenger RNA (mRNA) were sequenced in HBV DNA clones. Results: A point mutation from G to A at nucleotide 1896 in the precore region was detected in 519 (98%) of 529 HBV DNA clones from 38 patients. Two point mutations in the core promoter, from A to T at nucleotide 1762 and from G to A at nucleotide 1764, were detected in all 130 clones from the remaining 5 patients, who did not have mutations in the precore region, and in 20 (63%) of 32 clones from a patient with chronic hepatitis B who had transmitted HBV to 1 of these other 5 patients. Mutations in the core promoter were also detected in clones from 26 (68%) of the 38 patients with the precore mutation at nucleotide 1896. Neither HBeAg nor antibody to HBeAg was detected in 37 (90%) of the 41 patients tested. Conclusions: In Japan, fulminant hepatitis B is closely associated with HBV strains that do not produce HBeAg because of mutations in the precore region, which affect translation of HBeAg, or because of mutations in the core promoter, which affect transcription of the HBeAg coding region. COMMENTS
Infection with HBV leads to a wide spectrum of liver injury ranging from acute self-limited infection and ful-
m4533$0035
12-16-95 01:35:43
hepa
minant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Both viral factors as well as host immune response(s) may be important in determining the course of HBV infection. There is accumulating evidence that certain mutations in HBV may influence the course of infection and clinical manifestations of disease. In fulminant hepatitis B, mutations inactivating the precore reading frame have been described.1,2 Inactivation of the precore reading frame abolishes the synthesis of HBeAg. Whether the precore or other viral mutations are important for the pathogenesis of fulminant hepatic failure or are simply the effect of immune selection pressure is still unclear. In favor of the first is the following hypothesis: during the early stage of infection, mutant-infected hepatocytes are not eliminated efficiently by the host immune responses because HBeAg may play an important role in early viral clearance. Viral spread is dependent on the efficiency of viral replication and reinfection, as well as the vigor of host immune responses against the virus. Therefore, virus not expressing HBeAg may spread more efficiently to uninfected hepatocytes, causing widespread infection of hepatocytes. In the latter stage of infection, subsequent host immune responses triggered by viral components other than HBeAg are activated and lead to fulminant necrosis of hepatocytes. HBV DNA levels at this stage could again be low because of massive destruction of hepatocytes. Furthermore, functional studies of an HBeAg-negative HBV strain associated with an epidemic of fulminant hepatitis revealed a strongly enhanced replication compared with the wildtype strains in transfected human hepatoma cells. Such an observation is consistent with the above hypothesis. However, this study has shown that enhanced replication was not caused by the precore stop codon mutation at position 1896.3 Several questions remain unresolved: Why does the precore mutant in an animal model (woodchuck) have no fulminant phenotype?4 Why do asymptomatic carriers with low levels of HBV DNA or patients with chronic active hepatitis and high levels of HBV DNA harbor the HBeAg-negative strain as well? And, even more strikingly, why are many patients with fulminant hepatitis B not associated with mutations in the precore region? Recent studies have shown that only 10% to 50% of patients with fulminant HBV infection in the United States are infected by viruses containing precore mutations.5,6 One possible interpretation of all these data is that the HBeAg-negative mutants may be important but not sufficient for enhanced pathogenicity. It seems possible that either additional or other mutations are present outside the precore region and alter the biological behavior of the virus. Furthermore, different host immune responses may contribute to the development of fulminant hepatitis in certain individuals. A similar concept has been documented recently in a paper describing major histocompatibility complex alleleic-specific protection against HBV infection in Africa.7
WBS: Hepatology