Long-term Outcome for Wilson Disease: 85% Good

Abstract

The study by Beinhardt et al1Beinhardt S. Leiss W. Stättermayer A.F. et al.Long-term outcomes of patients with Wilson disease in a large Austrian cohort.Clin Gastroenterol Hepatol. 2014; 12: 683-689Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar is a unique report of a 5-decade experience of treating Wilson disease at a single center in Austria. During this time period, there have been advances in diagnostic testing and treatment for Wilson disease that have affected disease detection, referral, and patient survival. Molecular genetic testing for ATP7B mutations now aid in diagnosis confirmation for some difficult patients and are useful for family screening. There have been advances in therapy, including the introduction of the medications trientine and zinc salts that are effective therapies for initial and maintenance treatment, and advances in the field of liver transplantation, with excellent outcomes being reported for Wilson disease patients with acute or chronic liver failure untreatable by medical therapy.2Roberts E.A. Schilsky M.L. Diagnosis and treatment of Wilson disease: an update. American Association for Study of Liver Diseases (AASLD).Hepatology. 2008; 47: 2089-2111Crossref PubMed Scopus (909) Google Scholar, 3European Association for Study of LiverEASL Clinical Practice Guidelines: Wilson's disease.J Hepatol. 2012; 56: 671-685Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 4Arnon R. Annunziato R. Schilsky M. et al.Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.Clin Transplant. 2011; 25: E52-E60Crossref PubMed Scopus (63) Google Scholar Patients in this cohort were initially treated with d-penicillamine, and in the latter half of the study, some received liver transplants.The important feature of this study is the reporting of long-term treatment results for well-characterized patients with Wilson disease. Evaluation of the results of longitudinal follow-up of their cohort in the context of limitations of the group and the data allows us to establish expectations for outcomes for treatment of this relatively rare disorder. In rare diseases such as Wilson disease, there is frequently the need to rely on retrospective reviews of center experiences more so than prospective treatment trials. At this center, treatment guidelines were relatively conserved save introduction of transplant midway through the observation period. With respect to the potential referral bias, the authors make a valid point that some patients with advanced liver disease may not have been recognized and diagnosed correctly as having Wilson disease during the earlier years of the study, and perhaps because these more severe cases were not referred and included in the study, there may have been a lower number of patients with advanced disease seen at onset. Given that transplant was not an option then, this could have caused an underestimate of the difficult-to-treat population where survival was not ensured.Unfortunately, we do not get to learn about the efficiency of diagnostic testing for the diagnosis of Wilson disease in the cohort, but we do learn a lot about the phenotype of their patients on presentation. In particular, we learn about the state of the liver disease in most of these patients at their time of presentation. The patient population was heavily weighted toward adult patients with liver disease because of referral bias. Nevertheless, these data offer useful information and are representative of most adult patients presenting to gastroenterologists or hepatologists with a suspicion for Wilson disease.The age at diagnosis of Wilson disease in most (60.7%) of the study patients was between 11 and 30 years (mean age 21.2 years), and only 7.4% were diagnosed at age >45 years. As previously reported, there are outliers with late diagnosis of Wilson disease, even into the seventh and eighth decades of life,5Ala A. Borjigin J. Rochwarger A. et al.Wilson disease in septuagenarian siblings: raising the bar for diagnosis.Hepatology. 2005; 41: 668-670Crossref PubMed Scopus (157) Google Scholar, 6Perri R.E. Hahn S.H. Ferber M.J. et al.Wilson disease—keeping the bar for diagnosis raised.Hepatology. 2005; 42: 974Crossref PubMed Scopus (25) Google Scholar and consideration of Wilson disease should not be abandoned solely because of the age of the patient. Most study patients (61%) presented with a predominance of hepatic symptoms, and just under a third (27%) had mostly neurologic symptoms. In both of these groups, males and females were equally distributed. However, there was an astounding female predominance for the 5% presenting with fulminant liver failure, where 10 of 11 patients were female. This is higher than the 3:1 female predominance previously noted for fulminant liver failure because of Wilson disease in a study that included many centers in the United States and in Austria.7Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar The cause of the gender difference for fulminant liver failure due to Wilson disease is speculated to be due to both hormonal influences and potential autoimmune potentiation of the injury.8Kasai N. Miyoshi I. Osanai T. et al.Effects of sex hormones on fulminant hepatitis in LEC rats: a model of Wilson's disease.Lab Anim Sci. 1992; 42: 363-368PubMed Google Scholar, 9Yokoi T. Nagayama S. Kajiwara R. et al.Identification of protein disulfide isomerase and calreticulin as autoimmune antigens in LEC strain of rats.Biochim Biophys Acta. 1993; 1158: 339-344Crossref PubMed Scopus (18) Google ScholarSymptomatic patients, accounting for 90% at the time of diagnosis (the other 10% found by family screening), were mostly diagnosed within a year of the onset of their symptoms (65%). In 25% of patients, there was a delay of more than 3 years from the time of symptom onset to the diagnosis of Wilson disease. Although we are told that neurologic presentations and psychiatric presentations account for a minority of patients referred to this center, past reports indicate that these individuals accounted for the population with the most delayed diagnosis.10Walshe J.M. Yealland M. Wilson's disease: the problem of delayed diagnosis.J Neurol Neurosurg Psychiatry. 1992; 55: 692-696Crossref PubMed Scopus (157) Google ScholarThe majority, 72% (n = 165), of patients in this cohort had an initial liver biopsy. Copper content was higher than 250 μg/g dry weight liver in 85%, whereas only 15% had lower copper values. At the time of diagnosis, 54% of the patients had cirrhosis on their liver biopsy. It was this particular histologic finding that adversely affected overall survival. Cumulative 20-year survival was decreased in those presenting with cirrhosis at time of diagnosis (0.84–0.92, respectively), and this finding predicted a higher risk for the need for liver transplant or death. This is interesting in its parallel to a population with hereditary hemochromatosis where Niederau et al11Niederau C. Fischer R. Pürschel A. et al.Long-term survival in patients with hereditary hemochromatosis.Gastroenterology. 1996; 110: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar noted decreased survival when cirrhosis was present at the outset; however, by contrast in iron-overload patients, their deaths are usually related to the development of hepatocellular carcinoma or cardiac dysrhythmia or infection.In the cohort, there were 12 patients who had to undergo emergent liver transplantation, 11 for fulminant liver failure and 1 for worsening of decompensated cirrhosis. The majority of these patients did well, consistent with reported data from North America for outcomes of liver transplant for Wilson disease.4Arnon R. Annunziato R. Schilsky M. et al.Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.Clin Transplant. 2011; 25: E52-E60Crossref PubMed Scopus (63) Google Scholar, 7Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar How well did the others do with medical therapy? Twenty-six percent are reported to fully recover, 25% had stable disease, and 15% deteriorated—including 3 with medical nonadherence. Of this group, 12% required liver transplantation at various time points after starting medical therapy. Of note, 1 patient transplanted for neurologic worsening did not improve after transplant. The authors are to be commended for this honest reporting as transplant for neurologic features alone without liver failure is controversial because of the risk of poor outcome as well as the need to utilize available organs for other patients with liver failure.So how good are we at treating most Wilson disease patients presenting with liver disease? From these data that looked at a large cohort with Wilson disease observed for 5 decades, about 85% fared even or better overall. This includes the backup of transplant for those who need rescue because of fulminant liver failure or advanced liver disease. For those that survive the first 10 years after diagnosis and treatment initiation, their survival and clinical condition continues to be excellent. Is 85%—certainly an excellent but not perfect outcome—the best we can hope for? Perhaps it is not, and we will have to think carefully how to construct models of care for patients with rare diseases to achieve even better outcomes. Certainly identifying patients earlier in their disease, first by considering evaluating for Wilson disease in appropriate patients with unexplained liver disease, in those with neurologic or psychiatric disease with abnormalities of the liver, and timely family screening should improve the overall outcome. Screening of siblings by testing for common ATP7B mutations is now first line if available, and standard clinical and biochemical testing for Kayser-Fleischer rings and evidence of liver and neurologic disease, serum ceruloplasmin and serum and urine copper, and liver biopsy with copper quantitation when appropriate is very effective for identifying patients. Treatment efficacy and side effects remains another secondary end point for other long-term studies besides survival, and prospective studies are still wanting. In addition, as in the example of the care provided to this study group, the utilization of centers with expertise in diagnosis and treatment of Wilson disease would be important. Our liver society’s published guidelines2Roberts E.A. Schilsky M.L. Diagnosis and treatment of Wilson disease: an update. American Association for Study of Liver Diseases (AASLD).Hepatology. 2008; 47: 2089-2111Crossref PubMed Scopus (909) Google Scholar, 3European Association for Study of LiverEASL Clinical Practice Guidelines: Wilson's disease.J Hepatol. 2012; 56: 671-685Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar have helped many outside such centers with algorithms for diagnosis and therapy, but the careful characterization of patients and treatment monitoring is likely better where there are interested and experienced observers.What we have gained from this study is a bar to measure ourselves by. This provides us with metrics to judge our own outcomes and helps us inform our patients how well they will do when starting treatment. Our future challenges will be to identify more Wilson disease patients at the earliest stage of their illness and to provide careful monitoring and oversight of treatment to minimize side effects, nonadherence to treatment, and the development of irreversible injury or the need for transplantation. Perhaps in doing so, we can raise the bar above 85% for expected survival for our future patients. The study by Beinhardt et al1Beinhardt S. Leiss W. Stättermayer A.F. et al.Long-term outcomes of patients with Wilson disease in a large Austrian cohort.Clin Gastroenterol Hepatol. 2014; 12: 683-689Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar is a unique report of a 5-decade experience of treating Wilson disease at a single center in Austria. During this time period, there have been advances in diagnostic testing and treatment for Wilson disease that have affected disease detection, referral, and patient survival. Molecular genetic testing for ATP7B mutations now aid in diagnosis confirmation for some difficult patients and are useful for family screening. There have been advances in therapy, including the introduction of the medications trientine and zinc salts that are effective therapies for initial and maintenance treatment, and advances in the field of liver transplantation, with excellent outcomes being reported for Wilson disease patients with acute or chronic liver failure untreatable by medical therapy.2Roberts E.A. Schilsky M.L. Diagnosis and treatment of Wilson disease: an update. American Association for Study of Liver Diseases (AASLD).Hepatology. 2008; 47: 2089-2111Crossref PubMed Scopus (909) Google Scholar, 3European Association for Study of LiverEASL Clinical Practice Guidelines: Wilson's disease.J Hepatol. 2012; 56: 671-685Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 4Arnon R. Annunziato R. Schilsky M. et al.Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.Clin Transplant. 2011; 25: E52-E60Crossref PubMed Scopus (63) Google Scholar Patients in this cohort were initially treated with d-penicillamine, and in the latter half of the study, some received liver transplants. The important feature of this study is the reporting of long-term treatment results for well-characterized patients with Wilson disease. Evaluation of the results of longitudinal follow-up of their cohort in the context of limitations of the group and the data allows us to establish expectations for outcomes for treatment of this relatively rare disorder. In rare diseases such as Wilson disease, there is frequently the need to rely on retrospective reviews of center experiences more so than prospective treatment trials. At this center, treatment guidelines were relatively conserved save introduction of transplant midway through the observation period. With respect to the potential referral bias, the authors make a valid point that some patients with advanced liver disease may not have been recognized and diagnosed correctly as having Wilson disease during the earlier years of the study, and perhaps because these more severe cases were not referred and included in the study, there may have been a lower number of patients with advanced disease seen at onset. Given that transplant was not an option then, this could have caused an underestimate of the difficult-to-treat population where survival was not ensured. Unfortunately, we do not get to learn about the efficiency of diagnostic testing for the diagnosis of Wilson disease in the cohort, but we do learn a lot about the phenotype of their patients on presentation. In particular, we learn about the state of the liver disease in most of these patients at their time of presentation. The patient population was heavily weighted toward adult patients with liver disease because of referral bias. Nevertheless, these data offer useful information and are representative of most adult patients presenting to gastroenterologists or hepatologists with a suspicion for Wilson disease. The age at diagnosis of Wilson disease in most (60.7%) of the study patients was between 11 and 30 years (mean age 21.2 years), and only 7.4% were diagnosed at age >45 years. As previously reported, there are outliers with late diagnosis of Wilson disease, even into the seventh and eighth decades of life,5Ala A. Borjigin J. Rochwarger A. et al.Wilson disease in septuagenarian siblings: raising the bar for diagnosis.Hepatology. 2005; 41: 668-670Crossref PubMed Scopus (157) Google Scholar, 6Perri R.E. Hahn S.H. Ferber M.J. et al.Wilson disease—keeping the bar for diagnosis raised.Hepatology. 2005; 42: 974Crossref PubMed Scopus (25) Google Scholar and consideration of Wilson disease should not be abandoned solely because of the age of the patient. Most study patients (61%) presented with a predominance of hepatic symptoms, and just under a third (27%) had mostly neurologic symptoms. In both of these groups, males and females were equally distributed. However, there was an astounding female predominance for the 5% presenting with fulminant liver failure, where 10 of 11 patients were female. This is higher than the 3:1 female predominance previously noted for fulminant liver failure because of Wilson disease in a study that included many centers in the United States and in Austria.7Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar The cause of the gender difference for fulminant liver failure due to Wilson disease is speculated to be due to both hormonal influences and potential autoimmune potentiation of the injury.8Kasai N. Miyoshi I. Osanai T. et al.Effects of sex hormones on fulminant hepatitis in LEC rats: a model of Wilson's disease.Lab Anim Sci. 1992; 42: 363-368PubMed Google Scholar, 9Yokoi T. Nagayama S. Kajiwara R. et al.Identification of protein disulfide isomerase and calreticulin as autoimmune antigens in LEC strain of rats.Biochim Biophys Acta. 1993; 1158: 339-344Crossref PubMed Scopus (18) Google Scholar Symptomatic patients, accounting for 90% at the time of diagnosis (the other 10% found by family screening), were mostly diagnosed within a year of the onset of their symptoms (65%). In 25% of patients, there was a delay of more than 3 years from the time of symptom onset to the diagnosis of Wilson disease. Although we are told that neurologic presentations and psychiatric presentations account for a minority of patients referred to this center, past reports indicate that these individuals accounted for the population with the most delayed diagnosis.10Walshe J.M. Yealland M. Wilson's disease: the problem of delayed diagnosis.J Neurol Neurosurg Psychiatry. 1992; 55: 692-696Crossref PubMed Scopus (157) Google Scholar The majority, 72% (n = 165), of patients in this cohort had an initial liver biopsy. Copper content was higher than 250 μg/g dry weight liver in 85%, whereas only 15% had lower copper values. At the time of diagnosis, 54% of the patients had cirrhosis on their liver biopsy. It was this particular histologic finding that adversely affected overall survival. Cumulative 20-year survival was decreased in those presenting with cirrhosis at time of diagnosis (0.84–0.92, respectively), and this finding predicted a higher risk for the need for liver transplant or death. This is interesting in its parallel to a population with hereditary hemochromatosis where Niederau et al11Niederau C. Fischer R. Pürschel A. et al.Long-term survival in patients with hereditary hemochromatosis.Gastroenterology. 1996; 110: 1107-1119Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar noted decreased survival when cirrhosis was present at the outset; however, by contrast in iron-overload patients, their deaths are usually related to the development of hepatocellular carcinoma or cardiac dysrhythmia or infection. In the cohort, there were 12 patients who had to undergo emergent liver transplantation, 11 for fulminant liver failure and 1 for worsening of decompensated cirrhosis. The majority of these patients did well, consistent with reported data from North America for outcomes of liver transplant for Wilson disease.4Arnon R. Annunziato R. Schilsky M. et al.Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults.Clin Transplant. 2011; 25: E52-E60Crossref PubMed Scopus (63) Google Scholar, 7Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar How well did the others do with medical therapy? Twenty-six percent are reported to fully recover, 25% had stable disease, and 15% deteriorated—including 3 with medical nonadherence. Of this group, 12% required liver transplantation at various time points after starting medical therapy. Of note, 1 patient transplanted for neurologic worsening did not improve after transplant. The authors are to be commended for this honest reporting as transplant for neurologic features alone without liver failure is controversial because of the risk of poor outcome as well as the need to utilize available organs for other patients with liver failure. So how good are we at treating most Wilson disease patients presenting with liver disease? From these data that looked at a large cohort with Wilson disease observed for 5 decades, about 85% fared even or better overall. This includes the backup of transplant for those who need rescue because of fulminant liver failure or advanced liver disease. For those that survive the first 10 years after diagnosis and treatment initiation, their survival and clinical condition continues to be excellent. Is 85%—certainly an excellent but not perfect outcome—the best we can hope for? Perhaps it is not, and we will have to think carefully how to construct models of care for patients with rare diseases to achieve even better outcomes. Certainly identifying patients earlier in their disease, first by considering evaluating for Wilson disease in appropriate patients with unexplained liver disease, in those with neurologic or psychiatric disease with abnormalities of the liver, and timely family screening should improve the overall outcome. Screening of siblings by testing for common ATP7B mutations is now first line if available, and standard clinical and biochemical testing for Kayser-Fleischer rings and evidence of liver and neurologic disease, serum ceruloplasmin and serum and urine copper, and liver biopsy with copper quantitation when appropriate is very effective for identifying patients. Treatment efficacy and side effects remains another secondary end point for other long-term studies besides survival, and prospective studies are still wanting. In addition, as in the example of the care provided to this study group, the utilization of centers with expertise in diagnosis and treatment of Wilson disease would be important. Our liver society’s published guidelines2Roberts E.A. Schilsky M.L. Diagnosis and treatment of Wilson disease: an update. American Association for Study of Liver Diseases (AASLD).Hepatology. 2008; 47: 2089-2111Crossref PubMed Scopus (909) Google Scholar, 3European Association for Study of LiverEASL Clinical Practice Guidelines: Wilson's disease.J Hepatol. 2012; 56: 671-685Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar have helped many outside such centers with algorithms for diagnosis and therapy, but the careful characterization of patients and treatment monitoring is likely better where there are interested and experienced observers. What we have gained from this study is a bar to measure ourselves by. This provides us with metrics to judge our own outcomes and helps us inform our patients how well they will do when starting treatment. Our future challenges will be to identify more Wilson disease patients at the earliest stage of their illness and to provide careful monitoring and oversight of treatment to minimize side effects, nonadherence to treatment, and the development of irreversible injury or the need for transplantation. Perhaps in doing so, we can raise the bar above 85% for expected survival for our future patients. Long-term Outcomes of Patients With Wilson Disease in a Large Austrian CohortClinical Gastroenterology and HepatologyVol. 12Issue 4PreviewWilson disease is an autosomal recessive disorder that affects copper metabolism, leading to copper accumulation in liver, central nervous system, and kidneys. There are few data on long-term outcomes and survival from large cohorts; we studied these features in a well-characterized Austrian cohort of patients with Wilson disease. Full-Text PDF