Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Human Disorders of Copper Metabolism II
Liver transplantation for Wilson’s disease Michael L. Schilsky Sections of Digestive Disease and Immunology and Transplantation, Yale New Haven Transplant Center, Yale University School of Medicine, New Haven, Connecticut Address for correspondence: Michael L. Schilsky, M.D., Yale University Medical Center, 333 Cedar Street, LMP 1080, New Haven, CT 06520. [email protected]
Although Wilsons’s disease (WD) may be treated with copper chelation (to remove copper) or zinc salts (to prevent absorption) to alleviate or prevent symptom development in most patients, there are WD patients for whom medical therapy is inadequate and survival would be unlikely without liver transplantation. Liver transplantation is indicated for the 5% of WD patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades. Liver transplantation restores normal biliary copper excretion (thereby preventing disease recurrence) and promotes removal of copper from extrahepatic sites. Outcomes of liver transplantation for WD are excellent, including both cadaveric and living donors. Keywords: Wilson’s disease; liver transplant; liver failure; copper
Overview The natural history of untreated Wilson’s disease (WD) is premature death owing to liver failure or complications of neurological symptoms.1 Although WD may be treated with copper chelation (to remove copper) or zinc salts (to prevent absorption) to treat symptomatic disease or prevent symptom development in most patients, there are WD patients for whom medical therapy is inadequate and who would not survive without liver transplantation.1 These include the about 5% of WD patients who have acute liver failure (ALF) as their first presentation of their disease, most commonly in the second decade of life, or those that present with end-stage liver disease (ESLD) with severe hepatic insufficiency and complications of portal hypertension, most commonly in the third and fourth decades (Fig. 1). Liver transplantation is curative, replacing the host’s affected liver, restoring normal biliary copper excretion (thereby preventing disease recurrence), and promoting the removal of copper from extrahepatic sites where it may be toxic.2,3
Identification of patients with WD with ALF who should be considered for liver transplantation Patients with ALF due to WD may be diagnosed with WD by several features that distinguish them from other patients with ALF.4 On physical examination, about 50% will have detectable Kayser–Fleischer rings. On laboratory testing, these individuals almost always have a nonimmune (Coombs-negative) hemolytic anemia that may precede the development of liver failure or occur concurrent with the liver injury. With acute hepatic necrosis and hepatocellular apoptosis associated with ALF due to WD, there is further copper release into the circulation, with subsequent increased red blood cell (RBC) copper and cell membrane destabilization by oxidation of phospholipids,5 and perhaps by inhibition of glucose-6-phosphate dehydrogenase as well.6 Other diagnostic features of ALF due to WD include an increase in the alkaline phosphatase to bilirubin ratio of less than 4:1 owing to the relative decrease in alkaline phosphatase and increased
doi: 10.1111/nyas.12454 C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
45
Liver transplantation for Wilson’s disease
Schilsky
Copper accumulation
Urinary copper is also extremely elevated in ALF due to WD, consistent with the elevation in circulating copper; however, if renal injury occurs or hepatorenal syndrome develops, urine output may be low and 24-h collection is difficult. Identifying the cause of liver failure as WD enables consideration for interventions that may stabilize the patient and buy time while awaiting organ transplantation. Importantly, it also enables the screening of first-degree relatives of the proband to identify any other affected individuals, hopefully at a time when they are still asymptomatic. ALF due to WD may also develop in some patients with previously treated liver disease caused by WD who discontinue medical therapy.7 In these individuals, onset of jaundice, hemolytic anemia, severe coagulopathy, and thrombocytopenia are accompanied by the typical low alkaline phosphatase to bilirubin ratio and elevated ratio of AST to ALT. These individuals may behave clinically similar to those presenting the first time with ALF due to WD, and liver transplantation is indicated for their treatment. The same care measure that applied to the others applies to these individuals as well. Transplantation, primarily for neurological WD without the presence of liver failure, is controversial, but there are reports of neurological symptoms improving after transplant, as well as the presence of permanent disability if transplant is performed after severe injury.3,8,9 While a more systematic approach to these patients is needed, in the United States, where donor organ availability for liver transplant is in short supply, it is not easy to justify liver transplantation for patients that may do well enough with medical therapy alone.
Loss of antioxidant potential Cirrhosis Portal HTN Ascites Varices
Liver Injury Liver Failure
Less biliary excretion
Death
Hepatorenal syndrome
Less renal excretion
Transplant
Figure 1. Liver failure in chronic WD and the role of liver transplant. In patients where liver injury due to WD is uninterrupted by medical therapy, cirrhosis develops, along with the complications of portal hypertension. When liver injury has exceeded the regenerative capacity of the liver, liver failure results, with further complications of renal failure and other multiorgan failure. Without transplantation, these individuals will die. Transplantation can restore normal copper metabolism and give excellent long-term survival of patients with WD.
bilirubin (resulting from hemolysis and hepatic dysfunction), a ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) of greater than 2.2:1, and increases in serum copper, typically above 200 mcg/dL.4 If both the alkaline phosphatase to bilirubin ratio is greater than 4:1 and the AST to ALT ratio is above 2.2 concurrently, then the diagnosis of ALF due to WD is almost certain. Ceruloplasmin, a useful phenotypic marker for diagnosis in WD presenting with chronic liver disease, has poor sensitivity and specificity in the setting of ALF, especially when immunological methods for determination of ceruloplasmin are used. The range for ALT and AST elevations varies widely, but typically these patients do not have the severely elevated ALT and AST in the thousands that may accompany other patients with acute hepatic necrosis owing to other etiologies, as in WD the injury is more often acute on chronic injury, and hepatic reserve is diminished in most. Hepatic copper may be a useful measurement, but given the coagulopathy and thrombocytopenia in patients with ALF, transjugular biopsy may be the safest technique to perform. If the other measures indicate WD as the diagnosis, hepatic copper is not often measured prospectively, but high levels can be confirmed in the explanted liver (or on autopsy specimen), where, typically, above 250 mcg/g dry weight liver is considered diagnostic for patients with WD.1,4 46
Treatment of ALF due to WD while awaiting liver transplantation The focus of treatment in the setting of ALF due to WD is the reduction in serum copper, which may help break a vicious cycle of liver injury and other organ damage that ensues in ALF due to WD (Fig. 2). In this cycle, necrosis and apoptosis of liver cells leads to acute release of tissue copper into the circulation, where it may exacerbate hemolysis through its effect on RBC membranes (as described above) and injure the renal tubules, leading to reduced renal function and renal filtration of copper. The release of heme iron from the RBCs causes further injury to the liver cells and thereby causes further release of
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
Schilsky
Liver transplantation for Wilson’s disease
Copper accumulation Loss of antioxidant potential Liver Injury
Release of Heme iron
Copper release
Hemolysis Renal Injury Figure 2. Cycle of perpetuating liver injury and hemolysis in ALF due to WD. The cycle of liver injury begins after some insult to the liver causes a loss of antioxidant potential, which begins the acute liver failure (ALF). Release of copper from injured or dying liver cells causes further injury to the remaining liver and likely further reduces the level of biliary copper excretion. Copper causes red blood cell injury, and hemolysis results, with release of heme iron into the circulation. Heme iron is typically removed from the circulation by the liver, but heme iron is also toxic. Elevated circulating copper also causes renal tubular injury, reduces renal function, and further reduces the clearance of copper by the kidney.
copper, continuing the cycle of injury. By filtering or removing the copper from the circulation, the cycle can be broken and the patient better stabilized, but this is a fluid process, and with inhibition of regeneration owing to hepatic injury and injury of progenitor cells, liver transplantation is ultimately needed for almost all of these individuals.1 Several methods may be useful to accomplish the reduction in circulating copper, including exchange transfusion, plasmapheresis, hemofiltration, albumin dialysis, and the molecular absorbent recirculating system (MARS), which combines albumin dialysis with charcoal and ion exchange–column adsorption.1,10–12 For any of these interventions, it will be necessary to repeat the treatments or consider ongoing treatment to stabilize the patient. Often, there is renal insufficiency that accompanies the liver failure; in the setting of WD, the excess copper may play a role in causing acute tubular injury. Currently approved therapies for WD that normally remove copper from the body, namely d-penicillamine and trientine, are cleared by the kidneys and are not effective for copper removal when renal clearance is severely diminished. Zinc blocks new dietary copper absorption, but would not directly accelerate copper removal. In theory, there could be a role for tetrathiomolybdate in binding copper as a protein complex and helping to detoxify excess circulating
copper; however, while it has been used for this purpose in veterinary practice for animals with liver injury, human data for its use have focused on the acute neurological symptoms in WD,13 and there are no data in the setting of severe liver injury. ESLD due to WD requiring liver transplantation Patients with ESLD due to WD include new patients with advanced disease or treated patients who stopped therapy and worsened. A scoring system to predict whether a WD patient will respond to medical therapy was developed by Nazer et al.14 in a cohort that was followed before liver transplant was possible, and was re-examined and modified by Koppikar and Dhawan in a pediatric cohort where medical therapy was the only option.15 Patients with modified WD scores greater than 10 (components being white blood cells, albumin, international normalized ratio, and bilirubin) did not survive. Subsequently, this score was validated when applied to another group of pediatric patients followed prospectively by the same group. Therefore, we extrapolate that, for WD patients with advanced liver disease with scores >10, transplantation is indicated, as they will likely die otherwise. Indeed, this scoring system has two components in common with the MELD score used for liver organ–allocation prioritization, and it is not surprising that it is useful for predicting mortality owing to liver disease. With respect to transplant in the United States, decompensated WD is also granted an exception by the United Network for Organ Sharing (UNOS) for higher priority for transplantation.16 Although this modified scoring system is useful for predicting mortality, there may be exceptions to the rule, and, occasionally, patients may have an elevated score and still be treated medically. In one series from Pittsburgh, three of five patients with modified scores at or above 10 (one 13, two 11, and two 10) survived with their native livers.17 Therefore, if possible, treatment should be initiated in WD patients with chelation, and possibly with dual zinc and chelation therapy, and their course observed carefully while they are considered for transplant. The modified WD score can then be reassessed over time to see if there is clinical improvement that might indicate potential recovery with medical therapy and the possibility of avoiding liver transplantation.
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
47
Liver transplantation for Wilson’s disease
Schilsky
Other considerations in patients with WD and chronic liver failure include the management of complications of portal hypertension (Fig. 1). Appropriate surveillance for esophageal and gastric varices should be performed, along with management of volume with sodium restriction and diuretics as needed, and treatment for hepatic encephalopathy or prophylaxis for spontaneous bacterial peritonitis as indicated. Liver transplantation for WD: orthotopic, split-liver, living-donor, and auxiliary transplantation One of the first liver transplants, performed by Thomas Starzl in the United States in the 1970s, was for a patient with WD with liver failure.2 Since then, it has been accepted that liver transplant provides a cure for WD, replacing the defective liver with one that has normal biliary copper excretion. With the advances in pediatric liver transplant, the concept of using split-liver or a reduced-size graft was pioneered. Further advances in technical capabilities for liver transplant surgery permitted the use of living-donor grafts. With this advance came the question of whether the use of livers from parents of WD patients who would be obligate heterozygotes would be more successful in removing liver copper and preventing disease recurrence than the native liver was. Indeed, this was shown to be true, and donor grafts from adult to child and then adult to adult with liver failure, acute or chronic, due to WD was shown to be successful.18 While the use of a whole graft is often preferred in the setting of ALF, patients with ALF due to WD are different from chronic patients. They frequently are otherwise healthy and have not suffered from chronic liver disease, and may be better suited to have successful graft growth following transplantation of a partial graft and avoid graft failure due to smallfor-size syndrome or other complications such as infection. Auxiliary liver grafts are partial grafts that are placed in the patient in addition to some or all of the patient’s original liver. For WD, the ability to clear copper from the circulation to bile is enhanced by the new liver, which has homozygous wild-type or heterozygous ATP7B. An interesting and appealing use of these grafts for patients with ALF is the ability to later withdraw immune suppression if there has been adequate recovery of the native liver, leaving 48
the auxiliary graft to undergo acute and chronic rejection and, for practical purposes, elimination. The great degree of technical demand and the potential problems associated with leaving an injured organ in place has limited the use of this technology, but it has been utilized for WD.19 Outcomes for liver transplantation Long-term outcomes for adult and pediatric patients with WD posttransplant are excellent, and many single-center or multicenter analyses have shown that complications of portal hypertension and neurological symptoms may improve in most patients. However, some patients with neurological symptoms may not recover, and therefore careful patient selection and appropriate discussions with neurologists and hepatologists are important for those affected by neurological symptoms as well as liver disease. Furthermore, transplantation with normal or heterozygous livers for WD yields good outcomes and normal copper metabolism in recipients, the latter being very important for considering potential living donors. Living-donor outcomes are also very good, with Yoshitosi et al.20 reporting patient survival at 1 year of 90.6%, 5-year survival of 83.7%, and 10-year survival of 89%. Similarly, Cheng et al. found graft survival was 86.1% at 1 year and 75% at 5 years, and patient survival was 91.7% at 1 year and 75% at 5 years.21 One of the best reviews of outcomes of liver transplantation for WD comes from a review of data from the U.S. transplant registry for 170 pediatric patients (from 2003 to 2008) and 400 adult patients (from 1987 to 2008) with WD, which showed graft and patient survival for pediatric and adult patients with WD at 1 and 5 years was 90.1% and 89% for children and 88% and 86% for adults, respectively.22 Even better outcomes were noted for 1-year survival for transplantation for chronic liver failure versus ALF for WD adults. Overall, liver transplant is life-saving and appropriate therapy for patients with acute and chronic liver failure due to WD, and yields excellent longterm survival for adult and pediatric patients. Conflicts of interest The author declares no conflicts of interest.
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
Schilsky
Liver transplantation for Wilson’s disease
References 1. Roberts, E.A. & M.L. Schilsky. 2008. Diagnosis and treatment of Wilson disease: an update; American Association for Study of Liver Diseases (AASLD). Hepatology 47: 2089– 2111. 2. Groth, C.G., R.S. Dubois, J. Corman, et al. 1973. Metabolic effects of hepatic replacement in Wilson’s disease. Transplant. Proc. 5: 829–833. 3. Schilsky, M.L., I.H. Scheinberg & I. Sternlieb. 1994. Liver transplantation for Wilson’s disease: indications and outcome. Hepatology 19: 583–587. 4. Korman, J.D., I. Volenberg, J. Balko, et al. 2008. Pediatric and Adult Acute Liver Failure Study Groups. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 48: 1167–1174. 5. Forman, S.J., K.S. Kumar, A.G. Redeker & P. Hochstein. 1980. Hemolytic anemia in Wilson disease: clinical findings and biochemical mechanisms. Am. J. Hematol. 9: 269–275. 6. Passwell, J., B.E. Cohen, I.B. Bassat, et al. 1970. Hemolysis in Wilson’s disease. The role of glucose-6-phosphate dehydrogenase inhibition. Isr. J. Med. Sci. 6: 549–554. 7. Scheinberg, I.H., M.E. Jaffe & I. Sternlieb. 1987. The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson’s disease. Engl. J. Med. 317: 209– 213. 8. Schumacher, G., K.P. Platz, A.R. Mueller, et al. 2001. Liver transplantation in neurologic Wilson’s disease. Transplant. Proc. 33: 1518–1519. 9. Medici, V., V.G. Mirante, L.R. Fassati, et al. 2005. Monotematica AISF 2000 OLT Study Group. Liver transplantation for Wilson’s disease: the burden of neurological and psychiatric disorders. Liver Transpl. 11: 1056–1063. 10. Kreymann, B., M. Seige, U. Schweigart, et al. 1999. Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of proteinbound toxins. J. Hepatol. 31: 1080–1085. 11. Jhang, J.S., M.L. Schilsky, J.H. Lefkowitch & J. Schwartz. 2007. Therapeutic plasmapheresis as a bridge to liver trans-
12.
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22.
plantation in fulminant Wilson disease. J. Clin. Apher. 22: 10–14. Sen, S., M. Felldin, C. Steiner, et al. 2002. Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson’s disease. Liver Transpl. 8: 962–967. Brewer, G.J., F. Askari, M.T. Lorincz, et al. 2006. Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Arch. Neurol. 63: 521–527. Nazer, H., R.J. Ede, A.P. Mowat & R. Williams. 1986. Wilson’s disease: clinical presentation and use of prognostic index. Gut 27: 1377–1381. Koppikar, S. & A. Dhawan. 2005. Evaluation of the scoring system for the diagnosis of Wilson’s disease in children. Liver Int. 25: 680–681. OPTN Policy 3.6—Allocation of Livers—December 2012. Cited April 15, 2014. optn.transplant.hrsa.gov/Policie sandBylaws2/policies/pdfs/policy_8.pdf. Fischer, R.T., K.A. Soltys, R.H. Squires, Jr., et al. 2011. Prognostic scoring indices in Wilson disease: a case series and cautionary tale. J. Pediatr. Gastroenterol. Nutr. 52: 466–469. Yoshitoshi, E.Y., Y. Takada, F. Oike, et al. 2009. Long-term outcomes for 32 cases of Wilson’s disease after living-donor liver transplantation. Transplantation 87: 261–267. Park, Y.K., B.W. Kim, H.J. Wang & M.W. Kim. 2008. Auxiliary partial orthotopic living donor liver transplantation in a patient with Wilson’s disease: a case report. Transplant Proc. 40: 3808–3809. Yoshitoshi, E.Y., Y. Takada, F. Oike, et al. 2009. Long-term outcomes for 32 cases of Wilson’s disease after living-donor liver transplantation. Transplantation 87: 261–267. Cheng, F., G.Q. Li, F. Zhang, et al. 2009. Outcomes of livingrelated liver transplantation for Wilson’s disease: a singlecenter experience in China. Transplantation 87: 751–757. Arnon, R., R. Annunziato, M. Schilsky, et al. 2011. Liver transplantation for children with Wilson disease: comparison of outcomes between children and adults. Clin Transplant 25: E52–E60.
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
49
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Human Disorders of Copper Metabolism II
Liver transplantation for Wilson’s disease Michael L. Schilsky Sections of Digestive Disease and Immunology and Transplantation, Yale New Haven Transplant Center, Yale University School of Medicine, New Haven, Connecticut Address for correspondence: Michael L. Schilsky, M.D., Yale University Medical Center, 333 Cedar Street, LMP 1080, New Haven, CT 06520. [email protected]
Although Wilsons’s disease (WD) may be treated with copper chelation (to remove copper) or zinc salts (to prevent absorption) to alleviate or prevent symptom development in most patients, there are WD patients for whom medical therapy is inadequate and survival would be unlikely without liver transplantation. Liver transplantation is indicated for the 5% of WD patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades. Liver transplantation restores normal biliary copper excretion (thereby preventing disease recurrence) and promotes removal of copper from extrahepatic sites. Outcomes of liver transplantation for WD are excellent, including both cadaveric and living donors. Keywords: Wilson’s disease; liver transplant; liver failure; copper
Overview The natural history of untreated Wilson’s disease (WD) is premature death owing to liver failure or complications of neurological symptoms.1 Although WD may be treated with copper chelation (to remove copper) or zinc salts (to prevent absorption) to treat symptomatic disease or prevent symptom development in most patients, there are WD patients for whom medical therapy is inadequate and who would not survive without liver transplantation.1 These include the about 5% of WD patients who have acute liver failure (ALF) as their first presentation of their disease, most commonly in the second decade of life, or those that present with end-stage liver disease (ESLD) with severe hepatic insufficiency and complications of portal hypertension, most commonly in the third and fourth decades (Fig. 1). Liver transplantation is curative, replacing the host’s affected liver, restoring normal biliary copper excretion (thereby preventing disease recurrence), and promoting the removal of copper from extrahepatic sites where it may be toxic.2,3
Identification of patients with WD with ALF who should be considered for liver transplantation Patients with ALF due to WD may be diagnosed with WD by several features that distinguish them from other patients with ALF.4 On physical examination, about 50% will have detectable Kayser–Fleischer rings. On laboratory testing, these individuals almost always have a nonimmune (Coombs-negative) hemolytic anemia that may precede the development of liver failure or occur concurrent with the liver injury. With acute hepatic necrosis and hepatocellular apoptosis associated with ALF due to WD, there is further copper release into the circulation, with subsequent increased red blood cell (RBC) copper and cell membrane destabilization by oxidation of phospholipids,5 and perhaps by inhibition of glucose-6-phosphate dehydrogenase as well.6 Other diagnostic features of ALF due to WD include an increase in the alkaline phosphatase to bilirubin ratio of less than 4:1 owing to the relative decrease in alkaline phosphatase and increased
doi: 10.1111/nyas.12454 C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
45
Liver transplantation for Wilson’s disease
Schilsky
Copper accumulation
Urinary copper is also extremely elevated in ALF due to WD, consistent with the elevation in circulating copper; however, if renal injury occurs or hepatorenal syndrome develops, urine output may be low and 24-h collection is difficult. Identifying the cause of liver failure as WD enables consideration for interventions that may stabilize the patient and buy time while awaiting organ transplantation. Importantly, it also enables the screening of first-degree relatives of the proband to identify any other affected individuals, hopefully at a time when they are still asymptomatic. ALF due to WD may also develop in some patients with previously treated liver disease caused by WD who discontinue medical therapy.7 In these individuals, onset of jaundice, hemolytic anemia, severe coagulopathy, and thrombocytopenia are accompanied by the typical low alkaline phosphatase to bilirubin ratio and elevated ratio of AST to ALT. These individuals may behave clinically similar to those presenting the first time with ALF due to WD, and liver transplantation is indicated for their treatment. The same care measure that applied to the others applies to these individuals as well. Transplantation, primarily for neurological WD without the presence of liver failure, is controversial, but there are reports of neurological symptoms improving after transplant, as well as the presence of permanent disability if transplant is performed after severe injury.3,8,9 While a more systematic approach to these patients is needed, in the United States, where donor organ availability for liver transplant is in short supply, it is not easy to justify liver transplantation for patients that may do well enough with medical therapy alone.
Loss of antioxidant potential Cirrhosis Portal HTN Ascites Varices
Liver Injury Liver Failure
Less biliary excretion
Death
Hepatorenal syndrome
Less renal excretion
Transplant
Figure 1. Liver failure in chronic WD and the role of liver transplant. In patients where liver injury due to WD is uninterrupted by medical therapy, cirrhosis develops, along with the complications of portal hypertension. When liver injury has exceeded the regenerative capacity of the liver, liver failure results, with further complications of renal failure and other multiorgan failure. Without transplantation, these individuals will die. Transplantation can restore normal copper metabolism and give excellent long-term survival of patients with WD.
bilirubin (resulting from hemolysis and hepatic dysfunction), a ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) of greater than 2.2:1, and increases in serum copper, typically above 200 mcg/dL.4 If both the alkaline phosphatase to bilirubin ratio is greater than 4:1 and the AST to ALT ratio is above 2.2 concurrently, then the diagnosis of ALF due to WD is almost certain. Ceruloplasmin, a useful phenotypic marker for diagnosis in WD presenting with chronic liver disease, has poor sensitivity and specificity in the setting of ALF, especially when immunological methods for determination of ceruloplasmin are used. The range for ALT and AST elevations varies widely, but typically these patients do not have the severely elevated ALT and AST in the thousands that may accompany other patients with acute hepatic necrosis owing to other etiologies, as in WD the injury is more often acute on chronic injury, and hepatic reserve is diminished in most. Hepatic copper may be a useful measurement, but given the coagulopathy and thrombocytopenia in patients with ALF, transjugular biopsy may be the safest technique to perform. If the other measures indicate WD as the diagnosis, hepatic copper is not often measured prospectively, but high levels can be confirmed in the explanted liver (or on autopsy specimen), where, typically, above 250 mcg/g dry weight liver is considered diagnostic for patients with WD.1,4 46
Treatment of ALF due to WD while awaiting liver transplantation The focus of treatment in the setting of ALF due to WD is the reduction in serum copper, which may help break a vicious cycle of liver injury and other organ damage that ensues in ALF due to WD (Fig. 2). In this cycle, necrosis and apoptosis of liver cells leads to acute release of tissue copper into the circulation, where it may exacerbate hemolysis through its effect on RBC membranes (as described above) and injure the renal tubules, leading to reduced renal function and renal filtration of copper. The release of heme iron from the RBCs causes further injury to the liver cells and thereby causes further release of
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
Schilsky
Liver transplantation for Wilson’s disease
Copper accumulation Loss of antioxidant potential Liver Injury
Release of Heme iron
Copper release
Hemolysis Renal Injury Figure 2. Cycle of perpetuating liver injury and hemolysis in ALF due to WD. The cycle of liver injury begins after some insult to the liver causes a loss of antioxidant potential, which begins the acute liver failure (ALF). Release of copper from injured or dying liver cells causes further injury to the remaining liver and likely further reduces the level of biliary copper excretion. Copper causes red blood cell injury, and hemolysis results, with release of heme iron into the circulation. Heme iron is typically removed from the circulation by the liver, but heme iron is also toxic. Elevated circulating copper also causes renal tubular injury, reduces renal function, and further reduces the clearance of copper by the kidney.
copper, continuing the cycle of injury. By filtering or removing the copper from the circulation, the cycle can be broken and the patient better stabilized, but this is a fluid process, and with inhibition of regeneration owing to hepatic injury and injury of progenitor cells, liver transplantation is ultimately needed for almost all of these individuals.1 Several methods may be useful to accomplish the reduction in circulating copper, including exchange transfusion, plasmapheresis, hemofiltration, albumin dialysis, and the molecular absorbent recirculating system (MARS), which combines albumin dialysis with charcoal and ion exchange–column adsorption.1,10–12 For any of these interventions, it will be necessary to repeat the treatments or consider ongoing treatment to stabilize the patient. Often, there is renal insufficiency that accompanies the liver failure; in the setting of WD, the excess copper may play a role in causing acute tubular injury. Currently approved therapies for WD that normally remove copper from the body, namely d-penicillamine and trientine, are cleared by the kidneys and are not effective for copper removal when renal clearance is severely diminished. Zinc blocks new dietary copper absorption, but would not directly accelerate copper removal. In theory, there could be a role for tetrathiomolybdate in binding copper as a protein complex and helping to detoxify excess circulating
copper; however, while it has been used for this purpose in veterinary practice for animals with liver injury, human data for its use have focused on the acute neurological symptoms in WD,13 and there are no data in the setting of severe liver injury. ESLD due to WD requiring liver transplantation Patients with ESLD due to WD include new patients with advanced disease or treated patients who stopped therapy and worsened. A scoring system to predict whether a WD patient will respond to medical therapy was developed by Nazer et al.14 in a cohort that was followed before liver transplant was possible, and was re-examined and modified by Koppikar and Dhawan in a pediatric cohort where medical therapy was the only option.15 Patients with modified WD scores greater than 10 (components being white blood cells, albumin, international normalized ratio, and bilirubin) did not survive. Subsequently, this score was validated when applied to another group of pediatric patients followed prospectively by the same group. Therefore, we extrapolate that, for WD patients with advanced liver disease with scores >10, transplantation is indicated, as they will likely die otherwise. Indeed, this scoring system has two components in common with the MELD score used for liver organ–allocation prioritization, and it is not surprising that it is useful for predicting mortality owing to liver disease. With respect to transplant in the United States, decompensated WD is also granted an exception by the United Network for Organ Sharing (UNOS) for higher priority for transplantation.16 Although this modified scoring system is useful for predicting mortality, there may be exceptions to the rule, and, occasionally, patients may have an elevated score and still be treated medically. In one series from Pittsburgh, three of five patients with modified scores at or above 10 (one 13, two 11, and two 10) survived with their native livers.17 Therefore, if possible, treatment should be initiated in WD patients with chelation, and possibly with dual zinc and chelation therapy, and their course observed carefully while they are considered for transplant. The modified WD score can then be reassessed over time to see if there is clinical improvement that might indicate potential recovery with medical therapy and the possibility of avoiding liver transplantation.
C 2014 New York Academy of Sciences. Ann. N.Y. Acad. Sci. 1315 (2014) 45–49
47
Liver transplantation for Wilson’s disease
Schilsky
Other considerations in patients with WD and chronic liver failure include the management of complications of portal hypertension (Fig. 1). Appropriate surveillance for esophageal and gastric varices should be performed, along with management of volume with sodium restriction and diuretics as needed, and treatment for hepatic encephalopathy or prophylaxis for spontaneous bacterial peritonitis as indicated. Liver transplantation for WD: orthotopic, split-liver, living-donor, and auxiliary transplantation One of the first liver transplants, performed by Thomas Starzl in the United States in the 1970s, was for a patient with WD with liver failure.2 Since then, it has been accepted that liver transplant provides a cure for WD, replacing the defective liver with one that has normal biliary copper excretion. With the advances in pediatric liver transplant, the concept of using split-liver or a reduced-size graft was pioneered. Further advances in technical capabilities for liver transplant surgery permitted the use of living-donor grafts. With this advance came the question of whether the use of livers from parents of WD patients who would be obligate heterozygotes would be more successful in removing liver copper and preventing disease recurrence than the native liver was. Indeed, this was shown to be true, and donor grafts from adult to child and then adult to adult with liver failure, acute or chronic, due to WD was shown to be successful.18 While the use of a whole graft is often preferred in the setting of ALF, patients with ALF due to WD are different from chronic patients. They frequently are otherwise healthy and have not suffered from chronic liver disease, and may be better suited to have successful graft growth following transplantation of a partial graft and avoid graft failure due to smallfor-size syndrome or other complications such as infection. Auxiliary liver grafts are partial grafts that are placed in the patient in addition to some or all of the patient’s original liver. For WD, the ability to clear copper from the circulation to bile is enhanced by the new liver, which has homozygous wild-type or heterozygous ATP7B. An interesting and appealing use of these grafts for patients with ALF is the ability to later withdraw immune suppression if there has been adequate recovery of the native liver, leaving 48
the auxiliary graft to undergo acute and chronic rejection and, for practical purposes, elimination. The great degree of technical demand and the potential problems associated with leaving an injured organ in place has limited the use of this technology, but it has been utilized for WD.19 Outcomes for liver transplantation Long-term outcomes for adult and pediatric patients with WD posttransplant are excellent, and many single-center or multicenter analyses have shown that complications of portal hypertension and neurological symptoms may improve in most patients. However, some patients with neurological symptoms may not recover, and therefore careful patient selection and appropriate discussions with neurologists and hepatologists are important for those affected by neurological symptoms as well as liver disease. Furthermore, transplantation with normal or heterozygous livers for WD yields good outcomes and normal copper metabolism in recipients, the latter being very important for considering potential living donors. Living-donor outcomes are also very good, with Yoshitosi et al.20 reporting patient survival at 1 year of 90.6%, 5-year survival of 83.7%, and 10-year survival of 89%. Similarly, Cheng et al. found graft survival was 86.1% at 1 year and 75% at 5 years, and patient survival was 91.7% at 1 year and 75% at 5 years.21 One of the best reviews of outcomes of liver transplantation for WD comes from a review of data from the U.S. transplant registry for 170 pediatric patients (from 2003 to 2008) and 400 adult patients (from 1987 to 2008) with WD, which showed graft and patient survival for pediatric and adult patients with WD at 1 and 5 years was 90.1% and 89% for children and 88% and 86% for adults, respectively.22 Even better outcomes were noted for 1-year survival for transplantation for chronic liver failure versus ALF for WD adults. Overall, liver transplant is life-saving and appropriate therapy for patients with acute and chronic liver failure due to WD, and yields excellent longterm survival for adult and pediatric patients. Conflicts of interest The author declares no conflicts of interest.
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Liver transplantation for Wilson’s disease
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