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Wilson disease or hepatolenticular degeneration is an autosomal recessive disorder characterized by impaired biliary copper excretion resulting in the deposition of copper in various tissues, including the cornea, liver, and brain. Hepatic involvement of Wilson disease can vary from asymptomaticity to a mild elevation of liver enzymes, hepatomegaly, fatty liver, acute hepatitis, liver failure, cirrhosis, or even hepatocellular carcinoma.1, 2
Acute decompensated Wilson disease presenting as fulminant hepatic failure can occasionally be the initial presentation of otherwise asymptomatic patients.3 Treatment with copper-chelating agents such as penicillamine, trientine, and tetrathiomolybdate or the use of absorption blocking agents such as zinc acetate4 at this stage is usually not successful, as there is inadequate time for these therapeutic agents to take action. The condition is highly fatal, and liver transplantation is the ultimate treatment. In fact, acute decompensated Wilson disease is listed as a status 1 indication for liver transplantation according to the United Network for Organ Sharing classification.5
The Molecular Adsorbents Recirculating System (MARS; Gambro AB, Stockholm, Sweden) is a form of modified dialysis using albumin solution as a dialysate. This cell-free blood purification system was developed by Mitzner and Stange in Rostock, Germany in 1993.6 The basis of MARS is the removal of albumin-bound toxin from blood through a specialized membrane into the albumin-rich dialysate, which is then recirculated through an activated charcoal chamber and an anion resin exchange chamber in which bilirubin and other toxins are adsorbed and the dialysate is regenerated online. A third renal replacement circuit in the form of conventional hemodialysis or continuous venovenous hemofiltration is also coupled to the system to maintain electrolyte, acid-base, and fluid balance. Toxins removable by MARS other than bilirubin, as documented in the literature, include bile acids, ammonia, aromatic amino acids, mercaptans, short-chain fatty acid, manganese, and copper. The use of MARS in liver failure has been described in many reports, although most have been nonrandomized trials, and the benefit for survival is yet to be proven.7 Our center started a MARS program for liver failure patients in 2002, and our experience indicated that the treatment might be beneficial if started early in the course of liver failure.8
In this report, we present 2 cases of Wilson disease that were successfully bridged to liver transplantation with MARS therapy.
A 17-year-old young woman presented with fulminant hepatic failure, severe cholestasis, and intravascular hemolysis. She was transferred to us for consideration of liver transplantation. On arrival, her hemoglobin was 5.5 g/dL, and her reticulocyte count was 12.9%. Her liver biochemistry revealed a total bilirubin level of 63.1 mg/dL, a low alkaline phosphatase level of 20 IU/L, an alanine aminotransferase level of 7 U/L, an aspartate aminotransferase level of 124 U/L, and a prothrombin time of 20.9 seconds (reference range, 11.3-13.5 seconds). Her serum ceruloplasmin was less than 9 mg/dL (reference range, 14-37 mg/dL), and her serum copper was high at 286.6 μg/dL (reference range, 63.7-114.6 μg/dL). Her renal function was mildly abnormal with blood urea nitrogen at 46.5 mg/dL and serum creatinine at 1.24 mg/dL. Her glucose-6-phosphate dehydrogenase status was normal, a direct Coomb's test was negative, and tests for a panel of hepatitis viruses were all negative. Ultrasonography of the abdomen revealed a normal size liver with splenomegaly. There was also a small amount of ascites. An ophthalmologist confirmed the presence of Kayser-Fleischer rings in her corneas. A clinical diagnosis of Wilson disease was made. Penicillamine was started at 500 mg/day, but the effect was not good because the patient was oliguric. She was also started on lactulose and vitamin K. Repeated red cell transfusions were needed for her hemolysis. Her condition deteriorated despite these treatments, and she lapsed into stage III hepatic encephalopathy. In view of her deteriorating course, MARS with continuous renal replacement therapy was initiated. Her condition stabilized after a total of three 6-hour treatments performed on days 6, 7, and 10 after admission. She regained consciousness, and her renal function improved, although her liver synthetic function remained impaired with a serum prothrombin time greater than 20 seconds (reference range, 11.3-13.4 seconds). With an improvement in urine output, penicillamine treatment was increased to 1.0 g/day. Her pretreatment serum copper level was 286.6 μg/dL, and it fell to 165.6 μg/dL upon completion of MARS. Copper levels in the albumin dialysate were measured during the first treatment. Samples taken proximally and distally to the hemodialyzer, distally to the charcoal column, and distally to the cholestyramine column showed levels of 89.2, 101.9, 95.5, and 82.8 μg/dL, respectively. Her changes in biochemistry during this period are shown in Fig. 1. The patient underwent orthotopic liver transplantation 1 week later with a graft from a deceased donor. The explanted liver weighed 1580 g. The serosal surface showed nodularity, and the parenchyma was soft to firm on sectioning. There were nodules surrounded by fibrous tissue, bile ductular proliferation, and patchy chronic inflammation. The hepatocytes within the nodules showed vacuolated cytoplasm and marked cholestasis. Special stains with orcein and copper-binding protein were positive. She made an uneventful recovery. The patient's last follow-up was 5 months after transplantation, and she remained well.
This case was a 22-year-old male student from China with a known history of Wilson disease. His liver function was in the Child-Pugh C category before the present episode, and he had already been listed for liver transplantation. He complained of repeated vomiting with abdominal pain and distension for a few days and was admitted to a regional hospital in Hong Kong. Physical examination revealed a distended abdomen with no local tenderness. The patient did not have a previous operation or intestinal obstruction, but he was on long-term lactulose as prophylaxis for hepatic encephalopathy. An abdominal X-ray showed dilated small and large bowels, but there was no free gas under the diaphragm. Computed tomography revealed dilated bowel loops with no identifiable transitional points. Colonoscopy revealed no abnormality, and a diagnosis of paralytic ileus was made. After colonoscopy, his paralytic ileus resolved, but the patient lapsed into hepatic encephalopathy and coma. There was no clear evidence of sepsis, but the patient was treated with broad-spectrum empirical antibiotics when he was first admitted, and his blood, respiratory, and urine cultures were all negative. Clostridium difficile cytotoxin and a tissue culture assay were also negative. He was transferred to us for consideration of liver transplantation. On arrival at the intensive care unit (ICU), he was intubated and mechanically ventilated. His liver function revealed a total bilirubin level of 4.44 mg/dL, an alkaline phosphatase level of 61 IU/L, an aspartate aminotransferase level of 36 IU/L, an alanine aminotransferase level of 65 IU/L, and a serum prothrombin time of 25.3 seconds. His renal function revealed a serum creatinine level of 0.75 mg/dL and a urea level of 10.36 mg/dL. His ammonia level on admission was 340.7 μg/dL. No one in his family was considered an appropriate candidate for living donor liver transplantation. In the face of his rapid deterioration and lack of other therapeutic options, we started MARS dialysis. After 1 session of treatment, the patient regained consciousness and was successfully extubated. We planned to keep him in the ICU for further MARS treatment, but the family decided to transfer him to China where he would have a better chance of obtaining liver transplantation. He was discharged against medical advice but was in a relatively stable condition. We maintained contact with the family as well as the transplant center in China and were notified later that he had successfully undergone cadaveric donor liver transplantation. He later returned to our hospital for follow-up and remained well. The biochemistry changes of the patient in the ICU are illustrated in Fig. 2.
Acute decompensated Wilson disease is considered one of the most urgent indications for liver transplantation according to the United Network for Organ Sharing criteria. The mortality rate of acute decompensated Wilson disease approaches 100% if transplantation cannot be performed in time. Acute decompensated Wilson disease is indistinguishable from other causes of fulminant hepatic failure, except that a large amount of copper is released from the necrotic hepatocytes. The acute increase in the copper load is believed to be a pathogenic factor, inducing severe Coomb's negative hemolytic anemia9 and renal failure.10 We hypothesized that reduction of the copper load by MARS may confer benefit in the management of acute decompensated Wilson disease. This hypothesis is supported by other investigators who have used extracorporeal treatments to remove excessive copper in acute decompensated Wilson disease. Manz et al.11 reported the use of MARS in an 18-year-old girl presenting with acute decompensated Wilson disease and hepatic encephalopathy. The patient's pretreatment serum-free copper level was very high at 1970 μg/L. She underwent 18 MARS sessions and 4 plasma exchanges, and a substantial amount of copper was removed. According to the authors, approximately two-thirds of the removed copper was eliminated by the albumin dialysate of the MARS system. The condition of the patient gradually improved, and she underwent liver transplantation 17 days after admission. Sen et al.12 reported 2 patients with Wilson disease who were successfully treated with MARS. Both patients failed to respond to standard medical therapy and were suffering renal failure and hepatic encephalopathy prior to the MARS treatments. Substantial amounts of copper were removed by MARS in both cases. The first patient underwent 46 hours of continuous MARS treatment, and her serum copper fell from 342 to 110.8 μg/dL upon completion. The second patient underwent 2 weeks of intensified MARS treatment, and her serum copper decreased from 222.9 to 82.8 μg/dL. Both patients were stabilized and subsequently underwent liver transplantation.
MARS is not the only treatment capable of removing copper. Kreymann et al.13 reported the use of single-pass albumin dialysis in the management of a Wilson disease patient, from whom a significant amount of copper was removed, and the patient was stabilized and eventually received liver transplantation. Plasmapheresis using fresh frozen plasma as the replacement solution is another method that can induce a rapid negative copper balance in Wilson disease patients with hypercupremia. Clinical reports on this method have also indicated favorable results.14–16
On the basis of our findings, a copper assay performed at different sites within the albumin dialysate circuit did not show a concentration gradient across different components. A similar observation was noted by Sen et al.,12 who commented that the copper concentration did not differ significantly whether it was proximal or distal to the hemodialyzer, distal to the charcoal column, or distal to the resin column. Although the trans-column copper assay difference is small, a significant amount of copper may still be removed by these columns if there is a high flow rate along with a long treatment time. Alternatively, the albumin dialysate may form an extra pool for copper redistribution. At present, the mechanism of copper removal by MARS cannot be distinguished between these 2 possibilities, given the limited information available.
MARS is a rather safe procedure, and no mortality in our center was directly attributed to the use of this treatment. The only risk observed is the reduction of the platelet count. This is usually not of concern in patients with normal platelet levels from the beginning, but in patients with cirrhosis complicated by splenomegaly and in patients with severe sepsis, close monitoring is necessary. In the 2 currently reported patients, the platelet count was reduced after MARS treatment, but in both cases, a platelet transfusion was not necessary.
From our experience, we see the benefit of MARS mainly in reversing hepatic encephalopathy and lengthening the bridging time to transplant. In the first case, MARS helped to stabilize the acute episode, hence allowing her to undergo transplantation with a more favorable physical condition. The treatment also gained her more time, thereby significantly increasing her probability of obtaining a deceased donor liver. In patients with only a short history of presentation, stabilizing patients with MARS will allow a more thorough assessment to determine their eligibility for liver transplantation, particularly if there is a concern of preexisting neuropsychiatric involvement that could hinder the outcome.17–19
In our second patient, we believe that the main benefit of MARS was improvement of the patient's hepatic encephalopathy. Given that only 1 treatment was performed, the amount of copper removed would not have been significant. We “attempted” MARS in this case in the hope of clearing off the hepatotoxin load and restoring the balance of the internal milieu, although it might well have been the dialysis component of MARS that removed the ammonia and made him better or even a spontaneous recovery. Nevertheless, the treatment provided him time and stability so that he could be transferred to another center for transplantation.
There is no evidence that MARS improves survival or obviates the need for transplantation, and we do not support the indiscriminate use of this treatment in all patients with acute decompensated Wilson disease. We do believe that if the treatment is to be implemented, it should be started early in the course of illness, and we should not wait till the patient becomes too ill. Essentially, we see the treatment as a means of preventing deterioration rather than salvaging devastation. We believe that because the downhill course of acute decompensated Wilson disease can be very rapid, the opportunity cost of waiting is at least as high as, if not greater than, the risk of using this novel treatment. Given the infrequency of this condition, it might not be at all possible to conduct a powerful enough randomized controlled trial to determine the impact of MARS on the survival of liver failure patients. The paucity of evidence should not, however, hinder us from considering this option when standard treatment fails. Indeed, the challenge for us is to refine its utility and determine what subgroup of patients would respond to MARS and at what stage of liver failure should MARS be initiated.