Medical therapies for Wilson disease (WD), including the use of copper chelating agents and zinc salts, are most effective in patients without advanced liver disease such as decompensated cirrhosis or fulminant hepatic failure. In children facing said complications, liver transplantation may be the only effective therapeutic option (1–3). Efforts have been directed toward determining prognostic criteria to predict risk of death without transplant in patients with WD. In 1986, Nazer et al (4) devised a scoring system to predict the outcome for patients with hepatic decompensation in the setting of WD. More recently, the validity of the Nazar scoring system was reassessed retrospectively in a pediatric population treated by the Paediatric Liver Service at King's College Hospital (5). Following the analysis, Dhawan et al (5) put forth a new Wilson Index (WI) for predicting mortality without transplantation in WD. Criteria for the WI included the presenting laboratory values for total bilirubin, international normalized ratio (INR) for prothrombin time, aspartate aminotransferase (AST), white blood cell count (WBC), and albumin. Assigning a value ranging from 0 to 4 for each of these parameters permits calculation of a WI score of between 0 and 20. Patients with a WI score of ≥11 were predicted to need transplantation with a sensitivity and specificity of 93% and 97% and a positive predictive value and negative predictive value of 92% and 97%, respectively. In a prospective evaluation of the WI, all of the children who underwent transplantation had a WI score of ≥11.
Herein, we present a series of patients diagnosed with WD at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center between January 2005 and May 2009. The series is inclusive of all of the index cases of WD seen during that time frame. Siblings of these patients with WD, generally asymptomatic with few clinical abnormalities, have been excluded from the series. Clinical outcomes for some of the patients did not necessarily correlate with WI scoring at presentation, with a child scoring 10 going on to require liver transplantation, whereas another patient with a score of 13 recovered without need for an allograft. Additionally, a patient with a WI score of 8 has gone on to a prolonged and problematic treatment course, one that may beg us to question whether some children are better off receiving an organ sooner rather than later. These patients serve as a cautionary tale to pediatric specialists in their approach to the evaluation and assessment of children with WD, while urging us to push forward in continued evaluation of the best management options for WD.
PATIENTS AND METHODS
A retrospective chart review was undertaken to identify patients who received the diagnosis of WD. Clinical and demographic data were extracted by chart review, and histological materials were rereviewed by a single pathologist (R.J.). Mutational analyses for WD were not obtained for these patients and were not used for diagnosis. Patients with other causes of hepatic disease, including acute hepatitis A, chronic hepatitis B and C, α-1 antitrypsin deficiency, autoimmune liver disease, and other relevant metabolic conditions, were excluded. Acute liver failure (ALF) was defined as a clinical syndrome including coagulopathy (INR >2) with acute presentation of signs and symptoms of liver disease, with or without encephalopathy, and no history of previously known liver disease (6). This retrospective analysis was approved by the institutional review board of the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center.
A 17-year-old white girl presented with a 1-month history of lower extremity swelling, myalgias, weight gain, and jaundice, initially thought to be precipitated by the recent use of oral contraceptives. Initial laboratory testing (Table 1) was concerning for hyperbilirubinemia with low alkaline phosphatase, hypoalbuminemia, coagulopathy, and anemia (WI score 13). Physical examination revealed icterus, ascites, and 4+ pitting edema of the lower extremities. WD was diagnosed on the basis of a low ceruloplasmin level, elevated 24-hour urine copper, and Coombs-negative hemolytic anemia (Table 1). Her clinical presentation was consistent with ALF, although features of chronic liver disease were present. Her listing status during the first week of hospitalization fluctuated between 1A and a calculated model end-stage liver disease (MELD) score (23 at presentation) based upon her clinical status. Chelation therapy with trientene (500 mg twice daily) and zinc (50 mg elemental 3 times per day) was initiated within 48 hours of admission (immediately following the urine copper collection). She required plasmapheresis for 7 days and multiple packed red blood cell transfusions to treat her liver failure and hemolytic anemia. Two weeks after admission she was discharged from the hospital with a total bilirubin of 10 μmol/L and an INR of 1.8. She recovered without transplantation and is doing well with 5 years of follow-up care.
An 18-year-old white girl presented with elevated liver enzymes, identified as part of a follow-up to previously noted fatigue and anemia. She had elevated transaminases in addition to thrombocytopenia, progressive anemia, and coagulopathy (Table 1, WI score 7). WD was ultimately diagnosed on the basis of ceruloplasmin level, 24-hour urine, and hepatic copper determinations (Table 1). WD-associated ALF was diagnosed on the basis of her coagulopathy and Coombs-negative hemolytic anemia. In light of her highly suggestive presentation, she was started on trientene (500 mg twice daily) and zinc (50 mg elemental twice daily) at the time of hospital admission. She was evaluated for but not listed for liver transplantation (MELD score 16 at time of transplant evaluation) due to her rapid response to treatment. She was discharged on day 6 of her hospitalization with a stable hemoglobin, total bilirubin of 46 μmol/L, and an INR of 1.5. She has continued to do well for 4 years.
A 10-year-old white boy presented with fatigue, jaundice, and abdominal pain. Physical examination revealed hepatosplenomegaly and scleral icterus. He had hyperbilirubinemia, elevated transaminases, thrombocytopenia, and coagulopathy (Table 1). Studies and examination were consistent with decompensated cirrhosis; the diagnosis of WD was based upon a low ceruloplasmin, elevated 24-hour baseline urine copper level that increased with chelation, and excess hepatic copper via a transjugular biopsy (Table 1). His hepatic venous wedge pressure gradient was 11 mmHg. His WI score was 10, predictive of a response to medical therapy (Table 1). He was listed for transplant with his calculated pediatric end-stage liver disease score of 16. Chelation therapy with 500 mg of trientene twice daily and 50 mg of elemental zinc twice daily was initiated on hospital day 3 with a transient improvement in his clinical status. During the ensuing 10 weeks, he developed intractable ascites that was unresponsive to high-dose furosemide and spironolactone, with a clinical course necessitating hospitalizations for peritonitis and symptomatic hyponatremic ascites (sodium as low as 117). He underwent liver transplantation 4 months after his initial diagnosis, and has done well for more than 2 years. His explanted liver revealed features of well-established cirrhosis (Fig. 1A).
A 10-year-old white boy presented with abdominal pain and swelling, fatigue, and decreased appetite. Physical examination revealed ascites and splenomegaly; laboratory studies demonstrated thrombocytopenia, and elevated bilirubin and transaminases (WI score 11, a score indicative of the need for transplantation (5)). Ceruloplasmin level, presence of a Kaiser-Fleischer ring, and baseline and penicillamine-challenged 24-hour urine copper collection were highly suggestive of WD (Table 1), and the patient began chelation therapy with trientene (500 mg twice daily) and zinc (50 mg elemental twice daily) on day 2 of hospitalization. Subsequently, the patient spent more than 36 hours in a confused and uncoordinated/ataxic state following the administration of anesthetic for determination of hepatic venous pressure gradient (elevated at 20 mmHg) and an unsuccessful attempted transjugular liver biopsy. Encephalopathy was considered as a cause of his mental status change (along with the side effects of trientene or anesthesia), and the patient was monitored in the pediatric intensive care unit. As such, he was given status 1A priority for transplantation (7). Within 24 hours, an organ became available, but was refused by the family. Interestingly, his mental status and ataxia improved with a 3-day 50% reduction in his trientene dosing. His listing status was downgraded to his calculated pediatric end-stage liver disease score of 26. He had an initial response to chelation therapy with trientene, evidenced by improved bilirubin levels and transaminases. His ascites was also initially well controlled with diuretics. However, 2 months after his initial WD diagnosis, he developed peritonitis and—with the offer of a suitable deceased donor organ—liver transplantation was undertaken. His explanted liver also revealed well-established cirrhosis (Fig. 1B). He is doing well more than 2 years posttransplant.
A 16-year-old white boy presented with lower extremity edema and easy bruising. Physical examination revealed splenomegaly without hepatomegaly, ascites, and lower-extremity edema. Laboratory studies were consistent with decompensated cirrhosis without evidence of hemolytic anemia (Table 1; WI score 10). A diagnosis of WD was made on the basis of serum ceruloplasmin and baseline and penicillamine-challenged 24-hour urine copper collection (Table 1). Chelation therapy with trientine was initiated at half dosing (250 mg twice daily) for 3 days followed by full dosing (500 mg twice daily) and zinc sulfate therapy (50 mg elemental twice daily). His edema and ascites were managed with diuretics and prophylactic antibiotics. He was listed for liver transplantation with a MELD score of 18 with a diagnosis of decompensated cirrhosis secondary to WD. His ascites progressed significantly despite maximal diuretic therapy and sodium restriction. In 3 months he gained 30 kg. Aggressive diuretic therapy was ineffective in controlling his ascites and led to evidence of renal insufficiency (blood urea nitrogen 41 and creatinine of 1.3 mg/dL). Water immersion therapy was instituted in concert with intravenous albumin and diuretics and led to a remarkable clinical response with a reduction in clinically apparent ascites and the loss of 50 kg of presumed fluid weight (8,9). His most recent liver studies show significant but incomplete improvement in his liver function with persistent and profound hypersplenism (total bilirubin 2.7 mg/dL, direct bilirubin 0.3 mg/dL, albumin 3.8 g/dL, INR 1.44, alanine aminotransferase 40 IU/L, AST 49 IU/L, sodium 137 mEq/L, creatinine 0.8 mg/dL, white blood cell count 2.5 × 103/μL, platelet count 18 × 103/μL). He remains actively listed for transplantation with the plan to accept an organ should one become available, although his clinical improvement has led to a progressive reduction in his MELD score (maximal calculated MELD score 22, 3 months after presentation – 18 months later MELD score = 14).
A 13-year-old Asian girl without prior medical history presented with fatigue and jaundice. Laboratory studies at presentation were notable for hyperbilirubinemia with low alkaline phosphatase, coagulopathy, and anemia (Table 1). She had Kaiser-Fleischer rings, low ceruloplasmin, and elevated baseline and penicillamine-challenged 24-hour urine collections. Her WI score of 11 indicated that she could be a transplant candidate. On hospital day 2 she was started on a half dose of trientene (250 mg twice daily) and 50 mg of elemental zinc twice daily. Her trientene dose was increased to 500 mg twice daily on hospital day 5. Her INR rose slightly after admission to a level that would have increased her score to 12. In spite of this slight biochemical change, the patient improved rapidly after therapy was started. She was initially listed for liver transplantation (MELD 24), although consideration to proceed with transplantation was diminished in light of her rapid recovery. She was discharged from the hospital on day 8, with a total bilirubin of 53 μmol/L and an INR of 1.8. Eighteen months after presentation; she is doing well on continued chelation therapy and has been removed from the liver transplant waitlist.
Deciding whether a patient is a candidate for organ transplantation is a complex and by no means easy task. WD in particular holds an interesting, perhaps enviable (depending on your perspective), position in the realm of organ allocation. United Network for Organ Sharing guidelines (7) indicate that acute decompensated WD qualifies a pediatric or adult patient housed in a hospital's intensive care unit (ICU) for status 1A listing. However, acute decompensated WD in children is not a well-defined entity and is not necessarily the same thing as fulminant hepatic failure/acute liver failure. WD is a chronic disease. Most patients have cirrhosis at the time that they present with acute decompensated disease, and thus this really is an acute on chronic form of liver disease. The histologic findings in our patients clearly demonstrate the chronic nature of the disease. Thus, it can be difficult for clinicians to determine whether their patients should be listed status 1A when they present with severe hepatic dysfunction. Status 1A listing prioritizes individuals to the top of the liver transplant waitlist; thus, it markedly increases the likelihood of transplantation. Therefore, one needs to be relatively certain that liver transplantation is necessary when opting for this listing status.
We have noted a subset of our patients who did not conform to predicted outcomes, both for and against transplantation, based on WI scores calculated at presentation to our institution. Early initiation of chelation therapy and/or albumin dialysis has been suggested as a way to prevent the need for transplantation in WD, even fulminant WD (10–12). In the case of patient 1, a situation predicted to be dire was reversed with the early initiation of chelation therapy and plasmapharesis. Patient 3, however, presented in relatively stable condition with a WI score that did not predict transplantation, but clearly progressed to need transplantation 4 months later. In the case of patient 6, we see that laboratory values obtained within 12 hours of each other can change the WI score to one predictive of transplantation, in spite of a relatively benign clinical course. Thus, the “time of presentation” can make a difference in the WI; dynamic parameters that predict outcome are clearly needed. The current analysis is anecdotal in nature, and a prospective investigation of a larger cohort is needed to be adequately powered to fully assess the WI and to suggest alternative dynamic scoring systems.
Opting to defer status 1 listing has potentially significant consequences for a disease that has effective medical therapy that may improve but not completely reverse the underlying disease. An unfortunate situation has arisen with patient 5, who presented with decompensated cirrhosis but a low WI. Medical management has stabilized his disease and his listing parameters have slowly improved so that his transplant prioritization status has slowly diminished over time. Although he does not face the risks inherent in a major surgery and lifelong immunosuppression, he continues to require chronic diuretics and faces the ongoing risks associated with gastrointestinal varices, ascites, and the potential of malignancy (13). Ongoing medical care may reduce his chances of receiving a necessary liver transplant, but is unlikely to eliminate the need in its entirety. Hepatic insufficiency not responsive to 3 months of medical therapy is an indication for transplantation in WD (14), albeit an indication that lacks uniform criteria and does not receive prioritization from United Network for Organ Sharing. However, without prioritization on the wait list, patients who incompletely respond to medical therapy are left to face wait list mortality and the potential for continued decline both physically and neurologically.
Although WD is potentially treatable, acute presentations of decompensated disease in addition to classical acute liver failure are likely to force clinicians to recommend liver transplantation for patient survival. Our recent experience has shown that prognostic scoring systems, although useful, may not be entirely accurate. In particular, borderline cases are problematic. Aggressive utilization of status 1 prioritization is likely to result in unnecessary transplants and misallocation of a rare resource. Deferring status 1 prioritization may yield a clinical circumstance of incomplete response to medical therapy and preclude a lifesaving therapy. Continuing investigation of predictors of outcome in WD is necessary. New prioritization rules for patients who have clinical features of advanced liver disease that incompletely respond to medical therapy may need to be considered.
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