Rapid diagnosis of Wilson disease in acute liver failure: No more waiting for the ceruloplasmin level?
Authors: Alastair O'Brien, Roger Williams
Journal: Hepatology (2008)

The selection of patients for liver transplantation in acute liver failure (ALF) remains a significant challenge. The King's College Hospital and Clichy criteria have been extensively used, with both having an excellent positive predictive value but not nearly such an impressive negative predictive value.1, 2 In other words, cases not fulfilling criteria may still deteriorate and die when transplantation has been considered unnecessary. The King's College criteria have gained more widespread use due in part to the lack of availability of factor V measurements that are necessary for the Clichy criteria. Overall survival figures following transplantation for ALF are still not as high as for patients with chronic liver disease, which reflects the often poor clinical state of the patient with ALF with multiorgan failure at the time of transplant.3 Thus, it is not surprising that major efforts continue to be made to improve selection criteria so that transplantation can proceed earlier in the clinical course. The Model for End-Stage Liver Disease (MELD) score,4, 5 serum phosphate levels,6 APACHE (Acute Physiology and Chronic Health Evaluation) II7 score, and arterial blood lactate levels8 have all been the subject of studies in recent years; none have gained widespread use. Most recently, an enzyme-linked immunosorbent assay for actin-free Gc-globulin has been shown to provide the same prognostic information as the King's College Hospital criteria in a single measurement at admission.9 Mortality from ALF has been shown to be closely related to etiology;1 for Wilson disease (WD), the subject of this editorial, transplantation is currently recommended for all cases on the basis of an invariable mortality without transplantation.10 Thus, the earlier the diagnosis can be established in these cases and arrangements made for transplantation, the better the chances of a successful outcome. ALF, acute liver failure; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MELD, Model for End-Stage Liver Disease; WD, Wilson disease. The findings in this issue of HEPATOLOGY from Korman et al. (from the Pediatric and Adult Acute Liver Failure Study Groups, National Institutes of Health)11 are therefore of considerable interest because they demonstrate that there is no actual need to wait for specific biochemical tests of deranged copper metabolism, such as ceruloplasmin or copper, that are not often rapidly available. Previous studies that have attempted to define simple biochemical testing for the diagnosis of fulminant WD have been hampered by their small patient numbers due the rarity of this condition (overall prevalence 1:30,000). The first series of nine patients published in 1983 found higher serum, urine, and liver copper, less pronounced elevations in serum aminotransferase levels, higher bilirubin level, and lower hemoglobin level compared to five cases of idiopathic ALF.12 Serum copper was the most useful. Three years later, the unit at King's College Hospital published a series of 34 patients, which included pediatric patients and chronic cases, that used a scoring system based on serum bilirubin, aspartate aminotransferase (AST), and prolongation of the prothrombin time (Nazer score) which could predict mortality.13 Another series of six patients demonstrated that a ratio of alkaline phosphatase to total serum bilirubin of < 2 provided 100% sensitivity and specificity in identifying fulminant hepatic failure caused by Wilson disease from other types of fulminant hepatic failure.14 However, a subsequent study by us at King's College Hospital of 21 cases showed that serum bilirubin, alkaline phosphatase, and AST levels found in fulminant WD were significantly different from those found in other cases of fulminant liver failure, but that differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible.15 It should be noted that 15 of these patients were age 16 or under. In addition, the most recent series of seven adult cases found that the ratios of alkaline phosphatase to serum bilirubin or AST to alanine aminotransferase (ALT) failed to identify patients with ALF due to WD.16 The cohort of 16 patients in the study by Korman et al. derived from the National Institutes of Health–supported Acute Liver Failure Study Group registry demonstrated that by simply combining the ratio of serum alkaline phosphatase level to that of bilirubin (<4) sequentially to the ratio of serum AST to ALT (>2.2), sensitivity and specificity values approached 100%. Serum ceruloplasmin levels using either the oxidase method or by nephelometry showed marked variation, and serum copper was as elevated in ALF secondary to WD as it was in the comparison group of non-WD ALF. Kayser-Fleischer rings were tested for in only five patients and present in three; from other published series they are only detectable in 50% of patients with ALF.10 Splenomegaly combined with evidence of hemolysis has always alerted physicians to this diagnosis, but unfortunately no data on splenomegaly was available in this analysis. There was, however, a highly significant reduction in mean values of hemoglobin in patients with ALF secondary to WD compared to other causes, but also considerable overlap. Thus, although using hemoglobin as a screening test would provide good sensitivity (94%), the specificity was less impressive (74%). Consequently, in patients presenting with ALF, one should be able to make a confident diagnosis of WD based on tests readily available in laboratories which in turn means an earlier opportunity for listing for liver transplantation. The mortality in this series without transplant was 100% as was the case in previous studies referred to above.10 However, the series was made up of patients already admitted to a liver transplant center with a high median MELD score of 40, which was significantly greater than the median MELD score of 34 seen in patients with ALF who did not have WD admitted to these centers and cannot be considered as representing earlier stages of ALF from WD. Early establishment of the diagnosis of WD may allow the use of copper chelating agents, which the Clichy group has demonstrated to be both effective and may even obviate the need for transplant when penicillamine is administered in the early stages of ALF before the onset of encephalopathy.17 One also wonders whether the continuing development of liver support systems and the use of plasmaphereses or exchange transfusion by which it is possible to remove the harmful copper from the circulation and thereby ameliorate the extent or progression of the hepatic necrosis, may have a place in treatment if the diagnosis can be made at an earlier stage. Indeed, two patients at University College Hospital have been treated with albumin dialysis as a bridge to successful liver transplantation.18 Even though the crucial decision to perform transplant should not await the results of disturbed copper metabolism—ceruloplasmin, serum, and urinary copper—these tests are needed for confirmation of diagnosis and as a basis for screening family members. Homozygote or compound heterozygote family members may have evidence of the early stages of disease that will respond to treatment with chelating agents. However, it should be noted that approximately 20% of heterozygotes have a low ceruloplasmin level and so more detailed evaluation by haplotype or mutational analysis may be required for identification.10 The Korman study refers to adult cases only, and one should be cautious about its application to pediatric cases in which the clinical signs may be different, i.e., absence of encephalopathy. Indeed, a retrospective study of seven children demonstrated that an alkaline phosphatase-to-bilirubin ratio of <1 had an 86% sensitivity but only a 50% specificity in differentiating fulminant WD from other cases of ALF.19 A further interesting observation from this cohort is that patients with ALF secondary to treatment failure or noncompliance with penicillamine were biochemically indistinguishable from those with de novo ALF. This adds weight to the argument that fulminant WD is in fact an acute-on-chronic liver injury.20 Although the sensitivity and specificity values of 100% in the study by Korman et al. for the simple screening test in cases of ALF suspected to be secondary to WD are extremely impressive, it is important to stress again that this cohort contains patients with a very high MELD score and thus advanced liver failure secondary to WD. Whether such screening tests apply in the early stages of the clinical course of ALF secondary to WD has not been established. The series of seven adults in the study by Eisenbach et al., which found the ratios of alkaline phosphatase to serum bilirubin or AST to ALT to be unhelpful, had a mean MELD score of 28.16 Interestingly four of these patients were treated with chelating agents and survived without transplantation. An excellent practice update on WD in HEPATOLOGY10 provides a comprehensive account of clinical patterns of disease as well as provides data on the value of the different biochemical tests, mutational analysis, and the standard blood tests for copper excretion. The guidelines also give very useful guidance to the practicing hepatologist as to which of the various treatment agents are effective and tolerated by patients, including the copper chelators D-penicillamine and trientine, zinc which blocks enteral absorption of copper, or ammonium tetrathiomolybdate which does both. 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