Wilson disease 肝豆状核变性 EASL 2012

EASL Clinical Practice Guidelines: Wilson’s disease European Association for the Study of the Liver⇑ Summary This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers in the diagnosis and management of patients with Wilson’s disease. The goal is to describe a number of generally accepted approaches for diagno- sis, prevention, and treatment of Wilson’s disease. Recommenda- tions are based on a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases using entries from 1966 to 2011. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system used in other EASL CPGs was used and set against the somewhat different grading system used in the AASLD guidelines (Table 1A and B). Unfortunately, there is not a single randomized controlled trial conducted in Wilson’s dis- ease which has an optimal design. Thus, it is impossible to assign a high or even a moderate quality of evidence to any of the ques- tions dealt with in these guidelines. The evaluation is mostly based on large case series which have been reported within the last decades. � 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction Normal dietary consumption and absorption of copper exceed the metabolic need, and homeostasis of this element is main- tained exclusively by the biliary excretion of copper. Wilson’s dis- ease is an inherited disorder in which defective biliary excretion of copper leads to its accumulation, particularly in liver and brain [1,2]. Wilson’s disease is due to mutations of the ATP7B gene on chromosome 13 [3,4], which encodes a copper-transporting P-type ATPase (ATP7B) residing in the trans-Golgi network of hepatocytes. ATP7B is responsible for transporting copper from intracellular chaperone proteins into the secretory pathway, both for excretion into bile and for incorporation into apo-ceruloplas- min for the synthesis of functional ceruloplasmin [3,4]. The development of Wilson’s disease is due to the accumulation of copper in affected tissues. Clinical presentation can vary widely, but the key features of Wilson’s disease are liver disease and cirrhosis, neuropsychiatric disturbances, Kayser–Fleischer rings in Desçemet’s membrane of the cornea, and acute episodes of hemolysis often in association with acute liver failure. Wilson’s disease is not just a disease of children and young adults, but may present at any age [5]. Wilson’s disease is a genetic disorder that is found worldwide. Wilson’s disease is recognized to be more common than previ- ously thought, with a gene frequency of 1 in 90–150 and an inci- dence (based on adults presenting with neurologic symptoms [6]) that may be as high as 1 in 30,000 [7]. More than 500 distinct mutations have been described in the Wilson gene, from which 380 have a confirmed role in the pathogenesis of the disease [8]. Clinical presentation The most common presentations are with liver disease or neuro- psychiatric disturbances. Asymptomatic patients are most often detected by family screening. Age at onset of symptoms Wilson’s disease may present symptomatically at any age, although the majority presents between ages 5 and 35. The youn- gest patient reported with cirrhosis due to Wilson’s disease was 3-years-old [9]. About 3% of patients present beyond the fourth decade, either with hepatic or neurologic disease [5]. The oldest patients diagnosed were in their eighth decade [10,11]. Physical signs The clinical hallmark of Wilson’s disease is the Kayser–Fleischer ring, which is present in 95% of patients with neurologic symptoms and somewhat over half of those without neurologic symptoms [12,13]. In children presenting with liver disease, Kayser–Fleischer rings are usually absent [14]. Kayser–Fleischer rings are caused by deposition of copper in Desçemet’s mem- brane of the cornea. A slit-lamp examination by an experienced observer is required to identify Kayser–Fleischer rings. They are not entirely specific for Wilson’s disease, since they may be found in patients with chronic cholestatic diseases including children with neonatal cholestasis. Other ophthalmologic changes are rare and include sunflower cataracts, which are caused by deposits of copper in the center of the lens. They can also be found by slit- lamp examination [15]. Neurologic signs are variable, most often tremor, ataxia, and dystonia. Signs of liver disease are nonspecific, but any liver Contributors: Chairman: Peter Ferenci. Clinical Practice Guidelines Members: Anna Czlonkowska, Wolfgang Stremmel, Roderick Houwen, William Rosenberg, Michael Schilsky. EASL Governing Board Representatives: Peter Jansen and Darius Morad- pour. Reviewer(s): Jonathan Gitlin. Journal of Hepatology 2012 vol. 56 j 671–685 Received 28 November 2011; accepted 28 November 2011 ⇑ Correspondence: EASL Office, 7 rue des Battoirs, CH 1205 Geneva, Switzerland. Tel.: +41 22 807 0360; fax: +41 22 328 0724. E-mail address: easloffice@easloffice.eu Clinical Practice Guidelines disease of unknown origin should be considered as Wilson’s dis- ease until proved otherwise. Diagnostic vigilance is important because Kayser–Fleischer rings may be absent in up to 50% of patients with Wilson’s disease affecting the liver [12]. Liver disease Any type of liver disease may be encountered in patients with Wilson’s disease. Clinically evident liver disease may precede neurologic manifestations by as much as 10 years and most patients with neurologic symptoms have some degree of liver disease at presentation. Presenting symptoms of liver disease can be highly variable, ranging from asymptomatic, with only biochemical abnormalities, to overt cirrhosis with all its compli- cations. Wilson’s disease may also present as acute hepatic failure sometimes associated with Coombs-negative hemolytic anemia and acute renal failure. Patients diagnosed with Wilson’s disease who have a history of jaundice may have previously experienced an episode of hemolysis. Clinical symptoms are summarized in Table 2. Acute liver failure due to Wilson’s disease (former: ‘‘fulminant Wilson’s disease’’) Wilson’s disease enters into the differential diagnosis of any young patient presenting with acute hepatitis. Its clinical presen- tation may be indistinguishable from that of acute viral hepatitis, with jaundice and abdominal discomfort. In some patients symptoms resolve spontaneously, but once the diagnosis is made, lifelong treatment is necessary. On the other hand, rapid deterio- ration can occur with acute liver failure. Wilson’s disease accounts for 6–12% of all patients with acute liver failure who are referred for emergency transplantation [16,17]. Although cirrhosis is already present in most cases, the clinical presentation is acute and progresses rapidly to hepatic and renal failure and, when untreated, carries an almost 95% mortality. Acute liver failure due to Wilson’s disease occurs pre- dominantly in young females (female:male ratio 4:1) [18]. An acute presentation with rapid deterioration may also occur in patients who were previously treated but stopped their medica- tions [16]. Suspicion for acute Wilson’s disease should be partic- ularly high in patients with deep jaundice, low haemoglobin, low cholinesterase [17], only mildly increased transaminases, and low alkaline phosphatase. Chronic hepatitis and cirrhosis Many patients present with signs of chronic liver disease and evi- dence of cirrhosis, either compensated or decompensated. Patients may present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension. The presentation may be indistinguishable from other forms of chronic active hep- atitis, with symptoms including jaundice, malaise, and vague abdominal complaints. Hemolysis Coombs-negative haemolytic anemia may be the only initial symptom of Wilson’s disease. However, marked hemolysis is commonly associated with severe liver disease. Decay of liver cells may result in the release of large amounts of stored copper, which further aggravates hemolysis. In one series, hemolysis was a presenting feature in 25 out of 220 cases (12%); in these patients hemolysis occurred either as a single acute episode or Table 1. (A) GRADE system as used in EASL Clinical Practice Guidelines [159]. (B) System of Recommendations as used in AASLD Practice Guidelines [130]. Grade Evidence I Randomized controlled trials II-1 Controlled trials without randomization II-2 Cohort or case-control analytic studies II-3 Multiple time series, dramatic uncontrolled experiments III Opinions of respected authorities, descriptive epidemiology Evidence Description High quality Further research is very unlikely to change our confidence in the estimated effect A Moderate quality Further research is likely to have an important impact on our confidence in important impact on our confidence the estimate effect and may change the estimate B Low quality Further research is likely to have an in the estimate effect and is likely to change the estimate. Any change of estimate is uncertain Factors influencing the strength of C Recommendation Strong recommendation included the quality of evidence, presumed patient-important outcomes and costs 1 Weak Variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher costs or resource consumption 2 DescriptionClassification Class I Conditions for which there is evidence and/or general agreement that a given procedure or Conditions for which there is conflicting evidence ness/efficacy of a procedure or treatment treatment is beneficial, useful, and effective Class II and/or a divergence of opinion about the useful- Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy Class IIb evidence/opinion Usefulness/efficacy is less well established by Class III Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful. Level of evidence Description Level A Data derived from multiple randomized clinical trials or meta-analyses Level B Data derived from a single randomized trial, or nonrandomized studies Level C Only consensus opinion of experts, case studies, or standard of care A B Clinical Practice Guidelines 672 Journal of Hepatology 2012 vol. 56 j 671–685 recurrently or was low-grade and chronic [18]. In a series of 283 Japanese patients with Wilson’s disease, only three presented with acute hemolysis alone [19]. One quarter of the patients pre- senting with jaundice also had hemolysis. Acute liver disease and hemolysis as a presenting symptom can occur during delivery, mimicking HELLP syndrome [20]. Low-grade hemolysis may be associated with Wilson’s disease even when liver disease is not clinically evident. Some patients presenting with neurologic symptoms report that they have experienced transient episodes of jaundice previously, probably due to hemolysis [21]. On the other hand, rapid deterioration can occur with acute liver failure. Neurologic disease Wilson’s disease can manifest with an impressive spectrum of neurological, behavioral or psychiatric disorders, which may be its first clinical manifestation, appearing simultaneously with hepatic signs, or some years later. Neurological presentation can be extremely subtle, and inter- mitted for many years, but may also develop very rapidly, leading within a few months to complete disability. The neurological abnormalities can be classified as: (1) Akinetic-rigid syndrome similar to Parkinson’s disease; (2) Pseudosclerosis dominated by tremor; (3) Ataxia; and (4)Dystonic syndrome. Inmany cases, neu- rological signs are very difficult to classify as patients can have more than one abnormality, each with different levels of severity. The characteristic tremor is a coarse, irregular proximal trem- ulousness with a ‘‘wing beating’’ appearance. Dystonia can be focal, segmental or very severe, involving all parts of the body, leading to severe contractures. Very common motor impairments involve the cranial region, and manifest clinically as dysarthria (can be cerebellar or extrapyramidal leading to aphonia), drooling or oropharyngeal dystonia. Facial grimacing, open jaw, running saliva, and lip retraction are characteristic manifestations. Speech changes and drooling are often early neurologic symptoms. A tre- mor-rigidity syndrome (‘‘juvenile Parkinsonism’’) should raise suspicion of Wilson’s disease [22–24]. Because of an increasing difficulty in controlling movement or progressive dystonia, patients become bedridden and unable to care for themselves. Ultimately, the patient becomes severely dis- abled, usually alert, but unable to talk. In patients presenting with advanced liver disease, neurologic symptoms can be mis- taken for signs of hepatic encephalopathy. Psychiatric symptoms Behavioral and psychiatric symptoms are common and some of them may precede neurologic or hepatic signs and symptoms. About one-third of patients initially present with psychiatric abnormalities. In children with Wilson’s disease, declining school performance, personality changes, impulsiveness, labile mood, sexual exhibitionism, and inappropriate behavior are observed [24,25]. The initial symptoms are frequently misdiagnosed as behavioral problems associated with puberty. In older persons, psychotic features resembling paranoia, schizophrenia or depres- sion can be observed but behavioral changes are also common. Severe cognitive deterioration is observed in patients with advanced neurological disease, but in general, cognitive function is not markedly impaired [26]. A delay in diagnosing Wilson’s disease in patients with neuro- psychiatric presentations is frequent and was in one case as long as 12 years [27]. Patients presenting with neuropsychiatric symp- toms may have concurrent symptomatic liver disease, but in most patients liver disease can only be detected by laboratory evaluation, imaging studies of the liver or by liver histology. About half of the patients have advanced fibrosis or frank cirrho- sis. On the other hand, signs of liver disease may be even com- pletely absent at biopsy [28]. Other clinical manifestations Less common presentations include gigantism, lunulae, renal abnormalities including aminoaciduria and nephrolithiasis, hypercalciuria and nephrocalcinosis [29,30], cardiomyopathy [31], myopathy [32], chondrocalcinosis and osteoarthritis [33], hypoparathyroidism [34], pancreatitis [35], infertility or repeated miscarriages [36,37]. Prognosis UntreatedWilson’s disease is universally fatal, with most patients dying from liver disease and a minority from complications of Table 2. Clinical symptoms in Wilson’s disease patients presenting with liver disease. Author, Country, [Ref.] Walshe, UK, [157] Stremmel et al., Germany, [39] Schilsky et al., USA, [142] Scott et al., UK, [158] Ferenci, Austria, [44] N with liver disease (out of) 87 (>250) n.a. (51) 20* (320) 17* (45) 30 (64) Presenting symptom Jaundice, anorexia, vomiting (%) 44 14 15 41 37 Ascites/edema (%) 26 14 50 24 23 Variceal hemorrhage (%) 6 10 6 3 Hemorrhagic diathesis (%) 8 3 Hemolysis (%) 20 10 5 10 Hepatomegaly/splenomegaly (%) 16 49 15 29 17 Acute liver failure (%) n.a. n.a. n.a. n.a. 17 Asymptomatic$ (%) 18 5 23 ⁄Only cases with chronic active hepatitis. $Elevated ALT at routine testing, or accidental finding of cirrhosis or of Kayser–Fleischer rings. JOURNAL OF HEPATOLOGY Journal of Hepatology 2012 vol. 56 j 671–685 673 progressive neurologic disease. With chelation treatment and liver transplantation, prolonged survival has become the norm [27,38,39], although mortality has not been assessed prospec- tively. In general, prognosis for survival depends on the severity of liver and neurological disease and compliance with drug treat- ment. Liver function becomes normal over 1–2 years of treatment in most patients with no or compensated cirrhosis at presenta- tion, and then remains stable without progressive liver disease with adherence to treatment. At the other end of the spectrum, medical therapy is rarely effective in patients presenting with acute liver failure due to Wilson’s disease, mainly due to the time required to remove toxic copper from the organism. A prognostic index has been developed [40], and later modified by Dhawan et al. [41]. A score greater than 11 is always fatal without liver transplantation (Table 3). Patients presenting with neurologic symptoms fare better with respect to life expectancy, especially if liver disease is limited. However, neurologic symptoms appear to be only partly reversible with treatment and may even worsen following initiation of treatment. In patients undergoing orthotopic liver transplantation, sur- vival may be slightly reduced early on, but appears normal (for transplant population) thereafter [42]. Differential diagnosis Acute hepatitis with Wilson’s disease presents similarly to any other acute cases of hepatitis. Similarly, Wilson’s disease should enter into the diagnosis of all patients with chronic hepatitis and cirrhosis, as routine histologic changes are nonspecific. Wilson’s disease should be considered when acute hepatitis is accompanied by rapid onset of jaundice and hemolytic anemia. During adolescence, Wilson’s disease presenting with neurologic symptoms may be misdiagnosed as a behavioural problem because initial symptoms may be subtle. More advanced move- ment disorders in a young person should provoke consideration of Wilson’s disease, but the diagnosis may be overlooked where the presentation suggests a primarily psychological or psychiatric disorder. Diagnostic methods Typically, the combination of Kayser–Fleischer rings and a low serum ceruloplasmin (<0.1 g/L) level is sufficient to establish a diagnosis. When Kayser–Fleischer rings are not present (as is common in the hepatic manifestation of Wilson’s disease), ceru- loplasmin levels are not always reliable because they may be low for reasons other than Wilson’s disease (e.g. autoimmune hepati- tis, severe hepatic insufficiency in advanced liver disease, celiac disease, familial aceruloplasminemia) [43] or in heterozygous carriers of ATP7B mutations who do not show copper overload disease. On the other hand, inflammation in the liver or else- where may cause the ceruloplasmin concentration to rise to nor- mal levels, reflecting its identity as an acute phase protein. This is also true for treatment with estrogens. Thus, for many patients, a combination of tests reflecting disturbed copper metabolism may be needed. Not a single test is per se specific and, thus, a range of tests has to be applied (Table 4). A diagnostic score based on all available tests was proposed by the Working Party at the 8th International Meeting on Wilson’s disease, Leipzig 2001 [44] (Table 5). The Wilson’s disease scoring system provides a good diagnostic accuracy [45]. The diagnostic algorithm based on this score is shown in Fig. 1. Serum ceruloplasmin Ceruloplasmin is the major carrier of copper in the blood. It contains six copper atoms per molecule (holoceruloplasmin) but may be present just as the protein without the copper Table 3. Prognostic index in Wilson’s disease [40], modified by Dhawan et al. [41]. 1* 2* 3* 4* Serum bilirubin (µmol/L) 100-150 151-200 201-300 >300 AST (U/L) 100-150 151-300 301-400 >400 INR 1.3-1.6 1.7-1.9 2.0-2.4 >2.4 WBC [109/L] 6.8-8.3 8.4-10.3 10.4-15.3 >15.3 Albumin [g/L] 34-44 25-33 21-24 <21 ⁄= score points, upper limit of normal for AST = 20 IU/ml (at King’s College). A score P11 is associated with high probability of death without liver transplantation. Table 4. Routine tests for diagnosis of Wilson’s