Diagnostic criteria for acute liver failure due to Wilson disease

AIM: To describe the diagnostic criteria for acute liver failure due to Wilson disease (WD), which is an uncommon cause of acute liver failure (ALF). METHODS: We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS: Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate aminotransferase (AST) to alanine aminotransferase (ALT), failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities (53 ± 43 vs 1982 ± 938, P < 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively), low choline esterase activity (1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009), high urine copper concentrations (93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001) and low hemoglobin (7.0 ± 2.2 vs 12.6 ± 1.8, P < 0.0001) in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION: In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slit- lamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.     

暴发性肝豆状核变性的诊断

暴发性肝豆状核变性（fulminant Wilson disease，FWD）是肝豆状核变性病（WD）的一种少见而严重的临床类型，临床表现与其他原因引起的暴发型肝衰竭类似，国内外鲜见从临床、病理和分子生物学多个水平追踪观察的报道。我们对2例典型FWD的临床、病理和基因突变特点进行了分析，以提高对WD的认知性和诊断水平。     

暴发性肝衰竭型肝豆状核变性

暴发性肝衰竭型WD是肝豆状核变性中极为严重的类型,其主要的发病机理是由于体内铜负荷过重致细胞变性坏死,临床表现为乏力、纳差、恶心、黄疸进行性加深,可并发急性溶血、肝性脑病、出血倾向、原发性腹膜炎、肾功能衰竭等.此文就其发病机理、临床表现、实验室检查、诊断和治疗情况作一综述.     

Liver transplantation for Wilson disease

The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options mayinclude hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD.     

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 protein-bound toxins

BACKGROUND: Acute liver failure may be the first manifestation of Wilson disease. If copper elimination fails, liver transplantation is the only remaining therapeutic option. Albumin dialysis, a new method for the removal of protein-bound toxins, was performed in a patient with fulminant Wilson disease. METHODS: An 18-year-old man with Wilson disease presented with hyperacute liver failure, hepatic encephalopathy III, oligo-anuric renal failure, haemolytic anaemia, rhabdomyolysis, pancreatitis and thrombocytopenia. He was treated with albumin dialysis using a 44 g/l albumin-containing dialysate and a slow dialysate flow rate (1-2 l/h). The other details of the technique used are similar to routine continuous veno-venous haemodiafiltration. RESULTS: One hundred and five milligrams of copper were removed by albumin dialysis within the first six treatments, resulting in normalisation of blood-copper levels. Successful treatment of the multiorgan failure was achieved. Hepatic encephalopathy improved within 2 days. The patient initially refused liver transplantation. Therefore 35 additional albumin dialysis treatments were performed. Forty-three grams of bilirubin (an indicator of detoxified substances in the liver) and 196 mg of copper were removed. Multiorgan failure, in particular hepatic encephalopathy, did not recur during 59 days of treatment. Eventually, the patient agreed to liver transplantation and that was successful. CONCLUSION: Albumin dialysis is a new method for the effective treatment of fulminant Wilson disease, resulting in the removal of protein-bound toxins copper and bilirubin. It may serve as a new treatment option in hyperacute liver failure of other origin, acting as an extracorporeal detoxifier.     

76例药物性肝病的临床特点分析

目的通过对药物性肝病的病因、临床特点及预后等分析,加深对药物性肝病的认识,为预防和早期治疗该病提供参考。方法采用回顾分析的方法对我院76例药物性肝病的住院患者进行研究。结果引起药物性肝病最主要的药物为中药制剂、抗结核药、抗生素、化疗药物、解热镇痛药及抗甲状腺功能亢进药物;一般在用药后1~4周内起病;临床主要表现以肝细胞型最为常见;早期发现后积极治疗多数预后良好;疗程3周至数月不等。结论药物性肝病尤其要注意中药制剂导致的肝病,主要以肝细胞型最为常见;早期发现、及时停用肝损害药物是治疗的前提;绝大部分药物性肝病预后良好,少数病例可发展为重症肝炎或肝硬化。     

Dietary supplement implicated in fulminant hepatic failure in a well-controlled Wilson disease patient

We encountered a patient with previously well-controlled Wilson disease who experienced fulminant hepatic failure with hemolytic anemia, possibly caused by the dietary supplement Health Proportion^® (Jubilant Co., Ltd., Ehime, Japan). A 21-year-old woman was admitted to our hospital with marked liver dysfunction and severe hemolytic anemia. Free serum copper level was elevated at 101 μg/dl, and urinary copper excretion was extremely increased (25,600 μg/day). Plasma exchange and continuous hemodiafiltration were performed to remove serum copper and to treat the hemolytic anemia. However, liver function did not improve, and she underwent liver transplantation on 28th day after admission. Copper and iron contents in the resected liver were high at 851.9 μg and 551.7 μg/dry liver weight (g), respectively, despite the patient having regularly taken d-penicillamine since diagnosis and having a well-controlled copper level 1 year before her admission. Two months before admission, the patient had taken a dietary supplement made from soybeans for 1 month. This supplement was labeled as containing large amounts of copper and iron, and we assume that this caused fulminant hepatic failure with hemolytic crisis in this patient. It is important to be mindful of the micronutrient content of dietary supplements, especially for metabolic disorder patients.     

原位肝移植治疗暴发性肝衰竭型肝豆状核变性1例报道并文献复习

肝豆状核变性(Wilson’s disease,WD)是一种常染色体隐性遗传导致的铜代谢障碍性疾病,其中暴发性肝衰竭是WD的一种罕见类型,其病情进展迅速,具有高误诊率和高死亡率,早期诊断和积极治疗可挽救患者生命。     

Zinc monotherapy for young patients with oligosymptomatic Wilson disease: A single center,retrospective study

Background and aimsFew studies have focused on the treatment failure of zinc monotherapy for oligosymptomatic Wilson disease (WD) patients. Therefore, we aimed to evaluate the long-term ef?cacy of zinc monotherapy in oligosymptomatic patients and to analyze the possible factors that may influence the outcome of this treatment.MethodsWe retrospectively reviewed the medical records of oligosymptomatic WD patients who received zinc monotherapy from the time of diagnosis. Then, the characteristics of patients who were treated with zinc monotherapy successfully and those who experienced treatment failure were investigated.ResultsForty oligosymptomatic WD patients were identified that have received zinc monotherapy as initial treatment, with a median age of 3.83 years at the time of diagnosis. 36 (90%) patients had abnormal alanine transaminase/aspartate transaminase levels at baseline. None of the patients became symptomatic during zinc monotherapy. 28 (70%, Group 1) patients were treated with zinc monotherapy successfully for a median period of 2.4 years. In Group 1, serum aminotransferase levels significantly decreased 6 and 12 months after zinc therapy compared to the baseline levels (P < 0.05). 12 (30%, Group 2) patients experienced treatment failure with zinc monotherapy due to uncontrolled serum liver enzyme levels, and d-penicillamine was combined. The baseline 24-hour urine copper levels before treatment were significantly higher in Group 2 compared to that in Group 1 (182.5 vs 90.92 μg /day, P = 0.018). Comparing the age at onset; ceruloplasmin, serum copper, ALT, and AST levels; and proportions of abdominal ultrasonography abnormality at baseline between Group 1 and 2 revealed no statistically significant differences.ConclusionsWe found that high initial 24 -h urinary copper levels may lead to treatment failure of zinc monotherapy in oligosymptomatic WD patients. It might be reasonable to follow up liver function tests more closely during zinc monotherapy and to begin combination treatment with chelators early in patients with high level of 24 -h urinary copper.     

The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease

Background It has recently been demonstrated that the Wilson disease (WD) protein directly interacts with the human homolog of the MURR1 protein in vitro and in vivo, and that this interaction is specific for the copper transporter. The aim of the present study was to clarify the role of MURR1 in the pathogenesis of WD as well as in other WD-like disorders of hepatic copper metabolism of unknown origin. Methods Using the single-strand conformation polymorphism (SSCP) method followed by sequencing, we analyzed the 5′ untranslated region (UTR) and three exons of the MURR1 gene in three groups of patients: 19 wd patients in whom no mutations were detected in the ATP7B gene, 53 wd patients in whom only one mutation in the ATP7B gene was found, and 34 patients in whom clinical and laboratory data suggested a WD-like disorder of hepatic copper metabolism of unknown origin. Results We  detected in these patients six rare nucleotide substitutions, namely one splice-site consensus sequence and one missense and four silent nucleotide substitutions. All substitutions except one were found in the heterozygous state. No difference in the frequencies of the various substitutions was observed between patients and controls. Conclusions These data suggest that the MURR1 gene and its protein product are unlikely to play a primary role in the pathogenesis of Wilson disease. More extensive studies with larger numbers of clinically homogeneous patients should be carried out to establish whether nucleotide alterations in the MURR1 gene may have a role in causing WD or WD-like disorders or act as modifying factors in the phenotype variability in WD.     

肝衰竭合并侵袭性真菌病的诊断策略

肝衰竭患者发生侵袭性真菌病(IFD)的危险性增加,致死率增加,早期诊断、及时治疗是改善预后的关键。笔者梳理了肝衰竭合并IFD的流行情况及危险因素、肝衰竭患者的早期识别、肝衰竭合并IFD的诊断、中医对肝衰竭合并真菌感染的认识等内容。肝衰竭患者凝血机制差,获取病理确诊较为困难,详细分析患者的危险因素、早期识别临床特征、及时进行血液/体液微生物学检测是早期诊断的重要策略。     

肝豆状核变性基因表达产物的初步研究

目的 对肝豆状核变性（WD）基因编码产物WD蛋白进行检测,探讨WD的发病机制,方法 应用Western-blot蛋白印迹技术对诊断为WD的患才进行WD蛋白的研究。结果 发现患者WD在肝内表达缺失或者含量改变。结论 WD患者可能同时存在有WD基因exon8和exon5的突变,直接检测WD基因产物为进一步研究WD的病理机制奠定了基础。     

Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting

BACKGROUND:

Wilson disease (WD) is a rare disorder of copper metabolism.

OBJECTIVE:

To describe the authors’ clinical experience with a cohort of 48 adult patients followed in an ambulatory setting.

METHODS:

A retrospective chart review of patients with a diagnosis of WD was performed.

RESULTS:

Fifty-nine charts were identified and 11 were excluded on further review. At diagnosis, 14 patients were asymptomatic, with 13 hepatic, 15 neurological and six mixed hepatic/neurological presentations. Ceruloplasmin levels were low (<0.20 g/L) in 94%, and 24 h urinary copper levels high (>0.60 μmol/L) in 95% of cases. D-penicillamine was the most common initial therapy (48%), with zinc the most common at review (65%). Overall, biopsy and ultrasound reports documented cirrhosis in 53%. Portal hypertension, defined as splenomegaly (>12.0 cm), reversed portal venous flow on ultrasound or varices/gastropathy on endoscopy was seen in 63%. At last review, 39% had elevated aspartate aminotransferase (>34 U/L) and/or alanine aminotransferase levels (>40 U/L). One death and one transplant occurred, while three patients had encephalopathy, two became jaundiced, two developed ascites and one experienced variceal bleed. Of 21 neurological presenting patients, 14 improved compared with baseline, with four making almost complete recovery. Eleven patients experienced documented episodes of neurological decline, including four with non-neurological presentation. Diagnostic magnetic resonance imaging showed basal ganglia (64%), brainstem (64%) abnormalities and atrophy (36%); follow-up showed basal ganglia lesions (50%) and atrophy (55%).

CONCLUSION:

WD is a diverse chronic disease with generally favourable outcomes for patients who respond to initial therapy, which can be managed predominantly in an ambulatory setting.     

Wilson disease： Identification of two novel mutations and clinical correlation in Eastern Chinese patients

AIM To study mutations in the P-type ATPase (ATP7B)gene responsible for Wilson disease (WD) in the Eastern Chinese population, and the possible correlation of specific mutations with clinical characteristics.METHODS Mutations of the ATP7B gene were sought by means of direct sequencing in 50 Eastern Chinese WD patients of Han ethnic origin.RESULTS Two novel mutations, Asp96Gly and Asp196Glu, were first identified. We also compared the characterization of mutations in ATP7B with the clinical findings, and a significant correlation with hepatic manifestations between patients carrying the Arg778Leu mutation and those without was found.CONCLUSION Gene sequencing analysis was shown to have a high detection rate and accuracy. It may become the first priority in screening of WD patients.     

Survival following the development of ascites and/or peripheral oedema in primary biliary cirrhosis: A staged prognostic model

Objective. Current prognostic models in primary biliary cirrhosis (PBC) have low precision, partly due to the restricted inclusion criteria of some cohorts used for modelling but also because of the prolonged natural course of the disease. It is hypothesized that better precision could be achieved with a staged model, using ascites or peripheral oedema as a new starting-point for prediction.Material and methods. The study was based on an established database of 289 consecutive patients, followed between 1977 and 1998. Stepwise Cox regression was used to construct a staged model based on 143 patients who first developed ascites (n=111) or peripheral oedema (n=32) at entry or during subsequent follow-up. The model was compared with published models using graphical methods and receiver operating characteristics (ROCs).Results. Mean time from clinical diagnosis of ascites or peripheral oedema to death was 3.1?years. The following variables had independent prognostic significance: log₁₀(bilirubin) (p<0.001), albumin (p<0.001), age (p<0.001) and history of encephalopathy (p<0.001). Goodness of fit showed that the survival probabilities predicted by the Ascites Stage Model fitted well with the observed data. The Ascites Stage Model (ROC 0.8324 (SE 0.0348)) was a better predictor of survival than the Mayo long-term model (ROC 0.7833 (SE 0.0397)), the Mayo Repeated Patient Visits Model (ROC 0.7779 (SE 0.0399)) and the Royal Free PBC Prognostic Model (ROC 0.7785 (SE 0.0396)).Conclusions. The Ascites Stage Model gives a better survival estimate for PBC patients once they have developed ascites or peripheral oedema compared with the current models, and demonstrates an advantage of staged models in diseases with a prolonged natural history.     

自身免疫性肝病的临床特点

目的:探讨自身免疫性肝病(ALD)的临床特征.方法:ALD患者91例,其中自身免疫性肝炎(AIH)68例,原发性胆汁性肝硬化(PBC)23例,另选同期住院的41例HBsAg阳性的慢性乙型肝炎肝硬化患者作为对照.分析所有患者的临床特点以及血液生化和血清免疫学检查结果.结果:AIH和PBC均以女性患者多见,发病年龄AIH为...     

2008年非病毒性肝病临床进展回顾

回顾2008年关于肝豆状核变性、非酒精性脂肪肝、自身免疫性肝炎、原发性胆汁性肝硬化及原发性硬化性胆管炎在诊断、治疗及检测等方面的研究进展。