Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease

Ferenci, Péter; Stremmel, Wolfgang; Członkowska, Anna; Szalay, Ferenç; Viveiros, André; Stättermayer, Albert Friedrich; Brůha, Radan; Houwen, Roderick H. J.; Pop, Tudor Lucian; Stauber, Rudolf; Gschwantler, Michael; Pfeiffenberger, Jan; Yurdaydın, Cihan; Aigner, Elmar; Steindl–Munda, Petra; Dienes, Hans Peter; Zoller, Heinz; Weiss, Karl Heinz

doi:10.1002/hep.30280

Cited by 146 publications

(191 citation statements)

References 46 publications

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“…In the Taiwan study, the male/female ratio was 1.75/1, suggesting a number of undiagnosed cases among female populations, because the male/female ratio is 1 in other cohorts. (23) Because most patients in Taiwan were diagnosed in neurological departments, (21) hepatologic cases in which female patients predominate could have been overlooked. Thus, the best estimate for Taiwan is 1:29,100, as reported for male patients in 2011.…”

Section: Larger Populationsmentioning

confidence: 99%

“…The x axis displays the frequency of the most common predicted "pathogenic" or "likely pathogenic" variants of ATP7B in the gnomAD database (https ://gnomad.broad insti tute.org/), according to Gao et al (43) The y axis displays the frequency of disease-causing mutations in 1,346 European patients with WD. (23) On the assumptions that the non-Finnish samples in the gnomAD database are a relevant background population for the European WD patient database, that there is Hardy-Weinberg equilibrium, and that there is 100% penetrance, all data points should be on a straight line. If one assumes that the penetrance of the R969Q variant is 100%, data should be on the line depicted in the graph.…”

Section: Clinical Studiesmentioning

confidence: 99%

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The Prevalence of Wilson’s Disease: An Update

et al. 2020

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Background and Aims In 1984, Scheinberg and Sternlieb estimated the prevalence of Wilson’s disease to be 1:30,000 based on the limited available data. This suggested a large number of overlooked cases with potentially fatal consequences. The “Scheinberg‐Sternlieb Estimate” is still widely used, although more recent clinical and genetic studies of higher quality are now available. In the present study, we included these data to update the prevalence estimate. Approach and Results A MEDLINE Ovid, Science Citation Index Expanded, and PubMed systematic search for all relevant studies on the prevalence of Wilson’s disease was conducted. In total, 59 studies (50 clinical and 9 population‐based genetic) were included in the final analysis. We identified 4 recent clinical studies based on nationwide databases of high quality, providing prevalence estimates from 1:29,000 to 1:40,000. Higher frequency populations do exist because of frequent first‐cousin marriages and/or a higher mutation frequency. When calculating prevalence from the incidence related to number of births, estimates were 1:40,000‐1:50,000. Clinical screening studies, including examination for Kayser‐Fleischer rings or ceruloplasmin, did not improve these estimates because of insufficient sample size or selection biases. Population‐based genetic studies in US and UK populations were not in disagreement with the clinically based estimates. At the same time, studies from France and Sardinia suggested that the genetic prevalence may be 3‐4 times higher than the clinical disease prevalence. This raises the question whether the penetrance is indeed 100% as generally assumed. Conclusions The original prevalence estimate from 1984 of 1:30,000‐1:50,000 still appears valid, at least for the United States, Europe, and Asia. In some population‐based studies, the genetic prevalence was 3‐4 times higher than clinically based estimates. The question of penetrance needs further evaluation.

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Section: Larger Populationsmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

The Prevalence of Wilson’s Disease: An Update

et al. 2020

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“…All identified mutations have been described previously and are considered disease-associated. In our own databank, 13 we have 16 patients with p.M645R; 14 with symptomatic WD; and two asymptomatic siblings identified by family screening. Both were asymptomatic and had no evidence of liver disease.…”

Section: Discussionmentioning

confidence: 99%

“…13 Environmental, epigenetic and other genetic factors than ATP7B seem to play a pivotal role in the clinical manifestation and course of patients with WD. 13 Environmental, epigenetic and other genetic factors than ATP7B seem to play a pivotal role in the clinical manifestation and course of patients with WD.…”

Section: Discussionmentioning

confidence: 99%

The dilemma to diagnose Wilson disease by genetic testing alone

Stättermayer

Entenmann

Gschwantler

et al. 2019

Eur J Clin Investigation

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Background Wilson disease (WD) is an autosomal recessive disorder of hepatic copper excretion. About sixty per cent of patients present with liver disease. WD is considered a fatal disease if undiagnosed and/or untreated but recent data indicate that disease penetrance may not be 100%. Materials and Methods All patients underwent liver biopsy as part of the diagnostic workup. Genetic testing for ATP7B was performed by Sanger sequencing. Results We report on a large family with multiple affected siblings. The first patient (male, 31 years) underwent orthotopic liver transplantation (OLT) because of fulminant WD. He was homozygous for p.G710A. One asymptomatic brother (37 years) had the same mutation. He is doing well on chelation therapy. Fifteen years later, a second‐degree sibling (female, 16 years) presented with fulminant WD and underwent OLT. She was compound heterozygote (p.G710A/p.G710S). Further family screening revealed a third mutation (p.V536A) in a female (21 years) and male (16 years) compound‐heterozygote sibling (p.G710A/p.V536A). In both, serum ceruloplasmin and 24‐hour urinary copper excretion were normal. Liver biopsy showed normal histology and a quantitative hepatic copper content within the normal range or only slightly elevated (19 and 75 μg/g dry weight, respectively). No decoppering treatment was initiated so far. Conclusion Genetic testing alone is not always sufficient to diagnose WD in asymptomatic patients, and human mutation databases should be used with caution. Even patients carrying two disease‐causing mutations do not necessarily have demonstrable alteration of copper metabolism. Asymptomatic siblings diagnosed by genetic screening require further testing before initiating treatment.

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“…The key features of WD are all forms of liver disease, neuropsychiatric disturbances, Kayser‐Fleischer rings and acute episodes of haemolysis that often associate with acute liver failure. The clinical presentation is highly variable and patients may become symptomatic at any age, and about half of the patients develop cirrhosis …”

Section: Introductionmentioning

confidence: 99%

Non‐invasive diagnosis of cirrhosis and long‐term disease monitoring by transient elastography in patients with Wilson disease

Paternostro

Pfeiffenberger

Ferenci

et al. 2020

Liver International

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Background & Aims The value of liver stiffness measurement (LSM) by transient elastography (TE) for non‐invasive fibrosis staging and disease monitoring has not been established in patients with Wilson disease (WD). Methods Liver stiffness measurement by TE and non‐invasive fibrosis scores (APRI, FIB‐4) were analysed from 188 WD patients with liver biopsy (LBX). Longitudinal LSM was performed in 128 (68.1%) patients. Results One hundred and eighty‐eight patients (mean age: 35 ± 14 years, 54.8% women; 27.1% with histological cirrhosis) were studied. Forty‐four[23.4%] patients were recently diagnosed with WD, while 144[76.6%] were previously diagnosed (>1 year between LBX and LSM). Overall, LSM (11.3 vs 6.1 kPa, P < .001), APRI (0.72 vs 0.38, P < .001) and FIB‐4 (1.54 vs 0.89, P < .001) were higher in cirrhotic than in non‐cirrhotic patients. This was even more pronounced in recently diagnosed patients (35.2 kPa vs 6.4 kPa, P < .001). Accuracy for diagnosing cirrhosis at an LSM cut‐off ≥9.9 kPa was better in recently diagnosed (PPV: 74%, NPV: 100%) vs previously diagnosed (PPV: 53%, NPV: 82%) patients. Recently diagnosed patients had higher Area Under the Curve (AUC) for APRI (0.79 vs 0.61) and FIB‐4 (0.84 vs 0.65) than previously diagnosed patients. At APRI <1.5 and FIB‐4 <3.25 cirrhosis was ruled out with a specificity of 93% and 95% respectively. During a median follow‐up of 46 (24‐66) months, only 5.9% (5/85) of non‐cirrhotic WD patients showed progression to cirrhotic LSM values, while 30.8% (4/13) of cirrhotic WD patients showed LSM suggestive of cirrhosis regression. Conclusion TE‐based LSM ≥9.9 kPa accurately identifies cirrhosis in WD patients. Next to TE‐LSM <9.9 kPa, APRI <1.5 and FIB‐4 <3.25 values assist to non‐invasively rule out cirrhosis. LSM remains stable in most non‐cirrhotic patients on WD therapy, while one‐third of cirrhotic patients present clinically relevant decreases in LSM.

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Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease

Cited by 146 publications

References 46 publications

The Prevalence of Wilson’s Disease: An Update

The Prevalence of Wilson’s Disease: An Update

The dilemma to diagnose Wilson disease by genetic testing alone

Non‐invasive diagnosis of cirrhosis and long‐term disease monitoring by transient elastography in patients with Wilson disease

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