Never forget aceruloplasminemia in case of highly suggestive Wilson's disease score

Authors

  • Marjon Kerkhof,

    1. Department of Gastroenterology and Hepatology, Albert Schweitzer hospital, Dordrecht, the Netherlands
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  • Pieter Honkoop

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Albert Schweitzer hospital, Dordrecht, the Netherlands
    • Address reprint requests to: Pieter Honkoop, M.D., Ph.D., Department of Gastroenterology and Hepatology, Albert Schweitzer Hospital, P.O. Box 444, 3300AK Dordrecht, the Netherlands. E-mail: p.honkoop@asz.nl; fax: +31 (0)78 6541544.

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  • Potential conflict of interest: Nothing to report.

Abbreviations
EASL

European Association for the Study of the Liver

KF

Kayser-Fleischer

MRI

magnetic resonance imaging

WD

Wilson's disease

A 49-year-old male presented with a 1-year history of combined bulbar and pseudobulbar dysarthria, involuntary movements, and gait instability. Laboratory evaluation showed a decreased serum ceruloplasmin of <0.06 g/L. Despite mild elevation of aspartate aminotransferase (54 E/L) and alanine aminotransferase (101 E/L), liver function (international normalized ratio, albumin, and bilirubin) was preserved. Magnetic resonance imaging (MRI) showed an abnormal attenuation of bilateral basal ganglia and cerebellar atrophy (Fig. 1). A brain computed tomography scan revealed hyperdensity of the basal ganglia and dentate nucleus. Because these findings were strongly suggestive of Wilson's disease (WD), our workup continued to focus on further establishing this diagnosis. The ophthalmologist did not see Kayser-Fleischer (KF) rings, and 24-hour urine collection demonstrated a 0.6-umol copper loss per day (normal, 0.0-1.2 umol/day). According to the WD scoring system in the European Association for the Study of the Liver (EASL) guidelines,[1] the diagnosis of WD was established (Table 1). To confirm this diagnosis and evaluate the degree of fibrosis, a liver biopsy was performed. However, copper staining on the liver biopsy specimen was negative. Determination of dry weight of copper was not available. Minor fibrosis and mild steatosis was noted without inflammation. In addition, extensive deposition of iron was noted, inconsistent with the diagnosis of WD (Fig. 2). Serum ferritin was elevated (2,908 ug/L) with a normal transferrin. The elevated ferritin in combination with the neurological symptoms, liver biopsy, MRI findings, and low ceruloplasmin was consistent with the diagnosis of aceruloplasminemia and less so with WD. At this point, a positive family history of aceruloplasminemia in the children of the patient's maternal aunt was revealed. Finally, analysis for the ATP7B gene revealed no mutation and therefore did not support the diagnosis of WD.

Table 1. WD Scoring System as Reported in EASL Guidelines, Including Scoring of Our Patient
Typical Clinical Symptoms and Signs ScoreScore of Our Patient
  1. Abbreviation: ULN, upper limit of normal.

  2. a

    If no quantitative liver copper available.

  3. b

    or typical abnormalities at brain MRI.

KF ringsPresent2 
 Absent00
    
Neurologic symptomsbSevere22
 Mild1 
 Absent0 
    
Serum ceruloplasminNormal (>0.2 g/L)0 
 0.1-0.2 g/L1 
 <0.1 g/L22
    
Coombs-negative hemolytic anemiaPresent1 
 Absent00
    
Liver copper (in the absence of cholestasis)>5× ULN (>4 μmol/g)2 
 0.8-4.0 μmol/g1 
 Normal (<0.8 μmol/g)−1 
 Rhodanine-positive granulesa10
    
Urinary copper (in the absence of acute hepatitis)Normal00
 1-2× ULN1 
 >2× ULN2 
 Normal, but >5× ULN after D-penicillamine2 
    
Mutation analysisOn both chromosomes detected4 
 On 1 chromosome detected1 
 No mutations detected00
    
 Total 4
    
 Total score  
 4 or moreDiagnosis established
 3Diagnosis possible, more tests needed
 2 or lessDiagnosis very unlikely
Figure 1.

Brain MRI (T2 weighted) showing a hypointense signal of the basal ganglia (A) and dentate nucleus (B).

Figure 2.

Liver biopsy shows no copper accumulation (rhodanine-staining negative) (A) and reveals an abundant iron deposition (B).

Aceruloplasminemia is an extremely rare (1:2,000,000) autosomal recessive disorder associated with low serum ceruloplasmin and neurological symptoms.[2] In WD, neurological symptoms develop as a result of copper accumulation and in aceruloplasminemia as a result of iron accumulation in the central nervous system.

In aceruloplasminemia, iron accumulation in brain and liver is the result of disturbances of iron metabolism because of loss-of-function mutations of the ceruloplasmin gene. These adults present with basal gangliar neurodegeneration (leading to dementia, dysarthria, and dystonia[3]), retinal degeneration, diabetes mellitus, near-absent circulating serum ceruloplasmin, and elevated serum ferritin. Liver biopsy reveals normal hepatic architecture with abundant iron deposition without copper accumulation.[4]

In WD, copper accumulation in brain and liver is the result of defective biliary excretion of copper.[5] Key features are liver disease, neuropsychiatric disturbances, and KF rings of the cornea. Dry weight of >250 μg/g of copper in a liver biopsy establishes the diagnosis, but normal values can be found because of inhomogeneous distribution of copper in the liver.[1] Because clinical symptoms vary and no single test is specific,[1] a WD scoring system based on all available tests was developed,[6] with a good diagnostic accuracy[7] (Table 1). According to the EASL guideline, a score of ≥4 points establishes the diagnosis of WD.[1] This differs from the original scoring system,[6] which defines this score as “highly likely” for the diagnosis of WD, thus forcing the clinician to consider an alternative diagnosis. This is illustrated in our case with a score of 4 points (very low serum ceruloplasmin and severe neurological symptoms), who instead fits the diagnosis of aceruloplasminemia, rather than WD. The American Association for the Study of Liver Diseases guidelines emphasize more clearly that dry liver biopsy is needed to confirm the diagnosis.[8] Obviously, confirming the diagnosis is important because the treatment for the two diseases differs.

In conclusion, we present a case with aceruloplasminemia, which fulfilled the WD criteria as presented in the EASL guidelines. Therefore, we suggest to change the interpretation of a total score of 4 or more from “diagnosis established” to highly likely. Then, an alternative diagnosis, such as aceruloplasminemia, should be considered.

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