Indian Journal of Pathology and Microbiology

ORIGINAL ARTICLE
Year
: 2012  |  Volume : 55  |  Issue : 3  |  Page : 365--369

Analysis of clinical and biochemical spectrum of Wilson Disease patients


Sumreena Mansoor, Abdul Khaliq Naveed, Asifa Majeed 
 Department of Biochemistry and Molecular Biology, College of Medical Sciences National University of Sciences and Technology, Rawalpindi, Pakistan

Correspondence Address:
Sumreena Mansoor
Section of Biochemistry, Department of Basic Health Sciences, Shifa College of Medicine Pitras Bukhari Road, Sector H-8/4, Islamabad, 44000
Pakistan

Abstract

Background and Aims: Wilson disease (WD) is autosomal recessive disorder of copper metabolism. Wilson disease patients usually suffer from hepatic or neuropsychiatric complications. The symptoms appear between ages five to 35 but it can vary from two years to 72 years. Materials and Methods : Study was carried out from June 2008 to November 2010. This study included nine families with eleven cases of WD to determine clinical presentation, diagnostic findings (including laboratory results) and liver histology. It included 11 patients who presented with hepatic manifestations and/or Neuropsychiatric manifestations and/or family history suggesting features of WD. Patients with hepatitis B and C and those with history of taking antipsychotic drugs were excluded from the study. Patient«SQ»s data was included in a well designed performa. Liver function test, serum ceruloplasmin, serum copper, 24 hour urinary copper, blood complete picture were analyzed. Quantitative data such as age, hemoglobin etc were expressed as mean with ± SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. Results: There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. The mean age of presentation was 8.7±3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and Kayser-Fleischer rings (KF rings) in 72% of patients. In severe WD patients, serum prothrombin activity was less than 50%, serum ceruloplasmin were low and serum copper levels were high than those in non-severe WD patients. High degree of suspicion leads to early treatment with good outcome. Conclusions: The WD is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome.



How to cite this article:
Mansoor S, Naveed AK, Majeed A. Analysis of clinical and biochemical spectrum of Wilson Disease patients.Indian J Pathol Microbiol 2012;55:365-369


How to cite this URL:
Mansoor S, Naveed AK, Majeed A. Analysis of clinical and biochemical spectrum of Wilson Disease patients. Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Jul 23 ];55:365-369
Available from: http://www.ijpmonline.org/text.asp?2012/55/3/365/101746


Full Text

 Introduction



Wilson's disease (WD) is an autosomal recessive disease characterized by accumulation of intracellular copper in the liver and central nervous system. [1] It most commonly affects children and young adults. Patients present with a spectrum of clinical symptoms depending upon the most severely affected organ (e.g., acute liver failure, cirrhosis, neurologic or psychiatric syndromes). [2],[ 3] It runs an invariably fatal course if not adequately treated by chelating agents. [4] Increased understanding, better diagnostic facilities leading to earlier identification even in the pre-symptomatic phase, obvious distinction from mimicking conditions, therapeutic approaches owing to effective cure, and an on the whole reduction in the morbidity and mortality are some of the anticipated changes in future. [5] The clinical manifestations of WD are extremely diverse. In the first decade of life patients presents more frequently with hepatic manifestations. After the age of 20 years 75% of patients present with neurological manifestations and 25% with both hepatic and neuropsychiatric manifestations. [6]

The Leipzig WD diagnostic scoring system is useful in supporting an initial diagnosis of WD. [7],[ 8] This scoring system, proposed by the European association for the study of the liver (EASL) [Table 1], is in use prior to confirmatory mutation analysis. {Table 1}

The existing treatments for WD are chelating agents (D-penicillamine, trientine and tetrathiomolybdate) and zinc salts. On the whole, the approach for treatment depends on whether the patient is asymptomatic or symptomatic, and also on the chief manifestation of the symptoms (neurological and hepatic). [9] Patients with acute liver failure or with decompensated cirrhosis that is unresponsive to chelation treatment should be treated with liver transplantation. WD is the known etiology in less than 5% of acute liver failure patients. [10] Acute liver failure due to WD is fatal without liver transplantation and therefore a reliable method for early diagnosis is indispensable. The Acute Liver Failure Study Group (ALFSG) reported that the results of certain laboratory tests including a serum alkaline phosphatase (ALP) to total bilirubin (TB) ratio of less than four, and an aspartate aminotransferase (AST): ALT ratio of more than 2.2, provide rapid and accurate methods for the diagnosis of acute liver failure due to WD. [11] A prognostic index that could be applied at the time of diagnosis of acute liver failure due to WD may be helpful in predicting survival without liver transplantation. The King's College group accordingly proposed a Wilson Index based on total serum bilirubin, AST, prothrombin time (PT) international normalized ratio (INR), white blood cell count and serum albumin (Alb) [Table 2]. [12],[ 13] {Table 2}

They reported that all WD patients with a score of more than 11 died without transplantation, whereas all those with a score of less than 11 survived, indicating that the index is beneficial to those for whom a liver transplantation is indicated. We carried out analysis of eleven patients with WD from nine different families to determine clinical presentations, diagnostic findings (including laboratory results) and liver histology. The purpose of this study was to outline differences in the clinical and biochemical findings of various types of WD including severe WD.

 Materials and Methods



This study was approved by the ethical committee of college of medical sciences, national university of sciences and technology, pakistan where research was carried out. Patient's data was recorded in a well designed performa. There were five male and six female patients with the mean age 6.3 ±1.35 (hepatic manifestation), 15±5.6 (hepatic and neurological manifestation) and 19 years (neurological manifestation). Detailed family history was obtained along with pedigree pattern with emphasis on consanguinity.

Information regarding age, sex, mode of onset (hepatic, neurologic, psychiatric symptoms) was collected through a questionnaire and patients were classified as ''pure hepatic'', ''hepatoneurological'', ''neurologic'', ''pure psychiatric'' and ''pre symptomatic based on the mode of presentation''. [14]

Liver function test, serum ceruloplasmin, serum copper, 24 hr urinary copper, blood complete picture were analyzed. The patients were examined in ophthalmology department to detect the presence of KF ring. Hepatic changes, features of portal hypertension, gall stones, and polyps were examined in radiology department by an abdominal ultrasound.

The diagnosis of WD was based on the presence of liver disease and at least two of the following criteria: (i) a positive family history; (ii) low ceruloplasmin (<20 mg/dl); (iii) elevated liver copper (>250 μg/g dry weight) (iv) presence of KF rings; (v) elevated 24--h urinary copper (>100 μg/24h); and coomb's negative hemolytic anemia. These criteria were complemented with the use of the quantitative evaluation scale of the Leipzig WD scoring system: a score of four or more being highly probable for WD diagnosis [Table 1]. Each of these patients had a score of at least three according to a scoring system based on clinical and biochemical parameters. In patients of WD, other causes of liver disease namely autoimmune and cholestatic liver disease, viral hepatitis, a 1-antitrypsin deficiency and other metabolic liver disorders were excluded by appropriate investigations. Chronic liver disease was found in eleven WD patients, hemolytic anemia in ten patients, neurological symptoms in one patient, hepatic and neurological symptoms in two patients.

Severe WD is defined by a serum PT INR of serum prothrombin activity of less than 50%. The eleven WD patients were divided into two groups: one group comprising three non-severe WD patients and the other group containing eight severe WD patients.

 Results



There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. In patients the mean age of presentation was 8.7±3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and KF rings in 72% of patients. The WD diagnostic score was greater than three in all patients. Two (20%) were asymptomatic siblings of patients with WD. Two (20%) patients presented with fulminant hepatic failure. In four (40%) of the patients polyps or stones were detected in the gallbladder by abdominal ultrasonography. The ages of two of these four patients were only seven and 11 years. Liver biopsy for histological examination was performed in patients with hepatic and hepatoneurological type of WD patients and the specimens were evaluated for the presence of fibrosis and cirrhosis. At the time of diagnosis signs of chronic liver damage were present in all the patients, with fibrosis occurring in 70% and cirrhosis in 50% of patients. The patients diagnosed by family screening were asymptomatic at the time of diagnosis; however, their liver histology established chronic hepatitis. A WD prognostic score [Table 2] was used for identification of patients with fulminant WD who would not survive without liver transplantation (score >11). In this study, four patients had WD prognostic score of 12 and 14. All patients were treated with chelating agents (D-Penicillamine) and zinc salts. Three patients expired due to delayed and noncompliance of treatment. One patient with hepatic and neurological type of WD survived but deteriorated because of noncompliance of treatment [Table 3],[Table 4],[Table 5],[Table 6]. {Table 3}{Table 4}{Table 5}{Table 6}

Non-severe WD vis-à-vis severe WD

The patients were divided into two groups, one containing three non-severe WD patients and the other containing eight severe WD patients. Clinical and biochemical features and mutations of the patients in these two groups were compared. In non-severe cases one patient presented severe neurological symptom and two had both neurological as well as hepatic problems. Higher levels of serum AST were found in severe cases than in the non-severe. However, neither serum ALT nor serum ALP differed significantly between the two groups. The Child-Pugh score and its component factors (serum TB, Alb and PT activity) differed significantly between severe and non-severe. Further, patients with severe WD had lower serum ceruloplasmin and higher serum copper levels compared with the non-severe patients. Overall, patients with severe WD had a lower hemoglobin level. The details as given in [Table 7] below highlight the differences.{Table 7}

Statistical Analysis

All data was analyzed using SPSS version 17.0. Quantitative data such as age, hemoglobin etc were expressed as mean with ± SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. For comparison of severe vis-a-vis non-severe WD patient's independent t-test was used. A two-tailed P-value of less than 0.05 was considered significant.

 Discussion



Wilson disease is autosomal recessive disorder of copper metabolism. Most people have no known family history of the disease. [15] Initial symptoms may be non-specific and might not be easily recognized, resulting in considerable diagnostic delay and imprecise clinical data. [15] In our study, two patients presented severe hepatic symptoms but KF ring was not observed. Similarly, one patient had neurological type of WD but developed KF ring at the age of 20 years. The mean age of presentation was an 8.7±3.92 year (ranged 4-19 years) which is in concurrence with literature, which shows an age of onset at 11-13 years. [16],[ 17] 45% of patients were male. Similar observation of two-thirds being male was made by Dastur et al, [18] in a major Indian series, while 20 of 22 cases reported by Jha et al, [19] were male. There have been reports that hepatocellular carcinoma (HCC) is a complication of WD disease; however, none of our WD patients had HCC. [20],[21],[22] two of our patients had hepatic neurological and psychiatric symptoms and one had neuropsychiatric symptoms. The neurological manifestations of WD include rigidity, tremors, gait abnormalities and choreiform movements.

In terms of the WD diagnostic score, 100% of our patients were positive (10/10). American association for the study of liver disease guidelines was very useful in the diagnosis in our patients. [4] A serum ceruloplasmin concentration below 20 mg/dl was considered as one of the major diagnostic criteria. The serum ceruloplasmin level was less than 20 mg/dl in 72% patients (8 out of 11), whereas in 27% (3 out of 11) had serum ceruloplasmin level which was 20 mg/dl. Interestingly, our patients particularly the younger ones, had gallbladder stones or gallbladder polyps, which may have been caused by chronic cholestasis or hemolysis. Hemolytic anemia associated with acute liver failure is strongly suggestive of fulminant WD. [23],[ 24] Hemolytic anemia was present in all patients with fulminant WD. Most (70%) of our patients were classified as being in Child-Pugh class C based on the decreased PT% (<0.014) and an increased total bilirubin level.

According to the AASLD recommendations all our patients were prescribed chelating agent (D-penicillamine), after having being diagnosed. As a reference tool, the prognostic scoring system is useful for indicating of liver transplantation in patients with liver failure. Among our cases, four patients with acute liver failure had a WD prognostic score (a King's College score) of more than 11. In the present study, the levels of Urine copper were increased and serum ceruloplasmin was decreased in severe patients as well as in non-severe cases.

For early detection of Wilson disease we would suggest that in cases of patients with unexplained liver disease, clinicians should look for following: (i) low ceruloplasminemia; (ii) the presence of Kayser-Fleicher rings confirmed by an ophthalmologist; and (iii) high urinary copper concentration with or without the D-penicillamine load test. Furthermore, the presence of hemolytic anemia, high levels of serum ceruloplasmin and serum copper, Child-Pugh Class C and a prognostic score of more than 11 in WD patients are indicative of severe disease.

 Conclusion



The Wilson disease is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome.

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