A Prospective Study of the Clinical and Paraclinical Features of Wilson’s Disease in Iran
Reza Ansari MD, Reza Malekzadeh MD, Naser Ebrahimi-Daryani MD, Mohammad Javad Mirdamadi MD, Masoud Reza Sohrabi MD, Seyed Abdolreza Mortazavi-Tabatabaei MD
Digestive Diseases Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Objective- Wilson’s disease (WD) is
an autosomal recessive disease with different
manifestations. This study was aimed to assess the
clinical and paraclinical features of this disease in
different groups of patients in order to reach a
diagnostic algorithm.
Methods- Over a period of 10 years
(1990-1999), 84 patients with WD (mean age 27 years, 54
males) were studied in 6 referral university hospitals.
The presenting features were chronic liver disease in 37,
acute hepatitis in 9, hepatocerebral involvement in 10
and neurological disease in 11 patients. Further
seventeen patients were detected by a family screening
program. Diagnosis was based on clinical evaluation
including ophthalmologic and neurologic examinations,
positive laboratory investigations such as abnormal liver
function tests, serum ceruloplasmin level below 20 mg/dl,
and urinary copper excretion levels above 100
µg/day. The patients underwent treatment with a
daily dose of 1-2 g D-penicillamine.
Results- The most frequent abdominal
manifestations were splenomegaly (63%), jaundice (46%)
and hepatomegaly (46%). Decreased serum ceruloplasmin was
seen in 93.7% and urinary copper excertion was increased
in 68% of cases. Kayser-Fleischer rings were detected in
69% of the patients. In contrast to patients with
neurological disease, of whom 91% displayed the
Kayser-Fleischer rings, only 67.5% of patients with liver
disease showed such rings. Serum ceruloplasmin levels
were similar in the two groups and around 90% of the
patients had levels below 20 mg/dl . Mortality rate
related to WD was 10% over a period of 10 years.
Conclusion- According to our data, WD
should be considered in all young patients presenting
with acute or chronic liver disease and negative viral
markers. Decreased serum ceruloplasmin level was a good
screening test in all but the acute hepatitis group.
Keywords • Wilson’s disease • hepatolenticular degeneration
Introduction
Wilson’s disease is a hereditary autosomal recessive disease caused by excessive amounts of copper in the body. In western countries the prevalence of heterozygote and homozygote cases in the general population is one in 200 and one in 30,000 respectively.1 The abnormal gene lies on the long arm of chromosome 13 and results in decreased biliary excretion of copper by the hepatocytes.2 Recently, the gene related to this disease called the P-ATPase gene, which is 76% homologous to the gene for Menke’s disease, has been discovered and found to have about 60 mutations.3-6 With the deposition of copper in liver, brain, kidneys, heart and other organs, the clinical manifestations of the disease gradually appear7-9, amongst which the hepatic manifestations arise at an earlier age as compared to the neurological manifestations.10 The definitive diagnosis is made by measuring the level of serum ceruloplasmin, serum free copper, 24-hour urinary copper excretion, presence of the Kayser-Fleischer ring and determining the amount of copper in 1 g of dry liver specimen.11 Recently, DNA linkage analysis was accepted as one of the advanced diagnostic methods used in doubtful cases.12
Until 1940, most patients with this disease usually died before the age of 30. However, after the use of D-penicillamine by Walshe, which is a recipient and excretor of copper into the urine, treatment and prognosis of these patients have been revolutionized.13 Patients intolerant to D-penicillamine usually respond to other drugs such as trientine and terathiomolibdate zinc salts such as zinc acetate14-16 and zinc sulfate.17
Patients and Methods
Eighty-four patients with Wilson’s disease were studied at the Faghihi and Namazi Hospitals in Shiraz and the Imam Khomeini, Shariati, and Amir Al-Momeneen Hospitals in Tehran from 1990-1999. General practitioners primarily referred these patients to the above-mentioned hospitals because of unknown hepatic and neurologic abnormalities and suspicion of Wilson’s disease. Patients with unknown hepatic dysfunction were first fully investigated for viral markers, autoantibodies, serum iron and serum ferritin levels.
The diagnosis of the disease was based on clinical manifestations, positive history in the first degree relatives, exclusion of other apparent causes of the illness together with positive laboratory findings such as abnormal liver function tests, serum ceruloplasmin levels below 20 mg/dl, and urinary copper levels above 100 µg/day, presence of the Kayser-Fleischer ring (confirmed by an experienced ophthalmologist), liver biopsy, and a suitable response to therapy.
A number of patients did not undergo liver biopsy due to coagulative disorders or because the procedure seemed unlikely to assist in the diagnosis of disease.
Wilson’s disease was diagnosed on the basis of the following criteria: 1)Neurological manifes-tations of Wilson’s disease (confirmed by a neurologist) along with positive Kayser-Fleischer ring. 2)Positive Kayser-Fleischer ring, along with abnormal tests related to copper metabolism and the absence of evidence based on prolonged cholestasis. 3)Serum ceruloplasmin levels below 20 mg/dl along with more than 25 µg of copper obtained from 1 g of dry liver specimen. 4)Twenty-four hour urinary copper excretion less than 100 µg/day along with a positive family history of the disease or a suitable response to D-penicillamine therapy and the exclusion of other diseases.27
The patients underwent treatment with a daily dose of 1-2 g of D-penicillamine and were recommended not to use foods containing high levels of copper.
Results
Of the total number of patients under study, 54 (64.3%) were males and 30 (35.7%) females. The lowest and highest age for the appearance of this disease was 4 and 50 years respectively and it was most prevalent in the second decade of life. Sixty percent of the cases had a positive family history in their first degree relatives. In the majority of cases, the disease manifested with abdominal symptoms; 37 cases were diagnosed with chronic liver disease and 9 with acute hepatitis. Neurologic involvement was the sole presentation in 11 patients. Ten patients had both hepatic and neurologic involvement and 17 others were diagnosed after screening tests were performed. The clinical features at the time of diagnosis are summarized in table 1. The range of the follow-up period was 6 months to 9 years.
Fifty-six patients had abdominal manifestations out of which splenomegaly, ascites, hepatomegaly and jaundice were the predominant signs while vomiting was the least frequent; all of the above features being signs of hepatic cirrhosis.
Twenty-one patients displayed neurologic signs, the most prevalent being dysarthria, difficulty in writing, ataxic gait and tremor, and the least common being hypersalivation. Forty-five patients (53.6%) suffered from hematologic abnormalities in which thrombocytopenia was the most common finding, with anemia and leukopenia coming next in line.
The Kayser-Fleischer ring has a high diagnostic value in patients with Wilson’s disease and its presence is pathognomonic in persons not suffering from prolonged cholestasis. Fifty-eight (69.4%) patients were found to have positive Kayser-Fleischer ring on slit lamp examination. Also four patients complained of bone pain and arthralgia.
Table 2 shows the relation between diagnostic findings and manifestations of the disease. It is seen that on the whole, 91.7% of patients had serum ceruloplasmin levels below 20 mg/dl, 68% had urinary copper excretion levels above 100 µg/day and 51.2% had serum copper levels below 60 mg/dl. All the patients who presented with acute hepatitis had a positive family history of the disease. As shown in Table 2 only 91% of patients with pure neurologic signs showed the Kayser-Fleischer rings.
From a total of 21 liver biopsy specimens collected, the following pathologic results were obtained and reported: One normal case, one case of mononuclear fibrosis and infiltration, one case of periporal fibrosis, 13 cases of cirrhosis and 5 cases of chronic active hepatitis. Table 3
Results of D-penicillamine therapy
The patients were treated with a daily dose of 1-2 g of D-penicillamine until complete control of the disease, after which the dose was gradually tapered. The following results were obtained: The size of the Kayser-Fleischer ring diminished in 10 patients, 7 cases showed decreased hepatic enzyme levels, 4 cases had improved state of consciousness and 17 others showed generalized improvement. Hand tremor disappeared in 2 cases and in 8 cases there was a decrease in the size of the liver and the spleen.
In spite of treatment, the clinical condition deteriorated in 8 patients and critical states emerged. Unfortunately, 8 fatal cases were seen amongst the patients. These were mainly due to drug cessation, late diagnosis, and prolonged illness (more than 5 years from the time of diagnosis). Of the patients having neurological or hepatocerebral signs, 3 cases showed no changes in disease progression.
The major adverse effects of D-pencillamine treatment were reported as, skin rash in 3 cases, gastritis and gastrointestinal intolerance in one patient, one case of Steven Johnson’s syndrome, 2 cases of proteinuria and 2 cases of thrombocytopenia. In these cases the drug was substituted with zinc sulfate.
Discussion
The above prospective study shows the extent of the clinical manifestations of this hereditary metabolic disease, which often or usually presents with non-specific signs and symptoms. Abdominal distention, splenomegaly, hepatomegaly, jaundice, dysarthria, muscle stiffness, tremor, ataxia and thrombocytopenia put forward the diagnosis of Wilson’s disease.8
Although this disease is not sex-linked genetically, its prevalence was higher in boys than girls. This is probably related to the social conditions favoring the follow-up of the disease in boys. The earliest age at which the disease appeared was one year lower than world statistics.19 In this study a four-year old child with signs of hepatic involvement in the form of chronic hepatitis, low serum ceruloplasmin, Kayser-Fleischer rings and a positive family history, was diagnosed as a case of Wilson’s disease and brought under control with the use of therapeutics. In relation to the clinical features, the most common mode of appearance of the disease was uncompensated cirrhosis, which is indicative of delayed diagnosis in Iran. None of the hepatic manifestations were in the form of fulminant hepatic failure, which is probably due to the fact that the state usually goes undiagnosed.20 The onset of disease in the form of hepatic involvement, had a higher percentage in comparison to world statistics, probably due to a bias caused by selecting patients among referees to the gastroenterology wards. The neurologic signs were not common before puberty and mostly appeared thereafter.21 In this study, the age of the onset of neurologic signs was at 5 years, which again reflects the rapid rate of pathological copper deposition in the tissues among the Iranian patients.
Normally the Kayser-Fleischer ring in the absence of prolonged cholestasis is pathognomonic of Wilson’s disease.22 According to world statistics, the Kayser-Fleischer ring is positive in 70% of cases and in the rest it may not be visible due to being in the primary stages of evolution.23
In this study, the Kayser-Fleischer ring was reported to be present in 69% (58 patients) of the cases which corresponds to the statistics presented worldwide. Ophthalmic examination was negative in 9% of patients with pure neurological manifestations, which is at variance to the current belief.24 Although, a few similar instances have been reported25 but it is possible that faulty diagnosis has shaded the situation.
Most of the studies have shown normal blood ceruloplasmin levels in only 5% of patients.26 Similarly, in this investigation 8.3% of the patients had normal levels. The 24-hour urinary copper excretion is of prime importance in the diagnosis of Wilson’s disease but care must be taken about false positive cases (e.g. urinary contamination with copper during collection of the specimen and increase in urinary copper level in patients with extensive hepatocellular necrosis).
A number of patients presented atypically and did not show the above findings such as positive Kayser-Fleischer rings, serum ceruloplasmin levels below 20 mg/dl nor did they have typical neurological signs. The diagnosis in this group was based on ruling out the other causes of liver disease while having at least two of the following findings18: 1)Increased 24-hour urinary copper level. 2)Positive family history of the Wilson’s disease. 3)Considerable response to D-penicillamine.
Recent studies show variations in the age of appearance of Wilson’s disease, time of onset, and intensity of hepatic and neurological manifestations in relation to various P-ATPase mutations. Multicentered investigations in Europe for example, show that in H15 1070 Gln mutations, the onset of neurological manifestations is delayed whereas the liver remains normal or only slightly involved.19,27 Other mutations can be accompanied by serious liver disease in lower ages.
These findings may explain the appearance of the disease before the age of 5, intensity of liver involvement and onset of neurologic signs at lower ages in Iran.28
In a 6-month to 10-year follow-up, the mortality was around 10%, which is higher as compared to present data. This is probably due to later diagnosis, severity of hepatic lesions and restricted access to liver transplantation in Iran. Throughout this study, another hereditary metabolic disease i.e. primary hemochromatosis was also investigated. On the whole, only 3 patients were diagnosed with this disease, which indicates that the gene relevant to this disease is probably rare in Iran, despite its abundance in the West. Wilson’s disease is common in Iran, and necessary investigations for this disease must be conducted in all attendants from childhood to the middle ages not showing positive viral markers.
References