Clinical Laboratory Strategies: November 13, 2008

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Screening for Wilson Disease
New Strategy May Save Time and Lives
By Deborah Levenson

Wilson disease—a genetic disorder marked by the liver’s inability to rid the blood of excess copper—is both extremely rare and difficult to diagnose. The disease often goes unrecognized until patients are hospitalized with acute liver failure, making quick diagnosis crucial so that patients can get liver transplants. In the U.S., reference labs do most testing for Wilson disease, so patients often have to wait up to a week for the diagnosis that allows them to get on transplant waiting lists. A recent paper proposes a screening methodology that uses common automated assays. This issue of Strategies examines its findings.

Wilson disease—a rare cause of chronic liver disorder—affects about one in 30,000 people in the U.S. and causes about 5% of acute liver failure cases worldwide. The culprit is a genetic mutation that results in a faulty copper-transporting ATP-ase that exports copper from liver cells and incorporates it into ceruloplasmin, a circulating protein involved in iron metabolism. In Wilson disease, accumulation of liver copper causes liver damage, and in some patients, acute liver failure. The prognosis for acute liver failure patients with the disease is imminent death, unless the patient gets an immediate liver transplant. Most hospital labs, however, aren’t equipped to run the two tests that diagnose Wilson disease—ceruloplasmin and serum copper—so patients may lose precious days waiting for results.

Now a recent paper proposes a screening strategy that could speed placement of Wilson’s patients on liver transplant waiting lists (Hepatology 2008; 1167-1174). A multicenter team of researchers led by Michael Schilsky of Yale University Medical Center has concluded that conventional Wilson disease testing with ceruloplasmin and serum copper levels are less sensitive and specific than a group of common laboratory tests. Combining ratios of serum alkaline phosphatase to total bilirubin and AST to ALT achieved a diagnostic sensitivity and specificity of 100% for Wilson disease.

From a Small Cohort, a New Strategy

To identify the best way to diagnose acute liver failure due to Wilson disease, the research team collected serum and data from 140 acute liver failure patients. Of this group, just 16 had newly diagnosed Wilson disease, 17 had known, chronic and treated Wilson disease, and 29 had other types of chronic liver disease. The team measured ceruloplasmin via both oxidase activity and nephelometry, and serum copper by atomic absorption spectroscopy, along with alkaline phosphatase, total bilirubin, ALT, and AST.

In patients with acute liver failure, serum ceruloplasmin levels of 20 mg/dL by the oxidase method had a diagnostic sensitivity of 21% and specificity of 84%. By nephelometry, those figures were 56% and 63%, respectively. Serum copper levels exceeded 200
mg/dL in all study subjects with Wilson disease, but patients without the condition also had elevated values. An alkaline phosphatase to total bilirubin ratio <4.0 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing Wilson disease. Meanwhile, an AST to ALT ratio of >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7. Combining the tests provided a diagnostic sensitivity and specificity of 100%.

The cohort of Wilson disease patients is “quite large,” relatively speaking, according to Schilsky, associate professor of medicine and medical director of the Adult Liver Transplant Program at the Yale-New Haven Transplantation Center. His study’s strength, relative to others pertaining to Wilson disease, is that it included a larger control population of liver failure patients and, for comparison, patients with Wilson disease with chronic presentations. Schilsky expects larger studies to validate his results.

Copper Over Ceruloplasmin

Schilsky’s findings are important because they show that serum copper levels may be more important than ceruloplasmin values. “Ordering ceruloplasmin in acute liver failure isn’t particularly useful for Wilson disease, unless the value is absolutely zero,” commented Schilsky.“It can’t be used to discriminate [between diseases].” But the tests involved in Schilsky’s screening strategy “are run in every hospital laboratory as a standard of care,” he said. “Clinicians can get results in minutes.”

A positive screening test accomplishes two things, according to an accompanying editorial by
Alastair O’Brien, MD and Roger Williams, MD of the University College London Medical School’s Institute of Hepatology. First, the result could allow earlier listing on liver transplant waiting lists. Second, the results give a go-ahead to treatment with the copper-chelating agents such as D-penicillamine or trientine or with other measures that acutely lower circulating copper, like plasmapheresis, exchange transfusion, or albumin dialysis. These treatments could make Wilson disease patients more viable transplant candidates, or perhaps prevent transplant in the future, according to the editorial.

Confirmatory Tests Still Needed

Positive results from Schilsky’s screening strategy still need diagnostic confirmation with a copper test and ophthalmologic screening for Kayser Fleisher rings, copper deposits in the cornea that are present in 50% of Wilson disease patients, he noted.

An expert in Wilson disease agreed with the call for confirmatory testing. Schilsky’s screening strategy doesn’t directly measure features of Wilson disease, explained Eve Roberts, MD, adjunct professor of Pediatrics, Medicine and Pharmacology at University of Toronto. It’s especially important to “clinch the diagnosis” for the patient’s family, she added. “This is an autosomal recessive condition. Siblings of a Wilson disease patient run a 1 in 4 risk of having the disease, and it can present as late as age 60 or 70.”

Keeping Wilson’s In Mind

For the average clinician who may see only one case of the disease in his or her career, Schilsky’s screening strategy is worth considering in some cases. Before it causes acute liver failure, Wilson disease’s neuropsychological aspects—including motor difficulty, muscle spasms, and difficulty speaking and swallowing—can mimic other disorders. “If you have a young patient with liver dysfunction and no Tylenol toxicity, you should include the strategy in their workup,” explained gastroenterologist Thomas Puetz, MD. “You should keep Wilson’s in mind. The diagnosis can allow a patient to live a normal life or get a life-saving transplant.” Puetz serves on the board of the Wilson Disease Association and is a general gastroenterologist at Aurora Advanced Healthcare in Mequon, Wisc.

Both Puetz and Roberts said they would order the tests in the screening strategy in their own practices, even though the paper’s results are based on such a small cohort. Puetz would order the tests when Wilson disease could be a differential diagnosis, while Roberts would test the screening strategy “because it looks so good on paper.”

However, translating the findings into practice with children and teens warrants caution, Roberts maintained. While Schilsky’s cohort included a handful of teens, they are subject to growth spurts that can make alkaline phosphatase levels rise. The paper also lacks specific data for these youth. “But this paper does show that tests labs run routinely can be very informative in Wilson disease, and that knowing the serum copper level may be more important than ceruloplasmin. Lab directors—and we in the Wilson disease field—should pay attention to the numbers reported in the paper,” Roberts emphasized.

Deborah Levenson is a freelance writer in College Park, Md.

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