Acute Deep Venous Thrombosis Unmasking Wilson Disease

Authors:
Marwan Saad, MD, PhD; Upamanyu Rampal, MD; FNU Jaydev, MD; and Jill Butler, MD
Seton Hall University School of Health and Medical Sciences, Trinitas Regional Medical Center, Elizabeth, New Jersey

Citation:
Saad M, Rampal U, Jaydev FNU, Butler J. Acute deep venous thrombosis unmasking Wilson disease. Consultant. 2016;56(9):856-857.

A 32-year-old man had received a diagnosis of type 2 diabetes mellitus 6 months before he presented with pain and swelling of his right lower extremity. A review of systems revealed a 3-month history of intention tremors, dysphagia, hypophonia, sialorrhea, and progressive micrographia. Of note, the patient’s second-degree relative has Wilson disease.

Physical examination. Physical examination findings included a tender and swollen right calf, advanced intention tremors, cogwheel rigidity in the upper extremities, and gait abnormalities. The man also reported having olfactory dysfunction. Slit-lamp examination failed to reveal Kayser-Fleischer rings.

Diagnostic testing. Significant laboratory test findings included an elevated D-dimer level of 4335 ng/mL, an elevated prothrombin time with an international normalized ratio of 1.8, hypoalbuminemia, and normal transaminase levels.

Doppler ultrasonography confirmed right popliteal acute deep venous thrombosis (DVT). Magnetic resonance imaging (MRI) of the brain showed cortical atrophy (Figure 1) and cerebellar atrophy (Figure 2). Abdominal MRI showed liver cirrhosis with mild splenomegaly and small esophageal varices.

Figure 1. MRI of the brain showing marked cortical atrophic changes (arrows).

Figure 2. MRI of the brain showing marked cerebellar atrophy (arrow).

The diagnosis of Wilson disease was established based on a low serum copper level of 60 µg/dL (reference range, 70-175 µg/dL), a low serum ceruloplasmin level of 15 mg/dL (reference range, 20-40 mg/dL), and a high 24-hour urine copper excretion of 211 µg (reference range, 10-40 µg/24 h).

Liver biopsy demonstrated macrovascular steatosis of less than 5%, grade 3 portal and periportal chronic inflammation, grade 1 to 2 lobular inflammation, and stage 2 portal fibrosis with intact architecture (Figure 3). The biopsy was negative for iron stain. Chemical quantification of copper in the liver biopsy sample was 219 µg/g dry weight, which is more than 5 times the reference value.

Figure 3. Liver biopsy result showing macrovascular steatosis of less than 5%, grade 3 portal and periportal chronic inflammation (arrow), grade 1-2 lobular inflammation, and stage 2 portal fibrosis with intact architecture.

Outcome of the case. Presumably, liver disease caused the the patient’s hypercoagulable state that led to DVT formation. His neurologic symptoms improved with chelation therapy, and anticoagulation prevented any further episodes of venous thromboemboli.

Discussion. Wilson disease, also known as hepatolenticular disease, is an autosomal recessive disorder of copper excretion with myriad hepatic and neuropsychiatric manifestations. It is caused by mutation of the ATPase copper-transporting beta gene (ATP7B), on the long arm of chromosome 13, which codes for a protein responsible for incorporating excess copper into ceruloplasmin in order for it to be excreted from the body. Initially, the accumulated copper is evenly distributed throughout the cytoplasm after binding with metallothionein. As the disease progresses, the capacity of metallothionein to bind all the copper is exceeded, leading to hepatocyte injury and the release of copper into the blood. Subsequently, copper accumulates in several organs, mainly the liver, brain, and corneas, progressing inevitably to hepatic and neurologic dysfunction.¹

Hepatic manifestations of Wilson disease range from asymptomatic biochemical abnormalities to acute or chronic hepatitis and cirrhosis. Neurologic manifestations include dysarthria, dystonia, tremors, and Parkinson-like manifestations.² Less often, Wilson disease presents with cerebellar manifestations. Our patient had signs of cerebellar involvement as well as Parkinsonian features.

This case highlights a unique initial presentation of Wilson disease in the form of unprovoked DVT secondary to the hypercoagulable state complicating chronic liver disease. Chronic liver disease is associated with a defect in the synthesis of thrombopoietin and other hemostatic proteins. Moreover, a failure to metabolize tissue plasminogen activator by a diseased liver in persons with Wilson disease leads to increased fibrinolytic activity, increasing the tendency to bleed. However, a decrease in the physiologic anticoagulants produced by the liver has been noted in Wilson disease; this may lead to an increased risk of thrombosis in chronic liver disease.³ DVT is a rising concern in patients with chronic liver disease, affecting up to 0.9% of this population.⁴

Although DVT has not been reported previously in the literature as a presentation of Wilson disease, the fictional medical television show House depicted a similar case.⁵

Traditionally considered as being “auto-anticoagulated,” patients with chronic liver disease secondary to Wilson disease can present with hypercoagulable complications in spite of their coagulopathic profile. In our unique case, a man’s atypical presentation of DVT unmasked underlying Wilson disease.

References:

1. Purchase R. The treatment of Wilson’s disease, a rare genetic disorder of copper metabolism. Sci Prog. 2013;96(pt 1):19-32.
2. Lorincz MT. Neurologic Wilson’s disease. Ann N Y Acad Sci. 2010;1184:173-187.
3. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014;370(9):847-859.
4. Saleh T, Matta F, Alali F, Stein PD. Venous thromboembolism with chronic liver disease. Am J Med. 2011;124(1):64-68.
5. The Socratic method. House. Season 1, episode 6. First aired: December 21, 2004.