Wilson Disease is a rare autosomal recessive disorder of impaired copper metabolism caused by mutations in the ATP7B gene, the gene that codes for the intracellular copper-transporter ATP7B. It causes serious copper poisoning.

    The genetic defect severely affects the body´s ability to regulate copper balance, resulting in life-threatening damage to the liver, the brain and other organs if left untreated.

Autosomal recessive means that both copies of the ATP7B gene (one copy from the mother and one copy from the father) must be defective in order for the disease to develop. To date, more than 500 different mutations in the ATP7B gene have been identified.

The mutations impair the function of the intracellular copper-transporter to variable degrees. Lack of sufficient ATP7B function causes impaired biliary copper excretion and impaired incorporation of copper into ceruloplasmin, which results in accumulation of copper inside the liver cells. The liver cells have buffer systems, existing of different proteins, to protect the cell from the copper’s toxic effects. However, when copper levels in the liver cells exceed the buffer capacity, the excessive amount of intracellular free copper triggers pro-oxidant processes leading to organ damage and, subsequently, dysfunction (e.g. liver function).1

 

Wilson Disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, the gene that codes for the intracellular copper-transporter ATP7B. Autosomal recessive means that both copies of the ATP7B gene (one copy from the mother and one copy from the father) must be defective in order for the disease to develop. To date, more than 500 different mutations in the ATP7B gene have been identified.

The mutations impair the function of the intracellular copper-transporter to variable degrees. Lack of sufficient ATP7B function causes impaired biliary copper excretion and impaired incorporation of copper into ceruloplasmin, which results in accumulation of copper inside the liver cells. The liver cells have buffer systems, existing of different proteins, to protect the cell from the copper’s toxic effects. However, when copper levels in the liver cells exceed the buffer capacity, the excessive amount of intracellular free copper triggers pro-oxidant processes leading to organ damage and, subsequently, dysfunction (e.g. liver function).1

 

 

Wilson Disease affects approximately one in every 30,000 people worldwide.

In the US the prevalence is approximately 10,000 patients. In the EU the prevalence is 15,000.1

 

 

 

Complications of Injecting Drug Use

  • Local problems—Abscess (Figures 240-2 
    Image not available.

    A 32-year-old woman with type 1 diabetes developed large abscesses all over her body secondary to injection of cocaine and heroin. Her back shows the large scars remaining after the healing of these abscesses. (Courtesy of ­Richard P. Usatine, MD.)

    and 240-3; Abscess), cellulitis, septic thrombophlebitis, local induration, necrotizing fasciitis, gas gangrene, pyomyositis, mycotic aneurysm, compartmental syndromes, and foreign bodies (e.g., broken needle parts) in local areas.2
    • IDUs are at higher risk of getting methicillin-resistant Staphylococcus aureus(MRSA) skin infections that the patient may think are spider bites (Figure 240-4).
    • Some IDUs give up trying to inject into their veins and put the cocaine directly into the skin. This causes local skin necrosis that produces round atrophic scars (Figure 240-5).
  • IDUs are at risk for contracting systemic infections, including HIV and hepatitis B or hepatitis C.
    • Injecting drug users are at risk of endocarditis, osteomyelitis (Figures 240-6and 240-7), and an abscess of the epidural region. These infections can lead to long hospitalizations for intravenous antibiotics. The endocarditis that occurs in IDUs involves the right-sided heart valves (see Chapter 50, Bacterial Endocarditis).2 They are also at risk of septic emboli to the lungs, group A β-hemolytic streptococcal septicemia, septic arthritis, and candidal and other fungal infections.

 

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A 28-year-old man is admitted to the intensive care unit with fulminant hepatic failure and hemolysis. On further questioning, his family reports that he has been diagnosed with depression for 5 years and had a prior episode of acute hepatitis 2 years ago that resolved. At that time, his aspartate aminotransferase peaked at 1200 U/L and alanine aminotransferase peaked at 1900 U/L. He had only mild jaundice, with a total bilirubin of 7.2 g/dL. No cause of the hepatitis was found despite a workup that included viral and autoimmune causes. His liver function returned to normal. He is taking an antidepressant and occasional ibuprofen, but no other medications. Physical examination is notable for ascites and altered mental status with dystonia. Abdominal CT scan shows no biliary obstruction but a cirrhotic liver. Which of the following findings would be most likely to confirm the underlying diagnosis?



A

24-Hour urine level of iron



B

Brain MRI showing damage to the basal ganglia



C

Genotype for HFE mutation



D

Schistocytes on peripheral blood smear



E

Slit-lamp ocular examination showing Kayser-Fleischer rings



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The correct answer is E. You answered C.



Explanation:

The answer is E. This patient presents with liver disease, hemolysis, and psychiatric illness, which suggests the presence of Wilson disease. Wilson disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, a copper-transporting ATP-ase. As a result of this mutation, patients store abnormally high levels of copper in their liver initially, but later, copper is stored in other organs such as the brain. Although liver dysfunction is a hallmark of the disease, it may have several presentations, such as acute hepatitis, cirrhosis, or hepatic decompensation, as in this patient. Hemolysis may complicate acute decompensation because of massive release of copper from the liver into the blood, leading to hemolysis. Accumulation of copper in the basal ganglia results in Parkinson-like syndromes. Up to 50% of patients with Wilson disease will have Kayser-Fleischer rings on ocular slit-lamp examination. These brownish rings surrounding the cornea are due to copper deposition within the cornea and are diagnostic when found. Twenty-four-hour urinary copper levels are universally elevated in this disease and are the primary diagnostic modality when Kayser-Fleischer rings are absent. Liver biopsy can also be used to confirm increased copper content. Although MRI will show basal ganglia damage, it is not specific for Wilson disease. HFE mutation is present in hemochromatosis, which this patient does not have. Urine iron levels are not indicated.



Therapy for Wilson disease is dependent on the degree of disease at the time of presentation. Patients with mild hepatitis may be treated with zinc, which blocks intestinal absorption of copper, results in a negative copper balance, and induces hepatic metallothionein synthesis, which sequesters additional toxic copper. Trientine serves as a copper chelator and is used for more severe liver dysfunction or neurologic or psychiatric disease. In acutely decompensated liver failure, zinc should not be administered for at least 1 hour following trientine because the zinc could be chelated instead of copper if administered simultaneously. Liver transplantation is appropriate for patients who have experienced treatment failed with initial therapy.

A 75-year-old triathlete complains of gradually worsening vision over the past year. It seems to be involving near and far vision. The patient has never required corrective lenses and has no significant medical history other than diet-controlled hypertension. He takes no regular medications. Physical examination is normal except for bilateral visual acuity of 20/100. There are no focal visual field defects and no redness of the eyes or eyelids. Which of the following is the most likely diagnosis?

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The correct answer is A. You answered A.

Age-related macular degeneration is a major cause of painless, gradual bilateral central visual loss. It occurs as nonexudative (dry) or exudative (wet) forms. Recent genetic data have shown an association with the alternative complement pathway gene for complement factor H. The mechanism link for that association is unknown. The nonexudative form is associated with retinal drusen that leads to retinal atrophy. Treatment with vitamin C, vitamin E, beta-carotene, and zinc may retard the visual loss. Exudative macular degeneration, which is less common, is caused by neovascular proliferation and leakage of choroidal blood vessels. Acute visual loss may occur because of bleeding. Exudative macular degeneration may be treated with intraocular injection of a vascular endothelial growth factor antagonist (bevacizumab or ranibizumab). Blepharitis is inflammation of the eyelids usually related to acne rosacea, seborrheic dermatitis, or staphylococcal infection. Diabetic retinopathy, now a leading cause of blindness in the United States, causes gradual bilateral visual loss in patients with long-standing diabetes. Retinal detachment is usually unilateral and causes visual loss and an afferent pupillary defect.

 

Mr. Jenson is a 40-year-old man with a congenital bicuspid aortic valve who you have been seeing for more than a decade. You obtain an echocardiogram every other year to follow the progression of his disease knowing that bicuspid valves often develop stenosis or regurgitation requiring replacement in middle age. Given his specific congenital abnormality, what other anatomic structure is important to follow on his biannual echocardiograms?

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The correct answer is A. You answered A.

The answer is A. (Chap. 282) Bicuspid aortic valve is among the most common of congenital heart cardiac abnormalities. Valvular function is often normal in early life and thus may escape detection. Due to abnormal flow dynamics through the bicuspid aortic valve, the valve leaflets can become rigid and fibrosed, leading to either stenosis or regurgitation. However, pathology in patients with bicuspid aortic valve is not limited to the valve alone. The ascending aorta is often dilated, misnamed “poststenotic” dilatation; this is due to histologic abnormalities of the aortic media and may result in aortic dissection. It is important to screen specifically for aortopathy because dissection is a common cause of sudden death in these patients.

 


 

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