Wilson-Conovalov disease - Diagnosis

The Kayser-Fleischer ring is easily detected by routine examination (70%) or slit lamp examination (97%). The specificity of this sign for hepatolenticular degeneration is greater than 99%.

The most accurate laboratory test (in the absence of cholestatic liver disease, which can also lead to copper accumulation) is measuring the copper content in a liver biopsy. In untreated patients, this indicator should be above 200 μg per 1 g of dry weight. Normally, this indicator does not exceed 50 μg per 1 g of dry weight.

Measuring daily urinary copper excretion is a simple test that usually differentiates unaffected individuals from patients with hepatolenticular degeneration. Normally, daily copper excretion is 20-45 μg. In hepatolenticular degeneration, daily excretion always exceeds 80 μg. A daily copper excretion value exceeding 125 μg is an absolute diagnostic sign of the disease. If this value is in the range of 45 to 125 μg, the patient may be either heterozygous or homozygous for the hepatolenticular degeneration gene. Measuring copper excretion for 2 days can increase the accuracy of the test.

Serum ceruloplasmin levels are most often used to diagnose hepatolenticular degeneration. However, 10% of patients have normal ceruloplasmin levels (> 20 mg/dL). However, even in patients with low ceruloplasmin levels (< 20 mg/dL), they may increase at some point in the disease course due to liver disease, pregnancy, or estrogen administration. Decreased ceruloplasmin levels may also occur in other diseases, such as protein-losing conditions, copper deficiency, Menkes disease, fulminant hepatitis, and in individuals heterozygous for hepatolenticular degeneration.

Thus, if neurological and mental symptoms allow us to suspect hepatolenticular degeneration in a patient, he should be examined with a slit lamp. If Kayser-Fleischer rings are detected, the diagnosis is almost certain. Determination of the ceruloplasmin level, serum copper content, and daily urinary copper excretion are carried out to confirm the diagnosis and obtain initial guidelines for subsequent treatment monitoring. MRI can provide important diagnostic information. If the patient has developed neurological symptoms, he will usually have changes on MRI. Although the hepatolenticular degeneration gene has been identified, in most familial cases its unique mutation is detected, which complicates the diagnosis using molecular genetic testing in clinical practice. However, with the development of modern technology, the improvement of molecular genetic testing methods, this diagnostic method will become available.

In Wilson-Konovalov disease, serum ceruloplasmin and copper levels are usually decreased. Differential diagnosis of Wilson-Konovalov disease is carried out with acute and chronic hepatitis, in which the ceruloplasmin level may be decreased due to impaired synthesis in the liver. Malnutrition also contributes to a decrease in ceruloplasmin levels. When taking estrogens, oral contraceptives, with biliary obstruction, and during pregnancy, ceruloplasmin levels may increase.

Daily copper excretion is increased in Wilson's disease. To avoid distortion of the analysis results, it is recommended to collect urine in special wide-necked bottles with disposable polyethylene bags-liners that do not contain copper.

In the presence of contraindications to liver biopsy and normal serum ceruloplasmin levels, the disease can be diagnosed by the degree of incorporation of orally administered radioactive copper into ceruloplasmin.

1. Complete blood count: increased ESR.
2. Urine analysis: possible proteinuria, aminoaciduria, increased copper excretion more than 100 mcg/day (normal - less than 70 mcg/day).
3. Biochemical blood test: increased levels of ALT, bilirubin, alkaline phosphatase, gamma globulins, unbound ceruloplasmin copper in the blood serum (300 μg/l or more), decreased or absent ceruloplasmin activity in the blood serum (usually 0-200 mg/l with a norm of 350±100 mg/l).

Instrumental data

1. Ultrasound and radioisotope scanning of the liver: enlarged liver, spleen, diffuse changes.
2. Liver biopsy: picture of chronic active hepatitis, liver cirrhosis, excessive copper content in liver tissue. Despite the uneven deposition of copper in the cirrhotic liver, it is necessary to determine its quantitative content in the biopsy. For this purpose, tissue embedded in a paraffin block can be used. Normally, the copper content is less than 55 μg per 1 g of dry weight, and in Wilson's disease it usually exceeds 250 μg per 1 g of dry weight. High copper content in the liver can be detected even with a normal histological picture. High copper content in the liver is also detected in all forms of long-term cholestasis.
3. Scans. A CT scan of the skull, performed before the onset of neurological symptoms, may reveal enlarged ventricles and other changes. Magnetic resonance imaging is more sensitive. It may reveal enlargement of the third ventricle, lesions in the thalamus, putamen, and globus pallidus. These lesions usually correspond to the clinical manifestations of the disease.

Identification of homozygotes with asymptomatic Wilson-Konovalov disease

The patient's siblings should be examined. Homozygosity is indicated by hepatomegaly, splenomegaly, vascular asterisks, and a slight increase in serum transaminase activity. The Kayser-Fleischer ring is not always detected. Serum ceruloplasmin levels are usually reduced to 0.20 g/L or less. Liver biopsy with copper determination can confirm the diagnosis.

Distinguishing homozygotes from heterozygotes is easy, although sometimes difficulties may arise. In such cases, haplotype analysis of the patient and his or her siblings is performed. Homozygotes are treated with penicillamine, even if the disease is asymptomatic. Heterozygotes do not require treatment. In a study of 39 clinically healthy homozygotes receiving treatment, no symptoms were noted, while 7 untreated homozygotes developed Wilson's disease and 5 of them died.