Wilson-Konovalov disease (hepatolenticular degeneration). Diseases of the peripheral nervous system

Wilson's disease (Wilson-Konovalov) is a rare hereditary pathology, as a result of which excess copper accumulates in the liver, brain and other vital important organs. Symptoms usually begin to appear between the ages of 12 and 23.

Copper plays a key role in the development of healthy nervous system, bones, collagen production and skin pigment melanin. With normal metabolism, this element enters the body with food, and excess is excreted with bile, a substance produced by the liver.

However, in people with Wilson's disease, copper is not excreted from the body properly and accumulates in the internal organs, sometimes to levels life-threatening. If diagnosed early, this serious disease can be treated, and many patients with this pathology lead a normal lifestyle.

Symptoms

It is quite difficult to correctly diagnose Wilson's disease: the symptoms of this disorder are very similar to those of other, more common diseases. In addition, symptoms may vary depending on which organ is most affected by copper accumulation. Among the most obvious signs pathologies include the following:

feeling tired, loss of appetite, or abdominal pain;
jaundice - yellowing of the skin and whites of the eyes;
the so-called Kayser-Fleischer ring - a pathology detected during an ophthalmological examination;
easy and rapid occurrence of hematomas;
fluid accumulation (edema) in the legs or abdomen;
problems with speech, swallowing or coordination;
involuntary body movements or a feeling of muscle stiffness.

If you experience any symptoms that cause concern, you should contact your doctor as soon as possible. If your relative is diagnosed with Wilson's disease, diagnosis may be needed for all family members.

Causes

This pathology is one of the autosomal recessive traits. Hereditary diseases of this type develop only in cases where a child receives two identical defective genes - one from each parent. If you have only one gene with a pathology, you do not suffer from the disease, but you are a carrier of it, which means that your children can inherit the defective gene.

Risk factors

Relatives of those diagnosed with hepatocerebral dystrophy are at risk. If your parents, brothers or sisters suffer from this disease, you may need to undergo genetic testing to identify pathological genes. Early diagnosis significantly increases the chances of successful treatment.

Complications

The disease may lead to serious complications. Among them:

Scarring of the liver (cirrhosis). As hepatocytes try to heal the damage caused by excess copper, connective tissue forms in the liver. Its excess prevents normal functioning organ.
Liver failure. This complication may appear suddenly (acute liver failure) or develop slowly over time. for long years. If the disease progresses, the only effective treatment may be a liver transplant.
Permanent neurological disorders. Neurological problems usually disappear as Wilson-Konovalov disease is treated. However, some people remain permanently impaired regardless of the effectiveness of therapy.
Kidney disorders. The disease in question can damage the kidneys and lead to problems such as stones and increased excretion of amino acids through the urine.
Psychological disorders. These complications manifest themselves in the form of personality changes, depression, bipolar affective disorder, psychosis.

Before visiting the doctor

To make an accurate diagnosis and prescribe therapy, you need to contact a specialist in liver diseases - a hepatologist. However, if you are visiting a medical facility for the first time with complaints of symptoms similar to those of Wilson's disease, you should start by visiting a therapist. If necessary, he will redirect you to the right specialist.

Since medical consultations are most often limited in time, and doctors strive to convey as much material as possible to patients, it is better to prepare for the visit in advance. Experts give the following recommendations:

Find out if there are any conditions or restrictions that you must adhere to before visiting your doctor. In some cases, you may need to follow a certain diet or take blood tests in advance.
Make a detailed list of all the symptoms that, in your opinion, indicate the presence of pathology. It is important to write down even signs that at first glance are not related to the problem.
Write down key personal information, including recent events that have caused severe psycho-emotional overload (stress), changes in lifestyle, or a family history of Wilson's disease.
Make a list of all medications, vitamins and other medications you take regularly. food additives.
Bring a close relative or good friend. In some cases, it is difficult to immediately absorb all the information offered by the doctor, and a friend or family member may be able to remember or write down details that may escape your attention.

Questions for a specialist

Violation of the removal of copper from the body, like any other hereditary diseases, is a fairly broad topic. At the same time, the duration of a medical consultation is limited, and in order to obtain the full amount of information you are interested in, it is better to prepare a list of questions for the doctor in advance. List the things that concern you most and rank the issues in order of importance. So, if the diagnosis of “hepatolenticular degeneration” (also known as Wilson-Konovalov disease) is confirmed, it is necessary to clarify some points with a specialist:

What research needs to be done?
What treatment methods do you recommend?
What side effects are common with the therapies you recommend?
Are there other ways to cure this disorder?
I also suffer from other chronic diseases. How does this affect your proposed therapy?
Are there any restrictions that must be observed?
Should I avoid drinking alcoholic beverages and medications that can harm my liver?
Do my relatives and family members need to undergo genetic testing to detect Wilson-Konovalov disease?
Do you have brochures or other printed materials with information about this disease? What Internet sites do you recommend?

Under no circumstances should you hesitate to ask other questions, including clarifying ones, if you do not understand anything from the doctor’s explanations. All details matter, so try to take notes on key information.

Diagnostics

Hepatocerebral dystrophy is serious problem in terms of diagnosis, since the signs and symptoms of this disease are characteristic of many other, more common and studied disorders of the liver (for example, hepatitis). Moreover: many signs appear gradually, and over time they completely change in nature or intensity. Thus, changes in behavior that become noticeable with age are most difficult to associate with Wilson's disease. To make a diagnosis, doctors rely simultaneously on information about symptoms and on the results of diagnostic tests.

Research

The following methods are used to diagnose Wilson's disease:

Urine and blood tests. Your doctor will likely recommend blood tests to monitor your liver function and check your copper levels. In addition, the necessary information can be obtained from the results of a urine test. To do this, samples of biological material are submitted to the laboratory within 24 hours, and workers medical institution measure the amount of copper released over time.
Examination by an ophthalmologist (ophthalmologist). Using a special microscope with a high-power light source, the ophthalmologist examines the patient's eyes for golden brown discoloration (Kayser-Fleischer ring). This disorder is caused by copper accumulation in the eyes. In addition, due to the disease, the so-called copper cataract, or sunflower cataract, often develops - it can also be detected during an ophthalmological examination.
Removing a sample of liver tissue for analysis. In a procedure called a liver biopsy, the doctor inserts a thin needle through the skin into the liver. The specialist then removes a small sample of biological material and sends it for laboratory analysis to confirm or refute the suspicion of excess copper.
Genetic testing. A blood test can determine the type genetic mutation leading to specific hereditary diseases. If your siblings are known to have congenital disorder copper metabolism, genetic testing should be performed to prevent the development of symptoms.

Wilson's disease: treatment

Your doctor may recommend taking certain medications that promote chelation. This type of medication encourages internal organs to release excess copper into the bloodstream. It is then filtered by the kidneys and goes into the urine. Therapy then focuses on preventing further accumulation of the said element. If the liver is severely damaged, a transplant may be required.

Medicines

If a patient has deafness and Wilson's disease, the main medications prescribed by specialists usually include:

"Penicillamine." This is a medication that promotes the formation of chelates. Unfortunately, it is characterized by severe side effects, including skin diseases, suppression of activity bone marrow and worsening neurological symptoms.
"Trientin". This drug acts in many ways similar to Penicillamine, but is characterized by less intensity and danger of potential side effects. However, there is a possibility of worsening neurological symptoms, although the risk is much lower than with the medication mentioned in the previous paragraph.
"Zinc acetate" (zinc acetate). This medication interferes with the absorption of copper from food. Please note: the drug may cause stomach upset.

Features of taking zinc acetate

Many patients are interested in a controversial question: does the accumulation of zinc in the body cause harm, given that Wilson-Konovalov disease must be treated throughout life?

Experts advise not to worry: although the level of zinc in the body increases slightly at the very beginning of therapy, later the metabolism of this element normalizes. In addition, zinc, unlike copper, does not have an abnormal tendency to accumulate in the tissues of internal organs. The only real danger posed by long-term treatment with this drug is similar to the risks with any other therapy for Wilson's disease: overdose, which can lead to copper deficiency. This happens extremely rarely, because treating doctors always monitor the levels of these two elements, reflected in the patient’s urine tests. If copper becomes too low, you can reduce the dose of zinc acetate and thus prevent the development of anemia. It is enough to take tests once a year, since the levels of these chemical elements remain stable for a long time.

At the beginning of therapy, reception medicinal product may cause stomach upset, nausea and vomiting. To reduce the intensity of these side effects, some experts recommend taking morning dose zinc carbonate at the same time as a small piece of ham or turkey sausage. It is important not to combine taking medication with eating foods rich in simple and complex carbohydrates. Typically, nausea and other side effects gradually subside as you follow the prescribed course of treatment. IN in rare cases Even time does not reduce the intensity of nausea, but the combination of medication with sausage, oddly enough, helps almost everyone.

Surgery

At serious damage the liver may require a transplant of this organ. During surgery, the doctor removes the diseased liver and replaces it with a healthy organ transplant. Most transplants come from deceased donors. However, in some cases, a decision is made to transplant a liver from a living person, for example, from a close relative. Then the surgeon removes the damaged liver and replaces it with a fragment of a donor organ.

Independent fight against the disease

Wilson's disease in children and adults develops gradually, and sometimes its development can be significantly limited on our own. To do this, doctors recommend reviewing your usual diet and reducing the amount of copper consumed in the form of food. If you have a copper water supply at home, it would be useful to measure the level of this element in running water. And, of course, you should avoid taking vitamins and dietary supplements containing this substance.

Particularly rich in copper and therefore potentially dangerous following products power supply:

liver;
shellfish;
mushrooms;
nuts;
chocolate.

The term "peripheral neuropathy" refers to a condition in which the nerve endings associated with the brain and spinal cord are damaged or affected by disease.

Peripheral nerves are connected in an intricate system that allows impulses from the brain and spinal cord to be transmitted to the skin, muscles and internal organs. Peripheral nerves arise from the spinal cord and are arranged along specific lines and segments of the body called dermatomes. Typically, defeat nerve root affects the sensitivity of one or more of these dermatomes related to various areas body. Damage to peripheral nerves interrupts the transmission of information from the brain to certain parts body, which leads to impaired muscle contractions, loss of sensitivity in the arms or legs, and the appearance of pain.

Types of peripheral neuropathy

There are several types of peripheral neuropathy, differing in the causes that cause them. The range of disorders described includes both carpal tunnel syndrome (nerve damage caused by chronic repetitive movements of the hands and wrists, such as when working at a computer), and Gillan-Barre syndrome (a rare, sudden paralysis).

As a group of diseases, peripheral neuropathy is quite common, especially in people over 55 years of age. Almost 3 - 4% of representatives of this segment suffer from one of the ailments united by peripheral neuropathy.

Such disorders are usually classified based on the specific problem and the source of its occurrence. There are also medical terms, describing the intensity of nerve damage.

Mononeuropathy

Damage to a single peripheral nerve is called mononeuropathy. Physical trauma received, for example, during an accident, is one of the most common reasons. Long-term pressure nerve damage caused by prolonged periods of inactivity (this includes sitting in wheelchair or lying bedridden), as well as repeated movements over a long period of time can cause mononeuropathy. If the fibrous, shock-absorbing discs located between the bones of the spine are damaged, they begin to put pressure on the nerve endings and also lead to the disease described.

Carpal tunnel syndrome is considered a fairly common problem. office workers. Otherwise called occupational overload syndrome, it occurs when the nerve coming from the wrist is constantly pinched. People whose work involves repetitive movements involving the wrist (such as assembly line workers, office workers) are at risk.

Nerve damage manifests itself as numbness, tingling, unusual sensations and pain in the first three fingers, starting from the thumb. Symptoms are especially pronounced during sleep. Over time, a carpal tunnel injury causes the muscles in the arm to weaken. The listed signs of the disease can also be felt in the arm or shoulder.

Below are examples of some mononeuropathies that lead to weakness in the affected parts of the body, namely the arms or legs:

Paralysis ulnar nerve occurs if the nerve ending running close to the surface of the skin in the elbow area is injured.
Radial nerve palsy is a consequence of damage to the nerve ending passing along the bottom side hands.
Peroneal nerve palsy occurs when the nerve in the upper calf behind the knee experiences persistent pressure. This violation results in a condition known as foot drop, in which it is impossible to point the toes of one or both feet upward.

Neuropathy also includes problems with the nerves that control muscle contractions (motor nerves) and those responsible for sensations such as cold or pain (sensory nerves). In some cases, the disease affects the functioning of internal organs, namely the heart, blood vessels, Bladder and intestines. This type of disease is commonly called autonomic neuropathy.

Polyneuropathy

Polyneuropathy is responsible for most cases classified as peripheral neuropathy. It occurs when several peripheral nerve endings are impaired at the same time. A variety of factors can cause the development of polyneuropathy, including exposure to toxic substances, unbalanced diet(especially vitamin B deficiency) and complications of serious diseases such as cancer or renal failure.

The most common type of chronic polyneuropathy is diabetic neuropathy occurring in diabetic patients. Less commonly, pathological increases in blood sugar cause mononeuropathy, characterized by weakness of the eye or thigh muscles.

The predominant symptoms of polyneuropathy are:

Tingling
Numbness
Loss of feeling in arms and legs

Patients suffering from chronic polyneuropathy often cannot feel the difference in temperature and do not experience pain. Therefore, the danger of burns and wounds resulting from prolonged compression or friction increases many times over. If the disease affects the nerves associated with internal organs, diarrhea and constipation may occur, as well as uncontrolled urination and bowel movements. Also consequences of polyneuropathy are sexual dysfunction and abnormally low blood pressure.

The joints of people with the described illness are highly susceptible to injury, since the nerves no longer transmit information about pain and the non-physiological position of the limb to the brain.

One of the most serious types Polyneuropathy is considered to be Gillan-Barre syndrome. This disease is very rare, it affects the body suddenly when the person’s immune system begins to attack its own nerves. Symptoms occur very quickly and worsen at a significant rate, sometimes leading to complete paralysis. Early signs of the disease include weakness, tingling and loss of sensation in the legs, which soon spreads to the arms. In critical cases, the patient experiences problems with blood pressure, heart rate and respiratory system. Fortunately, despite the severity and danger of this syndrome, the likelihood of recovery is very high if the patient seeks help early enough.

Causes of peripheral neuropathy

There are a wide range of factors that determine the development of peripheral neuropathy, so it is often very difficult to determine the cause in a particular case. Disorders result from one of the following conditions:

Acquired neuropathies caused by environmental factors, which include toxic substances, trauma, previous diseases or infections. Known reasons acquired neuropathies are:

Diabetes
Some rare inherited disorders
Alcoholism
Unbalanced diet and lack of vitamins
Herniated disc
Certain types of cancer
Conditions in which nerves are mistakenly attacked protective forces body or are affected by an overly aggressive response to injury
Selected medications
Kidney and thyroid disorders
Infectious diseases such as Lyme disease, shingles and AIDS

Hereditary neuropathies not so common. This variety The disease is explained by a disease of the peripheral nerves transmitted from parents to the child. The most common type of Charcot-Marie-Tooth disease is type 1. It is characterized by weakness in the legs and, to a lesser extent, in the arms. Symptoms of the disorder begin between middle childhood and 30s. The disease is caused by the degeneration of tissues that normally surround the nerve and facilitate the transmission of electrical impulses that are necessary to initiate muscle movement.
Idiopathic neuropathies are noteworthy in that the causes of their occurrence cannot be identified. Approximately one third of all cases of the disease are classified as idiopathic.

As a result, copper accumulates in excess in tissues and poisons them. The disease is inherited in an autosomal recessive manner and is characterized by a combination of chronic liver damage and severe neurological disorders with degenerative changes in the lenticular nucleus, to a lesser extent in the globus pallidus, cerebral hemispheres and cerebellum, as well as the involvement of the organs of vision and kidneys in the process.

Causes of Wilson's disease

Wilson's disease is a hereditary, treatable disease in which there is a gradual accumulation of copper in the liver, brain (mainly in basal ganglia), cornea, kidneys, which causes severe functional disorders leading to irreversible damage. Without treatment, the disease ends in death, but timely diagnosis and treatment eliminate or prevent its symptoms.

Wilson's disease is inherited in an autosomal recessive manner. The prevalence of heterozygotes for the mutant gene is 1:200, and homozygotes - 1:30,000. The gene responsible for Wilson's disease is located on the 13th chromosome near the gene encoding esterase D. 95% of patients have a deficiency or complete absence ceruloplasmin (a whey protein that plays a major role in copper transport). This is due to a decrease in transcription of the ceruloplasmin gene, located on chromosome 3.

Copper (Cu) is an essential trace element that is part of enzymes, such as cytochrome oxidase, tyrosinase, superoxide dismutase, etc.

Metabolism of copper. The normal intake of Cu into the body is approximately 2-5 mg per day, of which 40-60% is absorbed in the stomach and upper duodenum. With the help of a carrier, Cu enters the liver cells, binds to proteins or is included in the composition of ceruloplasmin (ferroxidase), which binds six Cu atoms relatively tightly. In complex with ceruloplasmin, Cu is released into the plasma (approximately 93% of the plasma content), where it oxidizes Fe 2+ to Fe 3+. A small amount of Cu bound to ceruloplasmin is released in peripheral tissues. Excretion of Cu into bile is accomplished by a P-type ATPase called Cu-ATPase (ATP7B). “Aged” ceruloplasmin, which does not contain sialic acids, is destroyed in the liver, Cu is released, firmly binds to bile proteins and is excreted from the body with feces. Approximately 1.2 mg of copper is excreted per day.

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive disorder of Cu metabolism, in which its excessive deposition occurs in the liver, central nervous system, eyes and other organs. The disease is caused by mutations in the ATP7B gene, which encodes the CU-ATP7B protein. Mutation leads to decreased excretion significant amount Cu with bile and a decrease in the inclusion of Cu in ceruloplasmin. As a result, when the total Cu concentration is below normal, free or weakly bound copper accumulates in the liver and then in the plasma. In this form, Cu is toxic because it binds predominantly to the sulfhydryl groups of proteins and promotes the formation free radicals O 2 and lipid peroxidation.

The accumulation of free Cu causes the development of anemia and chronic hepatitis which subsequently leads to cirrhosis. In fulminant hepatitis, necrotic liver tissue suddenly releases a large number of Cu, which can cause hemolytic crisis. Accumulation of Cu in the central nervous system leads to numerous and varied neurological, neuromuscular and psychogenic disorders. The deposition of Cu as a granular mass in the Descemet's membrane of the eye contributes to the formation of a Kayser-Fleischer ring along the periphery of the cornea. The pathological process may involve the kidneys, skeleton and heart. Since excess Cu deposition is caused by a mutation in the ATP7B gene, a cure for Wilson's disease is possible through liver transplantation.

Copper metabolism in Wilson's disease

Liver copper concentration in a newborn is 6-8 times higher than in the liver of an adult. In the first 6 months of life, it decreases to 30 mg per 1 g of dry tissue, and then remains unchanged throughout life due to the careful regulation of copper absorption in the intestine, its transport to the liver, storage there with the help of serum and tissue proteins and excretion from the body through bile.

Absorption and excretion of copper. The average daily copper intake is 2 to 5 mg, approximately 50% of which is absorbed proximally small intestine and non-covalently binds to plasma albumin. In the liver, copper is released and binds to specific proteins, particularly cytochrome c oxidase and ceruloplasmin, or is taken up by lysosomes and excreted into bile. There are two main routes by which copper leaves the liver.

Synthesis of the copper-containing protein ceruloplasmin and its entry into the bloodstream.
Excretion with bile.

Genetic disorders. Increased accumulation of copper in Wilson's disease is due to reduced excretion in the bile, and not due to increased absorption in the intestine. The cause is mutations in the ATP7B gene, located on chromosome 13. This gene encodes a Cu 2+ -ATPase, which is expressed in the liver, kidneys and placenta. As a result of mutations, the transport of copper from the liver to bile is disrupted, and copper ions accumulate in hepatocytes. Cu 2+ -ATPase is present mainly in the transcisterns of the Golyzhi apparatus, where it ensures the excretion of copper into bile, as well as its binding to ceruloplasmin. With a lack of functional ATPase, the amount of copper that can bind to ceruloplasmin is reduced. In this case, ceruloplasmin, which does not contain copper (apoceruloplasmin), once in the bloodstream, is quickly destroyed. Therefore, a hallmark of Wilson's disease is a low level of ceruloplasmin in plasma.

Toxic effect of copper in Wilson's disease

Acute poisoning. Ingestion of copper salts in quantities expressed in grams causes severe damage to the gastrointestinal tract and other organs; sometimes liver necrosis develops. However, most often, vomiting and diarrhea caused by copper salts entering the gastrointestinal tract protect the patient’s body from the severe consequences of poisoning.

Chronic lesion. Excess copper in the liver may not only be a consequence of Wilson's disease; it is possible with primary biliary cirrhosis, extrahepatic atresia biliary tract, Indian childhood cirrhosis and other diseases accompanied by chronic cholestasis. Excess copper in the liver can aggravate the course of the underlying pathological process due to direct damage to hepatocyte organelles or stimulation of fibrosis.

Symptoms and signs of Wilson's disease

Manifestations of Wilson's disease are varied. It can occur under the guise of various neurological and mental disorders, manifest as an asymptomatic increase in aminotransferase activity, such as chronic active hepatitis, acute liver necrosis, liver cirrhosis, acquired hemolytic anemia, renal failure, and also cause ophthalmological disorders such as chalcosis of the lens and Kayser rings. Fleischer.

Liver damage. In childhood, this is the most common presentation of Wilson's disease. Approximately 40% of patients consult a doctor with symptoms of liver damage. An increase in copper concentration in the liver by 30-50 times is not accompanied by any clinical manifestations, so symptoms of liver damage do not appear before 6 years. However, by the age of 15, half of the patients have them. Thus, characteristic of Wilson's disease clinical picture It occurs primarily in older children, adolescents, young adults, and, rarely, in adulthood.

Liver damage in Wilson's disease can take different forms.

Most often, the disease begins gradually and proceeds as chronic. Characterized by weakness, malaise, lack of appetite, mild jaundice, splenomegaly, changes in biochemical parameters liver functions.
Acute liver necrosis with increasing jaundice, ascites and liver failure is possible, which usually ends in death, especially with the development of hemolytic anemia.
Some patients have a clinical picture typical of postnecrotic cirrhosis - spider veins, splenomegaly, portal hypertension, bleeding from esophageal varices, thrombocytopenia, simulating idiopathic platelet purpura. Liver enzyme activity may be normal. The possibility of Wilson's disease should always be considered in a patient under 30 years of age with negative serological tests for viral hepatitis; with a history of chronic active hepatitis; in the presence of juvenile liver cirrhosis, cryptogenic liver cirrhosis or liver cirrhosis in close relatives. Although Wilson's disease is found in less than 5% of these patients, it is one of the few liver diseases for which specific, effective treatment exists.

Histological picture. Wilson's disease does not have a sufficiently characteristic histological pattern for diagnosis to be made based on liver biopsy. In the early stages of the disease, when copper is diffusely distributed in the cytoplasm, it is not detected when stained with rhodamine or rubeanic acid. At this stage it develops fatty infiltration hepatocytes, the nuclei of hepatocytes are vacuolated and contain glycogen. Then fatty degeneration liver progresses to fibrosis and finally to cirrhosis. As the disease progresses, excess copper accumulates in the lysosomes of hepatocytes; in individual regeneration nodes it can be detected by histochemical staining. However, due to the uneven distribution of copper between the regeneration units and varying efficiency staining negative result staining the biopsy specimen with rhodamine or rubeanic acid does not exclude Wilson's disease. Lymphocytic infiltration of the liver parenchyma is characteristic. Cholestasis, focal necrosis and the presence of Mallory bodies are possible. In other cases, the histological picture resembles acute or chronic active hepatitis. After the development of large nodular cirrhosis, the microscopic picture becomes nonspecific. Fat droplets are visible in the cytoplasm of hepatocytes, vacuolated nuclei containing glycogen, and cytoplasmic inclusions containing copper-enriched lipofuscin granules.

Neurological symptoms- one of the most common manifestations of Wilson's disease; it usually appears between the ages of 12 and 32 years.

The most typical is the following.

Coordination disorders primarily affect fine movements, resulting in difficulties when writing, typing and playing the piano.
Tremor is usually observed at rest, but intensifies with voluntary movements and emotional stress. Its intensity varies - from a slight tremor of one hand to a generalized tremor of the upper extremities, tongue and head. It can be slow, large-swinging or choreoathetoid. Dystonia, cerebellar gait, spasticity and rigidity are late neurological manifestations of Wilson's disease.
Dysarthria begins with difficulty pronouncing words, then develops slurred speech, weakened voice, and aphasia.
Increased salivation is observed already in the early stages of the disease.
Dysphagia is caused by dysfunction of the muscles of the mouth and pharynx and progresses over time. Patients have difficulty swallowing, which leads to regurgitation and aspiration of food.

Mental disorders develop in almost all patients and can manifest themselves in the form of adaptation difficulties in adolescents, anxiety, hysteria, manic-depressive or schizoaffective psychosis. Psychotropic drugs can exacerbate the neurological symptoms of Wilson's disease and worsen the patient's condition.

Hematological manifestations. Wilson's disease is rarely accompanied by hemolytic anemia with a negative Coombs test and jaundice, which may be transient and benign, but may be a manifestation of acute liver necrosis. Hemolysis at acute necrosis liver disease is caused by the sudden release of copper from dead hepatocytes into the bloodstream. At the same time, the concentration of free in the blood increases sharply and its excretion in the urine increases.

Against the background of portal hypertension and splenomegaly, hypersplenism can cause thrombocytopenia and pancytopenia. Increasing liver dysfunction also leads to a deficiency of coagulation factors and bleeding.

Dysfunction kidneys is associated with copper deposition in their parenchyma. It may manifest as a decrease in GFR, and there may also be proximal tubular damage resembling Fanconi syndrome, with renal tubular acidosis, proteinuria, and microscopic hematuria.

Clinically on early stage the disease begins with chronic nonspecific hepatitis, signs of liver cirrhosis in the form of dyspeptic symptoms, jaundice, mild pain syndrome V right half abdomen, the presence of extrahepatic signs, hemorrhagic diathesis. An early sign liver damage is considered hepatomegaly, splenomegaly, jaundice, anorexia. Then signs of functional liver failure develop, an increase in the phenomena of portal hypertension and hypersplenism.

Changes in the liver consist of clinical manifestations hepatitis with asthenia, jaundice, abdominal pain and dyspeptic symptoms, hyperaminotransferasemia, hypoalbuminemia and moderate hypergammaglobulinemia, or in the form of sluggish or slowly progressive forms of liver cirrhosis. In the abdominal form, the disease proceeds as subacute liver dystrophy and the patient dies in a state of hepatic coma before the onset of neurological disorders. Neurological signs may develop gradually or appear suddenly. In such cases, neurological symptoms come first and are expressed by trembling of the hands, an increase in muscle tone, turning into pronounced rigidity. Subsequently, adynamia of movements develops; clonic and tonic convulsions occur.

On the part of the nervous system, extrapyramidal disorders are noted: sweeping tremor of the limbs, head, changes in speech and handwriting, as the disease progresses, muscle rigidity, followed by myogenic contractures and immobility, decreased memory. Due to prolonged muscle spasms, various pretentious poses arise. Typical sign diseases are corneal Kayser-Fleischer rings - deposition of a greenish-brown pigment containing copper. Kidney damage is detected osteoarticular system in the form of arthropathy, diffuse osteoporosis. The amount of copper in the urine increases to 1000J (daily norm 100J), aminoaciduria to 2000 mg (per day 100-350 mg).

Diagnosis of Wilson's disease

Serum concentration of ceruloplasmin in Wilson's disease in 95% of cases it is below 1.3 µmol/l. However, this is not enough to make a diagnosis of Wilson's disease - in approximately 20% of heterozygotes for the mutant gene, the amount of ceruloplasmin is also reduced. In acute liver necrosis and in 15% of patients with liver damage as the only manifestation of the disease, the concentration of ceruloplasmin, which is a protein in the acute phase of inflammation, may be slightly increased.

Serum copper concentration. Since ceruloplasmin is the main protein responsible for the transport of copper in the blood, the total concentration of copper in the serum in Wilson's disease is often reduced, but the concentration of free copper is increased, which contributes to its deposition in various tissues. Determination of free copper concentration in serum is the most reliable method preliminary diagnostics Wilson's disease. It is calculated as the difference between general content serum copper and its amount bound to ceruloplasmin.

Urinary copper excretion. Free copper in serum is easily excreted by the kidneys, so urinary copper excretion is increased in Wilson's disease.

Liver biopsy. For getting reliable result The tissue sample must be large enough (preferably a tissue column at least 1 cm long) and free of traces of copper (using disposable biopsy needles reduces this risk). A transjugular biopsy does not provide sufficient tissue to quantitative analysis. Other diseases, in particular primary and secondary biliary cirrhosis, long-term obstruction of the bile duct, can also greatly increase the copper content in the liver by impairing its excretion with bile. However, these patients have elevated serum ceruloplasmin levels.

In some cases, when the content of ceruloplasmin in the serum is normal and it is impossible to perform a biopsy due to blood coagulation disorders, stress test with copper isotope 64Cu, having a half-life of 12.8 hours. The drug is taken orally (2 mg) or administered intravenously (500 mg), after which the dependence of the concentration of radioactive copper in the serum on time is noted.

If Wilson's disease is not present, radioactive copper appears in the serum and disappears again after 4-6 hours. After the isotope is taken up by the liver and binds to newly synthesized ceruloplasmin, a second peak of radioactivity in the serum is observed. In Wilson's disease, the second peak is absent because the amount of copper taken up for binding to ceruloplasmin is reduced.

Kayser-Fleischer rings always find patients with neurological manifestations Wilson's disease; if there is only liver damage, they may be absent. If Kayser-Fleischer rings are not visible to the naked eye, a slit lamp examination is performed.

For acute liver necrosis Wilson's disease is characterized by a combination of low alkaline phosphatase activity and only small increase aminotransferase activity with jaundice, clinical and histological features liver necrosis. Diagnostic value also represents a low ratio of alkaline phosphatase activity to the level of total bilirubin.

All siblings of patients should be tested for Wilson's disease. A physical examination is performed.

Treatment of Wilson's disease

Treatment is determined by the characteristics of the course of the disease, the presence of signs of activity of the inflammatory process in the liver, ascites, anemia and other complications.

Without treatment, Wilson's disease causes progressive damage to the liver, brain, and kidneys. Until the end of the 1940s. Most patients died before reaching 30 years of age. The prognosis has improved significantly since its introduction in the 1950s. penicillamine, a complex-forming compound that binds copper ions. It is very important to firmly establish the presence of the disease, since treatment must be carried out throughout life.

Diet

Copper intake should not exceed 1 mg/day. Avoid foods rich in copper, such as organ meats (liver, kidneys, etc.), shellfish and crustaceans, dry beans and peas, whole wheat and chocolate.

Penicillamine

Penicillamine was the first drug to treat Wilson's disease at all stages. It complexes with heavy metals, especially copper, and facilitates their excretion in the urine, thereby reducing plasma copper concentrations and promoting its release from tissues into the bloodstream. In addition, penicillamine has anti-inflammatory properties and can inhibit collagen synthesis, preventing fibrosis. Penicillamine causes vitamin B deficiency, so pyridoxine is prescribed simultaneously with it.

Penicillamine is prescribed orally. The earlier treatment is started, the better the results. Histological abnormalities are reduced and many of the symptoms disappear; however, existing cirrhosis, portal hypertension and some neurological disorders (dystonia, rigidity, dysarthria, dementia) may be irreversible. In the first weeks of treatment, 20% of patients experience side effects such as fever, rash, enlarged lymph nodes, polyneuropathy, leukopenia and thrombocytopenia. To cope with them, it is usually enough to reduce the dose of penicillamine or interrupt treatment for a while, and then start it again, slowly increasing the dose. For severe side effects (drug-induced lupus syndrome, nephrotic syndrome, pemphigus and cutaneous elastosis, myasthenia gravis, thrombocytopenia, severe arthralgia), which are observed in 5-10% of patients, another complex-forming drug, for example trientine, is prescribed.

Trientin

Trientine, like penicillamine, binds copper and promotes its excretion in the urine. Although its ability to remove copper through the kidneys is less pronounced than that of penicillamine, clinical effectiveness the drugs are comparable. Trientine causes fewer side effects than penicillamine and does not cause allergic reactions. In case of an overdose of the drug with the development of copper deficiency, sideroblastic anemia and toxic damage to the bone marrow are possible, which are reversible by reducing the dose of trientine. During pregnancy, both drugs are not interrupted. Irregular use or discontinuation of penicillamine or trientine often leads to resumption of symptoms or acute liver necrosis.

Zinc preparations

Zinc sulfate is effective in Wilson's disease, especially in cases of intolerance to drugs that increase copper excretion in the urine. Zinc induces metallothionein synthesis in the intestine, thereby increasing copper binding epithelial cells intestinal mucosa and preventing its systemic absorption. Zinc may also induce metallothionein synthesis in hepatocytes, thereby reducing toxic effect copper In some patients large doses zinc cause headache, cramping abdominal pain, irritation of the gastric mucosa and loss of appetite. In addition, zinc interferes with the absorption of iron, causes autoimmune reactions and affects the composition of lipoproteins in the serum.

Zinc therapy may supplement standard treatment complexing drugs - penicillamine or trientine. However, there is evidence that the formation of zinc complexes with penicillamine may reduce the effectiveness of both drugs in combination therapy. It is not recommended to initiate treatment with zinc as monotherapy for symptomatic Wilson's disease; however, it is suitable for maintenance treatment to maintain a negative copper balance. Zinc acetate is better tolerated than chloride or sulfate.

Tetrathiomolybdate

Tetrathiomolybdate prevents the absorption of copper in the intestine by binding it in a strong, metabolically inactive form. It is indicated for use in patients who cannot tolerate penicillamine, but is not available on the pharmaceutical market in the United States and Canada. Tetrathiomolybdate is well tolerated, but at least 2 cases of hematopoietic depression caused by it have been described. Further clinical studies are needed before the drug can be used with confidence in Wilson's disease.

Monitoring the effectiveness of treatment

Monitoring the effectiveness of treatment: regular physical examination, examination of the cornea with a slit lamp to detect the disappearance of Kayser-Fleischer rings.

Marked clinical improvement occurs only after 6-12 months of continuous treatment.

Acute liver necrosis

In a small number of patients it may be the first manifestation of Wilson's disease. Acute liver necrosis can also develop due to non-compliance with the regimen drug treatment. A small number of patients, despite the treatment described above, still develop cirrhosis and liver failure.

Liver transplantation

Liver transplantation can save lives in cases of acute liver necrosis or irreversible liver failure caused by Wilson's disease. After transplant metabolic disorders disappear and a cure occurs. Replacement of the affected liver, in which the product of the mutant ATP7B gene is expressed, donor organ, expressing normal protein, normalizes copper metabolism in the liver. Thus, copper no longer accumulates in the transplanted liver.

Unfortunately, extrahepatic manifestations of Wilson's disease do not always resolve after liver transplantation. Therefore, in the absence of liver failure, only to eliminate extrahepatic manifestations of the disease (for example, neurological disorders), transplantation is not recommended. Hepatocyte transplantation is currently being studied as an alternative to whole liver transplantation.

Back in 1912 A.K. Wilson identified a disease associated with the inability to distribute copper. Among Russian scientists, the problem turned out to be interesting to N.A. Konovalov. After the discovery of the gene responsible for the development of a peculiar mutation in 1993, doctors took a closer look at the scientific works of scientists. Rare disease usually hidden behind symptoms puberty, and then the relationship between the teenager and the parents deteriorates so much that they hardly communicate. In such cases, there is no timely request for help. A decrease in the ceruloplasmin protein in the blood cannot go unnoticed and is determined by the symptoms of Wilson-Konovalov disease and test results confirming the uneven distribution of copper in the body.

Symptoms accompanying Wilson-Konovalov disease

Considering that the disease strikes two different organs(liver and diencephalon), the symptoms can be twofold. Liver damage manifests itself in the development of liver cirrhosis. People over 11 years of age are at risk.
From the age of 19, Wilson-Konovalov pathology syndrome can attack neurological form. In this case, the symptoms are more noticeable. Starting with mood swings and some aggressiveness typical of adolescents in adolescence, the disease continues with the appearance of tremors, incoherent speech and unusual movements of the limbs. In the future, the situation is aggravated by epileptic seizures. Often the victims are not young people, but pensioners or people of pre-retirement age.
Treatment by psychiatrists neurological abnormalities does not bring the desired result, which again should arouse suspicion among the doctor. He may refer the patient for additional tests. It should be remembered that the absence necessary treatment pushes the disease to further development at an accelerated pace.
Excessive amounts of copper in the body provokes accompanying illnesses. These include cirrhosis of the liver, pathological changes in the joints, diabetes mellitus, atherosclerosis and Fanconi syndrome. Another symptom of such dangerous changes is a change in the color of the iris. Its rim becomes yellow-brown in color.

Causes of mutation

Cases of detection of Wilson-Konovalov disease in last years began to be observed more and more often. As a result, it was possible to establish that the disease does not favor men or women. It was also possible to confirm her heredity. As Konovalov pointed out, the reason lies in a defect in one of the genes. Modern methods studies have shown that it is located on the thirteenth chromosome.
Among the reasons why Wilson-Konovalov disease develops, first of all, marriages between close relatives are noted. According to statistics, the largest percentage of patient registrations occur in regions where such connections are allowed. Other reasons include mandatory carriage by one of the parents of the altered gene. In some cases, both parents may be carriers.

Diagnosis of the disease

The disease can be determined based on tests for copper and zinc levels in the blood. The symptoms described above also indicate it. In the absence of a protein that promotes the movement of copper, it quickly penetrates into the tissue. Where it accumulates. A decrease in the amount of one essential element invariably leads to a decrease in the amount of zinc, which is also shown by the results laboratory research. Excess copper, affecting the liver and kidneys, is determined increased amount liver enzymes and excretion of amino acids in the urine, which determines the disease.
A detailed blood test shows reduced content copper and zinc. Increased concentrations are detected only in tissues. After taking the tests, you need to contact an experienced ophthalmologist who can determine the presence of changes associated with copper deposits and determine Wilson-Konovalov pathology syndrome.

Features of treatment

Timely diagnosis is the key to successful treatment. In advanced cases, Wilson-Konovalov disease syndrome is almost untreatable. Treatment of Wilson-Konovalov disease late stages most often it only slightly delays the approach of the sad end. Liver cirrhosis and fulminant liver failure lead to fatal outcome in young people.

Therapy is aimed at reducing the amount of copper in the body. For this purpose it is prescribed protein diet with restriction of products containing an element hazardous to the patient. To remove copper, it must first be bound. At the first stage of treatment, doctors usually prescribe British anti-Lewisite with its twice daily intramuscular injection for 20 days to weaken the disease. The duration of taking the drug coincides with the duration of the break. Depending on the individual characteristics patient, the drug can be administered for several months twice a day until positive dynamics appear.

Once every three months, a course of 25 Unitol injections is prescribed, with one dose every other day. D-penicillamine is responsible for the excretion of copper from tissues. It is taken daily. Daily dose determined based on the severity of the condition. During the first two weeks, taking the medicine may increase neurological symptoms and worsen the condition of the liver. But strictly following the doctor’s instructions, after just a few weeks (in difficult cases months), a sharp, serious improvement occurs, up to complete cure liver cirrhosis or chronic hepatitis, the disease recedes.
Drug treatment is not always effective, which causes progression of liver failure. In this case, only liver transplantation can help. If Wilson-Konovalov disease syndrome is detected and all the symptoms are present, the patient must be seen annually by his attending physician and have a blood test. necessary tests. Liver biopsy allows you to determine the effectiveness of therapy and adjust the amount of drugs.

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Interesting pallor, a mysterious sparkle of sad eyes, a mysterious appearance - this is the charming hero of the Twilight saga about vampires performed by Robert Pattinson, a performer who is admired by young females all over the world. So that’s what they are, bloodsuckers! And before, ghouls and ghouls seemed much less attractive to people. No wonder they were exterminated for many centuries in vain. And not at all with aspen stakes and silver bullets, as the legends prescribe, but with the very in the usual way: They were hanged or burned at the stake. In just one century, starting in 1520, more than 30 thousand people recognized as werewolves were executed in France alone.

About blue and simple blood

Modern scientists believe that, as often happens, innocent people suffered in the hunt for ghouls. Although the pursuers still had a reason. No, those who were accused of vampirism did not drink other people's blood and did not turn around at night wild animals, but at the same time they looked - God forbid, and their lifestyle was, to put it mildly, suspicious. But first things first.

Doctors believe that people unfairly accused of vampirism actually suffered from a rare genetic disease blood, called “porphyria” (from the Greek “porphyros” - “purple”). It is believed that marriages between close relatives contributed to the spread of this disease. Porphyria was most common in the small villages of Transylvania (the birthplace of Count Dracula) approximately 1,000 years ago. But there are rumors that the disease has not spared the royal families either. For example, historian Andrew Wilson, in his book The Victorians, mentions hereditary porphyria, which was rampant in Britain. royal family, and claims that it was this disease that deprived Queen Victoria's grandfather King George III of his mind. However, with Victoria's accession to the throne, the crowned family got rid of this curse. Wilson believes that this was not without adultery, as a result of which the future Queen of England was born.

So what kind of disease is this? Today, scientists know exactly what makes people like vampires. With porphyria, the reproduction of heme, the non-protein part of hemoglobin, is disrupted, which in turn leads to excessive accumulation in the body of toxic substances - porphyrins and their precursors, which have the ability to bind metals in the body, primarily iron and magnesium. Excess porphyrins have toxic effects for the whole body.

Vampire disease

The connection between these two phenomena: disease and ancient beliefs about bloodsucking people was first stated by Dr. Lee Illis from Great Britain. In 1963, he presented a monograph “On Porphyria and the Etiology of Werewolves” to the Royal Society of Medicine. The scientist's work contained a detailed comparative analysis of surviving historical evidence that described vampires and the symptoms of porphyria. It turned out that the clinical picture of a rare disease exactly copies the portrait of the most colorful ghoul.

In advanced forms of porphyria, the skin around the lips and gums of patients dries out, causing the incisors to be exposed to the gums, creating the impression of a grin. In addition, a special substance, porphyrin, is deposited on the teeth themselves, which colors a person’s smile (or rather, grin) in a reddish-brown color. The skin on the face and body of such people becomes thinner and bursts from exposure to sunlight, becoming covered with scars and ulcers. The disease also damages cartilage, as well as the organs of which they are composed (primarily the nose and ears). Fingers become crooked. sunlight causes the poor fellows the most severe torment, because it is under the influence of ultraviolet radiation that the breakdown of hemoglobin begins. Therefore, during the day, people suffering from porphyria try not to appear on the street, and are active only at dusk, closer to night. Either from the torment they experience, or from forced seclusion, or from some internal processes occurring in the body, these people also suffer neuropsychiatric disorders and inappropriate, including aggressive behavior.

One can imagine the horror of those who one evening or night by moonlight met one of these “cute guys” on a narrow path. Here you will believe not only in vampires and werewolves, but in anything!

Thought it was an allergy

Of course, frightening symptoms are characteristic only of the later stages of the disease, and even then not for all its types. Nevertheless, this disease, albeit not in such a pronounced form, exists to this day. The most common among all other forms, of which there are a great many, is acute intermittent porphyria (AIP).

It is believed that this rare genetic pathology affects 1 person out of 200 thousand (according to other sources, out of 100 thousand). Moreover, the heredity factor is the most important, because if one of the parents is sick, then in 25% of cases the defective gene will pass to his child. There is reason to believe that porphyria may also be a consequence of incest. But in addition to genetics, the role of accompanying circumstances and lifestyle is also important. The fact is that almost 85% of carriers of the abnormal gene live their lives without knowing about the disease they have. And manifestations of photodermatosis on the skin are considered a simple allergy. But as soon as some kind of malfunction occurs in the body, an exacerbation may occur.

Most often, an outbreak of the disease is provoked by:

● strict diets;

● stress;

● taking medications (including phenobarbital, tetracyclines, bismuth-containing drugs, oral contraceptives and etc.);

● contact with pesticides (for example, agricultural fertilizers) or work in hazardous, including chemical industries;

● changes in the hormonal profile in women associated with the onset of menstruation or pregnancy;

● infectious diseases (especially previous viral hepatitis C;

● alcohol intake (80% of all patients with porphyria are partial to alcohol).

People suffering from porphyria usually end up in hospitals with complaints of acute paroxysmal abdominal pain that does not have a clear localization, as well as nausea, vomiting and constipation. All these signs indicate surgical pathology, so diagnosis and treatment may go in the wrong direction. If the diagnosis, and therefore the treatment, is incorrect, acute porphyrias end tragically in 60% of cases. And timely diagnosis and adequate therapy save almost all patients, returning them to a full life.