Primary biliary cirrhosis of the liver

Biliary cirrhosis is a special form of liver cirrhosis that develops due to prolonged biliary tract damage and cholestasis. Primary biliary cirrhosis of the liver is an autoimmune liver disease that begins as a chronic, destructive, non-venous cholangitis, which lasts for a long time without significant symptoms, leading to the development of prolonged cholestasis and only at later stages to the formation of liver cirrhosis.

The disease was first described by Addison and Gall in 1851, and then by Hano. Because of the high level of cholesterol in the serum and the presence of xanthoma on the skin, the disease became known as xanthomatous biliary cirrhosis. The term "primary biliary cirrhosis" was suggested by Ahrens et al. This term is not entirely accurate, because in the early stages of the disease, regeneration sites are not detected and there is no cirrhosis yet. More correct would be the name "chronic non-venous destructive cholangitis", however it did not replace the generally accepted term "primary biliary cirrhosis".

[1], [2], [3]

Epidemiology

Primary biliary cirrhosis (PBC) is the most frequent chronic cholestatic liver disease in adults. More than 90% of cases occur in women aged 35-70 years. The prevalence of the disease is 23-25 patients per 1 million adults. There is a group morbidity in families.

Primary biliary cirrhosis is found all over the world. The morbidity in different countries and in different areas of one country varies considerably. Increased morbidity is associated with increased awareness of doctors, improved diagnosis, in particular, with the possibility of setting a response to serum AMA, and identifying patients in the early stages of the disease, occurring with minimal symptoms. The disease can be of a family nature; primary biliary cirrhosis is described in sisters, twins, mothers and daughters. In New York, the incidence of primary biliary cirrhosis in families was 1.33%, and in London - 5.5%. Usually, the disease is transmitted from mothers to daughters, and in the second generation it develops at a younger age. Circulating AMA occurs in relatives of patients more often than in the population.

In a study in Sheffield, England, the primary biliary cirrhosis was associated with a particular source of water supply. However, special factors associated with this source, could not be identified. In a study carried out in Ontario, Canada, there was no racial or geographical predisposition. To clarify the role of these factors, additional epidemiological studies are required.

There is a correlation between the incidence of primary biliary cirrhosis and histocompatibility antigens. Among the white population of the United States, who suffers from primary biliary cirrhosis, HLA-DRw8 antigen was often found.

C4A-QO antigen and HLA class III allele are detected in many autoimmune diseases. In genetic typing, the C4A-QO allele was detected more often than in healthy individuals, and a very significant proportion of patients with primary biliary cirrhosis had both DRw8 and C4A-QO alleles. At the mother and two sisters, who suffered from primary biliary cirrhosis, the haplotype of histocompatibility antigens was identical. HLA class III antigens belong to the complement system. This makes it possible to explain the partial deficiency of the complement C4A component in patients with primary biliary cirrhosis. In addition, the Germans identified a relationship of primary biliary cirrhosis with the genotype DRB1 * 0301 HLA, and in Japanese - with DRB1 * 0803 HLA.

All these observations are difficult to unite. They show that in the pathogenesis of primary biliary cirrhosis an important role is played by the immunogenetic background, which determines the hereditary predisposition. It is impossible to exclude the importance of environmental factors, especially infections; these factors affect mainly those who are predisposed to the disease.

[4], [5], [6], [7], [8]

Causes of the primary biliary cirrhosis

Its cause is unknown, but there is a suspicion of an autoimmune mechanism, since antibodies to antigens located on internal mitochondrial membranes are detected in more than 95% of cases. These antimitochondrial antibodies are not cytotoxic and are not involved in the destruction of the bile ducts.

CD4 nCD8 T-lymphocytes are typical mediators of inflammation in the layer of the epithelium of small bile ducts. There is proliferation of bile ducts. Bile acids maintain and cause inflammation of the liver parenchyma, leading to the development of fibrosis in the periportal areas. Eventually, the inflammation decreases, and the liver fibrosis progresses to cirrhosis.

The causes of primary biliary cirrhosis are unknown. Genetic factors may play a role, as evidenced by family cases of the disease, although their frequency is low (1-7%).

Primary biliary cirrhosis is an example of impaired immunoregulation, in which tolerance to tissues carrying a large number of histocompatibility antigens is lost. How and why these disorders occur in the bile ducts and what is the nature of these "autoantigens" is not known. The starting factors of the immunopathological reaction can serve as viral, bacterial, some other neoantigens, perhaps just a violation of immunoregulation.

In many respects, primary biliary cirrhosis resembles the "graft versus host disease" observed, for example, after bone marrow transplantation, when the immune system becomes sensitized to foreign proteins of the HLA system. With these diseases, similar structural changes develop in the bile ducts. Affected by other ducts, the epithelium of which contains large amounts of Class II HLA antigens, for example, the ducts of the lacrimal glands and pancreas. The disease can proceed according to the type of dry syndrome.

In patients with primary biliary cirrhosis, HLADR3, DR4, DR2 are often found.

[9], [10], [11], [12]

Risk factors

Primary biliary cirrhosis of the liver is associated with other autoimmune diseases, such as rheumatoid arthritis, Sjogren's syndrome, CREST syndrome, autoimmune thyroiditis, and tubular renal acidosis, which also suggest an autoimmune development mechanism.

[13], [14], [15]

Pathogenesis

The main pathogenetic factors of primary biliary cirrhosis:

1. Development of autoimmune reactions directed against bile ducts.

At the heart of primary biliary cirrhosis are aseptic autoimmune destructive cholangitis and cholangiolitis, which is associated with the formation of autoantibodies to intrahepatic biliary tracts (interlobular and septal bile ducts). The antigens of the main histocompatibility complex (HLA) of the bile ducts serve as a target of immune aggression. On the membranes of the biliary epithelium under the influence of hyperproduction of γ-interferon by T-lymphocytes and natural killers, HLA I and II class antigens are expressed. As a result, cells of the bile ducts are targeted by cytotoxic T-lymphocytes and antibodies. The main antibodies that have the leading pathogenetic importance are antibodies to the internal membrane of the bile ducts - antimitochondrial antibodies. Antibodies to 9 antigens of the inner and outer mitochondrial membrane are now known. Antibodies to the antigen of the inner membrane of mitochondria M _{2 are} found in almost all cases of primary biliary cirrhosis and are considered pathognomonic. Antimitohovdrialnye antibody (antigen mitochondria M ₄ ) detected in primary biliary cirrhosis, autoimmune hepatitis combined with, the antigen mitochondria M ₈ - with rapidly progressive form of primary biliary cirrhosis, antigen M ₉ - in the early stages of primary biliary cirrhosis.

Antimitochondrial antibodies are classified as IgM. Immune complexes are formed containing hepatobili-arny and mitochondrial antigens, antimitochondrial antibodies and complement C3-fraction. Immune complexes in large quantities circulate in the blood and deposited in the bile ducts, causing immune inflammation - autoimmune non-bacterial cholangitis and cholangiolitis. Stellate reticuloendotheliocytes (Kupffer cells) in primary biliary cirrhosis of the liver are not able to eliminate immune complexes, which creates the prerequisites for a long-lasting persistence of immune inflammation.

Antimitochondrial antibodies (AMA) are detected in the blood of almost 100% of patients with primary biliary cirrhosis. They are not organ- or species-specific. The antigens against which these antibodies are directed are located on the inner membrane of the mitochondria. For the serum of patients with primary biliary cirrhosis, the antigenic component of M2 is specific. Four antigenic M2 polypeptides have been identified, all of which are part of the pyruvate-dehydrogenase (PDH) complex of mitochondrial enzymes. El-2-oxo-acid dehydrogenase complex with a molecular mass of 50 kD, E2 is a complex of dihydrolipoamidacyltransferase with a molecular mass of 74 kD, an E3-2-oxoglutarate complex with a molecular mass of 50 kDa. In PDH enters and protein X (52 kDa), which cross-reacts with E2. E2 and the components of the M2 complex can be detected by enzyme immunoassay (ELISA). This study allows diagnosing primary biliary cirrhosis in 88% of cases. Its specificity is 96%. In the absence of antibodies to M2 in the serum, the diagnosis of primary biliary cirrhosis is unlikely. Conducting a specific sensitive ELISA is not always possible; in such cases, the serum is usually tested for antibodies to mitochondria by indirect immunofluorescence, using as a substrate the kidney of a rat. This is a complicated technique, which in laboratories that do not have sufficient experience can give false negative results.

There are other mitochondrial antigens and antibodies. Anti-M9 antibodies are detected in the early stages of primary biliary cirrhosis, they can also be found in healthy relatives of patients and in laboratory assistants working with the serum of patients with primary biliary cirrhosis. Anti-M9 antibodies are found in 10-15% of healthy people. In the presence of M2, M4 and M8 can also be detected; possibly, their presence indicates a more progressive course of the disease. M3 is associated with reactions to drugs, MB - with the intake of iproniazide, and M5 - with systemic diseases of connective tissue.

Antinuclear antibodies (AHA) to a polypeptide with a molecular mass of 200 kDa cause perinuclear emission in 29% of patients with primary biliary cirrhosis. Their relationship with AMA in primary biliary cirrhosis is not clear.

Along with antimitochondrial antibodies, other antibodies are found in primary biliary cirrhosis: antinuclear (in 20-40% of cases); antibodies to components of smooth muscles (in 10-50%); antibodies to bile duct components (in 60%); rheumatoid factor; antithyroid, antilymphocytic, antiplatelet antibodies; antibodies to ribonucleoprotein, to the acetylcholine receptor. However, antimitochondrial antibodies are most typical, they are detected in 80-100% of patients with primary biliary cirrhosis.

2. Expression of cell-cell adhesion molecules on epithelial cells of biliary tubules.

In recent years, a large pathogenetic role of a certain class of cell membrane proteins - intercellular adhesion molecules (MKAM) has been established. Induction and maintenance of T-cell cytotoxicity in the epithelium of the biliary tubules is accomplished by adhesion of lymphocytes to target cells and immunocytes. In turn, adhesion of lymphocytes is realized through the interaction of leukocyte antigen and intercellular adhesive molecules MKAM-1 and MKAM-2.

Expression of MKAM-1 on epithelial cells of biliary tubules is observed only in patients with primary biliary cirrhosis and primary sclerosing cholangitis.

MKAM-1 is a key mediator of adhesion of lymphocytes, therefore, increased expression of these molecules in interlobular ducts increases their damage mediated by 1-cells.

3. Development of delayed-type hypersensitivity.

In response to mitochondrial antigens of the bile duct epithelium, a delayed-type hypersensitivity reaction develops that causes cytolysis of the epithelium of the intrahepatic biliary tract (antigen-specific or antibody-dependent-K-cell). This is facilitated by the expression of MKAM-1 on the epithelial cells of the biliary tubules.

4. Disturbance in the subpopulation of T-lymphocytes.

Patients with primary biliary cirrhosis develop congenital or acquired deficiency of T-suppressor function of lymphocytes and a significant increase in the activity of T-lymphocytes-helpers, which contributes to the development of autoimmune reactions in relation to the components of the biliary tubules.

5. Disturbance of bile acid metabolism.

Damage to the epithelium of the bile ducts leads to the entry of bile acids into periductular spaces, which contributes to the development of inflammatory reactions, fibrosis, the formation of liver cirrhosis.

[16], [17], [18]

Symptoms of the primary biliary cirrhosis

Approximately 30-50% of patients develop the disease without clinical manifestations; primary biliary cirrhosis of the liver is detected accidentally by changes in functional liver tests, with an increase in alkaline phosphatase usually determined. Symptoms or signs may appear at any stage of the disease and include fatigue or symptoms of cholestasis (and, as a result, malabsorption of fat and vitamin deficiency, osteoporosis), hepatocellular dysfunction or cirrhosis. Symptoms usually appear gradually. Skin itching, fatigue or both symptoms together are the initial symptoms in more than 50% of patients and can outpace the appearance of other symptoms for months or years. Other common signs in the development of the disease include liver enlargement, densification, mild tenderness (25%); splenomegaly (15%); hyperpigmentation (25%); xanthelasma (10%) and jaundice (10%). Eventually, all the symptoms and complications of cirrhosis develop. Also, peripheral neuropathy and other autoimmune disorders associated with PBC can develop.

Primary biliary cirrhosis of the liver is mainly affected by women, more often at the age of 35-50 years. Men suffer from primary biliary cirrhosis very rarely. Mostly women are sick, more often at the age of 35-50 years. Men suffer from primary biliary cirrhosis very rarely.

The disease begins suddenly, most often with itching, not accompanied by jaundice. Initially, patients, as a rule, turn to a dermatologist. Jaundice may be absent, but in most cases it develops within 6 months - 2 years after the appearance of pruritus. About a quarter of cases of jaundice and itching appear simultaneously. The development of jaundice before the occurrence of pruritus is extremely rare; the presence of jaundice without itching is uncharacteristic for any stage of the disease. Itching may appear during pregnancy and be regarded as a cholestatic jaundice of the last trimester. Patients are often concerned about persistent pain in the right upper quadrant of the abdomen (17%). Over time, they can disappear. To clarify the diagnosis, an endoscopic examination of the upper sections of the gastrointestinal tract is necessary. Often there is increased fatigue.

The initial stage of primary biliary cirrhosis

1. Skin itching is the most characteristic symptom of the initial period of primary biliary cirrhosis. Initially, itching may be fickle, then permanent, painful, worse at night and after a warm bath.

Most often, itching is combined with jaundice, but in some patients it precedes jaundice, which can appear only a few months or even years later. Skin itching is accompanied by scratching, and often also by infection of the skin. Itching so badly bothers the sick that it may seem unbearable, the patients scratch even in their sleep. Itching is caused by the accumulation of bile acids in the blood and irritation of the cutaneous nerve endings. It is also assumed that the liver produces specific substances - pruritigens that cause skin itching. There is a skin lichenization (thickening, coarsening, emphasizing its pattern).

2. Dark brown pigmentation of the skin is observed in 55-60% of patients in the initial stage of the disease. It is caused by the deposition of melanin, appears first in the area of the scapula, then in the area of the extensor surface of the joints and in the remaining parts of the body.
3. Slowly increasing jaundice of the cholestatic type - in the early period of primary biliary cirrhosis occurs in approximately 50% of patients. Rapidly increasing jaundice in the early period of the disease is considered a prognostically unfavorable sign, indicating a high activity and rapid progression of the disease.
4. Xanthelases - observed in 20-35% of patients. They represent the formation of a yellow above the skin of soft consistency, due to the deposition of cholesterol. Xanthelases are located mainly in the upper eyelid, but can also be found on the palms, chest, back, extensor surface of the elbows, knee joints, buttocks.
5. Extrahepatic manifestations - "hepatic palms", "vascular sprouts" in the initial period of primary biliary cirrhosis are very rare (only in individual patients).
6. Hepatomegaly - a characteristic sign of primary biliary cirrhosis, is detected in most patients. The liver protrudes from the edge of the costal arch for 2-3 cm, it is dense, its edge smooth, pointed.
7. Splenomegaly - is detected in 50-60% of patients, the degree of splenomegaly is small, there are no signs of hypersplenism.
8. Nonspecific symptoms - in the initial stage of primary biliary cirrhosis, pains in the right hypochondrium, joints, myalgia, dyspeptic phenomena (lack of appetite, nausea, bitterness in the mouth) may occur, possibly a rise in body temperature.

The unfolded stage of primary biliary cirrhosis

1. General symptoms (nonspecific manifestations). In the expanded stage of primary biliary cirrhosis nonspecific symptoms of the disease are pronounced. Patients are disturbed by a pronounced general weakness, fever to subfebrile figures (sometimes to febrile), significant weight loss, and lack of appetite.
2. Skin itching, changes in the skin and its appendages. At this stage, painful itching is continuing. The pigmented skin thickens, coarsens, especially in the area of the palms and soles, in the far-reaching stage there is a dense swelling of the skin (resembling scleroderma, similarity is further enhanced by pigmentation). There are traces of numerous scratching that can become infected. Foci of depigmentation are often observed (resemble vitiligo), papular, vesicular rash, after opening the vesicles there are crusts. It is possible to pigment the nails and thicken them in the form of watchglasses, the terminal phalanges of the fingers of the hands thicken in the form of drumsticks. In rare cases, increased growth of hair on the face and limbs. Characteristic of xanthelasm. Characteristic of the appearance of "hepatic palms" and "vascular asterisks".
3. Enlargement of the liver and spleen. In the expanded stage of primary biliary cirrhosis, the liver sharply increases, becomes dense, its edge sharpens. The size of the spleen considerably increases, in some patients the hypersplenism syndrome develops (pancytopenia).
4. Syndrome of portal hypertension. In the expanded stage of primary biliary cirrhosis is characterized by the development of portal hypertension syndrome, in particular, the varicose veins of the esophagus and stomach are defined, bleeding from them is possible. However, ascites at this stage is infrequent, it is more typical for the final (terminal) stage of the disease.
5. Malabsorption syndrome fat-soluble vitamins. Violation of secretion and excretion of bile leads to atrophy of villi small intestine and the development of malabsorption syndrome fat-soluble vitamins D, A, K. Vitamin D deficiency manifests itself by the following symptoms:

• develops osteoporosis, which is characterized by pain in the joints ("biliary rheumatism"), bones, ribs, vertebrae; pathological fractures; kyphosis; detection of areas of rarefaction of bone tissue on the radiographs of bones (ribs, scapula, pelvis, cervical rib, etc.).
• the hard plate of teeth collapses, the teeth loosen and fall out.

Reducing the absorption of vitamin A contributes to trophic skin disorders, increased dryness, and visual impairment.

Violation of absorption of vitamin K contributes to the development of hemorrhagic syndrome, which is also aggravated by a violation of the synthesis in the liver of prothrombin and other procoagulants.

6. System manifestations. For the expanded stage of primary biliary cirrhosis, systemic lesions of various internal organs are also natural:

• Sjogren's syndrome is revealed in 70-100% of patients with expressed cholestasis. The manifestations of Sjogren's syndrome may be mild and unrecognized, especially since the subjective symptomatology of the disease is dominated by intense itching.
• endocrine disorders are manifested in impaired ovarian function in women (amenorrhea, dysmenorrhea), a violation of testicular function in men (decreased libido sexualis, sexual weakness, reduction of secondary sexual characteristics, testicular atrophy, reduction in penis size); development of hypofunction of the adrenal cortex; the hypothalamus; insufficiency of the incremental function of the pancreas in the form of impaired glucose tolerance or manifest diabetes mellitus;
• defeat of the lungs in the form of diffuse pneumosclerosis (deformation of the lung pattern, tight, loopy, cellular shadows on chest radiographs) and fibrosing alveolitis.
• renal damage is characterized by the development of glomerulonephritis, tubulointerstitial nephritis;
• the disturbance of the function of the digestive system is manifested by chronic gastritis, duodenitis, duodenesis, hypotonia of the small intestine. Often develops chronic pancreatitis with a decrease in the secretory function of the pancreas and steatorrhea;
• an increase in peripheral lymph nodes.

Systemic manifestations of primary biliary cirrhosis are caused by cross-immune reactions that develop due to the commonness of tissue antigens of intrahepatic bile ducts, salivary glands, kidneys, other internal organs and endocrine glands, and also due to the presence of vasculitis of various organs.

7. Accompanying illnesses.

A combination of primary biliary cirrhosis with almost all known autoimmune diseases is described. Especially often it is combined with systemic diseases of connective tissue, in particular with rheumatoid arthritis, dermatomyositis, mixed connective tissue disease and systemic lupus erythematosus.

In 4% of cases, primary biliary cirrhosis is combined with scleroderma, can also be combined with CREST-syndrome. Scleroderma is usually limited to sclerodactyly, the face, forearms, and tibia may be involved. There is keratoconjunctivitis. Ro-antibodies with a molecular mass of 20-52 kD are usually detected in these patients. Dryness in the mouth and eyes is detected in almost 75% of patients; in some cases, in combination with arthritis, these manifestations constitute a complete Sjogren's syndrome.

Other concomitant skin lesions include the immunocomplex capillary and red lichen planus. Autoimmune thyroiditis develops in about 20% of cases. The development of diffuse toxic goiter is described.

Possible atrophy of the cilia of the jejunum, reminiscent of celiac disease. Another rare combined disease can be ulcerative colitis.

The possibility of development in primary biliary cirrhosis of autoimmune thrombocytopenia and the appearance of autoantibodies to insulin receptors is shown.

Complications from the kidneys include IgM-associated membranous glomerulonephritis.

As a result of the deposition of copper in the distal renal tubules, renal tubular acidosis can develop. Other manifestations of damage to the tubules of the kidneys are hypouricemia and hyperuricosuria. In 35% of cases, bacteriuria develops, which can be asymptomatic.

A combination of primary biliary cirrhosis with selective IgA deficiency is described. This shows that IgA-dependent immune mechanisms do not participate in the pathogenesis of the disease.

The risk of developing breast cancer in patients with primary biliary cirrhosis is 4.4 times higher than in the population.

A combination of primary biliary cirrhosis with transverse myelitis, which develops as a result of angiitis and necrotizing myelopathy, has been identified. Often there is a change in the fingers in the form of tympanic sticks, hypertrophic osteoarthropathy can develop.

As a result of a decrease in the outflow of bile, and possibly, the immune damage to the pancreatic duct, pancreatic insufficiency develops.

Stones of bile ducts, usually of pigment type, with ERCPH were observed in 39% of cases. Sometimes they are accompanied by clinical manifestations, but rarely move into the common bile duct.

Disturbances in gas exchange in the lungs, apparently, are associated with the nodules and interstitial fibrosis revealed during X-ray examination. With lung biopsies, the lesion of the interstitial lung tissue is detected. In addition, the formation in the interstitium of light giant cell granules is described. Such patients often develop Sjogren's syndrome with the formation of Ro-antibodies.

CREST-syndrome is accompanied by interstitial pneumonitis and pulmonary vascular lesions.

In computed tomography, 81% of patients in the gastrohepatic ligament and in the portal of the liver show enlarged (lymphatic) nodes. There is also an increase in the pericardium and mesenteric nodes.

In men, primary biliary cirrhosis can be combined with lymphogranulomatosis, colon cancer, bronchi, and the prostate gland.

Terminal stage of primary biliary cirrhosis

Clinical manifestations in the terminal stage (stages of decompensated hepatic insufficiency and portal hypertension) are the same as in the II stage, but much more pronounced and steadily progressing. In addition, the manifestations of decompensated portal hypertension (edema, ascites, bleeding from varicose veins of the esophagus, stomach, hemorrhoidal veins), depletion of patients, severe malabsorption syndrome, and kidney damage are characteristic.

In the terminal stage, it is possible to reduce and even disappear the skin itching. Progression of hepatic, hepatorenal insufficiency, develops severe hepatic encephalopathy, which ends with a hepatic coma.

The main causes of death of patients with primary biliary cirrhosis are hepatic coma, bleeding from varicose veins of the esophagus, stomach.

"Asymptomatic" patient

The widespread use of automated biochemical studies has led to more frequent detection of cases at the asymptomatic stage, usually by increasing serum alkaline phosphatase. With liver biopsy performed in patients with an AMA titer of 1:40 and above, changes usually corresponding to the pattern of primary biliary cirrhosis are almost always detected, even if the subject does not have anything to worry about and the serum alkaline phosphatase level is normal.

Primary biliary cirrhosis can be diagnosed in patients undergoing examination for diseases that can be combined with it, for example, for systemic connective tissue diseases or thyroid diseases, as well as for a family history of a family history.

In clinical examination, signs of the disease may be absent. AMA is always detected. The level of alkaline phosphatase and bilirubin in the serum can be normal or slightly elevated. The level of cholesterol and transaminases can be unchanged.

[19], [20], [21], [22], [23], [24], [25],

The course of primary biliary cirrhosis

The life expectancy of patients with asymptomatic flow is usually 10 years. With clinical manifestations of the disease and jaundice, life expectancy is about 7 years.

Due to steatorrhea, diarrhea can develop. Slowly decreases body weight. Patients are most concerned about fatigue, but their normal lifestyle, as a rule, is not violated. The disease proceeds without fever; Pain in the abdomen is rare, but can be prolonged.

Often observed xanthomas on the skin, which sometimes appear acutely, but in many cases the disease occurs without the formation of xanthomas; in the terminal stage of the disease, xanthomas can disappear.

The skin on the fingers, ankles and lower legs thickens and coarsens. Xanthomatosis can cause peripheral polyneuropathy, which is manifested by pain in the fingers (especially when opening the doors) and legs. On the back, the area of intact skin in the form of butterfly wings can be preserved, to which it is impossible to reach and on which there are no traces of scratching.

Bone changes develop as a complication of chronic cholestasis and are especially pronounced with significant jaundice. On the far-reaching stages of patients, pain in the back and along the ribs disturb, and sometimes pathological fractures develop.

Ulcers are often formed in the duodenum, which are complicated by bleeding.

Bleeding from varicose veins of the esophagus may be the first manifestation of the disease, even before the appearance of the nodes. At this stage, portal hypertension is most likely a presynusoid. Over 5.6 years of follow-up, 83 (31%) of 265 patients developed varicose veins of the esophagus, 40 (48%) had bleeding.

Hepatocellular carcinoma (fcc) is very rare, because nodular cirrhosis only develops in later stages.

Stages

Classification of Childe-Turcott-Pugh

Clinical 1 and laboratory parameters	1	2	3
Encephalopathy (degree)	No	1-2	3-4
Ascites	No	Not expressed (treatable diuretics)	Moderate, despite diuretic therapy
PV (increase in seconds)	<4	4-6	> 6
MHO	<1.7	1.7-2.3	> 2.3
Albumin (g / dl)	> 3.5	2.8-3.5	<2.8
Bilirubin (mg / dL)	<2	2-3	> 3

¹ Classification of ratings: 5-6 points - class A (low risk); 7-9 points - class B; 10-15 points - class C (high risk).

• Stage 1: sleep disturbance; decrease in concentration; depression, anxiety or irritability.
• Stage 2: drowsiness; disorientation; decrease in short-term memory; disinhibited behavior.
• Stage 3: Substitution; confusion of consciousness; amnesia; anger; paranoia or other abnormal behavior.
• Stage 4: coma.

Macroscopically, the liver is enlarged, greenish in color, enlarged lymph nodes are defined in the portal of the liver.

According to the puncture biopsy, four morphological stages of the evolution of the primary biliary cirrhosis are isolated.

1. Stage of pulmonary destructive cholangitis: inflammatory infiltration and destruction of interlobular (portal) and septal bile ducts with a granulomatous response. The expanded portal tracts are infiltrated by lymphocytes, plasma cells, macrophages, eosinophils. The infiltration of portal tracts, as a rule, does not penetrate deeply into the parenchyma, only small lymphocytes or groups of lymphocytes penetrate into the liver lobules. An electron microscopic examination revealed a violation of the integrity of the basal membrane. Near the affected bile ducts are granulomas, consisting of epithelioid and giant multinucleated cells. There are no histological signs of cholestasis at this stage.
2. The stage of proliferation of cholangiol and periductular fibrosis. In the portal tracts, along with lymphoplasmocellular infiltration and collapsing bile ducts, proliferative foci of the biliary epithelium appear, which spread to the periportal parts of the lobes along with the infiltrates. There is a specific for the primary biliary cirrhosis symptom - "empty portal tracts", whose inflammatory infiltrates do not contain bile ducts. Around the surviving biliary tract, connective tissue proliferates. In connection with the reduction of the bile ducts, cholestasis develops. Later the number of granulomas in the liver decreases, many of them are subjected to fibrosis.
3. Strokes fibrosis in the presence of inflammatory liver infiltration.

At this stage, connective tissue interlayers form the portal tracts and connect to adjacent tracts (portoportal septa), and also connect the central veins with portal tracts (portocentral septa). The proliferation of the bile ducts decreases, the reduction of interlobular and septal bile ducts increases, which, naturally, leads to an increase in cholestasis. Along with this, cell infiltration of the parenchyma is enhanced, hepatocyte necrosis is more numerous, fibrosis is increased, monolobular pseudolulks are formed.

4. The final stage.

This stage is characterized by all signs of a large-nodular or mixed cirrhosis of the liver with pronounced cholestasis on the background of impoverishment of the parenchyma by the bile ducts.

[26], [27], [28], [29], [30], [31]

Diagnostics of the primary biliary cirrhosis

Primary biliary cirrhosis is suspected in middle-summer women for classic signs or changes in biochemical analyzes indicating cholestasis: increased alkaline phosphatase and gamma glutamyl transpeptidase levels, but minimal changes in the level of aminotransferases (ALT and ACT). In the early stages, serum bilirubin levels are usually within normal limits; its increase indicates a progression of the disease and an unfavorable prognosis. IgM level in serum is markedly increased. A positive result in the determination of antimitochondrial antibodies of blood serum (sometimes also positive in low titres for autoimmune hepatitis type 1) confidently indicates a diagnosis. Other autoantibodies in patients with PBC include rheumatoid factor (66%), anti-smooth muscle antibodies (66%), antithyroid antibodies (40%), and antinuclear antibodies (35%). A liver biopsy is usually performed to confirm the diagnosis and identify early pathognomonic symptoms of the lesions of the bile ducts during the course of the disease. However, the primary biliary cirrhosis of the liver has four stages, and as the progression of fibrosis becomes morphologically indistinguishable from other forms of cirrhosis of the liver.

Out-hepatic biliary obstruction should be excluded, if necessary, instrumental methods of investigation (including ultrasound, magnetic resonance cholangiopancreatography and, according to indications, ERCP) are used for this.

Laboratory data

1. General analysis of blood: signs of anemia, increased ESR, in the active period of the disease is possible leukocytosis, with the development of the syndrome of hypersplenism pancytopenia.
2. General urine analysis: proteinuria, bilirubinuria, absence of urobilin. The analysis of feces for strobobilin is weakly positive or negative, the stool is slightly colored or discolored (achiolia).
3. Biochemical blood test: biochemical syndrome of cholestasis is characteristic - hyperbilirubinemia (mainly due to an increase in the conjugated fraction of bilirubin); with complete cessation of outflow of bile, hyperbilirubinemia reaches 250-340 μmol / L, an increase in the content of alkaline phosphatase, 5-nucleotide, γ-glutamyltranspeptidase, bile acids (especially lithocholic acid), copper, cholesterol, beta-lipoproteins, phospholipids, unesterified fatty acids; decrease in the content of iron in the blood. The activity of the aforementioned enzymes of cholestasis increases with primary biliary cirrhosis already in the early stages. The activity of aminotransferases in blood serum also increases, the content of y and beta globulins increases, and the albumin level decreases.
4. Immunological analysis of blood: reduced the total number of T-lymphocytes, activated T-lymphocytes, as well as T-lymphocytes-suppressors. Characteristic is an increase in the number of circulating immune complexes. Increased blood IgM, often also IgA and IgG.

Extremely characteristic is the detection of antimitochondrial antibodies (AMA), they are detected already in the early stages of the disease. The AMA titer correlates with the degree of activity, stage and histological manifestations of primary biliary cirrhosis. AMA can be detected even at the preclinical stage and do not disappear during the entire period of the disease. The most characteristic is the detection of antibodies against the mitochondrial adenine nucleotide translocator (ANT antibody) or mitochondrial ATP-ase-antigen M ₂. Diagnostically significant is the titer of 1:20 - 1:40. In some cases, it is possible to detect antibodies to thyroglobulin in the serum, rheumatoid factor, etc.

[32], [33], [34]

Instrumental data

• Ultrasound of the liver and bile ducts: enlargement of the liver, unchanged large bile ducts. Possible detection of stones in the bile duct (in 20-30% of patients).
• Ultrasound of the spleen: splenomegaly.
• PHEGDS: in the stage of the formed cirrhosis of the liver, varicose veins of the esophagus and stomach are detected.
• Puncture liver biopsy.

The defeat of septal or interlobular bile ducts is a diagnostic feature characteristic of primary biliary cirrhosis. With puncture liver biopsy, these bile ducts are often not visualized, but are usually clearly identified in the liver tissue taken in an open manner. Such a biopsy is less and less, since the frequency of surgical interventions is decreasing. The material obtained by puncture biopsy should be studied by an experienced pathomorphologist.

The disease begins with damage to the epithelium of small bile ducts. Histometric examination showed that bile ducts with a diameter of less than 70 ± 80 μm are destroyed, especially in the early stages. Epithelial cells are swollen, more eosinophilic and have an irregular shape. The lumen of the bile ducts is uneven, the basal membrane is damaged. Sometimes there is a rupture of the bile ducts. Around the damaged duct, cell infiltration is detected by lymphocytes, plasma cells, eosinophils and histiocytes. Granules are often formed, usually in Zone 1.

The bile ducts are destroyed. In the course of their location, clusters of lymphoid cells are noted, and the bile ducts begin to proliferate. In the portal zones, branches of the hepatic artery can be seen, but without the accompanying bile ducts. Fibrosis extends beyond the portal zones, stepped necrosis is seen. Histochemical methods of investigation reveal the deposition of a significant amount of copper and copper-bound protein. Fibrotic septa gradually destroy the hepatic architectonics, regeneration sites are formed. The latter are often unevenly distributed, so that in some areas of the biopsy cirrhosis is visible, in others - not. In some areas the lobular structure is not broken. In the early stages, cholestasis is restricted to zone 1 (portal).

The deposition of hyaline, similar to that observed with alcoholic illness, is found in hepatocytes in 25% of cases.

Depending on the histological picture, there are 4 stages:

• Stage I - pronounced lesion of bile ducts;
• II stage - proliferation of the bile duct;
• III stage - scarring (fibrosis septal and bridge);
• IV stage - cirrhosis. The significance of this division at the stage is small, since changes in the liver are of a focal character and occur at different rates in different parts of it. There are no clear differences between the stages. It is especially difficult to distinguish between stages II and III. The course of the disease is marked by considerable variability, in the absence of symptoms, a picture corresponding to the far-advanced stage III can be observed. Moreover, with multiple biopsies it is shown that the same stage can persist for many years.

• Radioisotope hepatography with Bengal pink, labeled with 131I, reveals a sharp violation of the excretory function of the liver.
• Infusion cholangiography (performed with hyperbilirubinemia, which does not exceed the norm by 3-4 times): reveals unchanged extrahepatic bile ducts.

Diagnostic criteria

1. Intense skin itching, extrahepatic manifestations (dry Sjogren's syndrome, rheumatoid arthritis, etc.).
2. Increase in activity of enzymes of cholestasis in blood serum is 2-3 times in comparison with the norm.
3. Normal extrahepatic bile ducts with ultrasound and X-ray contrast study.
4. Detection of antimitochondrial antibodies in serum in a titer above 1:40.
5. Increase of IgM content in blood serum.
6. Characteristic changes in punctate liver.

The diagnosis of primary biliary cirrhosis is made in the presence of the 4th and 6th criteria or 3-4 of these signs. It should also be taken into account the absence of markers of hepatitis B, C, D.

[35], [36], [37], [38],

Survey program

1. General analysis of blood, urine, feces. Urine analysis for bilirubin, urobilin, analysis of feces for stercobilin.
2. Biochemical blood test: determination of the content of total protein and protein fractions, level of aminotransferases, sulemic and thymol samples; identification of biochemical cholestatic syndrome (determination of activity of alkaline phosphatase, γ-glutamyl transpeptidase, 5-nucleotidase, bilirubin, cholesterol, lipoproteins, NEFLC, copper). Determination of urea, creatinine.
3. Immunological examination of blood: determination of the content and activity of T-lymphocytes and their subpopulations, B-lymphocytes, immunoglobulins, antimitochondrial antibodies, rheumatoid factor, antibodies to smooth muscles, thyreoglobulin, circulating immune complexes.
4. Ultrasound of the liver, bile ducts, spleen, kidneys.
5. Radioisotope hepatography.
6. FEGDS.
7. Laparoscopy with targeted liver biopsy, with the impossibility of performing laparoscopy - puncture biopsy of the liver under the supervision of ultrasound.
8. Infusion cholangiography (with hyperbilirubinemia, which exceeds the norm by 3-4 times), if necessary, differential diagnosis with secondary biliary cirrhosis.

Differential diagnosis

Most often, primary biliary cirrhosis of the liver must be differentiated with secondary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis with cholestatic syndrome, liver and bile duct cancer, and cholestasis caused by medication.

Differential diagnosis of primary biliary cirrhosis of the liver and active hepatitis with cholestasis syndrome is very difficult in the early stages of primary biliary cirrhosis in the absence of a clear histological picture, especially since primary biliary cirrhosis for a long time proceeds as chronic destructive cholangitis without obvious signs of liver cirrhosis.

It is often necessary to differentiate primary biliary cirrhosis with drug cholestatic hepatitis. For medicinal cholestatic hepatitis in contrast to primary biliary cirrhosis are characterized by:

• a history of taking medications that cause cholestasis (steroid anabolic drugs, aminazine, oral contraceptives, methyltestosterone, chlorpropamide, bougamid, sulfonamides, etc.);
• absence of antimitochondrial antibodies in the blood;
• in liver biopsies, the destruction of interlobular bile ducts and cell infiltration of portal tracts are less pronounced;
• the abolition of drugs leads to the reverse development of the cholestatic syndrome.

It is often necessary to differentiate primary biliary cirrhosis with mechanical (subhepatic) jaundice.

The basis of diagnosis in these cases is the use of ultrasound (detection of stone, tumor, compression from the outside of the common hepatic duct, choledocha), retrograde cholangiography, computed tomography, in diagnostic and unclear cases, laparoscopy and even laparotomy.

Differential diagnosis of primary biliary cirrhosis

Disease	Features	AMA	Liver biopsy
PBC	Women are more often ill Itchy High serum amorphous serum levels	Identify	Damage of bile ducts Lymphoid cell aggregations Small stepped necrosis Lobules intact Peripheral cholestasis
Primary sclerosing cholangitis	Men are more often ill Combined with ulcerative colitis Diagnosed with cholangiography	None or in low titre	Fibrosis and proliferation of bile ducts Fibrosis of ducts in the form of onion husks
Cholestatic variant of sarcoidosis	Sexual differences in frequency are absent Negroes suffer from a bowl Itchy High serum amorphous serum levels Changes in chest radiographs	None	A large number of granules Moderate changes in bile ducts
Autoimmune cholangiopathy	Women are more often ill High serum FS level High serum AHA titer	None	Damage of bile ducts Lymphoid cell aggregations Small stepped necrosis
Cholestatic reactions to drugs	Anamnesis Development within 6 weeks from the beginning of taking the medicine Sharp beginning	None	Infiltration of portal tracts with mononuclears, sometimes eosinophils; formation of granules and fatty infiltration

[39], [40], [41], [42], [43]

Treatment of the primary biliary cirrhosis

Treatment objectives include stopping or reverse development of pathological changes in the liver, treatment of complications (chronic cholestasis and liver failure) and, ultimately, liver transplantation. The use of alcohol and any hepatotoxic drug should be ruled out. Ursodeoxycholic acid (4.3-5 mg / kg orally 2 times a day or 3.25-3.75 mg / kg orally 4 times a day during meals) reduces liver damage, prolongs life expectancy and delays the timing of liver transplantation . Approximately 20% of patients after 4 months of treatment have no improvement in biochemical parameters; the disease in these patients is likely to progress, and after a few years they will need liver transplantation. Other drugs offered for treatment do not improve the overall clinical outcome or give inconsistent results; such drugs include glucocorticoids, penicillamine, colchicine, methotrexate, azathioprine, cyclosporine and chlorambucil.

Cutaneous itching can be controlled by cholestyramine (6-8 g orally 2 times a day). Some patients with pruritus have a positive effect when treated with ursodeoxycholic acid and UFO; in others - when taking rifampin or opiate antagonists, for example naltrexone. Malabsorption of fat can require additional intake of calcium and vitamin A, D, E and K vitamins. For osteoporosis, vitamin D, exercise, bisphosphonates, estrogens or raloxifene should be added to calcium preparations. At later stages, it becomes necessary to treat portal hypertension or liver cirrhosis.

Liver transplantation leads to excellent results. A common indication is decompensation of the liver disease: repeated bleeding from varicose veins, refractory ascites, severe skin itching and hepatic encephalopathy. Survival within a year after liver transplantation exceeds 90%; over 5 years more than 80%. Primary biliary cirrhosis recurs in approximately 15% of patients during the first few years, although these data are not clinically relevant.

Symptomatic treatment

Symptomatic treatment of primary biliary liver cirrhosis is performed in all to reduce itching and steatorrhea.

Loss of vitamin D and calcium due to insufficient intake of bile in the intestine leads to osteomalacia, to eliminate which additionally prescribed vitamin D and calcium. Much more common and significantly more important is osteoporosis. It is not amenable to treatment, but nevertheless requires the appointment of calcium, insolation and increased levels of physical activity. You can conduct courses of hormone replacement therapy, although the risk of developing breast cancer increases. Treatment with calcitonin was ineffective.

Immunosuppressive drugs

Their effectiveness is low, much lower than with autoimmune chronic active hepatitis, in which the appointment of corticosteroids leads to a significant improvement. Ineffectiveness of azathioprine, penicillamine and chlorambucil is shown. The use of corticosteroids can reduce clinical manifestations and improve biochemical parameters, but is associated with increased bone resorption, and therefore their use is undesirable.

In small studies, it has been shown that cyclosporin A alleviates symptoms and improves biochemical performance. These liver biopsies indicate a slowdown in the progression of the disease. The use of this drug is limited to its nephrotoxicity and hypertensive effect; long-term admission is unsafe.

Methotrexate in a dose of 15 mg orally once a week also helps to reduce the severity of symptoms and lower levels of alkaline phosphatase and bilirubin in the serum. A liver biopsy shows a decrease in inflammation. The Mayo forecast index does not change. Among the side effects, there was a tendency to decrease the white blood cell and platelet counts, indicating reversible myelotoxicity. In 12-15% of cases interstitial pneumonitis develops, which undergoes reverse development after cessation of treatment and corticosteroids. Methotrexate has little effect on survival. The effect of the drug on the course of primary biliary cirrhosis is very diverse. In general, with this disease, prescribe the drug should not be; it is used only in ongoing clinical trials.

Colchicine inhibits the synthesis of collagen and enhances its destruction. In patients with primary biliary cirrhosis, the drug improves the synthetic function of the liver, but does not affect survival. Colchicine - an inexpensive drug and almost no side effects, but its effectiveness in primary biliary cirrhosis should be recognized as minimal.

Ursodeoxycholic acid is a non-toxic liver hydrophilic bile acid, which reduces the possible hepatotoxicity of endogenic bile acids. It is expensive, used in a total dose of 13-15 mg per 1 kg of body weight 2 times a day: after dinner and after dinner. A placebo study conducted in France showed that ursodeoxycholic acid slows the progression of the disease, increases survival and reduces the need for liver transplantation. The level of bilirubin in the serum is reduced. With a high baseline level of bilirubin and the presence of cirrhosis, the results of treatment were worse. A study in Canada showed less encouraging results: serum bilirubin levels declined, biochemical indicators improved, but clinical manifestations, histological pattern in the liver, survival or duration of treatment before liver transplantation did not change. In a study conducted in the Mayo clinic using placebo, patients who received ursodeoxycholic acid showed only a slight increase in the time at which serum bilirubin levels doubled. The histological picture in the liver did not change. At earlier stages of the disease, the results were better. A meta-analysis of the results of all studies on this issue revealed a significant but small increase in life expectancy and duration of treatment before liver transplantation. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis can not be considered a panacea. Nevertheless, it should be prescribed to all patients, with the exception of patients in the terminal stage, who are scheduled to perform liver transplantation. It is difficult to decide whether to treat ursodeoxycholic acid in patients at early, asymptomatic stages; the decision is made individually, taking into account the costs of treatment.

Combination treatment with lower doses of drugs may be more effective, for example, colchicine and ursodeoxycholic acid or ursodeoxycholic acid and methotrexate can be combined.

At present, there is no sufficiently effective specific therapy for primary biliary cirrhosis. In the early stages of the disease, some improvement is due to the use of ursodeoxycholic acid.

The carried out researches had many lacks, they were short, covered a small amount of patients. With a disease with such a long and volatile course, it is difficult to detect statistically significant long-term effects of any effects. In any study, the number of patients in each group should be indicated. At early, asymptomatic stages of the disease, patients with good health do not need treatment at all. With an unfavorable prognosis and a far-reaching disease, the effect of treatment is also unlikely. The study should include groups in the intermediate stages of the disease. When evaluating the effectiveness of any treatment methods, it is necessary to build on the results of large, controlled clinical trials.

Bleeding from varicose-extended veins of the esophagus can develop in the early stages, even before the development of true nodular cirrhosis. It is not surprising, therefore, that the conduct of portocaval shunting in such patients has a positive effect. Liver encephalopathy rarely develops. Especially favorable are the results of treatment of patients from low-risk groups. In some cases, effectively transgular intrahepatic portosystemic shunting with the help of stents.

Gallstones, if they do not cause severe pain or are not located in the common bile duct, should not be removed. Indications for cholecystectomy occur very rarely, the patient is not well tolerated.

Liver transplantation

Liver transplantation is indicated in case of a significant decrease in the patient's activity, when he is practically unable to leave the house. Indications for liver transplantation are also non-treatable itching, ascites, hepatic encephalopathy, bleeding from varicose-esophageal veins, recurrent infections. Transplantation is more successful and economically more profitable, if it is produced in the early stages of the disease. It is likely that patients should be referred to the liver transplant center at a serum bilirubin level of 150 μmol / l (9 mg%).

Survival in transplantation is significantly increased. The annual survival after liver transplantation is 85-90%, and the 5-year survival rate reaches 60-70%. In 25% of cases it is necessary to perform a second transplantation, usually due to the development of the syndrome of vanishing bile ducts. After the operation, the condition of the patients often improves significantly.

Although AMA titer decreases in the first few months, it subsequently rises again. Probably, the disease recurs as a result of lesions of the transplanted liver. In one group, histological signs of recurrence of the disease 1 year after transplantation were revealed in 16% of patients. Symptoms of the disease are usually absent, although some patients have itching.

During the first 1-3 months there is a decrease in bone density, which can have catastrophic consequences. Probably, osteoporosis is caused by bed rest and corticosteroid therapy. After 9-12 months after transplantation begins the formation of a new bone and an increase in its density.

Immune cholangiopathy

Almost 5% of patients with onset of the disease, reminiscent of primary biliary cirrhosis, AMA in the serum are not detected. At the same time, high titers of AHA and antibodies to actin are found in the serum. Clinical manifestations of the disease are usually absent. Histological changes in the liver correspond to the pattern of primary biliary cirrhosis. The appointment of prednisolone leads to some improvement in clinical and biochemical parameters. Histologically, a decrease in inflammation is observed in the liver, but the lesion of the bile ducts persists, and the level of GGTP in the serum is very high. The disease in these cases is a combination of primary biliary cirrhosis and autoimmune chronic hepatitis.

Forecast

The course of primary biliary cirrhosis in the absence of symptoms is unpredictable, which creates significant difficulties in diagnosing the disease in the patient and his family members. In some cases, the symptoms do not develop at all, others show a progressive deterioration. Currently, patients with primary biliary cirrhosis in the terminal stage with the help of liver transplantation manage to save life.

The lifespan with asymptomatic flow of primary biliary cirrhosis, as compared with the index in the population, does not decrease. The timing of the development of symptoms described in the literature is very different, which is probably determined by the characteristics of the study groups of patients and methods of research. The duration of the disease depends on the timing of the diagnosis. In specialized centers, for example, at the Mayo Clinic or Royal Free Hospital, patients with advanced stages of the disease are usually observed, so the probability of their clinical manifestations is higher than in patients in regional centers, for example in Oslo or in Newcastle. In general, clinical manifestations in patients with asymptomatic primary biliary cirrhosis develop after 2-7 years.

In the case of clinical manifestations, prediction is especially important, since it allows determining the optimal timing for liver transplantation. If the level of bilirubin in the serum constantly exceeds 100 μmol / l (6 mg%), then the patient's lifespan will not exceed 2 years. In addition, survival is reduced in the presence of clinical manifestations, in elderly patients with hepatosplenomegaly, ascites and serum albumin levels below 435 μmol / L (3 g%). The prognosis is worse if histological examination reveals step necrosis, cholestasis, bridging fibrosis and cirrhosis.

Varicose veins develop in 31% of patients on average after 5.6 years, and 48% of them subsequently bleed. The probability of varicose veins is higher with a high serum bilirubin level and with pronounced histological changes. If varicose veins of the esophagus are detected, the survival rate during the year is 83%, and within 3 years - 59%. After the first bleeding, the survival rate during the year is 65%, and for 3 years - 46%.

No one model can accurately assess the survival of an individual patient. These models do not take into account a number of factors that reflect the dynamics of the disease. They can not predict life-threatening sudden complications, such as bleeding from varicose veins.

The terminal stage lasts approximately 1 year and is characterized by rapid exacerbation of jaundice in the background of disappearance of both xanthoma and itching. The levels of albumin and total cholesterol in the serum are reduced. Develop edema and ascites. In the terminal stage there are episodes of hepatic encephalopathy with hard-to-stop bleeding, usually from varicose-dilated esophagus veins. The cause of death may also be a concomitant infection, sometimes sepsis caused by gram-negative bacteria.

Primary biliary cirrhosis usually progresses to the terminal stage within 15-20 years, although these terms vary. Primary biliary cirrhosis can not affect the quality of life for many years. In patients with asymptomatic course of the disease, clinical signs usually appear in 2-7 years, but they may appear in 10-15 years. After the appearance of clinical symptoms, the average life expectancy is 10 years. Prognostic signs of rapid disease progression are rapid increase in symptoms, progression of histological changes, elderly patient's age, the appearance of edema, the presence of associated autoimmune diseases and changes in bilirubin, albumin, PV or MHO. The prognosis is unfavorable if the itching disappears, the xanthomas contract and the serum cholesterol level decreases.

Primary biliary cirrhosis of the liver is an autoimmune liver disease characterized by progressive destruction of the intrahepatic bile ducts leading to cholestasis, cirrhosis of the liver and liver failure. Patients usually do not complain, but they may complain of fatigue, or they may have signs of cholestasis (eg, itching, steatorrhea) and liver cirrhosis (eg, portal hypertension, ascites). Laboratory studies indicate cholestasis, increased levels of IgM, and the presence of characteristic antimitochondrial antibodies in serum. A liver biopsy is usually necessary to verify the diagnosis and the stage of the process. Treatment includes ursodeoxycholic acid, cholestyramine (with itching), additionally fat-soluble vitamins, and with progression of the disease - liver transplantation.

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