Primary biliary cirrhosis of the liver

Biliary cirrhosis of the liver is a special form of cirrhosis of the liver, developing due to long-term damage to the bile ducts and cholestasis. Primary biliary cirrhosis of the liver is an autoimmune liver disease that begins as chronic destructive non-purulent cholangitis, which proceeds for a long time without pronounced symptoms, leading to the development of long-term cholestasis and only in the later stages to the formation of cirrhosis of the liver.

The disease was first described by Addison and Gall in 1851, and then by Hano. Due to the high level of cholesterol in the serum and the presence of xanthomas on the skin, the disease was called xanthomatous biliary cirrhosis. The term "primary biliary cirrhosis" was proposed by Ahrens et al. This term is not entirely accurate, since in the early stages of the disease, regeneration nodes are not detected and cirrhosis has not yet developed. A more correct name would be "chronic non-purulent destructive cholangitis", but it has not replaced the generally accepted term "primary biliary cirrhosis".

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Epidemiology

Primary biliary cirrhosis (PBC) is the most common 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. Group incidence in families is noted.

Primary biliary cirrhosis occurs worldwide. The incidence varies considerably between countries and between regions of countries. The increase in incidence is due to increased awareness among physicians, improved diagnostics, particularly the ability to test for serum AMA, and the detection of patients at early stages of the disease when symptoms are minimal. The disease may run in families; primary biliary cirrhosis has been described in sisters, twins, and mothers and daughters. In New York, the incidence of primary biliary cirrhosis in families was 1.33%, and in London, 5.5%. The disease is usually transmitted from mothers to daughters, with the disease developing at a younger age in the second generation. Circulating AMAs are more common in relatives of patients than in the general population.

A study in Sheffield, England, found a link between primary biliary cirrhosis and a particular water source. However, no specific factors related to the source could be identified. A study in Ontario, Canada, found no racial or geographic predisposition. Further epidemiological studies are needed to clarify the role of these factors.

There is a link between the incidence of primary biliary cirrhosis and histocompatibility antigens. HLA-DRw8 antigen has been frequently detected among whites with primary biliary cirrhosis in the United States.

The C4A-QO antigen and the 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 the C4A-QO alleles. The mother and two sisters who suffered from primary biliary cirrhosis had the same histocompatibility antigen haplotype. HLA class III antigens belong to the complement system. This helps explain the partial deficiency of the C4A component of complement in patients with primary biliary cirrhosis. In addition, a link was found between primary biliary cirrhosis and the DRB1*0301 HLA genotype in Germans and with DRB1*0803 HLA in Japanese.

All these observations are difficult to combine. They show that the immunogenetic background, which determines hereditary predisposition, plays a significant role in the pathogenesis of primary biliary cirrhosis. The importance of environmental factors, especially infections, cannot be excluded; these factors mainly affect individuals predisposed to the disease.

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Causes of primary biliary cirrhosis.

Its cause is unknown, but an autoimmune mechanism is suspected, since in more than 95% of cases antibodies to antigens located on the internal mitochondrial membranes are detected. 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 epithelial layer of small bile ducts. Proliferation of bile ducts is observed. Bile acids support and cause inflammation of the liver parenchyma, leading to the development of fibrosis in the periportal zones. Eventually, inflammation decreases and 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 of the liver is an example of a disorder of 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 unknown. The triggers of the immunopathological reaction can be viral, bacterial, some other neoantigens, or perhaps simply a disorder of immunoregulation.

In many ways, primary biliary cirrhosis resembles the graft-versus-host disease seen, for example, after bone marrow transplantation, when the immune system becomes sensitized to foreign proteins of the HLA system. In these diseases, similar structural changes develop in the bile ducts. Other ducts whose epithelium contains large amounts of class II HLA antigens are affected, such as the ducts of the lacrimal glands and pancreas. The disease may occur as a dry syndrome.

In patients with primary biliary cirrhosis of the liver, HLADR3, DR4, DR2 are often detected.

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Risk factors

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

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Pathogenesis

The main pathogenetic factors of primary biliary cirrhosis:

1. Development of autoimmune reactions directed against the bile ducts.

Primary biliary cirrhosis is based on aseptic autoimmune destructive cholangitis and cholangiolitis, which is associated with the formation of autoantibodies to the intrahepatic bile ducts (interlobular and septal bile ducts). The target of immune aggression is the antigens of the major histocompatibility complex (HLA) of the bile ducts. On the membranes of the biliary epithelium, under the influence of hyperproduction of γ-interferon by T-lymphocytes and natural killers, expression of HLA antigens of classes I and II occurs. As a result, the cells of the bile ducts become the object of action of cytotoxic T-lymphocytes and antibodies. The main antibodies that have a leading pathogenetic significance are antibodies to the inner membrane of the bile ducts - antimitochondrial antibodies. Currently, antibodies to 9 antigens of the inner and outer mitochondrial membrane are known. Antibodies to the antigen of the inner mitochondrial membrane M2 _are detected in almost all cases of primary biliary cirrhosis of the liver and are considered pathognomonic. Antimitochondrial antibodies (to the antigen of mitochondria M4 ₎ are detected in primary biliary cirrhosis of the liver combined with autoimmune hepatitis, to the antigen of mitochondria M8 _- in the rapidly progressing form of primary biliary cirrhosis of the liver, to the antigen M9 _- in the early stages of primary biliary cirrhosis of the liver.

Antimitochondrial antibodies belong to the IgM class. Immune complexes containing hepatobiliary and mitochondrial antigens, antimitochondrial antibodies and the C3 fraction of complement are formed. Immune complexes circulate in large quantities in the blood and are deposited in the bile ducts, causing immune inflammation - autoimmune nonbacterial 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 long-term 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 mitochondria. The antigenic component M2 is specific for the serum of patients with primary biliary cirrhosis. Four antigenic polypeptides of M2 have been identified, all of them are part of the pyruvate dehydrogenase (PDH) complex of mitochondrial enzymes. El-2-oxoacid dehydrogenase complex with a molecular weight of 50 kDa, E2 - dihydrolipoamide acyltransferase complex with a molecular weight of 74 kDa, E3-2-oxoglutarate complex with a molecular weight of 50 kDa. PDH also includes protein X (52 kDa), which cross-reacts with E2. E2 and components of the M2 complex can be detected by enzyme-linked immunosorbent assay (ELISA). This test can diagnose 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. Specific sensitive ELISA is not always possible; in such cases, serum is usually tested for antibodies to mitochondria by indirect immunofluorescence, using rat kidney as a substrate. This is a complex technique that may give false negative results in inexperienced laboratories.

There are other mitochondrial antigens and antibodies. Anti-M9 antibodies are detected in the early stages of primary biliary cirrhosis, and can also be found in healthy relatives of patients and in laboratory technicians working with serum from patients with primary biliary cirrhosis. Anti-M9 antibodies are present in 10-15% of healthy people. In the presence of M2, M4 and M8 may also be detected; their presence may indicate a more progressive course of the disease. M3 is associated with drug reactions, M6 with iproniazid, and M5 with systemic connective tissue diseases.

Antinuclear antibodies (AHA) to a polypeptide with a molecular weight of 200 kDa cause perinuclear luminescence in 29% of patients with primary biliary cirrhosis. Their relationship with AMA in primary biliary cirrhosis is unclear.

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

2. Expression of intercellular adhesion molecules on biliary tubule epithelial cells.

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

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

MCAM-1 is a key mediator of lymphocyte adhesion, therefore, increased expression of these molecules in interlobular ductules increases I-cell-mediated damage to them.

3. Development of delayed-type hypersensitivity.

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

4. Disruption in T-lymphocyte subpopulations.

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

5. Bile acid metabolism disorder.

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

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Symptoms of primary biliary cirrhosis.

Approximately 30–50% of patients have an inapparent onset of disease; primary biliary cirrhosis is discovered incidentally by abnormal liver function tests, usually with elevated alkaline phosphatase. Symptoms or signs may appear at any stage of the disease and may include fatigue or signs of cholestasis (and resulting fat malabsorption and vitamin deficiencies, osteoporosis), hepatocellular dysfunction, or cirrhosis. Symptoms usually begin gradually. Pruritus, fatigue, or both are the initial symptoms in more than 50% of patients and may precede the onset of other symptoms by months or years. Other common findings as the disease progresses include liver enlargement, induration, and mild tenderness (25%); splenomegaly (15%); hyperpigmentation (25%); xanthelasma (10%); and jaundice (10%). Eventually, all the symptoms and complications of liver cirrhosis develop. Peripheral neuropathy and other autoimmune disorders associated with PBC may also develop.

Primary biliary cirrhosis of the liver affects mainly women, most often at the age of 35-50 years. Men suffer from primary biliary cirrhosis very rarely. affects mainly women, most 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. Patients usually consult a dermatologist at first. Jaundice may be absent, but in most cases it develops within 6 months to 2 years after the onset of itching. In about a quarter of cases, jaundice and itching occur simultaneously. The development of jaundice before the onset of itching is extremely rare; the presence of jaundice without itching is not typical for any stage of the disease. Itching may appear during pregnancy and be regarded as cholestatic jaundice of the last trimester. Patients are often bothered by constant pain in the right upper quadrant of the abdomen (17%). Over time, it may disappear. To clarify the diagnosis, an endoscopic examination of the upper gastrointestinal tract is necessary. Increased fatigue is often noted.

Initial stage of primary biliary cirrhosis

1. Skin itching is the most characteristic symptom of the initial period of primary biliary cirrhosis. At first, skin itching may be intermittent, then it becomes constant, painful, and intensifies at night and after a warm bath.

Most often, skin itching is combined with jaundice, but in some patients it precedes jaundice, which may appear only after several months or even years. Skin itching is accompanied by scratching, and often by skin infection. Itching bothers patients so much that it may seem unbearable, patients scratch even in their sleep. Skin itching is caused by the accumulation of bile acids in the blood and their irritation of the skin nerve endings. It is also assumed that the liver produces special substances - pruritogens, which cause skin itching. Lichenification of the skin is observed (thickening, coarsening, accentuation of its pattern).

2. Dark brown pigmentation of the skin - 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 shoulder blades, then in the area of the extensor surface of the joints and in other areas 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 high activity and rapid progression of the disease.
4. Xanthelasmas are observed in 20-35% of patients. They are raised yellow soft formations above the skin caused by cholesterol deposits. Xanthelasmas are localized mainly in the upper eyelids, but can also be found on the palms, chest, back, extensor surface of the elbows, knee joints, and buttocks.
5. Extrahepatic manifestations - "liver palms", "vascular stars" in the initial period of primary biliary cirrhosis are very rare (only in individual patients).
6. Hepatomegaly is a characteristic sign of primary biliary cirrhosis, it is detected in most patients. The liver protrudes from under the edge of the costal arch by 2-3 cm, it is dense, its edge is smooth, pointed.
7. Splenomegaly - is detected in 50-60% of patients, the degree of splenomegaly is small, there are no signs of hypersplenism.
8. Non-specific symptoms - in the initial stage of primary biliary cirrhosis, pain in the right hypochondrium, in the joints, myalgia, dyspeptic symptoms (lack of appetite, nausea, bitterness in the mouth) may be observed, and an increase in body temperature may be possible.

Advanced stage of primary biliary cirrhosis

1. General symptoms (non-specific manifestations). In the advanced stage of primary biliary cirrhosis, non-specific symptoms of the disease are sharply expressed. Patients are concerned about sharply expressed general weakness, an increase in body temperature to subfebrile numbers (sometimes to febrile), a significant decrease in body weight, and a lack of appetite.
2. Skin itching, changes in the skin and its appendages. At this stage, excruciating skin itching continues. Pigmented skin thickens, becomes rough, especially in the palms and soles, in an advanced stage, dense skin edema appears (resembling scleroderma, the similarity is further enhanced by pigmentation). Traces of numerous scratches are visible, which can become infected. Often there are foci of depigmentation (resembling vitiligo), papular, vesicular rash, after opening the blisters, crusts remain. Pigmentation of the nails and their thickening in the form of watch glasses is possible, the terminal phalanges of the fingers thicken in the form of drumsticks. In rare cases, increased hair growth on the face and limbs is noted. Xanthelasma is characteristic. The appearance of "liver palms" and "vascular stars" is characteristic.
3. Enlargement of the liver and spleen. In the advanced stage of primary biliary cirrhosis, the liver increases sharply, becomes dense, and its edge becomes sharper. The size of the spleen increases significantly, and some patients develop hypersplenism syndrome (pancytopenia).
4. Portal hypertension syndrome. In the advanced stage of primary biliary cirrhosis, the development of portal hypertension syndrome is characteristic, in particular, varicose veins of the esophagus and stomach are determined, bleeding from them is possible. However, ascites at this stage is rare, it is more characteristic of the final (terminal) stage of the disease.
5. Fat-soluble vitamin malabsorption syndrome. Impaired secretion and excretion of bile leads to atrophy of the villi of the small intestine and the development of fat-soluble vitamin malabsorption syndrome D, A, K. Vitamin D deficiency manifests itself with the following symptoms:

• osteoporosis develops, which is characterized by pain in the joints ("biliary rheumatism"), bones, ribs, vertebrae; pathological fractures; kyphosis; detection of areas of bone rarefaction on bone radiographs (ribs, shoulder blades, pelvis, rib neck, etc.).
• the hard plate of the teeth is destroyed, the teeth become loose and fall out.

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

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

6. Systemic manifestations. For the advanced stage of primary biliary cirrhosis, the systemic nature of lesions of various internal organs is also typical:

• Sjogren's syndrome is detected in 70-100% of patients with severe cholestasis. The manifestations of Sjogren's syndrome may be mild and unrecognized, especially since intense skin itching dominates the subjective symptoms of the disease.
• endocrine disorders are manifested by dysfunction of the ovaries in women (amenorrhea, dysmenorrhea), dysfunction of the testicles in men (decreased libido sexualis, sexual weakness, reduction of secondary sexual characteristics, testicular atrophy, decrease in the size of the penis); development of hypofunction of the adrenal cortex; hypothalamus; insufficiency of the endocrine function of the pancreas in the form of impaired glucose tolerance or manifest diabetes mellitus;
• lung damage in the form of diffuse pneumosclerosis (deformation of the pulmonary pattern, stringy, looped, cellular shadows on chest radiographs) and fibrosing alveolitis.
• kidney damage is characterized by the development of glomerulonephritis, tubulointerstitial nephritis;
• dysfunction of the digestive system manifests itself as chronic gastritis, duodenitis, development of duodenostasis, hypotension of the small intestine. Chronic pancreatitis often develops with a decrease in the secretory function of the pancreas and steatorrhea;
• enlargement of peripheral lymph nodes.

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

7. Associated diseases.

The combination of primary biliary cirrhosis with almost all known autoimmune diseases has been described. It is especially often combined with systemic connective tissue diseases, in particular with rheumatoid arthritis, dermatomyositis, mixed connective tissue disease and systemic lupus erythematosus.

In 4% of cases of primary biliary cirrhosis, it is combined with scleroderma, and may also be combined with CREST syndrome. Scleroderma is usually limited to sclerodactyly, and the face, forearms, and shins may be involved. Keratoconjunctivitis occurs. These patients usually have Ro antibodies with a molecular weight of 20-52 kDa. Dry mouth and dry eyes are detected in almost 75% of patients; in some cases, in combination with arthritis, these manifestations constitute complete Sjogren's syndrome.

Other associated skin lesions include immune complex capillaritis and lichen planus. Autoimmune thyroiditis occurs in approximately 20% of cases. Development of diffuse toxic goiter has been described.

Atrophy of the cilia of the jejunum may occur, resembling celiac disease. Another rare associated disease may be ulcerative colitis.

The possibility of development of autoimmune thrombocytopenia and the appearance of autoantibodies to insulin receptors in primary biliary cirrhosis has been demonstrated.

Renal complications include IgM-associated membranous glomerulonephritis.

Renal tubular acidosis may develop as a result of copper deposition in the distal renal tubules. Other manifestations of renal tubular damage may include hypouricemia and hyperuricosuria. Bacteriuria develops in 35% of cases, and may be asymptomatic.

A combination of primary biliary cirrhosis with selective IgA deficiency has been described, indicating 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 greater than in the population.

A combination of primary biliary cirrhosis with transverse myelitis, developing as a result of angiitis and necrotizing myelopathy, has been identified. Clubbing of the fingers is common, and hypertrophic osteoarthropathy may develop.

As a result of decreased bile flow, and possibly immune damage to the pancreatic duct, pancreatic insufficiency develops.

Bile duct stones, usually pigmented type, were observed in 39% of cases at ERCP. They are sometimes accompanied by clinical manifestations, but rarely migrate to the common bile duct.

Gas exchange disturbances in the lungs are apparently associated with nodules and interstitial fibrosis detected by X-ray examination. Lung biopsy reveals damage to the interstitial tissue of the lungs. In addition, the formation of giant cell granulomas in the interstitium of the lungs has been described. Such patients often develop Sjogren's syndrome with the formation of Ro antibodies.

CREST syndrome is accompanied by interstitial pneumonitis and pulmonary vascular damage.

In 81% of patients, computed tomography reveals enlarged (lymphatic) nodes in the gastrohepatic ligament and in the liver hilum. Enlargement of the pericardial and mesenteric nodes is also observed.

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

Terminal stage of primary biliary cirrhosis

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

In the terminal stage, itching of the skin may decrease and even disappear. Liver and hepatorenal failure progresses, severe liver encephalopathy develops, which ends in liver coma.

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

"Asymptomatic" patient

The widespread use of automated biochemical testing has led to increased detection of asymptomatic cases, usually by elevated serum alkaline phosphatase levels. Liver biopsy performed in individuals with an AMA titer of 1:40 or greater almost always reveals changes usually consistent with primary biliary cirrhosis, even if the patient is otherwise asymptomatic and the serum alkaline phosphatase level is normal.

Primary biliary cirrhosis may be diagnosed in patients undergoing examination for diseases that may be associated with it, such as systemic connective tissue diseases or thyroid diseases, as well as in those with a positive family history.

Clinical examination may show no signs of the disease. AMA are always detected. Serum alkaline phosphatase and bilirubin levels may be normal or slightly elevated. Cholesterol and transaminase levels may be unchanged.

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The course of primary biliary cirrhosis

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

Steatorrhea may cause diarrhea. Weight loss occurs slowly. Patients are most concerned about fatigue, but their normal lifestyle is usually not disrupted. The disease is feverless; abdominal pain is rare but may be prolonged.

Skin xanthomas are often observed, sometimes appearing acutely, but in many cases the disease progresses without the formation of xanthomas; in the terminal stage of the disease, xanthomas may disappear.

The skin on the fingers, ankles and shins thickens and becomes rough. Xanthomatosis can cause peripheral polyneuropathy, which manifests itself as pain in the fingers (especially when opening doors) and toes. On the back, there may be an area of undamaged skin in the form of butterfly wings, which 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. At advanced stages, patients are bothered by pain in the back and along the ribs, sometimes pathological fractures develop.

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

Bleeding from esophageal varices may be the first manifestation of the disease, even before nodes appear. At this stage, portal hypertension is most likely presinusoidal. Over 5.6 years of observation, 83 (31%) of 265 patients developed esophageal varices, with 40 (48%) of them experiencing bleeding.

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

Stages

Child-Turcotte-Pugh classification

Clinical 1 and laboratory parameters	1	2	3
Encephalopathy (degree)	No	1-2	3-4
Ascites	No	Mild (responds to treatment with diuretics)	Moderate despite diuretic therapy
PV (increment 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 assessments: 5-6 points - class A (low risk); 7-9 points - class B; 10-15 points - class C (high risk).

• Stage 1: sleep disturbances; decreased concentration; depression, anxiety or irritability.
• Stage 2: drowsiness; disorientation; decreased short-term memory; disinhibited behavior.
• Stage 3: somnolence; confusion; amnesia; anger; paranoia or other abnormal behavior.
• Stage 4: coma.

Macroscopically, the liver is enlarged, greenish in color, and enlarged lymph nodes are visible in the liver hilum.

Based on puncture biopsy data, 4 morphological stages of the evolution of primary biliary cirrhosis of the liver are distinguished.

1. Stage of non-purulent destructive cholangitis: inflammatory infiltration and destruction of interlobular (portal) and septal bile ducts with granulomatous reaction. Dilated portal tracts are infiltrated with lymphocytes, plasma cells, macrophages, eosinophils. Portal tract infiltrate, as a rule, does not penetrate deeply into the parenchyma; only individual lymphocytes or groups of lymphocytes penetrate shallowly into the liver lobules. Electron microscopic examination reveals a violation of the integrity of the basement membrane. Granulomas consisting of epithelioid and giant multinucleated cells are found near the affected bile ducts. There are no histological signs of cholestasis at this stage.
2. Stage of cholangiole proliferation and periductular fibrosis. In the portal tracts, along with lymphoplasmocellular infiltration and disintegrating bile ducts, foci of biliary epithelium proliferation appear, which spread to the periportal sections of the lobules together with infiltrates. A sign specific to primary biliary cirrhosis appears - "empty portal tracts", the inflammatory infiltrates of which do not contain bile ducts. Connective tissue grows around the remaining bile ducts. Due to the reduction of the bile ducts, cholestasis develops. Subsequently, the number of granulomas in the liver decreases, many of them undergo fibrosis.
3. Stromal fibrosis in the presence of inflammatory infiltration of the liver.

At this stage, connective tissue layers are formed, extending from the portal tracts and connecting with adjacent tracts (portoportal septa), as well as connecting the central veins with the portal tracts (portocentral septa). The proliferation of bile ducts decreases, the reduction of interlobular and septal bile ducts increases, which naturally leads to increased cholestasis. Along with this, cellular infiltration of the parenchyma increases, hepatocyte necrosis is more numerous, fibrosis increases, and monolobular pseudolobules are formed.

4. The final stage.

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

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Diagnostics of primary biliary cirrhosis.

Primary biliary cirrhosis is suspected in middle-aged women by the classic features or biochemical changes suggestive of cholestasis: elevated alkaline phosphatase and gamma-glutamyl transpeptidase but minimal changes in aminotransferases (ALT and AST). In the early stages, serum bilirubin is usually normal; its increase indicates disease progression and a poor prognosis. Serum IgM is markedly elevated. A positive serum antimitochondrial antibody (sometimes also positive in low titers in autoimmune hepatitis type 1) strongly suggests the diagnosis. Other autoantibodies in patients with PBC include rheumatoid factor (66%), anti-smooth muscle antibodies (66%), antithyroid antibodies (40%), and antinuclear antibodies (35%). Liver biopsy is usually performed to confirm the diagnosis and to detect early pathognomonic signs of bile duct involvement during the course of the disease. However, primary biliary cirrhosis has four stages and, as fibrosis progresses, it becomes morphologically indistinguishable from other forms of cirrhosis.

Extrahepatic biliary obstruction should be excluded; if necessary, instrumental research methods are used for this purpose (including ultrasound, magnetic resonance cholangiopancreatography and, if indicated, ERCP).

Laboratory data

1. Complete blood count: signs of anemia, increased ESR, leukocytosis is possible during the active period of the disease, and pancytopenia may develop with the development of hypersplenism syndrome.
2. General urine analysis: proteinuria, bilirubinuria, absence of urobilin. Stool analysis for stercobilin is weakly positive or negative, stool is weakly colored or discolored (acholia).
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 bile outflow, hyperbilirubinemia reaches 250-340 μmol / l, an increase in the content of alkaline phosphatase, 5-nucleotide polypeptide, y-glutamyl transpeptidase, bile acids (especially lithocholic), copper, cholesterol, beta-lipoproteins, phospholipids, non-esterified fatty acids in the blood; a decrease in the iron content in the blood. The activity of the above-mentioned cholestasis enzymes increases in primary biliary cirrhosis already at the early stages. The activity of aminotransferases in the blood serum also increases, the content of y- and beta-globulins increases, the level of albumins decreases.
4. Immunological blood test: the total number of T-lymphocytes, activated T-lymphocytes, and suppressor T-lymphocytes is reduced. The number of circulating immune complexes is increased. The content of IgM in the blood is increased, and often also IgA and IgG.

Detection of antimitochondrial antibodies (AMA) is extremely typical; they are detected already at 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 typical detection of antibodies against the mitochondrial adenine nucleotide translocator (ANT antibodies) or mitochondrial ATPase antigen M ₂. A titer of 1:20 - 1:40 is diagnostically significant. In some cases, antibodies to thyroglobulin, rheumatoid factor, etc. can be detected in the blood serum.

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Instrumental data

• Ultrasound of the liver and biliary tract: enlarged liver, unchanged large bile ducts. Possible detection of stones in the biliary tract (in 20-30% of patients).
• Ultrasound of the spleen: splenomegaly.
• FEGDS: in the stage of developed liver cirrhosis, varicose veins of the esophagus and stomach are detected.
• Liver biopsy.

Septal or interlobular bile duct involvement is a diagnostic feature characteristic of primary biliary cirrhosis. These bile ducts are often not visualized in liver biopsy, but are usually clearly visible in liver tissue taken by open biopsy. Such biopsies are performed less and less frequently as the frequency of surgical interventions decreases. The material obtained by biopsy should be examined by an experienced pathologist.

The disease begins with damage to the epithelium of small bile ducts. Histometric examination shows that bile ducts with a diameter of less than 70-80 µm are destroyed, especially in the early stages. Epithelial cells are edematous, more eosinophilic and have an irregular shape. The lumen of the bile ducts is uneven, the basement membrane is damaged. Sometimes the bile ducts rupture. Around the damaged duct, cellular infiltration with lymphocytes, plasma cells, eosinophils and histiocytes is detected. Granulomas often form, usually in zone 1.

The bile ducts are destroyed. Clusters of lymphoid cells are noted along their course, and the bile canaliculi begin to proliferate. Branches of the hepatic artery can be seen in the portal zones, but without the accompanying bile ducts. Fibrosis extends beyond the portal zones, and stepwise necrosis is visible. Histochemical examination methods reveal the deposition of a significant amount of copper and copper-bound protein. Fibrous septa gradually destroy the liver architecture, and regeneration nodes are formed. The latter are often unevenly distributed, so that cirrhosis is visible in some areas of the biopsy, but not in others. In some areas, the lobular structure is not disrupted. In the early stages, cholestasis is limited to zone 1 (portal).

Hyaline deposition, similar to that observed in alcoholic liver disease, is found in hepatocytes in 25% of cases.

Depending on the histological picture, 4 stages can be distinguished:

• Stage I - pronounced damage to the bile ducts;
• Stage II - proliferation of bile ducts;
• Stage III - scarring (septal and bridging fibrosis);
• Stage IV - cirrhosis. The significance of such division into stages is small, since changes in the liver are focal 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 characterized by significant variability; in the absence of symptoms, a picture corresponding to an advanced stage III can be observed. Moreover, multiple biopsies have shown that the same stage can persist for many years.

• Radioisotope hepatography with 131I-labeled rose bengal reveals a marked impairment of the excretory function of the liver.
• Infusion cholangiography (performed when hyperbilirubinemia 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 the activity of cholestasis enzymes in the blood serum by 2-3 times compared to the norm.
3. Normal extrahepatic bile ducts on ultrasound and X-ray contrast imaging.
4. Detection of antimitochondrial antibodies in blood serum at a titer greater than 1:40.
5. Increased IgM levels in blood serum.
6. Characteristic changes in liver puncture.

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

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Survey program

1. General blood, urine, and stool analysis. Urine analysis for bilirubin, urobilin, stool analysis for stercobilin.
2. Biochemical blood test: determination of total protein and protein fractions, aminotransferase levels, sublimate and thymol tests; detection of biochemical cholestatic syndrome (determination of alkaline phosphatase activity, y-glutamyl transpeptidase, 5-nucleotidase, bilirubin, cholesterol, lipoproteins, NEFA, copper). Determination of urea and creatinine.
3. Immunological blood test: determination of the content and activity of T-lymphocytes and their subpopulations, B-lymphocytes, immunoglobulins, antimitochondrial antibodies, rheumatoid factor, antibodies to smooth muscles, thyroglobulin, circulating immune complexes.
4. Ultrasound of the liver, bile ducts, spleen, kidneys.
5. Radioisotope hepatography.
6. FEGDS.
7. Laparoscopy with targeted liver biopsy; if laparoscopy is not possible, puncture liver biopsy under ultrasound control.
8. Infusion cholangiography (with hyperbilirubinemia exceeding the norm by 3-4 times) if differential diagnosis with secondary biliary cirrhosis is necessary.

Differential diagnosis

Most often, primary biliary cirrhosis of the liver must be differentiated from secondary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis with cholestatic syndrome, liver and biliary tract cancer, and cholestasis caused by taking medications.

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

It is often necessary to differentiate primary biliary cirrhosis from drug-induced cholestatic hepatitis. Unlike primary biliary cirrhosis, drug-induced cholestatic hepatitis is characterized by:

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

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

The basis of diagnosis in these cases is the use of ultrasound (detection of stones, tumors, external compression of the common hepatic duct, common bile duct), retrograde cholangiography, computed tomography, in diagnostically unclear cases, laparoscopy and even laparotomy are used.

Differential diagnosis of primary biliary cirrhosis

Disease	Peculiarities	AMA	Liver biopsy
PBC	Women get sick more often Accompanied by itching High serum ALP	Are revealed	Bile duct injury Clusters of lymphoid cells Small stepwise necrosis Lobules are intact Periseptal cholestasis
Primary sclerosing cholangitis	Men get sick more often Associated with ulcerative colitis Diagnosed by cholangiography	Absent or in low titer	Fibrosis and proliferation of bile ducts Onion skin fibrosis of the ducts
Cholestatic variant of sarcoidosis	There are no gender differences in frequency. Blacks get sick more often Accompanied by itching High serum ALP Changes in chest x-rays	None	Large number of granulomas Moderate changes in the bile ducts
Autoimmune cholangiopathy	Women get sick more often High serum SF level High titer of AHA in serum	None	Bile duct injury Clusters of lymphoid cells Small stepwise necrosis
Cholestatic drug reactions	Anamnesis Development within 6 weeks from the start of taking the drug Sharp start	None	Infiltration of portal tracts by mononuclear cells, sometimes eosinophils; formation of granulomas and fatty infiltration

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Treatment of primary biliary cirrhosis.

The goals of treatment include arresting or reversing liver pathology, treating complications (chronic cholestasis and liver failure), and ultimately liver transplantation. Alcohol and any hepatotoxic drug should be avoided. Ursodeoxycholic acid (4.3–5 mg/kg orally twice daily or 3.25–3.75 mg/kg orally four times daily with meals) reduces liver injury, prolongs survival, and delays liver transplantation. About 20% of patients show no improvement in biochemical parameters after 4 months of treatment; these patients are likely to have progressive disease and require liver transplantation within a few years. Other proposed drugs do not improve the overall clinical outcome or give conflicting results; these drugs include glucocorticoids, penicillamine, colchicine, methotrexate, azathioprine, cyclosporine, and chlorambucil.

Pruritus can be controlled with cholestyramine (6-8 g orally twice daily). Some patients with pruritus respond to ursodeoxycholic acid and UFO; others respond to rifampin or opiate antagonists such as naltrexone. Fat malabsorption may require additional calcium and vitamins A, D, E, and K. In osteoporosis, calcium supplementation should be supplemented with vitamin D, exercise therapy, bisphosphonates, estrogens, or raloxifene. In later stages, treatment of portal hypertension or cirrhosis may be necessary.

Liver transplantation results in excellent outcomes. The general indication is decompensated liver disease: recurrent variceal bleeding, refractory ascites, severe pruritus, and hepatic encephalopathy. Survival at one year after liver transplantation exceeds 90%; at 5 years, more than 80%. Primary biliary cirrhosis recurs in approximately 15% of patients during the first few years, although this finding is not clinically significant.

Symptomatic treatment

Symptomatic treatment of primary biliary cirrhosis of the liver is carried out in all patients to reduce itching and steatorrhea.

Loss of vitamin D and calcium due to insufficient bile flow into the intestine leads to osteomalacia, which is treated with additional vitamin D and calcium. Osteoporosis is much more common and has much greater clinical significance. It is difficult to treat, but nevertheless requires calcium, insolation, and increased physical activity. Hormonal replacement therapy can be administered, although this increases the risk of breast cancer. Calcitonin treatment has proven ineffective.

Immunosuppressants

Their effectiveness is low, much lower than in autoimmune chronic active hepatitis, in which the administration of corticosteroids leads to significant improvement. Azathioprine, penicillamine and chlorambucil have been shown to be ineffective. The use of corticosteroids can reduce clinical manifestations and improve biochemical parameters, but is associated with increased bone resorption, which is why their use is undesirable.

Small studies have shown that cyclosporine A relieves symptoms and improves biochemical parameters. Liver biopsy data indicate a slowing of disease progression. The use of this drug is limited by its nephrotoxicity and hypertensive effect; its long-term use is unsafe.

Methotrexate 15 mg orally once a week also helps to reduce the severity of symptoms and lower serum alkaline phosphatase and bilirubin levels. Liver biopsy reveals a decrease in inflammation. The Mayo prognostic index is unchanged. Adverse effects include a tendency to decrease in white blood cell and platelet counts, indicating reversible myelotoxicity. Interstitial pneumonitis occurs in 12-15% of cases and reverses after discontinuation of treatment and administration of corticosteroids. Methotrexate has little effect on survival. The effects of the drug on the course of primary biliary cirrhosis are highly variable. In general, the drug should not be prescribed for this disease; it is used only in ongoing clinical trials.

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

Ursodeoxycholic acid is a non-toxic hydrophilic bile acid for the liver, which reduces the possible hepatotoxicity of endogenous bile acids. It is expensive, and is used in a general dose of 13-15 mg per 1 kg of body weight twice a day: after lunch and after dinner. A placebo-controlled study conducted in France showed that ursodeoxycholic acid slows disease progression, increases survival, and reduces the need for liver transplantation. Serum bilirubin levels are reduced. With high baseline bilirubin levels and the presence of cirrhosis, treatment outcomes were worse. A study conducted in Canada showed less encouraging results: serum bilirubin levels decreased, biochemical parameters improved, but clinical manifestations, liver histology, survival, or duration of treatment before liver transplantation did not change. In a Mayo Clinic study using placebo, patients receiving ursodeoxycholic acid showed only a small increase in the time it took for serum bilirubin levels to double. Liver histology was unchanged. Outcomes were better in earlier stages of the disease. A meta-analysis of all studies on this topic showed a significant but small increase in survival and time to liver transplantation. Ursodeoxycholic acid is not a panacea for the treatment of primary biliary cirrhosis. However, it should be given to all patients except those with terminal disease who are scheduled for liver transplantation. The decision to treat early, asymptomatic patients with ursodeoxycholic acid is difficult; the decision is individualized, taking into account the cost 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.

Currently, there is no sufficiently effective specific therapy for primary biliary cirrhosis. In the early stages of the disease, some improvement is brought by the administration of ursodeoxycholic acid.

The studies conducted had many shortcomings, they were short-term, and involved a small number of patients. In a disease with such a long and variable course, it is difficult to identify statistically significant long-term effects of any intervention. Any study should indicate the number of patients in each group. In the early, asymptomatic stages of the disease, patients who feel well do not require treatment at all. With an unfavorable prognosis and advanced disease, the effect of treatment is also unlikely. Studies should include groups in intermediate stages of the disease. When assessing the effectiveness of any treatment, it is necessary to rely on the results of large controlled clinical trials.

Bleeding from esophageal varices may develop at early stages, even before the development of true nodular cirrhosis. It is therefore not surprising that portocaval shunting in such patients gives a positive effect. Hepatic encephalopathy develops rarely. The results of treatment of patients from low-risk groups are especially favorable. In some cases, transjugular intrahepatic portosystemic shunting with stents is effective.

Gallstones should not be removed unless they cause significant pain or are located in the common bile duct. Indications for cholecystectomy are very rare, and patients do not tolerate it well.

Liver transplantation

Liver transplantation is indicated when the patient's activity has significantly decreased, and he or she is practically unable to leave the house. Indications for liver transplantation also include intractable pruritus, ascites, hepatic encephalopathy, bleeding from esophageal varices, and recurrent infections. Transplantation is more successful and cost-effective if performed early in the disease. Patients should probably be referred to a liver transplant center when the serum bilirubin level is 150 μmol/L (9 mg%).

Survival after transplantation increases significantly. One-year survival after liver transplantation is 85-90%, and 5-year survival reaches 60-70%. In 25% of cases, a repeat transplant is required, usually due to the development of vanishing bile duct syndrome. After surgery, the condition of patients often improves significantly.

Although the serum AMA titer decreases in the first few months, it subsequently increases again. The disease probably relapses as a result of damage to the transplanted liver. In one group, histological evidence of relapse at 1 year after transplantation was found in 16% of patients. Symptoms of the disease were usually absent, although itching developed in some patients.

During the first 1-3 months, bone density decreases, which can have catastrophic consequences. Osteoporosis is probably caused by bed rest and corticosteroid therapy. 9-12 months after transplantation, new bone formation and an increase in its density begin.

Immune cholangiopathy

In almost 5% of patients with the onset of the disease resembling primary biliary cirrhosis, AMA are not detected in the serum. At the same time, high titers of AHA and antibodies to actin are detected in the serum. Clinical manifestations of the disease are usually absent. Histological changes in the liver correspond to the picture in primary biliary cirrhosis. The administration of prednisolone leads to some improvement in clinical and biochemical parameters. Histologically, a decrease in inflammation is observed in the liver, but bile duct damage remains, and the GGT level 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, symptoms do not develop at all, while in others, progressive deterioration is noted. Currently, patients with primary biliary cirrhosis in the terminal stage can be saved by liver transplantation.

Life expectancy in asymptomatic primary biliary cirrhosis is not reduced compared to the population. The time periods for symptom development described in the literature vary greatly, which is probably determined by the characteristics of the patient groups studied and the research methods. The duration of the disease depends on the time of diagnosis. Specialized centers, such as the Mayo Clinic or the Royal Free Hospital, usually see patients with later stages of the disease, so the likelihood of clinical manifestations is higher for them than for patients in regional centers, such as Oslo or Newcastle. In general, clinical manifestations in patients with asymptomatic primary biliary cirrhosis develop after 2-7 years.

In case of clinical manifestations, prognosis is especially important, as it allows determining the optimal time for liver transplantation. If the serum bilirubin level is constantly higher than 100 μmol/l (6 mg%), the patient's life expectancy 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 level below 435 μmol/l (3 g%). The prognosis is worse if stepwise necrosis, cholestasis, bridging fibrosis and cirrhosis are detected in histological examination.

Varicose veins develop in 31% of patients after an average of 5.6 years, and 48% of these subsequently bleed. The likelihood of varicose veins is higher in the presence of high serum bilirubin levels and significant histological changes. When esophageal varices are detected, the 1-year survival rate is 83% and 3-year survival is 59%. After the first bleeding, the 1-year survival rate is 65% and 3-year survival is 46%.

No model can accurately estimate 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 cannot predict life-threatening sudden complications, such as bleeding from varicose veins.

The terminal stage lasts approximately 1 year and is characterized by rapidly worsening jaundice with resolution of both xanthomas and pruritus. Serum albumin and total cholesterol levels decrease. Edema and ascites develop. The terminal stage is characterized by episodes of hepatic encephalopathy with difficult-to-stop bleeding, usually from esophageal varices. Death may also result from concomitant infection, sometimes sepsis, caused by gram-negative bacteria.

Primary biliary cirrhosis usually progresses to the terminal stage within 15 to 20 years, although this time frame varies. Primary biliary cirrhosis may not affect quality of life for many years. In asymptomatic patients, clinical signs usually appear after 2 to 7 years, but they may appear after 10 to 15 years. After the onset of clinical symptoms, the average survival is 10 years. Prognostic signs of rapid disease progression include rapid worsening of symptoms, progression of histologic changes, advanced age, the appearance of edema, the presence of associated autoimmune diseases, and changes in bilirubin, albumin, PT, or INR. The prognosis is unfavorable if skin itching disappears, xanthomas shrink, and the serum cholesterol level decreases.

Primary biliary cirrhosis is an autoimmune liver disease characterized by progressive destruction of the intrahepatic bile ducts, leading to cholestasis, cirrhosis, and liver failure. Patients are usually asymptomatic on examination but may complain of fatigue or have features of cholestasis (eg, pruritus, steatorrhea) and cirrhosis (eg, portal hypertension, ascites). Laboratory tests show cholestasis, elevated IgM levels, and characteristic antimitochondrial antibodies in the serum. Liver biopsy is usually necessary to verify the diagnosis and stage of the disease. Treatment includes ursodeoxycholic acid, cholestyramine (for pruritus), additional fat-soluble vitamins, and, if the disease progresses, liver transplantation.

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