Primary Biliary Cholangitis: Clinical Guidelines

List of Abbreviations

ASMA — anti-smooth muscle antibodies

AID — autoimmune diseases

AILD — autoimmune liver diseases

AIH — autoimmune hepatitis

ALT — alanine aminotransferase

AMA — antimitochondrial antibodies

AMA-M2 — anti-mitochondrial antibodies M2

ANA — antinuclear antibodies

AST — aspartate aminotransferase

EV — varices (esophageal varices)

ULN — upper limit of normal

GGT — gamma-glutamyl transferase

GC — glucocorticoids

HCC — hepatocellular carcinoma

GSD — gallstone disease

IB — immunoblotting

BMI — body mass index

IHC — immunohistochemical

IST — immunosuppressive therapy

ELISA — enzyme-linked immunosorbent assay

CT — clinical trial

CT — computed tomography

CG — clinical guidelines

HDL — high-density lipoproteins

VLDL — very low-density lipoproteins

LDL — low-density lipoproteins

INR — international normalized ratio

BMD — bone mineral density

MRCP — magnetic resonance cholangiopancreatography

LLN — lower limit of normal

IIF — indirect immunofluorescence assay with obeticholic acid

ABU — abdominal organs

OCA — obeticholic acid

RR — relative risk

OR — odds ratio

PBC — primary biliary cholangitis

PBC/AIH(PSC) — primary biliary cholangitis with features of autoimmune hepatitis (primary sclerosing cholangitis), variant (overlap) syndrome

PBC — primary biliary cirrhosis

PH — portal hypertension

PSC — primary sclerosing cholangitis

HE — hepatic encephalopathy

RCT — randomized controlled trial

LT — liver transplantation

TE — transient elastography (liver elastometry by transient elastography)

UDCA — ursodeoxycholic acid

LoE — level of evidence

LeR — level of recommendation validity

US — ultrasound

CLIA — chemiluminescent immunoassay

LC — liver cirrhosis

ALP — alkaline phosphatase

EMD — extracorporeal detoxification methods

APRI (Aspartate Aminotransferase-to-Platelet Ratio Index) — aspartate aminotransferase-to-platelet ratio index

AUROC — area under the ROC curve

EASL (European Association for the Study of the Liver) — European Association for the Study of the Liver

FRAX (The Fracture Risk Assessment Tool) — Fracture Risk Assessment Tool

HLA (human leukocyte antigen) — human leukocyte antigen

IAIHG (International AutoImmune Hepatitis Group) — International AutoImmune Hepatitis Group

IgG — immunoglobulin G

IgM — immunoglobulin M

ICAP (International Consensus on ANA Patterns) — International Consensus on ANA Patterns

MELD (The Model for End-Stage Liver Disease) — Model for End-Stage Liver Disease

PAMP (pathogen-associated molecular patterns) — pathogen-associated molecular patterns

PDH-E2/M2 — E2 subunit of the pyruvate dehydrogenase complex

NK (natural killers) — natural killer cells

NKT cells — lymphocytes expressing NK markers and T-cell differentiation antigens

TIPS (transjugular intrahepatic portosystemic shunt) — transjugular intrahepatic portosystemic shunt

TLR (toll-like receptors) — toll-like receptors

Terms and Definitions

Autoimmune hepatitis (AIH) — an immune-inflammatory liver disease of unknown etiology, developing predominantly in genetically predisposed individuals, with a wide spectrum of clinical manifestations, accompanied by elevated levels of alanine aminotransferase and aspartate aminotransferase, characterized generally by elevated immunoglobulin G and (or) gamma-globulins, the presence of autoantibodies, and morphological signs of active portal/lobular hepatitis, having a predominantly favorable response to immunosuppressive therapy and a progressive course in the absence of treatment.

AMA-negative PBC — a disease meeting the criteria for PBC in the absence of antimitochondrial antibodies in the blood serum.

Ductopenia (or vanishing bile duct syndrome) — a pathological condition characterized by the loss of interlobular bile ducts in 50% or more of portal tracts, confirmed by a histological report assessing at least 11 portal tracts.

Classic (or AMA-positive) primary biliary cholangitis — a disease meeting the criteria for PBC, in which antimitochondrial antibodies are detected.

Response to therapy — achievement of target indicator values as a result of prescribed treatment.

Primary biliary cholangitis (PBC) — an autoimmune cholestatic liver disease characterized by the presence of antimitochondrial antibodies or specific antinuclear antibodies, and, according to histological examination, non-suppurative granulomatous lymphocytic cholangitis of small bile ducts and ductopenia.

Seronegative PBC — a disease characterized by laboratory signs of cholestasis and histological criteria for PBC in the absence of antimitochondrial and specific antinuclear antibodies (anti-sp100, anti-gp210).

Florid duct lesion — a morphological term; focal lesions characteristic of PBC, involving intense inflammatory infiltration and destruction of bile ducts.

Level of evidence — the degree of confidence that the observed effect of a medical intervention is true.

Grade of recommendation — the degree of confidence in the reliability of the intervention effect and that following the recommendations will bring more benefit than harm in a specific situation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Primary biliary cholangitis (PBC, former name — primary biliary cirrhosis (PBC)) [1] is an autoimmune cholestatic liver disease characterized by the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies (ANA), and, according to histological examination, non-suppurative granulomatous lymphocytic cholangitis of small bile ducts and ductopenia [2]. PBC is distinguished by a chronic progressive course with the development of fibrosis, and in the terminal stage, liver cirrhosis (LC) and hepatic failure.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology and pathogenesis of the disease are not fully elucidated [3]. Genetic, epigenetic, immunological, and environmental factors play an important role [4]. The role of genetic predisposition is indicated by the fact that every 20th patient with PBC has a burdened family history of the disease. The probability of developing various autoimmune pathologies, in particular autoimmune thyroiditis, celiac disease, and scleroderma, is higher both in a patient with PBC and in their relatives. Although genetic factors obviously play a role in the occurrence of PBC, the disease is not the result of a single genetic mutation [5]. A triggering factor in a genetically susceptible individual is hypothesized. Such factors can include smoking, exposure to toxins and infectious agents capable of disrupting immunological tolerance [3, 5]. Microbes can act as cross-antigens and cause molecular mimicry, initiating autoimmune reactions against intrahepatic bile ducts [4]. Genome-Wide Association Studies (GWAS) have identified numerous genes responsible for susceptibility to PBC in both human leukocyte antigen (HLA) and non-HLA loci [6]. It has been shown that in Europeans, HLA-DRB1*11 and HLA-DRB1*13 possess protective properties against PBC [7].

The innate immune system is involved in the pathogenesis of PBC, which is confirmed by granulomatous inflammation, hypersecretion of pro-inflammatory cytokines and immunoglobulin M (IgM), and an increase in the content of NK (natural killers) and NKT cells [8]. Pathogen-associated molecular patterns (PAMP) can bind to toll-like receptors (TLR) on the surface of biliary epithelial cells and innate immune system cells, thereby acting as a trigger for the formation of an immune response [9]. In turn, monocytes activated by PAMP via toll-like receptors participate in modulating or enhancing the adaptive cellular immune response through the secretion of pro-inflammatory cytokines (interleukin-1, -6, -12, tumor necrosis factor-α) [10]. As PBC progresses, abnormally accumulating bile acids can signal through various nuclear receptors, thereby regulating immune responses [3].

Adaptive immunity is also involved in the pathogenesis of PBC, as indicated by the high concentration of AMA and an increase in the number of antigen-specific CD4⁺ and CD8⁺ T cells. CD8⁺ T lymphocytes dominate the lymphocytic infiltrate of liver tissue in PBC. They express FAS ligand and secrete perforins, leading to apoptosis of the biliary epithelium [11]. Patients with PBC and their relatives have a reduced number of regulatory T lymphocytes, which may explain the decrease in immunological tolerance in this disease. Damaged biliary epithelium can express increased levels of class II HLA molecules and act as non-professional antigen-presenting cells. The interaction between the biliary epithelium and T cells can lead to damage and loss of bile ducts, a key characteristic of disease progression [12]. Alteration in the physiology of biliary epithelial cells, in particular the loss of the so-called protective "bicarbonate umbrella," leads to the accumulation of hydrophobic bile acids, which further increases the susceptibility of cholangiocytes to apoptosis. The role of cytotoxic bile acids in the pathogenesis of the disease is confirmed by the fact that the most effective treatments for PBC are those involving the modulation of bile acid homeostasis, as opposed to immunomodulation [13, 14].

Thus, PBC reflects the consequences of immune and cellular damage to the biliary epithelium. Symptoms of PBC are caused by long-standing cholestasis. Destruction of the bile ducts ultimately leads to portal inflammation, fibrosis, and ultimately LC and hepatic failure [2, 3].

1.3 Epidemiology of the Disease or Condition

PBC affects people of all races and ethnic groups, but there are significant geographical variations in the prevalence of the disease [15–17]. In Europe, the incidence and prevalence of PBC are 0.3–5.8 and 1.9–40.2 per 100,000 population, respectively [2, 3]. In the Asia-Pacific region, the incidence and prevalence of PBC are 8.4 and 98.2–118.8 per 1 million population, respectively [3]. There are currently no reliable data on the incidence of PBC in the Russian Federation [18].

The overwhelming majority of patients are middle-aged women. PBC is typically diagnosed between the ages of 40 and 60 and is exceptionally rare in individuals under 25 years of age [19, 20]. Data from numerous studies indicate that 1 in 800–1000 women over 40–45 years of age are affected by PBC [2, 15]. In studies conducted in the 20th century, the female-to-male ratio was 9–10:1. Recent population-based studies have shown that this ratio may be lower, at 2–5:1 [21–23]. The possible reasons for such pronounced sex differences are diverse and remain not fully understood. In men, the disease is more frequently diagnosed at an older age and, as a rule, at a late stage. The biochemical response to ursodeoxycholic acid** (UDCA)** therapy is worse in men, the disease is more likely to progress to cirrhosis, and they have a higher risk of death, liver transplantation (LT), and the development of hepatocellular carcinoma (HCC) than women [24, 25] (see Section 3.1.4.2 "PBC in Men").

Epidemiological studies demonstrate a trend toward an increase in the prevalence and incidence of PBC in recent decades, which may be associated with increased exposure to a currently unknown environmental etiologic factor, an increase in the number of elderly individuals at risk for PBC, improved patient survival due to treatment, and better disease diagnosis [23, 26].

1.4 Features of Coding the Disease or Condition

K74.3 — Primary biliary cirrhosis (primary biliary cholangitis).

In PBC with signs of other autoimmune liver diseases (overlap syndromes), the diagnosis is established based on the leading process (PBC, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC)) (see details in Sections 1.6.2.1, 2.5.2).

1.5 Classification of the disease or condition

Classification, Staging, and Risk Stratification

There is no universally accepted classification of PBC. From the perspective of clinical practice and complication risk stratification, it is most convenient to divide PBC into early (histological stages I–II) and late (histological stages III–IV) stages, which have distinct clinical, pathogenetic, and prognostic features [2, 28–30].

Comments. Since liver biopsy is rarely performed in PBC, it has been proposed to use liver stiffness measurement obtained by transient elastography (TE) and the presence/absence of abnormalities in laboratory tests of liver function (serum albumin, bilirubin) for staging [2].

A. Criteria for early-stage PBC:

1. Serum bilirubin and albumin levels: both parameters within reference ranges.

2. Liver TE data: liver stiffness < 9.3 kPa.

3. If pathomorphological examination results of liver tissue are available: minimal or absent fibrosis.

B. Criteria for late-stage PBC:

1. Serum albumin and total bilirubin levels: bilirubin > upper limit of normal (ULN) and/or albumin < lower limit of normal (LLN) (in the absence of other obvious causes for their deviation).

2. Liver TE data: liver stiffness ≥ 9.3 kPa.

3. Upon pathomorphological examination of liver tissue: bridging fibrosis or cirrhosis [2, 28–31].

Liver stiffness values used for staging are constantly being revised. In 2017, the EASL (European Association for the Study of the Liver), based on data from a small cohort clinical trial (CT), proposed a threshold of 9.6 kPa [2, 32]. However, a later meta-analysis determined the mean liver stiffness threshold for stage F3 to be 9.28 kPa [31] (in clinical practice, it is advisable to round to 9.3 kPa).

In addition to the PBC stage based on liver stiffness measurement, it is possible to indicate the risk of complications: low, medium, and high (< 8, 8–15, and > 15 kPa, respectively) [33] (see Section 5.1 "Stratification of Progression and Complication Risks").

When describing individual phenotypes and specific forms of PBC, it is possible to use the terms:

- classical (AMA-positive) PBC;

- AMA-negative (anti-gp210/anti-sp-100-positive PBC) (see Sections 1.6.3 "Special Forms", 2.3.2 "Immunological Diagnostics");

- seronegative PBC (AMA/anti-gp210/anti-sp-100-negative PBC);

- PBC with features of AIH (PBC/AIH), PBC with features of PSC (PSC/AIH) (also called overlap syndromes) (see Section 1.6.2.1) [2, 39–41].

Morphological Classifications.

Numerous morphological classifications of PBC have been proposed (see Appendix A3.2). The main classifications developed in the 20th century (P. J. Scheuer, 1967; H. Popper, F. Schaffner, 1970; J. Ludwig, 1978) [34–37] stage PBC primarily based on the extent of lesion involvement and severity of fibrosis:

Stage I — limited portal inflammation with or without prominent bile duct damage;

Stage II — periportal lesion extending into the hepatic parenchyma (interface hepatitis);

Stage III — formation of fibrous septa as a consequence of hepatic parenchymal damage;

Stage IV — development of cirrhosis [43].

Y. Nakanuma et al. (2013) developed a scoring system that introduces a new concept of PBC grading, evaluates cholangitis activity, hepatitis activity, and determines the disease stage based on the presence of fibrosis, deposition of orcein-positive granules, and loss of bile ducts. It has demonstrated the highest prognostic value, especially regarding the development of cirrhosis and its complications [97, 184, 185], but requires additional orcein staining. The scoring system by D. Wendum et al. evaluates fibrosis, ductopenia, and interface hepatitis separately and has shown good correlation with laboratory indicators of liver function [38].

1.6 Clinical presentation of the disease or condition

1.6.1 Clinical manifestations of PBC

PBC lacks strictly specific clinical symptoms, often remains asymptomatic for many years, and is diagnosed based on laboratory abnormalities detected during routine examinations. The asymptomatic course of PBC complicates timely diagnosis and generally leads patients to seek medical care at advanced stages (including the stage of decompensated cirrhosis) [2, 22]. PBC becomes symptomatic in 36–89% of cases over a period ranging from 4.5 to 17.8 years, and the average time from diagnosis to the onset of symptoms ranges from 2 to 4.2 years [43].

Fatigue/tiredness is one of the most common symptoms and may be the sole manifestation of the disease for 50–78% of PBC patients. It is relatively constant or, progressing slowly over time, has a significant negative impact not only on quality of life but also on overall survival [43]. Fatigue/tiredness is also associated with orthostatic hypotension, daytime sleepiness, and cognitive impairment [44–47].

Pruritus is the second most common symptom in PBC, affecting 40 to 80% of patients [48]. This symptom is not pathognomonic for PBC, can occur at any stage of the disease [49], and its intensity can vary, often showing no clear correlation with the stage or activity of the disease [2, 45, 47]. Itching most commonly intensifies at night, predominantly on the palms and soles, but can spread to other areas of the body with an intensity ranging from mild to unbearable, frequently leading to insomnia, increased fatigue, depression, significant deterioration in quality of life, social isolation, and suicide [50]. In the later stages of the disease, a decrease in pruritus intensity is often observed [48].

Physical examination findings in patients with PBC vary significantly and depend on the stage of the disease. Skin changes such as hyperpigmentation, excoriations, xanthomas, and xanthelasmas, as well as jaundice of the skin and mucous membranes, are common. In asymptomatic patients, physical examination may reveal no abnormalities. As the disease progresses, hepatosplenomegaly and other signs of portal hypertension (PH) and cirrhosis are detected.

Patients with severe cholestasis and/or late-stage disease may exhibit signs of steatorrhea, up to the development of a clinical picture of fat-soluble vitamin deficiency [51].

Impaired bone mineral density (BMD) in PBC is clinically silent until osteoporotic fractures occur, with symptoms developing depending on the fracture location. A typical sign of vertebral compression fracture is back pain, often chronic; however, a prominent clinical picture may be absent, and physical examination may reveal only height loss and/or kyphotic spinal deformity ("dowager's hump") (for details, see the Clinical Guidelines on "Pathological Fractures Complicating Osteoporosis") [52].

1.6.2 PBC and other immune-mediated diseases

1.6.2.1 PBC/AIH and PBC/PSC variant syndromes

AIH, PBC and PSC are currently considered independent autoimmune liver diseases [27, 53]. However, in some cases, patients may simultaneously exhibit clinical, biochemical, serological and histological features of two or more of these conditions at once [27, 53].

The experts who compiled these clinical guidelines support the proposal by the International AutoImmune Hepatitis Group (IAIHG, 2011) [27], according to which autoimmune liver diseases should be classified in accordance with the predominant features of AIH, PBC or PSC, and patients with overlapping features are not considered to have multiple nosological entities. This nomenclature is intended to simplify the diagnostic process, formulation of the diagnosis, and choice of therapy for practicing physicians [27]. In English-language literature, the term PBC-AIH variant syndrome has recently been used and supported by the IAIHG [582] (the concept of "variant syndrome" is used to describe the atypical course of a known disease). In recent years, the term "overlap syndrome" has fallen out of use as it does not reflect the essence of the condition.

PBC with features of AIH, PBC with features of PSC/small duct PSC, and AIH with both cholestatic diseases—PBC and PSC—have been described [27, 53]. Data on the incidence and prevalence of PBC variant syndromes vary, which is explained by the lack of uniform validated diagnostic criteria. Up to 13% [54] of patients with AIH have features of PBC [53]. In PBC, features of AIH are detected in 8–10% of patients [55]. Features of PBC and AIH most often occur simultaneously, but may debut sequentially in various orders [56].

Isolated cases and case series of the PBC/PSC variant syndrome have been described, the majority of which have been registered in women aged 35–72 years [57, 58]. Early symptoms of PBC/PSC include asthenia, fatigue, and pruritus [59]. As the disease progresses, symptoms are caused by the development of cirrhosis complications, cholestasis, strictures of the large bile ducts, etc. [57].

Similarly to classical forms of PBC, AIH and PSC, patients with PBC variant syndrome may be asymptomatic in the early stages [60, 61], while up to 50% of patients present only with changes in liver laboratory markers at the time of diagnosis [2, 56, 59].

PBC/AIH has a worse prognosis compared to the classical course of PBC. In a six-year observational study of 135 PBC patients, of whom 29 had PBC/AIH, the latter more frequently had complications such as portal hypertension, as well as a worse life expectancy prior to liver transplantation [62]. In a large study involving a retrospective evaluation of 142,594 patient charts, patients with variant syndrome had a worse prognosis with a high rate of cirrhosis complications and sepsis risk [63].

1.6.2.2 PBC and other immune-mediated diseases

In more than half of cases, PBC is combined with other immune-mediated, primarily autoimmune diseases (AIDs), which is due to the existence of common pathogenetic mechanisms, including genetic predisposition [6, 64]. Over 80% of genetic loci determining predisposition to PBC development overlap with loci associated with other AIDs [65, 66].

A correlation has been demonstrated between PBC and other AIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune thyroiditis, inflammatory bowel diseases, psoriasis, and others [67–71].

AIDs comorbid with PBC can manifest at any time—both before and after the formation of the full clinical picture of the underlying disease—and cause damage to a wide range of organs and systems.

A systematic review and meta-analysis (including 129 publications and 133 studies) showed that in PBC, the most common disease was Sjögren's syndrome (21.4% vs 3% in individuals without PBC), followed by Raynaud's syndrome (12.3% vs 1%), rheumatoid arthritis (5% vs 3%), systemic sclerosis (3.7% vs 0%), and systemic lupus erythematosus (2% vs 0%) [72]. A frequently detected condition in PBC is autoimmune thyroiditis (see Table 1). Due to comorbid AIDs, symptoms such as dryness of the eyes and/or oral mucosa, arthralgia, and myalgia are common in patients with PBC.

Table 1. Spectrum of autoimmune comorbid diseases most frequently detected in patients with PBC [70, 564–569]

The high prevalence of concomitant immunopathology in PBC, in the spectrum of which systemic autoimmune rheumatic diseases significantly predominate, and the possibility of their masked, latent course dictate the need for a high level of diagnostic vigilance during the management of this category of patients (see sections 2.5.2 "Diagnosis in special populations" and 3.1.4.6 "Treatment of immune-mediated diseases associated with PBC"). The presence of concomitant AIDs complements the clinical characteristics of PBC, making it possible to distinguish its various phenotypes (variants), but does not affect the outcome of PBC [73].

Total screening of all patients with PBC to rule out concomitant AIDs is impractical. However, if there is a clinical suspicion of the coexistence of another AID, an appropriate evaluation must be performed [2, 74] (see Table 2, as well as section 2.5.2 "Diagnosis in special populations").

Table 2. Spectrum of clinical manifestations allowing suspicion of the development of comorbid rheumatic pathology associated with PBC, and main changes detected upon examination [219, 222, 570–572].

1.6.3 Special forms of PBC

Special forms, or variants, of PBC are distinguished that differ from the classical form: PBC/AIH and PBC/PSC (variant syndromes discussed above in section 1.6.2.1); seronegative PBC; AMA-negative and seronegative PBC, as well as isolated AMA-positivity without laboratory signs of cholestasis.

Seronegative PBC is characterized by the presence of laboratory signs of cholestasis and histological criteria for PBC in the absence of AMA and specific ANA (anti-sp100, anti-gp210). According to small cohorts, it occurs in 9.75–22% of PBC cases [75, 76]. In 30% of such patients, non-specific ANA for PBC may be detected. Other manifestations of the disease in seronegative PBC are comparable to those in classical PBC [76].

AMA-negative PBC — a form of the disease characterized by the absence of AMAs, but the presence of specific ANAs (anti-sp100, anti-gp210) combined with laboratory signs of cholestasis and/or histological criteria of PBC. It is more common than other special forms of PBC. It is characterized by less pronounced pruritus and a more frequent association with other autoimmune diseases [77]. According to some data, in AMA-negative PBC, the levels of laboratory markers of cholestasis and serum immunoglobulin G (IgG) are slightly lower [77], while the serum γ-globulin concentration is higher than in classic PBC [78]. Also, DRB1*08 and DQB1*04 are less frequently detected in these patients [79]. Morphological changes in AMA-negative PBC differ little from the AMA-positive form, showing only slightly more pronounced damage and ductopenia [80, 81]. The response rate to ursodeoxycholic acid** therapy in AMA-negative PBC is considered comparable to the classic form of PBC [82], although there is evidence of a worse prognosis than in AMA-positive PBC, which may be a consequence of late diagnosis of this form [83].

AMA-positivity without biochemical and clinical manifestations of cholestasis. Specific AMAs are detected both in healthy individuals and in other autoimmune diseases, such as autoimmune hepatitis and inflammatory myopathies. At the same time, it is known that AMA-M2 can circulate in the blood serum months or even years before the clinical and laboratory manifestation of PBC [84]. However, the risk of developing PBC in this case is quite low: the five-year incidence of PBC among patients with normal alkaline phosphatase (ALP) and detected AMAs is 4.2–16.0% [85, 86]. However, according to small studies, more than 80% of AMA-positive individuals without baseline laboratory markers of cholestasis have histological signs of PBC [87, 88].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition.

a) an increase in serum ALP activity > 1.5 upper limit of normal (ULN) for more than 24 weeks, accompanied by an increase in GGT activity;

b) pathognomonic autoantibodies (AMA/AMA-M2, and/or anti-sp100, and/or anti-gp210);

c) histological features typical of PBC (non-suppurative destructive cholangitis, loss of interlobular bile ducts).

The detection of two criteria is sufficient for making the diagnosis [43, 47, 135, 161, 178].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments. PBC criteria include [43, 161, 178]:

1) an increase in ALP levels > 1.5 ULN that cannot be explained by other diseases. In the classic course of PBC, ALP is persistently elevated (in the absence of treatment), and making a diagnosis requires at least a twofold detection of its elevation over 24 weeks. The hepatic origin of ALP is confirmed by a simultaneous increase in GGT [161]. Other causes of cholestasis must be excluded (e.g., extrahepatic cholestasis using imaging studies) [47];

2) the presence of AMA/AMA-M2 or other specific autoantibodies associated with PBC (anti-sp100 or anti-gp210) (see Section 2.3.2 "Immunological Diagnostics");

3) histological signs of non-suppurative destructive cholangitis and destruction of interlobular bile ducts [43] (see Section 2.5.1 "Morphological Diagnostics").

In the presence of criteria a and b, a liver biopsy (percutaneous liver biopsy, laparoscopically guided liver biopsy) and pathological examination of biopsy (surgical) material from a liver needle biopsy are not required to diagnose PBC.

2.1 Complaints and Anamnesis

Taking the history of present illness and anamnesis in PBC is carried out according to standard principles. Symptoms may be absent (asymptomatic PBC). Characteristic symptoms of PBC—fatigue/asthenia, pruritus, skin and mucosal changes (dryness, hyperpigmentation, xanthomas/xanthelasmas), etc.—are described in detail in Section 1.6.1 "Clinical Manifestations of PBC".

When taking the anamnesis, risk factors for other liver diseases that can present with cholestasis should be clarified (medication history, use of herbal products, dietary supplements, bad habits, history of past or chronic infections, prior abdominal surgeries, etc.). It is necessary to identify when the first signs of the disease appeared (complaints, symptoms, changes in liver-specific laboratory data). Family history is also important. Comorbid status (previously diagnosed autoimmune conditions and other diseases that may affect liver status and treatment) should be assessed, along with identifying potential signs of metabolic syndrome and previously undiagnosed autoimmune diseases.

2.2 Physical Examination

Physical examination, palpation, and percussion in patients with PBC are performed according to standard protocols. External manifestations may be completely absent upon inspection.

Most frequently, examination of a patient with PBC reveals various skin changes: hyperpigmentation and dry skin, excoriations, eyelid xanthelasmas, xanthomas over joints, tendons, and buttocks [2]. Jaundice typically develops 6 months to 2 years after the onset of pruritus in untreated patients. Progressive weight loss and steatorrhea may be observed [41].

Attention should be paid to signs of autoimmune diseases associated with PBC: enlargement of the thyroid gland, eye symptoms (signs of thyroid disease), skin and mucosal changes (areas of depigmentation (vitiligo), livedo reticularis, dryness, cyanosis, signs of cutaneous vasculitis), changes in the fingertips (sclerodactyly, signs of Raynaud's syndrome), changes in joint shape and mobility, etc. [90].

Palpation may, but does not necessarily, reveal signs of hepatomegaly of varying severity [41]. With the development of fibrosis, liver consistency changes towards increased firmness with a loss of elasticity, and in cirrhosis, a sharp, sometimes nodular liver edge can be palpated. At the cirrhosis stage, vascular spiders (spider angiomas), splenomegaly, ascites, edema, sarcopenia, and signs of hepatic encephalopathy (HE) may be detected. To identify signs of decompensation of cirrhosis, the clinical guidelines on "Liver Cirrhosis and Fibrosis" should be followed.

2.3 Laboratory Diagnostics

2.3.1 Main laboratory parameters

Comments. An elevated ESR is frequently observed in patients with PBC [92]. Abnormalities in the hemogram usually occur at the stage of cirrhosis (thrombocytopenia, as well as anemia, leukopenia). Furthermore, thrombocytopenia and leukopenia have prognostic significance [2, 93]. Changes in complete blood count parameters (anemia, leukopenia) may indicate extrahepatic autoimmune diseases associated with PBC, such as autoimmune hemolytic anemia, thrombocytopenic purpura, etc. [73, 93].

Comments. Cholestasis is considered chronic if it lasts for more than 6 months [2]. It can be asymptomatic or manifest as hepatogenic fatigue/asthenia, pruritus, discomfort in the right upper quadrant, jaundice, and the development of xanthomas and xanthelasmas [95]. Among serum markers of cholestasis, an increase in ALP activity > 1.5 ULN is considered diagnostically significant for PBC [2, 96] and is an early sign of the disease [91, 97]. The hepatic origin of elevated ALP activity is confirmed by a simultaneous increase in GGT activity, as intrahepatic cholestasis shows a correlation between these parameters [2, 47, 91]. Elevated GGT levels may be observed before an increase in ALP activity [98]. Early PBC with normal ALP levels is possible [87] (see Sections 1.6.3 "Special Forms of PBC", 2.5.2 "Diagnosis in Special Groups").

Detection of chronic cholestasis requires the exclusion of extrahepatic biliary obstruction using imaging diagnostic methods (see Section 2.4 "Instrumental Diagnostic Procedures").

Comments. PBC is characterized by a moderate increase in transaminases, and their normal levels may also be observed [41, 91, 94]. If a patient with PBC has an ALT (AST) level > 5 ULN, the possibility of PBC/AIH overlap syndrome should be discussed [27] (for details, see section 2.6.2.1 "Diagnosis of PBC/AIH, PBC/PSC").

The AST/ALT ratio in patients with patients with PBC has been investigated as a potential marker for the development of liver cirrhosis [99, 100]. It has been shown that an elevated AST/ALT ratio > 1.1 is a predictor of liver cirrhosis in patients with PBC [99], although the sensitivity of this method is low [100].

Comments. An increase in total bilirubin and a decrease in albumin are typically signs of the late stage of the disease [15]. The development of hyperbilirubinemia (primarily due to the conjugated (direct, bound) fraction) is primarily caused by impaired bile flow resulting from bile duct damage [91], and its severity is determined by the severity of ductopenia and biliary piecemeal necrosis [102]. Serum bilirubin is considered the main predictor of adverse outcome in PBC [2, 103] and is included in the main prognostic indices (see section 5.1 "Stratification of risks of progression and development of complications").

An increase in bilirubin can be observed at initial presentation. In 9% of cases, cholestatic jaundice was observed in patients with early histological stages of PBC, but with morphological signs of severe bile duct damage and prolonged cholestasis [104].

When hepatic failure develops, there is a decrease in albumin levels with a remaining normal or slightly decreased total protein concentration [91]. Serum albumin is not only an indicator of the synthetic function of the liver, but also a marker of nutritional disorders and a prognostic factor [91, 105].

Based on serum albumin and bilirubin levels, liver function can be assessed using the Albumin-Bilirubin (ALBI) grade (see Appendix G5). In a clinical trial involving 409 patients with PBC, the areas under the ROC curves (AUROC) at 3, 5, and 10 years after baseline were 0.94, 0.91, and 0.90, respectively, for the ALBI index, which were higher than those for the Child-Pugh score [101]. In another clinical trial, an ALBI threshold of –2.24 effectively identified patients with a positive response to UDCA** therapy, while an ALBI threshold of –2.07 effectively excluded PBC patients at low risk of 5-year liver-related events [106].

The above laboratory parameters are used to determine the Child-Pugh prognostic class of liver cirrhosis and to calculate MELD (Model for End-Stage Liver Disease) (see Appendices G1, G3) [107].

Comments. Several large-scale case-control clinical trials have demonstrated an association between PBC and recurrent urinary tract infection [110–112]. In addition, PBC is associated with a number of renal diseases, primarily distal renal tubular acidosis, less frequently Fanconi syndrome, membranous nephropathy, microscopic polyangiitis, and tubulointerstitial nephritis [108, 109, 113, 114].

Comments. The aforementioned association of PBC with a number of renal diseases necessitates the assessment of their function (creatinine level with glomerular filtration rate calculation). A decrease in creatinine level reflects muscle tissue deficiency (sarcopenia) and is an adverse prognostic marker [115]. Assessment of renal function is important when planning fibrate therapy [116] and in the late stages of the disease. In patients with liver cirrhosis, creatinine is used to calculate MELD and its modifications (see Appendix G3) [107]. Changes in potassium levels in PBC are usually secondary to renal disease [117]. Hyponatremia in patients with liver disease, including PBC, is associated with increased mortality and is typically observed in patients with decompensated liver cirrhosis and hepatic failure [118]. Hyperlipidemia present in patients with PBC can affect the determination of electrolyte levels (especially when using indirect measurement methods), leading to falsely decreased values [119].

Comments. At an early stage of PBC, laboratory parameters of procoagulation, anticoagulation, and fibrinolysis remain within the normal range [91]. However, hypercoagulation may occur in some patients [121]. When hepatic failure develops in PBC, there is a decrease in the synthesis of plasma coagulation factors, which is reflected by an elevation of the international normalized ratio (INR) [91, 107]. It should be taken into account that in late stages of PBC, an elevated INR may result from vitamin K deficiency rather than decreased liver function [120].

Comments. Hyperlipidemia is a typical manifestation of cholestasis, observed in 80% of patients with PBC [122]. An increase in total cholesterol is characteristic, which does not have a negative impact on cardiovascular risk in patients with PBC [123]. At an early stage of PBC, the levels of very-low-density lipoproteins and LDL increase, and HDL increases significantly. As the disease progresses, LDL levels may increase, while HDL decreases (but remains elevated). Part of the excess LDL in PBC consists of an abnormal lipoprotein particle (lipoprotein X) that is rich in free cholesterol and phospholipids and is antiatherogenic. Triglyceride levels are usually normal or slightly elevated [123–125]. Since patients with PBC have predominantly elevated HDL levels rather than LDL, they usually do not have an increased risk of death from atherosclerotic diseases (unlike patients with hyperlipidemia without PBC) [122, 123]. Cardiovascular risk assessment in PBC and hyperlipidemia is discussed in section 5.1 "Stratification of risks of progression and development of complications".

Comments. Non-invasive laboratory tests (calculated indices) for the diagnosis of fibrosis are widely used in many liver diseases, but their diagnostic value in PBC is controversial. The possibility of using tests such as the Fibrosis-4 (FIB-4) index, Aspartate-to-Platelet Ratio Index (APRI), FibroTest, and Enhanced Liver Fibrosis (ELF) test (the latter is not registered in the Russian Federation) for staging and prognosis assessment in PBC has been studied predominantly in small cohorts [100, 127–134].

Serum tests for fibrosis assessment are considered to have an AUROC of 0.85–0.90 [100], but in PBC, the studied tests do not reach these values in most studies (see also section 2.6.3 "Risk stratification").

In patients with PBC at the cirrhosis stage, the scope of additional laboratory and instrumental examinations is determined in accordance with the current version of the clinical guidelines on "Liver Cirrhosis and Fibrosis" for the timely detection of complications [107].

2.3.2 Immunological diagnostics

More than 60 types of autoantibodies have been detected in patients with PBC, but only some are considered PBC-specific. Serum antimitochondrial antibodies (AMAs) are the primary immunological marker of PBC [2, 43, 135–138]. AMAs are a heterogeneous group of autoantibodies reacting with various proteins located on the inner and outer mitochondrial membranes (M1–M9). In PBC, AMAs are produced predominantly against the inner mitochondrial membrane antigen M2, which is the E2 subunit of the pyruvate dehydrogenase complex (PDH-E2/M2) that is part of the 2-oxoacid dehydrogenase complexes (2-OADC). AMA-M2 (AMAs to PDH-E2/M2) is a pathognomonic, most specific marker of PBC, found in 90–95% of patients [43, 136, 139]. Other variants of PBC-associated AMAs recognize other components of 2-OADC (the E2 subunit of the oxoglutarate dehydrogenase complex [OGDC-E2], the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex [BCOADC-E2], the E1α subunit, and the E3-binding protein of PDH), but they are detected less frequently than AMA-M2 [135, 136, 140, 141].

If the patient has undergone an indirect immunofluorescence assay (IFA) on the HEp-2 cell line, the presence of AMAs can be suspected due to mitochondrial/reticular cytoplasmic staining (cytoplasmic, mitochondrial staining pattern—AC-21 in accordance with the nomenclature of the International Consensus on ANA Patterns [ICAP], diagnostic titer ≥ 1:160) [142]. Other cytoplasmic autoantibodies, such as anticardiolipin antibodies, demonstrate a staining pattern similar to AMAs [143]. The detection of antibodies using IFA can be confirmed by antigen-specific tests, including enzyme-linked immunosorbent assay (ELISA), line immunoassay, or immunochemiluminescence.

Determination of other AMA subtypes, including antibodies to OGDC-E2, BCOADC-E2, E1α, and the E3-binding protein of PDH, as well as to the recombinant MIT3 antigen containing immunodominant regions of PDH-E2, BCOAD-E2, and OGDC-E2, is carried out using ELISA, chemiluminescent immunoassay (CLIA), and immunoblotting (IB) and is usually not required in routine clinical practice [135, 140, 141, 143–145]. ANAs in PBC can be directed against specific targets: the nuclear pore membrane protein gp210 and the nuclear antigen sp100 [145, 146]. In AMA-negative PBC patients, antibodies to sp100 and/or gp210 are detected in 20–35% of cases [135, 136, 147–150]. When using IFA on the HEp-2 cell line, staining patterns such as multiple nuclear dots (ICAP AC-6) and nuclear envelope/dot-like rim (ICAP AC-12), characteristic of antibodies to anti-sp-100 and anti-gp210, respectively, can be detected. Autoantibodies are determined using confirmatory tests (IB, ELISA) [140, 142]. Along with anti-sp100, antibodies to promyelocytic leukemia proteins (PML, sp140)—also characterized by the AC-6 nuclear staining pattern—may be detected, but their clinical significance remains unclear [3, 136, 142].

In addition, homogeneous (ICAP AC-1), centromeric (ICAP AC-3), and fine speckled (ICAP AC-4) ANA patterns are encountered in PBC. Antibodies to centromeres (directed against centromere proteins CENP-A, B, C) are detected in 16% of AMA-negative PBC patients [136, 147]. In IFA on HEp-2 cells, these autoantibodies induce a nuclear centromeric staining pattern (AC-3 pattern); confirmatory tests include ELISA, IB, CLIA, and multiplex immunoassay [142]. In PBC, the detection of these autoantibodies is of limited value, as they are diagnostic markers of a number of autoimmune diseases associated with PBC (limited systemic sclerosis, Raynaud's syndrome, Sjögren's disease) [142, 147].

New additional immunological markers of PBC have been described: antibodies to Kelch-like 12 and hexokinase-1. Their detection rate is 10–35% [3], but their diagnostic and prognostic significance requires clarification [3, 145].

Comments. The primary (screening) test for AMAs (determination of blood antibodies to mitochondrial antigens) is usually performed by IFA using a tissue complex of rat (mouse) liver/kidney/stomach cryosections as a substrate [143]. If the result is positive, the detection of PBC-specific AMA-M2 can be performed using confirmatory solid-phase immunoassay methods based on ELISA, IB, CLIA, and multiplex immunoassay, most frequently via ELISA [2, 43, 140, 142, 144, 153].

According to a meta-analysis of 24 clinical trials (including 2,992 patients with PBC, 18,467 patients with other liver diseases, and healthy individuals), the detection of AMAs/AMA-M2 by various methods (IFA, ELISA, IB) in PBC was characterized by high sensitivity (84.5%) and specificity (97.8%) [151]. Similar sensitivity and specificity values allow ELISA to be used not only as a confirmatory test, but also as a screening test [143, 144, 151]. The detection of AMA-M2 by line immunoassay, which has high specificity but lower sensitivity, is used to confirm positive results of the screening AMA test when necessary [136, 143, 154].

Serum AMA and AMA-M2 levels do not correlate with the activity and severity of the clinical course of PBC [147].

Comments. In AMA-negative patients with suspected PBC, the presence of serum PBC-specific ANAs anti-sp100 and gp210 should be evaluated by IFA on the HEp-2 cell line (determination of antibodies to cell nuclear antigens and DNA). Nuclear staining patterns AC-6 and AC-12 are detected (diagnostic titers ≥ 1:160). This is followed by IB as a confirmatory test [2, 3, 15, 43, 47, 140, 146, 148]. The meta-analysis showed that the detection of anti-gp210 using various immunoassay methods (IFA on HEp-2 cells, ELISA, IB), as well as the detection of anti-sp100, is characterized by low sensitivity (23–25%) and high specificity (95%) [148]. At the same time, ELISA and IB have somewhat greater sensitivity and specificity compared to IFA on HEp-2 cells [140].

Comments. A characteristic feature of PBC is an increase in the concentration of serum immunoglobulins, especially IgM. Elevated serum levels of IgM and IgG were noted in PBC (on average 2.4 and 1.16 ULN, respectively) [155]. Polyclonal hyperproduction of IgM in PBC is non-specific in nature and does not reflect the presence of IgM-class autoantibodies in patients [15]. The detection of elevated IgM is considered an alarming sign that may help suspect PBC [2]. Since it is not among the diagnostic criteria for the disease, IgM determination is not required in typical cases, but may be useful in diagnostically challenging cases [15].

Comments. Diagnosis of PBC/AIH is described in detail in Section 2.6.2.1 "Diagnosis of PBC/AIH, PBC/PSC".

Comments. Elevated serum IgG levels in PBC are a poor prognostic sign. They are frequently observed in PBC with marked fibrosis/cirrhosis. In the absence of cirrhosis, according to a retrospective analysis of 675 patients with PBC, elevated serum IgG (especially > 1.5 ULN) is associated with more rapid disease progression and an increased probability of liver-related death [156]. The significance of elevated IgG in differential diagnosis is determined by the fact that it is one of the criteria for diagnosing AIH or PBC/AIH [158].

An elevated serum concentration of anti-gp210 predicts the development of severe interface hepatitis and lobular inflammation, serves as a risk factor for disease progression toward liver failure (odds ratio [OR] 33.77), and is associated with severe cholestasis [147]. According to a meta-analysis including 737 patients with PBC, the detection of anti-gp210 correlated with adverse outcomes—patterns of PBC progression, especially liver failure [157]. The detection of anticentromere antibodies in PBC is accompanied by the rapid development of liver failure, severe histological damage to the bile ducts, and an increased incidence of portal hypertension [147] (for details, see Section 5.1 "Stratification of Risks for Progression and Development of Complications").

2.4 Instrumental Diagnostics

Instrumental diagnostic methods are of minor importance for the diagnosis of PBC itself, as this disease lacks specific features on imaging. These methods (ultrasound [US], computed tomography [CT], and magnetic resonance imaging [MRI]) can reveal non-specific changes, most of which are observed at late stages and upon the development of cirrhosis: hepatomegaly, hepatic parenchyma heterogeneity, lymphadenopathy in the hepatoduodenal ligament region, disproportion of liver lobes due to a combination of segmental atrophy and/or hypertrophy, signal alterations in the portal vein region (periportal halo sign), periportal edema, altered configuration of predominantly intrahepatic secondary bile ducts, portal vein dilation, splenomegaly, portosystemic collaterals, and ascites [159].

Instrumental methods in PBC are primarily aimed at differential diagnosis, determining the stage of the disease and risk stratification, and detecting complications of PBC [15, 43, 159–161].

Comments. Non-invasive liver and bile duct imaging is mandatory for all patients with biochemical signs of cholestasis of unclear (or doubtful) etiology to detect intra- or extrahepatic bile duct dilation or focal liver lesions [161]. Ultrasound in patients with PBC may reveal increased echogenicity of the portal vein walls combined with hypoechoic periportal changes, as well as an enlarged left lobe of the liver (anteroposterior size greater than 90 mm). It is precisely the combination and severity of these signs that correlate with the histological stage of the disease, rather than the isolated detection of any single one [162]. Enlargement of periportal lymph nodes is frequently detected in PBC [15]. At a late stage, ultrasound allows the detection of signs of cirrhosis (such as a nodular liver surface), splenomegaly, and portal hypertension. However, the primary role of ultrasound at this stage is screening for hepatocellular carcinoma [160] (see Section 5.2 "Follow-up"). In a small clinical trial, spleen sizes assessed by ultrasound were used for PBC staging [130]. However, this method has not been sufficiently studied to be recommended for routine practice.

Ultrasound makes it possible to detect signs of individual parenchymal liver diseases (such as fatty liver disease) that may accompany PBC or require differentiation from it [163]. The frequent detection of asymptomatic cholelithiasis in PBC sometimes leads to it being unjustifiably considered the cause of cholestasis, which results in delayed diagnosis of PBC [15].

Comments. Detailed cholangiographic evaluation of the biliary tree is essential for differentiating PBC from PSC, IgG4-related cholangitis, and secondary sclerosing cholangitides, which may present with disease-specific features [159, 164]. If bile duct dilation is detected on ultrasound, performing MRCP is mandatory [159].

Comments. TE is currently the primary non-invasive method for assessing liver fibrosis in PBC, and its results correlate with the histological stage of the disease and its prognosis [32, 165–169]. According to a meta-analysis for fibrosis diagnosis, the sensitivity of TE was 68% and specificity was 92% for stage F3, and 90% and 94% for stage F4, respectively. Mean liver stiffness threshold values were 9.28 kPa for stage F3 and 15.2 kPa for stage F4 [31]. In a multicenter clinical trial in treatment-naive patients with PBC, liver stiffness threshold values (≤ 6.5 and > 11.0 kPa) were determined to differentiate between the absence or presence of fibrosis. Exact staging by TE is not possible between these two thresholds [165]. Nevertheless, as discussed above, in clinical practice, the rounded threshold value of 9.3 kPa should be used for staging (fibrosis severity) [31]. Importantly, body mass index (BMI) and laboratory markers of liver function did not affect TE results in PBC [165].

Comments. It is hypothesized that the measurement of liver tissue stiffness (liver elastography) using point or two-dimensional shear wave elastography (2D-SWE, 3D-SWE) implemented on modern ultrasound systems is comparable to TE results. However, there are only pilot study data in patients with PBC confirming this [170].

Magnetic resonance elastography (MRE) of the liver accurately detects advanced fibrosis with a threshold value of 4.60 kPa (AUROC 0.82) and can predict hepatic decompensation and liver-related complications (odds ratio [OR] 2.09). However, it showed inferior performance in differentiating early stages of fibrosis compared to TE [171].

Comments. Esophageal varices typically develop in patients with cirrhosis. However, in PBC, clinically significant portal hypertension can occur even at an early stage of the disease, which is a unique feature rarely seen in other liver diseases. Portal hypertension in early PBC is considered pre-sinusoidal, likely caused by nodular regenerative hyperplasia. Esophageal varices prior to the development of cirrhosis are generally moderate and do not carry a bleeding risk, although it has been described that complications of portal hypertension such as splenomegaly, hypersplenism, and bleeding can occur even at pre-cirrhotic stages [172–174].

Comments. Osteoporosis is associated with PBC and occurs in 20–44% of patients, leading to an increased risk of bone fractures due to bone fragility [175, 179, 180]. The mechanisms of bone metabolism disorders in patients with PBC are complex; risk factors for osteoporosis in PBC include female sex, menopausal status, older age, low BMI, advanced stage of PBC, and vitamin D deficiency [181]. In the absence of age and menopausal risk factors, the severity of cholestasis and liver damage has the greatest impact on BMD reduction [175, 176].

2.5 Other Procedures

2.5.1 Morphological diagnostics

In most cases, the diagnosis of PBC is established based on serological markers, while morphological diagnosis is required in diagnostically complex cases [2]: usually in seronegative PBC, suspected PBC/AIH, or other concomitant liver pathology [3, 15, 43].

A classic manifestation of PBC is non-suppurative destructive cholangitis affecting interlobular and septal bile ducts, using the term "florid duct lesion". Duct damage is characterized by 1) intraepithelial mononuclear infiltration, 2) damage to the biliary epithelium; 3) destruction of the basement membrane of the bile ducts [2, 34, 36, 40, 97], resulting in the development of the ductopenia phenomenon [182]. The inflammatory infiltrate in PBC is in close contact with the bile ducts and consists of lymphocytes, plasma cells, macrophages, and polymorphonuclear leukocytes (often eosinophils). There are two main types of periportal (interface) hepatitis in PBC: a) lymphocytic piecemeal necrosis, similar to the lesion in AIH; b) biliary neutrophilic piecemeal necrosis (causing cholestasis) with a stage of ductular proliferation of varying severity. The infiltration may contain epithelioid cell granulomas without necrosis, usually at an early stage of the disease [183]. Changes in the hepatic arteries are uncommon, and deformation and occlusion of portal venules due to the inflammatory reaction are frequently noted [43]. The biopsy specimen may simultaneously exhibit pathological changes characteristic of different stages of the disease. The possibility of therapeutic pathomorphosis (mild intrahepatic cholestasis, reduction of inflammatory infiltration) during UDCA** therapy should be taken into account.

When evaluating a biopsy specimen, any of the numerous morphological classifications of PBC can be used — by P.J. Scheuer, 1967; H. Popper, F. Schaffner, 1970; J. Ludwig, 1978; Y. Nakanuma et al., 2010; D. Wendum et al., 2015 (see Appendix A3.2) [34–38].

Comments. According to the diagnostic criteria (see Section 2 "Criteria for Establishing Diagnosis / Condition"), in a patient with a persistent increase in ALP and negative autoantibody test results, morphological confirmation of the diagnosis is required. Other situations where pathomorphological examination of liver tissue material may be required include: recent increase in ALP (< 24 weeks) with positive autoantibodies; cases where alternative causes of the disease have not been established/excluded by non-invasive methods; combination of PBC with other liver diseases or systemic diseases [2]. Histological diagnosis of PBC is carried out as part of a standardized morphological examination of a liver biopsy for light microscopy, and usually includes the following histological stains: a) hematoxylin and eosin, b) PAS reaction, c) PAS reaction with diastase, d) Masson's trichrome and (or) Van Gieson's stain with additional staining for copper with orcein or rhodanine. The main spectrum of morphological differential diagnosis in suspected PBC includes drug-induced liver injury (cholestatic and mixed type), biliary obstruction, sarcoidosis, AIH, PSC, ABCB4 deficiency, and IgG4-related cholangitis [43].

Comments. For the diagnosis of PBC/AIH, morphological examination of liver tissue is mandatory (percutaneous liver biopsy is the preferred method for obtaining material) [27]. Mild interface hepatitis, as described above, may be observed in PBC, which does not always indicate AIH. Such patients respond well to UDCA** and do not require immunosuppressive therapy (IST) [187]. The presence of moderate to severe interface hepatitis in liver biopsy specimens generally indicates an overlap with AIH and is an indication for IST [27, 188, 189].

Comments. According to clinical studies, the prevalence of AMA in first-degree relatives of patients with PBC is 13.1% (compared to 1% in healthy individuals). Identification and subsequent monitoring of first-degree relatives of patients with PBC have enabled early diagnosis of PBC [191]. Extrahepatic autoimmune diseases represent another risk factor for PBC [110–112]. For AMA-positive patients at high risk for PBC, performing a liver biopsy (preferably percutaneous liver biopsy) for early diagnosis is advisable without a prolonged period of observation [47, 85].

Comments. In typical morphological presentations of PBC, IHC examination of biopsy specimens is not required, but it can be useful in diagnostically complex cases and differential diagnosis. Abnormal expression of cytokeratins 7 or 19 by hepatocytes (CK7, CK19) is a hallmark of cholestatic diseases, reflects the phenomenon of metaplasia, and is often combined with ductopenia [194]. Pathomorphological examination of the liver biopsy using IHC methods allows for the objective characterization of the lesion. Thus, hepatocyte CK7/CK19 IHC improves the efficacy of morphological differential diagnosis of liver diseases involving bile ducts, including determining the degree of ductopenia in PBC [194]. For the differential diagnosis of PBC, AIH, and PBC/AIH, plasma cell immunophenotyping (CD38/CD138/IgG/IgM) [192, 195] and evaluation of bcl-2 expression [193] are advisable. Differentiation from IgG4-related disease may require the identification of IgG4-positive plasmacytes [196], though cases of coexisting PBC and IgG4-related disease have been described [197, 198].

2.5.2 Diagnostics in special populations

Diagnosis of PBC/AIH, PBC/PSC

AMAs are detected in 8–12% of patients with AIH without histological signs of bile duct damage or loss [199]. These patients respond to immunosuppressive therapy (IST), and PBC does not develop in them [200]. Therefore , the presence of AMA in patients with AIH is likely insufficient for a diagnosis of PBC. Indications for diagnostic evaluation in AIH patients to rule out PBC include elevated laboratory markers of cholestasis (ALP ≥ 2 ULN and/or GGT ≥ 5 ULN), as well as a poor response to IST [27].

Patients with PBC may have a moderate elevation in transaminase activity, which typically normalizes with UDCA therapy [102, 155, 202]. Evaluation (described in sections 2.3, 2.5) to rule out PBC/AIH is indicated in cases of prolonged (recurrent) transaminase elevation ≥ 5 ULN, as well as a poor response to therapy for 6–12 months [2].

Establishing a diagnosis of PBC/AIH is only possible in combination with histological data, since the presence of moderate and severe interface hepatitis in liver biopsies of patients with PBC determines the course of AIH and the indications for IST [27, 188]. Therefore, performing a pathological examination of liver biopsy (surgical) material to confirm the diagnosis of PBC/AIH is mandatory [27, 196, 201] (see section 2.5 "Morphological Diagnostics").

Comments. In variant (overlap) syndromes of AILD, the diagnosis is established based on the leading process: K74.3 — primary biliary cirrhosis (primary biliary cholangitis); K83.0 — cholangitis (primary sclerosing cholangitis); K75.4 — autoimmune hepatitis. It is acceptable to establish two diagnoses (K74.3 + K75.4, K83.0 + K75.4) [27].

Comments. Diagnostic scales for PBC/AIH are not validated. This is primarily explained by the similarity of laboratory, serological, and morphological signs of the diseases. Thus, in some patients with PBC, antibody titers and IgG levels, which are part of standard AIH diagnostic scales, may be elevated, making diagnosis difficult [203]. The Paris criteria (see below) showed higher sensitivity and specificity compared to AIH diagnostic scales in PBC/AIH [188].

Comments. The Paris criteria (see Appendix G2) allow for the identification of patients with PBC and an AIH component who are indicated for IST [27, 188, 205]. The diagnosis can be established if two out of three criteria in each section are met.

PBC criteria:

1. ALP level ≥ 2 ULN and (or) GGT ≥ 5 ULN.

2. Presence of AMA.

3. Characteristic morphological pattern — typical bile duct lesions ("florid bile ducts").

AIH criteria (two of the three criteria must be met):

1. Serum ALT level ≥ 5 ULN.

2. Serum IgG level ≥ 2 ULN or the presence of ASMA.

3. Histological picture of moderate or severe interface hepatitis (periportal or periseptal lymphocytic piecemeal necrosis) in the biopsy specimen.

According to the original Paris criteria, meeting any two criteria for each disease is sufficient for diagnosis. However, considering that the morphological picture is of primary importance in the diagnosis and choice of treatment for PBC/AIH, the histological criterion is mandatory.

The Paris criteria have high specificity but low sensitivity, which is due to the potential exclusion of patients with variant syndrome who have less pronounced signs of cholestasis [204, 207].

W. Zhang et al. (2018) proposed a new AIH/PBC diagnostic system, which has higher sensitivity and specificity compared to the Paris criteria [39], but is difficult for practical use. Also, some morphological criteria of AIH presented in this classification were later rejected as signs of AIH [208]. The classification by W. Zhang et al. is used predominantly in clinical trials [209].

Comments. MRCP is required to exclude PBC/PSC and identify other causes of cholestasis [57]. Due to the poor understanding of the PSC/PBC variant syndrome, an individualized approach is required for its diagnosis. Importantly, AMA are detected in 2% of PSC cases [210], which does not always indicate PSC/PBC.

The following criteria, based on the diagnostic features of classical forms of PBC and PSC, are considered [57].

A. Cholangiographic signs of PSC.

B. Two of the three PBC criteria:

1) cholestasis syndrome in blood biochemistry for more than 6 months;

2) detection of AMA and (or) PBC-specific antinuclear antibodies (ANA) (anti-gp210 and (or) anti-sp100);

3) histological picture obtained from a liver biopsy (destructive cholangitis): performed in the absence of antibodies or for differential diagnosis.

Diagnosis of AMA-negative PBC

A special form of PBC — AMA-negative PBC — includes patients with a clinical picture of the disease and liver histological changes identical to the classical form of AMA-positive PBC, but with the absence of specific serum AMA, accounting for 5–15% of patients with PBC [83, 211–213].

If the AMA/AMA-M2 test is negative, the diagnosis should be based on typical pathological features of PBC [78]. It is advisable to determine specific antinuclear autoantibodies — anti-gp210 and anti-sp100 [146, 214] (see also section 2.3.2 "Immunological Diagnostics"). A higher sensitivity of the combination of these two markers has been reported [215, 216]. According to meta-analyses, anti-gp210 and anti-sp100 have high specificity but low sensitivity in the diagnosis of PBC [146, 148]. The detection of ANA cannot guarantee the correct diagnosis of PBC even in patients with cholestatic biochemical parameters and requires the exclusion of other diseases [217].

AMA-positivity without biochemical changes

AMA-positive patients without clinical manifestations of PBC and laboratory signs of cholestasis represent a heterogeneous group requiring a differentiated approach [3].

Comments. In healthy individuals, AMA are detected in 0.07–9.9% of cases [217–219]. However, long-term follow-up of such healthy individuals has revealed their heterogeneity. In clinical trials about 80% of patients with positive AMA and (or) PBC-specific ANA and a normal serum ALP level had histological signs of PBC [87, 190]. During an 18-year follow-up of asymptomatic AMA-positive patients (PBC was diagnosed by biopsy in 40% of cases), 76% of patients developed symptoms, and 83% developed an increase in ALP activity [220].

High-risk groups for developing PBC in the presence of AMA-positivity, who should be considered for a liver biopsy, were discussed earlier in section 2.5.1 "Morphological Diagnostics".

Diagnosis of immune-mediated diseases associated with PBC

Comments. The development of comorbid pathology should be suspected based on clinical and (or) laboratory data indicating extrahepatic involvement. Upon clinical suspicion of a comorbid immune-mediated disease in a patient with PBC, a screening examination should be performed and a referral to a relevant specialist should be scheduled in accordance with current clinical guidelines for the suspected disease [2]. Table 2 (section 1.6.2) lists the range of clinical manifestations and examination results that allow one to suspect the development of the most frequent comorbid rheumatological pathology associated with PBC. Further examination in case of suspected AILD associated with PBC is carried out in accordance with the clinical guidelines for the corresponding nosological form.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1 Non-pharmacological treatment

Non-pharmacological treatment of PBC is poorly developed. There are no evidence-based dietary recommendations for PBC [3, 15, 259].

There is limited evidence on the negative impact of smoking and overweight on the course of PBC [263, 264], therefore PBC patients should be informed about the advisability of smoking cessation and the need to maintain a normal body weight, and in later stages — alcohol abstinence [3]. There is evidence that alcohol consumption increases the risk of HCC in PBC, although this is not confirmed in other studies [262, 265].

PBC patients should maintain physical activity. Exercising with PBC is safe, moreover, data from pilot studies indicate that therapeutic exercise is beneficial for treating fatigue [259] (see further section 3.1.3 «Symptomatic treatment»).

Patients with PBC and decompensated cirrhosis should follow the nutritional principles for cirrhosis [107]. Patients with PBC and osteopenia/osteoporosis should follow the nutritional and physical activity recommendations for osteoporosis [52]. Patients with PBC and obesity and/or non-alcoholic fatty liver disease should follow the dietary and lifestyle modification principles for these conditions [43].

3.1.2 Medical treatment

3.1.2.1 Basic (disease-modifying) therapy

Disease-modifying therapy for PBC is generally prescribed lifelong and is reviewed in the event of non-response, contraindications, or side effects from baseline treatment.

Currently, disease-modifying therapy includes:

a) 1st-line therapy drugs — UDCA**;

b) 2nd- and 3rd-line therapy drugs — PPAR agonists (fibrates), obeticholic acid (OCA).

UDCA**. Its beneficial effect on the course of PBC is likely associated with multiple mechanisms of action: reducing the toxic bile acid pool; suppressing apoptosis; regulating cholangiocellular Ca²⁺-dependent Cl^–/HCO₃^– secretion; and an immunomodulatory effect [266]. For a long time, the efficacy of UDCA** was a subject of debate because some meta-analyses did not show its effect on transplant-free survival in PBC [267, 268]. This was likely the result of methodological flaws in the clinical trials included in the meta-analyses (insufficient sample sizes, short follow-up periods, low doses) [15] and contradicted real-world clinical practice data, where the widespread use of UDCA** globally led to a sharp decrease in the number of PBC patients requiring liver transplantation [269]. A meta-analysis evaluating large and long-term studies (≥ 48 months) and large real-world clinical practice studies showed a positive effect of UDCA** therapy on reducing the need for liver transplantation and mortality in PBC [270, 271].

UDCA** is used in patients at any stage of PBC, but patients in the early stage of the disease generally respond better to treatment [249, 275]. Even in late stages, UDCA** therapy increases transplant-free survival [271].

The use of UDCA** in PBC is accompanied by a decreased risk of esophageal varices development [272] and a reduction in serum LDL cholesterol levels [274], but it does not reduce PBC-associated symptoms and conditions such as fatigue [273, 276] and systemic autoimmune manifestations [43].

UDCA** is generally well tolerated, and the incidence of adverse events is low [277]. In case of poor tolerability (e.g., diarrhea), the drug should not be discontinued completely, but rather divided into multiple doses, decreased, and gradually titrated to the maximum tolerated dose [266]. The bioavailability of various UDCA** preparations may vary [278]. Cholelithiasis frequently accompanies PBC [588]. Sufficient experience has been accumulated proving the safety of UDCA** use in cholestatic diseases and cholelithiasis [279, 576–578].

Currently, there is insufficient evidence to recommend prophylactic UDCA** use solely based on a positive AMA test result [47].

Fibrates are peroxisome proliferator-activated receptor (PPAR) nuclear receptor agonists [280]. According to a meta-analysis, in the absence of a response to UDCA** therapy, the addition of #fenofibrate** significantly reduces laboratory parameters, including ALP [281]. An important additional effect of fibrates is their ability to relieve cholestatic pruritus [282–284] (see section 3.1.3 «Symptomatic treatment»).

If UDCA** is well tolerated, fibrates are added to it. Monotherapy is used only in case of UDCA** intolerance. The combination of UDCA** + fibrate is generally well tolerated, but a slight increase in side effects compared to UDCA** monotherapy has been noted, predominantly myopathy [285]. A systematic review including 37 clinical trials indicated a low incidence of adverse events with fibrate therapy for cholestatic diseases [116]. According to a meta-analysis, no significant increase in therapy-related adverse events was recorded when using fibrates in PBC [286]. Nevertheless, when prescribing fibrates, monitoring of liver function tests, muscle tissue parameters (creatine kinase), and renal function (creatinine) is required a few weeks after treatment initiation [266]. Caution should be exercised when concurrently using fibrates and HMG-CoA reductase inhibitors (statins) due to potential drug interactions and a slightly increased risk of myopathy [266].

Since safety monitoring schedules for this therapy specifically for PBC have not been established, one should be guided by the monitoring schedules and drug discontinuation parameters used when prescribing fibrates for hypertriglyceridemia [257].

OCA is a derivative of chenodeoxycholic acid and a farnesoid X receptor (FXR) agonist. These receptors are a crucial regulator of bile formation and enterohepatic circulation, playing a decisive role in bile acid homeostasis and liver regeneration. By modulating FXR activation and the-mediated release of fibroblast growth factor-19 (FGF-19), OCA regulates the synthesis and secretion of bile acids and alters their composition. The effect on hepatic sinusoidal endothelial cells and Kupffer cells provides anti-inflammatory and antifibrotic action of the drug. The mechanisms of action of OCA and UDCA** are fundamentally different, as UDCA** has practically no effect on FXR [14, 287].

In a double-blind randomized clinical trial (RCT) in patients with an inadequate response to UDCA** or with its intolerance, a therapeutic response was observed in a significantly greater number of patients receiving 5 mg (46 %) and 10 mg (47 %) OCA compared to placebo (10 %). Furthermore, significant differences were recorded as early as 2 weeks after drug administration [288]. Compared to UDCA**, the combination of OCA + UDCA** reduces the 15-year cumulative incidence of decompensated cirrhosis (from 12.2 to 4.5 %) and increases 15-year transplant-free survival (from 61.1 to 72.9 %), reduces the rate of liver transplantation (from 4.5 to 1.2 %) and liver-related mortality (from 16.2 to 5.7 %), as well as the incidence of HCC development (from 9.1 to 4.0 %) [289].

At the same time, the post-marketing placebo-controlled RCT COBALT did not confirm the previously demonstrated efficacy of OCA in PBC, but functional unblinding and patient crossover to alternative therapy occurred, especially in the placebo group, which calls its results into question [290]. An open-label clinical trial with external control groups showed a reduction in the risk of death and liver transplantation with OCA therapy during a six-year follow-up [287]. In real-world clinical practice trials, OCA intake led to positive effects, including a 63 % reduction in the risk of hospitalization for hepatic decompensation, liver transplantation, or death [291, 292].

Exacerbation and onset of pruritus with OCA intake is the main reason for drug discontinuation [289]. According to a meta-analysis, therapy with OCA 5–10 mg / 10 mg compared to placebo is associated with a high risk of pruritus (RR 1.43/1.79) and serious adverse events (RR 3.82/2.67) [293]. Reported cases of severe liver injury leading to hepatic decompensation or liver failure while taking OCA have resulted in this drug being used with caution in cirrhosis, and it is contraindicated in decompensated cirrhosis (Child-Pugh class B and C) [294].

Glucocorticoids (GCs) and immunosuppressants are not used for the treatment of PBC per se. In a small study, the combination of #prednisolone** with UDCA** showed a positive effect on histological parameters, but GCs can exacerbate osteoporosis, which is a frequent complication of PBC [295, 296]. In a placebo-controlled double-blind RCT involving patients who did not respond to UDCA**, the administration of #budesonide** did not lead to histological improvement, although it did reduce ALP levels [297]. In addition, #budesonide** may also lead to a decrease in BMD in individual PBC patients [298].

A number of drugs belonging to immunosuppressants and biological therapy have been studied in PBC (#azathioprine**, #chlorambucil**, #cyclosporine**, #methotrexate**, #mycophenolate mofetil**, #rituximab**, and #ustekinumab**), but all of them proved to be either ineffective, marginally effective, or potentially dangerous, and are not used in the treatment of PBC [299–301]. GCs and immunosuppressants can be used in PBC/AIH or when PBC is combined with other AIDs. Their choice is determined by comorbidity. It should be taken into account that #methotrexate** has been shown to have a positive effect on cholestatic pruritus in PBC [302]. #Budesonide** is not used in patients with PBC and LC and/or PH, as it increases the risk of portal vein thrombosis [303].

3.1.2.1.1 1st-line baseline (disease-modifying) therapy

Comments. The largest multicenter international clinical trial (Global PBC Study Group; 3902 PBC patients, median follow-up 7.8 years) proved an independent association of UDCA** use with a reduced risk of LT or death (HR 0.46) compared with no treatment. It has been shown that even with an insufficient biochemical response after one year of UDCA** treatment, the risk of LT or death is reduced [271]. In an RCT comparing low, medium, and high doses of UDCA** in PBC, it was shown that a medium dose of 13–15 mg/kg of body weight per day is optimal [305]. The Global PBC Study Group clinical trial revealed a clear dose-response relationship with the greatest benefit for patients receiving an adequate dose of ≥ 13 mg/kg of body weight per day (OR 0.29, p < 0.001) [271].

3.1.2.1.2 2nd-line baseline (disease-modifying) therapy

Approximately 60% of patients respond to UDCA** therapy [288]. If a patient has not responded to treatment with UDCA** at an adequate dose for 6 or 12 months (see Section 3.1.2.2 "Assessment of Response to Therapy"), 2nd-line therapy should be considered. 2nd-line drugs are generally used in addition to UDCA**. In recent years, an individualized approach to treatment and the possibility of early initiation of 2nd-line therapy for patients with risk factors for non-response to UDCA** have been considered, but the criteria for this are not yet sufficiently developed [13].

The main risk factors for an inadequate response to UDCA** include young age; pruritus, low albumin levels, or high levels of ALT, GGT, and ALP before treatment initiation; presence of anti-gp210; PBC/AIH; ductopenia on histological examination; severe liver fibrosis (on histological examination or TE data); and presence of LC [249, 306, 307].

Comments. A meta-analysis including 4783 patients and 20 clinical trials demonstrated the effect of fibrates on ALP and GGT levels, and pruritus symptoms [286]. In a meta-analysis of clinical trials involving patients with no or incomplete response to UDCA**, the addition of #fenofibrate** at a dose of 100–200 mg/day (for 8 to 100 weeks) led to a complete response in 69% (OR 82.8) [281]. In an RCT, UDCA** + #fenofibrate** therapy in treatment-naive PBC patients led to a treatment response in 81.4% of cases (compared to 64.3% with UDCA** monotherapy) [308]. Therapy with UDCA** + #fenofibrate** at doses of 13–15 mg/kg and 200 mg/day, respectively, improves transplant-free survival [309].

3.1.2.1.3 3rd-line baseline (disease-modifying) therapy

3rd-line therapy is considered in patients who have not responded to 2nd-line therapy.

Comments. An increased risk of adverse events, primarily pruritus [292, 293], as well as contradictory data on the efficacy of OCA [290, 579, 580, 581], dictate that it should be prescribed for PBC when other treatment options are exhausted. OCA therapy is started at a dose of 5 mg once daily, which can be gradually increased to a maximum dose of 10 mg daily.

Comments. Data have emerged on triple combination therapy with #UDCA** + #OCA + #fibrate, which is considered as 3rd-line therapy. Compared with dual therapy, triple therapy was associated with a significant reduction in ALP (OR = 3.4 for achieving a normal ALP level). If OCA was used as 2nd-line therapy, the effect of the combination was higher, and in addition, a reduction in pruritus was observed (more pronounced than in the group where fibrates served as 2nd-line therapy) [312].

3.1.2.2 Assessment of response to therapy

About 30–40% of patients with PBC demonstrate an insufficient biochemical response to UDCA** with a risk of disease progression to a late stage, including LC [30].

Most clinical trials demonstrate the greatest significance of serum ALP and bilirubin in assessing response to UDCA** [103, 233]. An analysis conducted by the Global PBC Study Group showed that normalization of ALP and a total bilirubin level < 0.6 ULN are independently associated with lower rates of liver-related mortality and LT requirements [233].

Achieving target ALP values in clinical practice is not always feasible. It has been shown that transplant-free survival in patients with early-stage PBC who achieve ALP levels < 1.5 ULN and bilirubin within the normal range by 12 months of therapy does not significantly differ from that in a healthy control population [103].

Several prognostic scales have been developed and validated to identify non-responders to UDCA** and determine indications for initiating 2nd-line therapy (see Table 3, Appendix G4). The GLOBE and UK-PBC continuous assessment systems demonstrated better efficacy in predicting death or LT compared to dichotomous models [237, 313] (see Appendices G4.9 and G4.10). Risk assessment calculators are available online at the respective websites: http://www.uk-pbc.com/resources/tools/riskcalculator/ (accessed: July 7, 2025) and http://www.globalpbc.com/globe (accessed: July 7, 2025).

To date, there are no data on the prognostic reliability of using traditional UDCA** response assessment scales to determine the response to 2nd-line therapy [314]. The OCA Response Score (ORS) has been developed, which takes into account serum surrogate markers of PBC prognosis, the presence of pruritus and LC before treatment initiation, and the level of ALP and bilirubin at the 6th month of OCA therapy (https://ocaresponsescore.github.io/calculator/) [315].

To identify patients at high risk of UDCA** monotherapy failure before treatment initiation, the UDCA Response Score (URS) model was developed, which includes clinical and serological variables prior to treatment initiation: ALP level, patient age, and the interval between diagnosis and initiation of UDCA in years (https://www.mat.uniroma2.it/~alenardi/URS.html, accessed: July 7, 2025) [253, 254]. The URS scale has shown high accuracy, but has not yet been introduced into clinical practice.

Scales for assessing response to UDCA** therapy in patients with PBC are presented in Appendix G4.

Comments. The Paris I and Paris II scoring systems are the most accurate and widely used criteria for biochemical response in patients with late (histological stage III–IV) or early PBC (histological stage I–II), respectively [230] (Appendix G4.2 and G4.3). Most scales were developed to assess response after 12 months of UDCA** treatment, but a number of clinical trials demonstrate their equivalent prognostic value as early as 6 months of treatment [318, 321]. It was shown that out of 235 patients with ALP > 1.9 ULN at month 6 of UDCA** therapy, 210 individuals (89%) failed to achieve a biochemical response by month 12 of treatment and could have been identified earlier [322]. In another clinical trial, < 13% of patients with an incomplete response at 6 months achieved a response by the 12th month [323].

• If an inadequate response to UDCA** is detected in a patient with PBC according to the Paris I or Paris II criteria, it is recommended to additionally consider evaluation using the GLOBE score to clarify the indications for 2nd-line therapy [319, 320].

GGR ALOC 2Grade of recommendation A (Level of evidence 2).

Comments. According to meta-analyses, the GLOBE and UK-PBC risk scores are the most suitable for real-world allocation of 2nd- and 3rd-line therapy (OCA and fibrates) [319] (Appendix G4.9 and G4.10). An international multicenter meta-analysis involving 4,119 PBC patients treated with UDCA** demonstrated that the GLOBE score identified patients who would survive without adverse liver events at 5 and 10 years (responders to UDCA** therapy) with a positive predictive value of 98% and 88%, respectively [324].

3.1.3 Symptomatic treatment

3.1.3.1 Treatment of pruritus

Pruritus is one of the most severe symptoms in patients with PBC, having the greatest impact on quality of life and requiring a step-by-step approach prioritizing interventions with proven efficacy according to RCTs [325]. Non-pharmacological methods play an important role in relieving pruritus symptoms. Patients with pruritus should be advised to:

— regularly care for the skin using emollients [2];

— avoid overheating and skin irritation: use cool water for baths/showers; avoid intensive rubbing of the skin when washing (do not use hard washcloths, abrasive agents); avoid visiting saunas and bathhouses; do not use warm blankets, tight clothing, wool clothing; do not apply ice compresses or herbal remedies (chamomile, etc.); use mild non-alkaline soaps and shower/bath oils;

— keep nails trimmed short to minimize excoriations;

— to relieve itching, soda solution baths and cooling gels with menthol can be used [2, 326].

For compulsive scratching / scratching addiction, a psychological consultation may help [2]. Chronic pruritus and skin trauma due to scratching can lead to skin infections and secondary skin conditions (such as prurigo) — in these cases, a consultation with a dermatologist is required [327].

The efficacy of UDCA** in relieving pruritus is controversial, but according to a meta-analysis, its combination with bile acid sequestrants (not registered in the Russian Federation) or without them is more effective than placebo [302]. In some patients, pruritus may worsen with the use of OCA, requiring a dose adjustment or complete discontinuation of the drug [288, 328]. Given the frequent self-administration by patients with pruritus, it should be noted that systemic antihistamines do not reduce cholestatic pruritus, but may improve sleep. Their use does not have proven efficacy in the treatment of pruritus in patients with PBC [329, 330].

A step-by-step algorithm is adopted for the treatment of severe pruritus (Appendix B, Figure B4). Second-line methods for therapy-refractory severe pruritus include extracorporeal detoxification methods (EDM) (see section 3.3 "Other treatment: extracorporeal methods"), while LT is indicated for refractory pruritus (see section 3.2.1 "Treatment of portal hypertension").

Comments. According to meta-analysis data, fibrates (7 RCTs, 382 patients with PBC) can significantly alleviate pruritus symptoms in PBC (OR 6.52) [331].

Comments. According to meta-analyses, #rifampicin** effectively relieves cholestasis-induced pruritus [335, 336]. Its efficacy in PBC has been demonstrated in small RCTs [332–334]. It is hypothesized that rifampicin, by interacting with the nuclear pregnane X receptor, induces bile acid hydroxylation [337]. The starting dose of rifampicin is 150 mg twice daily. In patients without an adequate response, the dose may be increased to 600 mg/day [3, 43]. In studies, the duration of rifampicin therapy for PBC ranged from 2 weeks to 24 months [332–334]. Since rifampicin can cause drug-induced liver injury, hemolytic anemia, and renal impairment, and affect vitamin K metabolism, EASL suggests monitoring serum liver function tests at 6 and 12 weeks after initiating therapy or increasing the dose. If adverse effects occur, the drug should be discontinued [2]. The safety of rifampicin in decompensated cirrhosis has not been studied.

Comments. In small RCTs, a short course of #naltrexone** was effective for cholestatic pruritus without a negative impact on the underlying disease course [338, 339]. Adverse effects consistent with opioid withdrawal syndrome, predominantly transient, were observed in a quarter of patients [338].

Comments. In small RCTs, the administration of #sertraline** at a dose of 75–100 mg for 6 weeks to over 6 months reduced pruritus in PBC [340, 341].

Comments. In a small comparative RCT focusing on intrahepatic cholestasis in various liver diseases and including patients with PBC and PBC/AIH, the administration of a #fixed combination of inosine + meglumine + methionine + nicotinamide + succinic acid** (intravenous infusion, 400.0 ml once daily for 11 days) led to a reduction in pruritus in 76% of patients.

3.1.3.2 Treatment of fatigue/asthenia

Fatigue/asthenia is considered one of the most frequent and debilitating symptoms of PBC and does not correlate with disease activity markers [343]. The use of questionnaires can help objectify this symptom (see Appendix G7) [344, 345].

A structured approach to managing hepatogenic fatigue/asthenia involves the TrACE algorithm, named after the acronym: Treat the Treatable (anemia, vitamin D deficiency, pruritus, etc.); Ameliorate the Amelioratable (sleep disorders, depression, etc.); Cope (coping strategies, maintaining social connections, physical exercise, and diet); Empathise (empathy, understanding from those around) [346].

Patients must be counseled and supported in developing coping strategies for this problem. Pacing strategies (maximizing the efficient use of available energy) and time management are applied (since the symptom usually worsens towards the end of the day, major tasks should be shifted to earlier times). Awareness and understanding of this symptom by family members or caregivers must be promoted [15, 343].

Maintaining physical activity is important. In an open-label clinical trial, a 12-week home exercise program (aerobic and resistance) significantly reduced fatigue in PBC [347]. Standardized psychological or behavioral interventions have not yet shown a sustained effect according to clinical trials. Maintaining sleep hygiene and managing comorbid conditions (anemia, hypothyroidism, depression/anxiety, obstructive sleep apnea syndrome) are important [273]. Pruritus therapy and sleep normalization indirectly reduce daytime fatigue and sleepiness, but no direct effect on fatigue/exhaustion has been demonstrated [273].

The options for pharmacotherapy in managing severe fatigue/exhaustion in PBC are limited. First-line drugs UDCA**, OCA do not affect fatigue in PBC [273, 348]. TP reduces the severity of fatigue/exhaustion, but does not completely relieve it [273]. A small clinical trial showed a positive effect of plasma exchange [349] (see section 3.3 "Other treatment: extracorporeal methods").

Comments. Ademetionine** reduces hepatogenic fatigue/exhaustion in various liver diseases [350, 352]. In an open-label clinical trial, administration of ademetionine** 1,200 mg/day in PBC led to a decrease in hepatogenic fatigue/exhaustion and an improvement in quality of life scores after 3 months, which persisted throughout the entire course (6 months) based on standardized questionnaires [351]. Similar data were obtained earlier in domestic studies [353, 573]. In a small retrospective clinical trial with parenteral administration of ademetionine** at a dose of 800 mg/day, 78% of PBC patients noted a subjective decrease in fatigue/exhaustion [573].

3.1.3.3 Therapy for sicca syndrome

Mucosal dryness syndrome (sicca syndrome, sicca syndrome) of varying severity and localization is reported in 28–70% of cases in PBC [354, 355], which is significantly more frequent than in many other liver diseases [356]. In the majority of patients, sicca syndrome is non-specific and does not meet the criteria for primary Sjögren's syndrome [2]. It is important to note that there are no specially designed studies on the treatment of sicca syndrome in PBC; most cited data are extrapolated from clinical trials on models of Sjögren's syndrome and mucosal dryness syndrome. Specific recommendations for the treatment of sicca syndrome can be found in the guidelines for Sjögren's syndrome [357]. Depending on the predominant localization, there are specialized procedures performed by appropriate specialists. Various ophthalmological procedures have been developed for the treatment of dry eye [358].

Non-pharmacological measures, such as the use of air humidifiers and skin care products, are important. Patients with dry mouth syndrome should avoid factors that increase mucosal dryness (dry or conditioned air, prolonged speaking, consumption of dry, acidic and salty foods, alcohol, smoking) [359]. To stimulate salivation, it is important to consume an adequate amount of fluid throughout the day, especially during meals. Dry mouth can be alleviated by 1% malic acid-based sprays, sugar-free chewing gum and lozenges, mouth rinsing after meals, and the use of air humidifiers. Sugary chewing gum and lozenges must not be used due to the high risk of dental caries. Peppermint extract, lemon juice drops, and bitter herbal tinctures (if there are no contraindications to their use) can help stimulate salivation [360, 361]. Antihistamines, which are often unjustifiably used in PBC due to pruritus, can worsen dry mouth [43, 357]. To prevent xerostomia, moisturizing sodium lauryl sulfate-free toothpastes with added xylitol and alginate, as well as artificial oral moisturizers in the form of sprays and mouthwashes, can be used [362, 363]. The toothpaste should be used twice a day after meals for at least 3 min. [364]. Sprays are used throughout the day as needed [365].

Vaginal moisturizers for vaginal dryness can be useful and are not contraindicated from the standpoint of liver pathology, but estrogen creams in PBC can be prescribed by an obstetriciangynaecologist only in agreement with the attending physician [2]. Modulating the vaginal microbiome using topical products with lactobacilli may have an additional positive effect [366].

Dysphagia is a rare manifestation of sicca syndrome. It is hypothesized that esophageal mucosal dryness dysphagia can be alleviated by xerostomia management agents, as well as theoretically by rebamipide and the use of esophagoprotectors containing hyaluronic acid and chondroitin sulfate, although clinical trials in this area have not been conducted.

Comments. In PBC, dry eyes and (or) mouth are most frequently reported [61, 367], sicca syndrome manifests less frequently as vaginal dryness and most rarely as dysphagia [2, 367]. When managing patients with PBC, it is necessary to specifically inquire about dryness symptoms and refer them to experienced multidisciplinary specialists [2], since the frequency of sicca syndrome registration in expert centers is 14 times higher than in clinical practice [368].

Comments. For dry eye syndrome, it is preferable to use over-the-counter eye drops containing polymeric tear substitutes (artificial tears and other indifferent preparations) that coat the cornea and conjunctiva. A review of 43 RCTs (3,497 participants with dry eye syndrome) showed that over-the-counter eye drops are safe and effective [369].

Comments. Among immunosuppressants, the greatest efficacy in xerophthalmia was shown by the regimen of administering 0.05% #cyclosporine 1 drop twice daily for 12 weeks [371]. A number of hepatological associations suggest using parasympathomimetics prior to this as a first-line treatment step in PBC [2, 3, 43]. The efficacy of the latter for dry mouth and eye symptoms has been demonstrated in RCTs, but is associated with frequent side effects [372, 373]. According to domestic guidelines, oral #rebamipide is used for Sjögren's syndrome [357], which according to experimental studies inhibits the progression of Sjögren's disease and increases tear and saliva production [374, 375]. In a placebo-controlled clinical trial, oral administration of rebamipide led to a significant increase in tear and saliva secretion within 8 weeks, but showed no superiority over placebo [376].

Comments. Dryness in the oral cavity contributes to the development of inflammatory periodontal diseases and other oral cavity disorders [359, 377]. In clinical trials, periodontitis in PBC patients was registered in 98% of cases, one-third of which were severe, and was accompanied by an increased number of periodontopathogens. In addition, a high prevalence of dental caries, wedge-shaped defects, and increased tooth wear was found in PBC [359, 360, 377].

In severe xerostomia, strict oral hygiene should be maintained to prevent dental caries and oral candidiasis [2, 357]. Pharmacological stimulation of salivation can be prescribed by a dentist. In refractory cases, parasympathomimetics can be used taking into account the possibility of side effects [380], but they will be effective only if salivary gland parenchyma is at least partially preserved [381].

3.1.3.4 Therapy of complications associated with chronic cholestasis

Comments. Vitamin D deficiency is widespread in patients with PBC [383]. In these cases, the administration of oral cholecalciferol at a loading dose of 400,000 IU is indicated to achieve the target 25(OH)D level [384]. After correcting the deficiency, long-term continuous administration of maintenance prophylactic doses of cholecalciferol (400–2000 IU/day of vitamin D₃) is required to maintain serum 25(OH)D levels [17, 384].

Patients with PBC, jaundice, and established deficiencies of fat-soluble vitamins A, E, and K need to have these deficiencies replenished [17, 383, 386].

Comments. According to RCTs, #alendronic acid**, #ibandronic acid, as well as #etidronate (the latter is not included in the clinical guidelines for osteoporosis) have been shown to be effective in improving BMD in PBC [387, 388]. At the same time, two meta-analyses did not find sufficient evidence that bisphosphonates can prevent osteoporotic fractures in PBC [390, 391]. Bisphosphonates should be used with caution in patients with esophageal varices [3]. The efficacy and safety of #denosumab** therapy in PBC was demonstrated in a pilot 3-year study [389].

There is insufficient evidence that vitamin D and calcium supplements as monotherapy for osteoporosis improve BMD or reduce fracture risk in PBC [390, 392, 393]. No convincing data have been obtained on the efficacy of hormone replacement therapy for improving BMD in PBC [177, 394].

Comments. Patients with PBC and metabolic syndrome have significantly increased risks of cardiovascular events and mortality compared to the general population [122, 395]. No data have been obtained indicating a higher risk of hepatotoxicity from HMG-CoA reductase inhibitors in patients with PBC than in the general population [396, 399]. A meta-analysis showed their protective effect in reducing the risks of hepatic decompensation and mortality in compensated cirrhosis [400]. However, the likelihood of benefit from HMG-CoA reductase inhibitors for primary prevention in patients with a 10-year risk of cardiovascular events of less than 10% and without traditional cardiometabolic risk factors is negligible [401]. Combination therapy with a fibrate and UDCA** was associated with more frequent adverse effects than UDCA** monotherapy, including elevated serum creatinine levels and myalgia [402, 403].

There are no studies regarding the safety and efficacy of dyslipidemia therapy with #ezetimibe and PCSK9 inhibitors in PBC. Insufficient micelle formation observed in PBC suppresses cholesterol absorption, hypothetically diminishing the lipid-lowering effect of #ezetimibe [404].

3.1.4 Conservative therapy in special populations

3.1.4.1 Pregnancy in PBC

Comments. In women with PBC prior to the development of cirrhosis, fertility is usually not impaired, and pregnancy can occur [224, 406]. Pregnancy develops and successfully concludes in 80% of women with PBC, and spontaneous abortions occur in only 5% of pregnant women. In 70% of women with PBC, liver test parameters remained stable or even improved during pregnancy [405–408].

Comments. A population-based study found that cirrhosis, regardless of etiology, is an independent risk factor for adverse perinatal outcomes. An analysis of medical records of 2,022 pregnant women with compensated cirrhosis compared to 110 pregnant women from the general population showed that 2% of pregnant women with cirrhosis had complications associated with impaired liver function, which were more common in those with a history of hepatic decompensation (13%) than with compensated cirrhosis (1.2%) [409]. A retrospective multicenter clinical trial showed that in PBC and PSC, pregnancy is generally well tolerated, but it is important to inform women about the increased risk of preterm birth [410].

Comments. The use of #UDCA** at a dosage of up to 10–15 mg/kg of body weight per day throughout the entire pregnancy period is safe for patients with PBC and the fetus [408, 410–414]. A meta-analysis showed that #UDCA** treatment did not increase the rate of stillbirths [415]. In female patients with PBC who continued taking UDCA** during the 1st trimester, no adverse effects on the fetus were identified [410].

Comments. The use of #obeticholic acid is currently not recommended during pregnancy or lactation in women due to a lack of safety data. In cases of severe cholestasis observed prior to pregnancy, fibrates may be used after the 1st trimester if the benefits of their use outweigh the risks [416].

Comments. Observation of women diagnosed with PBC and PSC with pregnancy at a gestational age of ≥ 20 weeks showed that the rate of preterm birth was 28%, 76% of which were spontaneous. Preterm birth is associated with maternal bile acid levels [410, 417]. An increase in total bile acid levels up to 100 µmol/l is considered a high-risk factor for antenatal fetal death.

Comments. The use of UDCA** during breastfeeding is considered safe for the infant [414, 419]. No traces of UDCA** were detected in breast milk when administered at a dose of 750 mg [418]. A UDCA** dose of up to 1500 mg/day had no effect on bile acid content in breast milk or infant development [414, 420].

Comments. Immediately after delivery, laboratory indicators of liver functional impairment in 60–70% of female patients with PBC may increase, while more than half experience pruritus requiring symptomatic treatment [421], but over the course of several weeks they gradually decrease, returning to baseline levels observed before pregnancy [405, 407, 422, 423].

Comments. The safety of #rifampicin** in the 3rd trimester of pregnancy has been demonstrated in clinical trials in women with intrahepatic cholestasis [424].

Comments. In cases of severe pruritus, plasmapheresis may also be considered, which effectively reduced itching, including in pregnant women, and proved safe for the fetus [425, 426].

3.1.4.2 PBC in men

Although PBC is considered predominantly a female disease, recent studies report a more frequent detection of PBC in men than previously [25, 427]. According to clinical studies, male patients with PBC are older on average, and they less frequently present with pruritus, fatigue, abdominal discomfort, osteopenia, dyslipidemia, and concomitant autoimmune diseases. On the other hand, jaundice, gastrointestinal bleeding, and type 2 diabetes mellitus are detected more frequently. Male PBC is characterized by higher serum levels of ALT, ALP, and bilirubin, and a lower blood platelet count. There are no fundamental differences in immunological parameters, but centromere antibodies are detected less frequently. The histological pattern is characterized by a more frequent detection of severe fibrosis and cirrhosis [427]. The risk of developing HCC is higher in men [428]. There is reason to believe that the more aggressive course of PBC is partly due to a lack of awareness regarding the development of the disease in men, which in turn leads to delayed diagnosis.

Men with PBC respond less favorably to UDCA** therapy compared to women, although these results are not confirmed by all studies [25, 225, 429]. However, there is currently insufficient data to consider male sex as a factor for earlier initiation of 2nd-line therapy. The management of men with PBC should include the need for early HCC screening (see Section 5.2 "Monitoring"). The incidence rate of HCC in men with PBC is 9.82 per 1000 person-years (compared to 3.82 per 1000 person-years in women) [428].

3.1.4.3 Treatment for severe ductopenia

Ductopenia (or vanishing bile duct syndrome) is a pathological condition characterized by the loss of interlobular bile ducts in ≥ 50% of portal tracts, confirmed by a histological report assessing at least 11 portal tracts. PBC is one of the cholestatic diseases that ultimately lead to ductopenia [430].

Severe ductopenia is characteristic of late-stage PBC. However, a prognostically unfavorable form of PBC is distinguished, characterized by early severe cholestasis and extensive loss of bile ducts, but without baseline severe fibrosis or cirrhosis. This phenotype is frequently underestimated [431]. A severe form of ductopenia, characterized by progressive loss or complete disappearance of intrahepatic bile ducts in various diseases, primarily PBC, is also referred to as "vanishing bile duct syndrome" [432].

Early PBC with severe ductopenia is detected in 9–25% of cases in clinical studies [104, 431, 433, 434], but its true prevalence is unknown because liver biopsy is usually performed in AMA-negative patients with atypical manifestations or a poor response to therapy [431]. Early PBC with ductopenia is characterized by higher levels of biochemical markers, is frequently AMA-negative, and may present with jaundice in the early stages [431]. A high baseline total cholesterol level is considered a marker of early-stage ductopenia in PBC [431, 435, 436].

Severe ductopenia is confirmed by pathomorphological examination of liver tissue. Histological evaluation according to the system by Y. Nakanuma et al. (see Appendix A2.2) may be more suitable for patients with PBC in whom bile duct loss is a prominent feature, as it assesses bile duct loss along with fibrosis and necroinflammatory activity. For an objective morphological assessment of the severity of ductopenia, it is advisable to use a pathomorphological examination of a liver biopsy specimen using IHC methods to visualize the preserved bile ducts (see Section 2.5.1 "Morphological Diagnostics"). At the same time, the possibility of reactive biliary proliferation should be taken into account.

This phenotype is prognostically unfavorable. The presence of ductopenia along with portal and periportal fibrosis is among the key features characterizing the progression of PBC, correlating with a poor response to therapy and a negative prognosis for the patient [213, 249, 437]. Data from a clinical study involving 118 patients with PBC demonstrated that the presence of vanishing bile duct syndrome at the time of diagnosis led to liver transplantation or death within the next two years in 23% of cases [430].

Treatment for this variant of PBC has not been established and is carried out according to the standard regimen. Since severe ductopenia is a risk factor for a poor response to UDCA** [431], it is hypothesized that the early addition of 2nd-line drugs may improve prognosis [431].

3.1.4.4 Treatment of PBC at the cirrhosis stage

Management approaches for a patient with PBC upon the detection of cirrhosis and its complications are based on the relevant clinical guidelines for "Liver Fibrosis and Cirrhosis" [107]. At the same time, there are specific features and limitations in managing PBC at the stage of decompensated cirrhosis due to the development of severe ductopenia and the risks of adverse outcomes.

Comments. In a clinical study involving 501 patients with PBC and compensated cirrhosis, #UDCA** therapy was associated with a reduction in the rate of decompensation, overall mortality, liver-related mortality, or the need for liver transplantation in treatment responders [429]. According to the prescribing information for #UDCA**, its administration at the stage of decompensated cirrhosis, as well as in severe hepatic impairment, is contraindicated. In patients with late-stage PBC treated with #UDCA**, cases of cirrhosis decompensation with partial reversal after drug discontinuation have been extremely rare [439]. It is hypothesized that in these cases, severe ductopenia causes exacerbated jaundice during #UDCA** therapy [277, 439, 573]. At the same time, clinical studies have demonstrated the possibility of cirrhosis recompensation in PBC during #UDCA** treatment (1 year) in 41.7% and 9.5% of patients with and without a response to #UDCA**, respectively [438]. Presumably, decompensated cirrhosis with severe ductopenia may in individual cases require discontinuation or dose reduction of #UDCA** if jaundice worsens, but clear criteria for this have not been established.

Comments. Currently, fibrates and OCA are contraindicated in decompensated cirrhosis [17, 431, 440]. For instance, there are case series showing an increased risk of cirrhosis decompensation and mortality associated with OCA use [441]. OCA is contraindicated in patients with Child-Pugh class B or C cirrhosis, as well as in patients with class A cirrhosis who have any signs of portal hypertension [3, 17, 294, 440, 442, 443].

Comments. Regular #albumin** infusions improve survival in patients with decompensated cirrhosis [445], including those with PBC [444]. The administration of high-dose human #albumin** solution is regulated by the clinical guidelines for "Liver Fibrosis and Cirrhosis" (40 g twice a week for the first 2 weeks, followed by 40 g once a week in an outpatient setting for patients with decompensated cirrhosis for at least 3 months).

Upon detecting signs of cirrhosis decompensation with a bilirubin level > 100 µmol/L, patients should be evaluated as candidates for liver transplantation (see Section 3.2.2 "Liver Transplantation").

3.1.4.5 Treatment of PBC/AIH

The low prevalence of PBC variant syndromes complicates conducting large randomized controlled trials. The feasibility and criteria for initiating immunosuppressive therapy (IST), as well as its impact on the prognosis of patients with PBC/AIH, remain a subject of debate. In clinical practice, PBC/AIH is viewed as a combination of two diseases (PBC and AIH), with the corresponding prescription of therapy for each condition.

Treatment regimens typically include corticosteroids, azathioprine**, UDCA**, and combinations thereof [27]. For PBC/AIH, prednisolone**, #methylprednisolone**, budesonide**, azathioprine**, #mycophenolate mofetil**, #tacrolimus**, and #cyclosporine** have been used as components of IST [209]. The IST component in PBC/AIH is selected according to the treatment principles specified in the AIH agreement [186].

The combination of GCs (prednisone** or prednisolone** 30 mg/day with a gradual taper over 4 weeks to 10 mg/day) and UDCA + azathioprine** 50–150 mg/day) compared to UDCA monotherapy** [207]. Patients with PBC/AIH receiving combination therapy showed an improvement in laboratory markers, liver fibrosis scores, and 10-year transplant-free survival prognosis [188]. In a large multicenter CT in PBC/AIH patients with moderate borderline hepatitis, the efficacy of both regimens (UDCA monotherapy vs. UDCA + GC ± azathioprine**) regarding biochemical response was comparable (80%), whereas in severe hepatitis, the efficacy of UDCA monotherapy** was significantly lower [446]. The necessity of additionally prescribing UDCA** to IST in patients with a predominant morphological pattern of AIH without laboratory signs of cholestasis, but with serological and histological signs of PBC, remains controversial. Given the rarity of adverse events and potential beneficial effects, the administration of UDCA** is likely indicated for all patients who meet the Paris criteria for PBC [2].

To date, there is insufficient evidence of the efficacy of #OBCA and fibrates in PBC/AIH, but they are used by analogy with the classic form of PBC as 2nd-line therapy in the absence of a response to UDCA therapy** [209, 447].

Comments. Therapeutic tactics should be chosen based on the predominant morphological pattern [27]. This concept is based on the hypothesis of separate diseases with mixed atypical clinical features within variant syndromes, rather than comorbid conditions [449].

Comments. UDCA therapy** in standard doses for PBC is indicated for patients with predominant morphological features of PBC [2]. In a study of this patient group, a biochemical response to UDCA therapy was observed** [450].

In a CT involving 83 patients with PBC/AIH, the absence of IST in patients with severe periportal hepatitis was associated with a poorer transplant-free survival prognosis compared to patients receiving IST [209]. Patients with severe periportal hepatitis are indicated for IST [55, 209, 451, 452].

In moderately severe borderline hepatitis, IST may be prescribed immediately after diagnosis [55, 451, 452]. Also, in moderate activity of periportal hepatitis, UDCA monotherapy** is permissible, with the issue of prescribing IST addressed after 3 months in case of an inadequate response [2, 453].

3.1.4.6 Treatment of immune-mediated diseases associated with PBC

Concomitant extrahepatic autoimmune diseases are common in patients with PBC, but do not affect the long-term outcomes of PBC treatment [454].

Comments. The efficacy of standard disease-modifying antirheumatic drugs, targeted synthetic agents, GCs, and biologic agents regarding the course and outcomes of PBC has not been sufficiently studied. Therefore, the treatment of comorbid immune-mediated diseases in patients with PBC should be carried out by a specialist in the relevant field (rheumatologist, gastroenterologist, dermatologist, etc.) within a multidisciplinary approach in accordance with established therapeutic principles and current clinical guidelines for these nosologies. The use of potentially hepatotoxic drugs (#methotrexate**, #leflunomide**, #azathioprine**, tumor necrosis factor-α inhibitors) in patients with PBC and comorbid rheumatic diseases is not absolutely contraindicated, but requires careful risk-benefit assessment and strict monitoring of liver function [71]. The decision to prescribe these drugs should be made jointly by a rheumatologist and a gastroenterologist, taking into account PBC activity, the presence and severity of liver failure, the activity of the rheumatic disease and the spectrum of its systemic manifestations, as well as the availability of alternative therapies.

3.2 Surgical Treatment

3.2.1 Treatment of portal hypertension

Portal hypertension is a consequence of increased pressure in the portal vein due to various causes and is associated with clinical manifestations such as splenomegaly, hypersplenism, esophageal varices, and ascites, as well as the development of hepatic encephalopathy. Portal hypertension is the main cause of cirrhosis decompensation [455–457].

As noted above, patients with PBC are characterized by the development and progression of portal hypertension (including the development of esophageal varices) prior to the formation of cirrhotic transformation of the liver. When comparing hepatic venous pressure gradient measurement data with histological conclusions and clinical-laboratory parameters, it was demonstrated that portal hypertension occurs in the early stages of PBC long before an increase in serum bilirubin levels [458]. At the same time, determining the hepatic venous pressure gradient may underestimate the prevalence and severity of portal hypertension in patients with PBC [459]. According to some data, 82% of pre-cirrhotic patients with PBC have portal hypertension, and 34% have high-risk portal hypertension (hepatic venous pressure gradient > 12 mmHg) [458]. In another retrospective clinical trial, 24.2% were found to have portal hypertension at the pre-cirrhotic stage [172]. Transplant-free survival in early-stage PBC patients with clinically significant portal hypertension is significantly lower than in those without it. The most significant adverse prognostic factor is splenomegaly in the early stages of PBC [460]. The development of recurrent esophageal variceal bleeding in a patient with PBC in the absence of cirrhosis has been described [461]. There is evidence that early initiation of UDCA** therapy can delay the development of esophageal varices in patients with PBC [172, 462, 463].

Comments. Surgical aspects of treating complications of portal hypertension, such as refractory ascites and recurrent esophageal variceal bleeding, are discussed in detail in the current clinical guidelines "Liver cirrhosis and fibrosis" [107]. There are no specific features in the treatment of portal hypertension in patients with PBC compared to other types of cirrhosis [459]. Endoscopic treatment of varices in patients with PBC and complications of portal hypertension in the absence of cirrhosis increases transplant-free survival [14]. In patients with Child-Pugh class B and C cirrhosis with high-risk varices, the combination of oral #carvedilol** and endoscopic variceal ligation for the primary prevention of variceal bleeding is more effective than either therapy alone [3, 471].

TIPS (transjugular intrahepatic portosystemic shunt) is a procedure that improves the quality of life in patients with cirrhosis and refractory ascites, recurrent esophageal and gastric variceal bleeding, reduces the risk of rebleeding, and increases survival [15, 459, 464–468]. A retrospective clinical trial showed that it is as effective in treating portal hypertension in PBC as it is in cirrhosis of viral etiology [470].

3.2.2 Liver transplantation

Liver transplantation in PBC is performed to treat decompensated cirrhosis, hepatocellular carcinoma, and when certain symptoms and complications of the disease itself do not respond to drug therapy [472]. In PBC, one- and five-year patient survival rates after liver transplantation are 93–94% and 82–90%, respectively, and graft survival rates are 85–86% at 1 year and 81–82% at 5 years, representing some of the highest compared to other indications for liver transplantation [473].

Recurrence of PBC is possible after liver transplantation. It is defined as the reappearance of the disease in the liver graft [474–476]. The term "recurrence" is used because the concepts of "remission" and "relapse" do not exist for PBC [476].

According to international sources, the incidence of PBC recurrence ranges from 21 to 37% at 10 years and approximately 40% at 15 years after liver transplantation [477]. In a Russian clinical trial involving 50 liver transplant recipients, the detection rate of PBC within 5 years of follow-up was 10% [476].

The average time from liver transplantation (LT) to the detection of recurrent PBC is 3–5.5 years [478]. Recurrent PBC can lead to decreased graft and recipient survival, but the rate of graft loss due to recurrent PBC is low (1–5.4%) [479, 480]. The average time from recurrent PBC to decompensation or graft loss is 6–8 years [481, 482]. Risk factors for PBC recurrence after LT include: young recipient age — < 50 years at PBC diagnosis or < 60 years at LT [479]; donor-recipient sex mismatch, as well as short operative time; presence of HLA-B60 and HLA-DR8 in the recipient [483]. Clinical manifestations of recurrent PBC are less specific than those of native liver PBC. Fatigue/asthenia and pruritus are observed in approximately 10% of patients with recurrent PBC [484].

Comments. In the 1980s, PBC was one of the main indications for LT. The advent of UDCA** therapy improved the disease course and survival, and the number of PBC patients with decompensated LC requiring LT has decreased sharply over recent decades [487 – 490]. LC decompensation and the need for LT mainly occur in patients who do not respond to baseline therapy and (or) with late disease detection [224, 473, 477, 491].

Comments. The Child-Pugh prognostic class of LC and the MELD score (and its modifications) are used universally for prioritizing patients on the waiting list [494]. MELD allows predicting 3-month mortality in patients with end-stage liver disease [495]. Currently, priority is given to the MELD-Na score [496].

The MELD-Na score is based on determining the logarithmic relationship of serum creatinine, bilirubin, INR, and sodium levels (see Appendix G3). It allows refining the short-term mortality prognosis and assessing the need for referral to a transplant center. Online calculators are available for quick calculation: http://transpl.moscow/calc/meld, https://medicalc.pro/meld and others.

Experience has been accumulated with the use of the MELD 3.0 score, which incorporates albumin levels, sex, and candidate age. Its use slightly increases the priority of women on the waiting list (which is important in PBC given its sex-related features) and allows for a more accurate prognosis [497].

At the same time, a large clinical trial showed that the MELD-Na score underestimates the waiting list death risk for PBC patients compared to other diseases [492]. It does not account for the impact on life expectancy of complications such as refractory ascites, recurrent gastrointestinal bleeding, hepatic encephalopathy, or the presence of a malignant liver tumor. The mortality of PBC patients on the waiting list is higher compared to other liver diseases [498]. Therefore, various additional MELD score correction systems determined by local transplant center guidelines may be used [490, 499]. For instance, the Mayo risk score includes age, bilirubin, albumin, prothrombin time, presence of edema, and diuretic use (see Appendix G6), online calculator: www.mayoclinic.org/medical-professionals/transplant-medicine/calculators/the-updated-natural-history-model-for-primary-biliary-cholangitis/itt-20434724. It can be used as an additional tool [490, 500, 501].

Current criteria for placing PBC patients on the LT waiting list are based on a MELD-Na score ≥ 15, serum bilirubin level ≥ 6 mg/dL (≥ 102.6 µmol/L), or a Mayo score ≥ 7.8 [2, 29, 43, 488].

Comments. An additional, albeit rare, indication for LT is refractory pruritus unresponsive to medical treatment [485]. There are no standardized rules for prioritizing LT in patients with cholestatic pruritus. Transplant centers may evaluate each case individually.

Another indication for LT is the development of HCC in the setting of PBC [502].

Comments. PBC-associated conditions and specific complications can impact LT outcomes; therefore, their identification and treatment are required while the patient is on the waiting list [490]. For instance, osteoporosis is a common complication of PBC. At the same time, post-LT patients are prone to osteopenia and osteoporosis, with an expected bone loss of 8 to 18% in the first 3–6 months and the development of fractures in 20 to 40% of cases in the first year after LT. Therefore, prevention, timely detection, and treatment of osteoporosis before and after LT are mandatory in the overall management of PBC [177, 490, 503, 504]. Lipid-lowering therapy should be individualized based on cardiovascular risk assessment and comorbidities [396, 399, 505]. Diagnosis and treatment of PBC complications and associated diseases are described in detail in sections 2–4 of these clinical guidelines.

Comments. Diagnosis of recurrent PBC should be based on clinical, serological, and histological features. Clinical features include a cholestatic pattern of graft dysfunction, provided that LT was performed for PBC and other causes of graft dysfunction have been excluded. Determination of AMA is of little significance since their levels remain elevated post-LT in the majority of patients and do not correlate with PBC activity [481]. Conversely, serum IgM levels increase during PBC recurrence [507]. Ductopenia, which is characteristic of PBC, is not pathognomonic after LT as it can occur in other graft conditions [508]. Histological features of recurrent PBC are: 1) lymphoplasmacytic infiltrate in portal tracts; 2) lymphoid aggregates; 3) epithelioid granulomas; 4) bile duct damage [506, 509]. J. Neuberger et al. proposed that in seropositive patients who underwent LT for PBC, recurrence should be considered probable if two histological features are present, and definite if three are present [507]. Russian authors suggest diagnosing recurrent PBC based on serological (AMA-M2 + elevated IgM) and histological features and the exclusion of other causes of graft dysfunction, considering recurrence probable if all serological and two histological features are present, and definite if all four histological features are present [476].

When recurrent PBC is suspected after LT, differential diagnosis must be performed with acute cellular rejection, chronic rejection, drug-induced liver injury, graft steatosis, ischemic cholangiopathy, and biliary strictures [506].

Comments. Meta-analyses have demonstrated that prophylactic use of #UDCA** reduced the recurrence rate of PBC [510, 511]. Currently, there is insufficient robust evidence regarding the impact of any specific maintenance immunosuppressive regimen (calcineurin inhibitors, mycophenolic acid derivatives, #azathioprine**, and GCs) on the risk of PBC recurrence in the graft [479, 481, 512 – 514]. According to a meta-analysis, the use of tacrolimus** increased the risk of PBC recurrence [510]. At the same time, more recent large-scale studies do not confirm the impact of any calcineurin inhibitor on PBC recurrence [515, 516]. It has been shown that the use of mycophenolate mofetil** in patients with PBC following LT was associated with a reduced risk of graft loss and death, but did not affect disease recurrence [515].

Comments. The treatment for recurrent PBC has not been established. There are small-scale studies on treatment with #UDCA**. For instance, a study including 52 patients with recurrent PBC, of whom 38 received #UDCA** (including low doses), demonstrated biochemical but not histological improvement [519]. Another clinical trial involving 16 patients with recurrent PBC treated with #UDCA** also noted a positive effect on ALP activity [517]. Conducting clinical trials is complicated by the fact that many patients receive prophylactic #UDCA** after LT. Data have emerged on the use of 2nd-line drugs (#OCA, fibrates) for the treatment of recurrent PBC: they appear to be safe post-LT and lead to a decrease in laboratory parameters [521]. There are no recommendations for adjusting immunosuppressive regimens upon PBC recurrence [476, 521].

3.3 Other treatments: extracorporeal methods

Recommendations from several professional associations include EAD in the stepwise approach to the management of refractory cholestatic pruritus [2, 43, 522 – 524]. The efficacy of EAD in pruritus is presumably associated with the elimination of bile acids and autotaxin (lysophospholipase D) from the systemic circulation, suppressing the process that triggers itching [524]. Plasmapheresis and albumin dialysis are the most studied modalities in cholestasis. Guidelines from international associations indicate the potential efficacy of albumin dialysis methods in PBC, such as the Molecular Adsorbent Recirculating System (MARS) or fractionated plasma separation and adsorption system (FPSA or Prometheus) [2, 15, 43]. Albumin dialysis significantly reduced pruritus in 75% of patients with cholestatic diseases, including PBC and refractoriness to conservative therapy, when two consecutive procedures were performed with a mean total duration of 15 hours, alongside a significant reduction of more than 50% in bile acid levels [523, 524]. Several studies investigating small groups on the effect of hemoperfusion and plasmaperfusion through sorption columns on pruritus and fatigue showed their reduction according to rating scales along with decreased bile acid levels [525]. According to two large meta-analyses, a statistically significant reduction in the severity of HE (OR 0.67–0.71) was revealed when using various liver support systems, including plasmapheresis, hemoperfusion, and albumin dialysis [526, 527]. The use of selective plasma filtration and plasma diafiltration techniques is promising for the treatment of pruritus, asthenia/fatigue, and HE in PBC [527].

Importantly, plasmapheresis was safe and effectively reduced pruritus, including in pregnant women [24, 425] (see Section 3.1.4.1 "Pregnancy in PBC").

Comments. In a prospective cohort clinical trial, plasmapheresis demonstrated efficacy in reducing pruritus, bilirubin levels, and transaminase activity, as well as improving quality of life in 17 patients with chronic cholestasis refractory to therapy, including cirrhosis. The effect persisted for 90 days following plasmapheresis [523]. A single-center cohort clinical trial confirmed the efficacy of plasmapheresis in reducing pruritus and asthenia/fatigue [349]. For the treatment of cholestatic pruritus, the American Society for Apheresis recommends the following plasmapheresis regimen: a volume of 1–1.5 circulating plasma volumes with a procedure frequency of initially 3 procedures (weekly or biweekly), followed by 2–4 times per month to maintain the clinical effect [528].

The decision to perform EAD is made on an individual basis, and the choice of method depends on the patient's condition parameters and availability at the medical facility.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1 Rehabilitation

It is assumed that most patients with chronic liver diseases tolerate moderate physical activity well [560, 561], and exercise helps reduce hepatogenic asthenia/fatigue (see Section 3.1.1 "Non-pharmacological treatment"). It has been shown that even in end-stage PBC during the LT waiting period, individually tailored therapeutic exercise improves cardiorespiratory endurance [562]. Psychological rehabilitation can be of significant importance.

Comments. The quality of life of patients with PBC is impaired primarily due to symptoms such as pruritus and fatigue. Psychological rehabilitation aims at the social and psychological adaptation of patients to the disease, treatment, and lifestyle changes resulting therefrom. Clinical and psychological support can favorably affect patient adherence to treatment. A randomized controlled trial showed that psychological programs in PBC positively affect mental health, quality of life, and symptom severity [563].

5. Prevention and Dispensary Observation

5.1 Stratification of risks of progression and development of complications

Modern risk stratification assessment aimed at identifying patients with PBC at an increased risk of disease progression includes an in-depth analysis of demographic, clinical, and laboratory data, antibody profiles, and the assessment of liver fibrosis using both invasive and non-invasive methods, as well as treatment response [222].

Risk assessment begins at the time of PBC diagnosis verification. It includes demographic factors (age and health status), laboratory data (including liver function tests), clinical and serological parameters (such as antibody profile), and non-invasive fibrosis diagnostics [43].

1. Demographic data

1.1. Sex. PBC predominantly affects women, whereas in men the diagnosis is often established with a delay, leading to detection at a more advanced disease stage (cirrhosis). Male patients with PBC have an increased risk of developing jaundice, acute liver failure, spontaneous bacterial peritonitis, LT, and liver-related mortality. In women, the risk of HCC increases proportionally to the histological stage, whereas in men, HCC can occur at any stage [2, 43, 222].

1.2. Age. In the older patient group (age at diagnosis > 55 years), the mortality rate corresponds to that of the general population, whereas in young patients with PBC, liver-related mortality is seven times higher than expected. Age at diagnosis is associated with the response to UDCA** therapy (> 90% among patients older than 70 years and < 50% for patients younger than 30 years) and transplant-free survival. Young age is associated with an increased risk of treatment failure, LT, and death; the highest chances of response to UDCA** therapy are observed in patients older than 65 years [223 – 225].

2. Clinical factors

2.1. Symptomatic PBC. The presence of PBC symptoms is generally considered to indicate a worse prognosis, but data are contradictory. Likely, the presence of symptoms is an indicator of disease stage rather than an independent prognostic factor [226, 227].

2.2. PBC-associated diseases.

2.2.1. PBC/AIH has a worse long-term prognosis compared to isolated PBC or AIH: accelerated progression of liver fibrosis (69.6% vs. 46.2%), increased risk of liver-related death, and need for LT [228, 229].

2.2.2. Extrahepatic autoimmune diseases (AIIDs). Data on their impact on prognosis are contradictory. A large retrospective clinical trial demonstrated a negative impact on survival of the combination of PBC with systemic sclerosis [93]. Another large clinical trial showed no effect of AIIDs on PBC prognosis [73].

3. Laboratory data

3.1. Biochemical parameters. The relationship between serum ALP activity, the risk of LT, and mortality in patients with PBC is log-linear: higher ALP levels indicate a decrease in transplant-free survival (TFS) chances. Baseline ALP activity > 2 ULN (OR 2.13) and after 1 year of follow-up (OR 2.49) demonstrate the highest prognostic capacity, while lower levels indicate a better prognosis, reduced mortality, and longer TFS. The prognostic potential of ALP is enhanced when combined with bilirubin levels or GGT activity [103, 230].

The serum total bilirubin level plays a crucial role in predicting patient survival. However, its effectiveness in risk stratification at disease onset is limited, as elevated levels are typically observed at late stages. Total bilirubin has the ability to predict prognosis even if its levels are within reference ranges: values > 0.6 ULN are associated with worse outcomes [231–233].

3.2. Autoantibody profile. Neither the presence of AMA nor their titer is considered to have prognostic significance. A limited number of studies with small sample sizes have shown that AMA-negative patients have significantly lower survival and a lower risk of liver-related complications, including LT and death, compared to AMA-positive patients [83, 86, 136, 234–236]. The presence of anti-gp210 at diagnosis is associated with a higher incidence of liver failure (relative risk [RR] 5.77) and mortality (RR 2.38) [157]. Such patients responded less well to UDCA** treatment (16.7% vs. 39.3%), and their 5-year TFS was lower [149]. It has been discussed that the inclusion of anti-gp210 antibodies in scoring systems such as UK-PBC and GLOBE may potentially improve their risk stratification capabilities [237, 238]. The prognostic significance of anti-sp100 in PBC remains a subject of debate [239–241]. Clinical studies in Asian populations have shown a correlation between the presence of anticentromere antibodies and the development of portal hypertension, even in the absence of liver failure [242, 243].

Novel autoantibodies in PBC diagnosis, according to preliminary data, have prognostic significance. Anti-KLHL12 are associated with increased liver fibrosis and elevated bilirubin levels [244]. Anti-HK1 are associated with a higher probability of liver disease decompensation and lower TFS [240, 245–247].

4. Histological findings.

4.1. Fibrosis and inflammation. Liver biopsy in PBC is performed only in atypical manifestations of the disease, but its findings determine the disease stage and prognosis [2]. Fibrosis and inflammation in PBC can occur at different time intervals, demonstrate different therapeutic responses, and have different prognostic significance; their separate evaluation is important [248]. The system proposed by Y. Nakanuma et al. demonstrated superior prognostic value compared to classical histological scoring systems for PBC [184, 185].

4.2. Early ductopenic variant. The detection of significant ductopenia on liver biopsy during initial evaluation can serve as an important predictor of poor response to standard UDCA** therapy and disease progression [249, 250].

5. Non-invasive markers of fibrosis.

5.1. Biomarkers. The APRI score at diagnosis is associated with outcomes—LT/death (OR 1.95). An APRI > 0.4 at baseline is a predictor of LT/death and retains statistical significance at one year independently and additively with respect to the response to UDCA** [251]. An ELF ≥ 10.0 predicts a higher incidence of clinical complications and worse survival [252].

5.2. Liver stiffness. Elevated liver stiffness assessed by transient elastography (TE) is independently associated with adverse clinical outcomes (OR per each added kPa = 1.065), enhances the prognostic value of biochemical response criteria and fibrosis scores, and allows patients to be stratified into low-, intermediate-, and high-risk groups [33]. Liver stiffness assessed by TE, or its increase > 2.1 kPa/year, is used to predict the risk of hepatic decompensation or LT [32].

Response to therapy is the primary factor influencing prognosis [222]. The timing and criteria of response are detailed in section 3.1.2.2 "Assessment of response to therapy". At the diagnosis stage, the UDCA Response Score (URS) (Appendix G4.1) [253, 254] can be applied; online calculator: https://www.mat.uniroma2.it/~alenardi/URS.html.

Comments. The main parameters for risk stratification at the time of diagnosis are presented in Table 3. Stratified risk management is discussed in Section 3 "Treatment".

Table 3. Baseline risk stratification in PBC

Comments. Large clinical trials have demonstrated the role of liver stiffness assessment, including dynamics, in evaluating the prognosis of PBC. A large international multicenter retrospective study involving 3,985 patients with PBC followed in 23 centers across 12 countries evaluated the relationship between adverse outcomes in PBC (liver-related complications, LT, or death) and TE results. Liver stiffness was independently associated with adverse clinical outcomes: adjusted HRs per additional kPa were 1.040 and 1.042, respectively. Cutoff values of 8 and 15 kPa optimally separated low-, intermediate-, and high-risk groups [33].

• In all patients with PBC and dyslipidemia, it is recommended to assess the risks of atherosclerotic cardiovascular diseases and their complications in accordance with the clinical guidelines on "Lipid metabolism disorders" for the timely prescription of treatment [256, 257].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments. Hyperlipidemia, including hypercholesterolemia caused by cholestasis, does not independently increase the risk of cardiovascular events in patients with PBC [122, 123]. Accordingly, special attention should be paid to identifying patients with PBC and atherogenic dyslipidemias (characterized by high cholesterol, low HDL, and high LDL levels) [15].

• In all patients with PBC aged 40 years and older at the time of diagnosis, it is recommended to individually calculate the 10-year risk of major osteoporotic fractures using the FRAX (Fracture Risk Assessment Tool) method when X-ray absorptiometry is unavailable, for the timely identification of individuals requiring anti-osteoporotic therapy [176].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

Comments: osteopenia and osteoporosis are common complications of PBC and lead to the risk of low-energy fractures [73, 175, 258]. Risk factors for bone disease in PBC include female gender, menopausal status, low BMI (due to impaired bile acid homeostasis and pancreatic insufficiency observed in some PBC patients), older age, disease progression, and chronic cholestasis with subsequent vitamin D deficiency. Patients with PBC exhibit higher bone resorption markers (urinary hydroxyproline) and lower bone formation markers (osteocalcin) [181].

To assess the 10-year predicted absolute risk of fractures, the WHO-recommended FRAX tool should be used (https://frax.shef.ac.uk/FRAX/tool.aspx?lang=en). If available, BMD measurement should be performed using X-ray absorptiometry (dual-energy X-ray absorptiometry of the lumbar spine, dual-energy X-ray absorptiometry of the proximal femur) (see section 2.4 "Instrumental Diagnostic Examinations"), and the absolute risk should then be recalculated using FRAX adjusted for the BMD value.

5.2 Follow-up

Comments. The optimal intervals for physician examinations and monitoring of laboratory and instrumental markers of disease activity have not been studied in clinical trials, but it is generally recommended to perform them every 3–6 months depending on the patient's baseline condition, symptoms, disease stage, and ongoing therapy [43]. For patients in early stages without pronounced symptoms who respond to therapy, an evaluation every 6 months is sufficient; in late stages, evaluation every 3 months is required. In the case of severe symptoms, new complaints, or the need to adjust therapy, the intervals may be shortened.

Laboratory monitoring is required [2]. The aforementioned parameters may be supplemented with other tests (unconjugated and conjugated bilirubin, serum creatinine, blood glucose, international normalized ratio (INR), creatine kinase activity, total cholesterol, low-density lipoprotein cholesterol, and triglycerides) depending on the stage, clinical features, and prescribed therapy (see sections 2.3 "Laboratory Diagnostic Tests", 3 "Treatment"). Issues regarding the monitoring of laboratory parameters used to assess treatment response and safety profiles for specific medications are discussed in Section 3 "Treatment".

Comments. It has been demonstrated that UDCA** intake at a dose of < 13 mg/kg of body weight per day is associated with a higher frequency of non-response to treatment, need for liver transplantation, and mortality [270, 306]. In real-world clinical practice, every 4th patient with PBC is prescribed inadequate doses of UDCA** [311]. In some cases, insufficient dosing may be associated with changes in the patient's body weight [530]. In a clinical trial involving 823 PBC patients, a loss of initial treatment response was observed in 13.2% of cases, and recurrent loss and recovery of response occurred in 0.7% over five years of follow-up [531]. Overall, patients with PBC demonstrate good treatment adherence [532]. In a prospective open-label clinical trial investigating UDCA** adherence in autoimmune liver diseases (32% with PBC), only 11% of patients showed low treatment adherence [529].

Comments. Serum autoantibody levels in PBC do not correlate with disease activity, and therefore there is no need to measure them dynamically [533]. Exceptions include situations with significant changes in clinical manifestations, as well as cases of initially seronegative PBC, since autoantibodies may appear later and definitively confirm the diagnosis [246]. However, in such cases, repeat testing of autoantibodies aims to clarify the diagnosis rather than monitor disease activity.

Comments. PBC is a risk factor for the development of autoimmune thyroiditis and hypothyroidism [534, 535], which necessitates regular monitoring of thyroid function [43].

Comments. HCC in PBC typically develops against the background of cirrhosis: the incidence is 13 cases per 1000 person-years, compared to only 2.7 cases per 1,000 person-years among PBC patients without cirrhosis [160]. Risk factors for HCC development in PBC also include advanced fibrosis and male sex [160, 428] (see Section 3.1.4.2 "PBC in Men"). A multicenter study involving 4565 patients from the Global PBC Study Group database showed that an inadequate response to UDCA** is the most significant predictor of HCC development (OR 3.44) [537]. According to meta-analyses, cirrhosis and male sex are the main risk factors for HCC in PBC [428]. For the timely detection of HCC, according to domestic experts, a comprehensive abdominal ultrasound combined with alpha-fetoprotein testing should be performed in all patients at risk for HCC, including individuals with cirrhosis or advanced fibrosis of any etiology. If alpha-fetoprotein levels are ≥ 20 ng/ml or focal liver lesions measuring 1–2 cm are detected on ultrasound, it is advisable to perform MRI with a hepatospecific contrast agent (gadoxetic acid) to detect early-stage HCC [536].

Comments. Liver stiffness measurement using transient elastography is informative for assessing treatment response during patient follow-up [2]. Increasing liver stiffness in PBC is a predictor of adverse outcomes, whereas successful drug therapy is associated with improvements in liver stiffness [285, 538]. Liver stiffness correlates with the grade of histological fibrosis [2, 539–541]. A large retrospective clinical trial showed that changes in liver stiffness assessed by transient elastography are associated with the risk of severe liver-related events (death, liver transplantation, cirrhosis decompensation) regardless of treatment response or its duration [255]. Achieving a liver stiffness threshold of > 15 kPa identifies patients at high risk of adverse clinical events within 10 years. In patients with liver stiffness < 8 kPa, the risk of such events remains low (< 20%) [33].

Comments. The diagnostic performance of point and two-dimensional shear wave elastography for liver stiffness assessment has been sparsely studied in PBC. In a small study involving PBC patients, its diagnostic performance was comparable to transient elastography in staging and monitoring liver fibrosis [542].

Comments. UDCA**-induced changes in the GLOBE score are associated with transplant-free survival [544]. According to an international multicenter meta-analysis, transplant-free survival can be accurately calculated using the GLOBE score based on laboratory data obtained 2–5 years post-treatment [324].

Comments. Vitamin D deficiency is common in PBC, especially in patients with advanced disease and an inadequate response to UDCA therapy** [385, 544, 546]. Evidence suggests that baseline low serum 25-OH vitamin D levels are associated with a poor response to UDCA** [385, 544]. Deficiencies of other fat-soluble vitamins occur predominantly in patients with cirrhosis and jaundice [547]. In clinical trials, deficiencies of vitamins A, E, or K in PBC were observed in 33.5, 1.9, and 7.8% of patients, respectively [386]. Prothrombin time/INR measurement can serve as a surrogate marker for vitamin K status [43].

Comments. The Baveno VII consensus recommends performing EGD for the timely detection of clinically significant portal hypertension manifestations in patients with cirrhosis and liver stiffness > 20 kPa (by TE) or a peripheral blood platelet count ≤ 150 ⁹/L [459]. This recommendation applies to cirrhosis of any etiology. However, it has been shown that in PBC, the optimal threshold for predicting esophageal varices using TE is 12.1 kPa (area under the ROC curve 0.806) [548]. Other useful non-invasive markers suggesting esophageal varices in PBC include a splenic area > 56.8 ², the presence of a periportal hypoechoic band on liver ultrasound [548], and splenic stiffness by elastography > 40 kPa [549]. For previously detected esophageal varices, the optimal timing for the next EGD is determined by the observed changes [43]. In accordance with the clinical guidelines "Liver Cirrhosis and Fibrosis", EGD is performed annually in patients with compensated cirrhosis and esophageal/gastric varices, and in those with decompensated cirrhosis regardless of the presence of varices. In patients with PBC at the stage of decompensated cirrhosis, follow-up and preventive measures are carried out as for cirrhosis (according to the current clinical guidelines "Liver Cirrhosis and Fibrosis") [107].

5.3 Prevention

5.3.1 Prevention of PBC

Preventive measures for PBC have not been established. Evidence indicates that an elevated BMI contributes to the development of PBC, whereas adequate blood levels of vitamin D protect against its development [550]. Alcohol consumption appears to have no effect on the development of PBC [550]. Data on the impact of cigarette smoking on the development of PBC are contradictory [107, 550].

5.3.2 Prevention of complications

Comments. The relationship between PBC and osteoporosis is described above. Additionally, patients with PBC have a higher risk of falls and bone fractures, partly due to reduced muscle mass and stability [551].

General measures to prevent bone mass loss in PBC are based on well-known risk factors for osteoporosis. A sedentary lifestyle, alcohol consumption, and smoking are associated with osteoporosis in adults [552]. A clinical trial involving over 4 million individuals demonstrated a reduced risk of osteoporotic fractures following smoking cessation [553]. The adverse effect of regular consumption of even small amounts of alcohol on BMD was demonstrated in a meta-analysis [554]. Evidence for the efficacy of regular resistance exercise in reducing BMD loss in postmenopausal women was obtained in a 16-year prospective clinical trial [555] and confirmed in a Cochrane review [556].

Comments. Inadequate dietary calcium intake is associated with lower BMD values in women with PBC [557]. As noted above, vitamin D deficiency is prevalent among patients with PBC, particularly those with progressive disease, and may be associated with an inadequate response to therapy [385, 544, 546]. In patients who have developed vitamin D deficiency, the #cholecalciferol dosing regimen is discussed above (see Section 3.1.3.4, "Management of Complications Associated with Chronic Cholestasis").

Comments. Risk factors for HCC in PBC include advanced age, any signs of portal hypertension, thrombocytopenia, hepatitis B virus infection, diabetes, obesity, and alcohol consumption [558, 559]. Among these, obesity and alcohol consumption are modifiable risk factors.

6. Organization of Medical Care

6.1 Indications for emergency hospital admission:

— Decompensated cirrhosis with portal hypertension complications and/or signs of pronounced or progressive liver failure requiring immediate correction, including severe hepatic encephalopathy.

6.2 Indications for elective hospital admission:

— Need for diagnostic procedures that cannot be performed on an outpatient basis (e.g., liver biopsy).

— Need for differential diagnostic procedures to rule out other causes of liver disease that cannot be performed on an outpatient basis (e.g., liver biopsy).

— Decompensation of cirrhosis with portal hypertension complications and liver failure not requiring immediate correction.

— Pronounced clinical manifestations (other than those requiring emergency hospitalization) when outpatient therapy is ineffective.

— Combination of PBC with other conditions complicating the course of the disease and requiring multidisciplinary patient management and/or round-the-clock monitoring.

— For planned hospitalizations indicated for surgical diagnostic procedures (e.g., liver biopsy), admission is carried out in a surgical inpatient unit.

6.3 Indications for patient discharge from the medical facility:

— Compensation of the developed complications that served as the reason for hospitalization.

— Completion of diagnostic or differential diagnostic procedures planned in the inpatient setting.

— Ability to take medications orally and no need for regular parenteral administration.

6.4 Other organizational technologies

Telemedicine technologies (see Section 2.5).

7. Additional Information

No additional information.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Working Group Head:

1. Ivashkin Vladimir Trofimovich — MD, Professor, Academician of the Russian Academy of Sciences, Head of the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, Sklifosovsky Institute of Clinical Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), President of RSG, President of the Russian Gastroenterological Association. No conflict of interest.

Working Group Co-Heads:

2. Drapkina Oksana Mikhailovna — MD, Professor, Academician of the Russian Academy of Sciences, Director, National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health, President of RNMIC, RNSMOT. No conflict of interest.

3. Lila Alexander Mikhailovich — MD, Professor, Corresponding Member of the Russian Academy of Sciences, Director, Nasonova Research Institute of Rheumatology, Head of the Department of Rheumatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Member of the Board and Presidium of the Association of Rheumatologists of Russia. No conflict of interest.

4. Nasonov Evgeny Lvovich — MD, Professor, Academician of the Russian Academy of Sciences, Scientific Advisor, Nasonova Research Institute of Rheumatology, President of the Association of Rheumatologists of Russia. No conflict of interest.

Working group secretariat:

5. Vinnitskaya Elena Vladimirovna — MD, Head of the Hepatology Department, Loginov Moscow Clinical Scientific Center of the Moscow City Health Department. No conflict of interest.

6. Ivashkin Konstantin Vladimirovich — MD, Professor of the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, Sklifosovsky Institute of Clinical Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). No conflict of interest.

7. Prashnova Maria Konstantinovna— PhD in Medicine, Associate Professor, Scientific, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, St. Petersburg State University. No conflict of interest.

8. Raykhelson Karina Leonidovna— MD, Professor, Scientific, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, St. Petersburg State University, Professor of the Department of General Practice (Family Medicine), Pavlov First St. Petersburg State Medical University of the Russian Ministry of Health. No conflict of interest.

Working Group:

9. Abdulganieva Diana Ildarovna — MD, Professor, Head of the Department of Hospital Therapy, Kazan State Medical University of the Russian Ministry of Health. No conflict of interest.

10. Abdurakhmanov Dzhamal Tinovich — MD, Professor of the Department of Internal, Occupational Diseases and Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). No conflict of interest.

11. Alexandrova Elena Nikolaevna — MD, Head of the Laboratory of Clinical Immunology, Loginov Moscow Clinical Scientific Center of the Moscow City Health Department. No conflict of interest.

12. Alikhanov Ruslan Bogdanovich — MD, Head of the Department of Surgical Organ and Tissue Transplantation, Loginov Moscow Clinical Scientific Center of the Moscow City Health Department. No conflict of interest.

13. Bakulin Igor Gennadievich — MD, Professor, Head of the Ryss Department of Propaedeutics of Internal Diseases, Gastroenterology and Dietetics, Mechnikov North-Western State Medical University of the Russian Ministry of Health. No conflict of interest.

14. Bueverov Alexey Olegovich — MD, Professor of the Hepatology Course, Leading Researcher, Hepatology Department, Moscow Region Research Clinical Institute named after M.F. Vladimirsky. No conflict of interest.

15. Vetsheva Natalia Nikolaevna — MD, Professor of the Department of Ultrasound Diagnostics, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, President of the All-Russian Public Organization «Russian Association of Ultrasound Diagnostics Specialists in Medicine» (RASUDM). No conflict of interest.

16. Vorobyov Sergey Leonidovich — PhD in Medicine, Director of the National Center for Clinical Morphological Diagnostics, Vice-President of the Russian Society of Oncopathologists. No conflict of interest.

17. Gerasimova Olga Anatolyevna — MD, Leading Researcher, Department of Transplantation and Cellular Technologies, Head of the Outpatient Center for Transplantology, Hepatology and Nephrology, Granov Russian National Research Center of Radiology and Surgical Technologies of the Russian Ministry of Health. No conflict of interest.

18. Grechishnikova Vasilisa Romanovna — Assistant Professor, Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, Sklifosovsky Institute of Clinical Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). No conflict of interest.

19. Zharkova Maria Sergeevna — PhD in Medicine, Head of the Hepatology Department, Vasilenko Clinic of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). No conflict of interest.

20. Lyudmila Yu. Ilchenko — MD, PhD, Professor at the Department of Hospital Therapy named after Academician G.I. Storozhakov, Institute of Clinical Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health. No conflict of interest.

21. Irina L. Klyaritskaya — MD, PhD, Professor, Head of the Department of Therapy, Gastroenterology, Cardiology and General Practice (Family Medicine), V.I. Vernadsky Crimean Federal University, Academy of Medicine named after S.I. Georgievsky. No conflict of interest.

22. Vadim E. Karev — MD, PhD, Professor at the Research, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, Saint Petersburg State University. No conflict of interest.

23. Yuri A. Kravchuk — MD, PhD, Professor at the 2nd Department of Therapy for Advanced Medical Training, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation. No conflict of interest.

24. Yuri A. Kucheryavy — PhD, Associate Professor, Head of the Gastroenterology Department, Ilyin Hospital JSC. No conflict of interest.

25. Sergey V. Lapin — PhD, Head of the Laboratory of Autoimmune Disease Diagnostics at the Research and Methodological Center for Molecular Medicine of the Russian Ministry of Health, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health. No conflict of interest.

26. Maria A. Livzan — MD, PhD, Professor, Corresponding Member of the RAS, Rector, Head of the Department of Faculty Therapy and Gastroenterology, Omsk State Medical University of the Russian Ministry of Health; Head of the Science Group, Siberian Scientific and Educational Medical Cluster; Chief Freelance Specialist Therapist of the Russian Ministry of Health in the Siberian Federal District. No conflict of interest.

27. Marina V. Maevskaya — MD, PhD, Professor, Consultant at Therapeutic Department No. 3, University Clinical Hospital No. 2, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Vice President of the Russian Society for the Study of the Liver (RSL). No conflict of interest.

28. Natalia V. Marchenko — PhD, Gastroenterologist at the A.M. Granov Russian Scientific Center of Radiology and Surgical Technologies of the Russian Ministry of Health, Associate Professor at the Research, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, Saint Petersburg State University. No conflict of interest.

29. Aleksey L. Maslyansky — MD, PhD, Head of the Research Laboratory of Rheumatology and Immunopathology, Almazov National Medical Research Centre; Professor at the Research, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, Saint Petersburg State University; Scientific Consultant at the V.A. Nasonova Research Institute of Rheumatology. No conflict of interest.

30. Sabir N. Mekhtiev — MD, PhD, Professor at the Department of Hospital Therapy, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health. No conflict of interest.

31. Igor G. Nikitin — MD, PhD, Professor, Head of the Department of Hospital Therapy named after Academician G.I. Storozhakov, Faculty of General Medicine, Pirogov Russian National Research Medical University of the Russian Ministry of Health. No conflict of interest.

32. Tatiana P. Nekrasova — PhD, Associate Professor, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health. No conflict of interest.

33. Sergey V. Okovity — MD, PhD, Professor, Head of the Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University of the Russian Ministry of Health. No conflict of interest.

34. Marina F. Osipenko — MD, PhD, Professor, Head of the Department of Propaedeutics of Internal Diseases, Novosibirsk State Medical University of the Russian Ministry of Health. No conflict of interest.

35. Ekaterina V. Pazenko — PhD, Researcher at the Research, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, Saint Petersburg State University; Gastroenterologist at Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health. No conflict of interest.

36. Yulia G. Sandler — PhD, Senior Researcher at the Department of Hepatology, Physician at the Center for Liver Disease Diagnostics, Moscow Clinical Research Center named after A.S. Loginov of the Moscow Healthcare Department. No conflict of interest.

37. Evgenia S. Sbikina — PhD, Senior Researcher at the Center for Liver Disease Diagnostics, Moscow Clinical Research Center named after A.S. Loginov of the Moscow Healthcare Department. No conflict of interest.

38. Ksenia S. Sokolova — Assistant Professor at the Research, Clinical and Educational Center for Gastroenterology and Hepatology, Medical Institute, Saint Petersburg State University; Gastroenterologist at Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health. No conflict of interest.

39. Vladimir E. Syutkin — MD, PhD, Professor at the Department of Surgery with Courses in Oncology, Anesthesiology and Reanimatology, Endoscopy, Surgical Pathology, Clinical Transplantology and Organ Donation, Institute of Professional Education, Burnasyan Federal Medical Biophysical Center of the Federal Medical-Biological Agency (FMBA of Russia); Leading Researcher at the Department of Liver Transplantation, Sklifosovsky Research Institute of Emergency Medicine of the Moscow Healthcare Department. No conflict of interest.

40. Tatiana Yu. Khaymenova — PhD, Head of the Liver Diseases Department, Moscow Clinical Research Center named after A.S. Loginov of the Moscow Healthcare Department. No conflict of interest.

41. Sergey G. Khomeriki — MD, PhD, Professor, Department of Pathomorphology, Moscow Clinical Research Center named after A.S. Loginov of the Moscow Healthcare Department. No conflict of interest.

42. Anna R. Khokhlova — Postgraduate Student, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health. No conflict of interest.

43. Elena N. Shirokova — MD, PhD, Professor at the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology named after V.Kh. Vasilenko, University Clinical Hospital No. 2, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health. No conflict of interest.

44. Anna F. Sheptulina — PhD, Leading Researcher, Head of the Laboratory of Experimental and Preventive Gastroenterology, Department of Fundamental and Applied Aspects of Obesity, National Medical Research Center for Therapy and Preventive Medicine of the Russian Ministry of Health. No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Clinical guidelines for the provision of medical care to patients with PBC have been drawn up in accordance with the requirements for the development of clinical guidelines by medical professional non-profit organizations under Part 2 of Article 76 of Federal Law No. 323-FZ dated November 21, 2011, 'On the Basics of Protecting the Health of Citizens in the Russian Federation', and Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, 'On approval of the procedure and timelines for the development of clinical guidelines, their revision, standard form of clinical guidelines and requirements for their structure, composition and scientific validity of the information included in clinical guidelines' (as amended on September 28, 2023).

The clinical guidelines are based on evidence-based clinical experience describing physician actions regarding the diagnosis, differential diagnosis, treatment, rehabilitation, and prevention of PBC.

Target audience for these clinical guidelines:

1. Gastroenterologist.

2. General practitioner / Physician.

3. General practitioner (family physician).

4. Physicians of other specialties involved in the diagnosis and management of patients with PBC, as well as associated and comorbid conditions.

Medical professionals should follow these recommendations when making clinical decisions. At the same time, the recommendations do not replace the personal responsibility of medical professionals in making clinical decisions, taking into account the individual features of the course of PBC and patient preferences. These recommendations take into account the accumulated Russian and international experience in managing patients with PBC and are based on clinical guidelines from major hepatology associations.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for evaluating the levels of убедительности рекомендаций (LoR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The guideline update mechanism provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law of the Russian Federation No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017 (as amended on July 12, 2018) "On Approval of the Nomenclature of Medical Services".

3. Order of the Ministry of Health of the Russian Federation No. 148n dated March 5, 2020 "On Amendments to Section II 'Nomenclature of Medical Services' of the Nomenclature of Medical Services Approved by Order of the Ministry of Health of the Russian Federation No. 804n Dated October 13, 2017".

Appendix A3.1 Main drugs for the treatment of PBC

** Medicinal product included in the Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on June 9, 2023) "On Approval of the List of Vital and Essential Medicinal Products, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for Medical Care".

# The use of a medicinal product in accordance with indications (characteristics) not specified in its instructions for use (off-label) is carried out in accordance with Federal Law No. 323-FZ dated November 21, 2011, as amended.

Appendix A3.2 Histological scoring systems

A3.2.1 Histological stages of PBC (according to Scheuer P., 1967 and Ludwig J., 1978):

Appendix A3.2.2 PBC staging system by Y. Nakanuma et al., 2013

Appendix B. Physician Action Algorithms

Abbreviations:

AMA — antimitochondrial antibodies

ANA — antinuclear antibodies

anti-sp100 — antinuclear antibodies to the sp100 antigen

anti-gp-210 — antinuclear antibodies to the gp-210 antigen

ULN — upper limit of normal

GGT — gamma-glutamyl transferase

DILI — drug-induced liver injury

MRCP — magnetic resonance cholangiopancreatography

PBC — primary biliary cholangitis

ALP — alkaline phosphatase

UDCA** — ursodeoxycholic acid

US — ultrasound

EUS — endoscopic ultrasonography

Abbreviations: UDCA** — ursodeoxycholic acid**, OCA — obeticholic acid.

Early stage: absent or minimal fibrosis on histology (if liver biopsy was performed); liver stiffness > 9.3 kPa by transient elastography; albumin and bilirubin levels within reference ranges.

Late stage: bridging fibrosis or cirrhosis on histology (if liver biopsy was performed); liver stiffness > 9.3 kPa by transient elastography; albumin level < LLN and (or) bilirubin level > ULN.

Risk factors for inadequate response to UDCA** therapy: young age; pruritus or low albumin level or high ALT, GGT, and ALP levels before treatment; presence of anti-gp210; PBC/AIH overlap; ductopenia on histological examination; advanced liver fibrosis (on histological examination or transient elastography) and presence of liver cirrhosis.

Abbreviations: GOV — gastroesophageal varices.

Notes:

* — adverse events: death, liver transplantation or placement on the liver transplantation waiting list, or complications of liver cirrhosis (gastroesophageal variceal bleeding, ascites, hepatic encephalopathy, or HCC).

** — necroinflammatory activity, venous congestion, intrahepatic cholestasis, and obesity reduce the reliability of liver stiffness measurement.

Figure B4. Algorithm for the management of pruritus

Appendix C. Patient Information

Dear Patient! Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic liver disease caused by the progressive destruction of the bile ducts within the liver. Bile produced by the liver flows through these ducts into the small intestine, where it aids in the absorption of fats and fat-soluble vitamins (A, D, E, and K). When the ducts are destroyed, bile accumulates in the liver, causing inflammation and scar tissue formation (fibrosis). Ultimately, this can lead to liver cirrhosis and its related complications as scar tissue replaces healthy liver tissue and liver function progressively declines.

The exact cause of the disease is unknown. There is strong evidence linking it to immune system dysfunction: our immune defense cells begin to perceive the cells of the bile ducts as foreign and attack them, resulting in inflammation and damage to the biliary tract. Although PBC is not strictly a hereditary disease—i.e., caused by a specific genetic defect passed from parents to children—there appears to be a familial predisposition to developing the condition. PBC is more common in families where one of the members has the disease.

Untreated PBC leads to irreversible liver damage. Unfortunately, no medications have yet been developed that can completely cure this condition. However, effective and relatively safe drugs exist that must be taken for life, with periodic evaluation of their efficacy to transition to the next treatment option in a timely manner if necessary.

The main medication for treating PBC is ursodeoxycholic acid (UDCA**), which helps promote bile flow from the liver into the small intestine. When used in a timely manner, ursodeoxycholic acid** can improve liver function and prevent or delay the need for a liver transplant. People with PBC must take this medication every day for the rest of their lives. Ursodeoxycholic acid** is effective in more than half of patients and is generally well tolerated.

Other medications are used in patients who have an inadequate response to UDCA** treatment and are prescribed as an add-on therapy.

If treatment for PBC achieves a good effect (response to therapy), life expectancy becomes comparable to that of the general population (i.e., individuals without this disease). However, symptoms may persist.

The most common and distressing symptoms of PBC are pruritus (itching), fatigue, and sicca syndrome.

There are several ways to manage pruritus. If you experience itching, avoid hot baths and showers, apply moisturizing creams after showering, use cooling gels (e.g., containing menthol), and keep your fingernails trimmed short. Choose clothing made from natural fabrics and avoid excessive sun exposure. Your doctor can prescribe anti-itch therapy based on your individual characteristics and the stage of the disease.

People with PBC often experience severe weakness, fatigue, and tiredness. This is not a sign of advanced disease—sometimes individuals in the early stages experience severe fatigue, whereas others with more advanced disease do not report it. To cope with fatigue, a nutritious and balanced diet, adequate physical exercise, and an optimal sleep routine are necessary. Certain comorbidities (thyroid disease, depression, anemia, etc.) can also manifest as fatigue. Your doctor will determine the extent of evaluation needed regarding your weakness and fatigue.

Artificial tears can help with dry eyes, while dry mouth can be relieved by chewing gum or hard candies, as well as artificial saliva.

There is no evidence-based data indicating that any specific diet improves the course and outcomes of PBC.

The use of dietary supplements with immunostimulatory effects, herbal remedies, prolonged sun exposure, and certain physiotherapeutic procedures should be avoided.

Liver transplantation is considered in cases where medical treatment is no longer able to adequately control the disease and severe, irreversible liver damage has occurred (decompensated liver cirrhosis).

PBC is not a contraindication to pregnancy, and female patients with PBC generally do not have conception issues. The risk of maternal and fetal complications is slightly increased compared to healthy women, but spontaneous abortions occur in only 5% of pregnancies. Patients should continue taking ursodeoxycholic acid during pregnancy and breastfeeding, as it is safe for the unborn child.

Strict adherence to medical recommendations and regular medical follow-up are the keys to successful treatment and increased life expectancy.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Child — Turcotte — Pugh (CTP) Classification of Liver Cirrhosis Severity

Russian title: Child — Turcotte — Pugh Classification of Liver Cirrhosis Severity.

Original title: Child — Turcotte — Pugh (CTP) score.

Source: Child C.G., Turcotte J.G. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85; Pugh R.N., Murray-Lyon I.M., Dawson J.L., Pietroni M.C., Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–649. https://doi.org/10.1002/bjs.1800600817; Durand F., Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol. 2005;42(Suppl. 1):S100–S107. https://doi.org/10.1016/j.jhep.2004.11.015.

Type: rating scale.

Purpose: assessment of the prognostic class of liver cirrhosis.

Content (template):

Key (interpretation):

Notes: Class A (well-compensated liver function); one-year survival is approximately 100%; Class B (significant impairment of liver function); one-year survival is approximately 80%; Class C (decompensation of disease and liver function); one-year survival is approximately 45%. With a total score of < 5, the median life expectancy of patients without liver transplantation is 6.4 years, and with a score of ≥ 12, it is 2 months.

Appendix G2. Paris criteria for AIH/PBC overlap syndrome

Source: Chazouilleres O., Wendum D., Serfaty L., Montembault S., Rosmorduc O., Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology. 1998;28(2):296–301. https://doi.org/10.1002/hep.510280203.

Type: rating scale (criteria).

Purpose: diagnosis of AIH/PBC overlap syndrome.

Content (template):

Key (interpretation): diagnosis of AIH/PBC overlap syndrome requires meeting two of the three AIH criteria and two of the three PBC criteria.

Appendix G3. MELD (Model for End-Stage Liver Disease)

Model to predict survival in patients with end-stage liver disease (Model for End-Stage Liver Disease, MELD).

Source: Kamath P.S., Wiesner R.H., Malinchoc M., Kremers W., Therneau T.M., Kosberg C.L. et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–470. https://doi.org/10.1053/jhep.2001.22172; Sharma P., Schaubel D.E., Goodrich N.P., Merion R.M. Serum sodium and survival benefit of liver transplantation. Liver Transpl. 2015;21(3):308–313. https://doi.org/10.1002/lt.24063.

Type: scoring model.

Purpose: evaluation of survival in liver disease, determination of indications for liver transplantation.

Content (template):

MELD = (0.957 * ln (serum creatinine, mg/dL * 88.4¹) + 0.378 * ln (serum bilirubin, mg/dL * 117.104²) + 1.120 * ln (INR) + 0.643) * 10 (if hemodialysis was performed at least twice over the past 7 days, creatinine is set to 4.0 mg/dL)

MELD-Na = MELD (original) + 1.32 * (137 - sodium) — [0.033 * MELD (original) * (137 - serum sodium)]

ln — natural logarithm; INR — international normalized ratio.

¹ conversion factor for creatinine from mg/dL to µmol/L.

² conversion factor for bilirubin from mg/dL to µmol/L.

Values < 1 mg/dL (< 88.4 µmol/L for creatinine and < 17.104 µmol/L for bilirubin) are considered equal to 1.

Key (interpretation):

MELD score and 3-month mortality:

40 and over — mortality 71.3%;

30–39 — mortality 52.6%;

20–29 — mortality 19.6%;

10–19 — mortality 6.0%;

< 9 — mortality 1.9%.

Appendix G4. Scoring systems for assessing response to UDCA** therapy in patients with PBC

G.4.1 Types of scoring systems for assessing response to UDCA** therapy in patients with PBC

Appendix G4.2 Paris I scoring system for assessing treatment response in PBC

Russian name: Paris I criteria.

Original name: Paris-I.

Source: Corpechot C., Abenavoli L., Rabahi N., Chrétien Y., Andréani T., Johanet C. et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871–877. https://doi.org/10.1002/hep.22428.

Type: rating scale (criteria).

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): ALP ≤ 3.0 ULN and AST ≤ 2.0 ULN and bilirubin within normal limits after 12 months of UDCA** therapy.

Key (interpretation): death or liver transplantation occurred 2.5 times more frequently in patients who had ALP > 3 ULN, AST > 2 ULN, or serum bilirubin level within normal limits after 1 year of treatment.

Appendix G4.3 Paris II scoring system for assessing treatment response in PBC

Russian name: Paris II criteria.

Original name: Paris-II.

Source: Corpechot C., Chazouillères O., Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55(6):1361–1367. https://doi.org/10.1016/j.jhep.2011.02.031.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): ALP and AST ≤ 1.5 ULN and bilirubin within normal limits after 12 months of UDCA** therapy.

Key (interpretation): ALP and AST levels ≤ 1.5 ULN and bilirubin within normal limits after 12 months of treatment allow identification of patients with early histological stage who do not require second-line therapy for PBC.

Appendix G4.4 Barcelona scoring system for assessing treatment response in PBC

Russian name: Barcelona criteria.

Original name: Barcelona.

Source: Parés A., Caballería L., Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006;130(3):715–720. https://doi.org/10.1053/j.gastro.2005.12.029.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): decrease in ALP > 40% or normalization of ALP from baseline after 12 months of UDCA** therapy.

Key (interpretation): a decrease in ALP levels by less than 40% from baseline after 12 months of treatment helps identify patients who need to be prescribed second-line therapy for PBC.

Appendix G4.5 Rotterdam scoring system for assessing treatment response in PBC

Russian name: Rotterdam criteria.

Original name: Rotterdam.

Source: Kuiper E.M., Hansen B.E., de Vries R.A., den Ouden-Muller J.W., van Ditzhuijsen T.J., Haagsma E.B. et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136(4):1281–1287. https://doi.org/10.1053/j.gastro.2009.01.003.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): normalization of abnormal bilirubin and/or albumin after 12 months of UDCA** therapy.

Key (interpretation): long-term prognosis, regardless of disease severity, improves if UDCA** treatment leads to normalization of previously abnormal bilirubin and/or albumin concentrations.

Appendix G4.6 Mayo scoring system for assessing treatment response in PBC

Russian title: Mayo score.

Original title: Mayo.

Source: Momah N., Silveira M.G., Jorgensen R., Sinakos E., Lindor K.D. Optimizing biochemical markers as endpoints for clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790–795. https://doi.org/10.1111/j.1478-3231.2011.02678.x.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): reduction of ALP < 2 ULN after 6 months of UDCA therapy**.

Key (interpretation): failure to reduce ALP levels < 2 ULN after 6 months of treatment identifies patients who require 2nd-line therapy for PBC.

Appendix G4.7 Ehime scoring system for assessing treatment response in PBC

Russian title: Ehime score.

Original title: Ehime.

Source: Azemoto N., Abe M., Murata Y., Hiasa Y., Hamada M., Matsuura B., Onji M. Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis. J Gastroenterol. 2009;44(6):630–634. https://doi.org/10.1007/s00535-009-0051-9.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): GGT reduction ≥ 70% or GGT normalization after 6 months of PBC therapy.

Key (interpretation): a GGT level greater than 70% of baseline after 6 months of treatment identifies patients who require 2nd-line therapy for PBC.

Appendix G4.8 Toronto scoring system for assessing treatment response in PBC

Russian title: Toronto score.

Original title: Toronto.

Source: Kumagi T., Guindi M., Fischer S.E., Arenovich T., Abdalian R., Coltescu C. et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105(10):2186–2194. https://doi.org/10.1038/ajg.2010.216.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): ALP ≤ 1.67 ULN after 24 months of UDCA therapy**.

Key (interpretation): an ALP level > 1.67 ULN after 24 months of treatment identifies patients who require 2nd-line therapy for PBC.

Appendix G4.9 Global Longitudinal Outcomes in PBC (GLOBE) score

Russian title: The Global Assessment of Liver Outcomes (GLOBE) score.

Original title: The GLOBE (The Global Assessment of Liver Outcomes) score for patients with Primary Biliary Cholangitis (PBC).

Source: Lammers W.J., Hirschfield G.M., Corpechot C., Nevens F., Lindor K.D., Janssen H.L. et al. Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. Gastroenterology. 2015;149(7):1804–1812.e4. https://doi.org/10.1053/j.gastro.2015.07.061.

Type: rating scale.

Purpose: to identify high-risk patients for closer monitoring and 2nd-line therapy, as well as low-risk patients who can potentially be managed within primary care.

Content (template): GLOBE score = (0.044378 × age at initiation of UDCA therapy** + 0.93982 * ln (bilirubin-to-ULN ratio after 1 year of follow-up)) + (0.335648 × ln (ALP-to-ULN ratio after 1 year of follow-up)) – 2.266708 × albumin-to-LLN ratio after 1 year of follow-up – 0.002581 × platelet count per 10 ⁹/L after 1 year of follow-up) + 1.216865.

Key (interpretation): the probability of transplant-free survival at 3, 5, 10, and 15 years of follow-up is calculated as a percentage and compared with the average survival of an age- and sex-matched population. Assessment is performed after 1 year of UDCA therapy**.

Appendix G4.10 UK-PBC risk calculator

Russian title: United Kingdom Primary Biliary Cholangitis (UK-PBC) Risk Score Calculator.

Original title: UK-PBC (United Kingdom primary biliary cholangitis) Risk Score Calculator.

Source: Carbone M., Sharp S.J., Flack S., Paximadas D., Spiess K., Adgey C. et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63(3):930–950. https://doi.org/10.1002/hep.28017.

Type: rating scale.

Purpose: to identify high-risk patients for closer monitoring and 2nd-line therapy, as well as low-risk patients who can potentially be managed within primary care.

Content (template): UK-PBC = 1 − baseline survival function ∧ exp(0.0287854 × [baseline ALP and at 12 months of treatment × ULN − 1.722136304] − 0.0422873 × [{(ALT where available, otherwise AST, baseline and at 12 months of treatment × ULN/10)∧−1} − 8.675729006] + 1.4199 × [ln{total bilirubin at months of treatment × ULN/10} + 2.709607778] − 1.960303 × [baseline albumin × LLN − 1.17673001] − 0.4161954 × [baseline platelets × LLN − 1.873564875]).

Key (interpretation): to assess the risk (expressed as a percentage) of a patient with PBC receiving UDCA treatment (UDCA**) developing liver failure requiring liver transplantation within 5, 10, or 15 years from diagnosis.

Appendix G4.11 Urso-Response Score (URS)

UDCA Response Score (URS) ALP ≤ 1.67 ULN.

Russian title: UDCA Response Score.

Original title: UDCA Response Score (URS).

Source: Carbone M., Nardi A., Flack S., Carpino G., Varvaropoulou N., Gavrila C. et al. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score. Lancet Gastroenterol Hepatol. 2018;3(9):626–634. https://doi.org/10.1016/S2468-1253(18)30163-8.

Type: rating scale.

Purpose: assessment of response to UDCA** therapy in patients with PBC.

Content (template): ALP ≤ 1.67 ULN after 12 weeks of UDCA therapy**.

Key (interpretation): an ALP level > 1.67 ULN after 12 months of treatment identifies patients who require 2nd-line therapy for PBC.

Appendix G5. Albumin-Bilirubin (ALBI) grade

Russian title: Albumin-Bilirubin (ALBI) score.

Original title: The albumin-bilirubin (ALBI) score.

Source: Johnson P.J., Berhane S., Kagebayashi C., Satomura S., Teng M., Reeves H.L. et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33(6):550–558. https://doi.org/10.1200/JCO.2014.57.9151.

Type: rating scale.

Purpose: to identify high-risk patients for closer monitoring.

Content (template): 0.66 × log₁₀ [total bilirubin (μmol)] – 0.085 × [albumin (g/L)]. Based on this calculation, patients can be divided into three classes: grade 1 (≤ – 2.60), grade 2 (> – 2.60, but ≤ – 1.39), and grade 3 (> – 1.39).

Key (interpretation): the 5-year cumulative liver transplantation-free survival rate for patients in ALBI grades 1, 2, and 3 was 97.2%, 82.4%, and 38.8%, respectively.

Appendix G6. Mayo risk score

Russian title: Mayo survival model.

Original title: Mayo primary biliary cirrhosis survival model.

Source: Dickson E.R., Grambsch P.M., Fleming T.R., Fisher L.D., Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology. 1989;10(1):1–7. https://doi.org/10.1002/hep.1840100102.

Type: rating scale.

Purpose: survival assessment, decision-making regarding liver transplantation waiting list placement.

Mayo model (R = 0.039 × age in years + 0.871 × ln (bilirubin in mg/dL) + 0.859 × edema – 2.53 × ln (albumin in mg/dL) + 2.38 × ln (prothrombin time in seconds)).

Key (interpretation): criteria for placement on the liver transplantation waiting list for patients with PBC according to the Mayo score is ≥ 7.8.

Appendix G7. Fatigue Assessment Scale (FAS)

Russian title: Fatigue Assessment Scale.

Original title: FATIGUE ASSESSMENT SCALE (FAS).

Purpose: to identify and assess asthenia/fatigue symptoms.

Content (template)

Key (interpretation): questionnaire scores are calculated by summing the points, with items 4 and 10 scored in reverse order from 5 to 1. Total scores can range from 10 to 50 points. The higher the score, the greater the severity of fatigue. A score of 22 points or higher indicates the presence of chronic fatigue syndrome in the patient.