Primary Biliary Cholangitis

Etiopathogenesis

The current consensus is that PBC is an organ-specific autoimmune disease that occurs in genetically predisposed individuals. Most patients with PBC have AMAs directed against the 2-oxo acid dehydrogenase family of multienzyme complexes (2-OADC), of which the main targets are the E2 and E3 subunits of the pyruvate dehydrogenase complex (PDC-E2 and PDC-E3). Interestingly, a key shared component of the B-cell autoepitope within all these enzymes is a lipoic acid cofactor.

Although the 2-OADC is located in the inner mitochondrial membrane and is present in all nucleated cells, the immunologic response in PBC is primarily against biliary epithelial cells. In this population, PDC-E2 appears to be aberrantly expressed on the cell surface, especially in small bile duct biliary epithelial cells. Thus, one of the most fascinating challenges in PBC is to explain the mechanisms leading to this localized breakdown in immune tolerance. In this regard, emerging data suggest a potentially crucial role of apoptosis of biliary epithelial cells as a mechanism for the tissue-specific autoimmune reactivity that is typical of PBC.

Biliary epithelial cells, or cholangiocytes , can regulate expression of adhesion molecules, major histocompatibility complex (MHC) Classes I and II, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and interleukin 1 (IL-1) in the setting of stimulation by specific proinflammatory cytokines. Biliary epithelial cells can also act as antigen-presenting cells. Furthermore, these cells are susceptible to apoptosis. Several stimuli can trigger apoptosis of these biliary epithelial cells, including immune-mediated injury, oxidative stress, toxins, and infectious agents. Over time, when an imbalance occurs between biliary epithelial cell death and the ability of residual biliary epithelial cells to proliferate, ductopenia prevails. Thus, phagocytosis of apoptotic cells by biliary epithelial cells could lead to the expression of endogenous autoantigens, which in turn would lead to autoreactivity, progressive cholangiocyte destruction, and ductopenia, one of the hallmarks of PBC progression.

Accumulation of bile acids follows the progressive biliary injury and ductopenia, and bile acids in excess are toxic. In PBC, cholestasis also results from defective regulation of the cholangiocyte anion exchanger 2 (AE2), leading to loss of the protective “bicarbonate umbrella”. These accumulating bile acids are important signaling molecules, functioning as natural ligands for several receptors that can further modulate the immune response. The best example is farnesoid X receptor (FXR), a nuclear receptor predominantly expressed in the gastrointestinal tract, although G protein–coupled bile acid receptors (TGR5s) and other signaling pathways are also involved. In preclinical and clinical studies, FXR activation modulates bile acid homeostasis, lipid and glucose metabolism, fibrosis pathways, and immune regulation. In addition, FXR activation has been shown to inhibit the nuclear factor κB (NF-κB) signaling pathway, with decreased production of TNF-α, IL-1, IL-17, and IFN-γ, and therefore modulating inflammation.

Genetics

Several lines of evidence point to a strong role for genetics in the etiopathogenesis of PBC. First, the disease occurs much more frequently among relatives of patients with PBC, with a reported rate ranging between 1% and 7%. Second, the concordance rate among identical twins is 63%, which is among the highest reported in autoimmune diseases. Finally, the well-described female predominance and the increased frequency of X monosomy in women with PBC suggest a role for X chromosome defects in PBC. The genetic background in PBC, however, is complex and cannot be explained by a single gene abnormality. Thus, a “multihit” genetic model was conceived in which specific genes would predispose to a breach in immune tolerance, leading to disease onset, whereas others would determine disease progression. In addition to genetics, various other external factors are proposed to affect both disease onset and disease progression.

Given that specific MHC alleles have been found in association with other autoimmune diseases, their association with PBC has been explored as well. To date, the association with MHC Class I genes is regarded as weak. The study of MHC Class II alleles, on the other hand, provides important clues to the pathogenesis of PBC. In multiple studies from Germany, Spain, Italy, Sweden, and the United States, human leukocyte antigen (HLA)-DR8 (DRB1*08) was found with higher frequency among Caucasian patients with PBC as compared with controls, suggesting that DR8 might be a risk factor for PBC. In Great Britain, the linkage of DQA1*0401 and DR8-DQB1*0402 was associated with disease progression, not onset. These findings have not been consistent throughout the rest of Europe and Japan, indicating perhaps that different alleles have a different impact on the disease depending on the geographic location. In addition, preliminary data suggest that specific HLA associations may underlie the various immunologic phenotypes in PBC. Interestingly, although further characterization and unifying data are still needed, a large study from Canada and the United States strongly suggested that most of the risk of PBC derives from common variants across the HLA-DQB1, IL12A, and IL12RB2 loci. In turn, protection against PBC has been associated with the DRB1*13 and DRB1*11 haplotypes.

Investigation of non-HLA risk loci has been powered by new genome-wide association studies (GWAS). GWAS have shed light into important associations between non-HLA risk loci and PBC, and confirmed most, but not all, of the previously reported associations. Cytotoxic T-lymphocyte antigen-4 (CTLA-4), for instance, has not come up as a risk locus in PBC in these powerful genome-wide studies. GWAS including patients and controls from North America, United Kingdom, Italy, and Japan identified multiple risk loci previously found in association with various other immune-related diseases. In particular, a strong role has emerged for interleukin-12 (IL-12) and downstream janus kinase and signal transducer and activator of transcription proteins (JAK-STAT) signaling pathways in the development of PBC. Other important loci associated with PBC were NF-κB, the interferon regulatory factor 5 (IRF5), and suppressor of cytokine-signaling 1 (SOCS1) genes. Very few genes identified in GWAS are likely to be disease-specific. Rather, it appears that genetic risk identified so far relates to predisposition to autoimmunity in general. Furthermore, the impact of such genetic variations on specific disease phenotype is unknown. Table 42-2 shows non-HLA risk associations emerging from genome-wide studies.

Clinical Manifestations

PBC affects predominantly middle-aged women, with mean age at presentation of 52 years. A minority of patients are male (at most 10%). Up to 40% of patients present at age 65 years and older, with the clinical features of the disease in this population being identical to those observed in younger patients.

Symptomatic Disease

Fatigue and pruritus are by far the most common symptoms reported by patients with PBC. Jaundice, on the other hand, is a late event and is associated with a poor prognosis. Right upper quadrant abdominal pain is reported by approximately 10% of patients. Symptoms related to portal hypertension and those attributed to extrahepatic complications are discussed later in this chapter.

Fatigue

In North America and Northern Europe, fatigue is reported in up to 85% of patients with PBC, and approximately 50% of these patients consider it their worst symptom. Even though this has been considered a subjective complaint, questionnaires assessing symptoms and health-related quality of life can provide some insight with respect to the impact of fatigue in patients with PBC. Using the Fatigue Impact Scale (FIS), investigators have shown that patients with higher fatigue scores may have increased mortality, mostly attributable to cardiovascular causes, and excessive daytime somnolence. Fatigue is known to impact family life and job performance, and a Canadian study using the Fatigue Assessment Instrument showed that individuals with PBC and fatigue had poor-quality sleep and were significantly more depressed. In that study, fatigue did not correlate with severity of liver disease and was not alleviated by the use of UDCA, findings which were validated by other groups. The association with depression was also noted in other studies, at variable rates.

Patients with PBC who are fatigued, both with and without cirrhosis, have lower heart rate variability and tend to be more hypotensive, all indicating autonomic dysfunction with sympathetic overactivity and impaired baroreflex sensitivity. Furthermore, these patients have accelerated reduction in muscle function on repeated sustained activity that correlates with the severity of fatigue. Such peripheral muscle fatigability appears to be related to excess muscle acidosis after exercise and recent studies point to the possibility of mitochondrial dysfunction as a contributing factor.

Data from the UK PBC cohort demonstrates lower rates of fatigue in men with PBC as compared with women. Additionally, autonomic symptoms were less common in men than women. Further demonstrating the link between fatigue and autonomic dysfunction, in a matched-pair analysis of women and men the differences between fatigue scores were proportional to the differences in autonomic dysfunction scores. Fatigue is also less common in younger patients.

Thus, a hypothesis to explain the pathophysiology of fatigue involves both central and peripheral processes. Structural abnormalities in areas of the brain linked to autonomic regulation are seen in patients with PBC and fatigue, and there is a correlation between lesion load, degree of cognitive impairment and a loss of cerebral autoregulation. With autonomic dysregulation there is increased tendency to fall, and increased risk of progressive cognitive deterioration over time. It is conceivable that the autonomic dysregulation also affects blood supply to peripheral muscles and the function of proton and/or lactate transporters involved in adaptation to the anaerobic metabolism, thus leading to muscle fatigue. Other factors that contribute to the development of fatigue include depression, sleep deprivation, medication side effects, anemia, and hypothyroidism.

Pruritus

Defined as an unpleasant sensation that triggers the need to scratch, pruritus is a common complaint among patients with PBC. It has been reported in up to 70% of patients, with more recent studies indicating a lower prevalence of approximately 20% to 30%. Prince et al. followed 770 patients with PBC for symptom progression and found that 18.9% reported pruritus at the time of diagnosis; the cumulative risk of having pruritus was 45% at 5 years and 57% at 10 years. Later, the natural history of pruritus in PBC was evaluated in patients participating in clinical trials at the Mayo Clinic. The annual risk of developing pruritus among patients who did not have this complaint at entry and who were randomized to the placebo arm was 27%, whereas the annual risk of reporting resolution or improvement of pruritus was 23%. Although this particular study indicated that the serum alkaline phosphatase (ALP) level and the Mayo risk score were independent predictors of pruritus, this relationship has not been shown consistently. Indeed, it appears that no direct correlation exists between biochemical markers of cholestasis or disease stage and the presence of pruritus, except perhaps for an increased incidence of severe pruritus in patients with florid duct lesions. In addition, pruritus is known to improve or resolve once liver failure ensues in some patients.

Pruritus in PBC is often generalized and intermittent, although it can certainly be relentless, and the severity will more typically be mild to moderate. It leads to marked impact on quality of life because of impaired sleep and depression. Rarely, pruritus can be severe enough to be considered disabling, and there are reports of liver transplantation indicated on the basis of this symptom alone. Even though the pruritus in PBC is not secondary to skin lesions, the physical exam will often reveal evidence of chronic scratching, such as excoriations, hyperpigmentation, and prurigo nodularis .

Our knowledge on the pathogenesis of pruritus in PBC has grown substantially over the past several years. The pruritogenic substance in cholestasis is thought to be formed or biotransformed in the liver and be secreted into bile. It is further thought to accumulate in the systemic circulation and, finally, to affect the endogenous opioidergic system. Early speculations that bile acid accumulation in the plasma and tissues of patients with PBC would cause pruritus remain largely unproven. Nevertheless, bile acid-induced activation of TGR5, a receptor expressed in dorsal root neurons, can trigger an increase in basal scratch activity. The interest in bile acids as pruritogenic substances is dampened by a lack of correlation between serum bile acid concentration and the intensity of itching. Furthermore, the concentrations of bile acids used to stimulate TGR5 in the study described earlier were much higher than that observed in clinical cholestasis. Neurosteroids, on the other hand, can also stimulate TGR5 in the central nervous system and could potentially contribute to itching. Importantly, other endogenous pruritogenic substances and pathways have been under scrutiny, including opioid peptides, serotonin, acetylcholine, endothelins, substance P, kallikreins, leukotrienes, prostaglandins, and, more recently, lysophosphatidic acid (LPA).

Several lines of evidence support a role for an increased opioid­ergic tone in the pathogenesis of pruritus in PBC. First, as opposed to healthy volunteers, patients with PBC develop withdrawal-like symptoms after taking an opioid antagonist. Second, central administration of opioids induces pruritus, which is then improved by an opioid antagonist. Third, patients with cholestatic liver disease have increased serum levels of the endogenous opioid peptides methionine-enkephalin and leucine-enkephalin, with down-regulation of µ-opioid receptors. Fourth, clinical trials show that opioid antagonists improve pruritus in the setting of cholestasis. Taken together, the data suggest that either there is increased central opioidergic neurotransmission leading to pruritus or the opioid antagonists can possibly inhibit the release of a pruritogen that has not yet been identified. With regard to genetics, a single nucleotide polymorphism has been reported in exon 1 of opioid receptor µ-1, which possibly protects against the scratching behavior, and another in exon 25 of the multidrug resistance protein 2 gene, which was significantly associated with the presence of pruritus.

Because an itch-specific neural pathway has been recently described, investigators now turned their attention to identifying itch-specific neurotransmitters and receptors. Specifically, the LPA-autotoxin (ATX) axis was identified as a key component in cholestatic itch. Six G-protein-coupled receptors for LPA have been well identified on itch-selective neurons. ATX is the enzyme responsible for formation of LPA from its precursor, lysophosphatidylcholine. As LPA is a rather unstable neuronal activator, serum ATX activity has been used as a more reliable marker, and found to correlate with intensity of pruritus and with response to therapeutic interventions. Furthermore, rifampin, a drug with strong antipruritic effects, was found to inhibit ATX expression at the transcriptional level in human liver-derived cell lines, possibly through pregnane X receptor (PXR) activation.

Several questions remain unanswered, including the source of serum ATX, identification of LPA-ATX axis regulatory pathways, which specific LPA receptors and signaling pathways are required for LPA-induced pruritus, and which other factors are involved in initiation and potentiation of itching. Better understanding of the pathogenesis of pruritus will obviously lead to novel targeted approaches to therapy.

Portal Hypertension

Only a minority of patients with PBC will have signs and symptoms consistent with portal hypertension at the time of their diagnosis. In one of the largest population-based studies, 3% of patients had ascites, 1.3% had bleeding esophageal varices, and 1.4% had hepatic encephalopathy at presentation. It was estimated that 10 years later 20% would have ascites, 10% would have bleeding esophageal varices, and 12.6% would have hepatic encephalopathy. Interestingly, complications of portal hypertension can precede the histologic development of cirrhosis in 10% to 20% of patients, due to portal venous compression, perisinusoidal fibrosis, and nodular regenerative hyperplasia. Clinical features of portal hypertension in PBC are similar to those in patients with other forms of chronic liver disease.