Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
Hannover Medical School, Hannover, Germany.
Clin Gastroenterol Hepatol. 2023 Jul;21(8):2076-2087. doi: 10.1016/j.cgh.2023.02.005. Epub 2023 Feb 19.
Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.
原发性胆汁性胆管炎（PBC）是一种典型的自身免疫性疾病。慢性淋巴细胞性胆管炎与界面肝炎、胆管减少、胆汁淤积和进行性胆管纤维化有关。患有 PBC 的人经常出现症状，生活质量受到疲劳、瘙痒、腹痛和干燥综合征等因素的影响。尽管女性患病率较高、特定的血清自身抗体、免疫介导的细胞损伤以及遗传（HLA 和非 HLA）危险因素将 PBC 确定为自身免疫性疾病，但迄今为止，治疗重点一直放在胆汁淤积的后果上。胆管上皮细胞的稳态异常并导致疾病发生。胆管细胞衰老、凋亡和碳酸氢盐分泌受损会加剧慢性炎症和胆汁酸潴留。一线治疗是非特异性的胆汁淤积药物，熊去氧胆酸。对于那些仍有生化性胆汁淤积的患者，引入了奥贝胆酸，这种半合成法尼醇 X 受体激动剂具有利胆、抗纤维化和抗炎作用。未来 PBC 的许可治疗可能包括过氧化物酶体增殖物激活受体（PPAR）途径激动剂，包括特定的 PPAR-δ激动剂（seladelpar），以及 elafibrinor 和 saroglitazar（均具有更广泛的 PPAR 激动作用）。这些药物与非标签使用 bezafibrate 和 fenofibrate 的临床和试验经验一致。症状管理至关重要，令人鼓舞的是，PPAR 激动剂可减轻瘙痒；IBAT 抑制（例如，linerixibat）似乎对瘙痒也有希望。对于那些以肝纤维化为目标的患者，NOX 抑制正在评估中。正在开发的早期阶段治疗包括针对患者免疫调节的治疗，以及治疗瘙痒的其他方法（例如，MrgprX4 拮抗剂）。总的来说，PBC 的治疗前景令人兴奋。治疗目标越来越具有前瞻性和个体化，旨在迅速实现正常的血清测试和生活质量，并预防终末期肝病。
