原发性胆汁性肝硬化的治疗

本病属自身免疫性疾病 ,主要治疗策略在于调节机体免疫机能。熊去氧胆酸是目前唯一被认为具有肯定疗效的药物 ,长程应用可延缓肝组织学进展。●　皮质类固醇在疾病早期应用 ,可能有效 ,但需注意骨病加剧等不良反应。硫唑嘌呤、环孢素、苯丁酸氮芥等的疗效尚待进一步评价。●　青霉胺、马洛替酯、秋水仙碱对本病的疗效未得到证实。抗纤维化治疗以应用“活血化瘀”中药为宜。●　由于本病病程甚长 ,对症治疗甚为重要。瘙痒主要采用消胆胺 ;骨营养不良主要由于维生素D和钙吸收不良 ,应予补充。●　肝移植可消除免疫性破坏的靶目标 ,为最后治疗措施 ,适用于进展型病例     

Treatment of primary biliary cirrhosis.

Although primary biliary cirrhosis (PBC) is generally a progressive disease, the rate of progression varies greatly from one patient to another. The terminal phase is characterized by hyperbilirubinaemia (>100 micromol/l), a major decrease in the number of intrahepatic bile ducts, and extensive fibrosis or cirrhosis. It is now well established that orthotopic liver transplantation is the treatment of choice for patients entering the terminal phase of the disease.A variety of therapeutic agents have been proposed for treatment of patients with PBC. However, most have been found ineffective or too toxic to be widely used. In contrast, there is accumulating evidence from large therapeutic trials that long-term administration of ursodeoxycholic acid (UDCA) is safe and prolongs survival free of liver transplantation. Treatment with UDCA slows the histological progression and delays the onset of cirrhosis.In patients who have a sub-optimal response to UDCA therapy alone, the combination of colchicine or methotrexate with UDCA has minimal or no additional benefit, whereas that with corticosteroids is more promising but not yet demonstrated.Among causes of non-response to UDCA therapy, the most common is the PBC-autoimmune hepatitis overlap syndrome. The benefit from the combination of corticosteroids and UDCA in this setting is obvious.Further studies are needed to define the patients who are most likely to respond to UDCA therapy and to assess the benefit of combined medical treatments.     

Review: Treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic disease of the liver thought to be caused by immune destruction of the interlobular bile ducts. One-third of patients are asymptomatic and one-third of these develop symptoms within 5 years. Therapeutic regimens should be directed at the control of symptoms, prevention of complications and specific therapy aimed at controlling progression of the disease. Symptoms may be secondary to cholestasis or due to other associated diseases. The cause of pruritus secondary to cholestasis remains unknown; the anion exchange resin cholestyramine generally brings relief. In patients resistant or intolerant to this therapy, rifampin may be helpful, as well as ultraviolet light without sunblock. Liver transplantation may rarely be the only option for uncontrollable pruritus. Clinical manifestations of keratoconjunctivitis sicca and xerostomia need constant attention to prevent corneal ulcers and dental caries. Preventative therapy includes regular screening for thyroid dysfunction and replacement therapy when necessary and the administration of the fat soluble vitamins A, D and K once hyperbilirubinaemia is present. Osteoporosis is a complication of all cholestatic liver disease. There is no satisfactory preventative therapy. It may be appropriate to give hormone replacement therapy to all post-menopausal women with PBC to reduce osteoporosis. Liver transplantation is the best option for those with fractures. Oesophageal varices may develop early in the course of PBC, non-selective beta-blocker therapy should be used as prophylaxis against variceal haemorrhage. The only specific therapy shown to cause both a biochemical and survival benefit in patients with PBC is ursodeoxycholic acid (UDCA). Treatment with UDCA delays progression, but does not result in a cure of this disease. Currently, liver transplantation is the only definitive treatment available for end-stage disease.     

Treatment of primary biliary cirrhosis with ursodeoxycholic acid

This study was undertaken to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis (PBC). Three patients with PBC (stage II) have been treated with UDCA (Ursofalk and Falk Pharma, Freiburg, Germany)--of 10 mg/kg daily dosage in the course of three years. Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography and liver biopsy. Liver chemistries were determined every three months. A control liver biopsy was performed to one of the patient, an year after the beginning of the treatment. UDCA was well tolerated and showed no side effects. The most obvious benefit of UDCA was its favourable effect on serum biochemistries. Its use was associated with the delayed progression of the disease.     

Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis

Opinion statement Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients’ well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.     

Treatment of pruritus of primary biliary cirrhosis with rifampin

Pruritus can be a debilitating symptom in patients with chronic cholestasis. Based on previous reports of its efficacy, we evaluated the impact of rifampin on the pruritus associated with primary biliary cirrhosis. Fourteen patients were included in a randomized, crossover study. After a 15-day washout period, subjects were followed for three weeks. During the first and third week, patients received 600 mg of rifampin or placebo; no treatment was administered during the second week. Pruritus was subjectively scored on a scale from 0 to 100. With rifampin, pruritus disappeared in 11 patients and partially improved in three; with placebo, only two had a partial response (P<0.001). Six patients with a prior poor or no response to cholestyramine improved with rifampin. No changes in biochemical tests or side effects were observed during this period. We conclude that short-term administration of rifampin relieves pruritus in primary biliary cirrhosis. When administered over a period of eight months in an open study, the relief of pruritus was maintained, while one individual developed an allergic reaction. Rifampin appears to be a safe drug in the management of the pruritus of primary biliary cirrhosis.     

Treatment of primary biliary cirrhosis with low-dose weekly methotrexate

Nine women with symptomatic precirrhotic primary biliary cirrhosis have been treated with oral pulse methotrexate, 15 mg/wk, for 12-34 months. Three women had pruritus, two fatigue, and four pruritus and fatigue. Itching disappeared and fatigue lessened or disappeared in all within 4-11 months after starting methotrexate. All who itched were able to discontinue cholestyramine (five) or antihistamines (two). Biochemical tests of liver function improved in all patients and then worsened in three when methotrexate was discontinued or the dose lowered. Mean serum alkaline phosphatase decreased from 471 to 171 U/L (P less than 0.01), serum bilirubin from 0.99 to 0.59 mg/dL (P less than 0.05), and serum alanine aminotransferase from 132 to 61 U/L (P = 0.02), and serum cholesterol fell from 265 to 213 mg/dL (NS). The decrease in serum cholesterol was significant, P = 0.05, if data were used just from the six women whose baseline serum cholesterol levels were elevated. Serum albumin remained normal in all. The serum bilirubin levels became normal in three of four patients with elevated levels. The serum alkaline phosphatase levels became normal in four patients and the alanine aminotransferase levels in three. Liver histology improved in five patients and was stable in the remaining four based on a quantitative evaluation of coded liver biopsy specimens. The improvement in histology was primarily due to decreased portal inflammation and bile duct injury. The titer of antimitochondrial antibody decreased in seven patients. The data suggest that methotrexate may be effective treatment for precirrhotic primary biliary cirrhosis. Controlled trials are needed to evaluate long-term efficacy and toxicity.     

Pediatric-onset primary biliary cirrhosis

Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has not been reported in childhood. We report 2 cases of PBC diagnosed at 16 and 15 years of age, respectively. The first girl was noted to have increased liver enzyme levels at 16 years of age. Antimitochondrial antibody (AMA) was strongly positive, and serum quantitative immunoglobulin M level was 8.26 g/L (normal, 0.6-3 g/L). A liver biopsy specimen showed stage II PBC. Despite treatment with ursodeoxycholic acid, she developed progressive cholestasis, intractable pruritus, and a significant sensory neuropathy and weight loss eventually requiring liver transplantation. Her mother had PBC/autoimmune overlap syndrome and underwent successful liver transplantation at 34 years of age. The second girl had persistently elevated liver enzyme levels following cholecystectomy at 15 years of age for symptomatic cholelithiasis. Endoscopic retrograde cholangiopancreatography showed no abnormalities. AMA was positive at 1:160, and serum quantitative immunoglobulin was 6.96 g/L. A liver biopsy specimen showed stage II PBC, and her liver enzyme levels almost normalized after starting treatment with ursodeoxycholic acid. In conclusion, we present 2 liver biopsy-confirmed cases of pediatric-onset AMA-positive PBC. With increased awareness of early-onset PBC, further pediatric cases may be discovered.     

Asymptomatic primary biliary cirrhosis

Four asymptomatic patients are described with raised serum alkaline phosphatase values and a positive serum mitochondrial antibody test. In all four needle liver biopsy showed destructive bile duct lesions. Lymphocyte transformation to phytohaemagglutinin was normal in three and impaired in one who also suffered from rheumatoid arthritis. Two patients showed normal skin and serological test responses to dinitrochlorobenzene and haemocyanin.These four patients are believed to be suffering from asymptomatic primary biliary cirrhosis.     

Management of primary biliary cirrhosis

Opinion statement Primary biliary cirrhosis is a chronic, progressive disease for which there is no definitive treatment. Ursodeoxycholic acid, however, is of benefit for delaying progression to irreversible end-stage liver disease and prolonging survival free of transplantation. It is, therefore, the standard medical therapy for primary biliary cirrhosis. Orthotopic liver transplantation can be offered for patients with end-stage disease. Other important endpoints of treatment in this condition include management of the long-term complications of cholestasis such as pruritus, osteoporosis, and fat-soluble vitamin deficiencies. Pruritus is best treated with cholestyramine; rifampicin, antihistaminics, opioid-antagonists, and ondansetron can also be tried. Osteoporosis should be treated with calcium and vitamin D supplementation. Bisphosphonates or vitamin K2 may be of additional benefit to decrease the risk of fractures, but this is unproved as of yet. Deficiencies of vitamins A, D, E, and K should be treated with appropriate replacement. Finally, orthotopic liver transplant is indicated for cases of liver failure, intractable pruritus, or severe osteoporosis.     

Immunology of primary biliary cirrhosis

(1) The serological diagnosis of PBC is possible in almost 100% of cases when appropriate methods and specific antigen preparations are used such as the purified ATPase fraction by ELISA for the detection of anti-M2, sonicated mitochondria by immunodiffusion for the demonstration of precipitating antibodies against M-A or M-B, and cell cultures by immunofluorescence for the detection of antibodies against nuclear dots. (2) The establishment of AMA profiles obtained by ELISA and CFT seems to be a sensitive approach to a better definition of the natural course of PBC. A distinction between a rather benign and a more progressive course seems especially possible in the presence of the AMA profiles A and B (anti-M9 and/or anti-M2-positive only by ELISA) versus D (anti-M2-, anti-M4-, anti-M8-positive in the CFT). (3) The analysis of cellular immune reactions in vitro and in vivo suggests an activation of cytotoxic T cells as well as a defect in the function of T suppressor cells. (4) Although the aetiology of PBC is unknown, the detection of MHC Class II antigens on bile duct epithelial cells in liver biopsies of patients with PBC but not of normal individuals may imply that an infectious agent being exposed in association with these MHC structures may trigger the disease. The inability of the immune system in controlling this infectious process would then lead to an ongoing inflammatory reaction which is responsible for the continuous destruction of bile ducts within portal triads.     

Pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis is an enigmatic autoimmune disease that predominantly affects women. The serologic signatures of PBC are high titer antimitochondrial antibodies that are directed at the inner lipoyl domains of the 2-oxo-dehydrogenase enzymes, particularly PDC-E2. Of note, is that the antibody response and the CD4 and CD8 response, are all directed at a similar epitope, the inner lipoyl domain. This unique immunologic response suggests that modification of the inner lipoyl domain is associated with the immunogenetic basis of disease.     

Immunopathogenesis of primary biliary cirrhosis

Although the autoantigens of antimitochondrial antibodies (AMA) have been defined and epitope mapped for both autoreactive B and T cells, the pathogenesis of primary biliary cirrhosis (PBC) still remains a mystery. The data gathered so far address several important aspects of this intriguing puzzle. First, biliary epithelial cells (BECs) seem to be immunologically active because they express molecules such as major histocompatibility complex (MHC) antigens, and adhesion and costimulatory molecules. Second, although pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen in PBC, is upregulated in BECs when examined immunohistochemically, this abnormal staining seems to be secondary to immune complexes of AMA bound to PDC-E2 present in the BECs. Third, in addition to CD4(+) T cells, CD8(+) T cells also recognize the inner lipoyl domain of PDC-E2. Fourth, modification of mitochondrial antigens by xenobiotics may lead to the induction of the disease. These findings help to clarify the pathogenic mechanism of PBC and suggest that (l) induction may be secondary to a primary response to a xenobiotic that is normally metabolized in an estrogen-dependent pathway and (2) pathology is mediated by and orchestrated by a highly directed and specific CD4, CD8 and autoantibody response to the lipoyl domain of the mitochondrial autoantigens, with tissue destruction based on the immunoglobulin A (IgA) receptor, apoptosis, and the mucosal organization of biliary and salivary duct cells.     

Pathogenesis of primary biliary cirrhosis

Autoimmune phenomena have been recognized in primary biliary cirrhosis (PBC) for more than 50 years and the specificity of the characteristic responses directed at highly conserved mitochondrial antigens determined in detail over the past 20. Effecter autoreactive immune responses are characterized and potential mechanisms of breakdown of tolerance to self proposed. Elements of the clinical pattern of PBC, including the recurrence of the disease across HLA boundaries after liver transplantation, remain difficult to reconcile with a simple autoimmune model. Alternative (but not necessary mutually exclusive) pathogenetic models have been outlined, including a potential role for retroviral pathogens and directly cytopathic effects.