Primary Biliary Cirrhosis (PBC) is an autoimmune disease characterized primarily by nonsuppurative progressive injury to small and medium-sized bile ducts in the liver. The clinical manifestations of PBC have been recognized for 150 years, but it was only after the discovery of the specific marker of the disease, anti-mitochondrial antibody (AMA), in 1965 that the diagnosis of PBC began to be widely performed clinically; it is no longer recommended to perform liver histological examination on every patient for purely diagnostic purposes. The titer of AMA does not correlate with the severity of the disease, and the role of AMA in the development of PBC is not clear. PBC is characterized by abnormal immune response to normal bile duct epithelial cells or normal immune response to abnormal bile duct epithelial cells. The same epithelial damage also occurs in the salivary gland and possibly the pancreatic epithelium, and the clinical symptoms of the so-called “dry syndrome” appear. The incidence of PBC in women over 40 years of age has been found to be about 1 in 600 in epidemiological surveys in Europe and the United States, and its incidence has increased significantly in the last 20 years, probably due to the early detection of early cases and the increased life expectancy of patients. The incidence of PBC varies significantly by region, with the highest rates in northern England and North America. The disease was previously thought to be rare in China, but in recent years, as people’s understanding of the disease has deepened, it has been found that patients with PBC are not uncommon in China, and a review of the domestic literature shows that before 2000, there were only case reports of PBC in China. In 2005, more than 40 articles were reported, and the number of reported cases exceeded 5000. Anti-mitochondrial antibody testing has been routinely performed in our hospital since 2001, and an average of 1-2 new cases of PBC have been detected each week, and more than 300 cases of PBC have been detected so far. The clinical manifestations of PBC lack specificity and are therefore easily misdiagnosed. Some units have reported an initial misdiagnosis rate of 60-90%, with most misdiagnosed as viral hepatitis (untyped) or non-A-non-E hepatitis, and some misdiagnosed as drug-related hepatitis, fatty liver, gallstone disease, etc. Most of the misdiagnosed cases have been misdiagnosed for a long period of time, reaching several years or even more than a decade. Most of the misdiagnosed cases are treated inappropriately, and some treatments aggravate liver damage and accelerate the progression of the disease. PBC is an immune-mediated disease, but immunotherapy is not effective. Moreover, experimental treatment in patients with PBC is difficult to accomplish, as most cases are early and asymptomatic. No good alternative markers have been found for long-term follow-up of the disease. If the disease progresses to liver failure, liver transplantation is the only effective method. But this is a “fuzzy” endpoint for any study. The treatment of PBC also includes the management and prevention of hepatic and extrahepatic complications arising from the disease. Only when we truly understand the pathogenesis of the disease can we hope to find a specific targeted therapy. 1. Historical review of PBC The first authors in the literature to describe a disease that may be the same as the present PBC were Addison and Gull, who reported a patient with the disease in 1851 while treating a case of cutaneous yellow tumor at Guys Hospital. 1875 Hanot recognized cholestasis as the essence of the disease, so some scholars later called it Hanot ‘s cirrhosis or yellow tumor-like cirrhosis because of the association of this cholestatic liver disease with yellow tumors of the skin. The name primary biliary cirrhosis was established in 1949, when it was intended to be distinguished from secondary cirrhosis caused by extrahepatic bold duct obstruction. 1950 Ahrens et al. described in detail the clinical manifestations of primary biliary cirrhosis, which was considered a rare disease at the time, with no more than 100 cases reported worldwide before 1950. Because it was originally named a form of cirrhosis, this name is often misunderstood and many patients are diagnosed with PBC when they do not actually have true cirrhosis, a name that can cause psychological discomfort. Attempts have also been made to use other different nomenclature, such as chronic nonsuppurative granulomatous intrahepatic biliary disease, which was ultimately not universally accepted. Therefore, PBC is still used as the name of this disease until now. 2. Description of the initial clinical manifestations of PBC In 1959 Sheila Sherlock described 42 cases of PBC that she personally followed from 1944 to 1959. 20 cases presented with pruritus of the skin, even before the appearance of significant jaundice 11 years earlier. However, in 14 cases, the jaundice was followed by pruritus. A few cases presented with hepatomegaly but no complaints (probably the earliest description of asymptomatic PBC). At that time, there was no effective way to differentiate between intrahepatic and extrahepatic bile duct obstruction, and no patient in this group presented with fever or abdominal pain. The color of the stool was more variable, mostly normal and rarely white stools. Because ultrasound was not available at the time, the diagnosis was often established after surgical biliary exploration or liver biopsy. only 5 of the 42 patients were diagnosed without surgical exploration. Yellow tumor skin changes were very common in the cases reported by Sherlock. 16 of the 42 cases presented with yellow tumors, some of which were flat, others with nodular deposits on the medial canthal surface of the eyelids, and also on the wrists, buttocks, knees, and ankles, but never on the tendon sheaths. Not all of these patients were due to cholesterol deposition in the skin caused by hypercholesterolemia. A study of 15 autopsy patients revealed that vascular atherosclerosis was not uncommon in these cases. She reported a significant correlation between the degree of hyperbilirubinemia and the percentage of dietary fat absorption. X-rays of the spine and ribs showed vertebral degeneration and rib fractures in some cases. In some patients, the patient’s bone mass thinned even after exogenous VitD supplementation, so patients with PBC often have a combination of osteoporosis. Sixteen of the 42 patients had gastrointestinal bleeding, 9 due to peptic ulcers and only 7 due to esophageal varices. Routine portal vein pressure measurement by trans-splenial intravenous leads to bleeding complications. Determination of hepatic arteriovenous wedge pressure prior to the formation of cirrhosis resulted in patients developing portal hypertension prior to the formation of cirrhosis. The concept of “perisinusoidal portal hypertension” exhibited by patients with PBC has not been fully accepted to date. Hepatic failure, the main cause of death in these 42 cases, is also a late manifestation of the disease and does not occur within the first 4 years. In advanced liver failure, serum cholesterol may drop, skin yellow tumors may disappear, and serum ALP may return to normal levels. 3.Discovery of specific diagnostic test for PBC In 1965 Walker et al. established a milestone discovery in the history of PBC research. They discovered a specific granulosa-like cytoplasmic fluorescence stain, and when they tested with double-layer fluorescence in embedded and unembedded frozen sections of thyroid and human gastric mucosal tissues, the test was positive in all 32 cases of suspected PBC, while 21 cases with common bile duct obstruction, 5 cases of drug-related cholestasis, 4 cases of cholestatic viral hepatitis, and 3 cases of chronic cholestasis with ulcerative colitis all showed negative results. Since ultrasound, retrograde cholangiopancreatography, CT scan and MRI were not available at that time, serum test was the most important diagnostic reagent at that time. Later researchers discovered specific mitochondrial antigens, and anti-mitochondrial antibodies (AMA) in serum could be detected by ELISA and immunostaining techniques. Although these new methods have high specificity and sensitivity, immunofluorescence testing is still one of the most valuable tests. 4. Hepatic histological description of PBC The manifestation of hepatic histological changes associated with PBC was first described by Rubin et al. in 1965, and further summarized by Schemer in 1967 into four phases: (1) red bile duct injury phase (2) bile duct proliferation phase (3) fibrous septum formation phase (4) cirrhosis phase. Although there were different modifications later, these four stages have been adopted. It is now known that those patients with positive serum AMA as the only manifestation have typical pathological changes in their liver tissues. 5. natural history of PBC Early on, due to the limitation of testing conditions, asymptomatic PBC was not recognized. since the discovery of AMA and the promotion of the application of routine screening of liver biochemistry, true early asymptomatic PBC and subclinical PBC were only recognized. Asymptomatic PBC cases now outnumber symptomatic PBC. asymptomatic PBC is usually found in the elderly population and many patients remain asymptomatic, with nearly 50% of these patients dying from non-hepatic factors. Therefore, at this time, physicians cannot and should not speculate on when a patient with a confirmed PBC will die from liver failure. 6.Diseases associated with PBC With the recognition of AMA as a marker of PBC, it was found that the positive rate of this serum marker in the relatives of patients was significantly higher than that of the normal population, and thus the family risk of PBC was proposed. Moreover, the age of the 1st generation of PBC relatives with the disease is young, so relatively young patients should be investigated for the presence of the disease in their immediate family members. PBC is significantly associated with several other diseases, and therefore these diseases have a common pathogenetic basis, such as PBC combined with Heshinoto’s thyroiditis, which is caused by abnormal immune function. Genetic genetic polymorphisms are associated with many factors such as control of antigen processing and cytokine production in relation to the disease. Nevertheless, so far, any related studies have not been reported. Currently, with the Human Genome Project, it is believed that genetic results of PBC patients may be available in the near future. 7. PBC and environmental factors In 1972, Douglas and Pinlayson reported that a mother and a neighbor who cared for a patient with a definite diagnosis of PBC developed PBC one after another, and the results of this phenomenon suggested for the first time that environmental and genetic factors play a role in the development of PBC. Shortly after this report, David Trigger also found a relatively high incidence of PBC in residents around a particular reservoir. A similar report came from the Hiroshima area of Japan, suggesting that exposure to atomic bombs may be a risk factor for PBC. A recent report from the northeast of England shows a clustering of PBC. In two reports, one from the United Kingdom, all cases and age- and sex-matched controls were selected in a region of northeast England from 1993 to 1995 and were asked to complete a self-administered postal questionnaire that included medical history and lifestyle components, and information was collected on 100 patients and 223 controls. A familial predisposition to PBC was found to be less pronounced than previously thought: only weak associations with other autoimmune diseases, no associations with previously thought factors such as surgery, pregnancy, past infections, vaccinations and medications, and no associations with lifestyle factors not previously considered (alcohol consumption, pet ownership or stressful events) were found, but surprisingly an association with a history of smoking was found (ever smoked: 76% in the case 76% of cases and 57% of controls, odds ratio 2.4; smoking for 20 years or more: 64% of cases and 35% of controls, odds ratio 3.5), as well as significant associations with psoriasis (13% of cases and 3% of controls, odds ratio 4.6) and eczema (3% of cases and 11% of controls, odds ratio 0.13), findings that could be useful for further investigation. Recent experimental studies suggest that exogenous organisms can induce alterations in endogenous PDC-E2 protein (AMA substrate), making it possible to detect AMA in serum tests, suggesting infection as a pathogenetic factor. There are several reports in the literature involving several different infections, the most frequent being bacterial, closely related to PBC. The liver responds to infection or xenobiotics by the presence of sarcoid or eosinophilia, and these are very common in the histological changes of PBC liver. 8. Treatment of PBC Since the stimulating antigens in the pathogenesis of PBC have not been identified, the treatment for the disease is non-specific. Treatment is mainly directed at some specific symptoms related to chronic cholestatic liver disease, such as treatment for pruritus and prevention of long-term complications of osteoporosis. Specific treatment aims to prevent further progression of liver disease, including immunosuppression, antifibrosis and cholestasis, but effective treatment for PBC that meets these requirements is lacking, partly due to the great difficulty in guiding therapeutic trials for the disease. The disease is still clinically rare (1994 its factor 14.1/106), so large multicenter studies are needed to obtain a sufficient number of people. Since the main observation should be death or the need for liver transplantation, the duration of clinical trials in early asymptomatic cases needs to be very long. To replace this, several prognostic risk factor scores have been developed in patients with PBC, but they are only applicable to symptomatic patients. There are no good criteria to test the efficacy and survival of early cases. Perhaps in the future molecular indicators of liver disease prognosis will become alternative indicators in the future. Once disease co-activators are identified, the development of targeted therapies will increase the effectiveness of treatment. In the meantime, researchers need to establish: how to distinguish the early asymptomatic population of presenting patients, those who are more prone to progress to decompensated liver disease.