Primary sclerosing cholangitis

　　The causes of primary biliary cholangitis include infection factors, enterotoxin absorption factors, genetic factors, immune factors, and cholangiostenic factors. The specific introduction is as follows:

　　1. Infection factors

　　The etiology of primary biliary cholangitis has not been elucidated, and infection is one of the earlier views. It is common for primary biliary cholangitis to be accompanied by inflammatory bowel disease (IBD), with a general incidence of about 70%, among which ulcerative colitis (UC) is the most common, followed by Crohn's disease. It is believed that bacteria and their toxins pass through the inflamed intestinal wall via the portal vein to the pericholangial area, leading to disease.

　　2. Factors of enterotoxin absorption

　　As mentioned above, primary biliary cholangitis (PBC) and inflammatory bowel disease (IBD) are closely related, and IBD as a potential pathogenic factor has long been of concern. It is speculated that the increased permeability of the inflammatory intestinal mucosal barrier leads to increased absorption of bacterial endotoxins and toxic bile acids, activating Kupffer cells within the liver to produce more tumor necrosis factor (TNF), resulting in bile duct destruction and hyperplasia similar to the pathological changes of primary biliary cholangitis. In animal studies, many drugs such as antibiotics, antibodies against bacterial cell wall components, and TNF inhibitors can block the pathological changes of primary biliary cholangitis in experimental animals. Regarding the inconsistency in the incidence, onset time, severity of the disease, and the timing of primary biliary cholangitis, such as 25% of patients with primary biliary cholangitis have normal colons, primary biliary cholangitis occurs before colonic disease, and there is no effect on the course of primary biliary cholangitis after colonic resection, recent scholars have proposed that some lymphocytes involved in immune reactions have memory function, become quiescent after early activation, and initiate disease occurrence upon subsequent stimulation. Although this view can explain some contradictory phenomena between the two, there is no direct evidence to prove that IBD is a direct cause of primary biliary cholangitis. The most reasonable explanation is the difference in pathophysiological responses of two different organs to a common etiology.

　　3. Genetic Factors

　　The fact that primary biliary cholangitis often occurs in family members and is closely related to HLA suggests the important role of genetic factors in the pathogenesis of primary biliary cholangitis. There are many HLA alleles associated with primary biliary cholangitis, which may play different roles in the occurrence and development of primary biliary cholangitis. HLA-B8 is seen in 60%-80% of patients with primary biliary cholangitis, and HLA-DRB1 and DRw52a may determine the genetic susceptibility of primary biliary cholangitis, while the presence of DR4 is a sign of rapid deterioration of the disease. There are reports that primary biliary cholangitis is associated with the polymorphism of TNF-α receptor gene, and the base G at position 308 of the TNF-α gene is replaced by A, which is significantly associated with the susceptibility to primary biliary cholangitis. The polymorphism of matrix metalloproteinase (MMP-3) may affect the susceptibility and the progression of the disease. Another study shows that the base of MICA-002 can significantly reduce the risk of developing primary biliary cholangitis, while MICA-008 can increase the risk. All these facts suggest that the occurrence and development of primary biliary cholangitis have an inherent genetic basis.

　　4. Immune Factors

　　Currently, more emphasis is placed on the immune mechanism. In cell-mediated immunity, it is found that the inflammatory cells infiltrating around the porta hepatis and the bile ducts are mainly T lymphocytes. Most of the porta hepatis are T lymphocyte subtypes CD4 with immune辅助inductive function, while the bile ducts are mainly composed of another subtype CD8 cells with inhibitory immune and cytotoxicity. The bile duct epithelium of normal people is expressed by HLA-Ⅰ antigens. Research has found that the bile duct epithelium of patients with primary biliary cholangitis is expressed by HLA-Ⅱ antigens - DR. However, in some patients with primary biliary cirrhosis and extrahepatic bile duct obstruction caused by various reasons, the same abnormal findings are also found in the bile duct epithelium, and the relationship between the HLA-DR granules in the bile duct epithelium and the pathogenesis of primary biliary cholangitis is still unclear. Evidence of humoral immunity is mostly non-specific: various immunoglobulins in the blood of patients with primary biliary cholangitis are elevated to varying degrees; positive for anti-nuclear factor and anti-smooth muscle antibody; the level of immune complexes in blood and bile is increased and clearance is impaired; and anti-neutrophil cytoplasmic antibodies are often found. Some studies have found that a peptide substance located only on the extrahepatic bile duct epithelium and colonic epithelium is positive in about 2/3 of the serum tests in 16 cases of primary biliary cholangitis, while tests in other liver diseases and secondary extrahepatic bile duct stenosis are all negative. The pathophysiological effect of this substance is not yet clear.

　　5. Factors of Biliary Ischemia

　　Biliary ischemia can cause ischemic necrosis, leading to biliary fibrosis and sclerosis, and the imaging and histopathological changes of cholestasis and primary biliary cholangitis. It often occurs after interventional chemotherapy, liver transplantation, and cholecystectomy. In a strict sense, cholangitis caused by biliary ischemia does not belong to the category of primary biliary cholangitis. Although various pathogenic factors may play a role in the pathogenesis of primary biliary cholangitis, one or more factors may play a major role at different stages.

　　Follow-up of primary biliary cholangitis patients for 5 to 10 years found that 50% of patients may have chronic liver disease, portal hypertension, ascites, portosystemic encephalopathy, bone metabolic disorders, diarrhea, steatorrhea, deficiency of fat-soluble vitamins, and liver failure, and a series of consequences caused by liver function damage will appear as the condition progresses. The characteristic complications of primary biliary cholangitis are bacteremia, cholelithiasis, and biliary tract carcinoma.

　　1, Bacteremia

　　It can occur repeatedly and may be secondary to chronic biliary tract infection or hematogenous bacterial spread. The frequency and severity of bacteremia in PSC patients are difficult to estimate and may lead to liver abscess or infection in other organs (such as heart valves).

　　2, Cholelithiasis

　　About 1/3 of PSC patients have a history of cholecystectomy at some stage of the disease process, of which about 20% are asymptomatic gallstones. The ultrasound examination results of PSC patients show that 25% have gallstones. Since most PSC patients are young males, this indicates an increased incidence of cholelithiasis in PSC. Biliary calculi can also occur in PSC, but since cholangitis may occur in PSC patients without biliary calculi, diagnosis is more difficult. Direct bile duct造影 should be performed for suspected cases to confirm it. Some recurrent cholangitis is caused by bile duct calculi, and the progression of PSC can be slowed down by treating and clearing bile duct calculi to eliminate attacks.

　　3, Biliary tract carcinoma

　　Autopsy reports of primary biliary cholangitis show that 50% develop biliary tract carcinoma on the basis of PSC pathology. Patients with primary biliary cholangitis complicated with biliary tract carcinoma usually have liver cirrhosis, portal hypertension, and long-standing ulcerative colitis (UC), usually older in age and with progressive changes in bile duct angiography, such as bile duct cystic dilatation, suggesting that biliary tract carcinoma occurs in primary biliary cholangitis. If the bilirubin level of a primary biliary cholangitis patient rises from 85.5μmol/L (5mg/dl) to 171μmol/L (10mg/dl) within a short period of time, malignancy should be considered, but it needs to be confirmed by biopsy or surgery. However, the Mayo Clinic recently performed liver transplantation on 60 PSC patients, and only one had papillary dysplasia of the common bile duct and right and left hepatic ducts (considered to be a possible non-invasive papillary dysplasia), and no bile duct dysplasia or biliary tract carcinoma was found, so the incidence of biliary tract carcinoma in PSC may not be high, and it is generally considered to be 10% to 15%.

　　The onset of primary biliary cholangitis is often obscure, with no obvious prodromal symptoms or specific symptoms at the beginning. It is often discovered accidentally with jaundice that progresses, and patients often have little or no gray-white stools. Clinically, it is often misdiagnosed as 'acute infectious hepatitis'. With the progression of jaundice, there may be skin itching. If there is biliary tract infection, there may be upper right quadrant abdominal pain, fever, and chills. As the condition progresses, with the prolongation of jaundice time, patients may develop liver and spleen enlargement. In the later stage, due to liver function failure, ascites, oliguria, and hepatic encephalopathy may occur.

　　Primary biliary cholangitis, according to clinical symptoms, is divided into two types: asymptomatic and symptomatic.

　　1. Asymptomatic: The patient has no obvious symptoms, often in the early stage or early stage of the disease. Although the imaging examination is consistent with the manifestation of cholangitis, the patient has no jaundice.

　　2. With symptoms:It is divided into mild and severe cases. Mild patients have discomfort, fatigue, anorexia, weight loss, abdominal pain, fever, jaundice, and skin itching, without symptoms and signs of portal hypertension. Severe patients have obvious jaundice, enlargement of the liver and spleen, ascites, encephalopathy, or esophageal variceal bleeding, etc., which are symptoms of advanced liver cirrhosis.

　　Primary biliary cholangitis is a chronic cholestasis disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts, leading to multifocal bile duct stenosis. For patients diagnosed with primary biliary cholangitis without inflammatory bowel disease, full colonoscopy and biopsy should be performed; for patients with colitis who have been diagnosed with primary biliary cholangitis, full colonoscopy and biopsy should be performed annually or every 1-2 years depending on individual circumstances. Abdominal ultrasound should be performed once a year to detect gallbladder abnormalities in a timely manner.

　　There are currently no biochemical markers or imaging methods recommended for the early detection of bile duct cancer. If there are clinical indications, ERCP-assisted cell brushing and/or biopsy can be performed.

　　Primary biliary cholangitis is a cholestasis syndrome characterized by the gradual narrowing of the intrahepatic and extrahepatic bile ducts due to fibrotic inflammation, accompanied by the symptoms of primary biliary cholangitis. This disease requires the following laboratory tests:

　　1. Cholangiography examination

　　It is the most persuasive method for determining the diagnosis and extent of PSC, including ERCP, PTC, intraoperative cholangiography, and retrograde cholangiography through T-tube, among which ERCP is the most advantageous. It not only can ideally display the morphological changes of intrahepatic and extrahepatic bile ducts but also show pancreatic duct lesions, etc. The detailed information of intrahepatic bile ducts can only be obtained when the catheter used during ERCP is further inserted above the cystic duct. For this purpose, it is often necessary to apply balloon occlusion technology for assistance. PTC has a success rate of only half, and is mostly used for those who have failed ERCP or have undergone biliary-enteric anastomosis after bile duct surgery. Intraoperative cholangiography and retrograde cholangiography through T-tube are suitable for assisting in diagnosis during or after surgical treatment. The cholangiographic features of PSC are as follows:

　　① The bile duct at the site of the lesion presents irregular multiple stenoses, while the bile duct mucosal surface is smooth.

　　② The narrowed lesions can be localized or diffuse, or even segmental changes.

　　③ The proximal part of the narrowed bile duct is slightly expanded.

　　④ When the lesions involve intrahepatic bile ducts, there is a reduction in intrahepatic bile duct branches, stiffening and thinning resembling dead branches or bead-like, with hemispherical expansion and an internal diameter of 2-3mm.

　　About 80% of the cases are affected by both intrahepatic and extrahepatic bile ducts, 20% only involve extrahepatic bile ducts, with a CBD diameter less than 4mm, significantly thickened walls, and no signs of gallbladder stones or tumors in the biliary system. When the gallbladder is involved, the gallbladder wall becomes thick, function is reduced or disappears. When intrahepatic or extrahepatic bile duct stenosis is confirmed by cholangiography, and there is no evidence to prove non-PSC, the diagnosis of PSC can be established. Therefore, the typical radiological changes are confirmed to be the gold standard for PSC diagnosis.

　　2. B-ultrasonography examination

　　Since endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography are invasive examination methods, B-ultrasound technology has become a non-invasive alternative method for diagnosing PSC. Although ultrasound itself cannot diagnose PSC or exclude PSC, it can be of great help in screening suspected PSC patients for further injurious examinations and in differential diagnosis. The typical B-ultrasound imaging is:

　　① The bile duct lumen is significantly narrowed, usually uniform and consistent, generally 4mm, and in segmental or localized PSC, there may be dilated bile ducts;

　　② The bile duct wall is significantly thickened, generally 4-5mm;

　　③ The echo of intrahepatic bile ducts is enhanced;

　　④ Involvement of the gallbladder can be seen with wall thickening and reduced function;

　　⑤ Ultrasound images show no stones or tumors; it is very important to learn to recognize the manifestations of PSC in ultrasound. The accurate judgment of the above ultrasound images depends on the clinical experience of the ultrasonic physician.

　　3. Magnetic Resonance Cholangiography (MRC)

　　Cholangiography technology is helpful in the diagnosis of PSC. The mild expansion of peripheral bile ducts not connected to the central bile duct in several liver lobes is a PSC MRI sign, but due to the limited spatial resolution of MRC, it is difficult to find minor degrees of bile duct stenosis and expansion like ERCP or PTC, reducing its role in revealing bile duct stenosis.

　　4. 99mTc-DISIDA scan

　　The use of 99mTc-labeled diisopropyl iminodiacetic acid for cholangiography is a non-invasive examination for suspected PSC patients. After intravenous injection, continuous gamma imaging is performed, because of the delayed liver parenchymal clearance, it is used to determine the obstruction of different branches of the main bile duct, showing the expansion of intrahepatic bile ducts and the narrowing of intrahepatic and extrahepatic bile ducts, but its low resolution is a disadvantage.

　　5. CT

　　It can show the expansion and deformation of intrahepatic bile ducts in PSC patients, if CT shows irregular branching or focal expansion of the bile duct tree, it suggests the possibility of PSC.

　　6. Liver histological examination

　　Most PSC patients can see histological abnormalities in liver biopsies, common histological abnormalities include: peripheral bile duct fibrosis and inflammation, edema and fibrosis, focal proliferation of bile ducts and small ducts (ductules), focal bile duct obstruction and atresia, copper deposition and bile stasis. The typical manifestation is peripheral bile duct concentric fibrosis, with or without hyperplasia of the portal bile ducts, but these changes are only visible in wedge biopsies, and are rarely seen during fine needle aspiration.

　　Primary biliary cholangitis is a chronic and relatively rare biliary tract disease. The disease is characterized by extensive fibrosis of both intrahepatic and extrahepatic bile ducts, with明显 thickened walls and significantly narrowed lumens. In terms of diet, it is important to avoid the following foods:

　　1. Try to reduce the intake of fats, especially animal fats, do not eat fatty meat and fried foods, and as much as possible, replace animal oil with vegetable oil.

　　2. A considerable number of cholecystitis and gallstone formation are indeed related to excessively high cholesterol levels and metabolic disorders in the body, therefore, it is necessary to limit the intake of high-cholesterol foods such as caviar, yolks of various eggs, and the livers, kidneys, hearts, and brains of various carnivorous animals.

　　3. It is best to cook food by steaming, boiling, stewing, and braising, and avoid eating a large amount of fried, baked, roasted, smoked, or preserved food.

　　4. Increase the intake of fish, lean meat, dairy products, fresh vegetables, and fruits that are rich in high-quality protein and carbohydrates to ensure heat supply and promote the formation of glycogen, protecting the liver.

　　5. Eat more tomatoes, corn, carrots, and other foods rich in vitamin A to maintain the integrity of gallbladder epithelial cells and prevent the shedding of epithelial cells to form the core of stones, thereby triggering stones or causing stones to increase in size and quantity.

　　6. If conditions permit, drink more fresh vegetable or melon juice, such as watermelon juice, orange juice, carrot juice, etc., and increase the frequency and quantity of drinking water and eating, to increase the secretion and excretion of bile, and reduce inflammation and bile stasis.

　　7. Eat less cabbage, celery, and other foods rich in fiber to avoid increased peristalsis of the gastrointestinal tract due to difficulty in digestion, which may trigger biliary colic.

　　8. Quit smoking and drinking and reduce the intake of spicy and irritating foods and strong seasonings, such as mustard oil, to avoid stimulating the gastrointestinal tract and triggering or aggravating the condition.

　　9. It is advisable to consume light, easy-to-digest, low-fiber, temperature-appropriate, non-irritating, low-fat liquid or semi-liquid food. It is absolutely not advisable to eat and drink freely for a moment of pleasure, as this may cause unnecessary trouble and even trigger biliary bleeding, which may be life-threatening.

　　Primary biliary cholangitis can be divided into diffuse type, local type, segmental type, etc., and the treatment methods are different. The specific introduction is as follows:

　　(1) Diffuse type, bile duct lumen

　　(2) For local and segmental types, with extrahepatic bile duct >4mm and severe jaundice, surgical treatment can be performed.

　　(3) For those with complete obstruction of the bile duct or long-term obstructive jaundice, leading to poor liver function and the appearance of ascites and edema, non-surgical treatment can be performed first. If the effect is not significant, surgery can be performed to explore, but the prognosis is poor.

　　(4) After surgery, a combination of traditional Chinese and Western medicine can be used for treatment to consolidate the efficacy.

　　(5) With the development of treatment endoscopy, its application in the treatment of primary biliary cholangitis is becoming more and more extensive.