OVERVIEW
因胆道阻塞、胆汁淤积引起的肝硬化
主要表现为疲乏、皮肤瘙痒等症状，少数患者可能会伴有肝脾肿大
可能与自身免疫、胆汁排泄障碍等因素有关
根据病情采取药物、手术治疗等方案
Definition of Biliary Cirrhosis
Biliary cirrhosis is a cirrhosis of the liver caused by a variety of causes that result in obstruction of the bile ducts and the accumulation of bile that cannot be excreted smoothly.
Half of the patients are asymptomatic at the time of diagnosis, and those who are symptomatic mainly present with symptoms such as itching of the skin, fatigue, poor appetite, jaundice, and ascites.
Staging and Classification
According to the etiology of the occurrence of biliary cirrhosis, it can be divided into primary biliary cirrhosis and secondary biliary cirrhosis.
Primary biliary cirrhosis: It is caused by chronic progressive non-suppurative inflammation of the small bile ducts in the liver, and is generally considered to be an autoimmune disease. It is often accompanied by other autoimmune diseases, such as dry syndrome, systemic lupus erythematosus and rheumatoid arthritis.
Secondary biliary cirrhosis: the disease occurs on the basis of other diseases. It is more common in clinic and mostly develops due to long-term obstruction of the biliary system leading to impaired bile excretion.
Morbidity
Biliary cirrhosis occurs more often in women, mainly in women aged 40-60 years [6].
The prevalence of primary biliary cirrhosis in China is (19-402) cases per 1 million people [6].
Causes
Causes
Biliary cirrhosis can be caused by immunologic factors, obstruction of the biliary system, and other factors. The common causes of biliary cirrhosis in general are as follows.
Immunologic factors
It may be mainly related to the development of primary biliary cirrhosis. The exact cause of the disease is unknown, but it may be related to autoimmune reaction.
The body’s immune response can lead to bile duct damage, causing obstruction of bile discharge, resulting in bile retention in the liver and eventually developing into cirrhosis.
Obstruction of the biliary system
It is mainly related to the development of secondary biliary cirrhosis.
Various diseases cause obstruction of the bile ducts, resulting in bile not being excreted and stagnating in the liver. The stagnant bile constantly stimulates and damages the liver cells, causing chronic inflammation, extensive fibrosis, nodular hyperplasia and other changes in the liver, leading to cirrhosis.
Common diseases such as recurrent biliary tract infections, bile duct stones, choledochal cysts, pancreatic head carcinoma, bile duct carcinoma, parasitic diseases, Vater’s jugular carcinoma and so on.
Childhood patients are mostly due to congenital atresia of the extrahepatic bile ducts, and biliary cirrhosis is usually caused by complete occlusion of the biliary system for more than 6 months.
Risk factors
The following conditions are prone to cause biliary cirrhosis.
Patients with immune system diseases: such as dry syndrome, systemic lupus erythematosus, rheumatoid arthritis, etc., may damage the bile ducts due to immune reaction, causing biliary stasis and leading to biliary cirrhosis.
Middle-aged and elderly women: relevant statistics show that middle-aged and elderly women between 40 and 60 years old are more likely to develop primary biliary cirrhosis [1].
Symptoms
Main Symptoms
Itchy skin
Patients with biliary cirrhosis will have itchy skin in the early stage, the symptoms are mild during the day, and the itchy feeling is more obvious at night, which may affect the patient’s sleep.
Fatigue
In the early stage, patients with biliary cirrhosis may feel a little bit weak all over the body, get tired easily, and gradually develop a lack of interest in social activities and a lack of concentration.
Jaundice
Patients with biliary cirrhosis may have jaundice in the jaundice stage, which mainly manifests as yellowing of mucous membranes, skin and sclera (white of the eyes).
Ascites
Patients with biliary cirrhosis in the terminal stage may have obvious ascites, hepatosplenomegaly, which is mainly manifested as abdominal distension, and there may be a sense of turbulence when touched by hand.
Other symptoms
Some patients may have poor appetite, dyspepsia, diarrhea, bleeding from the gums and nasal cavity, edema of the lower limbs, vomiting blood or blood in the stool.
Complications
Biliary cirrhosis may lead to the following complications:
Osteoporosis
The prevalence of osteoporosis in patients with primary biliary cirrhosis is 20-45%, and its incidence is higher in liver transplanted, postmenopausal patients.
Fat-soluble vitamin deficiency
Vitamin D deficiency is common in patients with biliary cirrhosis, and levels of vitamins A, E, and K are also decreased.
Hypercholesterolemia
Hypercholesterolemia in patients with biliary cirrhosis is associated with increased lipoproteins and decreased functional LDL receptors.
It may be manifested by the appearance of yellow plaques on the eyelids, neck and other areas.
Steatorrhea
Patients with advanced biliary cirrhosis may have steatorrhea due to decreased bile acid secretion, which interferes with lipid absorption.
Patients may exhibit diarrhea, passing greasy or foamy stools with foul odor, and weight loss.
Other immune diseases
Dry syndrome is the most common, and may be accompanied by systemic lupus erythematosus, scleroderma, Raynaud’s phenomenon, capillary dilatation, rheumatoid arthritis and so on.
Consultation
Department of Medicine
Gastroenterology
Patients with symptoms such as fatigue, jaundice, poor appetite and itchy skin may consult the Department of Gastroenterology.
Hepatobiliary Surgery
Patients with symptoms such as fatigue, jaundice, right upper abdominal pain, or with bile duct stones may consult the Department of Hepatobiliary Surgery or the Department of General Surgery.
Preparation for medical treatment
Preparing for your visit: registering, preparing your documents, and frequently asked questions.
Tips
Avoid excessive scratching of the skin to avoid infection.
Wear loose-fitting and easy-to-remove clothing to facilitate blood sampling and other related tests.
Preparation Checklist
症状清单
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Are there any symptoms such as itching of the skin, fatigue, etc.?
Are there any symptoms such as vomiting blood, increased abdominal circumference, abdominal pain, diarrhea, etc.?
How long have these symptoms been present?
Under what circumstances are these symptoms aggravated or relieved?
病史清单
Are there any bile duct stones, pancreatic head cancer, or choledochal cysts?
Are there any abnormalities of the biliary tract or liver on physical examination of the newborn, or is there congenital biliary atresia?
Any previous diseases such as dry syndrome, rheumatoid arthritis, systemic lupus erythematosus?
检查清单
Test results in the last six months, which can be brought to the doctor’s office
Laboratory tests: biochemical, immunologic tests, etc.
Imaging tests: abdominal ultrasound, CT, MRI
用药清单
Medication in the last 3 months, if available in boxes or packages, bring with you to the doctor’s office
Ursodeoxycholic acid, azathioprine.
Diagnosis
Diagnosis is based on
medical history
The following diseases may be present:
History of bile duct stones, choledochal cysts, pancreatic head carcinoma, bile duct carcinoma, parasitic diseases, Vater’s jugular carcinoma.
Dry syndrome, systemic lupus erythematosus, rheumatoid arthritis, etc.
Children with pre-existing congenital biliary atresia.
Clinical manifestations
症状
Symptoms such as skin itching, malaise, jaundice and ascites are present.
Some patients may present with poor appetite, dyspepsia, diarrhea, bleeding from the gums and nasal cavity, edema of the lower extremities, vomiting blood or blood in the stool.
体征
Yellow staining and hyperpigmentation of the skin, and some patients may have localized skin breakage and bleeding due to scratching.
Hepatosplenomegaly, ascites, lower extremity edema in advanced patients, and positive mobile turbidity on percussion.
Laboratory tests
生化检查
Liver injury can be determined.
Serum alkaline phosphatase (ALP) and/or glutamyl transpeptidase (GGT) concentrations are markedly elevated and may be accompanied by mild to moderate elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
A progressive increase in serum bilirubin with disease progression often suggests a poor prognosis.
免疫学检查
The anti-mitochondrial antibody AMA is a specific marker for primary biliary cirrhosis [7].
Antinuclear antibody ANA is also a more common marker.
其他
Virology: viral infections can be excluded and need to be checked for hepatitis virus, herpes virus and cytomegalovirus infections.
Lipid tests: mainly cholesterol and phospholipids are elevated.
Imaging examination
腹部超声检查
It can initially determine whether there is extrahepatic bile duct obstruction or not, which is valuable for the diagnosis of the disease.
Primary biliary cirrhosis ultrasonography shows thickening of liver parenchyma echogenicity, streak-like or nodular changes, dilatation of bile ducts, biliary stasis.
Secondary biliary cirrhosis can usually find bile duct stones, cysts, tumor-like changes.
磁共振胆胰管成像（MRCP）
It can understand the morphology and structure of the liver, bile and pancreas and their internal stones, tumors, obstruction and dilatation.
MRCP can show the image of the whole biliary system, such as primary sclerosing cirrhosis image shows generalized or limited narrowing of the bile ducts, which is obvious at the bifurcation of the hepatic ducts, with fewer and stiffer thinning of the bile ducts’ branches, or segmental narrowing.
腹部CT
It is able to show the cause and location of biliary obstruction and can detect areas of bile duct dilatation and stone formation.
The examination can rule out extrahepatic bile duct obstruction, pancreatic head cancer, bile duct cancer, parasitosis, and Vater’s jugular cancer.
Endoscopy
内镜下逆行胰胆管造影（ERCP）
It can observe the structure of the bile ducts and rule out other biliary pathologies.
ERCP examination of biliary cirrhosis reveals dilatation or narrowing of small bile ducts, bile duct stenosis, enlarged gallbladder, and cholestasis in the hepatic lobules.
Liver biopsy
Used in cases where the diagnosis is uncertain; or to determine the stage of the disease and provide prognostic information.
Differential Diagnosis
Chronic active hepatitis
Similarities: both may present with symptoms such as malaise, jaundice, abdominal distension, and gastrointestinal bleeding, and both may show liver damage on laboratory tests.
Differences:
胆汁性肝硬化则可出现典型症状皮肤瘙痒，且白天症状比较轻，晚上瘙痒的感觉比较明显。
慢性活动性肝炎一般实验室检查可出现病毒学检查阳性，胆管检查无明显异常。
Primary sclerosing cholangitis
Similarities: both may present with malaise, itching of the skin, and jaundice.
Points of difference:
胆汁性肝硬化主要为肝小叶内小胆管的破坏，血清标志物AMA阳性，MRCP或ERCP检查提示肝内小胆管扩张或狭窄。
原发性硬化性胆管炎主要为大胆管炎性狭窄，血清标志物AMA为阴性，MRCP或ERCP检查显示肝内大胆管狭窄、闭塞，无肝外胆道梗阻。
Treatment
Treatment aim: control the development of the disease, improve the patient’s symptoms, prolong the survival time.
Treatment principle: drug treatment is the mainstay and surgical treatment is supplementary to achieve relief of patient-related symptoms and reduce the occurrence of complications.
Drug treatment
Ursodeoxycholic acid
It is suitable for patients with primary biliary cirrhosis [8-9].
It can reduce serum bilirubin, transaminase, serum alkaline phosphatase, and cholesterol.
Some patients may experience gastrointestinal symptoms such as diarrhea, neurological symptoms such as dizziness and headache, or adverse reactions such as skin itching and muscle aches.
D-Penicillamine
It is indicated for biliary cirrhosis caused by autoimmune diseases.
It can reduce intrahepatic copper level, inhibit inflammatory reaction, reduce fibrosis and prolong survival time.
Some patients may experience adverse reactions such as rash, proteinuria, thrombocytopenia or granulocytopenia. It is contraindicated in renal insufficiency and pregnant women.
Immunosuppressant
For patients with biliary cirrhosis due to autoimmune disease.
Common drugs include cyclosporin A, methotrexate, azathioprine and so on.
Cyclosporin A can significantly reduce serum alkaline phosphatase; methotrexate can improve histologic changes; azathioprine can improve bile duct excretion and reduce pruritus.
Some patients taking methotrexate can cause nausea, vomiting, bone marrow suppression, renal damage and other side effects; cyclosporine A should not be used for a long time because of hepatorenal toxicity; azathioprine can have serious bone marrow suppression when high dose and overdose.
Glucocorticoid
Glucocorticoids can effectively improve the liver biochemical indexes and histologic changes in patients with primary biliary cirrhosis.
Frequently available drugs include budesonide and prednisolone [10].
Endoscopic treatment
Surgery is now rarely used with the development of endoscopy.
ERCP treatment is only applicable to obvious stenosis of extrahepatic bile ducts and bold intrahepatic ducts, which can reduce symptoms such as skin itching and cholangitis, as well as provide early diagnosis of cholangiocarcinoma and improve survival.
For the main site of bile duct stenosis clearly identified by imaging, cytologic and histologic examination should be performed by ERCP to exclude the diagnosis of cholangiocarcinoma, and balloon dilatation should be applied to dilate the main stenosis site.
Routine stent placement is usually not required after dilatation, but for severe stenosis, stents can be placed for a short period of time for transition.
Liver transplantation
It is indicated for patients with end-stage cirrhosis [11].
Patients who cannot tolerate anesthesia for surgery and have other infections in the abdominal cavity cannot complete the procedure, and postoperative care should be taken to prevent complications such as thrombosis, bile duct obstruction, and rejection.
Symptomatic treatment
Itching: Kaolinamide, paracetamol, etc. can be used.
Osteoporosis: intramuscular injection of vitamin D can be used.
Night blindness: oral vitamin A can be used.
Coagulation disorders: vitamin K1 can be used.
Prognosis
Cure
In patients with biliary cirrhosis, the appearance of related symptoms, if not treated in time, may cause patients to further aggravate the burden on the liver or cause multi-systemic lesions, such as: liver cancer, hepatic encephalopathy, hepatorenal syndrome.
After active treatment, the prognosis of biliary cirrhosis patients is generally good, which can improve the symptoms of patients, slow down the development of the disease, reduce the occurrence of complications, and most of the early patients can have a normal life expectancy.
Daily
Daily Management
Dietary management
Reasonable dietary arrangements, pay attention to low-fat, low-salt, high-protein diet, not sudden overeating, prefer light.
Intake of fresh vegetables, especially green leafy vegetables, can be increased to meet the body’s need for vitamins and promote repair.
Avoid spicy and stimulating foods, such as coffee and strong tea, so as not to aggravate skin itching.
Prohibit drinking alcohol, which will aggravate the degree of liver function damage.
Life management
Appropriate daily exercise to improve immunity and prevent infectious diseases.
Combine work and rest, avoid exertion and pay attention to rest.
Daily life needs to pay attention to adjusting the psychological state.
Minimize the use of unnecessary drugs to aggravate the burden on the liver.
Follow-up and review
Patients receiving medication should follow the doctor’s instructions to use the medication in full dosage and course, and do not stop taking the medication without authorization, so as not to affect the efficacy of the medication.
If symptoms such as itching, fatigue and jaundice are not relieved during the treatment period, it is necessary to consult a doctor in time.
Prevention
There is no specific preventive measure for this disease. Early detection and treatment can effectively delay the progression of the disease. The following high-risk groups should be screened regularly.
Children with congenital biliary atresia.
People with liver and gallbladder diseases.
People with autoimmune diseases.
First-degree female relatives of patients with primary biliary cirrhosis over 30 years of age.
参考文献
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王辰，王建安. 内科学：下册[M]. 3版. 北京：人民卫生出版社，2015.
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GranitoA, MuratoriP, QuarnetiC, et al. Antinuclear antibodies as ancillary markers in primary biliary cirrhosis[J]. Expert Rev Mol Diagn, 2012, 12(1): 65-74.
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HarmsMH, van BuurenHR, CorpechotC, et al. Ursodeoxycholic acid therapy and iver transplant-free survival in patients with primary biliary cholangitis[J]. J Hepatol, 2019, 71(2): 357-365.
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Montano-LozaAJ, HansenBE, CorpechotC, et al. Factors associated with recurrence of primary biliary cholangitis after liver transplantation and effects on graft and patient survival[J]. Gastroenterology, 2019, 156(1): 96-107.e1.