cholestasis

by



OVERVIEW

各种原因引起胆汁排泄障碍，分为肝内胆汁淤积和肝外胆汁淤积
主要表现有黄疸、皮肤瘙痒、疲劳等
发病与药物、酒精、病毒、胆管结石、胰腺肿瘤等因素有关
根据病情采取病因治疗、对症治疗（如药物治疗、产科处理等）

Definition

  • Cholestasis is a pathologic condition in which bile formation, secretion, and excretion are impaired for a variety of reasons both inside and outside the liver, resulting in bile failing to flow into the duodenum and entering the bloodstream.
  • It is related to various factors such as drugs, alcohol, bile duct stones, etc. The main clinical manifestations are yellowing of the skin and sclera and itching of the skin.

    • Classification

    According to the anatomical site of the onset of the disease, it can be divided into intrahepatic cholestasis and extrahepatic cholestasis.

  • Intrahepatic cholestasis: cholestasis is caused by hepatocellular dysfunction or lesions or obstruction of capillary bile ducts, fine bile ducts (<15 μm, also known as intercalary ducts) and interlobular bile ducts (15-100 μm).
  • Extrahepatic cholestasis: Cholestasis is caused by lesions or obstruction of the septal bile ducts (>100 μm), regional bile ducts (300-400 μm), segmental bile ducts (400-800 μm), right and left hepatic ducts, and the common bile ducts up to the jugular area.

    • Causes

    Causes

    Causes of intrahepatic cholestasis

  • Drugs, alcohol, viral, bacterial, and immunologic factors, as well as endocrine and metabolic load factors in late pregnancy and multiple pregnancies, can cause abnormal bile secretion and excretion, leading to intrahepatic cholestasis.
  • Idiopathic adult intrahepatic bile duct deficiency, tuberculosis, and idiopathic amyloidosis can cause interlobular bile duct lesions or obstruction, leading to intrahepatic cholestasis.

    • Causes extrahepatic cholestasis

    Bile duct stones, carcinoma of the pancreas, bile ducts and jugular abdomen, and benign bile duct stenosis can cause extrahepatic bile duct lesions or obstruction, leading to extrahepatic cholestasis.

    Symptoms

    Main Symptoms

    Jaundice

  • Jaundice is the most important clinical manifestation of cholestasis, and the severity of jaundice varies according to the different causes of the disease, the severity of the disease and the duration of the disease.
  • It is characterized by yellow staining of the skin and sclera.

    • Itching

  • This is the main feature of cholestasis.
  • Sometimes it appears before jaundice or after the symptoms of jaundice. Itching can be present in most patients.
  • The degree of itching varies and tends to be persistent, mild during the day and worse at night. It usually begins on the palms of the hands and feet and gradually extends to the proximal extremities and even to the face.
  • Itchy areas will appear skin scratches, which can reflect the degree of the patient suffering from itching, and can be spread all over the body where the hands can grasp.

    • Yellow Tumor

  • Lipid deposits in the skin form yellow tumors, which occur in relation to blood lipid levels.
  • They are found in the inner canthus of the eye or the crease of the palm of the hand, as well as on the wrist, elbow, ankle, arm, and perineum, and usually appear as multiple nodular elevations.
  • Cholestasis resolves or in advanced stages of liver failure, when lipid and cholesterol synthesis decreases and the yellow tumor shrinks or even disappears.

    • Fatigue

  • Fatigue is often present in patients with cholestasis and can be present in most patients with chronic cholestasis.
  • Fatigue can manifest as a lack of ability to function normally and a decline in mental and physical function.

    • Lipid metabolism disorders

  • Patients with cholestasis often have lipid disorders due to elevated bile acids that inhibit cholesterol metabolism.
  • Both cholesterol and triglycerides may be elevated in patients.

    • Lipodystrophy

  • Cholestasis results in a lack of adequate bile salts in the intestine, causing impaired digestion and absorption of fatty foods and fat-soluble vitamins (A, D, E, and K).
  • Steatorrhea is proportional to the depth of jaundice and is usually characterized by large, loose, oily stools that are grayish-white and have an unpleasant odor.

    • Other symptoms

  • Patients may have no uncomfortable symptoms in the early stage, and some patients have non-specific symptoms such as poor appetite, nausea and epigastric discomfort.
  • Some symptoms of the primary disease, such as abdominal pain, chills, fever, etc., may occur.

    • Complications

    Hepatic osteodystrophy

  • Bone disease is a complication of chronic liver disease and occurs by the mechanism of osteoporosis and osteochondrosis.
  • Bone pain and fractures may occur.

    • Fat-soluble vitamin deficiency

  • Fat-soluble vitamin deficiencies can occur when bile secretion from the liver to the small intestine is impaired by cholestasis, and bile salts in the intestines are reduced.
  • Vitamin A deficiency can cause night blindness. Vitamin E deficiency manifests as muscle weakness, dizziness, and lower limb edema.

    • Consultation

    Department of Medicine

    Gastroenterology

    When yellowing of the skin and sclera and itching of the skin occur, it is recommended to consult a doctor promptly.

    Obstetrics

    If itching, jaundice, or skin scratching occurs during pregnancy, it is recommended to consult a doctor promptly.

    Preparation for medical treatment

    Preparation for consultation: registration, preparation of documents, FAQs

    Tips for seeking medical treatment

  • Try to keep a record of symptoms, duration, and information about previous treatment for liver and gallbladder diseases and obstetrics and gynecology diseases, so that you can give your doctor more information.
  • Take photos of abnormal skin symptoms, such as skin color changes and scratches.

    • Preparation checklist for medical consultation

    症状清单

    Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.

  • Is there any itching of the skin?
  • Is there fatigue, poor appetite, abdominal discomfort?
  • Are there any oily, grayish-white stools?
  • How long have these symptoms lasted?
  • Under what circumstances do the above symptoms worsen or subside?
    • 病史清单
  • Are there any liver or gallbladder diseases such as bile duct stones?
  • Does the woman of childbearing age have a history of multiple pregnancies?
    • 检查清单

    Test results in the last six months to bring to the doctor

  • Laboratory tests: blood routine, blood biochemistry.
  • Imaging tests: abdominal ultrasound, abdominal CT, magnetic resonance pancreaticobiliary reconstruction
  • Endoscopy: endoscopic retrograde cholangiopancreatography.
    • 用药清单

    Medication in the last 3 months, if available, bring the box or package with you to the doctor’s office

  • Bile acid-lowering medications: ursodeoxycholic acid, S-adenosylmethionine.
  • Drugs of the beta class: Fenofibrate, Benzafibrate.
  • Drugs for itching: calamine.

    • Diagnosis

    Diagnosis is based on

    Medical history

  • Female in advanced stages of pregnancy, or history of multiple pregnancies.
  • May have hepatic, biliary, or pancreatic disease.

    • Clinical manifestations

    症状
  • Patients may present with symptoms of jaundice with yellow-green or dark yellow skin, itching with scratching, multiple nodular elevations, and fatigue.
  • A small number of pregnant women with intrahepatic cholestasis in pregnancy may experience epigastric discomfort, nausea and vomiting, lack of appetite, abdominal pain, and mild steatorrhea, but the symptoms are usually unremarkable or mild, and the mental status is good.
    • 体征
  • If the disease progresses to cirrhosis, there may be hepatosplenomegaly and abdominal distension.
  • In case of extrahepatic bile duct obstruction, an enlarged gallbladder or tumor mass may be palpated in the upper abdomen.

    • Laboratory tests

    血常规
  • Changes in blood cells (red blood cells, white blood cells, platelets) and hemoglobin may be seen.
  • Mild to moderate anemia may be seen in longer term disease.
    • 血生化
  • Reflects characteristic manifestations of cholestasis.
  • Elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) are the most characteristic early manifestations of cholestasis. Cholestatic liver disease is diagnosed if ALP exceeds 1.5 times the upper limit of normal and GGT exceeds 3 times the upper limit of normal.
  • Bile acids are more sensitive than bilirubin for the diagnosis of impaired bile production, but less sensitive than ALP for most cholestasis. Fasting serum total bile acids ≥10µmol/l are diagnostic of intrahepatic cholestasis in pregnancy.
  • Cholestasis can cause elevated bilirubin, with predominantly elevated direct bilirubin.
    • 其他
  • Virology: Viral infections should be excluded from the diagnosis of intrahepatic cholestasis in pregnancy, and hepatitis virus, herpes virus and cytomegalovirus infections should be examined.
  • Lipid test: mainly cholesterol and phospholipids are increased.

    • Imaging examination

    腹部超声
  • Ultrasound can determine the nature of jaundice and the location of biliary obstruction based on the presence or absence of bile duct dilatation, the location and degree of dilatation.
  • Intrahepatic bile ducts >4mm in diameter and extrahepatic bile ducts >10mm in diameter suggest bile duct dilatation; dilatation of the common bile duct and above suggests obstruction of the lower end of the common bile duct or the jugular area.
    • 腹部CT
  • It can show the cause and site of bile duct obstruction, and can detect the site of bile duct dilatation and stones.
  • The examination can rule out extrahepatic bile duct obstruction and gallbladder cancer.
    • 磁共振胰胆管造影（MRCP）
  • It can understand the morphology and structure of liver, bile and pancreas and their internal stones, tumors, obstruction and dilatation.
  • MRCP can show the image of the whole biliary system. For example, the image of primary sclerosing cholangitis shows generalized or limited narrowing of the bile ducts, which is obvious at the bifurcation of the hepatic ducts, with fewer and stiffer and thinner bile duct branches, or segmental narrowing.

    • Endoscopy

    内镜逆行胰胆管造影（ERCP）
  • ERCP directly observes the bile duct morphology.
  • In the case of cholestasis, the negative image of stones in the bile ducts, bile duct stenosis and proximal bile duct dilatation can be observed, or the biliary tree can be incompletely displayed, a certain part of the bile ducts does not appear, and the left and right bile ducts are asymmetrically shadowed.

    • Pathologic examination

  • The basic pathologic changes of intrahepatic cholestasis show intrahepatocellular bile siltation, feathery degeneration of hepatocytes, accompanied by dilatation of capillary bile ducts and bile plug formation. In severe cases, the dilated capillary bile ducts containing bile plugs are the center, and the hepatocytes are arranged in the form of adenoidal vesicles, forming bile wreaths.
  • The pathology of extrahepatic obstructive cholestasis is characterized by intrahepatic bile lakes with biliary granuloma formation around the portal area, and prolonged extrahepatic obstruction may cause secondary intrahepatic cholestasis. Later stages may cause fibrosis in the portal area and even biliary cirrhosis.

    • Genetic testing

  • Hereditary cholestatic liver disease is associated with genetic variations.
  • The mutated genes associated with hereditary cholestatic liver disease are JAG1, NOTCH2, SERPINA1, AMACR and so on.

    • Differential diagnosis

    Hereditary hyperbilirubinemia

  • Similarities: both present with yellowing of the skin and sclera.
  • Points of difference:
    • 遗传性高胆红素血症主要出现在青少年，黄疸可持续存在若干年，往往随年龄增长而逐渐减退。仅有胆红素代谢障碍，而胆汁其他成分正常。
    胆汁淤积症主要好发于妊娠期妇女以及有肝胆疾病的患者。胆汁淤积早期，黄疸并不一定会出现，只有碱性磷酸酶和γ-谷氨酰转移酶升高，而当胆红素超过34.2μmol/L时才显现黄疸。

    Hemolytic disorders

  • Similarities: both present with jaundice.
  • Point of difference:
    • 溶血性疾病如地中海贫血、阵发性睡眠性血红蛋白尿等发生溶血时，黄疸也会出现，但是肝酶却不升高。
    胆汁淤积症会出现肝酶如碱性磷酸酶和γ-谷氨酰转移酶升高。

    Treatment

  • Treatment aims: relieve cholestasis symptoms, improve liver function, prevent and reduce complications.
  • Treatment principle: The treatment of cholestasis mainly consists of removing the cause of the disease and symptomatic treatment. Specific methods need to be evaluated according to the cause of the patient’s disease, the severity of the disease, etc., and drug treatment or other treatments can be chosen.

    • Treatment of the cause of the disease

  • When caused by stones, tumors, etc., surgery, endoscopic removal of stones or surgical removal of tumors can be performed to relieve obstruction.
  • Drug-induced cholestasis requires timely discontinuation of the relevant drugs.
  • Alcoholic liver disease should quit drinking actively.
  • Viral hepatitis can be treated with appropriate antiviral therapy.
  • Autoimmune hepatitis can be relieved with glucocorticoids and/or immunosuppressants.
  • Metabolism-related steatohepatopathy requires lifestyle interventions such as diet and exercise.

    • Medication

    Bile acid-lowering drugs

  • Commonly used drugs include: ursodeoxycholic acid, S-adenosylmethionine.
  • Drug indications:
    • 熊去氧胆酸可用于治疗原发性胆汁性肝硬化、原发性硬化性胆管炎、妊娠期肝内胆汁淤积症、囊性纤维化、肝移植后淤胆、药物性胆汁淤积等。
    S-腺苷蛋氨酸可用于治疗肝细胞性胆汁淤积、妊娠期肝内胆汁淤积症和药物性胆汁淤积。
  • Action of the drug:
    • 熊去氧胆酸：具有亲水性、细胞保护作用，且无细胞毒性，可代替毒性胆汁酸，同时能促进肝细胞的分泌作用和免疫调节。
    S-腺苷蛋氨酸：作为转甲基作用和转硫基作用中的一部分，参与体内重要生化反应。
  • Precautions for the use of drugs: during the treatment period, according to the condition, check the liver function every 1~2 weeks to monitor the changes of biochemical indicators.

    • Beta drugs

  • Common drugs include: fenofibrate, benzofibrate.
  • Drug indications: hepatocellular cholestasis, intrahepatic cholestasis in pregnancy and drug-induced cholestasis.
  • Action of the drug: inhibits the synthesis of bile acids, increases the excretion of bile.
  • Precautions for use of the drug: possible gastrointestinal reactions such as bloating and diarrhea.

    • Drugs for itching

  • Common drugs include: kolestenamine.
  • Drug indication: cholestatic itching.
  • Action of the drug: reduce itching symptoms by reducing the reabsorption of bile acids.
  • Precautions for the use of the drug: note that it should be taken at intervals of 4~6h with other drugs to avoid affecting the absorption of other drugs.

    • Obstetric treatment

  • For severe intrahepatic cholestasis in pregnancy with early onset and long course, the expectation of treatment should not be too long.
  • In patients with mild intrahepatic cholestasis in pregnancy, termination of pregnancy is usually at 38-39 weeks of gestation; in patients with severe intrahepatic cholestasis in pregnancy, termination of pregnancy is usually at 34-37 weeks of gestation, but it needs to be evaluated in conjunction with the patient’s therapeutic effect, fetal status and the presence of other comorbidities.

    • Other treatments

  • For cholestasis mediated by immune mechanisms, glucocorticoids such as prednisone, and/or immunosuppressive agents such as cyclosporine may be used as appropriate; the application of ultraviolet irradiation, extracorporeal albumin dialysis, and nasobiliary drainage may also be considered.
  • Cholestatic liver disease patients by active internal medicine treatment is invalid, and 6 ~ 12 months may die, feasible liver transplantation treatment.
  • Traditional Chinese medicine (TCM), such as gardenia yellow and bitter yellow, have some therapeutic effects on cholestatic liver disease.
  • Novel drugs in development, including FGF19 analogs, norUDCA, Simtuzumab, Infliximab, and fecal transplantation, are expected to provide new therapeutic approaches for cholestatic liver disease in the future.

    • Prognosis

    Cure

  • If the cause of the disease can be removed and the clinical symptoms are controlled, the disease will improve more rapidly after treatment.
  • If the cause of the disease is not removed, the treatment is unsatisfactory.

    • Daily

    Daily management

    Dietary management

  • Diet should be low fat, high protein, light and easy to digest.
  • Reduce the intake of high cholesterol food.
  • Consume more fresh vegetables and fruits.

    • Life management

  • For pregnant women, pay attention to proper rest, and left lateral lying position mainly in late pregnancy to increase placental blood flow.
  • Keep the skin of itchy area clean and dry, avoid scratching and infection.
  • Change underwear frequently to increase comfort, and the itchy parts can be washed with warm water.
  • Live a regular life, pay attention to the combination of work and rest, and often participate in sports activities.

    • Psychological management

  • Listen carefully to the patient’s complaints, advise the patient to distract his/her energy according to his/her interests such as listening to music, reading books, watching TV, etc. Provide positive psychological support to reduce anxiety.
  • Maintain a positive and optimistic state of mind, avoid mental tension, anxiety and other bad emotions.

    • Prevention

  • People with high risk factors such as liver and gallbladder diseases and multiple pregnancies need to undergo regular medical checkups.
  • Eat a regular diet and avoid heavy alcohol consumption to prevent liver and gallbladder diseases.
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