bubble_chart Overview

Any intrahepatic or extrahepatic biliary tract disease caused by any reason that leads to bile stasis can develop into biliary cirrhosis. It is classified into primary biliary cirrhosis and secondary biliary cirrhosis.

bubble_chart Etiology

Biliary cirrhosis is divided into primary biliary cirrhosis (Primary Biliary Cirrhosis, PBC) and secondary biliary cirrhosis (Secondary Biliary Cirrhosis). The latter is caused by long-term obstruction of the extrahepatic bile ducts. PBC is generally considered an autoimmune disease, where activated lymphocytes attack the small and medium-sized bile ducts, leading to an inflammatory response. Histologically, it closely resembles the host's rejection of a graft, sharing many similarities with the rejection reaction in liver allograft transplantation. Clinically, the disease alternates between remission and exacerbation, often accompanied by other autoimmune disorders such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and chronic lymphocytic thyroiditis. Humoral immunity is significantly abnormal, with a positive anti-mitochondrial antibody rate of 90–100%. In 80% of patients, the antibody titer exceeds 1:80. Some researchers even use the presence of anti-mitochondrial antibodies as an inclusion criterion for PBC cases. Some patients also test positive for anti-nuclear antibodies, rheumatoid factor, thyroid antibodies, etc. These antibodies can form large immune complexes with their corresponding antigens, causing immune injury through the complement system.

bubble_chart Pathological Changes

The liver is enlarged, pale green in color, with a smooth surface or fine granular appearance, and a firm texture. Tissue injury follows a general process: infiltration of lymphocytes and plasma cells, deposition of IgM and immune complexes, which contribute to granuloma formation. Gallbladder reflux, bile duct injury, and periductal inflammation lead to bile duct destruction and small bile duct proliferation. Periportal inflammation and scarring result in septal formation, peripheral cholestasis, and deposition of copper and iron, further injuring hepatocytes. Fibrosis extends, ultimately leading to cirrhosis. Based on the progression of PBC, its pathological changes are divided into four stages.

**Initial stage (first stage)**: The cholangiolitis stage is characterized by chronic non-suppurative inflammation of the interlobular or septal bile ducts. Inflammatory cell infiltration is present in the bile duct lumen, wall, and surrounding areas, primarily lymphocytes and plasma cells. The portal area expands due to inflammatory cell infiltration and granulomatous changes, but hepatocytes and the limiting plate remain normal.

**Intermediate stage (second stage)**: The bile duct proliferation stage involves progressive destruction of bile ducts due to chronic inflammation, replaced by fibrous tissue. Most portal areas show a loss of interlobular bile ducts but exhibit atypical small bile duct proliferation. Granulomas may still be observed. Perilobular bile canaliculi are markedly dilated, containing concentrated bile plugs. Ruptured bile canaliculi form bile lakes, with surrounding hepatocytes showing swelling, loose cytoplasm, and a translucent网状 appearance, known as feathery degeneration.

**Late stage (third stage)**: The scarring stage features increased collagen in the portal areas with reduced inflammatory cells and bile ducts. Lymphoid follicles with germinal centers may occasionally be seen. Medium-sized portal areas show the most prominent fibrosis, while granulomas are uncommon. Fibrous septa extend from one portal area to another or into the hepatic lobules. Due to piecemeal necrosis, cholestasis, and deposition of iron and copper, hepatocyte injury occurs, blurring the limiting plate.

**Fourth stage (cirrhosis stage)**: Fibrous septa in the portal areas expand and interconnect, dividing hepatic lobules to form pseudolobules. Regenerative nodules are visible, typically presenting as micronodular cirrhosis, though incomplete septal cirrhosis may also occur. Necrosis is present in the center of pseudolobules.

bubble_chart Clinical Manifestations

90% of cases occur in women, particularly those aged 40–60, with a male-to-female ratio of 1:8. Reports indicate that about 10% of cases develop during pregnancy. The disease has an insidious onset and progresses slowly.

1. Early Stage

Symptoms include only grade I fatigue and intermittent cutaneous pruritus. Half of the patients exhibit hepatomegaly, while a quarter have splenomegaly. Elevated serum alkaline phosphatase and γ-GT are often the only positive findings. Nocturnal cutaneous pruritus, which worsens at night, is the first symptom in 47% of cases. A quarter of patients initially experience fatigue, which may lead to depression, followed by cutaneous pruritus. Jaundice as the first manifestation occurs in 13% of patients, often accompanied by hepatosplenomegaly, xanthomas, corneal arcus, palmar erythema, spider angiomas, and butterfly-shaped pigmented patches at scratch sites. The skin may become rough and thickened, possibly due to scratching and vitamin A deficiency.

2. Non-Jaundice Stage

A few patients may have serum cholesterol levels as high as 8 g/L. Nodular xanthomas may appear on the palms, metatarsus, chest, and back, or along the knees, elbows, buttock tendons, and nerve sheaths. Clubbing of the fingers and long bone periostitis may be accompanied by pain and tenderness.

3. Jaundice Stage

The appearance of clinical jaundice marks the beginning of the jaundice stage. Worsening jaundice indicates progression to an advanced stage, with a life expectancy of less than 2 years. This stage is often accompanied by osteoporosis, osteomalacia, vertebral compression, and even rib or long bone fractures, which are related to impaired vitamin D metabolism.

4. Terminal Stage

Serum bilirubin levels rise sharply, with significant hepatosplenomegaly, worsening cutaneous pruritus, and fatigue. Chronic liver disease manifestations intensify, with an increasing number of patients experiencing gastroesophageal variceal bleeding and ascites. Due to copper deposition, a few may develop corneal pigment rings. The lack of bile salts in the intestinal lumen leads to fat malabsorption, resulting in steatorrhea. Malabsorption of vitamins A, D, and K can cause night blindness, skin keratosis, skeletal changes, and coagulation disorders. Cholangiography shows normal large bile ducts but distorted small bile ducts. Ultimately, liver failure, variceal rupture, hepatic encephalopathy, ascites, edema, and profound jaundice mark the terminal stage.

Associated Diseases and Manifestations: Two-thirds of patients have connective tissue diseases, and autoimmune thyroiditis is also common. Other associations include scleroderma, calcinosis, Raynaud's phenomenon, and dry keratoconjunctivitis in 75% of cases. Asymptomatic bacteriuria occurs in 35%, along with hypertrophic osteoarthropathy. One-third have pigment gallstones, and membranous glomerulonephritis and renal tubular acidosis may also occur.

bubble_chart Auxiliary Examination

1. Laboratory Tests

(1) Increased blood bilirubin, predominantly direct bilirubin, with positive urinary bilirubin. Due to reduced bilirubin excretion from the gallbladder, both fecal urobilinogen and urinary urobilinogen are decreased.

(2) Elevated serum alkaline phosphatase. Alkaline phosphatase originates from the bile duct epithelium, and PBC may exhibit a significant increase in alkaline phosphatase even before clinical symptoms appear.

(3) Elevated blood lipids, particularly phospholipids and cholesterol, which are most pronounced. Triglycerides may be normal or show grade II elevation.

(4) Liver function tests: Increased serum bile acid concentration, prolonged prothrombin time, which can normalize after early vitamin K administration but cannot be corrected in advanced-stage liver failure. Serum albumin is normal in the early and intermediate [second] stages of the disease but decreases in the advanced stage; globulin increases, mainly due to elevated α₂, β, and γ globulins.

(5) Immunological tests: The positivity rate for anti-mitochondrial antibodies can reach 90–100%, serving as an important diagnostic reference. This antibody has a positivity rate of 10–25% in chronic active hepatitis, and a minority of cases of occult cirrhosis, systemic lupus erythematosus, and rheumatoid arthritis may also test positive. One-third of patients have anti-bile duct cell antibodies, a minority have anti-smooth muscle antibodies and anti-nuclear antibodies, and half test positive for rheumatoid factor. Serum IgM may be elevated.

The coexistence of anti-mitochondrial antibodies, alkaline phosphatase, and IgM is diagnostic for PBC.

2. Biliary Tract Imaging

Methods such as intravenous cholangiography, percutaneous transhepatic cholangiography, or endoscopic retrograde cholangiopancreatography may be used to exclude extrahepatic biliary obstruction.

3. Liver Biopsy

Pathological examination of biopsy samples has diagnostic value. However, if gallbladder stasis is severe or there is a bleeding tendency, caution is advised. If necessary, exploratory laparotomy and biopsy may be performed during seasonal epidemics.

bubble_chart Diagnosis

Diagnostic basis: ① Middle-aged or older women with obvious cutaneous pruritus, hepatomegaly, and xanthomas; ② Markedly elevated serum total cholesterol, mild to grade II elevation of serum bilirubin, increased alkaline phosphatase, and elevated bile acid concentration; ③ Elevated IgM, positive anti-mitochondrial antibodies with high titers. Obtaining histological evidence through biopsy would further aid in confirming the diagnosis.

bubble_chart Treatment Measures

1. Ursodeoxycholic Acid

Heathcote et al. treated 222 PBC patients with ursodeoxycholic acid (14 mg/kg daily) and found that it improved serum markers of cholestasis. Within 3 months, serum bilirubin levels significantly decreased, along with notable reductions in serum alkaline phosphatase, transaminases, cholesterol, and IgM. Some patients also showed improvement in liver histopathology.

2. D-Penicillamine

This drug reduces hepatic copper levels, suppresses inflammatory reactions, alleviates fibrosis, and prolongs patient survival. The initial dose is 0.125 g daily, increased by 0.125 g every 2 weeks until reaching a maintenance dose of 0.5 g daily, which should be continued long-term. Severe adverse effects include rash, proteinuria, and thrombocytopenia or granulocytopenia. Weekly urine protein tests are required, transitioning to monthly tests after 4 weeks. White blood cell counts should be monitored, and treatment may need to be discontinued if necessary.

3. Immunosuppressants

① Cyclosporine A has a significant effect on Ts but should not be used long-term due to hepatorenal toxicity. At a dose of 10 mg/kg daily, serum alkaline phosphatase levels markedly decrease after 8 weeks of treatment. ② Methotrexate, when used early at a low dose (15 mg daily, divided into 3 oral doses per week), can improve histological changes. ③ Azathioprine enhances biliary excretion and appears effective against cutaneous pruritus, but its side effects are significant, and it does not prevent hepatic failure. The dose is 2 mg/kg, requiring long-term administration.

4. Symptomatic Treatment

(1) For cutaneous pruritus, antihistamines such as promethazine, chlorpheniramine, or diphenhydramine can be used. Cholestyramine, 5–10 g daily, should be started at a low dose and adjusted to control pruritus. Aluminum hydroxide, 4–20 g daily, binds bile acids and is effective for hepatic pruritus.

(2) For osteoporosis and ossification, vitamin D (10,000–20,000 IU daily) can be administered intramuscularly. Calcium gluconate (15 mg/kg daily) diluted in glucose solution can be given intravenously once daily for 10 days per course, repeated every 2–3 months if needed.

(3) For nyctalopia, vitamin A (25,000–50,000 IU daily) is recommended. If serum zinc is below normal, zinc sulfate (220 mg daily) can be taken orally for 4 weeks until dark adaptation normalizes.

(4) For coagulation disorders, vitamin K1 (10 mg daily) is used. ₁ , 10 mg daily.

(5) Liver transplantation is indicated for end-stage PBC patients.

(6) Dietary recommendations include a low-fat diet (less than 50 g daily), high in carbohydrates and protein, with plenty of vegetables.

(7) Treatment for esophageal and gastric variceal bleeding or hepatic encephalopathy follows the same protocols as for cirrhosis.

bubble_chart Prognosis

Associated with serum total bilirubin, albumin, age, prothrombin time, and the degree of edema, in 1989, Dickson et al. developed the Mayo score based on these five indicators.

R=X₁β₁+X₂β₂+…X_Kβ_K

X₁=ln serum total bilirubin (mg/dL), X₂=ln serum albumin (mg/dL), X₃=age (years), X₄=ln prothrombin time (seconds), X₅=degree of edema (0: no edema, 0.5: edema removable by diuretics, 1: edema not removable by diuretics).

Mayo constants: β₁=0.871, β₂=-2.533, β₃=0.039, β₄=2.38, β₅=0.859

S_(t,x)=[S_0(t)]_exp^(R-R0)

R0 is a risk score constant for S_0(t), R0=5.07

The corresponding survival rate S_0(t) values for the given years are:

From the above formula, the survival probability for the corresponding years of the prognostic subject can be calculated.

In 1994, the same laboratory further modified the mathematical model, suggesting that the new model was better for estimating prognosis within two years, while the old model was superior for periods of 3 to 7 years.

bubble_chart Differentiation

Including obstructive jaundice, such as common bile duct stones, common bile duct tumors, pancreatic head and bile duct strictures, the primary diagnostic method is cholangiography. It should be differentiated from the following diseases:

1. Chronic active hepatitis

For patients with positive anti-mitochondrial antibodies, accompanied by cholestasis and histological bile duct abnormalities, chronic active hepatitis should first be ruled out. In China, cholestatic chronic active hepatitis is more common than PBC. Short-term corticosteroid treatment and observation of its effects can help differentiate between these two conditions.

2. Sclerosing cholangitis

This disease is rare and primarily affects the large bile ducts. The aforementioned immunological markers are negative, and bacterial infection-related fever is often present. Biliary system imaging can aid in differentiation.

3. Drug-induced jaundice

Examples include chlorpromazine, methyltestosterone, sulfonamides, and arsenic preparations. Most cases are caused by individual hypersensitivity, with a history of medication use and onset within weeks of taking the drug. Jaundice can persist for several years, often accompanied by elevated blood eosinophils. Liver biopsy does not show the typical histological features of PBC.