Primary biliary cirrhosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Primary biliary cirrhosis is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. When these ducts are damaged bile builds up in the liver (cholestasis) and over time damages the tissue. This can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. In 1851, Addison and Gull first described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. There is no established system for the classification of primary biliary cirrhosis. However, it can be classified into four stages according to histological classification of Ludwig. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex. Primary biliary cirrhosis is strongly associated with a variety of rheumatologic conditions, most commonly Sjogren’s syndrome. The cause of primary biliary cirrhosis has not been identified fully, some environmental factors such as cigarette smoking, infections and chemical exposure have also been found to play a role in causing primary biliary cirrhosis. The prevalence is estimated to be as high as 1 in 4000 with a female:male ratio at least 9:1. Pharmacologic medical therapies for primary biliary cirrhosis include immunomodulators, antifibrotics, and anticholestatics. The anticholestatic ursodeoxycholic acid(UDCA) is recommended as the first line medical therapy for PBC. Surgery is usually reserved for patients with either decompensated cirrhosis and endstage liver failure who do not show any improvement with medical therapy.

In 1851, Addison and Gull first described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al in 1950 coined the term primary biliary cirrhosis for this disease. In 1986, the association between primary biliary cirrhosis and anti-mitochondrial antibodies was first reported.

There is no established system for the classification of primary biliary cirrhosis. However, it can be classified into four stages according to histological classification of Ludwig. It can also be classified into four stages according to the histological classification of P. Scheuer.

Primary biliary cirrhosis also known as primary biliary cholangitis is an autoimmune cholestatic disease. The disease is chronic and slowly progressive. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Overexpression of Bcl-2 in small apoptotic biliary epithelial cells and cell lineage-specific lack of glutathione prevents loss of immunogenicity of the PDC-E2 component after apoptosis of biliary epithelial cells which finally results in autoimmunity. Primary biliary cirrhosis may be familial and is related to factors inherited maternally. Primary biliary cirrhosis is strongly associated with a variety of rheumatologic conditions, most commonly Sjogren’s syndrome. On gross pathology, characteristic findings of primary biliary cirrhosis include hepatomegaly, splenomegaly, and cirrhosis (in late stage). On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis. It is important to differentiate PBC from other disease that may cause cholestasis including autoimmune hepatitis, common bile duct stone, hepatitis A (choelstatic type), EBV or CMV hepatitis, primary sclerosing cholangitis, pre-ampullary cancers, AIDS cholangiopathy, parasites induced cholestasis, and intrahepatic cholestasis of pregnancy.

The cause of primary biliary cirrhosis has not been identified. However, it is thought that hyper-functioning immune system attributed to genetic predisposition is thought to have a role in causing primary biliary cirrhosis. Few environmental factors such as cigarette smoking, infections and chemical exposure have also known to play a role in causing primary biliary cirrhosis.

Primary biliary cirrhosis must be differentiated from other disease that may cause cholestasis including autoimmune hepatitis, common bile duct stone, hepatitis A (choelstatic type), EBV or CMV hepatitis, primary sclerosing cholangitis, pre-ampullary cancers, AIDS cholangiopathy, parasites induced cholestasis, and intrahepatic cholestasis of pregnancy.

The female:male ratio is at least 9:1. In some areas of the US and UK the prevalence is estimated to be as high as 1 in 4000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but there is debate if this risk is greater in the same generation relatives or the one that follows.

The most potent risk factor in the development of primary biliary cirrhosis is positive family history. Other risk factors include age (30-60 years), female sex, infections and environmental toxins.

There is insufficient evidence to recommend routine screening for primary biliary cirrhosis. However, in patients with PBC having elevated alpha feto protein and male sex, more frequent screening for surveillance of hepatocellular carcinoma is recommended.

The symptoms of primary biliary cirrhosis usually develop in the fourth and fifth decade of life and start with symptoms such as fatigue and pruritis. If left untreated, patients with primary biliary cirrhosis may progress to develop an advanced stage of liver fibrosis and its subsequent complications such as portal hypertension and liver failure. Patients with untreated primary biliary cirrhosis have an increase risk in the incidence of hepatocellular carcinoma. Prognosis of the disease is generally good with the mild disease and early treatment with ursodeoxycholic acid.

Anti-mitochondrial antibody (AMA) titer is the diagnostic study of choice for the diagnosis of primary biliary cirrhosis. The diagnosis of primary biliary cirrhosis is made in the absence of extrahepatic biliary obstruction, no other comorbid condition affecting the liver with the presence of at least two of the criteria including an alkaline phosphatase 1.5 times the upper limit of normal, anti-mitochondrial antibodies with titer 1:40 or higher, and histology of liver demonstrating primary biliary cirrhosis.

The majority of patients with early primary biliary cirrhosis are asymptomatic.The hallmark of primary biliary cirrhosis is pruritis, worse at night. The most common symptoms of primary biliary cirrhosis include fatigue, pruritis, and jaundice.

Physical examination of patients with primary biliary cirrhosis in early stages of diseases is usually normal. Patients have clinical manifestations as the disease progress. Physical examination of patients with primary biliary cirrhosis is usually remarkable for fatigue. Late stage disease is characterized by liver failure manifesting as abdominal distension and altered mental status.

Laboratory findings consistent with the diagnosis of primary biliary cirrhosis include elevated levels of bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, anti-mitochondrial antibodies, lipids, immunoglobulin M, liver aminotransferases.

There are no ECG findings associated with primary biliary cirrhosis.

There are no x-ray findings associated with primary biliary cirrhosis.

There are no CT scan findings associated with primary biliary cirrhosis. However, a CT scan may be helpful in the diagnosis of complications of primary biliary cirrhosis, which include hepatocellular carcinoma, cirrhosis, and varices.

Abdominal MRI may be helpful in the diagnosis of primary biliary cirrhosis. Findings on MRI suggestive of primary biliary cirrhosis are parenchymal lace-like fibrosis and periportal halo sign.

There are no ultrasound findings associated with primary biliary cirrhosis. However, the ultrasound is mandatory for liver and biliary tree for all cholestatic patients for the differentiation of intrahepatic cholestasis from extrahepatic cholestasis.

Cholangiography may be helpful for the diagnosis of primary biliary cirrhosis with noninvasive magnetic resonance imaging or endoscopically to rule out primary sclerosing cholangitis. Findings on an cholangiography diagnostic of primary biliary cirrhosis include shortened and diminished branches of the intrahepatic bile ducts. Transient elastography (Fibroscan) is used to evaluate the extent of fibrosis in advanced disease.

Other diagnostic studies for primary biliary cirrhosis include liver biopsy, which demonstrates inflammation of the bile ducts,characterized by intraepithelial lymphocytes and periductal epithelioid granulomata.

Pharmacologic medical therapies for primary biliary cirrhosis include immunomodulators, antifibrotics, and anticholestatics. The anticholestatic ursodeoxycholic acid(UDCA) is recommended as the first line medical therapy for PBC.

The mainstay of treatment for primary biliary cirrhosis is medical therapy. Surgery is usually reserved for patients with either decompensated cirrhosis and endstage liver failure who do not show any improvement with medical therapy.

Effective measures for the primary prevention of primary biliary cirrhosis include preventive measures for cirrhosis, sicca syndrome and thyroid disease.

Effective measures for the secondary prevention of primary biliary cirrhosis include follow up with liver function tests, thyroid status, upper GI endoscopy, bone mineral density, fat-soluble vitamin levels, ultrasound and alpha-fetoprotein levels to screen for hepatocellular carcinoma among aged men and patients with underlying cirrhosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2], Anmol Pitliya, M.B.B.S. M.D.[3]

In 1851, Addison and Gull first described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al in 1950, coined the term primary biliary cirrhosis for this disease. In 1986, the association between primary biliary cirrhosis and anti-mitochondrial antibodies was first reported.

• In 1851, Addison and Gull first described primary biliary cirrhosis in the Guys hospital report titled as “On a Certain Affectation of the Skin Vitiligoiidea-alpha plana, beta tuberosa”.^[1]
• In 1950, Ahrens et al. coined the term “primary biliary cirrhosis.^[2]
• In 1956, Walker et al first described the association between anti-mitochondrial antibodies and primary biliary cirrhosis.^[3]
• In 1986, the association between primary biliary cirrhosis and anti-mitochondrial antibodies was first reported.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2] Anmol Pitliya, M.B.B.S. M.D.[3]

There is no established system for the classification of primary biliary cirrhosis. However, it can be classified into four stages according to histological classification of Ludwig. It can also be classified into four stages according to the histological classification of P. Scheuer.

• There is no established system for the classification of primary biliary cirrhosis.
• However, it can be classified into four stages according to histological classification of Ludwig. According to Ludwig classification, all four stages may be present on a single liver biopsy.^[1][2]
• It can also be classified into four stages according to the histological classification of P. Scheuer.^[3]

Classification of Primary biliary cirrhosis on the basis of histology
Stage	Histologic appearance
	Ludwig classification	Scheuer’s classification
Stage 1	Portal inflammation	Florid duct lesion or chronic non-suppurative destructive cholangitis
Stage 2	Extension of inflammation beyond portal tracts into surrounding parenchyma with or without ductal loss	Proliferation of the small bile ductules
Stage 3	Presence of fibrous septa linking adjacent portal tracts	Fibrosis or scarring
Stage 4	Cirrhosis	Cirrhosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Primary biliary cirrhosis also known as primary biliary cholangitis is an autoimmune cholestatic disease. The disease is chronic and slowly progressive. The exact pathogenesis of primary biliary cirrhosis is not fully understood. It is postulated that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Overexpression of Bcl-2 in small apoptotic biliary epithelial cells and cell lineage-specific lack of glutathione prevents loss of immunogenicity of the PDC-E2 component after apoptosis of biliary epithelial cells which finally results in autoimmunity. Primary biliary cirrhosis may be familial and is related to factors inherited maternally. Primary biliary cirrhosis is strongly associated with a variety of rheumatologic conditions, most commonly Sjogren’s syndrome. On gross pathology, characteristic findings of primary biliary cirrhosis include hepatomegaly, splenomegaly, and cirrhosis (in late stage). On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.

• The exact pathogenesis of primary biliary cirrhosis is not fully understood.
• It is thought that primary biliary cirrhosis is the result of antimitochondrial antibodies (AMAs), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2).^[1]

Biliary epithelial cells (BEC)

Overexpression of Bcl-2 in small apoptotic BEC

Cell lineage specific lack of glutathione

Inhibition of PDC-E2 glutathiolation

Prevents loss of immunogenicity after apoptosis of BEC

PDC-E2 component remains intact and antigenic in apoptotic blebs of BEC

Antigenic PDC-E2 are engulfed by intrahepatic dendritic cells

Dendritic cells transfer antigenic PDC-E2 to regional lymph nodes

Antigenic PDC-E2 is recognized by MHC class I restricted CD8+ T cells

Initiates autoimmunity

Primary biliary cirrhosis

• Primary biliary cirrhosis may be familial and is related to factors inherited maternally.^[6]
• Primary biliary cirrhosis tends to present at an earlier age in the second generation.

Conditions associated with primary biliary cirrhosis include:^[7][8][9]

• Addison’s disease
• Autoimmune thrombocytopenic purpura
• Celiac disease
• CREST syndrome
• Crohn’s disease
• Dermatomyositis
• Diabetes mellitus type 1
• Gallstones
• Glomerulonephritis
• Grave’s disease
• Hashimoto’s thyroiditis
• Lichen planus
• Mixed connective tissue disorder
• Myasthenia gravis
• Pemphigoid
• Pernicious anemia
• Polymyositis
• Psoriasis
• Pulmonary fibrosis
• Raynaud’s disease
• Rheumatoid arthritis
• Sarcoidosis
• Scleroderma
• Sjogren’s syndrome
• Systemic lupus erythematosus
• Ulcerative colitis

• On gross pathology, characteristic findings of primary biliary cirrhosis include:^[7]
  • Hepatomegaly
  • Splenomegaly
  • Cirrhosis (late stages)

• On microscopic histopathological analysis, asymmetric destruction of the intralobular bile ducts within portal triads is characteristic findings of primary biliary cirrhosis.
• Primary biliary cirrhosis can be classified into four stages according to histological classification of Ludwig. According to Ludwig classification, all four stages may be present on a single liver biopsy.^[10][11]
• It can also be classified into four stages according to the histological classification of P. Scheuer.^[12]

Classification of Primary biliary cirrhosis on the basis of histology
Stage	Histologic appearance
	Ludwig classification	Scheuer’s classification
Stage 1	Portal inflammation	Florid duct lesion or chronic non-suppurative destructive cholangitis
Stage 2	Extension of inflammation beyond portal tracts into surrounding parenchyma with or without ductal loss	Proliferation of the small bile ductules
Stage 3	Presence of fibrous septa linking adjacent portal tracts	Fibrosis or scarring
Stage 4	Cirrhosis	Cirrhosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

The cause of primary biliary cirrhosis has not been identified. However, it is thought that hyper-functioning immune system attributed to genetic predisposition is thought to have a role in causing primary biliary cirrhosis. Few environmental factors such as cigarette smoking, infections and chemical exposure have also known to play a role in causing primary biliary cirrhosis.

• The cause of primary biliary cirrhosis has not been identified. However, it is thought that hyper-functioning immune system attributed to genetic predisposition is thought to have a role in causing primary biliary cirrhosis.^[1][2][3]
• Few environmental factors such as cigarette smoking, infections and chemical exposure are also known to play a role in causing primary biliary cirrhosis.^[1][2][3]
• To learn more about the risk factors for the development of primary biliary cirrhosis, click here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2], Anmol Pitliya, M.B.B.S. M.D.[3]

Primary biliary cirrhosis must be differentiated from other disease that may cause cholestasis including autoimmune hepatitis, common bile duct stone, hepatitis A (choelstatic type), EBV or CMV hepatitis, primary sclerosing cholangitis, pre-ampullary cancers, AIDS cholangiopathy, parasites induced cholestasis, and intrahepatic cholestasis of pregnancy.

Primary biliary cirrhosis must be differentiated from other disease that may cause cholestasis.^{[1][2][3][4][5]}

Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALP BLR Indirect BLR Direct Viral serology Primary biliary cirrhosis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – AMA positive Liver biopsy Autoimmune hepatitis -/+ – – -/+ ↑ ↑ N ↑/N N – Anti-LKM antibody Liver biopsy Common bile duct stone -/+ – + + N N ↑ N ↑ – Dilated ducts on ultrasound CT/ERCP Hepatitis A (cholestatic type) – -/+ + + N/↑ N/↑ ↑ N ↑ + HAV- Ab Abdominal ultrasound EBV / CMV hepatitis – -/+ + + N N ↑ N ↑ + Positive serology – Primary sclerosing cholangitis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – ↑Autoantibodies (P-ANCA), hypergammaglobulinemia MRCP, Liver biopsy Pre-ampullary cancers + – -/+ -/+ N/↑ N/↑ ↑ N ↑ – – CT scan for diagnosis AIDS cholangiopathy – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – HIV Ab Ultrasound or ERCP Parasites induces cholestasis – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – Serology Ultrasound or ERCP Intrahepatic cholestasis of pregnancy -/+ – -/+ + ↑ ↑ ↑ N ↑ – Thrombocytopenia Diagnosed clinically

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

The prevalence of primary biliary cirrhosis is approximately 19 to 402 cases per 100,000 individuals worldwide. Primary biliary cirrhosis commonly affects individuals in their 40s or 50s. There is no racial predilection to primary biliary cirrhosis. Females are more commonly affected by primary biliary cirrhosis than males. The majority of primary biliary cirrhosis cases are reported in northern Europe and North America (particularly in Scandinavia, Great Britain, and the northern midwest regions of the United States).

• The prevalence of primary biliary cirrhosis is approximately 19 to 402 cases per 100,000 individuals worldwide.^[1][2]

• Primary biliary cirrhosis commonly affects individuals in their 40s or 50s.^[3][4]

• There is no racial predilection to primary biliary cirrhosis.

• Females are more commonly affected by primary biliary cirrhosis than males.^[5]

• The majority of primary biliary cirrhosis cases are reported in northern Europe and North America (particularly in Scandinavia, Great Britain, and the northern midwest regions of the United States).^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

The most potent risk factor in the development of primary biliary cirrhosis is positive family history. Other risk factors include age (30-60 years), female sex, infections and environmental toxins.

• The most potent risk factor in the development of primary biliary cirrhosis is positive family history. Other risk factors include age (30-60 years), female sex, infections and environmental toxins.

• Common risk factors in the development of Primary biliary cirrhosis may be occupational, environmental, genetic, and microbial.^[1][2][3]
• Common risk factors in the development of primary biliary cirrhosis include:
  • Age: Patients with age between 30-60 years are at highest risk
  • Sex: Female sex is at higher risk
  • Geographic distribution: Increased risk in North America and Northern Europe.
  • Genetic predisposition: HLA-DRB1*0801 haplotype^[4]

• Less common risk factors in the development of primary biliary cirrhosis include:^[1][4][3]
  • Infections
  • Cigarette smoking^[5]
  • Environmental toxins

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]

There is insufficient evidence to recommend routine screening for primary biliary cirrhosis. However, patients with PBC having elevated alpha feto protein and male sex, more frequent screening for surveillance of hepatocellular carcinoma is recommended.

• There is insufficient evidence to recommend routine screening for primary biliary cirrhosis.
• However, patients with primary biliary cirrhosis having elevated alpha feto protein and male sex, more frequent screening for surveillance of hepatocellular carcinoma is recommended. ^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2], Anmol Pitliya, M.B.B.S. M.D.[3]

The symptoms of primary biliary cirrhosis usually develop in the fourth and fifth decade of life and start with symptoms such as fatigue and pruritis. If left untreated, patients with primary biliary cirrhosis may progress to develop an advanced stage of liver fibrosis and its subsequent complications such as portal hypertension and liver failure. Patients with untreated primary biliary cirrhosis have an increased the incidence of hepatocellular carcinoma. Prognosis of the disease is generally good with the mild disease and early treatment with ursodeoxycholic acid.

• The symptoms of primary biliary cirrhosis usually develop in the fourth and fifth decade of life and start with symptoms such as fatigue and pruritis.^[1][2][3]
• If left untreated, patients with primary biliary cirrhosis may progress to develop advanced stage of liver fibrosis and its subsequent complications such as portal hypertension and liver failure.
• Patients with untreated primary biliary cirrhosis have increased the incidence of hepatocellular carcinoma.

• Common complications of primary biliary cirrhosis include:^{[1][2][3][4][5][6][7]}
  • Cirrhosis
  • Hepatocellular carcinoma
  • Portal hypertension
  • Liver failure
  • Hepatic encephalopathy
  • Varices
  • Osteoporosis
  • Malabsorption
  • Fat soluble vitamin deficiency (Vitamin A, D, E, K)

Prognosis is generally good with the mild disease and early treatment with ursodeoxycholic acid. Factors associated with poor prognosis include: ^{[8][9][10][2][11][12][13]}

• Advanced disease
• Co existing autoimmune disorders such as sicca syndrome, thyroiditis, and scleroderma
• Symptomatic disease
• Increased levels of alkaline phosphatase and bilirubin levels at the time of diagnosis
• Stage III and IV disease on histological examination
• Presence of antinuclear antibodies (antiGp210, antiSp100)
• Cigarette smoking
• Genetic polymporphism

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