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{{Primary biliary cirrhosis}}
{{Primary biliary cirrhosis}}
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{{CMG}}; {{AE}} {{Anmol}}


==Overview==
==Overview==
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]].
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 [[Immunomodulator|immunomodulators]], antifibrotics, and anticholestatics. The anticholestatic [[ursodeoxycholic acid]](UDCA) is recommended as the first line medical therapy for [[Primary biliary cirrhosis|PBC]]. Surgery is usually reserved for patients with either decompensated [[cirrhosis]] and endstage [[liver failure]] who do not show any improvement with medical therapy.
 
==Historical Perspective==
==Historical Perspective==
Addison and Gull in 1851 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. The association with anti mitochondrial antibodies was first reported in 1986.<ref name=Mitchison1986>{{cite journal |author=Mitchison HC, Bassendine MF, Hendrick A, ''et al.'' |title=Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? |journal=Hepatology |volume=6 |issue=6 |pages=1279–84 |year=1986 |pmid=3793004 |doi=10.1002/hep.1840060609}}</ref>
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.  
 
==Classification==
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.
 
==Pathophysiology==
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]].
 
==Causes==
The cause of primary biliary cirrhosis has not been identified. However, it is thought that [[Autoimmunity|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.
 
==Differentiating primary biliary cirrhosis from other diseases==
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]].
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
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 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.
==Risk Factors==
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]].
==Screening==
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.
==Natural History, Complications, and Prognosis==
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]].
==Diagnosis==
==Diagnosis==
===CT===
===Diagnostic Study of Choice===
Abdominal [[medical ultrasonography|ultrasound]] or a [[CT scan]] is usually performed to rule out blockage to the bile ducts.
[[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.
 
===History and Symptoms===
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===
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===
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]].
 
===Electrocardiogram===
There are no ECG findings associated with primary biliary cirrhosis.
 
===X-ray===
There are no x-ray findings associated with primary biliary cirrhosis.
 
===CT scan===
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]].
 
===MRI===
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 [[Halo sign|periportal halo sign]].
 
===Ultrasound===
There are no ultrasound findings associated with primary biliary cirrhosis. However, the ultrasound is mandatory for liver and [[biliary tree]] for all [[Cholestasis|cholestatic]] patients for the differentiation of [[intrahepatic cholestasis]] from [[Extrahepatic cholestasis|extrahepatic cholestasis.]]
 
===Other Imaging Findings===
[[Cholangiogram|Cholangiography]] may be helpful for the diagnosis of primary biliary cirrhosis with noninvasive [[magnetic resonance imaging]] or endoscopically to rule out [[Primary sclerosing cholangitis|primary sclerosing cholangitis.]] Findings on an [[Cholangiogram|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===
Other diagnostic studies for primary biliary cirrhosis include [[liver biopsy]], which demonstrates [[inflammation]] of the [[Bile duct|bile ducts]],characterized by [[Intraepithelial lymphocyte|intraepithelial lymphocytes]] and periductal [[epithelioid]] [[Granuloma|granulomata]].


==Treatment==
==Treatment==
===Medical Therapy===
Pharmacologic medical therapies for primary biliary cirrhosis include [[Immunomodulator|immunomodulators]], antifibrotics, and anticholestatics. The anticholestatic [[ursodeoxycholic acid]](UDCA) is recommended as the first line medical therapy for [[Primary biliary cirrhosis|PBC]].
===Surgery===
===Surgery===
In advanced cases, a [[Liver transplantation|liver transplant]], if successful, results in a favorable prognosis. After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. There is no consensus on risk factors for recurrence of the disease. <ref>Medical care of the Liver Trasplant Patient, 3rd Edition published 2006, editied by Paul G. Killenberg, page 429</ref>
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.
===Future or Investigational Therapies===
 
[[Obeticholic acid]] is in phase III clinical trials for PBC.<ref>http://www.genengnews.com/gen-news-highlights/dainippon-sumitomo-pays-intercept-15m-for-phase-iii-liver-disease-drug/81244901/</ref>
===Primary Prevention===
Effective measures for the primary prevention of primary biliary cirrhosis include preventive measures for [[cirrhosis]], [[sicca syndrome]] and [[thyroid disease]].


===Secondary Prevention===
Effective measures for the secondary prevention of primary biliary cirrhosis include follow up with [[liver function tests]], [[Thyroid function tests|thyroid status]], [[Endoscopy|upper GI endoscopy]], [[bone mineral density]], [[Fat soluble vitamins|fat-soluble vitamin]] levels, [[ultrasound]] and [[alpha-fetoprotein]] levels to screen for [[hepatocellular carcinoma]] among aged men and patients with underlying [[cirrhosis]].
==References==
==References==
{{reflist|2}}
{{reflist|2}}
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[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Hepatology]]
[[Category:Hepatology]]
[[Category:Autoimmune diseases]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Rheumatology]]
[[Category:Medicine]]
[[Category:Up-To-Date]]

Latest revision as of 23:49, 29 July 2020

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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]

Overview

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.

Historical Perspective

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.

Classification

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.

Pathophysiology

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.

Causes

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.

Differentiating primary biliary cirrhosis from other diseases

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.

Epidemiology and Demographics

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.

Risk Factors

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.

Screening

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.

Natural History, Complications, and Prognosis

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.

Diagnosis

Diagnostic Study of Choice

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.

History and Symptoms

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

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

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.

Electrocardiogram

There are no ECG findings associated with primary biliary cirrhosis.

X-ray

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

CT scan

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.

MRI

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.

Ultrasound

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.

Other Imaging Findings

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

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.

Treatment

Medical Therapy

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

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.

Primary Prevention

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

Secondary Prevention

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.

References

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