Diagnosis of primary biliary cirrhosis

doi:10.1016/j.bpg.2011.10.005

Best Practice & Research Clinical Gastroenterology

Volume 25, Issue 6, December 2011, Pages 701-712

https://doi.org/10.1016/j.bpg.2011.10.005 Get rights and content

Primary biliary cirrhosis is the archetypal autoimmune liver disease, with the disease label describing a chronic granulomatous lymphocytic small bile duct cholangitis, which now most commonly presents asymptomatically and at an early pre-cirrhotic stage. Disease is more common than thought, with 1 in 1000 women over the age of 40 affected. Characteristic immunologic features of the disease assist clinicians in ready non-invasive diagnosis of patients, even if asymptomatic with only anicteric/cholestatic liver biochemical profiles. Over 90% of patients are anti-mitochondrial antibody positive, and for those negative, a significant proportion have highly specific anti-nuclear antibody profiles. Liver biopsy remains useful in certain settings where clarity is needed to confirm diagnosis, exclude alternative disease, and assess the relative contribution of PBC to other co-existent liver injury, and seeks to demonstrate in particular the classic bile duct lesions, as well as the degree of interface activity.

Introduction

Primary biliary cirrhosis (PBC) is the most common of the autoimmune liver diseases, and is broadly speaking at least twice as common as the other members of the “autoimmune liver disease family” which constitutes autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) [1], [2]. Present estimates place the prevalence of disease at around 1 in 1000 women over the age of 40 [3], [4]. Whilst the classic patient might be stereotyped as a Caucasian woman in her 50 s, in fact PBC is prevalent in all ethnicities (albeit very uncommon in African Americans), can present in young pre-menopausal fertile women, and does affect men. Given that PBC is a chronic granulomatous lymphocytic cholangitis, classically associated with the presence of circulating anti-mitochondrial antibodies, and a disease that necessitates lifelong therapy, it remains important to establish a clear diagnosis at the outset (see Table 1 for the differential diagnosis), in order to help patients be well educated about their disease and its expected course. Except in the earliest of disease, this is generally possible so long as a systematic approach to investigation is taken. This review outlines the facets relevant to making an appropriate diagnosis of PBC, in order that intervention if appropriate can be started (Fig. 1).

Section snippets

Historical perspective

Some recognition of the historical perspective helps present day care, as it highlights disease concepts still pertinent to patient management [5]. Addison and Gull in 1851 made the original description, recognizing PBC not because it was a clear liver disease, but as patients presented with significant skin manifestations of cholestasis i.e. xanthelasmas composed of cholesterol. Subsequently Thannhauser [6] described PBC as “xanthomatous cirrhosis” with the more classic description of PBC as a

Epidemiologic perspectives

In approaching a patient being reviewed for possible PBC it is also helpful to appreciate some of the epidemiologic observations made from retrospective/cross-sectional analysis of large cohorts of patients and controls. Aside from the value such studies offer in terms of determining relative contributions of environmental and genetic influences on disease (e.g. spatial and temporal associations with the diagnosis of PBC [24], [25]), they also provide important points to discuss with patients.

Clinical presentation

Of asymptomatic patients diagnosed today many are screened following routine identification of an elevated serum alkaline phosphatase (ALP) or gamma-glutamyltransferase (GGT) e.g. life insurance bloods, annual screening labs. Frequent other scenarios of course arise, including screening of patients with autoimmune diseases such as scleroderma, investigation of elevated cholesterol, incidental liver bloodwork as part of evaluation for abdominal discomfort, evaluation of itch, unresolved

Clinical investigations

Diagnosing PBC is generally not difficult, and this is important because it facilitates early diagnosis and treatment. Presently the challenges faced by clinicians come when disease is at a very early stage, when the patient is AMA negative and when there is potential disease overlap, predominantly with fatty liver. Individuals are most often diagnosed with PBC between the ages 40 of 60 years. Symptomatic patients seem likely to be diagnosed younger than asymptomatic subjects, partly because

Variant presentations/differential diagnosis

Clearly patient presentation can be quite varied, and careful history taking can identify patients for whom different evaluation is needed. Additionally it remains the case that co-existent viral and metabolic liver disease should always be sought. The broad differential diagnosis of PBC is as shown in Table 1. AMA-negative patients with PBC lack AMA (by immunofluorescence, ELISA and Western blotting) but have a clinical presentation, liver histology, and natural history essentially equivalent

Summary

PBC is the classic autoimmune liver disease. Whilst patients are presenting at an earlier asymptomatic stage, diagnosis generally remains simple, and rests upon taking a good history, simple examination, and timely testing for readily available serologic markers of disease. Common symptoms such as fatigue, itch and sicca complex should be ascertained as should risk factors for disease (e.g. smoking, family history of autoimmunity, personal history of autoimmunity), whilst at the same time,

Conflict of interest

The author declares no relevant conflict of interest relevant to the preparation of this review.

References (67)

R. Poupon
Primary biliary cirrhosis: a 2010 update
J Hepatol
(2010 May)
J.G. Walker et al.
Serological tests in diagnosis of primary biliary cirrhosis
Lancet
(1965 Apr 17)
J.V. Metcalf et al.
Natural history of early primary biliary cirrhosis
Lancet
(1996 Nov 23)
G.M. Hirschfield et al.
Pathogenesis of cholestatic liver disease and therapeutic approaches
Gastroenterology
(2010 Nov)
C.O. Zein et al.
When is liver biopsy needed in the diagnosis of primary biliary cirrhosis?
Clin Gastroenterol Hepatol
(2003 Mar)
A. Parikh-Patel et al.
Risk factors for primary biliary cirrhosis in a cohort of patients from the united states
Hepatology
(2001 Jan)
C. Corpechot et al.
Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis
J Hepatol
(2010 Jul)
T. Kumagi et al.
Presentation and diagnosis of primary biliary cirrhosis in the 21st century
Clin Liver Dis
(2008 May)
J.L. Newton et al.
Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure
J Hepatol
(2006 Apr)
F. Colina et al.
Nodular regenerative hyperplasia of the liver in early histological stages of primary biliary cirrhosis
Gastroenterology
(1992 Apr)

A. Pares et al.

Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid

Gastroenterology

(2006 Mar)

G.M. Hirschfield et al.

Antimitochondrial antibody-negative primary biliary cirrhosis

Clin Liver Dis

(2008 May)

S. Shimoda et al.

CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis

J Autoimmun

(2008 Sep)

O. Bandin et al.

Specificity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis

Hepatology

(1996 May)

D. Zuchner et al.

Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis

Hepatology

(1997 Nov)

P. Milkiewicz et al.

Value of autoantibody analysis in the differential diagnosis of chronic cholestatic liver disease

Clin Gastroenterol Hepatol

(2009 Dec)

H. Liu et al.

PBC screen: an IgG/IgA dual isotype ELISA detecting multiple mitochondrial and nuclear autoantibodies specific for primary biliary cirrhosis

J Autoimmun

(2010 Dec)

N. Rabahi et al.

Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone

Gastroenterol Clin Biol

(2010 Apr-May)

J. Ludwig

The pathology of primary biliary cirrhosis and autoimmune cholangitis

Baillieres Best Pract Res Clin Gastroenterol

(2000 Aug)

K.M. Boberg et al.

Overlap syndromes: the international autoimmune hepatitis Group (IAIHG) position statement on a controversial issue

J Hepatol

(2011 Feb)

K.D. Lindor et al.

Primary biliary cirrhosis

Hepatology

(2009 Jul)

EASL Clinical practice guidelines: management of cholestatic liver diseases

J Hepatol

(2009 Aug)

O.F. James et al.

Primary biliary cirrhosis once rare, now common in the United Kingdom?

Hepatology

(1999 Aug)

A. Reuben

The serology of the Addison-Gull syndrome

Hepatology

(2003 Jan)

M.H. Mac et al.

Xanthomatous biliary cirrhosis; a clinical syndrome

Ann Intern Med

(1949 Jan)

E.H. Ahrens et al.

Primary biliary cirrhosis

Medicine (Baltimore)

(1950 Dec)

J. Ludwig et al.

Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)

Virchows Arch A Pathol Anat Histol

(1978 Aug 22)

P. Scheuer

Primary biliary cirrhosis

Proc R Soc Med

(1967 Dec)

E. Rubin et al.

Primary biliary cirrhosis. chronic non-suppurative destructive cholangitis

Am J Pathol

(1965 Mar)

F. Paronetto et al.

Immunocytochemical and serologic observations in primary biliary cirrhosis

N Engl J Med

(1964 Nov 26)

D. Doniach et al.

Tissue antibodies in primary biliary cirrhosis, active chronic (lupoid) hepatitis, cryptogenic cirrhosis and other liver diseases and their clinical implications

Clin Exp Immunol

(1966 Jul)

R.B. Goudie et al.

Serological and histological diagnosis of primary biliary cirrhosis

J Clin Pathol

(1966 Nov)

P.A. Berg et al.

Mitochondrial antibodies in primary biliary cirrhosis. I. Localization of the antigen to mitochondrial membranes

J Exp Med

(1967 Aug 1)

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Rheumatoid arthritis (RA) is characterized by synovitis of multiple joints which if untreated progresses to joint destruction. Primary biliary cholangitis (PBC) is an autoimmune and progressive disease of the liver of unknown origin. About 1.8–5.6% of individuals with PBC have RA and patients with RA are at higher risk of developing PBC compared to the general population.
We report a case of a 76-year-old man, with a history of PBC, and a recent RA diagnosis, in which tocilizumab therapy was effective in the control of RA and PBC, and a literature review was performed.
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Inflammatory and autoimmune disease of the bile duct
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Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba
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UDCA-responsive patients will generally show biochemical improvement within 6–9 months; however, non-responder patients, up to 40%, are at risk for progressive decline of their condition [33]. Factors that influence response to treatment and therefore PBC outcome are: sex and age at diagnosis, with male sex and young age at diagnosis being independent predictors of UDCA non-response [34], in addition to PBC-specific Anti-Nuclear Antibodies (ANA) positivity (anti-multiple nuclear dot, anti-nuclear envelope protein, and anti-rim-like/membranous anti-nuclear autoantibodies) [1,2], biochemical markers of fibrosis, liver stiffness, presence of cirrhosis and/or portal hypertension, and ductopenia [35,36]. A number of options are under investigation as second line treatment for patients non responders to UDCA.
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Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics
2016, Journal of Clinical and Experimental Hepatology
Citation Excerpt :
Hepatocyte expression of major histocompatibility complex (MHC) class I is also induced by BAs, which provides another mechanism by which immune cell-mediated injury can occur.19 The diagnosis of PBC may be implicated in the setting of cholestatic liver injury and supported with demonstration of circulating AMAb—though the presence of AMA is not absolute and may be absent in 10% of cases.20 The American Association for the Study of Liver Disease recommends that diagnosis be based on two of the three following criteria: “(1) biochemical evidence of cholestasis with elevation in alkaline phosphatase (ALP); (2) presence of AMAb; and (3) histopathological evidence of nonsuppurative cholangitis and destruction of small or medium-sized interlobular bile ducts on biopsy.21”
Primary Biliary Cholangitis is a progressive, autoimmune cholestatic liver disorder. Cholestasis with disease progression may lead to dyslipidemia, osteodystrophy and fat-soluble vitamin deficiency. Portal hypertension may develop prior to advanced stages of fibrosis. Untreated disease may lead to cirrhosis, hepatocellular cancer and need for orthotopic liver transplantation. Classically, diagnosis is made with elevation of alkaline phosphatase, demonstration of circulating antimitochondrial antibody, and if performed: asymmetric destruction/nonsupperative cholangitis of intralobular bile ducts on biopsy. Disease pathogenesis is complex and results from innate and adaptive (cell-mediated and humoral) responses that lead to inflammation of biliary duct epithelium. Ongoing damage is amplified and sustained through bile acid toxicity. Use of weight based (13-15mg/kg) ursodeoxycholic acid is well established in retarding disease progression and improving survival; however, is ineffective in achieving complete biochemical remission in many. Recently, a Farnesoid X Receptor agonist, obeticholic acid, has been approved for use. A number of ongoing clinical studies are underway to evaluate utility of fibric acid derivatives, biologics, antifibrotics, and stem cells as monotherapy or in combination with ursodeoxycholic acid for primary biliary cholangitis. The aim of this review is to discuss disease pathogenesis and highlight rationale/implications for both established and novel therapeutics.

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6Diagnosis of primary biliary cirrhosis

Introduction

Section snippets

Historical perspective

Epidemiologic perspectives

Clinical presentation

Clinical investigations

Variant presentations/differential diagnosis

Summary

Conflict of interest

J Hepatol

Lancet

Lancet

Gastroenterology

Clin Gastroenterol Hepatol

Hepatology

J Hepatol

Clin Liver Dis

J Hepatol

Gastroenterology

Gastroenterology

Clin Liver Dis

J Autoimmun

Hepatology

Hepatology

Clin Gastroenterol Hepatol

J Autoimmun

Gastroenterol Clin Biol

Baillieres Best Pract Res Clin Gastroenterol

J Hepatol

Primary biliary cirrhosis

Hepatology

EASL Clinical practice guidelines: management of cholestatic liver diseases

J Hepatol

Primary biliary cirrhosis once rare, now common in the United Kingdom?

Hepatology

The serology of the Addison-Gull syndrome

Hepatology

Xanthomatous biliary cirrhosis; a clinical syndrome

Ann Intern Med

Primary biliary cirrhosis

Medicine (Baltimore)

Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)

Virchows Arch A Pathol Anat Histol

Primary biliary cirrhosis

Proc R Soc Med

Primary biliary cirrhosis. chronic non-suppurative destructive cholangitis

Am J Pathol

Immunocytochemical and serologic observations in primary biliary cirrhosis

N Engl J Med

Tissue antibodies in primary biliary cirrhosis, active chronic (lupoid) hepatitis, cryptogenic cirrhosis and other liver diseases and their clinical implications

Clin Exp Immunol

Serological and histological diagnosis of primary biliary cirrhosis

J Clin Pathol

Mitochondrial antibodies in primary biliary cirrhosis. I. Localization of the antigen to mitochondrial membranes

J Exp Med

6
Diagnosis of primary biliary cirrhosis