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Primary biliary cirrhosis

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Primary biliary cirrhosis (PBC) is an idiopathic chronic autoimmune liver disease that primarily affects women. It is believed that the aetiology for PBC is a combination between environmental triggers in genetically vulnerable persons. The diagnosis for PBC is made when two of the three criteria are fulfilled and they are: (1) biochemical evidence of cholestatic liver disease for at least 6 month’s duration; (2) anti-mitochondrial antibody (AMA) positivity; and (3) histologic features of PBC on liver biopsy. Ursodeoxycholic acid (UDCA) is the only FDA-approved medical treatment for PBC and should be administered at a recommended dose of 13–15 mg/kg/day. Unfortunately despite adequate dosing of UDCA, approximately one-third of patients does not respond adequately and may require liver transplantation. Future studies are necessary to elucidate the role of environmental exposures and overall genetic impact not only in the development of PBC, but on disease progression and variable clinical response to therapy.

Introduction

Primary biliary cirrhosis (PBC), a chronic progressive inflammatory liver disease of unknown aetiology, is characterised by high titre of serum anti mitochondrial antibodies (AMA) and immune-mediated destruction of small and medium-sized intra-hepatic ducts. The histologic hallmark of the disease is a loss of biliary epithelial cells and small intrahepatic bile ducts with portal infiltration of T cells, B cells, macrophages, eosinophils, and natural killer cells. [1], [2] Similar to other autoimmune diseases, PBC primarily affects women, with a 10:1 female to male ratio. [3] Addison and Gull first described a PBC-like disease in 1851, but the term PBC was not coined until a case series of 18 patients was described in 1949. [4] The most frequently reported symptoms are fatigue and pruritus, which occur in up to 85% and 70% of patients, respectively. [5], [6] The pathogenesis of PBC is thought to be related to environmental exposures in genetically vulnerable patients, [7] but further studies are necessary to understand this complex interaction between genes and environment. Long-term treatment with ursodeoxycholic acid (UDCA) appears to slow disease progression and has altered the natural history of PBC. [8] The aim of this review is to provide an overview of current knowledge on the pathophysiology, clinical features and therapy of PBC.

Section snippets

Epidemiology

To date, all population-based studies provide only estimated prevalence and incidence rates based on the identification of cases already diagnosed. PBC primarily affects patients around the fifth decade of life and is uncommon in patients under 25 years old. [3] Initial studies published between 1974 and 1986 reported an annual incidence rates for PBC ranging between 0.6 and 13.7 cases per million population with prevalence rates varying from 23.1 to 128 cases per million population. [9], [10]

Pathogenesis

At present, the pathogenic mechanisms governing the development of PBC remains unknown. However, the development of PBC is believed to be a result from a combination of multiple genetic factors inter-playing with environmental triggers. As currently understood, PBC is initiated when tolerance to a ubiquitously expressed subunit of pyruvate dehydrogenase complex (PDC-E2) of mitochondria is lost as a result of the development of PDC-E2 specific anti-mitochondrial antibodies (AMAs). [17] AMAs are

Diagnosis

The diagnosis of PBC is based on the following clinical criteria: (1) biochemical evidence of cholestasis with elevation of alkaline phosphatase for at least 6 month’s duration; (2) presence of AMA; and (3) histopathologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts on liver biopsy. The expert consensus recommends that the diagnosis of PBC is established when two of the three criteria are met. [41]

In patients with biochemical evidence of

Clinical manifestations and patient management

PBC is now diagnosed earlier in its clinical course than in the past with more than half of patients being asymptomatic at the time of diagnosis. [42] Fatigue and pruritus are the two most common symptoms in PBC patients. Fatigue does not appear to correlate with disease severity, histologic stage, or duration and is strongly associated with excessive daytime somnolence. [43] The aetiology for fatigue is unknown, but may be related to autonomic dysfunction. [44] Fatigue may be multifactorial

Natural history

The rate of disease progression varies among individual patients and the natural history has become more difficult to characterise given the recognition of earlier stage disease, which requires long-term follow-up. Prince et al, described a series of 770 patients and at diagnosis approximately 61% were asymptomatic. [49] Among the asymptomatic patients, the probability of remaining symptom-free up to 10 years after diagnosis was only 20%. Ten years from diagnosis, the cumulative incidence rates

Therapy for primary biliary cirrhosis

UDCA at the recommended dose of 13–15 mg/kg is considered the first-line therapy for PBC. [41] UDCA is a hydrophilic naturally occurring bile acid, which has several interrelated functions including expansion of the hypdrophilic bile acid pool with direct choleretic, anti-inflammatory, and anti-apoptotic properties on hepatic epithelia. [56] Multiple randomised, placebo-controlled trials demonstrated that UDCA improves both serum liver biochemistries and histology of PBC patients. *[57], [58] A

Conclusion

PBC is an autoimmune liver disease characterised by destruction of small to medium intrahepatic bile ducts, resulting in chronic cholestasis and fibrosis, with progression to cirrhosis and end-stage liver disease. The exact pathogenesis of PBC is not fully understood, but is likely the interplay between environmental exposures in genetically predisposed patients. The advancement of genetics/genomics will likely bridge this knowledge gap and provide better understanding the full scope of genetic

Acknowledgements

This work was supported by grants to Dr. K.N. Lazaridis from the NIH (RO1 DK80670), Palumbo Charitable Trust, and Mayo Clinic College of Medicine.

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