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Primary Biliary Cirrhosis – Causes, Symptoms, Diagnosis And Treatment

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Primary Biliary Cirrhosis – Causes, Symptoms, Diagnosis And Treatment

Primary biliary cirrhosis is a chronic and progressive cholestatic disease of the liver of unknown etiology, although is presumed to have an autoimmune etiology. Primary biliary cirrhosis evolves with chronic cholestasis, progressive destruction of intrahepatic bile ducts, portal inflammation and final evolution to cirrhosis and liver failure. Inflammation particularly affects small and medium bile ducts, reason for which the disease was also called destructive non-suppurative cholangitis.

Clinical picture of primary biliary cirrhosis was first described in 1851 by Addison and Gull, noting the presence of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. In 1950, Ahrens and colleagues named this condition  primary biliary cirrhosis and in 1969, Doniach and Walker first reported the association between primary biliary cirrhosis and mitochondrial antibodies.

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

Primary biliary cirrhosis is more prevalent in the white population, accounting for 2% of deaths due to cirrhosis. The disease is more frequent in women than in men, thee incidence of the disease has been estimated as 4.5 cases for women and 0.7 cases for men per 100,000 population. Primary biliary cirrhosis symptoms may affect patient’s quality of life and may induce incapacitation. Various therapeutic approaches have been implemented with variable results, but liver transplantation is the only treatment option for the terminal stages of the disease. It was observed that after this procedure, primary biliary cirrhosis has a relatively high recurrence rate despite immunosuppressive therapy.

Primary Biliary Cirrhosis Causes

The exact cause of primary biliary cirrhosis is not known exactly, but is assumed that liver damage is the result of two phenomena: immunological abnormalities interest both cellular and humoral  immunity. It was observed that in patients with primary biliary cirrhosis is an impaired regulation of both B and T lymphocytes, serum titers of immunoglobulin M (IgM) is greatly increased and mitochondrial antibodies are present in about 95% -100% of cases. Primary biliary cirrhosis is associated with several autoimmune diseases such as lupus erythematosus, scleroderma, dermatomyositis, autoimmune thyroiditis, rheumatoid arthritis, ankylosing spondylitis.

The second phenomenon is represented by continuous destruction of small and medium bile ducts mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding and once destroyed, the regeneration of bile ducts is either not possible or inefficient. The result of intrahepatic bile ducts destruction, is the disruption of the normal bile flow which leads to retention and deposition of toxic substances, that are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and of the hepatocytes.

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Symptoms

Half of patients diagnosed with primary biliary cirrhosis are asymptomatic, but all patients present signs of cholestasis: increased alkaline phosphatase and gammaglutamyl transpeptidase.

In symptomatic forms of the disease, the onset is insidious. Fatigue is the main symptom and can cause disability in some patients. It was observed that fatigue may be associated with depression and obsessive-compulsive behavior. Fatigue etiology is unknown, but however, sleep abnormalities, particularly excessive daytime somnolence was identified in an increased proportion of patients and may be associated with the degree of fatigue. Pruritus is present in 55% of patients with primary biliary cirrhosis and 10% of patients experience severe pruritus. The cause of this symptom is unknown, but it seems that pruritus appears unrelated to the deposition of bile acids in the skin. Right upper quadrant discomfort occurs in 8-17% of patients.

In patient with primary biliary cirrhosis, physical examination findings depend on the stage of the disease. In the first stages of the disease, physical examination findings are normal. As the disease evolves, excoriations of the skin, xanthelasmata, cirrhosis signs, such as hepatomegaly, skin hyperpigmentation, splenomegaly, jaundice, spider nevi, palmar erythema, ascites, temporal and proximal muscle wasting, and peripheral edema  may be present. Sicca syndrome, consisting of xerophthalmia (dry eyes) and xerostomia (dry mouth) may be present in 50%-75% of patients with primary biliary cirrhosis.

Biliary system

Biliary system

Primary Biliary Cirrhosis Diagnosis

In most patients with primary biliary cirrhosis elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be identified, but elevated levels of the alkaline phosphatase (ALP), gammaglutamyl transpeptidase (GGTP), and immunoglobulin levels (mainly IgM) are usually the most prominent findings. Serum lipids levels and cholesterol levels (especially HDL fraction) are also elevated, explaining the low risk of these patients for atherosclerosis. Increased erythrocyte sedimentation rate may be present and as the disease progresses to cirrhosis, elevated bilirubin level, prolonged prothrombin time, and decreased albumin level may be present. Increased bilirubin level represent an indicator factor for liver transplantation.

Immunological abnormalities are highlighted by the presence of antimitochondrial antibodies (AMA) which are found in 90%-95% of patients with primary biliary cirrhosis and poses a specificity of 98% for this condition. Antinuclear antibodies (ANA) were reported in 20%-50% of cases.

Imaging studies such as abdominal ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) do not show specific modifications for primary biliary cirrhosis, but are useful in excluding biliary obstruction. FibroScan (impulsional elastography) is useful in detecting the degree of liver fibrosis.

Liver biopsy is the gold-standard diagnosis method for primary biliary cirrhosis because can confirm the diagnosis and provides information about disease stage and prognosis.

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis Treatment

Treatment of primary biliary cirrhosis has the following objectives: to alleviate symptoms, to slow the immune process and disease progression.

Ursodeoxycholic acid (UDCA) is very effective, especially in the early stages of primitive biliary cirrhosis. This drug is administered lifelong and studies suggest that UDCA delays the need for transplantation or delays death.

Immunosuppressive agents such as methotrexate, corticosteroids and cyclosporine inhibit immune reactions that mediate disease progression.

Pruritus is the most disturbing symptom and is often refractory to treatment. In the early stages of primary biliary cirrhosis, pruritus is alleviate with antihistamines, but this class of drugs has short-term effects. Cholestyramine is also effective in the treatment of pruritus and posses the capacity to sequester bile salts in the enteric lumen. In primary biliary cirrhosis with pruritus refractory to treatment phenobarbital may be administered and ultraviolet therapy or plasmapheresis may be tempted.

As the disease progress to cirrhosis, liver transplantation should be considered because seems to represented the only life-saving procedure.

Primary biliary cirrhosis has a slow and progressive evolution to cirrhosis. Average survival in asymptomatic forms disease is over 10 years and in symptomatic forms is approximately 7 years. Along with cirrhosis development, primary biliary cirrhosis prognosis becomes reserved.