PBC is a chronic progressive liver disease mediated by autoimmune destruction of the small-to-medium bile ducts. It is not common in males. We describe a case where the patient underwent renal transplant for polycystic-kidney-disease-mediated renal failure. He was placed on immunosuppressive medications - prednisone, tacrolimus and mycophenolate. He was also on amiodarone for atrial fibrillation. Upon cessation of the regime he progressed to develop PBC. He developed graft failure and later on end stage renal failure.
Delay was made in diagnosis because some of the manifestations including pruritus and fatigue which are common to PBC are also seen in end stage renal disease. It is possible that he gradually developed the auto antibodies and PBC, but the manifestations were likely suppressed by immunosuppressive medications, or brought on by altered immunity secondary to immunosuppressive therapy. It may also be possible that the amiodarone caused his cholestatis as it is rarely known to do. However, positive antimitochondrial antibodies titers have not been described with amiodarone-induced cholestatic liver disease. Allopurinol has been reported to cause some liver toxicity including granulomatous hepatitis and pancreatitis, but not PBC like process.
History and examinationA 58-year-old Caucasian male presented to Emergency room with abdominal pain and jaundice. His symptoms started a few days earlier, but worsened steadily over time. He had nausea and one episode of non-bloody, non-bilious emesis. Examination was significant for icterus; abdominal exam was remarkable for generalized tenderness. He had minimal liver enlargement. Spleen was enlarged. Other pertinent features were a large multinodular goiter. Vital signs were normal. Alcohol intake was reported as heavy during weekends when younger, but minimal for past 5 years. He quit smoking 30 years ago. Past medical history was very complicated and significant for ESRD secondary to polycystic kidney disease, hypertension, coronary artery disease and rhythm-controlled atrial fibrillation with amiodarone. He also had hypothyroidism and multinodular goiter. He had bilateral nephrectomies done in 11/ 99 secondary to hemorrhage in the kidney cysts. He was maintained on hemodialysis until he received renal transplant in 1/2001. He was maintained on Prednisone, Tacrolimus, and Mycophenolate for almost three years for immunosuppressive therapy. He regained some kidney function. His immunosuppressive therapy was tapered toward the end of 2003 and discontinued in 2/2004 due to graft failure and was put back on dialysis in May 2004. He had elevated alkaline phosphatase first documented in 1/2004. He also had ascites at that time, but the rest of his liver chemistries and abdominal imaging were unremarkable. Pruritus and fatigue were significant in 2005, but were attributed to ESRD. First significant rise in bilirubin was in 12/17/06 at 7.6 mg/dl - with admission for abdominal pain. Home medications were significant for allopurinol, amiodarone, omeprazole, sevelamer, gemfibrozil, fish oil, thyroxin, cinacalet, minoxidil, aspirin, and vitamins. None of these medications were new, none had doses altered recently.
InvestigationsThe patient was managed with pain control and hydration. Laboratory work was significant for lipase level of 1819 Units/ L, amylase of 737 Units/L. Bilirubin on admission as above was 7.6 mg/dl, peaked 3 days later to 11.3 mg/dl, with direct fraction of 4.4 mg/dl and 7.2 mg/dl respectively. Alkaline phosphatase on admission was 136 Units/L, peaked at 269 Units/L. His alanine aminotranferase was normal throughout, and aspartate aminotranferase peaked at 62 Units/L. Ultrasound showed thickened gall bladder, but no gallstones or dilatation of bile ducts. Pancreas was not well visualized. MRI of abdomen was done after gastroenterology consult was obtained and it showed irregularly dilated intrahepatic ducts, diffuse enlargement of pancreas, ascites and abnormal appearing kidneys-consistent with rejection. Antimitochondrial antibody titres were significantly elevated at 118 Units (normal<20), ANA tires were negative, IgM was normal. ERCP showed normal esophagus, stomach, and duodenum. Intrahepatic ducts were narrow and irregular. Cytology of the brushings showed inflammatory changes, no malignancy was found. Liver biopsy showed hepatocanalicular cholestasis, sinusoidal fibrosis, and ductopenia (see slides).
Management outcomeThe patient required large volume paracentesis once, but continued to have minimal ascites after that. His bilirubin and alkaline phospahatase trended down, but have not normalized. UDCA was suggested by gastroenterologist, but was refused by patient. His amiodarone therapy was discontinued.
Symptoms Fatigue and pruritus are the two most common symptoms. The degree of fatigue is independent of the degree of liver damage, makers, age or thyroid status, and there are no effective treatments for this symptom to date. Pruritus can be moderate to severe, occasionally disabling. It is not related to deposits if bile acids in the skin. Increased production of endogenous opioid peptides appears to be the major mechanism. The level of serum bilirubin parallels the level of these peptides. Right upper quadrant pain is noted in some patients.
Approximately 20 per cent of patients with PBC develop hypothyroidism . It may precede the onset of primary biliary cirrhosis as in this case or occurs during its course. Other findings are hyperlipidemia, malabsorption, hepatic osteodystrophy   and other auto immune disorders such as Sjogren's syndrome, renal tubular acidosis. Manifestations of portal hypertension do not occur until later on the disease process.
One of the criteria for diagnosis of PBC, antimitochondrial antibody, is important for establishing the diagnosis of PBC. There are four principal auto antigens that are targets for antimitochondrial antibodies. Most AMA reacts against E2 subunit of pyruvate dehydrogenase (PDC-E2). PBC is the only disease in which there are B- and T-cells that are auto reactive against PDC-E2. 95% of patients diagnosed with PBC are AMA positive while the others are AMA negative. There is no difference the clinical course, response to Urso, or liver transplant in patients who are AMA positive or AMA negative.
Evidence for an immunologic cause of PBC includes the presence of activated T cells in areas of bile duct destruction, the presence of highly specific auto-antibodies that react with antigens localized on biliary epithelial cells, and the association of PBC with other disorders thought to be autoimmune in nature.
In addition, markers associated with other autoimmune processes are found though less frequently-rheumatoid factor (70%), anti-smooth-muscle antibodies (66%), antithyroid antibodies (41%), and antinuclear antibodies (35%). IgM levels tend to be variably elevated.
Staging - according to histopathology 
- Stage 1: inflammation confined to the portal areas
- Stage 2: Periportal fibrosis is present, with or without periportal inflammation.
- Stage 3: Bridging fibrosis
- Stage 4: Cirrhosis with nodules with various degrees of inflammation
Treatment of primary biliary cirrhosisTreatment is mainly for symptom control, and to prevent the progression of complications. UDCA is widely used, results in improvement in chemistries and histological staging  while all patients do not respond well, UDCA delays the progression to end-stage liver disease, and improves survival. Several mechanisms for the protective actions of UDCA have been proposed, including inhibiting absorption of toxic, hydrophobic, endogenous bile salts; stabilizing hepatocyte membranes against toxic bile salts; replacing endogenous bile acids, some of which may be hepatotoxic, with the nonhepatotoxic UDCA. Following AMA titres is not recommended to assess the response to therapy, since the titres are not a reflection of clinical course. Other therapies that have been evaluated but found to be of limited value are Methotrexate and Budesonide  . Colchicine is associated with improvement of liver tests in some patients with PBC and improved itching. However, there was no improvement in liver biopsy findings. Liver transplantation in PBC is recommended for liver failure - the same indications which apply to patients with other chronic liver diseases also apply for patients with PBC. These include manifestations of portal hypertension, including bleeding from gastroesophageal varices, diuretic-resistant ascites, hepatorenal syndrome, and hepatic encephalopathy. Liver transplantation may be recommended in appropriately selected patients for:
Current data shows 5-year survival more than 80% in most centers. The auto antibodies persist after transplantation; histological changes recur after transplantation, with clinical recurrence rate of PBC of up to 32% after transplantation. 
- Uncontrollable pruritus, and
- Severe osteoporosis- according to AASLD guidelines.
This article was first published on GastroHep.com in 2007.
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This article was first published on GastroHep in June 2007.