Gastroenterology Hepatology

Primary biliary cholangitis

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How can I be sure that the patient has primary biliary cholangititis?

What signs and symptoms are usually found?

Fatigue and pruritus are the most common symptoms of primary biliary cholangitis (PBC), but many patients are completely asymptomatic. The fatigue is insidious and leads to a gradual reduction in the amount of daily living activities that can be completed by an individual. The pruritus has a diurnal variation and tends to be worst in the evenings. The pruritus is systemic and may involve any part of the body, although it characteristically and rather uniquely sometimes involves the palms and soles once it is well established. 

The typical patient with PBC is female and middle aged. The female/male ratio is 12:1, and the mean age of presentation is 52. The disease has only been reported in a handful of teenagers, and none of them have been male or pre-pubertal. PBC affects all races, although there is geographic variation in the prevalence reported with higher prevalences reported in primarily Caucasian, Westernized locations.

Physical exam findings are often absent in early stages of the disease. With severe pruritus, patients will develop stigmata of chronic scratching such as excoriations, red crusted papules, or hyperpigmented nodules, but a rash never precedes the itch. In later phases of the disease, patients may develop hepatomegaly, xanthomas/xanthalasmas, melanotic patches, or evidence of portal hypertension (splenomegaly, ascites, edema, encephalopathy).

Other common exam findings are not due to the disease per say but due to other commonly associated autoimmune disorders. Approximately 50% of PBC patients will have sicca syndrome and will have xerophthalmia and/or xerostomia. Approximately 15% of patients with PBC will also have limited scleroderma, or CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia) syndrome and may have telangiectasias of the lips or fingertips, sclerodactyly. Patients may have complaints of their hands turning blue with cold exposure or of GERD (gastroesophageal reflux disease) symptoms. Note that the syndrome is often incomplete and patients only need two of the C-R-E-S and -T features to establish the diagnosis.

Laboratory abnormalities are the most sensitive and specific features of the disease, particularly early in the disease course when symptoms and exam findings may be absent. Approximately 95% of patients will test positive for antimitochondrial antibodies (AMA). AMAs are highly specific for PBC and are usually the first laboratory abnormality to occur. They have been reported in very low prevalence (1-15%) in other liver diseases, such as nonalcoholic steatohepatitis (NASH), hepatitis C, and autoimmune hepatitis (AIH), but it is not known whether this represents a false positive AMA or the presence of very early PBC in conjunction with another liver disease.

Patients with acute liver failure may also test positive for AMA and in such cases, it is thought to be an immune reaction to the release of hepatocellular contents from massive hepatocyte death. PBC itself has never been reported to cause acute liver failure. Patients with positive AMA and no other clinical, laboratory, or histological evidence of PBC should be followed to determine if other features of the disease develop.

The second most common (but not specific) laboratory abnormality is an elevated alkaline phosphatase (ALP). Transaminases (AST/ SGOT and ALT/SGPT) may also be elevated, but less than 400 U/L. Once the ALP begins to rise, the degree of ALP elevation exceeds that of the transaminase elevations. The ALP is typically between 1- to 6-fold elevated and is usually less than 1000 U/L. GGT (gamma-glutamyltransferase) rises in conjunction with the ALP. Lactate dehydrogenase (LDH) is lower than the ALT, which reflects the observation that hepotocyte death occurs in response to bile salt-induced apoptosis rather than liver necrosis.

Other commonly encountered laboratory abnormalities include abnormal globulins, lipid profiles, cell differential, and positive ANA (antinuclear antibodies). Total globulins may be elevated, although typically not to the high degree that is found in AIH. Even with a normal total globulin level, the levels of individual immunoglobulin subclasess may be abnormal. The IgM is specifically elevated in PBC, although IgG is often elevated as well. IgA levels are usually normal.

Lipid profiles can be markedly abnormal. Triglycerides are not affected by PBC, but total cholesterol is often elevated and may reach levels as high as 300 to 600 U/L. Early in the disease process, the elevation is due to mostly HDL, but as time progresses, the HDL will fall and LDL will rise. In late disease, lipoprotein X may be produced, which has a similar density as VLDL and may be misinterpreted as an elevated LDL on automated densitometry. Lipoprotein electrophoresis can correctly identify the presence or absence of lipoprotein X.

Another peculiar (i.e., not understood) yet characteristic laboratory abnormality is elevated serum eosinophils, which is present in the very early stages of the disease and disappears after several years.

Other autoantibodies besides AMA are frequently found in PBC. The most common is antinuclear antibodies (ANA), which are present in 60% to 80% of PBC patients. Almost all (80-100%) of patients with AMA-negative PBC will test positive for ANA. The pattern of ANA may be any variety, although the anticentromere pattern is fairly specific to the presence of limited scleroderma (CREST) syndrome, and the PBC-specific ANAs (anti-sp100, anti-gp-210) will appear as speckled multiple nuclear dots or nuclear membrane patterns on immunofluorescence.

A tabular or chart listing of features and signs and symptoms

Are there pathognomonic or characteristic features?

There are no absolutely pathognomonic features of the disease. However, two features are more than 95% specific for the disease: the presence of antimitochondrial antibodies and florid duct lesions on liver biopsy. Whereas the AMA is also highly sensitive (95%), florid duct lesions are often hard to find. They are most commonly found in stage 2 disease, but are patchy and disappear as the disease progresses and ductopenia develops.  

What are some less common clinical presentations?

AMA-negative PBC (also called autoimmune cholangitis or autoimmune cholangiopathy) and PBC overlap with autoimmune hepatitis (overlap syndrome) are relatively uncommon and are often overdiagnosed variants of PBC. Because low titer AMAs may fluctuate into the negative range, low or negative values in a patient with suspected PBC should be repeated, ideally with an ELISA test, which is more sensitive and less operator-dependent than immunofluorescence. After three negative AMAs, the diagnosis of AMA-negative PBC can be made, although treatment and response to treatment are identical to AMA-positive PBC.

Overlap with autoimmune hepatitis can be challenging to diagnose because most of the laboratory and histological features of AIH are also found in PBC. The presence of severe interface hepatitis and elevated IgG are the most specific features of PBC-AIH overlap syndrome, although both can be seen to a lesser degree in routine PBC. Very high transaminases (AST or ALT >400 U/L) also suggests the presence of overlap syndrome. The determination of what is disproportionate for PBC alone should be made by an expert who sees large volumes of patients with both diseases because the consequence of diagnosing PBC-AIH overlap syndrome is the addition of long-term immunosuppression to the patient's treatment plan. (See Table I.)

Table I. Differential diagnoses of PBC
Disease Similarities Differences
Primary sclerosing cholangitis Chronic cholestasis, fatigue, pruritus, elevated IgM Strictures and dilations on MRCP/ERCP; male >female
Autoimmune hepatitis Female, autoimmune, elevated IgG, plasma cells and interface hepatitis on biopsy, ANA positive Elevation of IgG >IgM, transaminases disproportionately elevated compared to ALP
Secondary biliary cirrhosis Chronic cholestasis, pruritus Extrahepatic biliary strictures from stones or surgical complication
Drug-induced cholestasis Elevated ALP, GGT History of drug ingestion
Congenital ductopenia Elevated ALP, GGT ductopenia Lack of inflammatory destruction of ducts
BRIC Periods of elevated ALP and pruritus Periods of spontaneous normalization of all liver enzymes
Hepatic sarcoidosis Elevated ALP, GGT, hepatomegaly, pruritus Elevated ACE level, granulomas are larger, better formed, and scattered throughout the lobule; splenomegaly in the absence of portal hypertension

How can I confirm the diagnosis?

What tests should be ordered first?

Initial testing should include bilirubin, ALP, transaminases, antimitochondrial antibody, and abdominal sonogram to exclude biliary obstruction.  

What tests should be used to confirm the initial tests?

A middle aged female with positive AMA, no extrahepatic obstruction, and elevated ALP has a 95% positive predictive value for having PBC and does not need confirmatory testing if there is no suspicion for other conditions. If the patient does not meet these exact criteria, or if there is suspicion for another concurrent liver disease, then liver biopsy is needed to establish the diagnosis. The diagnostic finding in a liver biopsy is nonsuppurative granulomatous cholangitis (i.e., a florid duct lesion), but this is infrequently found. Small, poorly formed granulomas that are not centered on bile ducts may also be seen in the portal tracts or in the lobules.

Early PBC is characterized by lymphocytes and some plasma cells and eosinophils infiltrating the portal triads, often damaging the small bile ducts (Figure 1). The inflammation will spread beyond the portal triad and may cause interface hepatitis or small amounts of isolated lobular inflammation. The native bile ducts eventually succumb to the inflammatory insult and disappear so that ductopenia develops.

The hepatocytes at the edge of the portal tract may try to compensate by undergoing mesenchymal transformation into bile duct epithelial cells and form pseudoducts or bile ductular proliferation. These newly formed and poorly functional ducts attract neutrophils. Prolonged cholestasis from damaged or absent ducts may result in feathery degeneration or cholestasis changes. Over time, fibrosis deposits in the portal tracts and spreads through a bridging pattern between portal tracts. These fibrotic bands eventually distort the architecture of the liver into irregularly shaped nodules described as looking like "jig-saw" puzzle pieces. When biliary excretion is severely impaired, there may be Mallory's hyaline, bile droplets, or copper deposits that accumulate in the liver.

What tests are useful if the diagnosis is still in doubt?

Supportive but not diagnostic tests include quantitative IgM, cholesterol, and ANA. Tests to help exclude other diseases in the differential diagnosis include MRCP/ERCP (magnetic resonance cholangiopancreatography/endocscopic retrograde cholangiopancreatography), ANCA (antineutrophil cytoplasmic antibody), and ACE (angiotensin converting enzyme).

See Table II, Table III, and Table IV for laboratory, radiographic, and histological findings, respectively, in PBC.

Table II. Laboratory findings in PBC
Biochemical feature Expected Consistent Inconsistent
Bili Normal or elevated    
ALP Elevated    
GGT Elevated    
LDH Normal    
AST Normal     elevated     >400
ALT Normal     elevated     >400
AMA Positive     negative  
ANA Positive or negative    
IgM Elevated     normal  
IgG Elevated normal  
IgA Normal    
Chol Elevated     normal  
Trig Normal       elevated
Table III. Radiographic findings in PBC
Radiographic test Expected Consistent Inconsistent
Sonogram     Normal Abnormal echotexture, nodular liver, portal hypertension, hepatomegaly, gallstones, perihepatic adenopathy Dilated bile ducts
ERCP     Normal Pruning of ducts in cirrhosis Bile duct dilation or stricture
MRCP     Normal Pruning of ducts in cirrhosis Bile duct dilation or stricture
Table IV. Histological findings in PBC
Histological feature Expected Consistent Inconsistent
Bile duct damage Lymphocytic or granulomatous inflammation of ducts No evidence of bile duct damage may be found in very early disease. Neutrophilic inflammation of bile ducts
Granulomas Small, portal Small, lobular Large, well-formed, lobular granulomas or caseating granulomas
Bile ductular proliferation Typical of middle stage disease; neutrophils may be present.    
Cholate stasis Present    
Interface hepatitis   Present: may be confused with AIH  
Lymphocytes in portal tracts Most common finding May be absent in advanced cirrhosis  
Plasma cells in portal tracts Scattered in portal areas   Dense sheets of plasma cells
Lobular inflammation   Mild, patchy  
Mallory's hyaline   Present in advanced cholestasis Steatohepatitis
Copper accumulation   Present in advanced cholestasis  

What other diseases, conditions, or complications should I look for in patients with primary biliary cholangitis?

Major risk factors for patients with primary biliary cholangitis

The cause of PBC is still unknown. However, the strongest risk factor for PBC is genetic. PBC appears to be a multigenic disease and does not follow the principles of Mendelian genetics, but familial clustering does occur. The risk of PBC in a first-degree relative is approximately 4%. The concordance rate among monozygotic twins is reported to be 63%, which is one of the highest reported for any autoimmune disease. Often, there is a personal or family history of other autoimmune diseases, such as thyroid disease, rheumatoid arthritis, lupus, or Sjogren's syndrome.

Two large epidemiological studies from the United States and Europe sought potential risk factors for PBC and found slightly increased odds (<2-fold) with previous exposure to various toxins such as cigarette smoke, nail polish, and hair dye. However, these represented fairly small increased risks and confounding factors could not be excluded in the retrospective study design.

Diseases that may occur with primary biliary cholangitis

PBC is very commonly associated with other autoimmune diseases, as listed in the Table V.

Table V. Diseases associated with PBC
Disease Prevalence
Autoimmune anemias 1-2%
Grave's disease 3-6%
Gallstones 30-50%
Hypothyroidism 11-32%
Lichen planus 0.5-6%
Limited scleroderma (CREST) 3-17%
Psoriasis 1-13%
Renal tubular acidosis 20-33%
Rheumatoid arthritis 3-26%
Serogenative arthropathy 4-38%
Sicca syndrome 30-60%
Ulcerative colitis 0.5-1%
Urinary tract infections 11-35%

Because synchronous thyroid disease is commonly present, excessive or abrupt change in fatigue should prompt investigation with thyroid function testing. 

Commonly encountered complications of primary biliary cholangitis

Complications of PBC may be due either to long-term cholestasis or the development of portal hypertension. Long-term cholestasis results in poor bile acid delivery to the intestine and subsequent malabsorption of fat soluble vitamins A, D, E, and K. Vitamin A is often the first vitamin to become deficient, followed by D, and annual screening is recommended.Prolonged cholestasis also results in activation of osteoclasts and modulation of osteoblast activity, resulting in early osteoporosis. Periodic screening by bone density examination is recommende

The complications of portal hypertension encountered are not unique to PBC but are present in all other forms of cirrhosis: varices, ascites, and encephalopathy. Their management is similar to portal hypertension in other chronic liver disease

One caveat is that some patients with PBC will develop either nodular regenerative hyperplasia or severe granulomatous inflammation of the portal tracts, which may rarely lead to the development of varices before the onset of cirrhosis. The risk of hepatobiliary carcinoma is increased in those who progress to cirrhosis. (See Table VI.)

Table VI. Potential complications of PBC
Deficiency of vitamins A, D, E, K
Osteoporosis
Varices
Ascites
Hepatic encephalopathy
Hepatocellular carcinoma
Cholangiocarcinoma

What is the right therapy for the patient with primary biliary cholangitis?

What treatment options are effective?

Ursodeoxycholic acid (UDCA), at doses of 13 to 15 mg/kg daily, is considered standard of care for PBC. Aggregate data suggest that it prolongs survival without transplantation and delays the development of portal hypertensive complications, although it does not cure the disease. It is well tolerated in all phases of disease, although the degree of benefit in advanced disease is less certain.

A listing of all options, lifestyle, medical, endoscopic, surgical, and other estimates of efficacy

Numerous other therapies have been tried but deemed ineffective in controlled trials, including corticosteroids, azathioprine, colchicine, methotrexate, cyclosporine, and penicillamine. There is no role for endoscopic or biliary treatment because the disease is focused on the small intrahepatic ducts.

What is the most effective initial therapy?

All patients without decompensated cirrhosis should be started on UDCA at a daily dose of 13 to15 mg/kg, which is the only FDA-approved therapy for PBC.

Obeticholic acid, a derivative of a primary human bile acid that is a potent agonist of the farnesoid X receptor, is currently being studied for the treatment of PBC. Available research shows that it appears to be effective at reducing alkaline phosphatase and aminotransferase levels and is a promising alternative therapy currently undergoing clinical research trials.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails, including definitions of failure?

Usually, treatment with UDCA will result in improvement in liver biochemistries, although about 20% of patients will not respond to UDCA. An adequate response to UDCA is defined as an improvement in ALP to less than approximately 1.67 times the upper limit of normal. The improvement occurs steadily over the first 3 to 6 months. Normalization of ALP in response to UDCA is associated with an excellent prognosis.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies.

For patients who respond inadequately or not at all to UDCA treatment, there are no other FDA-approved medical treatments, although several are currently under investigation. Higher doses of UDCA have not been shown to be helpful, and very high doses of UDCA may result in conversion of excess UDCA by gut bacteria into lithocholic acid, which is more toxic to the liver.

Patients with PBC-AIH overlap syndrome may require the addition of immunosuppression (azathioprine with or without corticosteroids). Liver transplantation is a highly effective salvage therapy for progressive PBC in patients who have MELD scores of at least 15. Survival post transplantation is excellent (90%, 5-year). PBC recurs in the grafted liver at a rate of 20% to 40%, but the disease progression is so slow that it appreciably does not impact the survival or quality of life of the patient.

See Table VII.

Table VII. First- and second-line therapies for PBC
Symptom 1st-line therapy 2nd-line therapy
Pruritus Bile acid binding resins Sertraline, rifampicin, naltrexone,,
Fatigue Rest, exercise Modafenil
Vitamin deficiency Oral vitamin replacement Parenteral vitamin replacement
Varices (non- bleeding) Nonselective beta blocker Endoscopic ligation
Ascites Spironolactone +/- loop diuretic TIPS or serial paracentesis
Osteoporosis Calcium + bisphosphonate, smoking cessation, exercise Oral selective estrogen receptor modulator
Raynaud's Calcium channel blocker Topical glyceryl trinitrate, phosphodiesterase 5 inhibitors

Listing of these, including any guidelines for monitoring side effects.

N/A

How should I monitor the patient with primary biliary cholangitis?

Osteoporosis and fat-soluble vitamin deficiencies are often asymptomatic and thus annual screening should be performed with bone density, serum levels of vitamin A, D hydroxy, E, and prothrombin time. For patients who are known to be cirrhotic, biannual endoscopic screening for varices and semiannual screening for hepatobiliary carcinoma with sonogram, alpha fetoprotein, and CA 19-9. If it is not known whether the patient is cirrhotic or not, then the platelet count can be used as a surrogate marker for cirrhosis and screening for varices implemented when the platelet count drops below 140 to 200K.

How should I monitor progress of the disease?

Progress of PBC is monitored by serial blood tests every 3 to 6 months. The initial ALP response to UDCA predicts long-term survival. Elevated serum bilirubin is the single most important prognostic marker of shortened survival. Along with bilirubin, the creatinine and INR should be followed in order to track the MELD score and determine optimal timing for liver transplantation, if necessary. The risk/benefit ratio of repeating serial liver biopsies for staging purposes is high and thus not recommended. Serum fibrosis markers may serve as a substitute non-invasive marker but are not substantially better than bilirubin, which is less expensive.

In addition to UDCA, patients with PBC should take supplemental calcium to help prevent osteoporosis (1200 mg for postmenopausal females and 1000 mg for males and premenopausal females). Patients with PBC may require additional medication for symptom control or management of complications, as indicated in the table below.

What's the evidence?

Clinical features of primary biliary cholangitis

James, O, Macklon, AF, Watson, AJ. "Primary biliary cirrhosis: a revised clinical spectrum". Lancet. vol. 1. 1981. pp. 1278-81.

(This paper describes the spectrum of clinical findings in patients with PBC.)

Heathcote, J. "The clinical expression of primary biliary cirrhosis". Semin Liver Dis. vol. 17. 1996. pp. 23-33.

(Describes the spectrum of clinical findings in patients with PBC.)

Professional society management guidelines for PBC

Lindor, KD, Gershwin, ME, Poupon, R. "American Association for the Study of Liver Diseases: primary biliary cirrhosis". Hepatology. vol. 50. 2009. pp. 291-308.

(Current American practice guidelines for the management of PBC.)

"Clinical Practice Guidelines: management of cholestatic liver diseases". J Hepatol. vol. 51. 2009 Aug. pp. 237-67.

(Current European clinical practice guidelines for the management of PBC.)

Risk factors for primary biliary cirrhosis

Gershwin, ME, Selmi, C, Woramn, HJ. "USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients". Hepatology. vol. 42. 2005. pp. 1194-202.

(An article identifying and quantifying the risk factors for developing PBC.)

Prince, MI, Ducker, SJ, James, OF. "Case control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations". Gut. vol. 59. 2010. pp. 508-12.

(Identifies and quantifies the risk factors for developing PBD.)

Research Regarding the Use of Obeticholic Acid in PBC

Kowdley, KV, Kuketic, VA, Jones, DE. " The first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid X receptor agonist obeticholic acid in PBC". Hepatology. vol. 54. 2011. pp. 416A.

Hirschfield, GM, Mason, A, Kuketic, V. "Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to usrodeoxycholic acid". Gastroenterology. vol. 148. 2015. pp. 751.

Variants of PBC: AMA-negative PBC and PBC-AIH overlap syndrome

Invernizzi, P, Crosignani, A, Battezzati, PM. "Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and negative primary biliary cirrhosis". Hepatology. vol. 25. 1997. pp. 1090-5.

(Article describes the clinical features and responses to treatment of the PBC variant syndromes.)

Joshi, D, Cauch-Dudek, K, Wanless, IR. "Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid". Hepatology. vol. 35. 2002. pp. 409-13.

(Describes the clinical features and responses to treatment of the PBC variant syndromes.)

Günsar, F, Akaraca, US, Ersöz, G. "Clinical and biochemical features and therapy response in primary biliary cirrhosis and primary biliary cirrhosis-autoimmune hepatitis overlap syndrome". Hepatogastroenterology. vol. 49. 2002. pp. 1195-200.

(Describes the clinical features and responses to treatment of PBC variant syndromes.)

**The original author for this chapter was Marlyn Mayo. The chapter was revised by Dr. Bruce R. Bacon.

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