Etiology of PBC
PBC is often considered a classic immune disorder because of its hallmark serologic marker anti-mitochondrial antibody AMA and specific biliary pathology.The etiology of PBC is thought to be the result of a combination of genetic qualities and environmental factors.
Although its genetic qualities are relatively well understood, the correlation of major histocompatibility complexes (MHC) is variable. Several large epidemiological studies have been completed showing associations with urinary tract infections, reproductive hormone replacement, nail polish, past smoking history and exogenous chemicals in toxic waste disposal sites and animal models of PBC.
An important and unique feature of PBC is the high degree of specificity associated with small intrahepatic bile ducts. Staining of the small bile ducts with monoclonal antibodies to mitochondrial autoantigens showed intense staining of the apical surface of the bile duct epithelium.
The characteristic serologic marker of PBC, AMA, is a highly disease-specific autoantibody seen in 90-95% of patients compared to less than 1% of normal controls. The target site of the disease-specific anti-mitochondrial response is all membranes containing a family of enzymes 2-oxo-acid dehydrogenase complex, including pyruvate dehydrogenase complex (PDC-E2), branched 2-oxo-acid dehydrogenase complex, and 2-ketoglutarate dehydrogenase complex. These enzymes catalyze the oxidative decarboxylation of ketoacid substrates and are localized to the inner mitochondrial membrane. In one study, less than 5% of PBC patients were negative for AMA. Immunofluorescence assays and now more commonly ELISA are used for the detection of AMA.
Autoreactive PDC-E2-specific CD4 T cells were increased 100-fold to 150-fold in the liver and local lymph nodes of PBC patients compared to blood, and autoreactive PDC-E2-specific CD8 T cells infiltrating the liver were increased 10-fold to 15-fold compared to blood. These data strongly suggest that the anti-mitochondrial response is either directly associated with pathological changes or closely related to etiologic invasion.
Natural history
PBC is a chronic biliary depressive disease with a progressive course that can extend over decades. The rate of progression is highly variable between patients. Over the past decade or so, many changes have occurred in the diagnosis and management of PBC. More patients are being identified at an early stage, and many of these patients respond well to medical therapy. The number of liver transplants for PBC is decreasing in Europe and North America.
AMA can be detected in the plasma of asymptomatic patients with normal liver function, and based on the results of a small study, it is believed that many patients may eventually develop liver function abnormalities and symptoms. In this study, the average follow-up time from the first positive AMA test to the development of persistent liver function abnormalities was 6 years (1-19 years). However, no patients developed cirrhosis during the follow-up period.21 The estimated rate of AMA positivity in the general population is 0.5%, which means that less than 10% of AMA-positive patients will develop PBC.
Several studies from the United Kingdom, North America, and Sweden have investigated the proportion of asymptomatic patients (whose definition is variable) who will subsequently develop PBC-related symptoms. Each of these studies provided the proportion of patients with progressive progression, with 36% to 89% of patients developing symptoms during a mean follow-up period of 4.5-17.8 years. In the two most recent studies, the mean time from diagnosis to symptom onset was found to be 2 years and 4.2 years.
Prior to the advent of UDCA treatments, early stage patients, whether symptomatic or not, had a shorter survival time compared to the healthy population. In three contemporary studies, the 10-year survival rate for asymptomatic patients was 50-70%, while the average survival interval for symptomatic patients was 5-8 years from the onset of symptoms.
In a previous US study with 279 patients, the mean survival time for symptomatic patients was 7.5 years, significantly shorter than the mean survival time of 16 years for asymptomatic patients. The study from the northeast of England did not find this significant difference in survival, perhaps explained by the fact that asymptomatic patients had more deaths from liver-unrelated disease, while asymptomatic patients lived an average of 10 years longer.
Histological staging has been found to predict survival. The rate of histologic progression was evaluated in three major groups of patients when no effective therapeutic agents were available. The mean time to progression to extensive fibrosis was 2 years. after 4 years, the likelihood of remaining in early disease was 29% (confidence limits/confidence interval: 15%-52%), and 50% of patients who started with only interface hepatitis without fibrosis were diagnosed with cirrhosis. Only a minority (20%) of patients in the early stages of cirrhosis showed histologic stability. Overall, histological staging progressed by one stage every 1.5 years.
Liver failure (ascites, hemorrhage, hepatic encephalopathy, or hyperbilirubinemia [>6 mg/dL]) during 5 years of follow-up was estimated at 15% in the large community-based study of 770 patients in the northeast of England, compared with 25% in 236 patients enrolled in the European azathioprine trial.
In a prospective study of 256 patients (28% with cirrhosis) observed for a mean of 5.6 years, the rate of appearance of esophageal varices and their impact on survival were evaluated.34 A total of 31% of patients developed esophageal varices. The 3-year survival rate after the appearance of varices was 59%, compared with 46% after the appearance of the first bleeding.
Natural history of UDCA after its application (around 1990)
UDCA is the only drug currently approved for the treatment of patients with PBC. Several randomized trials, combination analyses and long-term observational studies have shown that this drug not only improves biochemical parameters but also delays histological progression and improves survival without liver transplantation. Therefore most patients are currently treated with UDCA.
In an early study, the rate of histologic progression to cirrhosis was significantly lower in the UDCA group than in the control group (13 vs. 49%). In a trial with 192 patients, UDCA treatment significantly delayed the progression of histologic staging after a mean follow-up of 3.4 years. In the UDCA trial conducted in France, the risk of progression from stage I-II to III-IV was 7% ± 2% in the UDCA group compared with 34% ± 9% in the placebo group. Predictors of progression to cirrhosis included blood bilirubin > 1 mg/dL and moderate to severe lymphocyte debris necrosis on liver biopsy.
A prospective study conducted in 180 patients receiving UDCA and placebo observed patients for 4 years and published the effect of the UDCA regimen on the appearance of esophageal varices. 139 patients had no varices and 41 patients started with varices. after 4 years, the risk of developing varices was 16% for UDCA-treated patients compared with 58% for patients receiving placebo. However, UDCA does not reduce the low rate of bleeding.
Survival
To avoid the lack of capacity of clinical trials to assess the long-term effectiveness of treatment, the effect of UDCA on the natural history of PBC was studied using the Markov model.46 The study included 262 patients taking UDCA 13-15 mg/kg/d for a mean of 8 years (1-22 years), and patient survival was significantly better than predicted according to the model. Overall survival rates for patients without liver transplantation were 84% at 10 years and 66% at 20 years, respectively. Survival was better than the natural survival predicted according to the updated Mayo model (relative risk: 0.5, P < 0.01). Six percent of early-stage patients were predicted to progress to the need for liver transplantation or death at 10 years and 22 percent at 20 years. Survival rates for these patients were similar to the control population. In contrast, patients treated at an advanced stage of the disease were significantly more likely to die or require liver transplantation (relative risk: 2.2, P < 0.05).
Although bilirubin levels are the best predictor of survival and the most important element of the full mathematical model of PBC prognosis, several clinical, biochemical and histological features of PBC are also predictive. Some of these models are also useful in predicting survival in patients treated with UDCA
Diagnosis of PBC
Chronic cholestasis requires suspicion of PBC after exclusion of other causes of liver disease. liver function showing cholestasis is considered for PBC, mostly established by AMA testing. If necessary, liver biopsy can be used to further confirm the diagnosis.
Elevated blood ALP
Exclude other causes of liver disease, including alcoholic, drug-related
Liver section imaging to rule out bile duct obstruction
AMA, ANA, ASMA
Consider liver biopsy, especially if AST > 5 x normal or AMA?
Liver biochemical tests
Most patients with PBC have abnormal liver function, including elevated ALP, slightly elevated transaminase activity (ALT or AST) and elevated immunoglobulins (mainly immunoglobulin M). Some patients with PBC may have high ALT or AST and hyperglobulinemia (elevated IgG). Altered biochemical tests correlate to some extent with disease stage and severity of histologic damage. In patients without cirrhosis, the degree of ALP elevation is mainly related to the absence of intrahepatic bile ducts and the severity of inflammation; transaminase activity and IgG elevation mainly reflect the degree of necrosis and inflammation in the confluent area and lobules; hyperbilirubinemia reflects the degree of intrahepatic bile duct absence and bile duct fragmentation-like necrosis. Elevated blood bilirubin, gamma globulin and hyaluronic acid, as well as decreased albumin and platelet counts are early indicators of cirrhosis and portal hypertension. As in other cholestatic diseases, blood cholesterol levels are often elevated. Individual patients may have elevated blood bile acid levels but this is not common.
Autoantibodies
AMA is found in about 95% of patients with PBC, and ANA and anti-smooth muscle antibodies are found in about half of patients with PBC. About 5-10% of patients are negative or only low (≤1/80) positive for AMA antibodies using immunofluorescence techniques. The presence or absence of antibodies is more important than the level of antibodies. Some patients with positive ANA, especially anti-GP210 and/or anti-SP100, may be associated with prognosis54; some patients with negative AMA may be found positive for antibodies to major M2 components (PDC-E2, 2-ketoglutarate dehydrogenase complex) by applying ELISA or protein blotting techniques.
Histology
PBC is characterized by chronic, nonsuppurative cholangitis that primarily involves interlobular and septal bile ducts. The term “”bloom-like bile duct lesion”” is commonly used to describe localized damage if it shows marked inflammatory changes and necrosis around the bile ducts. The inflammatory infiltrate consists mainly of lymphocytes and monocytes and is closely associated with the basement membrane of necrotic bile duct cells. The infiltrate consists of plasma cells, macrophages, polymorphonuclear cells (especially eosinophils), and sometimes epithelioid granulomas, the latter more often seen early in the disease.5 There is little (if any) arterial damage. Relatively often, the small portal veins are compressed and occluded by the inflammatory response. As fibrosis and sometimes cirrhosis progress, the terminal small hepatic veins are often preserved at their central sites. Lack of bile ducts is usually defined as less than 50% of the portal tract of the hepatic portal bundle containing the bile ducts.
The size of the liver biopsy specimen is important. The probability of observing cholangitis and bile duct damage increases with the number of hepatic portal tracts, as the damage is typically patchy in distribution. At least 10-15 portal bundles should be present and multiple views should be performed to confirm or exclude (with good reason) cholangitis and bile duct deficiency. (Observations) include periportal/periseptal copper deposits, periportal/periseptal feathery degeneration with or without Mallory-Denk vesicles, and siltation-type nodules. True cholestasis does not occur until the onset of decompensated liver disease.
The classic histologic damage is divided into four stages. stage I is characterized by inflammation of the confluent area with or without bloom-like bile duct lesions, with inflammation confined to the confluent area. Disease progression is characterized by progressively more damage around the confluent area extending into the liver parenchyma, called interfacial hepatitis (stage II). The damage around the confluent area is locally irregular, and the damage is characterized by cell necrosis or apoptosis, hepatocytes separated by inflammatory cells, and macrophages. There are two main types of interfacial hepatitis. The first is lymphocytic debris-like necrosis, in which hepatocyte necrosis or apoptosis is associated with lymphohistiocytes, similar to the damage seen in autoimmune hepatitis (AIH). The second type is biliary debris necrosis with a significant biliary response and sometimes bile duct hyperplasia with edema, neutrophil infiltration, peribiliary fibrosis and hepatocyte necrosis, the latter associated with bile depression. French studies have shown that the severity of interfacial hepatitis is highly predictive of the formation of extensive fibrosis. stage III is characterized by distorted deformation of the hepatic stent with more fibrous septum formation. Cirrhosis with widespread regenerative nodules is stage IV. Regenerative nodular hyperplasia is a well-known complication of PBC and should be differentiated from cirrhosis.
The usefulness of liver biopsy and ALP ≥ 1.5 times normal and AST < 5 times normal for the diagnosis of PBC becomes problematic due to the high disease specificity of a positive AMA test. Liver biopsy in AMA-negative patients can be recommended and used to exclude other concomitant conditions such as AIH and nonalcoholic steatohepatitis.
Role of imaging
Non-invasive imaging of the liver and bile ducts is necessary in all patients with biochemical evidence of biliary depression. If the diagnosis is uncertain, then MRI cholangiography or endoscopy may be indicated as a priority to rule out primary sclerosing cholangitis or other bile duct disease. Instant elastography (Fibroscan; Echosens, Paris, France) is a new non-invasive tool to assess the extent of liver fibrosis that has been studied in patients with PBC but has not been approved by the FDA.
Diagnostic methods
The diagnosis of PBC is generally based on the following criteria: (1) elevated biochemical evidence of biliary depression ALP; (2) positive AMA; and (3) histopathological evidence of nonsuppurative cholangitis and small or moderate bile duct destruction if a biopsy is performed. The differential diagnosis includes drug-induced biliary depression reaction, biliary obstruction, nodal disease, AIH, and primary sclerosing cholangitis.
Recommendations: Diagnosis
1: The diagnosis of PBC can be established if two of the following three criteria are met.
● Biochemical evidence of biliary depression: primarily based on elevated ALP.
● Positive AMA.
● Histological evidence of non-suppurative destructive cholangitis and interlobular bile duct destruction (Class I, Level B).
Clinical manifestations of PBC
Symptoms
Fatigue. Fatigue is the most common symptom of PBC and is seen in more than 78% of patients. Fatigue is non-specific and can be seen in many conditions other than PBC. Fatigue is not related to the severity of PBC, histologic stage, or disease duration. Severe fatigue can affect the quality of life of patients with PBC and may be associated with reduced overall survival. Its aetiology is unknown. Recent studies have found that autonomic neurology may be associated with fatigue in patients with PBC. Fatigue does not improve with treatment of depression, often persists, and is often associated with significant daytime sleepiness and may be a manifestation of untreated hypothyroidism, the latter seen in approximately 20% of PBC patients.
Pruritus. Pruritus is a more specific symptom of PBC than fatigue and was previously seen in 20-70% of PBC patients. It is now less common, as patients with PBC are usually diagnosed in the absence of symptoms. Pruritus may be localized or generalized, usually worse at night after bedtime, and exacerbated by exposure to wool, other fiber products, heat, or pregnancy, and may decrease in severity over time after the onset of PBC. However, it is unlikely to disappear completely without treatment unless the patient develops cirrhosis and liver failure. the cause of pruritus in PBC is unknown. Cholestasis-induced pruritus, including secondary to PBC, is presumed to be triggered at least in part by increased opioid neurotransmission, while other studies support a role for certain components of bile
Other symptoms. Dryness syndrome (dry eyes and/or dry mouth) is common. Skin calcification, Raynaud’s phenomenon, and dysphagia are uncommon.
Physical examination
Physical examination is usually normal. Occasionally, macular tumors and yellow tumors may be present. Spider nevi and splenomegaly are seen in the presence of portal hypertension. Jaundice is a more advanced manifestation in patients with progressive liver disease.
Portal hypertension
Similar to other liver diseases, portal hypertension is most commonly seen in the late stages of PBC, when the patient has been diagnosed with cirrhosis. However, in contrast to other liver diseases, portal hypertension can also be seen in early, pre-cirrhotic PBC. these patients may have esophageal varices, gastric varices, or bleeding from portal hypertensive gastropathy, even though their liver synthesis is normal or near normal. Nodular regenerative hyperplasia is associated with the loss of small portal veins and can lead to portal hypertension in some patients. Patients with variceal bleeding without liver transplantation can survive for years afterwards. Ascites and hepatic encephalopathy are seen in patients with histology showing progressive PBC or cirrhosis.
Bone disease
Osteoporosis is the most common skeletal disorder in PBC and is seen in more than 1/3 of patients. The relative risk of osteoporosis in PBC is 4.4 compared to an age- and sex-matched healthy population. it is usually asymptomatic, normal on all laboratory tests, and detectable by bone density testing. debilitating bone disease was seen decades ago, often with multiple fractures, and is now less common. the cause of osteoporosis in PBC is unclear. patients with PBC appear to have Patients with PBC appear to have “low-turnover” osteoporosis, with suppressed internal bone formation and low or normal resorption. Vitamin D metabolism is normal in patients with PBC except for the presence of jaundice and clinically progressive disease.
Hyperlipidemia
The mechanism of hyperlipidemia in PBC is different from other diseases. HDL cholesterol is usually elevated, and rare lipoprotein particles such as lipoprotein X can accumulate. Mean cholesterol levels in two studies of patients with PBC were 370 and 265 mg/dL, with individual variation of 120-1775 mg/dL. HDL cholesterol is disproportionately elevated compared to LDL cholesterol, and patients with PBC do not have an increased risk of death due to atherosclerosis.
Vitamin deficiency
Although bile acid secretion may be reduced in patients with PBC leading to lipid malabsorption, deficiencies of clinically important fat-soluble vitamins A, D, E, and K are uncommon. Most patients, including those with osteoporosis, have normal vitamin D metabolism, and plasma levels of 25-hydroxyvitamin D and 1-25 dihydroxyvitamin D are often normal. Exceptions are seen in patients with severe jaundice awaiting liver transplantation, where osteoporosis may also be present. Vitamin A, D, E, and K levels may be reduced, leading to night blindness, osteomalacia, neurological impairment, and decreased prothrombinogen activity, respectively.
Special Conditions
AMA-negative PBC
AMA-negative PBC refers to patients who are AMA-negative but whose clinical presentation, liver histology and natural history are basically consistent with typical AMA-positive PBC. Almost all of these patients have antinuclear and/or anti-smooth muscle antibodies.
Slight differences in histopathology, immunology and HLA statusstatus existed between the AMA-positive and negative populations. Mitochondrial antigen was expressed in the parietal membrane of biliary epithelial cells in individual AMA-negative and positive PBC patients, suggesting a similar pathogenesis.
The diagnosis of AMA-negative PBC requires liver biopsy to confirm the presence of bile duct damage characteristic of PBC. The diagnosis is more definitive if granulomas are present.