Primary Biliary Cholangitis (PBC)

Primary biliary cholangitis (PBC) is the most common liver disease associated with chronic cholestasis in adults. Most (95%) cases occur in women aged 40 to 70 years (1). PBC also clusters in families. A genetic predisposition, primarily but not exclusively involving HLA alleles, contributes. Environmental triggers, the gut microbiome, and disordered immune regulation likely also play roles.

Antibodies to antigens located on the inner mitochondrial membranes occur in 90 to 95% of cases (2, 3). These antimitochondrial antibodies (AMA), the serologic hallmarks of PBC, are not cytotoxic and are not involved in bile duct damage.

PBC is associated with other autoimmune disorders, such as systemic sclerosis, Sjögren syndrome, CREST syndrome (also known as limited scleroderma), and autoimmune thyroiditis (1).

T cells attack the small bile ducts. CD4 and CD8 T lymphocytes directly target biliary epithelial cells (1). The trigger for the immunologic attack on bile ducts is unknown. Exposure to foreign antigens, such as an infectious (bacterial or viral) or toxic agent, may be the instigating event. These foreign antigens might be structurally similar to endogenous proteins (molecular mimicry); then the subsequent immunologic reaction would be autoimmune and self-perpetuating. Destruction and loss of bile ducts lead to impaired bile formation and secretion (cholestasis). Retained toxic materials such as bile acids then cause further damage, particularly to hepatocytes. Chronic cholestasis thus leads to liver cell inflammation and scarring in the periportal areas. Eventually, hepatic inflammation decreases as hepatic fibrosis progresses to cirrhosis.

AMA-negative PBC is characterized by autoantibodies, such as PBC-specific antinuclear antibodies (anti-gp210/anti-sp100), and has a clinical course and response to treatment that are similar to those of PBC (2, 3). However, AMA is absent.

Approximately half of patients present without symptoms (1). Symptoms or signs may develop during any stage of the disease and may include fatigue or reflect cholestasis (and the resulting fat malabsorption, which may lead to vitamin deficiencies and osteoporosis), hepatocellular dysfunction, or cirrhosis.

Symptoms usually develop insidiously. Up to 80% of patients experience pruritus and fatigue (1). Pruritis and fatigue, along with dry mouth and eyes, can precede other symptoms by months or years. Fatigue may be accompanied by cognitive symptoms, including difficulty concentrating and brain fog. Other initial manifestations include right upper quadrant discomfort; an enlarged, firm, nontender liver; splenomegaly; hyperpigmentation; xanthelasmas; and jaundice. Eventually, the features and complications of cirrhosis occur. Peripheral neuropathy and other autoimmune disorders associated with primary biliary cholangitis may also develop.

• History and physical examination

• Laboratory tests including liver tests (including alkaline phosphatase), autoantibody tests (antimitochondrial antibody [AMA], primary biliary cholangitis [PBC]-specific antibodies)

• Imaging (eg, ultrasound, MRCP or ERCP, elastography) to exclude other causes of cholestasis

• Sometimes liver biopsy

Diagnosis is confirmed if 2 of the following 3 criteria are present (1):

• Liver blood tests: Cholestasis with elevated alkaline phosphatase

• AMA or PBC-specific auto-antibodies (eg, anti-sp100 or anti-gp210) positivity

• Liver biopsy: nonsuppurative destructive cholangitis and destruction of interlobular bile ducts

PBC is suspected in middle-aged women with classic symptoms (eg, unexplained pruritus, fatigue, right upper quadrant discomfort, jaundice) or laboratory results suggesting cholestatic liver disease: elevated alkaline phosphatase (usually higher than 1.5 times the normal range) and gamma-glutamyl transpeptidase (GGT) but minimally abnormal aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], usually less than 5 times normal ranges). In asymptomatic patients, primary biliary cholangitis (PBC) is detected incidentally when liver tests detect abnormalities, typically elevated levels of alkaline phosphatase and GGT. Serum bilirubin is usually normal in the early stages; elevation indicates disease progression and a worsening prognosis. Serum cholesterol may also be elevated.

If PBC is suspected, liver blood tests and tests to measure serum IgM (increased in PBC) and AMA testing should be performed. Enzyme-linked immunosorbent assay (ELISA) tests for the M2 subtype of AMA are approximately 90% sensitive and 96% specific for PBC (2); false-positive results can occur in autoimmune hepatitis (type 1). Other autoantibodies (eg, antinuclear antibodies [ANAs], anti–smooth muscle antibodies, rheumatoid factor) may be present. Extrahepatic biliary obstruction should be excluded.

Ultrasound must be performed first, but ultimately magnetic resonance cholangiopancreatography (MRCP) and sometimes endoscopic retrograde cholangiopancreatography (ERCP) are necessary to evaluate the hepatobiliary system and exclude other causes of cholestasis. Noninvasive elastography (ultrasound or MR-based) is helpful to evaluate for fibrosis and cirrhosis (1).

Liver biopsy is not required in most patients but is required to confirm AMA-negative or PBC-specific autoantibodies negative PBC (1). Liver biopsy helps exclude other cholestatic diagnoses (drug-induced liver disease, sarcoidosis, PBC, biliary obstruction, autoimmune hepatitis) or coexisting liver diseases (autoimmune hepatitis or metabolic dysfunction-associated steatohepatitis [MASH], formerly known as nonalcoholic steatohepatitis [NASH]). Liver biopsy may detect pathognomonic bile duct lesions, even in early stages. As PBC progresses, it becomes morphologically indistinguishable from other forms of cirrhosis. Liver biopsy also helps stage PBC, especially to confirm the presence of cirrhosis.

Primary Biliary Cirrhosis (Light Micrograph)

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NIGEL DOWNER / SCIENCE PHOTO LIBRARY

Some patients with PBC have findings that overlap with autoimmune hepatitis (ALT more than 5 times the normal range, IgG more than 2 times the normal range, positive anti-smooth muscle antibody, and moderate to severe interface hepatitis in liver biopsy).

• Discontinuing hepatotoxic agents including alcohol

• Ursodeoxycholic acid (UDCA)

• Adding or switching to peroxisome proliferator-activated receptor (PPAR) agonist as a second-line therapy if inadequate response to UDCA

• Treating complications (chronic cholestasis, pruritus, and liver failure)

• Sometimes liver transplantation

All alcohol use and hepatotoxic medications should be stopped.

Ursodeoxycholic acid (UDCA) at 13 to 15 mg/kg/day orally decreases liver damage, prolongs survival, and delays the need for Ursodeoxycholic acid (UDCA) at 13 to 15 mg/kg/day orally decreases liver damage, prolongs survival, and delays the need forliver transplantation (1). Approximately 40% of patients do not have biochemical improvement after ≥ 12 months (alkaline phosphatase less than 1.5 to 2 times the normal range and normalization of total bilirubin); they may have advanced disease and require liver transplantation in a few years.

AMA-negative primary biliary cholangitis (PBC) has similar treatment response to UDCA.

PPAR agonists (including some fibrates) may be used as second-line therapy for patients who do not respond adequately to UDCA. Seladelpar (PPAR delta agonist) (PPAR agonists (including some fibrates) may be used as second-line therapy for patients who do not respond adequately to UDCA. Seladelpar (PPAR delta agonist) (2) or elafibranor (PPAR alpha and delta agonist) are used in combination with UDCA, or, for patient who cannot tolerate UDCA, as a single agent. Both have been shown to be effective in clinical trials () or elafibranor (PPAR alpha and delta agonist) are used in combination with UDCA, or, for patient who cannot tolerate UDCA, as a single agent. Both have been shown to be effective in clinical trials (2, 3).

Fibrates, which are PPAR-alpha agonists, are also used as second-line therapy (4). For patients who do not respond adequately to UDCA and do not have access to seladelpar or elafibranor, bezafibrate may be used in combination with UDCA. Bezafibrate has been shown to be more effective than UDCA alone in UDCA nonresponders but is not available in the United States (). For patients who do not respond adequately to UDCA and do not have access to seladelpar or elafibranor, bezafibrate may be used in combination with UDCA. Bezafibrate has been shown to be more effective than UDCA alone in UDCA nonresponders but is not available in the United States (5, 6). Fenofibrate, another fibrate that is available in the United States, has not been as well studied in this population, but it is still used. Fibrates can cause elevated aminotransferases and worsening renal function, which should be monitored.). Fenofibrate, another fibrate that is available in the United States, has not been as well studied in this population, but it is still used. Fibrates can cause elevated aminotransferases and worsening renal function, which should be monitored.

PPAR agonists, including fibrates, are not recommended in decompensated cirrhosis (7, 8, 9).

Obeticholic acid was another second-line agent but was voluntarily withdrawn from the United States market following safety concerns (Obeticholic acid was another second-line agent but was voluntarily withdrawn from the United States market following safety concerns (10).

Pruritus may be controlled with cholestyramine 4 to 16 g/day. This anionic-binding medication binds bile salts and thus may aggravate fat malabsorption. If cholestyramine is taken long term, fat-soluble vitamin supplements should be considered. Cholestyramine can decrease absorption of UDCA, so these medications should not be given simultaneously. Cholestyramine can also decrease absorption of various other medications; if patients take any medication that could be affected, they should be told not to take the medication within 1 hour before or 4 hours after taking cholestyramine. Several ileal bile acid transporters (IBAT) show promising results for pruritus treatment in PBC.Pruritus may be controlled with cholestyramine 4 to 16 g/day. This anionic-binding medication binds bile salts and thus may aggravate fat malabsorption. If cholestyramine is taken long term, fat-soluble vitamin supplements should be considered. Cholestyramine can decrease absorption of UDCA, so these medications should not be given simultaneously. Cholestyramine can also decrease absorption of various other medications; if patients take any medication that could be affected, they should be told not to take the medication within 1 hour before or 4 hours after taking cholestyramine. Several ileal bile acid transporters (IBAT) show promising results for pruritus treatment in PBC.

Some patients with pruritus respond to UDCA and ultraviolet light; others may warrant a trial of rifampicin, naltrexone, sertraline, phenobarbital, or an antihistamine (Some patients with pruritus respond to UDCA and ultraviolet light; others may warrant a trial of rifampicin, naltrexone, sertraline, phenobarbital, or an antihistamine (1). Dry eyes may be managed with artificial tears, pilocarpine, cevimeline, or other therapies under the supervision of an ophthalmologist; xerostomia may be managed with saliva substitutes, pilocarpine, or cevimeline.). Dry eyes may be managed with artificial tears, pilocarpine, cevimeline, or other therapies under the supervision of an ophthalmologist; xerostomia may be managed with saliva substitutes, pilocarpine, or cevimeline.

Patients with fat malabsorption due to bile salt deficiency should be treated with vitamin A, vitamin D, vitamin E, and vitamin K supplements (Patients with fat malabsorption due to bile salt deficiency should be treated with vitamin A, vitamin D, vitamin E, and vitamin K supplements (1). For osteoporosis, weight-bearing exercises, bisphosphonates, or raloxifene may be needed in addition to calcium supplements and vitamin D supplements. In later stages, , weight-bearing exercises, bisphosphonates, or raloxifene may be needed in addition to calcium supplements and vitamin D supplements. In later stages,portal hypertension or complications of cirrhosis require treatment.

Liver transplantation has excellent results. The general indication is decompensated liver disease (Model for End-Stage Liver Disease [MELD] score ≥ 15, uncontrolled variceal bleeding, refractory ascites, intractable pruritus, and hepatic encephalopathy) (1). A long-term retrospective study of 785 patients in North America and Europe who had undergone liver transplantation for primary biliary cholangitis reported patient survival rates of 90% at 5 years, 81% at 10 years, 70% at 15 years, and 53% at 20 years (11). Antimitochondrial antibodies tend to persist after transplantation. Primary biliary cholangitis recurs in 15% of patients in the first few years and in > 30% by 10 years. Recurrent PBC after liver transplantation appears to have a benign course. Cirrhosis rarely occurs (12).

Median time until symptom development in asymptomatic patients is approximately 2 to 4 years (1), but patients may not develop symptoms for 10 to 15 years. PBC may not diminish quality of life for many years. Once symptoms develop, median life expectancy is 10 years.

With treatment, including UDCA, 10-year liver transplant–free survival is approximately 80% (versus approximately 60% in untreated patients) (2).

Multiple scoring systems exist for risk stratification and assess the response to treatment (1). Predictors of progression and non-response to therapy include the following (3, 4):

• Higher serum alkaline phosphatase and bilirubin

• Lower serum albumin and platelet countLower serum albumin and platelet count

• Greater degree of hepatic fibrosis

• Younger age (< 45 to 50 years) at diagnosis

• Male sex

The prognosis is ominous when pruritus disappears, xanthomas shrink, jaundice develops, and serum cholesterol decreases.