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Once clinical suspicion has been established for primary biliary cholangitis (PBC), the "" of the autoimmune disease are anti-mitochondrial antibodies (AMA), present in approximately 90% to 95% of all patients. In fact, positive results for AMA in a patient with cholestasis is enough for diagnosis of PBC without a liver biopsy.

"The diagnosis is not hard to make if somebody is thinking about it," Lucy Mathew, NP, of Cedars Sinai in Los Angeles, told MedPage Today. "If you have positive AMA and an elevated alkaline phosphatase, you're done, the diagnosis is made."

That said, AMA positivity is not exclusive to PBC -- it's present in in the general population -- and about 5% to 10% of people with PBC are negative for AMA.

Making the Diagnosis

Workup should include imaging, ideally with magnetic resonance cholangiopancreatography, to exclude extrahepatic biliary obstruction. In people without extrahepatic biliary obstruction or another established liver comorbidity, two of the following criteria are sufficient for a PBC diagnosis:

• An alkaline phosphatase level at least 1.5 times the upper limit of normal
• Presence of AMA at a titer of 1:40 or higher, or, in those negative for AMA, other PBC-specific autoantibodies
• Histologic evidence of РBС, such as non-suppurative destructive cholangitis and destruction of interlobular bile ducts

For the 5% of people who are AMA-negative, a liver biopsy is often necessary to confirm the diagnosis, but it can sometimes be avoided based on other lab results.

"The hepatologist might make a diagnosis without a biopsy if the patient is positive for ANA [antinuclear antibodies] or other antibodies," Mathew said, but it depends on the hepatologist.

Other include anti-multiple nuclear dot antibodies (anti-MND), anticentromere antibodies, and antinuclear envelop antibodies.

ANA -- present in of people with PBC -- and anti-MND in particular are surrogate markers of PBC in those with negative AMA, and presence of anti-sp100 and anti-gp210 antibodies as pointing toward a PBC diagnosis in AMA-negative patients.

Hatef Massoumi, MD, of the Northwell Health Center for Liver Disease and Transplantation in New York City, told MedPage Today that a negative result for AMA should prompt clinicians to look for other causes of elevated alkaline phosphate levels, such as medications and supplements, other biliary diseases including primary sclerosing cholangitis, alcohol consumption, infiltrative or granulomatous liver diseases such as hepatic sarcoidosis, and bone diseases.

Biopsies remain useful for staging or if the patient also has evidence of autoimmune hepatitis or does not respond to first-line treatment.

Primary Management of PBC

First-line treatment for PBC, regardless of presence of symptoms, is ursodeoxycholic acid (UDCA) at a twice-daily oral dose of 13-15 mg/kg.

UDCA "has been shown to slow the progression of the disease, to improve transplant-free survival, and to lower or normalize alkaline phosphatase in the majority of patients," Robert S. Brown Jr., MD, MPH, chief of the division of gastroenterology and hepatology at Weill Cornell Medicine in New York City, told MedPage Today.

The impact of UDCA on patient outcomes since its has been substantial.

"In the 70s and 80s, most people unfortunately presented with advanced disease because diagnosis and recognition was not quite as good, so most patients already presented with cirrhosis and jaundice," said David N. Assis, MD, of Yale Liver Clinics and Yale New Haven Hospital in New Haven, Connecticut.

Management goals include slowing the pathogenic process, treating PBC symptoms, and preventing or managing complications. About two-thirds of patients respond to UDCA, with response defined as an alkaline phosphatase level less than 1.67 times the upper limit of normal after 2 years of therapy. A smaller proportion will have normalization of alkaline phosphatase, an increasingly preferred treatment goal if it can be achieved with adjunctive therapies.

UDCA is usually a very well-tolerated drug, Brett E. Fortune, MD, medical director of the liver transplant program at Montefiore Medical Center in Bronx, New York, told MedPage Today, but about 5% of patients cannot tolerate it due to gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal discomfort.

Until the FDA's accelerated approval of two peroxisome proliferator-activated receptor (PPAR)-delta agonists -- seladelpar (Livdelzi) and elafibranor (Iqirvo) -- this year, the only alternative or adjunctive therapies available were obeticholic acid (Ocaliva) or .

However, the future of obeticholic acid remains uncertain. Though initially in 2016 as a second-line therapy for PBC, subsequent trials' failure to establish adequate efficacy and safety -- particularly for patients with advanced cirrhosis -- led the FDA to decline full approval for the farnesoid X receptor (FXR) agonist, though the agency has not withdrawn the initial accelerated approval.

Several other FXR agonists are for PBC, but increased itching and other safety concerns have remained a barrier.

Clinical response to the FDA's decision about obeticholic acid has been mixed, particularly since "we may have patients who need triple therapy" to achieve the goal of decreasing alkaline phosphatase to delay PBC progression for as long as possible, Brown said.

Managing Symptoms and Lifestyle

Since PBC is a chronic, incurable disease, "all we can do is control it and slow down the progression," while managing the symptoms that impact quality of life, Mathew said. Clinicians should ensure patients' "alkaline phosphatase and bilirubin are completely normalized and they're getting the maximum treatment for optimal response," she noted.

Monitoring patients every 6 months, or every 3 months if adjusting the medication, and periodically assessing for progression of fibrosis are important as well.

Even liver transplant is not a cure. "A liver transplant does basically reset the liver by getting a new one," Fortune said. "The problem is there is a one in five chance of recurrent disease because it's an immune disease and we're not replacing the immune system."

Managing the most bothersome symptoms of fatigue and pruritus can be very challenging, Brown said. Although UDCA can help with itch in some patients, it can worsen it in others, and obeticholic acid often worsens it. Seladelpar was shown to reduce itch in clinical trials, but elafibranor did not.

To manage the itching, antihistamines, particularly hydroxyzine, may be helpful, and sometimes naltrexone can help, Fortune said.

"The fatigue is nigh-on impossible to manage, and it doesn't seem to necessarily correlate with disease activity," Brown said. "That's something we need to do more research on to address."

Fortune also noted that "bone density is definitely a problem because you need bile acid transporting for vitamin D and other processes related to chronic liver disease, so it is important to address."

"If you're able to improve the bile acid metabolism, that reduces the risk of bone disease, but for those who have ongoing elevated liver tests or progressive liver disease, or they develop worsening scarring or fibrosis, they definitely are at risk for osteopenia or osteoporosis," he added. "We try to address that with vitamin D supplementation and calcium, but obviously it's not perfect."

Assis said that obesity, consumption of alcohol and ultra-processed foods, and other general health risks could all be "potential triggers for more injury over time" in managing PBC, but "there is not as of yet a particular diet or dietary components that are known to make PBC worse or better."

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