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Primary biliary cholangitis (PBC) has typically been considered a rare condition, with a pooled global of two per 100,000 people per year and an estimated prevalence of 15 per 100,000 people per year. But both its incidence and prevalence have been increasing, and it's the cholestatic disease in middle-age women in the U.S.

The increase in prevalence has been attributed to improved survival from treatment with first-line ursodeoxycholic acid and earlier clinical diagnosis. As with multiple other autoimmune conditions, however, it's less clear what may be driving the increase in incidence. Fortunately, alongside the increase in cases is a recent expansion of therapeutic agents for PBC.

"If you talk to anyone who takes care of a lot of patients with PBC, we used to see a lot of advanced-stage PBC," 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. "If you talk to younger clinicians or to me now, you don't see it anymore."

Overview of PBC

PBC is a chronic autoimmune disease in which inflammation of the liver's bile ducts gradually leads them to break down, with the subsequent build-up of bile then damaging the liver. Previously known as primary biliary cirrhosis, the both better understanding of the condition's natural history and how better management is now preventing progression to cirrhosis in most patients.

The vast majority of patients with PBC are women, but growing incidence among men has reduced the gender gap from a ratio of about 9:1 to about 4:1 in the past two decades. Most diagnoses occur when patients are 45 to 65 years old, but men tend to be diagnosed at older ages.

Prevalence appears greatest in northern Europe and North America and used to be mostly in white patients, but "we're now seeing increasing prevalence of PBC in Black and Asian Americans," Hatef Massoumi, MD, of the Northwell Health Center for Liver Disease and Transplantation in New York City, told MedPage Today. In addition, has suggested that Hispanic patients tend to have more aggressive disease, lower response rates to ursodeoxycholic acid, and a greater risk of autoimmune hepatitis.

Like many autoimmune conditions, PBC etiology is not fully understood but thought to be a combination of genetic predisposition, , and environmental triggers. First-degree relatives of an individual with PBC are to have the condition themselves. Among the environmental triggers that evidence has are cigarette smoking, urinary tract infections, nail polish, hair dyes, toxic waste, and certain bacterial infections. But it remains T cells to attack small bile duct epithelial cells.

As with other autoimmune conditions, those with PBC are more likely to have other autoimmune diseases. The is Sjögren's disease, with symptoms occurring in 40% to 65% of PBC patients, particularly dry eyes and dry mouth. Around 10% to 15% of people with PBC also have thyroid disease, especially Hashimoto's, and 5% to 15% develop rheumatoid arthritis and/or have limited cutaneous scleroderma. Autoimmune hepatitis, while less common than other autoimmune conditions, can also co-occur with PBC.

Signs, Symptoms, and Diagnostic Suspicion

The most common and prominent symptoms of PBC are fatigue and pruritus, with about half of newly diagnosed patients experiencing fatigue and anywhere from a third to up to 70% reporting itching. The fatigue can be pretty extreme, interfering with people's ability to do daily activities, Brett E. Fortune, MD, medical director of the liver transplant program at Montefiore Medical Center in Bronx, New York, told MedPage Today. The itching, meanwhile, tends to concentrate in the extremities.

"A pattern of itching on the soles of the feet and palms of the hand is very unique to this disease, and it tends to be worse at nighttime," said Lucy Mathew, NP, of Cedars Sinai in Los Angeles.

The itching is not accompanied by a rash, Brown said, and sometimes he sees hyperpigmentation on a patient's anterior shins because they're scratching one shin with their opposite leg's heel while asleep at night without realizing it.

"Someone who has a lot of pruritus and not a lot of rash -- that's when I start to think about liver-related itching because it's related to bile acids underneath the skin, irritating the skin," Brown said.

Other common symptoms can include dry eyes and dry mouth, so patients rarely end up first in a gastroenterology/hepatology office, Brown said. "They're much more likely to go to an ophthalmologist or dermatologist or endocrinologist or their primary care doctor than they are to go to a gastroenterologist or hepatologist," he noted.

However, at least half of patients are typically asymptomatic at diagnosis, and it's usually abnormal liver labs that ultimately lead most patients to hepatology for diagnosis.

The key lab indicator for clinical suspicion is a high alkaline phosphatase level. Sometimes bilirubin will tend to rise as the disease progresses, but early on, bilirubin is often normal, and aspartate transaminase (AST) and alanine transaminase (ALT) may be normal as well, Brown said. Cholesterol levels may also be elevated but appear unremarkable since high-density lipoprotein cholesterol is elevated along with the total. Very elevated cholesterol can lead to xanthelasma.

"When you see a woman who has elevated cholesterol, xanthelasma, and elevated alkaline phosphatase," Brown said, "I would say that most of those patients are going to end up having PBC."

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