1 What is PBC? Primary biliary cholangitis, or PBC, is a chronic and progressive hepatitis of long duration affecting mostly women between 35 and 60. Men are less affected by PBC, probably not more than 1 out of 10 cases. However, their PBC prognosis tend to be poorer, compared to that of women. So in spite of men being less numerous, PBC diagnostics should be considered if the analysis shows signs of cholestasis.

2 Cause/causes: The origin of PBC is unknown but autoimmune, (when a person´s immune system attacks its own organism) genetic and/or environmental factors are probable causes. PBC is linked to other autoimmune diseases like scleroderma, thyroid, Sjögren´s syndrome, rheumatoid arthritis, celiac disease etc. It is estimated that 30 % of the patients with PBC are affected by at least one other autoimmune disease .

3 What kind of lesions can be seen in a liver biopsy? At present a liver biopsy is not needed to make a diagnosis. The histological lesions are characterized by inflammation and progressive destruction of biliary ducts with scarring and fibrosis creating a clinical picture of cholestasis caused by bile duct circulation difficulties and the persistence of the inflammation (cholangitis). Eventually leading to destruction of intrahepatic biliary ducts with cholestasis and fibrosis.

The bile has two essential functions, digestion and absorption of fat as well as elimination of organic toxins. When PBC has reached advanced stages, the bile no longer performs these functions, nor can it circulate, and therefore it produces jaundice, yellow coloration of the skin, when bilirubin levels rise to more than 2 to 3 mg/dl or from 34 to 51 umol/l.

4 PBC, a bit of history: In 2014 PBC had its name changed from Primary Biliary Cirrhosis to Primary Biliary Cholangitis (PBC). There were different reasons for the name change; the term cirrhosis did not seem appropriate since the patients, at the time of diagnosis, did not have cirrhosis, and recent decades have shown that cirrhosis can easily be avoided with early diagnostics and specific treatment. Furthermore, the concept of cirrhosis can be stigmatizing in many cultures as it is associated with excessive and damaging alcohol consumption.

PBC was in need of a reinterpretation so a group of international experts, PBC specialists, as well as patient groups recommended a name change to Primary Biliary Cholangitis (PBC). Cholangitis is a more appropriate name as the basic liver lesion is located in the bile ducts, and yet allows the acronym PBC to remain.

5 How to diagnose PBC? The diagnosis is based on three pillars, through analysis looking for an increase in alkaline phosphatase (ALP) levels and positive antimitochondrial antibodies (AMA) and the third criterion being liver biopsy in order to disclose the typical destructive, chronic, but not suppurative, cholangitis lesions. Currently, if the AMA are positive, a liver biopsy is unnecessary and it is recommended to initiate treatment immediately even if the patient, as yet, has no symptoms.6 Evolution in patients with PBC and negative AMA results: Antimitochondrial antibodies (AMA) constitute a sensitive and specific PBC marker and these are present in 90-95 % of the PBC cases. Nevertheless, there is little information on patients with negative AMA. In a retrospective long-term revision of patients with negative AMA, performed in the Mayo clinic and published in 2016, it was concluded that these patients had a poorer prognosis than the PBC patients with positive AMA. A possible cause being later diagnostics.

7 What are the manifestations of this disease? PBC has two different ways of appearing, with and without symptoms. The silent form is characterized by analytic alterations and positive antibodies, AMA. It is estimated that 60% of the patients are asymptomatic when diagnosed and that the majority prematurely show histological alterations in accordance with PBC, which is why, in the presence of positive AMA and an elevated ALP, it is recommended to begin treatment and to follow the normal PBC checks.

8 Epidemiology: The incidence and prevalence of the disease have increased in recent years. Probably because the majority of cases are diagnosed at early and asymptomatic stages with minor analytic alterations and the presence of antibodies, AMA, during a systematic clinical examination or detected in the process of diagnosing other associated illnesses. PBC is most frequent in North America and in the north of Europe.

9 Natural history of the disease: Even though it is not always the case, the disease can advance from a mild inflammation of the bile ducts into cirrhosis. It is very important to stress the fact that an elevated number of patients never get cirrhosis, not least during recent decades with specific treatments that hinder inflammation and progression of liver fibrosis. The survival rate of early diagnosed patients is comparable to the same gender and age in the population as a whole.

10 Analytic routine markers in checking PBC are: ALP, bilirubin and albumin. It is important to know what the normal levels in an analysis are and that a change within these markers can imply a potential risk of disease progression. An increased ALP level indicates an altered bile flow in the liver. An elevated bilirubin level might indicate liver damage and a reduction of albumin is associated with progressive liver disease as well as a deficit in the liver`s capacity to synthesize.

11 Clinical course, possible complications: Except for the analytic alterations patients diagnosed with PBC might also develop symptoms deriving from PBC as the disease progresses, such as fatigue/asthenia, itching (prurito) and vague disturbances in the right hipochondrium.

12 Signs and symptoms of PBC: The most common symptoms referred to by patients are: Fatigue; asthenia, and tiredness; Itching/pruritus; jaundice. The cause of PBC fatigue is unknown as well as potentially very debilitating. At present there are no accepted pharmacological treatments for fatigue, even though there are ongoing trials. Given the fact that fatigue is such a common and unspecific symptom, it is important to dismiss other causes for fatigue. The PBC fatigue is neither related to the gravity of the liver disease nor to its prognosis. Just as the fatigue, the cause of the PBC pruritus remains unknown and is not always related to the gravity of the liver disease in question. There are available pharmacological treatments against pruritus that are effective for the majority of the afflicted (see further ahead under Available treatments). Jaundice occurs when PBC is more advanced and is a prognostic factor. Occasionally PBC treatment can reverse this but some patients with jaundice have to have a liver transplantation, as an increase in jaundice symptoms indicate a deteriorating liver function.

13 Current treatment for PBC. Impact of treatment with ursodeoxycholic acid (UDCA): Introducing UDCA as a primary therapy for PBC has changed the natural history of the disease by reducing the need for Liver Transplantation (LT) as well as lowering mortality rates in patients with PBC, according to many studies, especially so if administrated at early stages. But not all PBC patients respond as well to UDCA treatment. As a matter of fact UDCA is efficient for up to 60 % of the patients. Biochemical treatment failure implicates the need for a second line treatment. The ursodeoxycholic acid, known as UDCA, is presently the only medical first line PBC treatment. It comes in capsules and the recommended dose is 13-15 mg/kg twice a day. UDCA is a bile salt which reduces duct inflammation, drains bile from the liver, inhibits disease progression and, in many cases, improve analytic liver results, especially bilirubin and ALP measurements.

14 Obeticholic acid (ocaliva, OCA) as second line treatment: Obeticholic acid (OCA) was tried out and authorized as a second line treatment for PBC, by the regulatory agencies FDA and EMA in 2016. This treatment is introduced when a patient does not respond to (or tolerate) the UDCA. Obeticholic acid (OCA) is a synthetic derivation of bile acid and a potent combattant of the farnesoid X receptor (FXR), the nuclear bile acid receptor, frequently expressed in the liver. It immediately regulates transported bile acid like an excretory bomb of bile salts determining the velocity of bile discharge (BSEP, Bile Salt Export Pump). In April 2014, results from a randomized, double blind, phase III, OCA study, with 5 to 10 mg or placebo, were presented, disclosing that OCA significantly managed to reduce the ALP serum concentration as a predicting biomarker for disease progression. Current OCA practice shows an improvement of fibrosis and bilirubin levels in PBC patients with earlier incomplete response to, or lower tolerance for, UDCA and in addition liver histology improves.

15 Available treatments for symptoms and complications associated with PBC: Apart from the above mentioned, specific treatment the symptoms and complications of chronic cholestasis have to be taken care of. The most common drugs to handle pruritus are: antihistamines, ion exchanged resins (as cholestyramine), antidepressants, rifampicin and/or opioid antagonists, sequentially administered. The initial treatment is cholestyramine and more than half of the patients with prurito respond to that therapy. Other treatment options include benzofibrate, colestipol, phototherapy etc. Hypercholesterolemia: Some patients show a noticeable increase in the plasma cholesterol. Treatment with fibrates and statins is advisable. It is interesting to register that there is no increase in risks of cardiovascular complications. Osteoporosis: As PBC appears more frequently in postmenopausal women and is a cholestatic liver disease, which might promote osteoporosis, it is advisable to control bone mineral density.

16 Possible complications in the advanced stages of the disease: PBC is divided into four stages from phase 1 (early disease without significant liver fibrosis) but if the fibrosis advances it might reach phase 4, liver cirrhosis and associated complications: portal hypertension (ascites, varicose veins, encephalopathy), malabsorption of fat and liposoluble vitamins, subcutaneous deposition of fat (xanthomas), osteoporosis/osteomalacia and/or hepatocarcinoma (HCC), screening for HCC is recommended for PBC patients in case of cirrhosis.

17 Why is PBC considered to be a rare disease? It meets the requirements for rare diseases. Nevertheless, it is underdiagnosed and more work should be done on medical information adressed to the general population, since it is easy to diagnose and the current treatment with UDCA in early stages improves both liver inflammation and prognosis. Prevalence and incidence vary with geographical locations. Present studies in the UK suggest that prevalence might be 250 cases per million inhabitants or affect one out of a thousand women, older than forty years. It is estimated that about 30-40 % of these women are asymptomatic.

18 Genetic PBC studies. Is it a familial disease? Even though there are some publications about familial cases and ocurrences in siblings, twins, mothers and daughters with this diagnose. There is no epidemological evidence suggesting that PBC is inherited nor is it limited to special social or ethnic groups. As of today it is neither needed nor recommended to examine family members of PBC patients, including patients´ daughters, unless they are symptomatic or have analytic results suggesting PBC.

19 Prognosis. Factors/Models: Since the introduction of UDCA treatment the natural course of this disease has been modified and the number of liver transplantations (LT) have decreased. Today PBC has a prolonged and benign development and for cases with a good therapeutic response the survival rate is comparable to that of the general population. Research has been done to identify variables that might predict the outcome, and results suggest that the biochemical response to UDCA is an important prognostic variable. A lot of definitions concerning the response to UDCA have been suggested but survival rate is much higher in patients responding to UDCA than among the ones who do not. Within the different published prognosis models bilirubin is the heaviest variable in establishing a prognosis.

20 UDCA treatment consequences for survival rates and changes in the prognosis of PBC in recent years: Originally the disease was described in patients with advanced symptoms, progressive cholestasis (jaundice, prurito, xanthomas, and xanthelasma) and clinical manifestations of portal hypertension and liver failure (malabsorption and advanced cirrhosis with complications). However, the pattern of the disease has changed in recent decades and currently the typical presentation is that of a middle aged woman without specific liver disease symptoms, who refers to asthenia or pruritus (vague symptoms) which can be diagnosed with a complete liver analysis and an AMA determination. If these are positive, specialized treatment will be initiated.

21 Clinical guides for diagnostics and management of PBC have been published, with recommendations and approved common practices. Furthermore, the PBC patients and their families can get support and information through patient organisations.

22 Different diagnostics of overlapping autoimmune liver diseases still imply individualized treatment in every case. For patients with a PBC variety associated with autoimmune hepatitis (AIH), it is recommended to add corticoids (budesonide included).

23 PBC and pregnancy: More than 25 % of the women diagnosed with PBC are in childbearing age. Publications on PBC and pregnancy are beginning to appear. This is still a debated subject because of the need to administer UDCA during pregnancy. That is why it is important for these PBC patients, or the ones with other cholestatic diseases, to get checkups by multidisciplinary and experienced teams.

24 PBC in Spain: There is an approximated number of 9400 PBC cases/100.000 inhabitants. However, the margin of error is probably large given a shortage of studies and a lack of registries. It is important to mention that the interval between suspicion and confirmed diagnosis could last for months.

25 PBC and health related quality of life (HRQL): The bad quality of life referred to by some PBC patients are proportional to the symptoms of the disease. There are a number of remaining needs related to the treatment for the disease, and the decrease of the symptoms, which are not covered. In addition there is the uncertainty of the long-term individual risks. These unmet needs are most concerning among the youngest patients and/or the non-responders to first line, authorized therapies.

26 PBC and liver transplantation (LT): When medical treatment does not succeed in halting the evolution of the disease it is recommended to proceed with a LT in order to promote excellent results regarding survival and quality of life. However, there are uncovered needs and some PBC patients deteriorate while on the transplant waiting list and do not get in time for a transplantation, which is why new therapies are being investigated. There is a discussion about whether PBC can reappear in the new liver but recently it has been recognized that prophylactic UDCA treatment after LT prevents PBC from reappearing in the graft.

27 PBC. Conclusions: With early diagnosis and current PBC treatment the outlook on life of these patients have improved. The initial diagnosis and PBC staging should, if possible, be based on non-invasive measures like anlaysis and imaging tests, fibroscan and ultrasound. All the diagnosed patients have received UDCA as a first line treatment and if they are not responding to, or tolerating, the treatment they have to consider second line options (OCA or fibrates). Evaluation of the biochemical response to UDCA normally takes about 12-14 months but if the patients suffer from acute or symptomatic (prurito) disease the evaluation will be quicker, at 6 months of therapy. Response criteria are levels of ALP and bilirubin. Patients who show adequate biochemical response to UDCA can remain on UDCA as monotherapy. Patients with jaundice (bilirubin >5 mg/dl) or with advanced cirrhosis (Child-Pugh B-C) have to be referred to centers with liver transplantation programs.