What are the other Names for this Condition? (Also known as/Synonyms)

• Hanot Syndrome
• PBC (Primary Biliary Cirrhosis)
• Primary Biliary Cholangitis

What is Primary Biliary Cirrhosis? (Definition/Background Information)

• Primary Biliary Cirrhosis (PBC) is an autoimmune disease that is characterized by inflammation of the biliary duct (duct that carries bile from the liver to the small intestine). This condition usually affects the small and medium sized intrahepatic bile ducts
• When inflammation and scarring of the bile duct occurs, the bile cannot be properly carried from the liver to the intestine. As a result, bile builds up in the liver (cholestasis) and causes the characteristic yellowing of the skin (jaundice)
• The name Primary Biliary Cirrhosis is a misnomer (misleading term) for this condition. Although the term “cirrhosis” usually refers to a terminal condition, it may not be so in this case, as individuals with PBC are usually diagnosed early, even before liver cirrhosis (scarring of the liver) occurs
• A majority of PBC cases are found in middle-aged women; and for some reason, the condition is more common in some European countries
• A family history of PBC, smoking, and other factors increase one’s risk of developing the disorder Though the exact cause of Primary Biliary Cirrhosis is mostly unknown, researchers believe that it may be due to multiple factors, such as autoimmune mechanisms, genetic predisposition, and other unknown factors
• Most patients are usually asymptomatic (without symptoms) and the diagnosis is suspected during blood tests for other conditions. Yellowing of the eyes, dark urine, itching, and diarrhea are commonly observed with Primary Biliary Cirrhosis
• The treatment options available include nutritional supplements, symptomatic treatment (treating only the symptoms), ursodeoxycholic acid, and liver transplantation
• Unfortunately, Primary Biliary Cirrhosis is a progressive condition that in most cases requires liver transplantation. This is not always curative. The average survival rate is 7-10 years after the onset of symptoms

Who gets Primary Biliary Cirrhosis? (Age and Sex Distribution)

• The typical age of onset for Primary Biliary Cirrhosis is between 40 and 50 years, though it can be seen in individuals between 30 and 70 years too. Onset of PBC in children is extremely rare
• Primary Biliary Cirrhosis is more common in middle-aged women (80-90% of the cases) than men
• PBC can be seen worldwide; however, it is more common in England, Scotland, and Sweden. In the US, it is more common in the state of Minnesota.  The disorder is also less common in South America and Africa, likely due to a lack of recognition tools and treatment options

What are the Risk Factors for Primary Biliary Cirrhosis? (Predisposing Factors)

Risk factors of Primary Biliary Cirrhosis include:

• Females are more likely to develop Primary Biliary Cirrhosis than males in a 9:1 ratio
• First-degree relatives (parents, siblings, and children) are at higher risk of PBC
• Exposure to chemicals (i.e. cigarette smoke, nail polish, and hair dye) and hormone replacement therapy (supplementation of low levels of naturally occurring hormones) can increase one’s risk
• History of frequent urinary tract infections

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Primary Biliary Cirrhosis? (Etiology)

The exact cause and mechanism of Primary Biliary Cirrhosis development is currently unknown. Scientists believe that it may be caused due to multiple factors (multifactorial).

• It is associated with histocompatible antigens (HLA) such as DRB1*08 and DQB1. HLAs are antigen molecules that are found on the surface of cells and are used to identify a cell as belonging to the body or a foreign entity. When the body identifies these HLAs as foreign entities, it leads to an autoimmune response
• Other factors such as smoking and urinary tract infections may play a role in the development of Primary Biliary Cirrhosis
• It is believed that genetic abnormalities (common in first degree relatives) or other unknown factors may be the causative factors in stimulating one’s immunity to act against specific tissues in the body (autoimmune mechanism)

What are the Signs and Symptoms of Primary Biliary Cirrhosis?

The signs and symptoms of Primary Biliary Cirrhosis may include:

• Most individuals are usually without symptoms for many years and the diagnosis is suspected during blood tests for other conditions; increased alkaline phosphatase or γ-glutamyl transferase levels may be observed
• Fatigue (excess daytime sleepiness) is one of the earliest symptoms
• Itching may also be one of the earliest symptoms
• Anorexia, malaise (general discomfort or unease)
• Liver and spleen enlargement (hepatosplenomegaly) and abdominal pain
• Xanthomas, or fat buildup, beneath the skin and tendons
• Yellowing of the eyes and skin (jaundice) can be caused by obstructive jaundice, a condition in which bile flow from the liver ducts is blocked. As a result, bile is redirected into blood and the bilirubin contained in bile, is responsible for the characteristic yellowing of the eyes and skin
• Diarrhea, which results from an inability to digest fats due to a lack of bile
• When the liver is not properly functioning, it cannot synthesize blood proteins to maintain oncotic pressure in blood. Oncotic pressure is a type of osmotic pressure in the blood vessels that pulls water into the circulatory system. As a result, edema or abnormal fluid accumulation in the belly can occur
• Elevated cholesterol levels due to improper fat absorption by the gut as a result of  lack of bile being delivered
• Orthostatic hypotension: Abnormal fall in blood when an individual stands up from a lying or sitting position. This drop in pressure may cause symptoms such as lightheadedness
• Cognitive dysfunction: Conscious intellectual activity, such as thinking and reasoning, is affected
• Liver cirrhosis can also occur as an end result of Primary Biliary Cirrhosis. This may result in signs of portal hypertension such as:
  • Blood in the stool
  • Enlargement of the spleen
  • Esophageal variceal bleeding (bleeding in enlarged veins of the lower esophagus)
  • Development of ascites (fluid accumulation in the peritoneal cavity)
  • Hepatic encephalopathy - confusion or forgetfulness as a result of liver dysfunction  

How is Primary Biliary Cirrhosis Diagnosed?

Primary Biliary Cirrhosis is diagnosed using the following tools:

• Thorough evaluation of the individual’s medical history and a complete physical examination
  • An evaluation of medical history will determine if there is a presence of predisposing factors such as family history, medication history, and history of exposure to toxins
  • Physical examination and clinical workup may uncover findings such as jaundice
• Blood tests:
  • Liver function tests are blood tests which provide information about the state of the individual’s liver. It is used to check the levels of albumin, bilirubin, liver transaminases (AST and ALT), and alkaline phosphatases
  • Antimitochondrial antibody (AMA) test is positive in 90% of the affected individuals
  • ANA (antinuclear antibody) and ANCA (antineutrophil cytoplasmic antibodies) levels are elevated in individuals with autoimmune diseases such as PBC
  • IgM and cholesterol levels may be  increased in these individuals          
• Ultrasound, MRI, and CT scans can be used to image the liver, to rule-out other diseases causing obstructive jaundice
• Liver biopsy: It is the most definitive diagnostic tool to establish Primary Biliary Cirrhosis.  In this procedure, the physician removes a sample of the liver tissue and sends it to the laboratory for a histopathological examination. The pathologist examines the biopsy under a microscope and arrives at a definitive diagnosis after a thorough evaluation of the clinical and microscopic findings, as well as by correlating the results of special studies on tissues (if required). The biopsy may help identify inflammation of the bile duct, loss of small and medium sized bile ducts, “florid duct lesion”, and many other conditions

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions in order to arrive at a definitive diagnosis.

What are the possible Complications of Primary Biliary Cirrhosis?

Complications associated with Primary Biliary Cirrhosis depend on the severity of the disease and can include:

• Nutritional deficiencies, especially of vitamins A, D, E, and K, due to the lack of bile in the gut to absorb these vitamins. Osteoporosis can occur as a result of a lack of vitamin D absorption
• If liver cirrhosis occurs, it can lead to:
  • Liver failure - liver damage beyond repair that results in lack of functioning of the liver
  • Blood protein synthesis is compromised and clotting does not effectively occur; this can result in massive bleeding
  • The affected liver may not filter blood effectively, which can lead to the accumulation of toxins in the body. These toxins can travel through the body and may have negative effects on the brain, leading to encephalopathy (confusion or forgetfulness, as a result of liver dysfunction)
  • Ascites (fluid accumulation in the peritoneal cavity) can develop           
• Portal hypertension due to liver cirrhosis: Cirrhosis slows down the normal flow of blood through the liver. Blood pressure in the vein that brings blood from the intestines to the liver is increased. This can result in the following:
  • Development of varices or enlarged blood vessels - the enlarged blood vessels can rupture and lead to internal bleeding within the gastrointestinal tract
  • The spleen can become enlarged, if too many red blood cells and platelets become trapped in the spleen
• PBC is associated with conditions such as Sjögren syndrome (70%), scleroderma, thyroid disease, and celiac disease. There may be further complications due to these conditions
• The risk of developing liver cancer (hepatocellular carcinoma) is also increased in these individuals

How is Primary Biliary Cirrhosis Treated?

A typical treatment plan for an individual with Primary Biliary Cirrhosis may include:

• Treatment of itching: There are various options available to treat itching. They include the use of cholestyramine, colestipol, colesevalam, naloxone, naltrexone, 5-hydroxytryptamine, ondansetron, etc. If the medications are unsuccessful, then plasmapheresis (plasma separation from other cell contents) or a special type of dialysis may be tried
• Modafinil may be a treatment option in individuals with PBC experiencing persistent day-time sleepiness
• Vitamins to supplement nutritional deficiencies
• Antibiotics to prevent infection and sepsis
• Ursodeoxycholic acid to slow the progression of PBC; it works by altering the composition of bile
• Liver transplant is the treatment of choice, if the condition has progressed to cirrhosis

Regardless of what treatment is received, follow-up care and regular screenings are important to ensure that Primary Biliary Cirrhosis does not progress and cause further complications.

How can Primary Biliary Cirrhosis be Prevented?

• Currently, no preventative measures are known for Primary Biliary Cirrhosis
• However, it is important to undergo regular medical screenings so that PBC does not advance and cause more complications

What is the Prognosis of Primary Biliary Cirrhosis? (Outcomes/Resolutions)

• Primary Biliary Cirrhosis is a progressive disease. Without liver transplantation, the average survival period of those affected is around 7-10 years, from the time of appearance of symptoms
• Individuals with mild conditions and on ursodeoxycholic acid treatment have a slightly a better prognosis than those with severe forms of PBC
• The prognosis is unfavorable in individuals with severe PBC. If severe liver injury and cirrhosis is present, there is a chance of developing end-stage liver disease and liver cancer
• Liver transplantation can prolong the survival of these individuals. However, some individuals may develop Primary Biliary Cirrhosis again after a transplantation

Additional and Relevant Useful Information for Primary Biliary Cirrhosis:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/immune-related-disorders/