Rare Classroom: Primary Biliary Cholangitis

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The rare disease that we will be learning about today is:

Primary Biliary Cholangitis

Also called primary biliary cirrhosis.

What is Primary Biliary Cholangitis?

  • PBC is a chronic disease that causes the small bile ducts in the liver to become inflamed and damaged and ultimately disappear. The bile ducts carry a fluid called bile from the liver to the gallbladder, where it is stored.​
  • Causing fatigue, or feeling tired, itching skin, and darkened skin in itching areas due to scratching, dry eyes and mouth. Some people may have jaundice, a condition that causes the skin and whites of the eyes to turn yellow.​
  • PBC is most commonly diagnosed after the age of 40 years. Of patients with PBC, 90% are female. ​
  • Patients most often take a daily dose of a drug called ursodiol. This is urseodeoxycholic acid, a naturally occurring bile acid. This drug improves the liver’s ability to function in PBC patients. It also extends life expectancy and may delay the need for a liver transplant.​
  • Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex) are diagnosed with PBC.​
  • It is estimated that there are up to 300,000 patients with PBC worldwide. ​
  • For females in the United States, PBC is the second most common cause of liver transplant.​

How Do You Get It?

  • The causes of primary biliary cirrhosis are unknown. Most research suggests it is an autoimmune disease. The immune system protects people from infection by identifying and destroying bacteria, viruses, and other potentially harmful foreign substances. An autoimmune disease is a disorder in which the body’s immune system attacks the body’s own cells and organs. In primary biliary cholangitis, the immune system attacks the small bile ducts in the liver.
  • It also has a genetic predisposition with a concordance rate of 60% among monozygotic twins. Combinations of genetic and environmental factors are proposed in the pathogenesis of this disease with a compelling body of evidence that suggests a role for both these factors.
  • Risk Factors
    • Sex
      • Most patients with PBC are female (about 9:1 female to male ratio) ​
      • Females are 10 times more likely to have PBC than males and 4 times as likely to have autoimmune hepatitis. The exact mechanism of gender differences in autoimmune liver disease and autoimmunity in general is not known; however, both immunogen tics and sex hormones play a complex and, perhaps, interactive role​
    • Age Onset
      • Uncommon <25 years​
      • Female peak onset is 1 in 1,000 females over 40 years of age​
      • Most commonly diagnosed between ages of 40s-50s​
    • Genetic Factors
      • A genetic predisposition to disease has been thought important for some time, as evident by cases of PBC in family members, concordance in identical twins, and clustering of autoimmune diseases.​
      • Familial PBC prevalence (i.e. multiple cases of PBC within the same index family) to range between 1.0% and 6.4%​
    • Hereditary Factors
      • There is strong evidence that PBC is a heritable condition. Some 1.33%-6.4% of PBC patients have a family history of the disease.​
      • In a study from the United States, 2.2% (24/1116) of the siblings of 379 PBC patients were reported to have PBC. ​
      • Disease concordance between dizygotic twins is used as the control for the shared environmental effect. In the only twins study of PBC to date, 63% (5/8)​
    • Race and Ethnicity Factors
      • Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women.​
      • In a study of 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic)​
    • Environmental Factors
      • It has a predilection to certain regions and is found in higher incidences in North America and Northern Europe.​
      • Combinations of genetic and environmental factors are proposed in the pathogenesis of this disease with a compelling body of evidence that suggests a role for both these factors.​
      • A number of environmental causes have been implicated, including several bacteria, viruses, toxins, and drugs.​
      •  Some of the most compelling evidence for an environmental factor has been derived from epidemiologic studies, which have demonstrated geographic clustering, clustering of cases across time, and seasonal variation in the diagnosis of PBC.​

What Are The Symptoms?

  • Although some people with primary biliary cirrhosis remain symptom-free for years after they’re diagnosed, others experience a number of signs and symptoms.​ With more advanced liver damage, people may have complications related to cirrhosis.
  • Early Symptoms
    • Fatigue (extreme tiredness) – this is the most common symptom and can have a significant impact on your daily activities​
    • Itchy skin– this can be widespread or it can only affect a single area; it may be worse at night, when in contact with fabrics, when warm, or during pregnancy​
    • Dry eyes and mouth
    • Problems sleeping at night and feeling very sleepy during the day​
    • Pain or discomfort in the upper right corner of the tummy​
    • Dizziness when standing up (postural or orthostatic hypotension)​
  • Late Symptoms
    • Pain in the upper right portion of the abdomen​
    • Bone, muscle, or joint (musculoskeletal) pain​
    • Yellowing of the skin and eyes (jaundice)​
    • Darkening of the skin that’s not related to sun exposure (hyperpigmentation)​
    • Swollen feet and ankles (edema)​
    • Buildup of fluid in the abdomen due to liver failure (ascites)​
    • Fatty deposits on the skin around your eyes, your eyelids, or in the creases in your palms, soles, elbows, or knees (xanthomas)​
    • Weak and brittle bones (osteoporosis), which can lead to fractures​
    • Elevated cholesterol​
    • Diarrhea that can be greasy (steatorrhea)​
    • Underactive thyroid (hypothyroidism)​

How Is It Treated?

  • Treatments are aimed at alleviation of symptoms and at slowing the progression of the disease that affects the liver. Other drugs are effective at relieving the symptoms of PBC.
  • Liver transplantation appears to be the only life-saving procedure.​
  • Ursodeoxycholic acid (UDCA) is the major medication used to slow the progression of the disease, 10 – 15mg ursodeoxycholic acid (UDCA) per kg per day in two to four divided doses orally with plenty of water.
    • First, it increases the rate of bile flow from the hepatocytes, thereby combating cholestasis and diluting toxic bile acids in bile.​
    • Second, it inhibits the body’s production of toxic bile acids, thereby preventing further injury to the hepatocytes.​
    • Third, it inhibits apoptosis (genetically programmed cell death), thereby preventing hepatocytes from dying.​
    • Fourth, it mildly inhibits the immune response in the liver, thereby possibly reducing immunological injury to the bile ducts and liver.​​
  • Obeticolic acid (Ocaliva)was approved by the FDA in May 2016 for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response or are intolerant to UDCA, or as a single therapy in adults unable to tolerate UDCA.​ 
  • Treatment barriers include: In very rare cases decompensation of hepatic cirrhosis has been observed, which partially regressed after the treatment was discontinued. If diarrhea occurs, the dose must be reduced and in cases of persistent diarrhea, the therapy should be discontinued. Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency, or glucose-galactose malabsorption should not take this medicine.​
  • Health care teams include General practitioners, Hepatologists, Gastroenterologists, Dermatologists, and Nurses.​
  •  The factors found to be predictive of treatment failure were high bilirubin level, low albumin level, high level of total bile acids, hepatomegaly, splenomegaly, advanced histologic stage, and a high Mayo risk score.​
  • Treatments for the symptoms, complications, and diseases associated with PBC
    • Immunosuppressive medications, for example, corticosteroids, azathioprine, cyclosporine (Sandimmune, Neoral, Gengraf), and methotrexate (Rheumatrex, Trexall) suppress immune reactions.​
    • Colchicine, a drug that reduces inflammation and scarring, has been used primarily to treat arthritis caused by gout.​
    • Corticosteroids, for example, prednisone, prednisolone, and budesonide (Entocort) inhibit the initiation of immune responses, including those initial responses required for perpetuation of autoimmunity reactions.​
    • Budesonide is a steroid that is more rapidly processed (metabolized) in the liver and, therefore, presumably would be less injurious to bone than other steroids.​
    • Azathioprine (Imuran) prevents the production of new lymphocytes (white blood cells that take part in immune responses) by blocking cell division (reproduction) of the lymphocytes.​
    • Cyclosporine is a powerful immunosuppressive drug, cyclosporine (Sandimmune, Neoral, Gengraf) is used primarily to prevent rejection of transplanted organs.​
    •  Methotrexate both suppresses the immune system and prevents cells from dividing.​
  • Complication Prevention
    • Increased pressure in the portal vein (portal hypertension). Your doctor is likely to screen for portal hypertension and enlarged veins when you’re first diagnosed and every few years thereafter. If you’re diagnosed with portal hypertension or bleeding, treatment may involve medications, such as a beta-blocker or nitrate, or surgery.
    • Weak bones (osteoporosis). Treatment for bone loss associated with primary biliary cirrhosis often involves calcium and vitamin D supplements. Your doctor may also recommend that you exercise most days of the week to help increase your bone density.
    • Vitamin deficiencies. Your doctor may recommend supplements of vitamins A, D, E, and K to counter vitamin deficiencies. Avoid taking herbs or nutritional supplements without talking to your doctor first.
  • Liver Function Supplements
    • A specific liver tonic which contains a high dose of the herb Milk Thistle with a high standardized concentration of the active ingredient silymarin. ​
    • Selenomune contains 200 mcg of organic selenium combined with high doses of other immune boosting minerals per capsule.​
    • MSM (Methyl-Sulphonyl-Methane) is an organic form of the mineral sulphur. Sulphur is a vital component of healthy bile. Sulphur is needed to produce the powerful liver antioxidant called glutathione. Vitamin C will neutralize free radicals generated during the phase 1 detoxification pathway in the liver. Toxic chemicals are far less dangerous if there is plenty of vitamin C in the liver.​
    • Vitamin E is required to protect cell membranes from free radical damage. Make sure you use vitamin E supplements which are natural (d-alpha-tocopherol); synthetic forms (dl-alpha-tocopherol) are derived from petrochemicals and are not well utilized by the body.​
    • Any powdered supplements could be stirred into fresh raw vegetable juices containing carrot, celery, and beet made with a juice extracting machine.  ​
    • Orthodox medicine​
    • Raw juices from a very young age. Raw juices are an incredibly powerful healing tool and can improve the function of the liver, bowels, and kidneys. This increases the elimination of toxins and waste products from the skin.​
    • Appropriate juice recipes include:​
    • Liver Tonic Juice​
    • Liver Cleansing Juice​
    • Orthodox medicine​
    • Cholestyramine (or colestipol) may reduce the itching by reducing blood levels of bile acids, and clearance of bile acids in the skin.​
    • Ursodeoxycholic acid (actigall or ursodiol) may also improve clearance of bile from the blood stream.​
  • Other Recommendations
    • Avoid ALL margarines and similar type spreads​
    • Avoid deep-fried foods.​
    • Avoid gluten (found in wheat, rye, oats, and barley).  This is essential in order to improve the immune system.​
    • Reduce alcohol intake.​
    • Drink 70 ounces (2 liters or 8 – 10 glasses) of filtered water each day.​
    • Avoid artificial sweeteners ​
    • Vitamin A, Vitamin K, and replacement therapy adds fat-soluble vitamins lost in fatty stools.​

Where Can I Learn More???

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