What is Progressive Familial Intrahepatic Cholestasis?
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic diseases that occur because of problems with bile secretion, which is a fluid your liver produces to help digests fats. These diseases are commonly identified into three types: PFIC type 1, PFIC type 2, and PFIC type 3. It’s typically diagnosed early in a person’s life and often shows through signs like itching (pruritis), dark-colored urine, light-colored stool, loss of appetite, and feeling tired.
What Causes Progressive Familial Intrahepatic Cholestasis?
Mutations, or changes, in the cells of the liver can lead to problems in the creation and release of a substance called bile. This, in turn, creates symptoms of a condition called cholestasis. There are three versions of this condition, known as subtypes, which are PFIC1, PFIC2, and PFIC3.
PFIC1 and PFIC2 usually start showing signs within a few months after a baby is born, while PFIC3 starts showing up early in childhood. Researchers have found three different genes that cause these conditions.
PFIC1 and PFIC2 are both caused by problems in the genes ATP8B1 and ABCB11, which typically occur early in life. Those genes are usually not a problem in PFIC3. Instead, PFIC3 involves a defect in a different gene, ABCB4. This gene is involved in making a protein known as multi-drug resistant 3. This protein belongs to a group of proteins called “flippases,” which help move a variety of phospholipids (a type of fats) from the cell membranes into the bile.
Risk Factors and Frequency for Progressive Familial Intrahepatic Cholestasis
Thanks to huge strides forward in medicine, especially in genetics, more people are being diagnosed with a certain disease. This disease is thought to occur in about 1 in 50,000 to 1 in 100,000 births, but it’s hard to say exactly how common it is. Of all children with cholestasis, a liver condition that slows or stops the flow of bile, about 10-15% have this particular disease. Furthermore, it is the reason for about 10% of liver transplants in children. The disease affects boys and girls equally. Even though it’s usually diagnosed in childhood, sometimes it isn’t discovered until adulthood.
Signs and Symptoms of Progressive Familial Intrahepatic Cholestasis
Cholestasis is a medical condition that causes symptoms primarily due to the build-up of bile in the liver. In infants, this condition may first be recognized with signs like a yellowish skin tone (known as jaundice), or with findings of high bilirubin levels in their blood tests. However, there may also be other initial signs including poor weight gain, difficulty feeding, vomiting, and swelling of the liver or spleen.
Since this condition is not as common as other pediatric conditions, sometimes signs of vitamin deficiencies may be the first symptoms noticed. This can include problems like bone fractures, dry skin, easy bruising or bleeding, or night blindness due to a lack of certain crucial vitamins absorbed with the help of bile.
Adults can experience similar symptoms as infants. However, adults may also have additional complications related to cirrhosis (a late-stage liver disease) and portal hypertension (high blood pressure in the liver). These might manifest as spider veins, redness of the palms, enlarged breast tissues in men, shrunken testicles, bleeding from enlarged veins in the food pipe, and swelling of the liver, spleen, and abdomen. If these signs are not picked up early, the patients can go into sudden liver failure. Liver failure symptoms can include abnormal blood clotting test (international normalized ratio or INR greater than 1.5), increased liver enzymes (ALT and AST), altered mental status, abdominal pain, and jaundice.
Testing for Progressive Familial Intrahepatic Cholestasis
If your child is suspected to have a condition called cholestasis, which means there’s a slowdown or stoppage of the flow of bile from the liver, then a condition called Progressive Familial Intrahepatic Cholestasis (PFIC) is something that might be considered after other more typical causes have been ruled out. To make this decision, a doctor may follow certain steps and use specific strategies.
First up, a round of lab tests might be carried out, including what’s called a complete metabolic panel. This set of tests can show if there are high levels of a chemical called bilirubin in your child’s blood, which can be a sign of cholestasis.
Once the lab results are back, an ultrasound of the liver becomes an important step. The scan will look at the size of your child’s bile ducts. If these ducts appear to be bigger than usual, then the cause of cholestasis is likely to be external to the liver. But if the ducts look normal, a test might be done for an enzyme called gamma-glutamyl transferase (GGT). It’s here that conditions like PFIC might come into play.
If your child has normal GGT levels along with an itching skin condition called pruritis, it might signal a type of PFIC or could be due to medication side effects or Hepatitis A. On the other hand, if your child’s GGT levels are high, then a liver biopsy (taking a small sample of liver tissue) might be needed to see if there’s any ductal proliferation, which is an increase in the number of bile ducts. If more bile ducts are present and a special type of imaging called cholangiography shows normal bile ducts, your child could possibly have another type of PFIC or an autoimmune condition called cholangitis.
All this might sound quite complex, but it’s important to remember that diagnosing PFIC is tricky and it often takes several different approaches. Along with ultrasounds, other imaging techniques like CT and MRI scans might be used. And a liver biopsy is vital. That’s because different types of PFIC can cause particular changes to the liver cells and structures that can be seen under the microscope.
The levels of lipids (fat-like substances) in the bile can also give clues to the cause of the cholestasis. The concentration of bile salts, which help with digestion, might differ in different types of PFIC. For instance, PFIC1 usually shows slight decreases in bile salt levels, PFIC2 tends to have the lowest levels, whereas levels in PFIC3 are typically normal.
Finally, your child might have a molecular analysis where cells or tissues are studied in order to identify specific genetic mutations that could be causing PFIC.
Treatment Options for Progressive Familial Intrahepatic Cholestasis
There are a variety of treatments available for the three types of Progressive Familial Intrahepatic Cholestasis (PFICs), a liver disease that can eventually lead to liver failure. The disease is treated in several ways, either with medication, surgery, or a combination of both.
Medication is often the first line of treatment. Ursodeoxycholic acid (UDCA) is a bile acid medicine often used first. This medicine can help reverse some liver damage by reducing the number of harmful bile acids, improving liver cell health, and reducing cholestasis – a condition where bile remains in the liver instead of flowing into the intestines. Other medications can also help manage symptoms. For example, cholestyramine can help ease itching, a common symptom of PFIC. Other medications can help detoxify the body and manage other symptoms, such as steroids, medications for nausea, and certain types of antihistamines.
However, sometimes PFICs can be resistant to medical treatment. When that happens, surgery is considered oftentimes because PFIC can lead to unmanageable itching. The most common surgeries involve diverting bile flow to prevent accumulation and reduce itching. One method creates a channel that diverts some bile from the liver to the outside of the body to help control symptoms and slow the progression of the disease. This could buy more time before a liver transplant is needed. It’s important to mention that these procedures have risks, which should be discussed with your doctor before making any decisions.
Another surgical option is a relatively new procedure that creates a connection between the gallbladder and colon. Although the long-term effectiveness and safety of this process are yet to be well-documented, early results show that it may help alleviate itching and potentially slow down the disease. Bypass procedures are another surgical choice. They involve changing the route of the small intestine to bypass bile absorption areas. Although the long-term results are currently inconclusive, some patients have shown symptom improvement within the first year after surgery.
For some patients, their symptoms may continue to return or may not improve with either medical or surgical interventions. In these cases or when the patient develops end-stage liver disease, a liver transplant might be an option. While liver transplants carry potential risks such as organ rejection or disease recurrence, it is often the best treatment for patients with PFIC. They have been shown to provide benefits for all kinds of PFIC patients. Nowadays, instead of being a last resort, liver transplants are being considered as a form of initial treatment even in patients who are not in the final stages of liver disease.
Finally, there is ongoing research into new therapies for PFIC. Promising new medical treatments are being tested, such as ASBT inhibitors and FXR agonists. These treatments could help to block the uptake of harmful bile acids and reduce bile acid production in the body. While these innovations have not yet been approved for human use, they show potential in animal testing.
What else can Progressive Familial Intrahepatic Cholestasis be?
Cholestasis, a condition affecting infants and children, can be associated with many other existing conditions, which makes the potential causes incredibly vast. Below are some of the most commonly seen causes for cholestasis, but keep in mind this list is not all-inclusive:
- Biliary atresia
- Infections (for example, cytomegalovirus, human immunodeficiency virus, syphilis)
- Alpha 1-antitrypsin deficiency
- Alagille syndrome
- Cystic fibrosis
- Neonatal/Infantile asphyxia
- Neonatal sclerosing cholangitis
- Common bile duct stones
- Panhypopituitarism (underactive pituitary gland)
- Choledochal cysts
- Galactosemia (high levels of galactose in the blood)
- Tyrosinemia (high levels of the amino acid tyrosine in the blood)
What to expect with Progressive Familial Intrahepatic Cholestasis
Most people with PFIC, a serious liver condition, will likely develop a more advanced stage of liver disease, known as end-stage liver disease, by the time they reach adulthood. This stage is usually accompanied by significant fibrosis, which is the formation of excess fibrous connective tissue in the liver.
Due to the progressive nature of PFIC, meaning it gets worse over time, if patients do not receive a liver transplant, they face high rates of illness and death. So, a liver transplant can be a life-saving treatment option for those with this condition.
Possible Complications When Diagnosed with Progressive Familial Intrahepatic Cholestasis
Most complications are related to the effects of high blood pressure in the liver. These include swollen veins in the esophagus and stomach, resulting in severe vomiting of blood, fluid build-up in the abdomen, hemorrhoids, and a decline in brain function due to severe liver disease. Apart from these complications, late-stage liver disease is a risk factor for liver cancer, and patients with this condition who also have cirrhosis are at an increased risk for this type of cancer. Those with PFIC2 (a type of genetic liver disease) appear to be at risk of cancer, regardless of their risk associated with cirrhosis.
In addition, there are possible complications and side effects associated with various treatment methods:
Common Side Effects of Different Treatments:
- Medical management
- UDCA: Diarrhea, possible itching
- Rifampicin: Liver damage, fever, stomach upset, skin rash
- Cholestyramine: Constipation, blockage in the intestines
- Phenobarbital: Sleepiness, dizziness, involuntary eye movement, lack of coordination
- Surgical management
- Liver transplant: Rejection, recurrence with PFIC2, side effects of drugs used to suppress the immune system
- External diversion: Bulging of the stoma and infection of the bile duct
- Internal diversion: Rectal bleeding and severe watery diarrhea
Preventing Progressive Familial Intrahepatic Cholestasis
Progressive familial intrahepatic cholestasis is a rare inherited liver disease that can often be difficult to identify. People with this disease often show signs such as yellowing of the skin or eyes (jaundice), intense itching (pruritis), an enlarged liver or spleen (hepatosplenomegaly), and failure to gain weight or grow as expected (failure to thrive).
Since it’s a rare condition and it requires both parents to pass on the faulty gene (known as an autosomal recessive condition), many times the parents don’t show any symptoms, which makes it even harder to diagnose in their children.
That’s why when there’s a case of unexplained liver symptoms, patients are often referred to larger hospitals or medical centers where experts in this field work. They are better equipped to make sure this rare condition isn’t overlooked and is correctly diagnosed.
