Progressive Familial Intrahepatic Cholestasis (PFIC)

Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare genetic disorder that affects the liver's ability to secrete bile, leading to the accumulation of toxic substances in the liver and other organs.

This is a devastating illness that frequently results in high morbidity and mortality rates. As per scientific evidence, PFIC has an estimated incidence between 1:50,000 to 1:100,000 births.

This illness frequently manifests during the newborn or the first year of life and causes liver failure, typically resulting in mortality between infancy and puberty.

There are three main types of PFIC, each caused by mutations in different genes and characterised by distinct clinical features.
Understanding the different types of PFIC can help in accurate diagnosis and appropriate management of the condition.

There are 3 main types of PFIC:

1. FIC 1 Deficiency (PFIC Type 1): This type was formerly referred to as Byler's sickness. In this type, the ATP8B1 gene undergoes a mutation.
   As a result of these mutations, PFIC 1 protein is not present. 

1. A deficiency of this protein can lead to Progressive Familial Intrahepatic Cholestasis 1 (PFIC1) and Benign Recurrent Intrahepatic Cholestasis (BRIC1).

2. This type of PFIC is characterised by impaired bile flow due to defects in the transport of bile acids across liver cells.

2. BSEP Deficiency (PFIC Type 2): The BSEP protein, which is necessary for bile sodium export, is lacking in PFIC Type 2 due to mutations in the ABCB11 gene. 

1. BSEP protein expels bile salts from liver cells in a manner similar to a pump. 

2. This protein deficit directly causes bile to accumulate in liver cells, which in turn damages the liver.
   The amount of BSEP protein varies depending on how severe the mutation is.

3. MDR3 Deficiency (PFIC Type 3): The MDR3 protein is lacking in people who have ABCB4 gene mutations, causing MDR3 deficiency. 

1. This protein plays a role in the movement of phospholipids (which are a kind of fat) from the liver cells into the bile, where it interacts with bile acids. 

2. A shortage of lipids for bile acid results from an MDR3 deficiency, which in turn damages the tubes that drain bile from the liver.
   This may further result in liver damage. 

Three more types of PFIC liver disease have been discovered recently:

1. TJP2 Deficiency (PFIC Type 4): 'Tight junctions' are complexes that include the TJP2 protein, also known as ZO2. The membranes of two neighbouring cells connect at tight junctions to form a barrier.
   The barrier regulates which molecules can move between cells. TJP2 is not only present in the liver; such junctions are significant throughout the body. 

Familial hyperchloremia (high bile salts in the blood) was the old name for a mild form of liver disease linked to mutations in the TPJ2 gene. 

1. The study of PFIC due to TJP2 mutation has only involved a few patients. 

2. Patients with TJP2 deficiency may experience other symptoms besides liver illness and its effects.
   

2. FXR Deficiency (PFIC Types 5): The regulation of bile acid metabolism in the liver and gut, as well as other areas of metabolism, depends on this FXR protein (Farnesoid X Receptor protein).
The NR1H4 gene encodes this protein. Patients with PFIC because of an FXR deficit appear to start developing fast progressive liver disease as early as infancy. 

3. MYO5B Deficiency: MMYO5B aids in the movement of proteins, including BSEP, to the places where they are required and helps maintain cell membranes' health.
MY05B has a connection to cholestasis, intestinal disorders, or both.

As a result of bile accumulation and liver damage, PFIC symptoms often appear in infancy. These signs can be noticed in infants from the first stage itself. Some common signs include:

1. Jaundice: Children affected with progressive familial intrahepatic cholestasis can have jaundice as a symptom.
   As a result, the white part of their eyes and their skin can have a yellowish tint.

2. Pruritus: Severe itching is a common symptom of PFIC.

3. Stunted Growth: PFIC-affected children can have extremely poor weight gain and may not grow up physically as expected.

4. Portal Hypertension: High blood pressure in the blood vessel that delivers blood to the liver is another sign of PFIC.

5. Hepatosplenomegaly: A condition of enlarged liver and spleen is also one of the symptoms of PFIC.

6. Deficiency of Vitamins: Low blood levels of fat-soluble vitamins (vitamins A, D, E, and K) can be seen in children with PFIC.

The symptoms can further be divided based on the type of PFIC: 

1. PFIC Type 1 Symptoms

1. Severe itching

2. Poor weight gain

3. Poor bone growth

4. Bleeding caused by Vitamin K deficiency

2. PFIC Type 2 Symptoms

1. Failure to thrive

2. Diarrhoea

3. Pancreatic inflammation

3. PFIC Type 3 Symptoms

1. Portal hypertension (elevated blood pressure in the vein that supplies blood to the liver)

2. Enlarged spleen and liver

4. PFIC Type 4 Symptoms

1. Chronic respiratory disease

5. PFIC Type 5 Symptoms

1. Pale stool

2. Severe diarrhoea

PFIC is brought on by mutations in specific genes (ATP8B1 gene, ABCB11 gene, ABCB4 gene, etc). 
These mutations disrupt the normal function of proteins involved in the transport of bile acids and phospholipids. 

The exact cause of these gene mutations is not fully understood, but several factors contribute to the development of PFIC.
Here are some key factors associated with the causes of PFIC:

1. Family History: If both parents have mutated genes, there is an increased risk for a child to develop PFIC. 

2. Consanguineous Relationships: Where individuals with a close blood relationship (such as first cousins) marry and have children can increase the risk of inheriting genetic conditions like PFIC.

Since PFIC is a genetic disorder, it cannot be entirely prevented; however, certain measures can help minimize the impact of the disease and improve the quality of life for affected individuals. 

1. Genetic Counseling and Testing: By understanding the genetic risk, individuals and families can make informed decisions about family planning and reproductive options.

2. Regular Medical Monitoring: Individuals diagnosed with PFIC should receive regular medical monitoring to detect and manage any complications or changes in liver function.
   Regular monitoring helps identify any emerging issues early on and allows for timely interventions.

3. Symptom Management: The symptoms of PFIC, such as itching and jaundice, can be managed with appropriate medical interventions.

The earlier the PFIC condition is diagnosed, the easier it will be for the patient to deal with the symptoms.
Ideally, the patient should be taken to a healthcare practitioner immediately after the first signs of PFIC are seen. The doctor will recommend a few routine tests to diagnose the disorder:

1. Blood Tests: To check for liver or biliary system damage. 

2. Genetic Testing: It can confirm the specific subtype of PFIC and help determine the appropriate management and treatment options.

3. Liver biopsy: To determine insights into the extent of liver damage, bile duct abnormalities, and inflammatory changes that are characteristic of PFIC.

4. Imaging Tests: Tests like ultrasound, CT scan, or MRI may be recommended to evaluate the anatomy and structure of the liver or biliary system.
   

How to Prepare for a Doctor's Consultation?

A doctor consultation is a valuable opportunity to discuss health concerns, seek medical advice, and develop a collaborative action plan with the healthcare provider.

Preparing for this appointment can maximise one's time and ensure a productive and informative discussion. Here are some basic things to prepare:

1. Book an appointment with the doctor.

2. Make a list of symptoms that the patient experiences, including when the first symptoms appeared.

3. List down all the medications and supplements that the patient takes.

4. Bring the medical records and reports, if any, during the appointment.

What to Expect from the Doctor?

1. The doctor will ask about the medical concerns of the patient, any medical history like family and genes of the patient, and signs and symptoms that the patient may be having. 

2. He/she may physically examine the patient as a preliminary diagnosis for PFIC liver to advise further diagnostic tests and suggest treatment courses.

3. The doctor will have a look at the test reports before advising a treatment course for the condition.

Questions to be Asked to the Doctor 

The doctor can clarify any questions related to the patient’s condition and disease, like 

1. How to prevent the progression of the disease?

2. Whether there are any risks involved that increase over time?

3. What symptoms need to be noted in future?

4. What is the recovery time?

5. If and why is surgery needed?

6. Can the disorder be kept in check without surgery?

7. Can it be kept under control with medication?

The treatment of Progressive Familial Intrahepatic Cholestasis (PFIC) aims to manage symptoms, prevent complications, and improve the patient's quality of life.
Since PFIC is a chronic and progressive condition, long-term management is required. Treatment options for PFIC may include:

1. Nutritional Support: Children with PFIC may require nutritional support to ensure adequate growth and development.
   This may include dietary modifications, vitamin supplementation, and monitoring of nutritional status.
   In some cases, specialized formulas or enteral nutrition may be necessary.

2. Medications: All progressive familial intrahepatic cholestasis patients receive drug therapy as their initial course of treatment.
   For all PFIC subtypes, ursodeoxycholic acid (UDCA) is the first line of treatment. 

Other medical treatment options include antihistaminic drugs, opiate inhibitors, ondansetron, steroid hormones propofol, and carbamazepine.

3. Surgical Treatment: In severe cases of PFIC, surgical interventions may be considered.
   Biliary diversion procedures, such as ileal exclusion or partial external biliary diversion, can help alleviate pruritus and reduce the accumulation of bile acids in the liver.
   In some instances, liver transplantation may be necessary if the liver function deteriorates significantly.

Cost of the PFIC Treatment

The cost of PFIC treatment in India may vary on several factors, including the patient’s age, the patient’s comorbidities, the doctor’s expertise, hospital type and location, insurance coverage, the severity of the condition, and much more.

To know the exact cost of PFIC treatment in India, one must consult their doctor. However, the table below also provides the cost of the treatment modalities performed to treat PFIC.

PFIC Survival Rate

Due to the complications of end-stage liver disease, PFIC might lead to death.
In general, PFIC 1 and 3 will result in end-stage liver disease by the age of 10 to 20 years, and PFIC 2 will lead to end-stage liver disease even sooner without therapy.
At the ages of 10 and 20, those who do not undergo surgery have a 50% chance of surviving.

The survival rate of individuals with PFIC can be significantly improved with early diagnosis and appropriate treatment.
Liver transplantation is considered the definitive treatment for end-stage liver disease associated with PFIC.
The outcome of liver transplantation in individuals with PFIC is generally favourable, with the majority of patients achieving long-term survival and improved quality of life.

Without proper diagnosis and treatment, all PFIC liver types and subtypes may lead to severe complications. These complications can include liver diseases or end-stage liver failure, which can pose a threat to life.
These are some of the other complications associated with PFIC:

1. Portal Hypertension and Enlarged Spleen: Increased resistance to the portal vein's ability to carry blood from the intestines into the liver is a result of the liver stiffening.
   The spleen may grow and develop as a result of the increased pressure. Internal bleeding may arise from these conditions.

2. Ascites (abdominal fluid retention): Excess fluid can build up in the abdomen due to elevated blood pressure in certain veins and the liver's diminished capacity to produce albumin, an essential protein.

3. Malabsorption and Malnutrition: The impaired bile flow in PFIC can interfere with the digestion and absorption of fats and fat-soluble vitamins, leading to malabsorption and malnutrition.
   This can result in deficiencies of essential nutrients, vitamins, and minerals, affecting growth and overall health.

4. Liver Cancer: The risk of liver cancer is higher in all liver illnesses. Certain types of PFIC carry a greatly elevated risk.

5. Impaired Liver Function and Quality of Life: Continuous liver dysfunction brought on by the progressive nature of PFIC may have an effect on everyday activities, physical health, and general quality of life. 

When to See a Doctor?

It is important to seek medical attention if the parents or the baby has PFIC. Early diagnosis and management can help optimize treatment outcomes and minimize the risks associated with the condition.
Here are some signs and symptoms that should prompt one to see a doctor:

1. Jaundice

2. Itching

3. Slow growth

4. Abdominal pain and swelling

5. Pale stool

6. Recurrent liver infection

Patients with PFIC liver need to take care of their diet. Doctors will give a specific set of diet, vitamins and minerals that the patient needs to intake, along with medications, to keep their condition in check.
Here are some of the items that can be given:

1. Low Fat Intake: Limiting the consumption of high-fat foods, such as fried foods, fatty meats, full-fat dairy products, and processed snacks, may help reduce the burden on the liver.

2. MCT (Medium Chain Triglyceride): When bile flow is inadequate, MCT fat is easier to digest than other fats and provides the required energy.
   Despite the rarity of MCT fat in foods, there are specialised milk formulas and supplements that include it.
   A verified nutritionist can offer thorough guidance on this matter.

3. Nutritional Supplements: The dietician may suggest special milkshake drinks that will provide more calories, protein, and vitamins if the child is not gaining weight. 

4. Hydration: Maintaining proper hydration is important for individuals with PFIC, as it helps support liver function and promotes healthy digestion. Drinking an adequate amount of water throughout the day is recommended.

In conclusion, Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare genetic disorder that affects the liver's ability to properly transport bile. While there is no cure for PFIC, early diagnosis and appropriate management strategies can help alleviate symptoms and improve quality of life. 

Treatment options may include medication, surgical interventions, and liver transplantation, depending on the severity of the condition. It is important for patients and their families to work closely with healthcare professionals to develop a comprehensive management approach tailored to their specific needs.

HexaHealth has the largest network of NABH-accredited hospitals, offering the top surgeons for liver transplants needed for PFIC patients. HexaHealth offers a seamless surgery experience across the country, so patients don’t have to worry about surgery stress. So contact the experts today!

Suggested Reads