Diagnosis and Treatment

Diagnosis of Progressive Familial Intrahepatic Cholestasis (PFIC)

Summary Diagnostic Tests

There are different diagnostic tests, which are used to identify PFIC and potentially determine which type of PFIC is present.

These are blood tests which may help to assess the general condition of the liver and can provide some information as to the type of PFIC. One particularly useful test is gamma GT (GGT), which is a type of liver enzyme which may help to distinguish between the types of PFIC. The GGT levels in the blood are low or normal in FIC1 and BSEP deficiencies but raised in MDR3 deficiency. Markers of liver injury (ALT and AST) may provide some differentiation between FIC1 and BSEP disease, these enzymes are often lower in FIC1 disease.

These are more specialized blood and urine tests. Children with PFIC will have quite elevated levels of bile acids in blood – 10 to 20 times the normal bile acid concentration. If bile acids are not elevated this may suggest a problem making bile acids (bile acid synthesis disease), which may be identified by looking at bile acids in the urine.

A small piece of liver tissue is extracted with a small needle, and then examined under the microscope. An open surgical operation is not usually needed. Results from the liver biopsy are used to help make the diagnosis, to assess the severity of the disease and to advise about the future (prognosis).

Genetic testing can reveal exactly which gene is mutated and provide information about the severity of the disease. This type of testing can therefore identify the subtype of PFIC. Genetic testing can be done with a blood sample, and involves extracting the code of the PFIC genes from the DNA in the blood. Note that these tests are expensive, might not be covered by insurance and are not available in all countries.

Possible Treatments of Progressive Familial Intrahepatic Cholestasis (PFIC)

Without any treatment, PFIC can lead to cirrhosis and end-stage liver disease at quite variable ages from infancy to adulthood. Some mild forms of MDR3 disease may get better with ursodeoxycholic acid (a helpful bile acid) treatment. Severe PFIC disease does not necessarily get better with medical therapy, although medical therapy may be essential to prevent complications of the underlying liver disease (e.g. nutritional problems). There are different treatments which depend on the severity, subtype of PFIC and the type(s) of symptoms.

Young children with PFIC may need to receive special infant formulas that contain MCT (medium chain triglycerides), a form of fat that is better absorbed in cholestasis. Other supplements that contain MCT may also be used in older children. Fat-soluble vitamin (A, E, D and K) monitoring and supplementation are equally important. For more information on formulas and foods that are better for children with cholestasis, click here.

A tube placed in the nose that goes down to the bile ducts to drain bile ducts, has had some success in breaking an episode of BRIC – this is a fairly invasive treatment and is a temporary approach.

The aim of this surgery is to reduce the amount of bile acids re-entering from the intestines into the liver and thereby reduce the itching and potentially slowing the progression of the liver disease. PEBD involves sewing a small piece of intestine between the gallbladder and a hole in the abdominal wall, called an ostomy. This ostomy allows contents within the segment of intestine to drain externally, typically into a small bag that is secured on the outside of belly. Approximately 30-50% of the bile drains out the ostomy. The fluid (bile) that collects in this small bag is discarded each day. The remainder of the bile follows the normal pathway through the bile ducts into the intestine. This surgical procedure has been used successfully for over 30 years, and is well tolerated and relatively safe.  It is difficult to predict who will respond well to this procedure.  Two procedures have been developed to avoid the need for the ostomy that drains bile into a bag – partial internal biliary drainage and ileal exclusion.  Overall, there is less information about the outcomes of these two procedures.

This is a modification of the PEBD operation where the piece of bowel connects the gall bladder to the large intestine. Concerns have been raised about bile infection due to connection to the colon and for the effect of bile draining directly into the colon.

This is a different operation in which a bypass is created around the distal ileum, the section of bowel where bile salts are usually reabsorbed. The aim of this operation is also to reduce the amount of bile salts reabsorbed into the blood stream. The success of the procedure may be dependent on the amount of intestine that is bypassed. Bypassing too much can lead to significant diarrhea, while excluding too little may not be effective. The ileum is critical for absorption of vitamin B12, which should be monitored in individuals who have undergone ileal exclusion.

Liver transplant is considered if there are severe complications of cirrhosis (advanced scarring of the liver), liver failure develops, there is no improvement after medical/surgical intervention, or if evidence of liver cancer exists. This is a major operation with significantly greater risk compared to the three procedures above. After surgery children need to take anti-rejection medicines for the rest of their life, have regular medical follow-up and will be at risk of side effects from the medicines. Many children with PFIC will require a transplant at some point in their lives. The response to liver transplant may depend upon the type of PFIC and the severity of the mutation. PFIC1 is a systemic disease and liver transplantation may not address all of the problems. In some circumstances severe diarrhea and/or fatty liver disease develops after liver transplantation for PFIC1. In contrast, PFIC2 is liver specific so transplant is a more definitive therapy for PFIC2. In some children with severe mutations in BSEP a type of recurrence of disease occurs after transplantation. MDR3 disease is not complicated by either of these issues after liver transplant. Less information is available regarding liver transplantation for defects in TJP2, FXR and MYO5B. The decisions about liver transplantation for PFIC are quite complicated and should be undertaken in consultation with centers experienced with liver transplantation for these diseases.

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The Itch                Types of PFIC              PFIC