Diagnosis

In order to make a diagnosis of PFIC, the patient is examined by a physician familiar with childhood liver diseases. A thorough medical and family history is taken and a complete physical examination is performed. A radiologist may do Ultrasound, CT scan or MRI testing of the liver. Laboratory testing of blood, urine and tissues are the usual tests needed to find out the causes of these diseases. Often a procedure called a liver biopsy is performed to obtain a sample of liver tissue is taken for a pathologist to analyze.

The first tests are used to confirm that cholestasis is present. These include measuring bilirubin (the yellow pigment in bile), bile salts and liver enzymes, including GGT, in blood. Because, certain other pediatric liver diseases can look like PFIC, these diseases are tested. A liver biopsy is usually needed to help make the diagnosis and to find out if scarring is present. FIC1 and BSEP deficiencies are suspected when there is chronic cholestasis and low GGT. MDR3 deficiency is suspected when there is chronic cholestasis and high GGT. Special tests on the liver biopsies may help with the diagnosis. Genetic tests for these forms of liver disease are also available. These genetic tests are expensive and may not be covered by insurance.

There are a growing list of labortories that do PFIC diagnostic testing. The link below is to GeneTests, a voluntary listing of US and international laboratories. If your lab is not included on GeneTests and you would like it added to this page please contact the site administrator. http://gov/sites/GeneTests/lab?db=GeneTests

Medication

Without any treatment, PFIC will lead to cirrhosis by age 10-20 years, and frequently earlier. Some mild forms may get better with ursodeoxycholic acid (a helpful bile acid) treatment. Severe disease does not usually get better with medical therapy. 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 also important. Children with BSEP deficiency, especially those with severe disease, should undergo regular screening (blood test and liver ultrasound) for liver cancer.

Surgery

One of the most apparent and debilitating problems associated with progressive familial intrahepatic cholestasis (PFIC) is pruritus (itching). This relatively constant problem has tremendously deleterious effects on children and their families. Child behavior and family dynamics are understandably and often adversely affected. Traditional remedies for itching associated with other diseases are typically ineffective. For instance, anti-histamines that are utilized and effective for allergy-related itching are rarely useful in the long-term for PFIC. Anti-histamines often sedate children and may facilitate going to sleep, although the effect may be transient. A variety of other medications has been tried as treatment for pruritus in PFIC, although most are not effective in the long run. The mechanisms that underlie the pruritus in PFIC and other forms of cholestatic liver disease remain unclear. Pruritus is often seen in individuals with high levels of bile acids in their blood, leading some to believe that bile acids are part of the pathogenesis of the pruritus.

Bile acids are chemicals that are made by the liver from cholesterol. The bile acids are secreted by the liver and stored in the gallbladder. After a meal, the gallbladder contracts and the bile acids are expelled into the first portion of the small intestine. In the small intestine they mix with juices from the pancreas and facilitate the absorption of fats and fat-soluble vitamins (vitamins A, D, E and K). Most (95%) of the bile acids that are secreted by the liver are reabsorbed in the last portion of the small intestine (terminal ileum). The bile acids that are reabsorbed cycle back to the liver through the bloodstream so that the bile acids can be conserved and reutilized. The cycle of bile acids going from the liver to the terminal ileum and back to the liver is referred to as the enterohepatic circulation of bile acids.

Interrupting the enterohepatic circulation of bile acids has the potential to reduce the total amount of bile acids in an individual’s body and could be useful as a treatment for the pruritus associated with certain types of liver disease. At present, there are primarily two surgical means by which interruption of the enterohepatic circulation of bile acid can be achieved – namely partial external biliary diversion and partial ileal exclusion.

Partial external biliary diversion (PEBD) is the surgical approach most commonly utilized for PFIC and another cholestatic liver disease called Alagille syndrome. This technique has been used successfully for over 15 years. The results can be quite dramatic and rewarding. In children who respond well to this procedure, pruritus diminishes markedly and often disappears completely. Blood tests of liver injury often improve and liver histology (examination of liver tissue under a microscope) stabilizes or may improve. PEBD involves sewing a small piece of intestine between the gallbladder and the abdominal wall. A small hole is made in the gallbladder and one end of the intestine is attached at that opening. The other end of the intestine is attached to 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 to the abdominal wall. Therefore after completion of the external biliary diversion, bile in the gallbladder has two routes of excretion. Approximately 30 to 50% of the bile goes into the diversion and drains out the ostomy. This bile is discarded each day. The remainder of the bile is excreted into the intestine following normal pathway through the bile ducts. This surgical procedure is well tolerated and relatively safe in the hands of a surgeon experienced with these kinds of procedures.

An alternative surgical approach is ileal exclusion. There is a limited experience with the use of this procedure for children with PFIC. Not all clinicians are convinced that it is as effective as PEBD, although success with this procedure has been reported at some centers including our own. This procedure has been performed successfully in over 400 adults as a means of treating elevated cholesterol levels. The procedure involves bypassing the last 15% of the small intestine. The first step of this procedure involves cutting the intestine at a point that divides the intestine into the proximal (upper) 85% and distal (lower) 15%. The proximal intestine is sewn to the colon and the distal intestine is closed off. Thus the distal 15% of the intestine is no longer in contact with the flow of intestinal contents and is bypassed. Bypassing the distal 15% of the small intestine reduces the ability of the intestine to reabsorb bile salts. Those bile salts pass into the colon and are excreted with stool. The distal intestine remains in the abdominal cavity and can be reutilized in the future if necessary. The major advantage of this procedure is that it does not require an ostomy. The success of the procedure may be dependent on the amount of intestine that is excluded. Excluding too much may lead to significant diarrhea, while excluding too little may not be effective.

At present, it is uncertain as to whether these procedures are equally effective for PFIC due to FIC1 disease (Byler’s disease = PFIC1) or due to BSEP disease (PFIC2). My own personal bias is that they are more effective for PFIC1 versus PFIC2, although milder PFIC2 disease may be very responsive to these surgical interventions. On-going investigations are attempting to answer this important question. Continued medical follow-up in children who undergo either of these surgical procedures is important even if there is complete resolution of the pruritus. Liver disease can still progress and nutritional problems related to vitamin deficiencies are still possible.

An alternative surgical procedure for PFIC is liver transplantation. A full discussion of liver transplantation is beyond the scope of this review. Suffice it to say, liver transplantation is associated with significantly greater potential morbidity and mortality than either PEBD or ileal exclusion. Both PEBD and ileal exclusion can be reversed if liver transplantation is required. The surgical procedures described above may be difficult and ill-advised for a child with cirrhosis, and liver transplantation may be essential in these circumstances. PFIC2 is a disease that appears to specifically affect the liver and liver transplantation corrects all of the problems associated with PFIC2. In contrast, PFIC1 is potentially a more systemic disease. A variety of medical problems may arise after liver transplantation for children with PFIC1. Therefore, in our program, we strongly encourage the use of either PEBD or ileal exclusion in children who we suspect have PFIC1. Decision-making for presumed PFIC2 may be more complicated, although a trial of PEBD may be very reasonable. Recent studies have revealed that PFIC2 may be associated with an increased risk of liver tumors. Therefore, screening for liver tumors needs to be conducted in children with PFIC2 who have had either successful PEBD or ileal exclusion.

ByBenjamin Shneider, MD Professor of Pediatrics

Chief, Division of Pediatric Hepatology Mount Sinai School of Medicine