Surgical Treatment of PFIC
ByBenjamin Shneider, MD
Chief, Division of Pediatric Hepatology
Mount Sinai School of Medicine
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.