Liver transplantation and the management of progressive familial intrahepatic cholestasis in children

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.

Key Words: Pediatric liver transplant, Progressive familial intrahepatic cholestasis, Familial intrahepatic cholestasis protein 1, Cholestasis, Multidrug resistance protein 3, Pediatric jaundice, Bile salt excretion protein

Core tip: Progressive familial intrahepatic cholestasis is a rare disorder that predominantly affects young children. If left untreated, children develop debilitating cholestasis and eventually progress to liver failure. Liver transplantation is curative of symptoms related to liver disease but in some cases worsens the extrahepatic symptoms. A multidisciplinary approach is critical to obtaining good long-term outcomes.

INTRODUCTION

Cholestasis in children is caused by many different entities. Progressive familial intrahepatic cholestasis (PFIC), which is also referred to as Byler’s disease, Byler’s syndrome, or Greenland-Eskimo familial cholestasis, is an autosomal recessive inherited disease that disrupts the genes encoding protein transporters responsible for bile formation[1]. These mutant proteins result in the impairment of bile flow through the liver leading to severe intrahepatic cholestasis and progressive chronic liver disease[2]. Recently, mutations in a gene important for the formation of tight junctions was also reported that leads to progressive intrahepatic cholestasis[3].

Familial conditions of cholestasis were first reported in the 1950s with Ahrens et al[4] reporting 4 patients with congenital absence of their intrahepatic bile ducts. These patients had persistent jaundice very early in life, severe growth retardation, malabsorption, pruritus and xanthomatosis with marked hypercholesterolemia. Liver biopsies of these patients revealed complete absence of interlobular bile ducts and bile stasis, despite a normal lobular architecture and extra hepatic biliary system. All four of these children died at an early age[4]. Similarly, in 1966, Gray et al[5] reported two sisters with jaundice, marked growth retardation, malabsorption, and pruritus. The course was progressive for both sisters and they died before the age 3[5]. Clayton et al[6], Juberg et al[7], and Sharp et al[8] also reported additional cases of children with progressive cholestasis and liver failure resulting in death. Similarities among these early reported cases were described in an early review on PFIC by Ballow et al[9] and included: A familial occurrence, a clinical history of fluctuating jaundice, pruritus, malabsorption, growth retardation early in life and hepatosplenomegaly. Similar biochemical findings included conjugated hyperbilirubinemic obstructive cholestasis with normal blood cholesterol levels[9].

SEARCH STRATEGY

A literature search of English language publications from 1990-2014 was used to identity published data on liver transplantation for PFIC using the Patients Intervention Comparator Outcomes outline (Table 1)[10]. Databases searched were PubMed, Ovid MEDLINE, and Cochrane Reviews. Terms used in the search were “liver transplantation” AND one of the following terms “progressive familial intrahepatic cholestasis”, “PFIC”, “PFIC1”, “PFIC2”, “PFIC3”, “Byler’s Syndrome” or “Byler’s Disease”.

Table 1 Patients Intervention Comparator Outcomes table for assessment of progressive familial intrahepatic cholestasis.

P	I	C	O
Pediatric patients with PFIC	Liver transplantation	Biliary diversion and medical management	Patients survival, graft survival, post operative morbidity

PFIC: Progressive familial intrahepatic cholestasis; P: Patients; I: Intervention; C: Comparator; O: Outcomes.

EPIDEMIOLOGY

The incidence of any of the defective genes involved in the development of PFIC is 1:50000-100000 births and has not shown predominance in any specific geographical area[2,11]. However, there have been communities that have noted cohorts of patients including Faeroe Islands, Inuit (Eskimo) Indians (Greenland and Canada), and the Amish[6,12-15]. PFIC is responsible for 10%-15% of cases of neonatal cholestasis syndrome and is one of the leading indications for pediatric liver transplantation[16,17].

PATHOPHYSIOLOGY

Bile formation at the level of the hepatocytes involves active transport of bile salts, phospholipids, and cholesterol from the portal blood at the basolateral membrane. In PFIC, these transporters function abnormally (Figure 1). Bile then flows from the bile canaliculi lined by adjacent hepatocytes into the canals of Hering that are lined on one side by hepatocytes and one side by cholangiocytes. From there, bile drains into the larger bile ductules.

Figure 1 Disruption of bile flow and progressive familial intrahepatic cholestasis. AP: Aminophospholipids; PS: Phosphatidylserine; PE: Phosphatidylethinolamine; BA: Bile acids; PC: Phosphatidylcholine; FIC1: Familial intrahepatic cholestasis protein 1; BSEP: Bile salt exporter pump; MDR3: Multidrug resistance protein 3; mFIC1: Mutant familial intrahepatic cholestasis protein 1; mBSEP: Mutant bile salt exporter pump; mMDR3: Mutant multidrug resistance protein; PFIC: Progressive familial intrahepatic cholestasis.

PFIC1

PFIC1 is an autosomal recessive condition. The mutant gene responsible for the disorder is the ATP8B1 gene encoding the FIC1 protein[18,19]. The gene locus for ATP8B1 is located on chromosome 18 (18q21-22). FIC1 is a member of the type 4 subfamily of P type adenosine triphosphatase transporters and is involved in phospholipid translocation. The protein is located on the canalicular membrane of hepatocytes and facilitates movement of phosphatidylserine and phosphatidylethanolamine from the outer to inner leaflet of the plasma membrane of the hepatocyte. In addition, it helps to protect the membrane from high bile salt concentration in the canalicular lumen[20].

Mutation of this protein significantly impairs bile salt secretion. The exact mechanism for how deficiency of FIC1 leads to cholestasis is not fully understood[1]. Varying severities of PFIC1 are however noted[11].

PFIC2

PFIC2 is caused by mutation of the ATP binding cassette family B member 11 (ABCB11) gene encoding the bile salt excretion protein (BSEP) protein. The gene locus is on chromosome 2 (2q24) and is similarly inherited in an autosomal recessive fashion. BSEP, like FIC1, is a transporter protein that is expressed at the canalicular membrane of hepatocytes, and is the primary exporter of bile acids[21]. BSEP malfunction leads to failure of bile salt secretion from hepatocytes into bile canaliculi and accumulation of bile inside the hepatocytes. This results in severe impaired bile flow and hepatocellular damage[1]. On immunohistochemical staining, BSEP is usually not detectable in PFIC2, and if there is any protein present, it is usually non-functional[22-26].

PFIC3

A mutation in adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) gene encoding the MDR3 protein leads to the development of PFIC3[27,28]. The gene locus is on chromosome 7 (7q21). MDR3 protein is a p-glycoprotein that secretes phospholipids, primarily phosphatidylcholine within bile acid. Dysfunction leads to a decrease in phospholipid excretion[28]. MDR3 defects results in biliary epithelium injury and bile canaliculi injury as well as cholestasis. In addition, there is destabilization of micelles and promotion of cholesterol crystallization that results in increased biliary lithogenicity. This subtype of PFIC is usually present on both alleles and yields complete loss of the MDR3 protein either from a truncated MDR3 from a premature stop codon or missense mutations. All mutations result in severe defective transport of phospholipids and intracellular misprocessing[29].

PFIC4

PFIC4 is a recently described genetic mutation involving the TJP2 gene that encodes for the tight junction protein 2[3]. TJP2 is a cytosolic protein that interacts with several cytoskeletal proteins and integral membrane proteins and plays an important role in localizing proteins such as Claudins (e.g., CLDN1) to these structures[30]. Patients who presented with PFIC were found to have protein-truncating mutations that resulted in inappropriate localization and disruption of the tight junctions[31].

HISTOLOGIC ALTERATIONS IN PFIC

Even within the different subtypes of PFIC, there are common features and some distinct features. Specific signs on biopsy of PFIC1 (Figure 2) include bland cholestasis, mild lobular fibrosis, and centrilobular canalicular cholestasis with acinar or pseudo rosette formation[1,32]. Early in the disease, the initial biopsy typically demonstrates hypoplastic and threadlike interlobular bile ducts. With progression of the disease, centrilobular hepatocyte loss occurs with resulting pericanilicular and periportal fibrosis. Over time, there is progression to portal-portal and portal-central bridging fibrosis that leads ultimately to micronodular cirrhosis. Interestingly, fibrosis progresses in the absence of significant inflammation and ductular reaction[32].

Figure 2 Progressive familial intrahepatic cholestasis type 1 with severe bland lobular cholestasis and lobular disarray. The image shows bile plugging with surrounding pseudorosette formation (arrows). In PFIC1, the canalicular bile is course on electronic microscopy and also referred to as “Byler bile”. Thick bile is seen within the pseudorosette here on H and E stain. There is an absence of lobular inflammation and typically no features of neonatal giant cell hepatitis. PFIC: Progressive familial intrahepatic cholestasis.

Findings in the PFIC2 subtype (Figure 3) include cholestasis, giant cell hepatitis, hepatocellular necrosis, portal fibrosis and neonatal giant cell hepatitis with hepatocellular and canalicular cholestasis[32]. The fibrosis begins both in the portal tracts and in centrilobular regions and progresses through a biliary pattern type cirrhosis leading to micro nodular cirrhosis with slight ductular reaction[32]. Both PFIC1 and PFIC2 can show a paucity of bile ducts (Figure 4).

Figure 3 Progressive familial intrahepatic cholestasis type 2 is characterized by mutations in the ABCB11 gene. A: Patients with progressive familial intrahepatic cholestasis type 2 (PFIC2) can initially present clinically similarly to PFIC1, but with more rapid progression of liver disease. Early on in the disease patients may present with neonatal giant cell hepatitis and lobular inflammation. However, there can be rapid progression with prominent duct reaction and progression to cirrhosis. This figure demonstrates prominent duct reaction in a patient with PFIC2 and advancing fibrosis (arrow). Duct reaction and cholestasis can also occur in patients with extrahepatic biliary obstruction so correlation with clinical findings is required; B: PFIC2 is also called BSEP disease and is characterized by mutations in the ABCB11 gene. ABCB11 encodes for the major canalicular bile salt exporter BSEP. Patients with normal BSEP expression show positive immunohistochemistry for BSEP with a canalicular pattern of staining (arrow). In some cases of PFIC2, there is complete lack of staining for BSEP. BSEP: Bile salt exporter pump.

Figure 4 Progressive familial intrahepatic cholestasis type 1 and 2 can also present with duct paucity. A and B: The portal tracts show an absence of bile duct with periportal duct reaction; B: A higher power view of the portal tract with vein on the left artery on the right (arrow) and no appreciable bile duct. Keratin 7 is negative in this portal tract in B and positive in the bile duct reaction (arrow) with some bile duct progenitor cells (paler brown staining arrowhead).

In PFIC3 (Figure 5), there is bile ductular proliferation, inflammatory infiltrate and biliary fibrosis with mild expansion of portal tracts due to a ductular reaction[32]. Canalicular cholestasis is present in centrilobular areas, and biliary/micro nodular cirrhosis supervenes with a biliary halo around cirrhotic nodules. There is also often the presence of ductular reaction and bile plugs[1].

Figure 5 Clinical presentation of progressive familial intrahepatic cholestasis type 3. A: Progressive familial intrahepatic cholestasis type 3 (PFIC3) has a variable clinical presentation and may show nonspecific biliary pattern of injury that can mimic extrahepatic biliary atresia such as bile duct proliferation and cholestasis. In this patient with PFIC3 there is cholestasis, inflammation, and bile duct proliferation; B: Biliary type cirrhosis in a patient with PFIC3 with severe cholestasis (arrow) and micronodular cirrhosis.

Immunohistochemistry (IHC), electron microscopy (EM) and bile analysis can also provide important information regarding the different subtypes of PFIC. IHC for the different proteins associated with the different PFIC phenotypes is typically performed. However, normal IHC does not necessarily rule out a diagnosis of PFIC since some mutations are solely functional mutations and do not alter protein synthesis or expression[22]. Immunohistochemical stains can be particularly helpful in the identification of the BSEP protein at the canalicular membrane[22]. In PFIC3 patients, canalicular MDR3 immunoreactivity is typically detectable and the diagnosis of PFIC3 requires gene sequencing[24].

EM is also useful in differentiating the different PFIC subtypes. In PFIC1, the EM is coarse and granular in appearance that is the characteristic “Byler’s bile”. In contrast, PFIC2 EM has an amorphous appearance[33,34]. EM findings in PFIC3 patients have not been reported. In PFIC4, EM of the liver tissue of these patients demonstrated elongated tight junctions that lacked the densest part of the zona occludens[3].

CLINICAL PRESENTATION

The hallmark sign and symptom of the disease is jaundice and pruritus. For children and their parents, pruritus is an extremely distressing manifestation of disease and its relief is often the goal of early therapy. Significant pruritus leads to cutaneous mutilation, loss of sleep, irritability, poor attention and impaired school performance. In addition to pruritus, other symptoms include icterus, hepatosplenomegaly, excoriations, hyperpigmentation of the skin, shiny nails, growth retardation, pale stools, and fat malabsorption[1,11]. Most cases of PFIC present in infancy or early childhood with jaundice, and progress rapidly to fibrosis and end-stage liver disease. If left untreated, end stage liver disease will result in death.

There are many similarities and few distinct differences between the different PFIC subtypes[35,36]. Signs specific to PFIC1 include presentation in early infancy as opposed to neonatal period or later in childhood. Foul-smelling, high volume stools and failure to thrive are also hallmarks for PFIC1[35]. Gastrointestinal involvement even after liver transplant with secretory diarrhea can be significant[35,37]. Hemorrhage is also a possible sequelae and is potentiated by vitamin K deficiency and similarly can be the first clinical manifestation[1]. Classic biochemical signs include low or normal gamma-glutamyl transpeptidase (GGT), high alkaline phosphatase and a lower serum albumin as compared to PFIC2. Additionally, there is typically more severe cholestasis and recurrent jaundice, extrahepatic disease and portal hypertension. These sequelae often lead to decompensation in early childhood.

In contrast to PFIC1, PFIC2 tends to present in the neonatal period rather than later in infancy or childhood and tends to progress more rapidly. Biochemically, patients generally have a low or normal GGT, higher serum aminotransferases, higher serum bile acids and higher α-fetoprotein[35]. Patients present with severe cholestasis and persistent jaundice typically within the first month of life. Consistent with the restricted expression of ABCB11 to the liver, there are no extrahepatic manifestations of PFIC2. Progression to end stage liver disease results in portal hypertension and other manifestations of end stage liver disease. PFIC2 tends to progress to end-stage liver disease more rapidly, with cirrhosis, liver failure and death in the first decade of life, most commonly in the first year of life, if a liver transplant is not performed[35].

PFIC3 usually presents in adulthood or late adolescence[38,39]. It is characterized by cholestasis and gastrointestinal bleeds secondary to cirrhosis and portal hypertension. Gastrointestinal bleeding may be the first presenting symptoms in older children or young adults. Biochemically, PFIC3 patients tend to have an elevated GGT. There is also an increased risk of cholesterol and drug induced cholestasis in patients with MDR3 mutations and PFIC3[40,41].

INVESTIGATIONS AND DIFFERENTIAL DIAGNOSIS

Initial investigations of the jaundiced child include a combination of clinical, radiological, and laboratory testing with the goal of ruling out biliary obstruction and extra hepatic causes of jaundice. In addition, infectious or metabolic etiologies should also be ruled out. Important screening and confirmatory laboratory tests include a complete blood count, chemistries including electrolytes, serum glucose, liver enzymes, total and direct bilirubin, GGT, thyroid function studies, C-reactive protein, ferritin, and coagulation studies. In addition to the above labs, serum bile acids, urinary bile acids, lactic acid, alpha-1-antitrypsin phenotype, alpha-fetoprotein, ammonia, cortisol, viral serologies, carnitine and acyl carnitine profile, and plasma amino acids levels should also be considered[14]. GGT levels not only assist in the differentiation of the type of PFIC, but may also be a helpful prognostic indicator[42]. A serum albumin, which if low, may indicate advanced disease or malnutrition[10]. The presence of coagulopathy may also increase the suspicion of advanced disease[10]. Genetic studies for JAG1 mutations as well as for the described PFIC mutations should also be performed to clarify the etiology of cholestasis. Once a diagnosis of PFIC is made, differentiating between the subtypes, such as PFIC1 and 2 in newborns and young infants, is important since options for optimal treatment may differ between subtypes. Genetic testing is the gold standard for diagnosis using a “gene chip”. One chip allows for the analysis of 27 coding regions and their splice junctions from 5 different genes known to be involved in inherited syndromes of intrahepatic cholestasis[43].

In addition to laboratory testing, radiologic investigations are also critical and almost always include an initial abdominal ultrasound. In addition, magnetic resonance cholangiopancreatography can provide additional information especially in older children and help exclude other diagnoses such as primary sclerosing cholangitis that may be high on the differential list particularly in patients with high levels of GGT and cholestasis.

ROLE OF LIVER TRANSPLANTATION

Liver transplantation is currently the only definitive treatment available for PFIC. It corrects the genetic defect and reverses many if not all of the effects of chronic liver disease. Several series have been published examining the outcomes of liver transplantation for PFIC (Table 2). Of the cumulative 131 patients of all subtypes documented, graft survival and patient survival was 76.6% and 85.2% respectively with the longest reported follow up interval being 19 years post-transplantation.

Table 2 Review of documented liver transplantation outcomes for progressive familial intrahepatic cholestasis patients (≥ 3 patients).

Ref.	PFIC type	Age at transplant (years old)	Previous management	Graft survival	Patient survival	Notes
Soubrane et al[45]	14 “byler disease” PFIC type unspecified	6.5 (0.4-13)	NR	93.3%	92.8%	Consanguineous to the 2nd degree in 8 cases
Emond et al[91]	11 PFIC unspecified type	4.6 ± 3.4	2 had previous partial biliary diversion procedures	76.9%	73%	LT performed on those with advanced cirrhosis (6 received diversion procedures only)
Ismail et al[80]	8 PFIC of unspecified type	Unknown	1 patient PEBD, all received cholestyramine, phenobarbital, rifampicin, UDCA	100%	85.7%	6 cadaver livers, 2 living donors
Kondo et al[63]	4 PFIC of unspecified type	2-7	NR	75%	75%
Bassas et al[56]	5 PFIC3 8 “low GGT PFIC” PFIC1/2	10-40 mo	NR	84.6%	84.6%	Parents of 12 out of 13 were 1st cousins
Cutillo et al[57]	6 PFIC1/2 1 PFIC3	4-53 mo	NR	100%	75%
Englert et al[44]	33 patients PFIC2 and 3	Unknown	UDCA 10 of 33 received biliary diversion then LT	100% with prior diversion 89% without prior diversion	100%
Aydogdu et al[52]	10 PFIC1/2 2 PFIC3	43.2 ± 27 mo	UDCA	69.2%	75%	Surviving patients show good quality of life, exacerbation of diarrhea as the exception, mix of LDLT and cadaveric
Hori et al[50,51]	11 PFIC1	0.6-18.2 years old	Total external biliary diversion performed at time of re-transplantation in one PFIC1 patient	82.4% total graft survival (14/17)	PFIC1 - 90.9% at 5 yr, 72.7% at 10 yr, 54.5% at 15 yr; PFIC2 - 100% at 5 yr	Digestive symptoms in 10 out of 11 PFIC1; 8 out of 11 PFIC1 recipients exhibited steatosis; 9 out of 11 PFIC1 recipients exhibited fibrosis
Miyagawa-Hayashino et al[54], Egawa et al[53]	3 PFIC2
Kaur et al[58]	2 PFIC3 2 PFIC1/2	2, 2.5, 6 and 9 years old males	UDCA, phenobarbital and ondansetron	100%	75%

LT: Liver transplantation; PEBD: Partial external biliary diversion; UDCA: Ursodeoxycholic acid; PFIC: Progressive familial intrahepatic cholestasis; GGT: Gamma-glutamyl transpeptidase; LDLT: Living donor liver transplantation; NR: Not reported.

In the largest series by Englert et al[44], 23 patients (PFIC2 or 3) underwent orthotopic liver transplantation as their first line of treatment and 10 received liver transplantation after an initial biliary diversion procedure. The graft survival rate of those who received a liver transplant initially was 89%, whereas graft survival rates of those who first received biliary diversion and subsequent transplantation were 100%. Patient survival between the two groups was 100%[44]. Soubrane et al[45] reported similar excellent outcomes. Of the 14 patients transplanted, 13 patients were alive at was an average follow up of 17 mo with normal family life and all children returning to school[45].

Earlier transplantation for PFIC2 appears to be warranted as this subtype appears to progress to cirrhosis faster and also carries an increased risk for the development of primary liver cancers. Hepatoblastoma, hepatocellular carcinoma, and cholangiocarcinoma have all been reported in PFIC2[46-48]. Transplantation in these patients is well tolerated with high graft and patient survival rates as well as great improvements in quality of life. Shimizu et al[49] reports two PFIC2 patients that were transplanted prior to the development of end-stage liver disease. Both siblings presented with jaundice and pruritus before 1 year of age. The elder sibling also demonstrated symptoms including acholic stools and failure to thrive. Histopathology revealed the classic findings of PFIC2 but no cirrhotic or malignant changes were identified. Neither sibling experienced major postsurgical complications.

Unlike in PFIC2, early transplantation in PFIC1 is controversial. Although liver transplantation corrects the FIC1 gene in the liver and theoretically reverses the symptoms related to liver disease, the outcomes post-transplant are mixed. Hori et al[50,51] reported one of the largest series for patients that underwent liver transplantation for PFIC1. Eleven PFIC1 patients who received living-donor liver transplants were reported. Post-transplant steatosis was significant (moderate-severe) in 8 of the PFIC1 recipients (72.7%). Four of the 11 recipients eventually showed signs of cirrhosis post-transplant such as esophageal varices and splenomegaly[50]. Two of the 11 PFIC1 patients suffered graft losses, and 10 of 11 patients (90.9%) reported digestive symptoms post liver transplantation. The survival rates of the PFIC1 patients at 5, 10 and 15 years liver transplantation were 90.9%, 72.7% and 54.5% respectively. Additional studies have also highlighted the presence or aggravation of severe digestive symptoms in addition to higher mortality rates following transplantation for PFIC1[52-55]. Therefore, an attempt at medical management of symptoms and/or biliary diversion in PFIC1 patients should be considered prior to transplant. In additions, medical and/or surgical procedures to post liver transplantation should also be considered[52-55].

In addition to considering delaying liver transplantation in PFIC1 patients, the exact mutation specific to the PFIC1 patient may play a role in the development of steatohepatitis in the transplanted liver graft. Three of the 11 patients in this study had distinct mutations in the FIC1 gene that did not result in persistent post-transplant diarrhea or steatosis[54]. Lykavieris et al[37] reported two PFIC1 patients with specific mutations that both resulted in diarrhea exacerbation, appearance of liver steatosis and no catch-up of stature growth at 11 and 7.5 years post-transplant. Nicastro et al[55] similarly reported a PFIC1 patient upon whom gene analysis was done and was found to have double heterozygosity for two missense mutations. This mutation was associated with unremitting diarrhea, steatohepatitis and progressive fibrosis.

There is less data reporting on the outcomes of transplantation for patients with PFIC3. In patients that require transplantation, small series have reported excellent graft and patient survival[44,52,56-58]. Like with PFIC2, liver transplantation is curative with resolution of pruritus and other manifestations of chronic liver disease. There are no reported cases of worsening of extrahepatic symptoms. The only post transplantation complications noted specifically for a PFIC3 patient was documented by Kaur et al[58] who noted grade 1 acute rejection in 1 post-operative patient. Greater than 80% patient survival rates in the groups that included known PFIC3 transplant recipients have been reported however post-operative quality of life for these patients needs to be further investigated.

In conclusion, liver transplantation is typically viewed as an option when patients have failed medical treatment and/or biliary diversion and have a poor quality of life due to refractory pruritus. Liver transplantation is also considered when patients have end stage liver disease or carcinoma. In regions where wait times potentially are shorter and/or living donation is available, liver transplantation can be considered earlier with excellent long-term survival and quality of life without the need to perform a biliary diversion. However, in cases of PFIC1, liver transplantation can be associated with an increase in extra hepatic manifestations, in particular chronic watery diarrhea and continued growth failure. Transplantation in this setting should be weighed against other options.

LIVING DONOR LIVER TRANSPLANTATION

Living donor liver transplantation (LDLT) has been shown to have outcomes equivalent to deceased donor liver transplantation[59-61]. There is a significant survival advantage to patients transplanted with living donors as compared to those patients on the deceased donor waiting list by preventing death on the waiting list. This can be as high as 20% at some United States centers[62]. In other parts of the world where deceased donation is non-existent, LDLT is the only option for patients with ESLD. However, given that PFIC is an inherited disease, there was some concern that outcomes post transplant might be compromised when compared with deceased donor grafts from non-related donors. There have been several reports examining outcomes from LDLT that have refuted this notion.

All 13 PFIC patients who received a liver transplantation reported by Bassas et al[56] received a living related donor transplant. Eleven of the 13 patients survived and were without complications. The authors commented on the success of the grafts being due to adequate matching and graft size rather than the presence or lack of heterozygosity of gene variants in the donor. Similarly, of the 12 patients reported by Aydogdu et al[52], 6 received left lateral segment from living donors. All donors were biological parents. Four of the 6 patients were alive (66.7%) at 1 year follow-up. One patient death was due to hepatic artery thrombosis requiring re-transplantation and subsequent early post-operative death and the other patient developed post-transplant lympho-proliferative disease at 6 mo.

Several other smaller series and case reports have also corroborated these findings[49,57,58,63]. Cutillo et al[57] reported 7 PFIC patients who received living related donor transplantation from parental donors. A previous family history of PFIC was found in three families and parental consanguinity in one family. Parental donors had normal liver functions tests and no personal past history of liver disease, gallstones, jaundice or cholestasis of pregnancy. They were alive and well at the time of follow up.

There is a natural concern for living related donor liver transplantation in patients with an inheritable intrahepatic cholestatic disease. However, grafts from related donors do not appear to be at higher risk for failure from PFIC-related causes. Living donation provides an excellent alternative to deceased donation and can provide timely liver transplant to patients.

ADVERSE OUTCOMES FOLLOWING LIVER TRANSPLANTATION

Like liver transplantation for other pediatric disorders, several well known complications have also been recorded such infection and rejection after transplantation for PFIC. These do not appear to occur at increased frequency post-transplant[64]. In addition to the general complications associated with transplantation, there are some that are specifically associated with PFIC.

In patients with PFIC1, an undesired effect of liver transplant is the potential worsening of the extra hepatic manifestations like diarrhea and short stature[52-55]. However, the manifestation and severity of these symptoms is unpredictable[54]. The diarrhea is almost always associated with steatosis on liver histology as well[50]. When these patients are treated with liver transplantation, the impairment of bile salt secretion is corrected, and subsequently, there is a large increase in bile acid secretion relative to what the patient’s body is accustomed to. The intestinal manifestations after transplant may reflect an important role for FIC1 in the intestine, where it is highly expressed. This increase in bile acids in the stool causes high volume osmotic diarrhea that has a significant impact on quality of life.

Bile acid resins and partial biliary diversion procedures have been shown to improve these symptoms. Cholestyramine has been reported to be very effective in these patients for managing post-operative diarrhea as well as aiding in overall growth progression[37,50,53,54]. External biliary diversion post-transplantation in patients with PFIC1 who are experiencing an exacerbation of watery diarrhea has also been shown to improve symptoms as well as improve the steatosis on liver histology[55,65].

PFIC2 patients with subtypes that have no immunodetectable BSEP in their native liver also appear to be at risk for the development of recurrent disease[66,67]. Certain patients have developed antibodies against the BSEP protein in the donor liver[66,68,69]. These antibodies cause similar symptoms of cholestasis, steatosis and fibrosis that were present in the original disease process. In some cases, these antibodies have resulted in recurrent graft failure[70]. When allo-antibodies are detected, changes in immunosuppression and implementing plasmapheresis/molecular adsorbent recirculating system therapies have been shown to improve cholestatic episodes post-transplant in some of these PFIC2 patients[70]. The use of rituximab has also been reported and shown to improve symptoms[71].

ALTERNATIVES TO LIVER TRANSPLANTATION: MEDICAL AND SURGICAL THERAPIES

Both medical and surgical therapies play important roles in the management of patients with PFIC both as definitive therapy and as a bridge to transplant. In some cases, they have also been used to manage post-transplant complications.

Medical treatment for portal hypertension includes β-blockers and endoscopic management of esophageal and gastric varices when amenable. Fat-soluble vitamin supplementation and aggressive nutritional support with medium chain triglyceride - rich and high calorie concentrated formulas in infants is also important for the treatment of these patients as well.

Urso-deoxycholic acid (UDCA) increases hepatocyte excretion of bile acids and limits return to the liver by inhibiting their intestinal reabsorption. UDCA has been shown to improve symptoms and liver function tests in some patients with PFIC and is typically viewed as frontline therapy[72-74]. Patients who experience the greatest benefit typically have milder forms of the disease, whereas patients with a total defect in MDR3 tend to be the non-responders to UDCA treatment. Recently, the degree of floppase activity in MDR3 was linked to response to UDCA treatment[39]. In some cases, reversal of fibrosis with long term UDCA therapy has been noted[75]. Combining 4-phenylbutyrate (4-PB) and UDCA treatment together has also been shown to be a promising pre transplant therapy for patients with PFIC2 in an effort to increase BSEP presence at the canalicular membrane[76].

Cholestyramine and rifampicin are also used to provide symptomatic relief. Cholestyramine is a resin that binds bile salts in the intestinal lumen and thus reduces absorption and increases fecal bile salt excretion. Cholestyramine is the first line oral management for pruritus and is effective in up to 80%. Rifampicin aids in the excretion of bile salts and bilirubin in the urine, and aids in the treatment of pruritis.

Recently, Engelmann et al[77] documented the use of steroids in PFIC2. These two patients were reported who were incidentally started on steroids for other medical reasons and who subsequently had complete resolution of symptoms and resolution of elevated bile salts.

Biliary diversion procedures

Biliary diversion procedures decrease the enterohepatic circulation of bile reducing its toxic effects. When offered early, biliary diversion is successful in reducing symptoms from pruritus and also slowing the progression of fibrosis[11]. There are both partial external and internal biliary diversions that have been described. Nasobiliary drainage procedures when performed preoperatively can be helpful in the selection of patients that will have the highest success rate from the surgical diversion procedure[17].

Partial external biliary diversion which was first described by Whitington uses a 10-15 cm jejunal conduit between the gallbladder and the abdominal wall creating a permanent biliary stoma[78]. This procedure has been shown to improve growth, normalize liver function, reduce serum bile acids and improve liver histology[79]. In many cases, this procedure is the first line surgical option and should be offered prior to the development of cirrhosis. However, once cirrhosis has been documented, these patients have poorer outcomes and should undergo liver transplantation[80]. Success as documented by not progressing to liver transplantation is reported to be 23%-75%[44,79-83]. This technique is also associated with significant complications including prolapse of the anastomosis, infection, and high volume bile excretion[84]. Additionally, 1/3 of patients experience moderate to severe dehydration and hyponatremia[84]. Modifications of this technique have included the use of a button cholecystostomy and also the use of the appendix in place of the jejunum as a conduit[85,86].

Partial internal biliary diversion has the advantage in that it avoids an external stoma and the complications associated with it. The most common partial internal biliary drainage links the gallbladder drainage to the colon[87-89]. A modification of this procedure involving a laparoscopic cholecystocolostomy has also been described[90]. Initial results from these techniques have been promising, but longer follow-up is needed. Internal diversion to bypass the distal 15% of the small intestine by creating an ileal colonic bypass has also been attempted but outcomes were poor[82].

CONCLUSION

Until more research regarding targeted gene therapies and an increase in the development of the medical management for PFIC, liver transplant remains the most definitive treatment for those with PFIC. However, it is also important to consider current medical therapies and additional surgical interventions like biliary diversion that can potentially create a synergistic outcome. In particular, in patients with PFIC1, often the best clinical outcome and quality of life is an appropriate combination of all three of these therapies. Identification and better understanding of certain mutations in FIC1 gene might lead to better patient selection. Similarly, in patients with PFIC2, the need for additional medical management can best be determined by pre-operative immunohistochemical studies which can help provide better clinical outcomes. Although the data for liver transplantation for PFIC3 is still lacking, it appears to be the preferred method of treatment with excellent long-term outcomes. There is currently no available clinical data regarding transplantation in the setting of mutations in TJP2 gene (PFIC4).