| Abstract|| |
Cholestatic liver disease in children represents a diagnostic and therapeutic challenge. The requirement of a multidisciplinary approach, high levels of professional expertise, and the costs of genetic testing are a few of the reasons why such patients may suffer for want of an accurate diagnosis. Progressive familial intrahepatic cholestasis (PFIC) is a hereditary cholestatic liver disease, afflicted children often progressing to liver failure. Despite its potential to cause significant morbidity, it has seldom been studied in India. Preliminary observations made previously at our center while dealing with such cases have suggested that PFIC may actually not be as rare as described in Western literature. A lack of understanding of actual disease burden in India and no data on genotype–phenotype correlation compounds the issue. The aim of this review is to make pathologists aware of the nuances involved in understanding this disease and its diagnostic clues. As a specific diagnosis has direct therapeutic implication for this subset of patients, the onus is on the pathologist to ensure an accurate opinion. A PubMed-based literature search using the keywords “PFIC” and “progressive familial intrahepatic cholestasis” was done to analyze and disseminate both global and Indian work in this arena.
Keywords: Cholestasis, liver, progressive familial intrahepatic
|How to cite this article:|
Gaur K, Sakhuja P. Progressive familial intrahepatic cholestasis: A comprehensive review of a challenging liver disease. Indian J Pathol Microbiol 2017;60:2-7
|How to cite this URL:|
Gaur K, Sakhuja P. Progressive familial intrahepatic cholestasis: A comprehensive review of a challenging liver disease. Indian J Pathol Microbiol [serial online] 2017 [cited 2018 May 28];60:2-7. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/2/200040
| Introduction|| |
Progressive familial intrahepatic cholestasis (PFIC) refers to a clinically distinct group of autosomal recessive hereditary liver disorders characterized by unremitting cholestasis and progression to liver failure. Defective bile secretion and metabolism underlies this heterogeneous group. PFIC comprises 10%–15% cases of pediatric cholestatic liver disease. Although its exact prevalence is unknown, its incidence is between 1:50,000 and 1:100,000 births. PFIC is a relatively recent discovery, described by Clayton in 1965. It was first reported in individuals of Amish kindred, descendants of Joseph Byler giving the nomenclature of “Byler disease.” It became evident later that the PFIC symptom complex was also found in non-Amish individuals where it was referred to as “Byler's syndrome.”
| Types of Progressive Familial Intrahepatic Cholestasis|| |
The Amish Byler “disease” and the non-Amish Byler “syndrome” as described above were the two earlier known types of this entity and were referred to as PFIC1 and PFIC2. Both these types are characterized by persistent cholestasis and a normal or low serum level of the canalicular enzyme gamma-glutamyl transferase (GGT). With advances in human genetics, it became known that PFIC1 is caused by mutations in the ATP8B1 gene. Mutations in the ABCB11 gene, on the other hand, cause PFIC2. The third type (PFIC3) was described by de Vree et al. in 1998. This subtype is caused by multidrug resistance protein 3 (MDR3) mutations. Unlike the other two types, PFIC3 is characterized by a high level of serum GGT. Recently, mutations of the gene TJP2 encoding a tight junction protein have been found to cause possibly the fourth type of PFIC. The clinical profile and genotype–phenotype correlations of this entity are, however, yet to be studied.
| Pathogenesis|| |
Irrespective of subtype, the pathogenesis of PFIC revolves around defective bile acid synthesis, transport, and/or excretion.
Progressive familial intrahepatic cholestasis 1
ATP8B1 (or FIC1) mutations in PFIC1 afflict a P-type ATPase 3 responsible for maintaining a higher proportion of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane. This altered proportion of aminophospholipids protects the canalicular lumen from injury due to a high concentration of bile salts. Mutations in FIC1 gene result in (a) Altered protein function hampering the secretion of bile acids into bile  and (b) Downregulation of the nuclear receptor farnesoid X which downregulates hepatic bile salt exporter protein (BSEP) upregulating bile acid synthesis. This causes an increased concentration of bile acids in the hepatocytes. Both these effects lead to persisting cholestasis and ensuing liver damage.
Progressive familial intrahepatic cholestasis 2
The gene implicated in this subtype, ABCB11 encodes the ATP-dependent transporter, and BSEP located at the hepatocytes canalicular membrane. Mutations in this protein result in reduced bile salt secretion and bile flow leading to cholestasis.
Progressive familial intrahepatic cholestasis 3
This subtype of PFIC occurs due to mutations in the ABCB4 gene encoding MDR3 protein. MDR3 has a critical role in transporting phosphatidylcholine (PC) across the canaliculus. Mutations in this protein result in a high biliary bile salt: PC ratio. This has two effects. The PC prevents injury to the bile epithelium from hydrophobic bile salts, in the absence of which cholangitis and injury ensue. Second, an altered bile salt/phospholipid ratio destabilizes micelles leading to cholesterol crystallization and lithogenicity of bile.
| Clinical Profile|| |
The typical “PFIC patient” usually presents with jaundice and pruritus disproportionate to the level of serum bilirubin. The onset, severity, and progression of symptoms, however, vary with each type. The onset of symptoms in PFIC1 is usually in the first 3 to 6 months of life. Initially, afflicted children present with pruritus and recurring episodes of jaundice which then become permanent. Malabsorption, especially of fats and associated fat-soluble vitamin deficiencies, follows  such as coagulopathy due to Vitamin K deficiency. Vitamin D deficiency manifests as rickets. PFIC1 is notorious for its extrahepatic symptoms and therefore is considered a systemic disease. These manifestations include sensorineural hearing loss, persistent diarrhea, cholecystitis, pancreatitis, failure to thrive, short stature, elevated sweat chloride concentration, respiratory symptoms such as persistent intractable cough, pneumonia, amenorrhea, and delayed sexual development.,,,
The initial presentation and evolution of PFIC2 is considered to be more severe than PFIC1. Patients generally present with jaundice at onset. Evolution and progression to end-stage liver disease is rapid with a usually fatal course in the absence of transplantation. An association of this subtype with malignancy, specifically hepatocellular carcinoma, and cholangiocarcinoma  has been described in literature. Cholelithiasis has also been reported in these patients. Extrahepatic symptoms are conspicuously absent in PFIC2. This disease is “liver specific,” a point having definite therapeutic implications in the context of success of orthotopic transplant.
PFIC3 rarely presents in neonates with only one-third of cases presenting within the 1st year. Patients present with jaundice, pruritus, and hepatosplenomegaly. The intensity of jaundice and pruritus in this variant is less severe. Young adults commonly present with gastrointestinal bleeding secondary to portal hypertension. Cholelithiasis is a common accompaniment. The evolution to cirrhosis in this variant is slow and may occur even in the absence of frank cholestasis.
| Diagnosis|| |
The diagnosis of PFIC can be arrived at by correlating patients' clinical presentation with imaging, biochemical, histopathological as well as ultrastructural findings. An interdisciplinary collaborative approach is necessary to (a) Strongly suggest the likelihood of PFIC and (b) Select candidates to undergo confirmatory molecular analysis.
Radiology and nuclear studies
Routine ultrasonography (USG) is frequently used in the evaluation of pediatric cholestasis and aids in narrowing the differential diagnosis down to PFIC. It finds application in ruling out extrahepatic or “surgical” causes of jaundice, commonly extrahepatic biliary atresia (EHBA), and choledochal cysts. In expert hands, USG can detect the absence of the gallbladder and the “triangular cord” sign (triangular or band-like periportal echogenic density cranial to the portal vein). Both these features together have a 95% positive predictive value in diagnosing EHBA. Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition  for infantile cholestasis state that hepatic scintigraphy does not add substantially to the diagnosis of EHBA and may be omitted. Choledochal cysts, tumors, and lymphadenopathy - important causes of obstructive jaundice - can also be excluded by a meticulous USG.
In the context of PFIC, after common causes of cholestasis have been ruled out, the typical ultrasonogram is normal. Some cases may, however, show a marked enlargement in gallbladder size and the presence of stones. Cholangiography, a specialized technique available mostly at tertiary centers, can confirm EHBA, rule out sclerosing cholangitis  and clearly delineate biliary anatomy. It can also be used for sampling bile  but requires a high level of expertise.
PFIC is essentially characterized by conjugated hyperbilirubinemia. Serum bilirubin is hence an important initial test despite it not being a reliable marker of cholestasis. Liver enzyme analysis, especially GGT, is imperative for diagnosing PFIC. Most cholestatic pathologies are characterized by an elevated GGT except PFIC and bile acid synthesis defects. Further within the PFIC spectrum, low GGT indicates PFIC1 or PFIC2 while high levels would be seen in PFIC3. Evaluation for TORCH and other viral infections by serological tests is essential to rule out infectious etiology. Metabolic screening including urinalysis for reducing substances, ketones, copper excretion, and gas chromatography–mass spectrometry for organic acids is required. Further, blood sugar, serum lactate, ammonia, alpha-fetoprotein, and ceruloplasmin can rule out a large gamut of metabolic disorders including Wilson's disease and help in excluding/confirming the PFIC picture.
Other tests include prothrombin time and activated partial thromboplastin time are necessary to detect associated coagulopathy. Serum cholesterol and bile acids complete the basic evaluation. Bile analysis is technically demanding but if possible can also help in pinpointing the exact disease subtype. The different parameters as described in various studies ,,,,, and their features in PFIC are highlighted in [Table 1].
|Table 1: Laboratory parameters aiding in the diagnosis of progressive familial intrahepatic cholestasis|
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Histomorphological findings of the biopsied liver tissue give useful insight to the PFIC diagnosis. PFIC1 biopsies are characterized by a maintained lobular architecture and bland canalicular cholestasis devoid of inflammation [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Canalicular bile is pale or wispy. Hepatocytes are orderly and small in early biopsies. Pseudorosettes may be seen along with periportal biliary metaplasia. Interlobular bile ducts are hypoplastic and thread-like. Paucity of ducts is occasionally seen. Fibrosis is not a feature on the early biopsy. PFIC1 progresses slower than PFIC2, and when fibrosis develops, a centrilobular prominence is seen. Perivenular and pericellular accentuation of the fibrosis may be noted, and micronodular cirrhosis may eventually develop.
|Figure 1: Histomorphological pointers to suspect a case of progressive familial intrahepatic cholestasis (in this case progressive familial intrahepatic cholestasis 1). (a) Marked hepatocyte resetting. (b) Canalicular cholestasis devoid of inflammation. (c) The lack of significant fibrosis. (d) Focal loss of canalicular enzyme expression such as polyclonal carcinoembryonic antigen on immunohistochemistry|
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PFIC2 is characterized by a deranged lobular architecture, canalicular, and hepatocellular cholestasis with khaki-colored bile. A “neonatal hepatitis” picture characterized by giant-cell transformation, lobular inflammation, hepatocyte necrosis, edema, apoptosis, and hepatocyte ballooning is seen in biopsies done early. PFIC2 is notorious for morphological heterogeneity with histological findings varying with time, within samples, and among different patients., Giant-cell transformation is seen even in patients older than 1 year in PFIC2. Some authors suggest that the typical giant-cell picture is not a sine qua non for diagnosing PFIC2. Differences also exist in the long-term histological features of PFIC1 and PFIC2. Mallory bodies, chronic hepatitis, frank cirrhosis, thickened central vein, and perivenulitis have been noted more in hepatectomy specimens of PFIC2.
PFIC3 is primarily characterized by biliary pathology. Diffuse hepatocellular cholestasis, true ductular proliferation, mixed inflammation, portal fibrosis, and canalicular cholesterol clefts characterize the picture., Jacquemin has described two histological patterns of MDR3 disease - one of ductular proliferation with portal fibrosis and secondly of extensive biliary cirrhosis.
Immunohistochemistry (IHC) antibody for detection of the ATP8B1 protein applicable to paraffin-embedded tissue does exist, but the applications and results have not been referenced yet in medical literature. Antibodies commonly used for research, function on snap-frozen liver tissue. Surrogate evaluation is thus done, wherein the expression of canalicular markers, GGT, and polyclonal CEA is analyzed. In PFIC1, these markers either show a diminished or absent expression at the canaliculus while staining well at the cholangiolar apices and canal of Hering. However, literature in this area of IHC is sparse.
Similarly, a lack of expression of BSEP and MDR3 protein at the canalicular membrane suggests ABCB11 and ABCB4/MDR3 mutations, respectively., However, a few caveats exist. Experts suggest that any marker must not be used in isolation while interpreting possible cases. All the above markers must be put up with antibody to MRP2 to rule out a general impairment of ATP-cassette transport exporters., Researchers have suggested that complete absence of immunoexpression is generally seen in large frameshift or truncating mutations. Missense mutations, on the other hand, might be associated with residual expression. A few studies have revealed patients with missense BSEP mutations at nucleotide folds showing BSEP immunoexpression. Such patients had a documented indolent clinical course., It is imperative to note that a positive expression does not necessarily translate into a functionally effective protein. Thus, it has been suggested that IHC be used as a screening tool to direct further mutational analysis., A recent albeit small study has also raised the possibility that BSEP IHC may not be able to usefully discriminate between PFIC and non-PFIC cohorts in contrast to MDR3 immunostain. Further research on the correlation of immunoexpression with actual clinical profiles is required.
Ultrastructural analysis of the glutaraldehyde-fixed liver biopsy can provide useful supportive diagnostic evidence. In fact, the most specific pathological finding in the diagnosis of PFIC1 is the presence of the coarse granular “Byler bile” seen on transmission electron microscopy (TEM). PFIC2, on the other hand, is characterized by amorphous fine filamentous bile. TEM analysis does not have much role to play in the diagnosis of MDR3 disease where at best it rules out “Byler bile.” Interestingly, Bull et al. have reported the presence of “Byler bile” in non-Amish children as well. The further correlation of this feature with genetic mutations hence would be interesting. Other features which are nonspecific and common to both PFIC1 and PFIC2 are loss of microvilli, canalicular dilatation, pericanalicular cuff of intermediate filaments, and abnormal mitochondrial internal structure., It must be mentioned that ultrastructural study on paraffin-embedded blocks or paraffin blocks reinfiltrated with resin has failed to yield typical diagnostic features. Patients on choleretics such as ursodeoxycholic acid (UDCA) also do not show characteristic diagnostic features.
The diagnosis of PFIC is confirmed by DNA sequencing of the 27 coding exons (2–28) of each of the three implicated genes, i.e., ATP8B1, ABCB11, and ABCB4 along with their splice junctions.,, Detection of biallelic mutations is diagnostic. Genetic heterogeneity is the hallmark of this disease entity , with a wide variety of mutations being described such as missense, splicing, nonsense, small insertions/deletions, frame shifts, and large deletions.,,,, Till date, more than 80 mutations have been identified in the ATP8B1 gene  and more than 100 in the ABCB11 gene. Mutations in the ATP8B1 gene are common in certain families/ethnicities such as G308V in the Amish population and D554N in the Greenland Inuits. Likewise, E297G/D482G mutations of ABCB11 are found in 30% Europeans afflicted with PFIC2. Interestingly, Klomp et al. in a study of 180 families of PFIC1 and benign recurrent intrahepatic cholestasis found that 30% of PFIC1 patients harbored diagnostic biallelic mutations. Similar findings were described by Jacquemin et al. in MDR3 disease. This implies that unidentified disease causing loci still remain. Mutations of associated chaperone proteins such as CDC50A in PFIC1 are yet to be studied. In the event that both mutant alleles are not identified quantitative polymerase chain reaction and multiplex ligation-dependent probe identification may be used for identifying deletions/duplications. Validation of mutations is done by independent sequencing of both strands of DNA, testing parents in the event of heterozygous mutations. Novel mutations must be distinguished from polymorphisms and their pathogenicity verified by in silico techniques. Certain mutations such as E297G and D482G have been associated with a milder disease course  and good response to biliary diversion procedures. Truncating mutations in particular have been associated with severe clinical disease. The latest genes to be implicated in the causation of PFIC are TJP2 and NR1H4 encoding nuclear bile acid receptor FXR., The advent of next generation sequencing methodologies has accelerated research on unraveling more genes behind pediatric cholestatic disease. Further work on the genotype–phenotype correlation of PFIC is required and is a potential area of clinically relevant research.
| Management|| |
The management of PFIC comprises medical and surgical modalities. Medical therapy is based on the administration of choleretics such as UDCA, cholestyramine, and phenobarbital. Many authors have suggested that UDCA should be used as first-line option in all types of PFIC.,, Especially, in patients of PFIC3 with missense mutations, this choleretic is an effective modality vis-a-vis in those bearing protein-truncating mutations. In a study by Davit-Spraul et al. as many as one-third of patients had a favorable outcome with UDCA, some even reaching adolescence on this therapy alone. Others suggest variable results. The general consensus, however, is that other therapies should be considered only after failure of a trial of UDCA. Other choleretics such as phenobarbital and cholestyramine have limited clinical efficacy.
Nontransplant surgical interventions such as partial external biliary diversion, ileal bypass, and partial internal biliary diversion (PIBD) are also effective in PFIC1 and PFIC2 patients. Improvement in clinical, biochemical, and histological parameters has been documented. These interventions base their effect on interrupting enterohepatic circulation, thereby inhibiting bile salt toxicity. These diversion procedures are believed to be more effective early in the disease course. Although data on genotype–phenotype correlations are limited, certain ABCB11 mutations such as E297G and D482G have shown a good response to biliary diversion.
Failure of the above interventions leaves liver transplantation (LT) as the last resort. Its resultant morbidity renders it as a less preferred option. Patients of PFIC2 and PFIC3 may exhibit reversal of phenotype with LT. However, liver allografts have reported to show secondary steatosis and steatohepatitis. Post-LT intractable diarrhea has also been reported. Recurrence of the pathology has also been reported in PFIC2 where in some cases antibodies to BSEP have been demonstrated. LT is considered an inferior option for PFIC1, a systemic disease, where it is not curative. Future therapeutic options include the administration of 4-phenylbutyrate, a chaperone drug correcting misfolded protein., A German group has also recently described two cases of PFIC2 being successfully treated with steroids opening up a new therapeutic avenue for these patients.
| Indian Perspective|| |
Dearth of Indian literature on progressive familial intrahepatic cholestasis
An extensive PubMed search in August 2016 done for articles pertaining exclusively to this disease entity yielded 407 articles, out of which a total of seven articles (1.71%) have been published from India.,,,,,, Four of the articles were case reports,,,, three of which ,, described favorable outcomes after biliary diversion procedures. One highlighted an incidental association of PFIC with infarction. One article was a review of existing literature. Two original research articles have been published from the country till date. One from North India  focused on the outcomes of medical and surgical therapeutic approaches on seven afflicted patients. The other study from Southern India exclusively dealt with the favorable outcome of PIBD in a series of ten PFIC children. Research on the genetic and morphological diagnosis of PFIC is an unchartered area. The genetic, histopathological, and ultrastructural aspects of PFIC in an Indian population have hitherto been unstudied. It must be mentioned that out of all of the 407 PubMed articles written on PFIC, only five articles ,,,, (1%) are specific to diagnostics. From a pathologist's perspective, this presents a tremendous possibility of studying a relatively unchartered territory and furthering pathology-based research.
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Prof. Puja Sakhuja
Department of Pathology, Academic Block, G. B. Pant Institute of Postgraduate Medical Education and Research, Jawaharlal Nehru Marg, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None