Continuing Education Activity

Progressive familial intrahepatic cholestasis is a condition in which genetic mutations result in abnormal bile secretion and/or production. Though uncommon, this is a serious condition that, in many cases, leads to significant morbidity and mortality. In order to prevent the disease process from progressing rapidly, this condition should be addressed and diagnosed appropriately. This activity will address the pathophysiology, evaluation, and management of patients diagnosed with this condition.

Objectives:

• Identify the etiology and epidemiology of progressive familial intrahepatic cholestasis.
• Review the pathophysiology and 3 main variants of progressive familial intrahepatic cholestasis.
• Outline the treatment and management options available for progressive familial intrahepatic cholestasis.
• Describe some interprofessional team strategies for improving care coordination and communication to advance the care of progressive familial intrahepatic cholestasis and improve outcomes.

Introduction

Progressive familial intrahepatic cholestasis refers to a collection of rare genetic disorders due to defective mechanisms of bile secretion. Typically divided into three subtypes, PFIC type 1, PFIC type 2, PFIC type 3, the condition is usually diagnosed in the early years of life and often presents with signs and symptoms of intrahepatic cholestasis such as pruritis, dark urine, pale stool, loss of appetite, and fatigue.[1]

Etiology

As a result of mutations within the hepatocellular system, individuals have impaired bile formation resulting in impairment of the mechanisms of secretion, which results in signs and symptoms of cholestasis. Three known subtypes exist, the first two PFIC1 and PFIC2, often present within the first few months after birth, while PFIC3 often presents early in childhood. Three known genes have been discovered that are responsible for this condition. Just as PFIC1 and PFIC 2 present early in life, they also share a defective gene, ATP8B1, and ABCB11. On the contrary, these aforementioned genes are thought to be intact in PFIC3, rather this variant has defects in ABCB4, a gene involved in the production of a protein known as multi-drug resistant 3 which is part of a group of proteins known as “flippases” which assist in translocation of a variety of phospholipids from cell membranes into the bile.[2]

Epidemiology

With the advances in medicine, both in molecular and genetic testing, the incidence of the disease is rising. It is now thought to be anywhere between 1 in 50,000 to 1 in 100,000 births, though the prevalence is largely unknown. It is thought that of all the cases of cholestasis observed in the pediatric population, nearly 10-15% are due to PFIC. In addition to this, approximately 10% of liver transplants in children are a result of this genetic condition. There does not seem to be a documented difference between males and females. Although a condition often diagnosed in children, it can go undiagnosed until adulthood.

Pathophysiology

The pathogenesis of progressive familial intrahepatic cholestasis differs slightly, given which of the three variants is being discussed.

PFIC1

PFIC1, as mentioned prior, occurs due to mutations within the ATP8B1 gene. This protein, which is located on various canalicular membranes, cholangiocytes, and the small intestine, is involved in a variety of functions, which is why a spectrum of phenotypes exists amongst these mutations. From its most benign form known as benign recurrent intrahepatic cholestasis type 1 to the most severe phenotype PFIC1, the condition results in various degrees of cholestasis among the patients it affects. ATP8B1, the gene responsible for producing a protein known as FIC1, is responsible for maintaining the aminophospholipid plasma membrane. Various theories exist in terms of exactly why patients with PFIC1 develop signs and symptoms of cholestasis. One being that the imbalanced distribution of lipids within the membranes provides a protective role. Other theories include that these mutations directly affect the secretion of bile acids into the intestines, hence explaining why it has been demonstrated previously that patients with PFIC1 have reduced levels of bile acid in their intestinal secretions. Furthermore, there is an additional nuclear receptor, commonly referred to as the bile acid receptor (BAR) or farnesoid receptor (FXR), that seems to be downregulated in patients with known PFIC1, resulting in further dysregulation of bile secreting mechanisms. Lastly, it has been discovered that the ATP8B1 gene is most highly expressed within the small bowel and that defects within the gene result in abnormal bile salt enterohepatic cycling.  There is still much research that needs to be performed to fully understand the variability in presentation amongst patients that exist on this disease spectrum. However, from our current understanding, these appear to be associated with the severity of genetic alterations that are present at the DNA level.[3][4][5]

PFIC2

PFIC2, caused by mutations within the ABCB11 gene and located on chromosome 2, encodes for a bile salt export pump (BSEP). Just as it sounds, this protein is responsible for the export of bile salts into the bilious fluid. This defect has a two-fold effect in that is prevents adequate bile salt concentration within the bile and causes a buildup of bile salts within hepatocytes. This results in overload within the hepatocellular system leading to eventual destruction and architectural damage within the liver. As discussed previously, there exists a continuum of genotypic and phenotypic appearances amongst this variant, however, no documented relationship has been established. Literature, however, demonstrates that depending on the type of mutation, whether that be an insertion, deletion, missense, or splicing, the downstream effects tend to reflect the severity and whether there is a complete failure of production of these export proteins versus decreased expression and/or reduced function.

PFIC3

PFIC3 occurs due to a defective ABCB4 gene located on chromosome 7. This gene encodes for a translocator protein involved in phosphatidylcholine excretion. It is thought that these patients have prolonged exposure to hydrophobic bile salts since there is a lack of phospholipids, resulting in hepatocellular damage. The majority of these defective genes result in a shortened protein. A study performed in 50 patients known to have PFIC3 demonstrated that about a third of the tested patients had no detected MDR3 P-glycoproteins within the liver, likely related to rapid destruction of the prematurely formed protein from an early stop codon within the genetic sequence. Newer studies are now discovering that these MDR3 defects, similar to PFIC1 and 2, reflect a spectrum upon which this variant falls upon and may even be related to other conditions such as adult idiopathic cirrhosis, drug-induced cholestasis, and transient neonatal cholestasis.[6][7][8]

History and Physical

Most patients diagnosed will present with signs and symptoms of cholestasis. Infants who have objective findings of hyperbilirubinemia or are visibly jaundiced are often first to be worked up. However, other findings, such as poor weight gain, poor feeding, vomiting, and hepatosplenomegaly, could be the initial presenting findings. Given that this condition is not as common as other pediatric conditions, occasionally, it can present with signs or symptoms related to fat-soluble vitamin deficiencies such as fractures, dry skin, easy bleeding or bruising, and even nocturnal blindness.

In adults, symptoms similar to those mentioned above consistent with cholestasis are, again, often the presenting signs of this underlying condition. However, other findings may also be present. Stigmata of cirrhosis and portal hypertension, including telangiectasias, palmar erythema, gynecomastia, testicular atrophy, variceal bleeding, hepatosplenomegaly, and ascites, may be present. Rarely if these signs are missed, patients can present with acute liver failure with findings of international normalized ratio (INR) > 1.5, elevations in alanine transaminase (ALT) and alanine aminotransferase (AST), encephalopathy, abdominal pain, and jaundice.

Evaluation

In children with suspected cholestasis, PFIC should be considered after ruling out more common causes of cholestasis. Various algorithms exist that can help guide decision making. Initial evaluation often begins with laboratory studies, including a complete metabolic panel, which can demonstrate elevations in bilirubin. A pivotal decision-making step occurs with ultrasonography. If dilated bile ducts are observed, than extrahepatic causes of cholestasis should be ruled out. However, if normal bile ducts are observed, then acquiring a gamma-glutamyl transferase (GGT) can be obtained. If there is a normal activity of GGT and the patient has pruritis, it can be due to PFIC1, PFIC2, BRIC or either from drug toxicity or Hepatitis A. However, if patients have elevated GGT levels, then the next step is often a liver biopsy to determine if there is ductal proliferation that is observed. If ductal proliferation is present and cholangiography demonstrated normal bile ducts, the patient may have either PFIC3 or autoimmune cholangitis.

Although the above is an algorithmic approach in the evaluation of patients with observed cholestasis, the diagnosis of PFIC is a difficult one to confirm. A multi-modal approach is often required. Radiographically speaking, ultrasound is the only required modality, although computed tomography (CT) and magnetic resonance imaging (MRI) are often utilized as well. Liver biopsy is crucial in the diagnosis. Patients with PFIC can have significant changes at the histologic level. PFIC1 often exhibits an absence of ductal proliferation, and metaplasia of hepatocytes is typically observed. PFIC2 is similar to PFIC1, however, there is more disruption of hepatocellular architecture seen in PFIC2 tissue samples. PFIC3, unlike PFIC1 and PFIC2, will exhibit ductal proliferation with portal fibrosis. In addition to the above histologic findings, these tissue samples can be sent in for immunochemical staining.

Analysis of biliary lipid levels is another part of the workup of the condition. Given the nature of various mutations seen amongst PFIC patients, the concentration of bile salts also differ. Patients with PFIC1 seem to exhibit mild reductions in bile salt concentrations with levels often between 3-8 mM. The lowest concentrations, often <1mM, are seen in patients with PFIC2, whereas patients with PFIC3 typically exhibit normal levels.

Lastly, molecular analysis exists as a means of determining and identifying such defects as well.[9][10][11][12][13]

Treatment / Management

A variety of treatments exist which include both medical and surgical interventions. The front-line treatment available for all three variants of PFICs is medical management with ursodeoxycholic acid (UDCA). This secondary bile acid has numerous benefits, including reversal of hepatotoxicity from bile acid accumulation, increasing mitochondrial integrity, and decreasing the degree of cholestasis present. Additional agents such as cholestyramine, a bile acid-binding resin, can be used to treat pruritis associated with PFIC. Rifampicin is thought to work via FXR related mechanisms to upregulate specific detoxification enzymes. Phenobarbital has long been used in the treatment of newborn hyperbilirubinemia through its ability to induce CYP enzymes. Lastly, there are other medications such as antihistamines, steroids, anti-emetics, all of which have been utilized for symptomatic relief.

Often this disease process remains resistant to medical therapy and surgical intervention is required. Intractable pruritis is often a reason for surgery, the most common type being biliary diversion procedures, either internal or external, to prevent the enterohepatic circulation of bile acids and to reduce the accumulation of these acids to alleviate a patients pruritis. External diversions create a conduit connecting the gallbladder to the abdominal skin with the formation of a permanent stoma. In many cases, up to fifty percent of bile flow can be diverted away from the enterohepatic circulation alleviating many of the detrimental effects. In addition to the symptomatic relief that patients experience, external diversion procedures can even help to improve hepatocellular function, slowing down and even reversal of disease progression and increase the time to transplant, thus prolonging many patients' lives. Patient to patient results may vary. However, it has been demonstrated that external diversion procedures are often more beneficial early in the disease course, and if significant liver disease exists may provide little benefit. As with any procedure, complications may arise from external diversions, most commonly stoma prolapse. However, there have also been cases of cholangitis which have been observed, so the risks and benefits should be discussed with patients before proceeding with any such procedure.

Partial internal biliary drainage procedures are much newer, with less evidence to back their efficacy and safety. This procedure involves the formation of a small intestinal or appendiceal conduit between the gallbladder and colon. Though the long-term evidence behind this procedure is still limited, patients seem to demonstrate improvement in their pruritis and theoretically should have similar effects when it comes to disease progression and hepatocellular function.

Another procedure that may start getting more attention in the coming years are ileal bypass procedures. In this type of procedure, the distal 15% of the small intestine is bypassed via an anastomosis with the colon, which is the area where the majority of enterohepatic circulation of bile acids occur. Often utilized in patients who have had a previous cholecystectomy, its long-term efficacy is still unknown, and patients seem to have recurring symptoms often within the first year of this operation.

Many patients’ symptoms will eventually recur or can even be refractory to both medical management, diversion procedures, or a combination of the two. These patients or those who develop end-stage liver disease will often be referred for a liver transplant. Liver transplant thus far has been demonstrated to provide benefits in all variants of PFICS. As with any transplant, the risk of rejection remains, and in some studies, specifically in patients with PFIC2, recurrence of the disease has been noted. Nonetheless, Liver transplant is still the best treatment option for patients with PFIC and is now being considered a first-line option in many centers, even in patients without evidence of end-stage liver disease. Though no new novel therapies have been approved by the FDA, there are some currently being tested which seem to be promising. Of these, apical sodium-dependent bile acid transporter (ASBT) inhibitors seem to significantly reduce intestinal uptake of bile acids and prevent the majority of enterohepatic circulation. Other agents, such as FXR agonists, have already been tested on animal models and seem promising to reduce the synthesis of bile.[14][15][16]

Differential Diagnosis

Given that so many other conditions are associated with cholestasis in infants and the pediatric population, the differential is alarmingly broad. The following is a list of etiologies of cholestasis that are more commonly seen and is not an exhaustive list:

• Biliary atresia
• Infections (e.g., cytomegalovirus, human immunodeficiency virus, syphilis)
• Alpha 1-antitrypsin deficiency
• Alagille syndrome
• Cystic fibrosis
• Neonatal/infantile asphyxia
• Neonatal sclerosing cholangitis
• Common bile duct lithiasis
• Panhypopituitarism
• Choledochal cysts
• Galactosemia
• Tyrosinemia

Prognosis

Most patients with PFIC will develop end-stage liver disease with significant fibrosis by adulthood. Given the progressive nature of this condition, if patients do not undergo a liver transplant, there is high morbidity and mortality associated with it.

Complications

Most complications are related to the sequela of portal hypertension. Esophageal and gastric varices resulting in large volume hematemesis, ascites, hemorrhoids, and hepatic encephalopathy are just some of the complications that can arise. In addition to the above-listed complications, end-stage liver disease itself is a risk factor for hepatocellular carcinoma, and patients with this condition whose disease has progressed to cirrhosis are at a heightened risk for malignancy. Those with PFIC2 appear to be at risk of malignancy independent of their risk associated with cirrhosis.

Also, on top of the complications of the disease process itself, the complications and adverse effects of the various treatment modalities are listed below:

• Medical management
  • UDCA: Diarrhea, +/- pruritis
  • Rifampicin: Hepatotoxicity, fever, gastrointestinal disturbances, rash
  • Cholestyramine: Constipation, intestinal obstruction
  • Phenobarbital: Sedation, dizziness, nystagmus, ataxia
• Surgical management
  • Liver transplant: Rejection, recurrence with PFIC2, adverse effects of immunosuppressant drugs
  • External diversion: Stoma prolapse and cholangitis
  • Internal diversion: Rectal bleeding and choleretic diarrhea

Deterrence and Patient Education

Progressive familial intrahepatic cholestasis frequently poses a diagnostic dilemma. These patients often present with signs and symptoms consistent with cholestasis such as jaundice, pruritis, hepatosplenomegaly, failure to thrive. However given the rarity of the condition and that it is autosomal recessive, often the parents of these children are asymptomatic and the diagnosis can be missed. That is why patients with unexplained cholestasis must be referred to larger institutions where experts in the field exist to ensure that this condition does not go undiagnosed.

Enhancing Healthcare Team Outcomes

Patients and their families who receive this diagnosis should receive adequate counseling from medical providers regarding this condition. An interprofessional team should be organized to assist in answering questions and providing anticipatory counseling. A gastroenterologist, preferably a hepatologist should be involved in the care, as should a pediatrician, interventional radiologist, transplant surgeon as well as a pharmacist. Patients should be given referrals to counseling for therapy as this condition can result in significant mental stress and financial burden on families.