The common features of all three types are jaundice and pruritus which are a hallmark of the disease. Moreover, the pruritus is devastating and stressful for patients and their caretakers as it causes irritability, sleep loss, low attention span, and poor performance in school.

PFIC type 1

This type presents in early infancy. Hemorrhage may be the initial sign as it stems from vitamin K deficiency [10]. Also, these patients produce copious amounts of foul-smelling stool, which may persist following liver transplant [20] [21].

Complications include recurrent jaundice, severe cholestasis, portal hypertension, and extrahepatic involvement such as short stature and sensorineural deafness [16]. Typically these patients are identified due to failure to thrive [20].

PFIC type 2

This manifests in the neonatal period and progresses faster than type 1. Individuals with type 2 develop persistent jaundice and significant pruritus. In the absence of liver transplant, this rapidly evolving disorder reaches end-stage liver disease with liver failure within the first year of life [20].

PFIC type 3

Type 3 occurs in late infancy to early adulthood [19]. Initial presenting signs may be gastrointestinal hemorrhage due to cirrhosis and portal hypertension. Cholestasis manifests in an age range that spans infancy to adolescence [19].

Note that individuals with MDR3 mutations are susceptible to developing drug-induced cholestasis [22] [23].

PFIC type 4

In the small group of patients evaluated for this form, all had severe livere disease and the majority needed liver transplantation [14]. Some exhibited extrahepatic features such as respiratory and neurological manifestations [15].

Physical exam

Remarkable findings on examination include: [3] [10]

• Icterus
• Hepatosplenomegaly
• Hyperpigmentation
• Growth retardation
• Shiny nails

The newborn with unexplainable cholestasis should be suspected to have PFIC. The clinical assessment consists of detailed patient history, family history, a physical exam, and key studies.

Genetic testing

The diagnostic study of choice is genetic testing.

Laboratory tests

PFIC type 1

The laboratory values for type 1 are as follows 1) GGT is normal or low, 2) serum transaminases are mildly increased, 3) serum cholesterol is normal or low [16], 4) serum bile acid concentration is increased [20] [24], and 5) biliary bile salt concentration is slightly decreased [21].

PFIC type 2

The laboratory values for type 2 are 1) GGT is normal or low, 2) serum transaminases level is raised to at least 5 times the normal, 3) serum cholesterol is normal or low, 4) serum bile acid concentration is increased [20] [24], 5) biliary bile salt concentration is very low, and 6) α-fetoprotein level is higher in this type compared to type 1 [8] [20].

PFIC type 3

The laboratory values for type 3 are 1) GGT is increased and may be as high as 10 times the normal, 2) serum transaminases, conjugated bilirubin, and alkaline phosphatase are profoundly high [1] [20], 3) serum cholesterol is normal or low [14], and 4) serum bile acid concentration is increased [20] [24].

The biliary bile salt level is normal but the biliary bile phospholipid concentration is severely low. The latter is the cardinal laboratory finding in this type.

Imaging

Ultrasonography is the initial imaging technique used in the evaluation of PFIC patients. The findings are usually normal with the exception of cholelithiasis in those with PFIC type 3.

Furthermore, cholangiography can be performed to rule out sclerosing cholangitis and to collect bile for analysis [3].

Immunohistochemistry

Antibodies to BSEP and MDR3 can be used for immunostaining on the biopsy specimens. The lack of staining is indicative of the diagnosis.

The therapeutic approach of PFIC is to alleviate pruritus, replace deficient vitamins, improve nutritional status, and manage the complications associated with PFIC. The multidisciplinary medical team should consist of hepatologists, surgeons, primary pediatricians, nutritionists, social workers, and other professionals.

Medical treatment

Pruritus is commonly treated with Ursodeoxycholic acid (UDCA). Other options include antihistamines, rifampicin, and skin moisturizers.

Diet

Diet is a strong component of the overall management. The patient's caloric consumption should be approximately 125% of the recommended daily allowance (RDA). The diet should contain fat in the form of medium chain triglycerides (MCT) since these are absorbed without the need for bile salts.

Fat and water soluble vitamin replacement is essential in patients with PFIC. There are specific dietary recommendations for water and fat soluble vitamin replacement.

Surgery

Surgical intervention such as biliary diversion aims to modify the enterohepatic circulation and is a method to decrease the bile salt accumulation.

Liver transplantation is indicated in patients with end-stage liver disease, decompensated cirrhosis, or pruritus unresponsive to biliary diversion or other treatment.

Other

It is important for parents to receive various types of support while caring for a child with PFIC. There are numerous resources available to assist and guide parents.

The outcome in these patients varies according to the severity of the genetic defect and the type of PFIC.

Many patients manifest symptoms in infancy or childhood. They develop fibrosis and liver failure at a rapid rate. Mortality is typically inevitable in untreated patients. Moreover, it is rare that an untreated child survives into the third decade of life [16] [17].

PFIC is the leading cause of 10% to 15% of cases of neonatal cholestasis syndrome [18] [19]. Furthermore, PFIC is responsible for 10% to 15% of liver transplantations in the pediatric population. In a short follow-up of post-liver transplantation patients, at least 75% demonstrated an improvement in cholestasis and its symptoms [18] [19].

Pruritus can be devastating as it causes a significant impact on the patient's daily life. One treatment, ursodeoxycholic acid (UDCA), achieves a response in 30% of PFIC individuals while up to 80% are alleviated by biliary diversion in early stages of the disease [20].

Note that there is an increased risk of developing hepatocellular carcinoma (HCC) in type 2 patients [20].

Complications

The following are consequences of PFIC: [20]

• Severe growth failure
• Rickets secondary to vitamin D deficiency
• Vitamin E neuropathy
• Gallstones
• Gastrointestinal bleeding

The etiology of most types of PFIC is attributed to mutations in the genes coding for hepatocanalicular transporter proteins. The latter play a vital role in bile formation and secretion [1]. Specifically, PFIC types 1, 2, and 3 are the result of mutations in the genes called ATP8B1, ABCB11, and ABCB4, respectively. Additionally, the recently described type 4 is associated with a mutation in the TJP2 gene. The mode of inheritance is autosomal recessive.

The incidence of PFIC is 1 per 50,000 to 100,000 births [2] [3]. With regards to demographics, there is no gender preference.

Certain populations have been more commonly affected with this disorder such as the Amish, communities in the Faeroe Islands, and Inuit Indians in Greenland and Canada [4] [5] [6].

There are four main variants of PFIC, which develop due to genetic mutations. The underlying cellular processes targeted in these diseases involve the transporters that play an essential role in the synthesis and secretion of bile.

PFIC type 1

The ATP8B1 gene codes for the FIC1 protein [7] [8], which is located on the canalicular membrane of hepatocytes. FIC1 normally enables the transport of phosphatidylserine and phosphatidylethanolamine from the outer to the inner leaflet of the cell membrane. Another function of FIC1 is to prevent the accumulation of bile salt in the membrane [9].

While it is not understood how cholestasis occurs [10], the genetic mutation leads to FIC1 deficiency and the resultant impairment of bile acid secretion.

PFIC type 2

The gene implicated in this disease is the ABCB11, which codes for the bile salt excretion protein (BSEP) protein. Absence or insufficient function of this protein consequently leads to defects in bile salt secretion and the accumulation of this substance in the hepatocytes. This reduces bile flow and causes hepatocellular destruction [10].

PFIC type 3

Development of this type of PFIC arises from a mutation in the ABCB4 gene, which encodes the multidrug resistance class III (MDR3) protein [11] [12]. The absence of MDR3 causes a malfunction in the transport of phospholipids [13]. Without the latter, there is micelle instability and biliary obstruction. Hence, cholestasis develops secondary to the damaged biliary epithelium and bile canaliculi.

PFIC type 4

This form was recently identified. It results from mutations in the TJP2 gene, which is responsible for the production of the tight junction protein 2 [14], also known as zona occludens 2 (ZO-2) [15]. A defect in the latter impairs its interaction with integral membrane proteins and cytoskeletal proteins [14] [15].

Histology

The histological findings of the three types of PFIC demonstrate progressive fibrosis. Type 1 reveals canalicular cholestasis. Type 2 features canalicular cholestasis accompanied by hepatocellular necrosis and giant cell hepatitis. Finally, type 3 displays bile duct proliferation and biliary fibrosis [3].

Since this is an inherited disorder, it cannot be prevented. However, patients and family members should seek genetic counseling to learn about PFIC, what it entails, its mode of inheritance, and other important information.

Progressive familial intrahepatic cholestasis (PFIC) refers to a collective group of cholestatic conditions that develop as a result of genetic mutations that affect biliary epithelial transporters. There are four types of PFIC and each is inherited through an autosomal recessive pattern. The first two types are characterized by the impaired export of bile acids while type 3 is explained by the defective export of phospholipids and type 4 results from a defect in a tight junction protein.

The clinical presentation of all types is relatively similar. They manifest in infancy or childhood. The notable features are cholestasis, jaundice, and pruritus. As the name of the condition indicates, the cholestasis is progressive and culminates into cirrhosis and end-stage liver disease either rapidly or at a slower pace. Liver transplantation may be necessary in infancy or childhood.

The clinical assessment is comprised of a physical exam, laboratory tests, immunochemistry staining, and imaging modalities. Genetic testing is the definitive test to confirm the disease. Additionally, pertinent laboratory studies include levels of gamma-glutamyl peptidase (GGT), serum and biliary bile acids, and biliary phospholipids. The levels of these variables help differentiate between the three types. Furthermore, imaging techniques such as ultrasonography and cholangiography can be performed to evaluate other biliary tract pathologies.

The therapeutic approach in these children is directed towards providing relief for pruritus, correcting nutritional deficiencies, and treating the complications. Medical treatment consists of drugs to address the above goals. However, surgery is often required in these patients. Biliary diversion procedures can be beneficial although liver transplantation is required in those with advanced liver disease or persistent pruritus refractory to medication and biliary diversion.

The prognosis is poor in untreated children. PFIC is associated with serious complications such a failure to thrive, cirrhosis, gastrointestinal hemorrhage, vitamin deficiencies, etc. Therefore, early recognition and prompt intervention may lead to a better prognosis.

What is Progressive familial intrahepatic cholestasis?

Progressive familial intrahepatic cholestasis (PFIC) refers to a group of disorders that causes cholestasis in infant and children. Cholestasis is the condition in which bile flow is decreased. Bile is the fluid that is normally made by the liver cells with components such as bile salts, water, and other substances. After bile is synthesized in the liver, it is released and eventually stored in the gallbladder. After eating fatty meals, the gallbladder releases bile acid to digest the fat.

In PFIC, the liver cells fail to properly synthesize the bile and/or they cannot release the bile from liver cells.

What causes this condition?

These are disorders occur due to mutated genes that are inherited through an autosomal recessive pattern. This means that the affected child receives a bad copy of the gene from each parent. In other words, the patient has two bad copies in order to have the disease.

What are signs and symptoms of PFIC?

The symptoms begin during infancy or childhood. The patients have varying degrees of severity with symptoms such as:

• Itching
• Jaundice
• Discoloration of the skin
• Diarrhea with pale and smelly stool
• Enlarged liver
• Gallstones
• Poor growth
• Vitamin deficiencies
• Dark colored urine
• Deafness

How is it diagnosed?

In babies and children with cholestasis, the doctor will obtain the history of the patient and the family and perform a physical exam. A genetic test will confirm the diagnosis. Also, the doctor will order key laboratory tests such a:

• Blood transaminases
• Blood cholesterol
• Blood bile acid
• Biliary bile salt
• Biliary phospholipid
• GGT

Imaging studies include

• Ultrasonography
• Cholangiography

How is it treated?

The treatment aims to relieve the itching, correct the nutritional and vitamin deficiencies, and manage the complications.

The following treat itching:

• Antihistamines
• Ursodeoxycholic acid (UDCA)
• Rifampicin
• Lotions

Diet is very important as there are nutritional recommendations for these patients. Since they have vitamin deficiencies, those vitamins should be replaced. Additionally, they should consume fat in the form of medium chain triglycerides (MCT)

Children with severe symptoms and complications may require surgery. There are two options:

• Biliary diversion: this seeks to alter the route of bile drainage. Specifically, it allows the bile to drain out through the skin.
• Liver transplantation: this can save a patient's life and should be performed in patients with advanced liver disease and those who still have itching despite other treatments or surgery.

What is the prognosis?

Without treatment, the patient has a poor prognosis. However, a liver transplant can prolong the survival and improve the outcome. The itching can be stressful and devastating for the patients. Therefore, this should be treated with medications or surgery.

Can this be prevented?

As this is an inherited disorder,it cannot be prevented. But affected patient and their family member should be offered genetic counseling in order to learn more about the disease.

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