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

• Splenomegaly

  She had no splenomegaly. Stool was normally colored and the urine was dark. Laboratory investigations are reported in table I. [latunisiemedicale.com]

  […] right upper quadrant abdominal pain, and weight loss – Frequently complicated by cholesterol cholelithiasis • MDR3 disease PFIC3 presents during infancy with pruritus, jaundice, pale stools, hepatomegaly, or complications of portal hypertension, such as splenomegaly [basicmedicalkey.com]

  An abnormally small gallbladder with an irregularly stiff wall, and splenomegaly were also shown. A drainage tube was placed; location of the end of the drainage tube was confirmed in the lower duodenum by X-ray. [journals.lww.com]

  […] progressive familial intrahepatic cholestasis (PFIC) Jaundice Scleral icterus Cutaneous jaundice Dark urine Physical See the list below: Pruritus Scratching Cutaneous mutilation Irritability in infants Jaundice Scleral icterus Cutaneous jaundice Hepatomegaly Splenomegaly [emedicine.medscape.com]

• Short Stature

  We searched for FIC1 mutations and analyzed the outcome of extrahepatic features after liver transplantation in two children with this form of progressive familial intrahepatic cholestasis associated with chronic unexplained diarrhea and short stature [ncbi.nlm.nih.gov]

  Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness. [orpha.net]

  The ATP8B1 protein is found throughout the body, but it is unclear how a lack of this protein causes short stature, deafness, and other signs and symptoms of PFIC1. Mutations in the ABCB11 gene are responsible for PFIC2. [ghr.nlm.nih.gov]

  Other extrahepatic manifestations associated with PFIC1 include short stature, sensorineural deafness, pancreatitis, and hepatic steatosis. [emedicine.com]

• Anemia

  A management approach includes ruling out potentially contributing factors like depression, anemia, thyroid dysfunction, renal dysfunction, and sleep disturbances. [hindawi.com]

  […] de Macedo, Sarah Cristina Bassi, Joao Victor Piccolo Feliciano, Fernanda Borges Ribeiro, Benedito de Pina Almeida Prado, Gil Cunha De Santis, Ivan de Lucena Angulo and Dimas Tadeu Covas, Intrahepatic Cholestasis in Sickle Cell Disease: A Case Report, Anemia [doi.org]

  カルニチン欠乏症 carnitine deficiency カロリ病 Maladie de Caroli (仏), Caroli disease カロチン血症 carotenemia 川崎病 Kawasaki disease 肝アスペルギルス症 hepatic aspergillosis 肝アミロイドーシス，アミロイド肝 hepatic amyloidosis, amyloid liver 肝炎 hepatitis 肝炎後再生不良性貧血 hepatitis-associated aplastic anemia [jsge.or.jp]

• Candidiasis

  症 hepatic aspergillosis 肝アミロイドーシス，アミロイド肝 hepatic amyloidosis, amyloid liver 肝炎 hepatitis 肝炎後再生不良性貧血 hepatitis-associated aplastic anemia 肝外傷 hepatic trauma 肝外門脈閉塞症 extrahepatic portal obstruction 肝吸虫症 clonorchis sinensis, liver flukes 肝カンジダ症 hepatic candidiasis [jsge.or.jp]

• Diarrhea

  Post-LT refractory diarrhea was present in all 8 having steatosis. Three without post-LT diarrhea showed no allograft steatosis. Bile adsorptive resin therapy reduced the diarrhea and steatosis. [ncbi.nlm.nih.gov]

• Failure to Thrive

  This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation. [en.wikipedia.org]

  She also presents a sever failure to thrive, despite adequate nutritional support by gastric tube at home. [latunisiemedicale.com]

• Steatorrhea

  Episodes resolve spontaneously without histologic progression • BSEP disease Depending on nature of mutation, may present as BRIC2 or PFIC2 PFIC2 – Presents as severe intrahepatic cholestasis in infancy BRIC2 – Presents as recurrent episodes of pruritus, steatorrhea [basicmedicalkey.com]

  Case reports of vitamin E deficiency due to steatorrhea causing reversible neurologic symptoms after supplementation and achievement of detectable serum levels have been reported. 4,5 We found no reports of refractory vitamin E deficiency caused by PFIC [acgcasereports.gi.org]

  Typical features included jaundice, pruritus, malnutrition, steatorrhea, osteodystrophy, short stature, and hyperbilirubinemia. Eight patients had died between the ages of 6 weeks and 3 years. [ncbi.nlm.nih.gov]

  Clinical features included severe pruritus, steatorrhea, poor growth and progression to cirrhosis in early childhood. [intechopen.com]

  Cholestasis should be considered in a baby with irritability, pruritus, cutaneous mutilation, scratching, jaundice, watery diarrhea, steatorrhea and failure to thrive.1,3,9 Physical examination Cholestatic liver diseases have a wide spectrum of presentation [dovepress.com]

• Nausea

  […] spontaneously without histologic progression • BSEP disease Depending on nature of mutation, may present as BRIC2 or PFIC2 PFIC2 – Presents as severe intrahepatic cholestasis in infancy BRIC2 – Presents as recurrent episodes of pruritus, steatorrhea, nausea [basicmedicalkey.com]

  He reported worsening nausea but denied experiencing any fevers, chills, cough, muscle aches, night sweats, or vomiting. [hindawi.com]

  Itching may disturb sleep and contribute to fatigue, tiredness, irritability as well as reduced appetite, nausea and vomiting. Failure to thrive: This refer to poor weight gain and possibly slower growth due to the reduced absorption of fats. [childliverdisease.org]

• Foul-Smelling Stools

  Also, these patients produce copious amounts of foul-smelling stool, which may persist following liver transplant. [symptoma.com]

  The main clinical features were early onset of loose, foul-smelling stools, jaundice, hepatosplenomegaly, impaired growth with short stature, and in 4 of 6 cases, death between 17 months and 8 years. [ncbi.nlm.nih.gov]

• Jaundice

  RESULTS: Six patients who underwent PBD experienced short-term resolution of jaundice and pruritus. Four patients experienced persistent stoma-related complications requiring a total of 14 revisions. [ncbi.nlm.nih.gov]

  She had no history of jaundice since birth and jaundice was not noted at several doctors’ visits prior to this presentation. Physical examination showed neither icterus nor hepatosplenomegaly. [hindawi.com]

  The age of presentation of the first attack of jaundice ranges from 1–50 years, but jaundice usually occurs before the age of twenty years. [intechopen.com]

• Hepatomegaly

  RESULTS: All four patients were presented with jaundice, pruritus, hepatomegaly, sleep disturbance. They fulfilled the criteria for PFIC. The surgery was uneventful. [ncbi.nlm.nih.gov]

  He had hepatomegaly (8 cm) which was firm. He had also a splenomegaly. Initial biological data were summarized in table I. Abdominal ultrasonography showed a homogeneous hepatomegaly. [latunisiemedicale.com]

  Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. [orpha.net]

• End Stage Liver Disease before Adulthood

  PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. [em-consulte.com]

  Patients usually develop fibrosis and end-stage liver disease before adulthood. Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness. [orpha.net]

• Hepatosplenomegaly

  […] yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly [ghr.nlm.nih.gov]

  Physical examination showed neither icterus nor hepatosplenomegaly. [hindawi.com]

  Physical exam Remarkable findings on examination include: Icterus Hepatosplenomegaly Hyperpigmentation Growth retardation Shiny nails The newborn with unexplainable cholestasis should be suspected to have PFIC. [symptoma.com]

  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 ]. [wjgnet.com]

• Recurrent Jaundice

  We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years, in addition to cholestasis that eventually became fatal. [ncbi.nlm.nih.gov]

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

  Additionally, there is typically more severe cholestasis and recurrent jaundice, extrahepatic disease and portal hypertension. These sequelae often lead to decompensation in early childhood. [wjgnet.com]

• Pruritus

  Persistent or recurrent pruritus after PFIC is associated with an increased risk of stoma prolapse or reflux. [ncbi.nlm.nih.gov]

• Hyperpigmentation

  Physical exam Remarkable findings on examination include: Icterus Hepatosplenomegaly Hyperpigmentation Growth retardation Shiny nails The newborn with unexplainable cholestasis should be suspected to have PFIC. [symptoma.com]

  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 ]. [wjgnet.com]

• Hearing Problem

  It can lead to a deficiency in fat soluble vitamins as well as diarrhoea, slow growth, short stature, pancreatitis (inflammation of the pancreas), thicker skin and hearing problems. [childliverdisease.org]

  Patients with FIC1 deficiency can also have hearing problems, a chronic cough, and inflammation of the pancreas causing abdominal pain. Patients with BSEP deficiency may be at an increased risk of liver cancer. [childrennetwork.org]

• Irritability

  History The following may be noted in the history of a patient with progressive familial intrahepatic cholestasis (PFIC) Jaundice Scleral icterus Cutaneous jaundice Dark urine Physical See the list below: Pruritus Scratching Cutaneous mutilation Irritability [emedicine.medscape.com]

  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. [symptoma.com]

  Instead, they may be irritable and sleep poorly. Scratching starts as digging at the ears and eyes, which are the first areas to show bleeding and scarring. The itching may be very disabling and does not usually respond to medications. [childrennetwork.org]

  Rectal bleeding may be due to irritation of bile acids in the first postoperative days. The risk of colon cancer due to bile acids is not yet known. [dovepress.com]

• Encephalopathy

  Symptoms of hepatic decompensation include jaundice, pruritus, hematemesis, melena, ascites, encephalopathy, easy bruising, and menstrual abnormalities [6]. [hindawi.com]

  She died at home at the age of 4 years, with worsening ascites and encephalopathy. All the coding exons of ATP8B1, ABCB11 and ABCB4 genes were amplified [2-4] and sequenced. [indianpediatrics.net]

  Familial Encephalopathy with Neuroserpin Inclusion Bodies  can manifest both as a PME syndrome or as a presenile dementia with frontal symptoms.  onset is between ages 13 and 30.  autosomal-dominant inheritance and is caused by mutations in the gene [slideshare.net]

  Decompensated cirrhosis [international normalized ratio (INR) > 1.5, albumin < 30 gram per liter (g/L), history or presence of clinically significant ascites, variceal hemorrhage, and/or encephalopathy]. ALT >15×ULN at screening. [clinicaltrials.gov]

• Dark Urine

  Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. [orpha.net]

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.

• Bilirubin Increased

  During the hospital admission the direct bilirubin increased to 8.2 mg/dL out of a total of 10.4 mg/dL. Abdominal ultrasound showed increased hepatic echogenicity with a contracted gallbladder. [scielo.org.mx]

• Enlargement of the Liver

  They will not be affected Severe itching caused by the buildup of bile salt in the body (pruritus) Poor weight gain (due to a lack of bile needed to digest and absorb fat) and poor growth Jaundice (yellowing of the skin) Other symptoms may include: Enlargement [cincinnatichildrens.org]

• Bile Acids Increased

  Concomitant with loss of canalicular bile secretion, cholestatic bile acid uptake increases and the bile acid pool increases across the intestinal wall because of reduced in farnesoid X receptor expression[19-22]. [ghrnet.org]

• Direct Bilirubin Increased

  During the hospital admission the direct bilirubin increased to 8.2 mg/dL out of a total of 10.4 mg/dL. Abdominal ultrasound showed increased hepatic echogenicity with a contracted gallbladder. [scielo.org.mx]

• Bile Acids Increased

  Concomitant with loss of canalicular bile secretion, cholestatic bile acid uptake increases and the bile acid pool increases across the intestinal wall because of reduced in farnesoid X receptor expression[19-22]. [ghrnet.org]

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.

1. Van der Woerd WL, van Mil SW, Stapelbroek JM, et al. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Practice and Research. Clinical Gastroenterology. 2010; 24(5), 541-553.
2. Nguyen KD, Sundaram V, Ayoub WS. Atypical causes of cholestasis. World Journal of Gastroenterology : WJG. 2014;20(28):9418-9426.
3. Srivastava A. Progressive familial intrahepatic cholestasis. Journal of Clinical and Experimental Hepatology. 2014; 4(1): 25–36.
4. Clayton RJ, Iber FL, Ruebner BH, et al. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. American Journal of Diseases of Children. 1969;117(1):112–124.
5. Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology. 2004;40(1):27–38.
6. Tygstrup N, Steig BA, Juijn JA, et al. Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity. Hepatology. 1999;29(2):506–508.
7. Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nature Genetics. 1998;18(3):219–224.
8. van Mil SW, Klomp LW, Bull LN. FIC1 disease: a spectrum of intrahepatic cholestatic disorders. Seminar in Liver Disease. 2001;21(4):535–544.
9. Paulusma CC, Folmer DE, Ho-Mok KS. ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity. Hepatology. 2008;47(1):268–278.
10. Nakanishi Y, Saxena R. Pathophysiology and Diseases of the Proximal Pathways of the Biliary System. Archives of Pathology and Laboratory Medicine. 2015;139(7):858–866.
11. de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proceedings of the National Academy of Scienced USA. 1998;95(1):282–287.
12. Deleuze JF, Jacquemin E, Dubuisson C, et al. Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology. 1996;23(4):904–908.
13. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Seminars in Liver Disease. 2001;21(4):551–562.
14. Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nature Genetics. 2014;46(4):326–328.
15. Sambrotta M, Thompson RJ. Mutations in TJP2, encoding zona occludens 2, and liver disease. Tissue Barriers. 2015;3(3):e1026537.
16. Davit-Spraul A, Gonzales E, Baussan C, et al Progressive familial intrahepatic cholestasis. Orphanet Journal of Rare Diseases. 2009; 4:1.
17. Alissa FT, Jaffe R, Shneider BL. Update on progressive familial intrahepatic cholestasis. Journal of Pediatric Gastroenterology and Nutrition. 2008; 46(3):241-52.
18. Hori T, Nguyen JH, Uemoto S. Progressive familial intrahepatic cholestasis. Hepatobiliary and Pancreatic Diseases International. 2010;9(6):570–578.
19. Jacquemin E. Progressive familial intrahepatic cholestasis. Clinics and Research in Hepatology and Gastroenterology. 2012;36 Suppl 1:S26–S35.
20. Davit-Spraul A, Fabre M, Branchereau S. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51(5):1645–1655.
21. Lykavieris P, van Mil S, Cresteil D, et al. Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. Journal of Hepatology. 2003;39(3):447–452.
22. Ganne-Carrié N, Baussan C, Grando V, et al. Progressive familial intrahepatic cholestasis type 3 revealed by oral contraceptive pills. Journal of Hepatology. 2003;38(5):693–694.
23. Pasmant E, Goussard P, Baranes L, et al. First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. European Journal of Hum Genetics. 2012;20(3):277–282.
24. Gonzales E, Davit-Spraul A, Baussan C, et al. Liver diseases related to MDR3 (ABCB4) gene deficiency. Frontiers in Bioscience. 2009; 14:4242-4256.