Medical Care
The general treatment of cholestasis applies to progressive familial intrahepatic cholestasis (PFIC); please see the article Cholestasis for treatment information. The disease typically does not respond to any form of medical therapy. Some have reported success in treating patients with progressive familial intrahepatic cholestasis with ursodeoxycholic acid (20-30 mg/kg/d), which may be tried as an initial treatment. [5] Other therapies for the symptomatic relief of pruritus include antihistamines, rifampin, and bile acid-binding agents.
The FDA approved the ileal bile acid transport (IBAT) inhibitor odevixibat (Bylvay) in July 2021 for treatment of pruritus in patients with progressive familial intrahepatic cholestasis aged 3 months and older. [17] Approval was supported by data from the Demonstrate Efficacy and Safety of A4250 in Children With Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1) and PEDFIC 2 phase 3 trials. [17, 18] In PEDFIC 1, a randomized, double-blind, placebo-controlled study, odevixibat showed improvement of pruritus (P = 0.004) and serum bile acid (P = 0.003) compared with placebo. PEDFIC 2, a long-term, open-label phase 3 extension study, showed sustained reductions in serum bile acids as well as improvements in pruritus assessments, growth, and other markers of liver function in patients treated up to 48 weeks. [17, 18]
Transfer
Transfer patients with progressive familial intrahepatic cholestasis (PFIC) to an appropriate transplant center, as the disease will progress to end-stage liver disease (ESLD).
Surgical Care
Surgical therapy that diverts bile salts from the enterohepatic recirculation relieves pruritus in most patients, decreases serum bile salt levels, improves growth, and may delay the progression of disease with PFIC1 and PFIC2. [19, 20] The most common procedure, partial cutaneous biliary diversion, diverts gallbladder bile to a cutaneous ostomy. Patients typically drain 30-120 mL of bile per day, which is discarded.
In a study following children with PFIC, 3 years after diversion procedure, 45% of patients had complete relief of pruritus, 27% had mild pruritus, and 27% experienced no relief. This procedure must be done prior to the development cirrhosis to be effective. [21] Another study that evaluated outcomes of partial external biliary diversion (PEBD) in 35 patients of whom data for 24 children were available found the procedure to be effective for reducing total biliary acid levels and improving PFIC symptoms. [22] However, PEBD was less effective in patients with PFIC2. Seven patients were converted to ilial bypass surgery, with no significant changes to their biliary acid levels. [22]
Alternatively, ileal bypass, a procedure in which the proximal ileum is attached to the cecum bypassing the distal 15% of the ileum and therefore avoiding ileal reabsorption of bile acids can be performed in patients that are not candidates for diversion. This procedure provides immediate relief similar the results seen in diversion, but cholestasis eventually returns in most patients. [23] Partial internal biliary drainage (PIBD) is another technique and involves creating a jejunal conduit from gallbladder to colon to bypass ileal reabsorption of bile acids. [24] There is no long term data on the efficacy of PIBD.
Liver transplantation is indicated in patients with decompensated cirrhosis or with a failed diversion with debilitating pruritus. [5] Historically, the clinical courses and outcomes for PFIC1 recipients after living-donor liver transplantation have not been that good when compared with PFIC2 recipients. Hori et al reported 14 PFIC patients who underwent living-donor liver transplantation, comprising 11 PFIC1 and three PFIC2 patients. Three of 11 PFIC1 recipients died, while the three recipients with PFIC2 survived. [25] A more recent report of seven patients who underwent liver transplantation for PFIC1 showed 100% patient and graft survival. [26] There wasno disease recurrence nor graft loss nor severe extrahepatic manifestations that necessitated hospitalization or surgery, but two patients had persistently high liver parameters albeit with "excellent" liver function. [26]
Liver transplantation is the only effective treatment of PFIC3.
Consultations
Refer all patients to centers with expertise in pediatric hepatology.
Diet
The treatment of fat malabsorption principally involves dietary substitution. In an older patient, a diet rich in carbohydrates and proteins can be substituted for a diet containing long-chain triglycerides. This may not be possible for infants, for whom substitution of a formula containing medium-chain triglycerides may improve fat absorption and nutrition. However, this substitution has not been proven, and therapeutic formulas containing medium-chain triglycerides may not be worth the expense. Bile salt therapy to replace missing bile salts is not practical. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption.
Pay careful attention to preventing fat-soluble vitamin deficiencies, accomplished by administering fat-soluble vitamins and monitoring the response to therapy. Administer vitamin E as tocopherol polyethylene glycol succinate (TPGS) to achieve sufficient absorption in the face of reduced intestinal bile salt concentrations.
Activity
No activity restrictions are needed until late stages of liver disease when precautions should be taken to avoid splenic injury.
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Progressive Familial Intrahepatic Cholestasis. Typical histologic findings of progressive familial intrahepatic cholestations (PFIC): Ballooned hepatocytes from cholate injury, scattered giant cells, cholestasis, and lacy fibrosis extending from central veins to portal areas.
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Progressive Familial Intrahepatic Cholestasis. Ballooned hepatocytes with cholestasis and some giant cell transformation. Note the sinusoidal lacy fibrosis.
Tables
Gene |
Protein |
Proposed Pathophysiology |
GGT |
Clinical considerations |
ATP8B1 |
FIC 1 (ATP8B1) |
Increased phospholipid membrane instability leads to decreased bile acid transport |
Low |
Extrahepatic manifestations: diarrhea, pancreatitis, hearing loss |
ABCB11 |
BPEP |
Mutation in bile acid export pump (BSEP) leads to cholestasis |
Low |
Increased risk of hepatobiliary malignancies |
ABCB4 |
MDR3 |
Decreased phospholipid concentration in bile leads to destabilized micelles within ductules causing inflammation/destruction and eventually cholestasis |
High |
Onset of cholestasis tends to be later in life |
