Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing.

 Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.

Bipolar and Related Disorders Induced by Sodium 4-Phenylbutyrate in a Male Adolescent with Bile Salt Export Pump Deficiency Disease.

Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug.

Non-alcoholic steatohepatitis and liver transplantation.

Non-alcoholic steatohepatitis is a growing liver-related health problem. In Europe, non-alcoholic fatty liver disease is the most usual reason of chronic liver illness while steatohepatitis, its progressive form, affects 1% of Europeans and North Americans. In the United States steatohepatitis-related cirrhosis is one of the main indications for liver transplant. A targeted stratification for patients waiting for transplant and affected by this disease is mandatory especially because of their increased cardiovascular and cancer risk. The adequate treatment of NAFLD is crucial for the reduction of the disease related morbidity and mortality. In post-transplant setting, the recurrent or de novo steatosis might seriously affect the allograft short- and long-term outcome. Many conditions can represent the basis of the post-transplant steatohepatitis: obesity, hyperlipidaemia, diabetes mellitus, arterial hypertension, immunosuppressant treatment, alcoholic habit and liver graft steatosis. Today, the only consolidated therapy is represented by a deep life-style intervention since the use of drug-based alternative strategies is still limited and a very few data are available for the post-transplant period. Targeted and personalized behaviour and pharmacological interventions have to be developed for both the pre- and post-transplant phase.