We report a case of significant clinical improvement after starting odevixibat in a 27-year-old patient with refractory pruritus due to progressive familial intrahepatic cholestasis type 1. He had poor response to multiple therapies and experienced profound decline in quality of life, describing his symptoms as emotionally exhausting and difficult to endure. He was evaluated for liver transplantation in March 2020 but was denied due to preserved liver function. Odevixibat was started in November 2021, resulting in biochemical improvement and dramatic sustained resolution of pruritus. He resumed normal activities, achieving excellent quality of life.

Mutations in ATP8B1 cause a spectrum of cholestatic liver disease, ranging from Progressive-Familial-Intrahepatic-Cholestasis type-1 (PFIC1) to Benign-Recurrent-Intrahepatic-Cholestasis type-1 (BRIC1). Manifestations of PFIC1 include severe pruritus, jaundice, and liver damage. Extrahepatic features sometimes observed in PFIC1 include sensorineural hearing loss, diarrhea, pancreatitis, and short stature. ATP8B1 was shown to translocate phospholipids across the plasma membrane; however, expression of ATP8B1 in many tissues and the range of pathological manifestations in ATP8B1 deficiency suggest diverse physiological functions of ATP8B1, and pleiotropic mechanisms regulating its activity. Recent studies suggest that phosphoinositides, including PIP2 and PIP3, can function as regulators, substrates, and binding partners of ATP8B1. New research shows that ATP8B1 modulates host immune system by regulating cleavage of pyroptotic-executioner Gasdermin D (GSDMD), and inflammation-resolution pathways such as phagocytosis/efferocytosis. Further mechanistic insights can accelerate development of new therapies for restoring membrane integrity, reducing inflammasome activity, and correcting metabolic imbalances caused by ATP8B1 dysfunction.

Patients with progressive familial intrahepatic cholestasis type 1 (PFIC1) who have undergone liver transplantation (LT) may have unmet needs and impacts on daily life due to post-LT complications, including diarrhea and hepatic steatosis. Here, we describe the effects of the ileal bile acid transporter inhibitor odevixibat on diarrhea and hepatic steatosis in a cohort of patients with PFIC1 post-LT. Treating physicians from six centers retrospectively collected data through July 2023 on patients with PFIC1 who received odevixibat post-LT. Data collected included demographics, medical history, and symptom presentation, characteristics of diarrhea, and liver imaging and/or histopathology. Overall, nine male patients with PFIC1 (seven aged <18 years at initial completion of the case report form) were included. In most patients, the primary indication for odevixibat treatment was diarrhea and/or steatosis post-LT. Odevixibat was initiated at a daily dose of 30-120 µg/kg (median exposure: 13 months). All patients had post-LT diarrhea, which was generally associated with negative impacts on daily life (e.g., ability to attend school, needing to wear diapers due to fecal urgency). After odevixibat initiation, most patients had improved diarrhea and positive impacts on daily life. Among five patients with post-LT steatosis and data available before and after odevixibat initiation, steatosis appeared to improve in three and did not change in two. Overall, the majority of patients with PFIC1 post-LT complications in this case series experienced improvements in diarrhea and daily activities with odevixibat. Treatment with odevixibat following LT also appeared to reduce steatosis in some patients. Further studies, particularly those with a prospective design, are needed to confirm these findings.

Neonatal cholestasis is a diagnostic challenge that warrants extensive investigation as there can be serious sequalae such as liver failure, cirrhosis, or other extrahepatic complications. To differentiate the etiology of cholestasis, a distinction can be made between high and low gamma-glutamyltransferase (GGT) cholestasis. Low GGT cholestasis points towards progressive familial intrahepatic cholestasis type 1-2 and 4-6, bile acid synthesis disorders, tight-junction protein type 2 deficiency and some forms of hypopituitarism. Classic galactosemia is generally not included in the differential diagnosis of low GGT cholestasis. Here, we demonstrate low GGT cholestasis in 9 consecutive patients with classic galactosemia at the University Hospitals of Leuven, Belgium. All neonatal cholestasis should be managed with prompt cessation of galactose intake, but in classic galactosemia it can be lifesaving. We now add that low GGT cholestasis increases the likelihood of galactosemia. Conversely, high GGT cholestasis could point to other causes, like biliary atresia, where there may be no need to stop breastfeeding. In galactosemia, we observe a rise in GGT after initiation of a galactose-free diet, which we suggest may be partially explained by the normalization of bile acid transporter glycosylation.

Progressive familial intrahepatic cholestasis type 1 (PFIC-1) is a genetic cholestatic disease causing end-stage liver disease, which needs liver transplantation (LT). Simultaneous biliary diversion (BD) was recommended to prevent allograft steatosis after transplantation, while increasing the risk of infection. Here, an attempt was made to perform BD using appendix to prevent bacterial translocation after LT. An 11-month-old boy diagnosed with PFIC-1 received ABO compatible living donor LT due to refractory jaundice and pruritus. His mother donated her left lateral segment with a graft-to-recipient weight ratio of 2.9%. Internal BD was constructed during LT using the appendix by connecting its proximal end with the intrahepatic biliary duct and the distal end with colon. Biliary leakage was suspected on the 5th day after transplantation and exploratory laparotomy indicated biliary leakage at the cutting surface of liver. The liver function returned to normal on the 9th day post-operation and maintained normal during the 15-month follow-up. Cholangiography at 10 months after transplantation confirmed the direct secretion of bile into colon. Computerized tomography scan (4 months and 10 months) and liver biopsy (10 months) indicated no steatosis in the allograft. No complaint of recurrent diarrhea, infection or growth retardation was reported during follow-up. Internal BD using appendix during LT is effective in preventing allograft steatosis and post-transplant infection in PFIC-1 recipients.