Post cholecystectomy pain is a common clinical problem. Investigation and management of patients with recurrent episodes of biliary pain and normal imaging is challenging. Low phospholipid associated cholelithiasis (LPAC) is a recently described syndrome that often presents with difficult to manage episodes of post cholecystectomy pain. Ursodeoxycholic acid (UDCA) treatment of LPAC is supported by animal studies and case series but has not been assessed in a randomised trial. This protocol presents the design and rationale for an investigator-initiated, prospective, randomised, placebo-controlled, double-blind, Phase 3 crossover trial: Ursodeoxycholic acid in LPAC treating Recurrent Abdominal Pain (ULTRA Pain). The study population consists of 24 patients with difficult to manage post cholecystectomy pain diagnosed with LPAC with no or minimal changes on liver ultrasound imaging. Participants will be recruited through the gastroenterology clinic at Royal Melbourne Hospital and randomly assigned to receive UDCA 10 mg/kg daily for 1 year followed by a matched placebo, or vice versa, separated by an effective 6-week washout period. The primary endpoint is the number of patient reported episodes of biliary pain. Secondary outcomes include the number of episodes of biliary pain with associated transiently elevated liver function tests (LFTs), and episodes of biliary pain in those with the diagnosis of LPAC confirmed by ultrasound, the Recurrent Abdominal Pain Intensity and Disability (RAPID) score, and the score of several questionnaires measuring quality of life. An independent monitor has been appointed to oversee safety of participants. An intention-to-treat analysis will be performed in accordance with CONSORT guidelines. Regression methods appropriate to the type of primary or secondary outcome, such as linear regression for continuous outcome or Poisson or negative binomial regression if found to be skewed, or binary logistic regression for binary outcomes will be employed. Alpha or level of statistical significance will be set to p <0.05 and 95% confidence intervals will be reported throughout. This trial will provide level 1 evidence on the efficacy of UDCA in treating LPAC presenting with post cholecystectomy pain. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000450819).

Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic form of intrahepatic cholesterol lithiasis, affecting mainly young adults. This review describes the recent advances in genetic and clinical characterization, diagnosis and management of LPAC syndrome. Recent publications report data from several retrospective cohorts. These cohorts describe the main clinical features, the most frequent radiological lesions, complications, the results of biliary endoscopic procedures and the prognosis associated with LPAC syndrome. LPAC syndrome has been linked to a partial defect in the ATP binding cassette subfamily B member 4 ( ABCB4 ) gene encoding the canalicular phospholipid transporter multidrug resistance protein 3, but this mechanism would explain only half the cases, or even fewer. This syndrome is characterized by the appearance of cholelithiasis at an abnormally early age (before 40) and by the persistence of biliary symptoms after cholecystectomy. The diagnosis is usually confirmed by an ultrasound scan of the liver, which reveals the presence of intrahepatic microlithiasis, as evidenced by comet-tail images or microspots along the intrahepatic bile ducts. Ursodeoxycholic acid, at a daily dose of 5-15 mg/kg, is the reference treatment. If not performed prior to diagnosis, cholecystectomy should be avoided wherever possible. In complicated or refractory forms, endoscopic biliary intervention may be necessary.

LOW PHOSPHOLIPIDASSOCIATED CHOLELITHIASIS (LPAC) SYNDROME. LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of intrahepatic cholelithiasis, associated in 30% to 50% of cases with a pathogenic variant of the phospholipid transporter MDR3 (multidrug resistance protein 3). Clinical presentation of LPAC syndrome is similar to that of common cholelithiasis, but young adult onset of symptoms (before the age of 40) and recurrence of biliary symptoms after cholecystectomy are highly suggestive of the syndrome. Ultrasound of the liver is key for diagnosis, showing intrahepatic microlithiasis in the form of ductal comet-tail images or microspots. Ursodeoxycholic acid (UDCA), at a dose of 5 to 15 mg/kg/d, is the reference treatment. Endoscopic treatment of lithiasis of the common main bile duct and/ or the main hepatic ducts is sometimes necessary. LITHIASE BILIAIRE PAR DÉFICIT EN PHOSPHOLIPIDES. La lithiase biliaire par déficit en phospholipides, ou syndrome LPAC (low phospholipid-associated cholelithiasis), est une forme rare de lithiase biliaire intrahépatique d’origine génétique, associée dans 30 à 50 % des cas à un variant pathogène du transporteur biliaire des phospholipides MDR3 (multidrug resistance protein 3). Les symptômes et complications du syndrome LPAC sont similaires à ceux de la lithiase biliaire commune, mais le jeune âge de survenue (avant 40 ans) et la récidive des symptômes après cholécystectomie sont évocateurs. Le diagnostic positif repose sur l’échographie hépatique sensibilisée qui met en évidence des signes de microlithiases intrahépatiques (queues de comète, microspots). L’acide ursodésoxycholique (AUDC), à la posologie de 5 à 15 mg/kg/j, est le traitement de référence. Un traitement endoscopique de la lithiase de la voie biliaire principale et/ou des canaux hépatiques principaux est parfois nécessaire.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare and underdiagnosed cause of recurrent intrahepatic and extrahepatic bile duct stones. We report the case of a 32-year-old male with a history of laparoscopic cholecystectomy and multiple ERCPs who presented with acute epigastric pain and vomiting. He had recurrent episodes of cholangitis over several months, each managed with ERCP, balloon extraction, and biliary stenting. Imaging revealed biliary dilatation with obstructive stones. Emergency ERCP retrieved a large stone with pus and debris, followed by stent placement and clinical improvement. He was diagnosed with LPAC syndrome and discharged on ursodeoxycholic acid. Follow-up imaging demonstrated persistent but improving biliary dilation without structural anomalies or abscesses. This case underscores the recurrent nature of LPAC syndrome and the importance of considering this diagnosis in young adults with unexplained biliary symptoms post-cholecystectomy. Early recognition and long-term management are essential to reduce recurrence.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare biliary disorder caused by mutations in the ABCB4 gene, which encodes the MDR3 phosphatidylcholine transporter. It primarily affects young adults and may persist or recur following cholecystectomy. LPAC is characterized by intrahepatic lithiasis and recurrent biliary symptoms. We report the case of a 27-year-old woman with a history of recurrent acute pancreatitis and prior laparoscopic cholecystectomy, who presented with ongoing episodes of biliary colic. Laboratory tests revealed leukocytosis (12,000/μL), while liver function tests remained within normal limits. Abdominal ultrasound identified multiple echogenic foci with posterior acoustic shadowing in segment VII of the liver, along with bile duct ectasia. Further evaluation with computed tomography and magnetic resonance imaging excluded alternative diagnoses. A laparoscopic, ultrasound-guided resection of segment VII was performed. Histopathological analysis confirmed hepatolithiasis with associated acute and chronic cholangitis. LPAC syndrome presents both diagnostic and therapeutic challenges. Although its prevalence is low-estimated at approximately 1 % among patients with recurrent biliary symptoms after cholecystectomy-early recognition is essential for appropriate management. In selected cases with localized intrahepatic lithiasis and persistent symptoms, surgical resection may offer an effective therapeutic option. This case highlights the importance of considering LPAC in young patients with unresolved biliary symptoms post-cholecystectomy and demonstrates the feasibility of minimally invasive liver resection in specialized hepatobiliary centers.