Original article

# Endoscopic features of low-phospholipid-associated cholelithiasis syndrome: A retrospective cohort study

G. Salin<sup>a, *</sup>, C. Corpechot<sup>b, c</sup>, S. Ouazana<sup>a</sup>, C. Dong<sup>b, c</sup>, A. Becq<sup>d</sup>, S. Lemoinne<sup>b, c</sup>, K. Ben Belkacem<sup>b, c</sup>, R. Leenhardt<sup>a</sup>, U. Chaput<sup>a</sup>, O. Chazouillères<sup>b, c</sup>, J. Kirchgesner<sup>e</sup>, M. Camus<sup>a</sup>

<figure><img src="image_1.png" /></figure>

## ARTICLE INFO

### Keywords:

ERCP

Lpac

UDCA

## ABSTRACT

**Background and objective:** LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of cholelithiasis. ERCP (endoscopic retrograde cholangiopancreatography) is often used to remove gallstones in the bile duct. No published data is available on the role of ERCP in LPAC syndrome.

**Patients and methods:** In this retrospective cohort study, we included patients diagnosed with LPAC syndrome in a single tertiary referral center between 2009 and 2021. Our aim was to assess the frequency, indications, modalities, results, and complications of ERCP, as well as predictive factors for ERCP, in LPAC syndrome. Independent factors associated with ERCP occurrence were identified using a multivariable Cox regression analysis.

**Results:** ERCP was required in 31.2 % of the 269 patients included for analysis. Among patients who required ERCPs, 78.6 % had the procedure before diagnosis (i.e., starting UDCA). Most common indications were cholangolithiasis (53.6 %) and acute cholangitis (29.5 %). Post ERCP pancreatitis, perforation and bleeding rates were 7.2 %, 2.6 %, and 1.3 %, respectively. Age and history of cholelithiasis in first-degree relatives were associated with a higher risk of ERCP (Hazard-ratio [HR]=1.30 [95 %confidence-interval [CI] 1.04–1.62] and HR=1.88 [95 %CI 1.15–3.07] respectively). Female gender and UDCA intake ≥ 1 year were associated with a lower risk of ERCP (HR=0.49 [95 %CI 0.29–0.82] and HR=0.44 [95 %CI 0.22–0.90] respectively). Median follow-up was 10.8 years.

**Conclusion:** One-third of patients with LPAC syndrome undergo sphincterotomy. However, most procedures are performed before diagnosis and UDCA is associated with a lower risk of endoscopic procedure. Earlier diagnosis and treatment with UDCA may further reduce the need for ERCP in patients with LPAC syndrome.

## Introduction

LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of intrahepatic cholelithiasis described in the early 2000s [1]. LPAC syndrome approximately accounts for 1 % of all symptomatic cholelithiasis in adults [2]. It is defined by the existence of at least two of the three following criteria [3]: onset of biliary symptoms before the age of 40; recurrence of biliary symptoms after cholecystectomy; and presence of intraductal microlithiasis on ultrasound presenting as

intrahepatic hyperechoic foci ("comet tails" or spots). ABCB4 is the only gene known to be significantly associated with and predisposing to LPAC syndrome [4]. ABCB4 gene encodes the multidrug resistance 3 protein (MDR3) [1]. This protein, whose expression is potentially altered in LPAC syndrome, is a membrane transporter involved in the secretion of phospholipids and solubilization of cholesterol into bile and the protection of biliary epithelium from bile acids toxicity. Deficit in MDR3 results in an altered bile composition, cholesterol crystals formation and bile duct luminal membrane injuries by defective neutralization of

<footnote><sup>a</sup> Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France</footnote>

<footnote><sup>b</sup> Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique – Hopitaux de Paris, Paris, France</footnote>

<footnote><sup>c</sup> French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France</footnote>

<footnote><sup>d</sup> Paris-Est Creteil University, Department of Gastroenterology, Henri Mondor Hospital, Assistance Publique - Hopitaux de Paris, Paris, France</footnote>

<footnote><sup>e</sup> Sorbonne University, Department of Gastroenterology, Saint-Antoine Hospital and Research Center, Assistance Publique – Hopitaux de Paris, Paris, France</footnote>

<footnote>Abbreviations: ABCB4, ATP binding cassette subfamily B 4; ERCP, endoscopic retrograde cholangiopancreatography; LPAC, Low Phospholipid-Associated Cholelithiasis; NSAIDs, non-steroidal anti-inflammatory drugs; UDCA, ursodeoxycholic acid.</footnote>

<footnote>* Corresponding author: Endoscopy Department, Saint Antoine Hospital, 184 rue du faubourg St Antoine 75012, Paris, France.</footnote>

<footnote>E-mail address: gregoire.salin@aphp.fr (G. Salin).</footnote>
hydrophobic endogenous bile acids. Variants of ABCB4 (usually het-erozygous) are reported in 30–50 % of LPAC cases, suggestive of genetic heterogeneity [3,5].

Clinical presentation of LPAC syndrome is quite diverse. Onset usu-ally occurs in young adults, with biliary colic due to intrahepatic lithi-asis. Pharmacological treatment relies on ursodeoxycholic acid (UDCA) which appears to be effective in most cases, although no controlled studies assessing this drug are available [1,5].

Severe biliary complications may be observed in some patients such as acute pancreatitis (14 %), acute cholangitis (24 %), intrahepatic cholestasis of pregnancy (42 %) and cholangiocarcinoma (0.02 %) [2,5, 6]. Endoscopic retrograde cholangiopancreatography (ERCP) is the method of choice for the treatment of choledocholithiasis and its complication. A recent case-control study showed that approximately one-third of LPAC patients have required a sphincterotomy in their lifetime [2]. However, the prevalence of resorting to ERCP and predic-tive factors for ERCP in LPAC syndrome remain unknown. Occurrence and recurrence of biliary complications and ERCP after UDCA treatment persist unidentified.

Our main objective was to assess frequency, cumulative incidence of ERCP and predictive factors for ERCP in patients with LPAC syndrome. Our secondary objectives were to assess indications, modalities, results, and complications of ERCP. Finally, factors associated with UDCA treatment failure were investigated, based on a composite endpoint including acute pancreatitis, acute cholangitis, or the need for ERCP or hepato-biliary surgery.

## Patients and methods

### Study design

In this retrospective cohort study, all adult patients diagnosed with LPAC syndrome in a tertiary referral center (Saint-Antoine Hospital) between 2009 and 2021 were included. Patients were followed from diagnosis until December 2022 or the day of last visit.

### Participants

To be eligible, patients had to fulfill the usual criteria of LPAC syn-drome, i.e. the presence of at least two diagnostic criteria [3]:

- onset of biliary symptoms before 40 years of age

- recurrence of biliary symptoms after cholecystectomy

- spots, comet tails or intrahepatic lithiasis on imaging

### Data collection

Data were collected from medical records. Demographic character-istics and medical history were retrieved at the onset of biliary symp-toms. Biliary symptoms and complications, UDCA therapy and ERCP data were collected during patient follow-up.

Biliary colic was defined as a sudden, severe and episodic right upper abdominal or epigastric pain that often radiates to the back. It can be associated to a transient elevation of transaminases, strongly suggestive of passage of a bile duct stone. ERCP success was defined as a final oc-clusion cholangiogram showing no residual biliary stone and no repeat ERCP within one month.

### Statistical analysis

Qualitative variables were expressed as numbers and percentages. Quantitative variables were expressed as means and standard deviations (SD) or medians and interquartile ranges (IQ) depending on the distri-bution. We compared categorical data using the Chi-2 test or Fisher's exact test if appropriate. Continuous data were compared using the Mann-Whitney U test.

Regarding the identification of factors associated with ERCP occur-rence, patients were followed from the date of the onset of biliary symptoms until the date of first ERCP or last visit if no ERCP was per-formed. The cumulative incidence of ERCP occurrence was estimated. Independent factors associated with ERCP occurrence were identified using a multivariable Cox regression analysis. Exposure to UDCA was defined as a time-dependent variable. Based on clinical experience, several months are usually required for UDCA to be fully effective on colic pain or microlithiasis disappearance. Patients were considered optimally exposed to UDCA after this impregnation period. Exposure to UDCA was thus considered effective starting from the end of the impregnation period until the end of the follow-up. The impregnation period was defined at 12 months in the main analysis. We performed sensitivity analyses with a period of impregnation of 3 and 6 months.

Regarding the identification of factors associated with failure of UDCA therapy, patients were followed from 1 year after the start of UDCA until the occurrence of UDCA treatment failure or until the date of last visit. UDCA treatment failure was defined by a composite end-point including the need for ERCP or hepato-biliary surgery, or the occurrence of acute pancreatitis or cholangitis.

Significant variables at a p-value < 0.20 in univariate analysis were included in the multivariable Cox analysis. We considered a two-sided p-value of less than 0.05 to be statistically significant. Analysis was per-formed using SAS software (SAS version 9.4, SAS Inc, Cary, NC).

This study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the local ethical committee. Informed consent was obtained from all participants with LPAC syndrome.

## Results

### Patients characteristics

A total of 336 patients suspected of having LPAC syndrome were screened during the inclusion period. 67 patients who did not meet the diagnostic criteria for LPAC syndrome were excluded, 269 patients were included in the analysis of which 84 (31.2 %) required at least one ERCP. The median (IQR) follow-up period after the onset of symptoms was 10.8 (15.6) years. The demographic characteristics are shown in Table 1. ERCP and no-ERCP groups were comparable at the time of symptoms onset except for history of cholelithiasis in first-degree relatives, more frequent in the ERCP group compared to the no-ERCP group (56 % vs 41 %, *p* = 0.023). Patients were mostly women (74 %) with no or only few elements of metabolic syndrome, including overweight. The median (IQR) age at the onset of biliary symptoms was 27 [11] years. The

<table><caption>**Table 1**

Characteristics of patients with LPAC syndrome at the onset of symptoms.</caption><thead><tr><th></th><th>ERCP (n = 84)</th><th>No ERCP (n = 185)</th><th>Total (n = 269)</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td><td></td><td></td></tr><tr><td>Female gender</td><td>57 (67.9)</td><td>142 (76.8)</td><td>199 (74)</td></tr><tr><td>BMI at diagnosis (kg/m<sup>2</sup>)</td><td>24 (6)</td><td>23 (5.5)</td><td>23 (5)</td></tr><tr><td>Age at diagnosis (y)</td><td>40 (21.3)</td><td>35 (19)</td><td>36 (21)</td></tr><tr><td><strong>Medical history</strong></td><td></td><td></td><td></td></tr><tr><td>Obesity</td><td>11/83 (13)</td><td>17/177 (9.6)</td><td>28/260 (10.8)</td></tr><tr><td>Hypertension</td><td>7 (8.3)</td><td>10 (5.4)</td><td>17 (6.3)</td></tr><tr><td>Diabetes</td><td>3 (3.6)</td><td>3 (1.6)</td><td>6 (2.2)</td></tr><tr><td>Dyslipidemia</td><td>10 (11.9)</td><td>10 (5.4)</td><td>20 (7.4)</td></tr><tr><td>History of cholelithiasis in first-degree relatives</td><td>47 (56)</td><td>76 (41.1)</td><td>123 (45.7)</td></tr><tr><td><strong>Imaging and genetics</strong></td><td></td><td></td><td></td></tr><tr><td>Intrahepatic lithiasis*</td><td>77 (91.7)</td><td>174 (94)</td><td>251 (93.3)</td></tr><tr><td>ABCB4 mutation</td><td>36/75 (48)</td><td>66 (42.3)</td><td>102/231 (44.1)</td></tr></tbody></table>

Shown are medians (IQR) and numbers (%).

<footnote>* including micro and macrolithiasis.</footnote>
diagnosis of LPAC syndrome was established after a median (IQR) delay of 5.9 (13.9) years after symptom onset.

## Clinical manifestations and treatments

The most common symptoms were biliary colic (96.7 %), biliary colic with elevated transaminase (48 %), pancreatitis (18.2 %), and acute cholangitis (16.7 %). Acute cholangitis (41.7 % vs. 5.4 %, *p* < 0.001) and biliary colic with transaminase elevation (84.5 % vs. 31.4 %, *p* = 0.001) were significantly more frequent in the ERCP group compared to the no-ERCP group (Table 2). Also, there were significantly more cholecystectomies in the ERCP group (91.7 % vs 75.6 %, *p* = 0.001). Of the 215 patients with cholecystectomy in the cohort, 204 (95 %) had surgery before the diagnosis of LPAC syndrome. Patients were mostly treated with a dose of 10 mg per kilo per day of UDCA. Only one patient did not receive UDCA therapy (<0.1 %). Eight patients were non-compliant (3 %), two of which because of side effects (abdominal pain and diarrhea). All patients who developed choledocholithiasis underwent ERCP. Sixteen patients (5.9 %) required surgery with no statistically significant difference between the ERCP and no-ERCP groups. These patients underwent biliary bypass, choledochostomy or hepatic resection. Most patients (75 %) underwent surgery before the start of UDCA, and in the ERCP group almost all the surgeries occurred after technical failure of ERCP. Two patients died of cholangiocarcinoma (one in each group).

## ERCP characteristics

As shown in Table 3, 166 ERCPs were required in 84 (31.2 %) patients with a median (IQR) of one [1] procedure per patient. Two-thirds of these patients had only one ERCP. The highest number of procedures per patient was 10 (in 2 patients). The median (IQR) interval between the first symptoms and the first ERCP was 6.7 (12.1) years. The most common indications for ERCP were common bile duct stones (53.6 %), acute cholangitis (29.5 %) and intrahepatic stones (7.8 %). The success rate of ERCP was 86.7 %. No stone was found in 10.2 % of cases. Stones were mainly cholesteric in appearance (i.e., soft and yellowish), when

<table><caption>**Table 2**
Clinical manifestations and treatments of patients with LPAC syndrome.</caption><thead><tr><th></th><th>ERCP (n = 84)</th><th>No ERCP (n = 185)</th><th>Total (n = 269)</th></tr></thead><tbody><tr><td><strong>Clinical manifestations</strong></td><td></td><td></td><td></td></tr><tr><td>Age at onset of symptoms</td><td>28 (13.2)</td><td>27 (14)</td><td>27 (13)</td></tr><tr><td>First symptoms before the age of 40</td><td>72 (85.7)</td><td>161 (87)</td><td>233 (86.6)</td></tr><tr><td>Recurrence after cholecystectomy</td><td>75 (97.4)</td><td>119 (85)</td><td>194 (89.4)</td></tr><tr><td>Biliary colic</td><td>81 (96.4)</td><td>179 (96.8)</td><td>260 (96.7)</td></tr><tr><td>Cholecystitis</td><td>5 (6)</td><td>6 (3.2)</td><td>11 (4.1)</td></tr><tr><td>Biliary colic with transaminase elevation</td><td>71 (84.5)</td><td>58 (31.4)</td><td>129 (48)</td></tr><tr><td>Pruritus</td><td>4 (4.8)</td><td>23 (12.4)</td><td>27 (10)</td></tr><tr><td>Acute pancreatitis</td><td>15 (17.9)</td><td>34 (18.4)</td><td>49 (18.2)</td></tr><tr><td>Acute cholangitis</td><td>35 (41.7)</td><td>10 (5.4)</td><td>45 (16.7)</td></tr><tr><td>Liver abscess</td><td>1 (1.2)</td><td>0 (0)</td><td>1 (0.4)</td></tr><tr><td>Intrahepatic Cholestasis of Pregnancy if history of pregnancy</td><td>8/37 (22)</td><td>32/84 (38)</td><td>40/121 (30)</td></tr><tr><td>Secondary sclerosing cholangitis</td><td>5 (6)</td><td>3 (1.6)</td><td>8 (3)</td></tr><tr><td>Cholangiocarcinoma</td><td>1 (1.2)</td><td>2 (1.1)</td><td>3 (1.1)</td></tr><tr><td><strong>Treatments</strong></td><td></td><td></td><td></td></tr><tr><td>UDCA</td><td>83 (98.8)</td><td>185 (100)</td><td>268 (99.6)</td></tr><tr><td>Ezetrol</td><td>7 (8.3)</td><td>3 (1.6)</td><td>10 (3.7)</td></tr><tr><td>Cholecystectomy</td><td>77 (91.7)</td><td>138 (75.6)</td><td>215 (79.9)</td></tr><tr><td>Hepatic surgery</td><td>8 (9.5)</td><td>8 (4.3)</td><td>16 (5.9)</td></tr></tbody></table>

Shown are medians (IQR) and numbers (%).

<table><caption>**Table 3**
Characteristics of ERCP procedures in patients with LPAC syndrome.</caption><thead><tr><th></th><th>Number of ERCP (n = 166)</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td></tr><tr><td>Numbers of patients sphincterotomyized</td><td>84/84</td></tr><tr><td>Age at the first ERCP (y)</td><td>37 (17.3)</td></tr><tr><td>Number of ERCP per patient</td><td>1 (1)</td></tr><tr><td><strong>Indications</strong></td><td></td></tr><tr><td>Common bile duct stone</td><td>89 (53.6)</td></tr><tr><td>Acute cholangitis</td><td>49 (29.5)</td></tr><tr><td>Intrahepatic bile duct gallstone</td><td>13 (7.8)</td></tr><tr><td>Common and intrahepatic bile duct stone</td><td>6 (3.6)</td></tr><tr><td>Biliary colic despite cholecystectomy and UDCA intake</td><td>4 (2.4)</td></tr><tr><td>Biliary stent removal</td><td>4 (2.4)</td></tr><tr><td>Repeat acute pancreatitis</td><td>1 (0.6)</td></tr><tr><td><strong>Stone location</strong></td><td></td></tr><tr><td>Common bile duct</td><td>134 (80.7)</td></tr><tr><td>Left hepatic duct</td><td>19 (11.4)</td></tr><tr><td>Right hepatic duct</td><td>11 (6.6)</td></tr><tr><td>No stone</td><td>17 (10.2)</td></tr><tr><td><strong>Modalities</strong></td><td></td></tr><tr><td>Prior cholecystectomy</td><td>135 (8.3)</td></tr><tr><td>PEP prophylaxis by NSAIDs*</td><td>9/80 (11.3)</td></tr><tr><td>PEP prophylaxis by pancreatic stenting*</td><td>3/144 (2.1)</td></tr><tr><td>PEP prophylaxis by IV fluid hydration*</td><td>2/67 (3)</td></tr><tr><td>Antibiotic therapy or prophylaxis during the procedure*</td><td>79/91 (86.8)</td></tr><tr><td><strong>Results</strong></td><td></td></tr><tr><td>ERCP success</td><td>144 (86.7)</td></tr><tr><td>Biliary stenting*</td><td>23/134 (17.2)</td></tr><tr><td>Enlargement of a prior sphincterotomy or a complementary papillary balloon dilation*</td><td>19/82 (23.2)</td></tr><tr><td><strong>Adverse events*</strong></td><td></td></tr><tr><td>Post-ERCP pancreatitis</td><td>11/153 (7.2)</td></tr><tr><td>Perforation</td><td>4/153 (2.6)</td></tr><tr><td>Bleeding</td><td>2/153 (1.3)</td></tr></tbody></table>

Shown are medians (IQR) and numbers (%).

†PEP: Post-ERCP pancreatitis.

* A denominator is added in case of missing data.

described. Biliary stenting was performed in 17.3 % of cases. Enlargement of a prior sphincterotomy or complementary papillary balloon dilation was required in 23.2 % of repeat ERCPs. Post ERCP pancreatitis, perforation and bleeding rates were 7.2 %, 2.6 % and 1.3 %, respectively.

The cumulative incidence of requiring an ERCP from the onset of symptoms increased with time, from 6.6 % at 5 years to 33 % at 20 years of follow-up (Fig. 1).

## Timing between ERCP and UDCA treatment

Among the 84 patients who required ERCP, 78.6 % had the procedure before LPAC diagnosis (i.e., starting UDCA). Thirteen (15.5 %) patients required a subsequent ERCP after at least 1 year of UDCA and 10 (11.9 %) patients had their first ERCP after at least 1 year of UDCA. Thus, only 27.4 % of patients (i.e., 8.5 % of all the cohort) required an ERCP after 1 year of UDCA treatment. Focusing on patients with a large number of ERCPs (8 to 10 procedures), most ERCPs were performed after initiation of UDCA and occurred over a wide period ranging from 5 to 13 years after the initiation of UDCA.

## Predictive factors for ERCP

In Cox multivariable analysis, age and history of cholelithiasis in first-degree relatives were associated with a higher risk of ERCP with a hazard ratio (HR) of 1.30 (95 % CI 1.04–1.62; *p* = 0.006) and 1.88 (95 % CI 1.15–3.07 *p* = 0.011), respectively. Conversely, female gender and UDCA intake for more than 1 year were associated with a lower risk of ERCP with a HR of 0.49 (95 % CI 0.29–0.82 *p* = 0.020) and 0.44 (95 % CI 0.22–0.90 *p* = 0.024), respectively (Table 4). Sensitivity analyses with varying UDCA impregnation duration provided similar results, although
<figure><img src="image_2.png" /><figcaption>Fig. 1. Cumulative incidence of ERCP from the onset of symptoms in patients with LPAC syndrome.</figcaption></figure>

<table><caption>**Table 4**
Univariate and multivariable analyses of factors associated with ERCP use in LPAC syndrome.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Univariate analysis<br>p value</th><th colspan="2">Multivariable analysis</th></tr><tr><th>HR (95 % CI)</th><th>p value</th></tr></thead><tbody><tr><td>Age at ERCP<sup>†</sup></td><td>0.04</td><td>1.30<br>(1.04–1.62)</td><td>0.006</td></tr><tr><td>Female gender</td><td>0.005</td><td>0.49<br>(0.29–0.82)</td><td>0.020</td></tr><tr><td>History of cholelithiasis in first-degree relatives</td><td>0.042</td><td>1.88<br>(1.15–3.07)</td><td>0.011</td></tr><tr><td>Hypertension</td><td>0.276</td><td>—</td><td>—</td></tr><tr><td>Dyslipidemia</td><td>0.884</td><td>—</td><td>—</td></tr><tr><td>Obesity</td><td>0.738</td><td>—</td><td>—</td></tr><tr><td>Diabetes</td><td>0.91</td><td>—</td><td>—</td></tr><tr><td>ABCB4 mutation</td><td>0.307</td><td>—</td><td>—</td></tr><tr><td>UDCA intake for more than 1 year</td><td>0.02</td><td>0.44<br>(0.22–0.90)</td><td>0.024</td></tr></tbody></table>

not statistically significant (UDCA intake for more than 3 and 6 months; HR, 0.58, 95 % CI 0.32–1.07 and HR, 0.56, 95 % CI 0.30–1.04, respectively).

### Predictive factors for UDCA failure

Among the 226 patients with at least 1 year of follow-up after starting UDCA, 33 (14.6 %) met the composite end-point combining the occurrence of ERCP, hepato-biliary surgery, acute pancreatitis or acute cholangitis, indicating failure of UDCA treatment. The cumulative risk of UDCA failure was 14.9 % at 5 years and 21.9 % at 10 years (Fig. 2). As described in Table 5, only a history of ERCP was associated with UDCA failure in univariate analysis (p = 0.005), thus multivariable analysis was not performed.

### Discussion

This study provides an estimation of ERCP occurrence in LPAC syndrome. We found that one-third of patients underwent ERCP and endoscopic sphincterotomy. The first ERCP was performed about 7 years after the onset of biliary symptoms. In addition, most endoscopic procedures occurred before the diagnosis was made and therefore before UDCA treatment: less than 8.5 % of all patients required ERCP after one year of treatment with UDCA. Furthermore, UDCA treatment for more than one year were associated with a lower risk of ERCP. Our results suggest the efficacy of UDCA therapy in patients with LPAC syndrome. This is an important finding because the recommendation to use UDCA in LPAC syndrome is currently based primarily on empirical experience indicating a reduction in the frequency and intensity of biliary crises. Our results also suggest that earlier diagnosis and initiation of UDCA treatment could reduce the need for ERCP in patients with LPAC syndrome.

History of cholelithiasis in a first-degree relative was associated with a higher risk of ERCP. In the patients who required a large number of ERCPs, most procedures occurred after UDCA initiation. Those findings suggest the existence of severe familial forms of LPAC syndrome, for which UDCA treatment seems to be less efficient. Since the presence of an ABCB4 mutation was not associated with higher risk of ERCP, one can speculate that other Lith genes, possibly in association with non-inherited lithogenic associated factors, such as bacterial colonization of common bile duct, could be responsible for these severe recurrent forms of LPAC syndrome. While female gender has been widely shown to be a predisposing factor for gallstone disease [7,8], our results surprisingly suggest that male gender is associated with a higher risk of ERCP occurrence in LPAC syndrome. In this regard, the distinction between predisposition factors and severity factors may make sense. Whether male gender could be a factor associated with severe LPAC syndrome remains to be determined.

Only a history of ERCP was significantly associated with UDCA

<footnote>† 10-year interval for age-related HR.</footnote>
<figure><img src="image_3.png" /><figcaption>Fig. 2. Cumulative incidence of UDCA treatment failure.</figcaption></figure>

<caption>**Table 5**</caption>

Univariate analysis of factors associated with UDCA failure after 1 year of treatment in LPAC syndrome.

<table><thead><tr><th rowspan="2"></th><th colspan="2">Univariate analysis</th></tr><tr><th>HR (95 % CI)</th><th>p value</th></tr></thead><tbody><tr><td>Age</td><td>0.99 (0.96-1.02)</td><td>–</td></tr><tr><td>Female gender</td><td>0.62 (0.29-1.3)</td><td>–</td></tr><tr><td>History of cholelithiasis in first-degree relatives</td><td>1.03 (0.52-2.04)</td><td>–</td></tr><tr><td>Hypertension</td><td>0.41 (0.6-2.98)</td><td>–</td></tr><tr><td>Dyslipidemia</td><td>0.64 (0.15-2.67)</td><td>–</td></tr><tr><td>Obesity</td><td>1.18 (0.45-3.05)</td><td>–</td></tr><tr><td>Diabetes</td><td>0.95 (0.13-6.97)</td><td>–</td></tr><tr><td>ABCB4 mutation</td><td>0.83 (0.41-1.67)</td><td>–</td></tr><tr><td>Cholecystectomy prior to UDCA</td><td>0.81 (0.37-1.81)</td><td>–</td></tr><tr><td>Acute cholangitis prior to UDCA</td><td>2.07 (0.9-4.78)</td><td>–</td></tr><tr><td>Acute pancreatitis prior to UDCA</td><td>1.2 (0.46-3.13)</td><td>–</td></tr><tr><td>ERCP prior to UDCA</td><td>2.74 (1.37-5.48)</td><td>0.005</td></tr><tr><td>Hepatobiliary surgery prior to UDCA</td><td>0.4 (0.06-2.96)</td><td>–</td></tr></tbody></table>

treatment failure in the univariate analysis. Several hypotheses may explain this result. First, it is clear that a history of ERCP may have introduced a selection bias by identifying patients with a more severe phenotype at baseline, and thus less likely to respond adequately to UDCA therapy. Second, other associated factors may have been overlooked due to a lack of statistical power (insufficient number of events, small number of patients and retrospective nature resulting in missing data). Third, the composite end-point used to define UDCA failure was based on clinical events (acute cholangitis, acute pancreatitis, ERCP or surgery) only, thus limiting the fine evaluation of UDCA efficacy. Unfortunately, both frequency and intensity of biliary colic pains were not included in the analysis due to their subjectivity, non-standardized assessment in routine practice, and frequent missing data in the medical records.

We reported an ERCP failure rate of 13%, comparable with those in “common” stones (10–15%) [9]. We did not have enough information about procedures to identify clearly the reasons for failure. Heavy stone burden which could not be extracted in a single procedure was

sometimes mentioned. There was no recourse to cholangioscopy guided lithotripsy. Although not documented, the friable texture of cholester- olic minicalculus aggregates in LPAC syndrome could explain this observation.

We observed a 7.2% rate of post-ERCP pancreatitis (PEP) in our study, which is a relatively high rate compared to the literature (3.5–9%) [10]. There are several hypotheses to explain this result. The study population was young and mostly women, known as independent PEP risk factors [11,12]. Data concerning PEP prophylaxis were missing for more than half of procedures. Thus, our analysis probably included an important number of procedures without PEP prophylaxis and may overestimate its occurrence.

We found a 23.2% rate of revision of previous sphincterotomy by re- cut or balloon dilatation in recurrent ERCP procedures. Limited data suggest a much lower rate of sphincterotomy revision in cases of “common” stones, ranging from 1 to 9% [13,14]. A large and complete sphincterotomy should be performed during the first ERCP in the spe- cific setting of LPAC syndrome.

Our study has certain limitations, particularly in relation to its retrospective and monocentric design. LPAC syndrome criteria being mainly based on clinical features, asymptomatic patients with intra- hepatic microlithiasis and ABCB4 mutation diagnosed during familial screening were not included. Sometimes data were missing, especially when ERCP occurred in an outside hospital. Some patients had a short follow-up time in the cohort. This can be explained by the fact that some patients were referred to Saint-Antoine Hospital for the initial man- agement and then continued their follow-up in another center.

In conclusion, one-third of patients with LPAC syndrome underwent ERCP and endoscopic sphincterotomy during their lifetime. However, most procedures were performed before the diagnosis was made and UDCA initiated. UDCA was associated with a lower risk of endoscopic procedure, suggestive of its efficacy. Earlier diagnosis and treatment with UDCA could further reduce the need for ERCP in patients with LPAC syndrome. Any associations found in this study do not prove an etiological relationship or an absolute indicator of UDCA efficacy, but they could be the result of confounding factors. Further prospective
studies are needed to confirm these data.

### CRediT authorship contribution statement

**G. Salin:** Methodology, Formal analysis, Data curation, Conceptualization. **C. Corpechot:** Conceptualization, Methodology, Validation. **S. Ouazana:** Data curation. **C. Dong:** Data curation. **A. Becq:** Writing – review & editing, Validation. **S. Lemoinne:** Validation. **K. Ben Belkacem:** Data curation. **R. Leenhardt:** Validation. **U. Chaput:** Writing – review & editing. **O. Chazouillères:** Validation. **J. Kirchgesner:** Software. **M. Camus:** Writing – review & editing, Conceptualization, Supervision, Validation.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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