Low phospholipid-associated cholelithiasis (LPAC) syndrome is a symptomatic and recurring form of cholelithiasis first described in 2001 by Rosmorduc et al.

No guidelines are available for the diagnosis of the syndrome. It was first suspected in patients with symptomatic cholelithiasis with at least one of the following criteria: (a) age below 40 years at the symptom onset, (b) recurrence after cholecystectomy, (c) intrahepatic hyperechoic foci with a topography compatible with lipid deposits along the luminal surface of the intrahepatic biliary tree, (d) intrahepatic sludge, (e) microlithiasis, (f) history of gallstones in first-degree relatives, or (g) history of intrahepatic cholestasis of pregnancy (ICP) [[1], [2]].

Other studies characterize the syndrome by the presence of at least two of the following criteria: (a) onset of biliary symptoms in patients younger than 40 years old; (b) recurrent biliary pain following cholecystectomy; or (c) typical radiological signs of intrahepatic lithiasis, considering the rest of the initial diagnostic criteria as minor criteria [3].

Ursodeoxycholic acid (UDCA) is the main treatment for this syndrome and is widely used due to its ability to dissolve cholesterol stones without causing any noticeable side effects [4].

LPAC syndrome has been related to ABCB4 gene mutations. ABCB4 gene encodes the protein ABCB4. This protein flops phosphatidylcholine (PC) from the inner leaflet into the outer leaflet of the membrane to be extracted by bile salts in the canalicular space. These mixed micelles reduce the detergent action of the bile salts and protect the biliary tree from their cytotoxic activity.

The defects of this protein result in low levels of bile phospholipids, coexisting with normal bile salt concentrations in the bile. Consequently, PC biliary micelles are destabilized, allowing non-micellar detergent bile acids to cause epithelial damage and promote crystal formation and biliary cholesterol microcalculations [[4], [5], [6]].

Abnormalities affecting the ABCB4 gene could be responsible for other syndromes, including ICP, oral contraceptive-induced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3) [7]. LPAC, ICP, and CIC affect young adults, typically those with monoallelic status, whereas patients with PFIC3 are homozygous or heterozygous composite [8].

LPAC syndrome is a rare pathology, with a prevalence rate of 5 % among patients with cholelithiasis [[2], [9]]. Mutations affecting the ABCB4 gene are found in 25 %–56 % of the patients with LPAC syndrome [[2], [10]]. Meanwhile, the mutations have been found in patients who do not have the clinical diagnostic criteria for this syndrome [[2], [11], [12]].

Anomalies in the proteins involved in the regulation of ABCB4 expression or activity could also lead to similar pathologies. Farnesoid X (FXR) receptor mutations have been identified in patients with similar phenotypes [[13], [14]].

Moreover, other genes could be involved. There are two main active transport proteins for ductal flow: the ABCB11/BSEP cassette transporters that bind the adenosine triphosphate coding for the bile salt export pump protein and the adenosine triphosphatase ATP8B1/P-type FIC1 transporters that encode familial intrahepatic cholestasis protein [15].

ATP8B1 has a cooperative role with ABCB4. It protects hepatocytes (and cholangiocytes lining the bile ducts) from the harmful detergent activity of bile salts [16] and the ABCB11/BSEP gene codes for the major bile acid transporter at the canalicular pole of hepatocytes Chen et al., [17].

Abnormalities affecting the ABCG5/ABCG8 genes are also likely to result in cholelithiasis or a defect in the secretion of phospholipids Lee et al., [18].

All these genes and others can be responsible for LPAC syndrome.

This study aimed to conduct the first Tunisian diagnostic research of LPAC syndrome in its epidemiological, clinical, biological, radiological, and molecular aspects in Tunisian patients and compare our results with those reported in the literature.