1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References

The low-phospholipid-associated cholelithiasis syndrome (LPAC; OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults, associated with ABCB4/MDR3 gene sequence variations. Our aim was to determine the genotype-phenotype relationships in 156 consecutive patients with the criteria of LPAC syndrome. A variant was detected in 79 (61 missense and 18 truncating sequence variants), 63 being monoallelic. The clinical features (age at onset, high prevalence in women, frequency and severity of acute and chronic complications, intrahepatic cholestasis of pregnancy [ICP]) were similar in the patients with or without ABCB4 gene sequence variation. Truncating variations were associated with an earlier onset of symptoms both in women and men. Acute and chronic biliary complications were variant-independent. Half of the women who had pregnancy developed ICP. The frequency of ICP and fetal complications were similar in patients with missense and truncating variants. Conclusion: The LPAC syndrome is more frequent in women and highly associated with ICP. Half of the patients harbored missense or truncating variants of the ABCB4 gene. The characteristics of the patients without detectable variant are similar to those with variant, indicating that yet unexplored regions of the ABCB4 and other genes may be involved. (Hepatology 2013;53:1105–1110)


intrahepatic cholestasis of pregnancy


low-phospholipid-associated cholelithiasis


progressive familial intrahepatic cholestasis type 3


ursodeoxycholic acid.

ABCB4/MDR3 is expressed at the apical membrane of hepatocytes and is essential for phosphatidylcholine secretion in bile.[1, 2] Gene alterations causing defective ABCB4 protein are associated with progressive familial intrahepatic cholestasis type 3 (PFIC3),[3, 4] low-phospholipid associated cholelithiasis syndrome (LPAC),[5-7] and intrahepatic cholestasis of pregnancy (ICP).[8-11]

LPAC (OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults characterized by at least two of the following criteria: (1) age at onset of biliary symptoms ≤40 years; (2) intrahepatic echogenic foci or microlithiasis; (3) recurrence of biliary symptoms after cholecystectomy. Severe biliary complications such as acute pancreatitis, recurrent cholangitis, segmental spindle-shape dilatation of the biliary tree filled with gallstones, and ICP may be observed in some patients.[12]

Since its first description and its association with a low biliary phospholipid concentration and ABCB4 gene sequence variation, several clinical observations have confirmed that this peculiar phenotype was part of the spectrum of liver diseases associated with ABCB4 deficiency.[13-20]

However, probably because of its rarity, no large cohort of patients has been reported and studied so far. We have also shown that some severe forms of the syndrome displayed the same biochemical, pathological, and radiological features of what is better known in the literature as (oriental) hepatolithiasis, recurrent pyogenic cholangitis, and chronic proliferative cholangitis.[21, 22]

The aim of the present study was to determine in a large series of 156 patients the genotype-phenotype relationships in the LPAC syndrome.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References

We studied 156 consecutive patients who were referred to our center from 2001 to 2005 for LPAC syndrome defined by at least two of the criteria: (1) age at onset of biliary symptoms ≤40 years; (2) intrahepatic hyperechoic foci with a topography compatible with lipid deposit along the luminal surface of the intrahepatic biliary tree or intrahepatic sludge or microlithiasis; (3) recurrence of biliary symptoms after cholecystectomy. In these patients four clinical features: (i) age at onset of the biliary symptoms; (ii) occurrence of acute complications, e.g., recurrent cholangitis or pancreatitis; (iii) occurrence of chronic complications, e.g., secondary sclerosing cholangitis, segmental dilatations of the intrahepatic biliary tract filled with gallstones; (iv) occurrence of ICP with or without severe complications (spontaneous premature delivery, fetal distress, stillborn fetus), were studied according to the presence or not of ABCB4 variant, and the type of variation if present. All patients were identified by the clinicians responsible for their care. Informed consent was obtained from all subjects and the study was approved by the local Ethical Committee.

ABCB4 Gene Analysis

Genomic DNA was obtained from peripheral white blood cells using standard procedures. To check for the presence of sequence variants of the ABCB4 gene, 27 pairs of exon-specific primers were used to amplify the 27 coding exons of the ABCB4 gene together with their respective exon/intron boundaries. After purification, the polymerase chain reaction (PCR) products were sequenced using amplification primers and the Big Dye Terminator Chemistry. Sequencing products were run after purification on an ABI 3130 Genetic Analyser (Applied Biosystems). Identification and localization of ABCB4 gene sequence variations were assessed by sequence comparisons with the SeqScape Software (v. 2.5; Applied Biosystems).

Statistical Analysis

Quantitative variables are expressed as means ± SD. Continuous variables were compared using the Wilcoxon rank sign test or the Kruskal-Wallis test when more than two groups were compared. Quantitative variables were compared using the chi-squared test. A difference was considered statistically significant when the P < 0.05. The R software was used for all comparisons.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References
ABCB4 Gene Sequence Variation

A variant was detected in 79 (61 missense and 18 truncating sequence variants) of the 156 patients. The lists providing the sequence variations (nature, location, status) are provided in Tables 1 and 2. Among the 61 patients with missense variants, three were homozygotes and nine were compound heterozygotes. All the patients with a truncating variant were heterozygotes and four were compound heterozygotes.

Table 1. Truncating Sequence Variations of ABCB4 Gene in LPAC Patients (n = 18)
PatientsFirst VariationSecond Variation
  1. a

    Variant found in ICP.

  2. Abbreviations: fs, frameshift; X, stop; Xn, stop after n codons; HTZ, heterozygous.

6ac.1015delTp.Ser339Gln fsX3HTZ   
7c.1015dupp.Ser339Phe fsX17HTZ   
8c.1015dupp.Ser339Phe fsX17HTZ   
9ac.1326dupp.Arg444Glu fsX5HTZ   
10ac.1420delGp.Val474Trp fsX2HTZ   
11ac.1553delTp.Leu518Tyr fsX16HTZ   
Table 2. Missense Sequence Variations of ABCB4 Gene in LPAC Patients (n = 61)
PatientsFirst VariationSecond Variation 
  1. a

    Variant found in ICP.

1c.139C>GArg 47 GlyHTZNter     
2c.212T>ALeu 71 HisHTZTM1     
3ac.217C>GLeu 73 ValHTZTM1     
4ac.233T>GPhe 78 CysHTZTM1c.2186C>TSer729LeuHTZTM7 
5c.296C>TSer 99 PheHTZEC1     
6c.296C>TSer 99 PheHTZEC1     
7ac.296C>TSer 99 PheHTZEC1     
8c.370G>AGly 124 SerHTZTM2     
9c.461T>CPhe 154 SerHTZIC1     
10ac.493T>APhe 165 IleHTZIC1    ([5, 6])
11c.523A>GThr 175 AlaHTZIC1     
12c.523A>GThr 175 AlaHTZIC1     
13c.523A>GThr 175 AlaHTZIC1     
14c.523A>GThr 175 AlaHTZIC1     
16ac.523A>GThr 175 AlaHTZIC1    ([5, 6])
17c.857C>TAla 286 ValHTZIC2    ([29])
18c.902T>CMet 301 ThrHTZTM5    ([5, 6])
19ac.959C>TSer 320 PheHMZTM5     
20c.959C>TSer 320 PheHTZTM5     
21c.959C>TSer 320 PheHTZTM5    ([5, 6])
22ac.1217G>AArg 406 GlnHTZIC3c.140G>AArg47GlnHTZNter 
23c.1217G>AArg 406 GlnHTZIC3     
24c.1217G>AArg 406 GlnHTZIC3c.140G>AArg47GlnHTZNter 
25c.1217G>AArg 406 GlnHTZIC3     
26c.1529A>GAsn 510 SerHTZIC3/NBD1     
27c.1529A>GAsn 510 SerHTZIC3/NBD1     
28ac.1529A>GAsn 510 SerHTZIC3/NBD1c.833G>AArg278LysHTZ  
29c.1529A>GAsn 510 SerHTZIC3/NBD1     
30c.1531G>AAla 511 ThrHTZIC3/NBD1c.2800G>AAla934ThrHTZIC5([5, 6, 29])
31c.1537G>AGlu 513 LysHTZIC3/NBD1     
32ac.1537G>AGlu 513 LysHTZIC3/NBD1     
34c.1584G>CGlu 528 AspHTZIC3/NBD1    ([5, 6])
35c.1584G>CGlu528AspHTZNBD1/IC3    ([5, 6])
37ac.1634G>AArg 545 HisHTZIC3/NBD1    ([5, 6])
38c.1646G>AArg 549 HisHTZIC3/NBD1    ([30])
39c.1675C>AAla559TyrHTZNBD1/IC3    ([16])
40c.167G>AAla 559 ThrHTZIC3/NBD1c.2800G>AArg590GlnHTZIC3([16])
41c.1765C>THis 589 TyrHTZIC3     
42ac.1769 G>AArg590GlnHTZIC3c.2177 C>TPro726LeuHTZTM7 
43c.1769G>AArg 590 GlnHTZIC3     
44c.1769G>AArg 590 GlnHMZIC3    ([29])
45c.1769G>AArg 590 GlnHTZIC3    ([31])
46ac.1772T>ALeu 591 GlnHTZIC3    ([5, 6])
47c.1778C>TThr593MetHTZIC3    ([5, 6])
48c.1939G>AGlu 647 LysHTZIC3     
49c.2177C>TPro 726 LeuHTZTM7    ([29])
50ac.2177C>TPro 726 LeuHTZTM7     
51ac.2186C>TSer 729 LeuHTZTM7     
52ac.2363G>AArg 788 GlnHTZIC4    ([14])
53c.2363G>AArg 788 GlnHTZIC4c.2177C>TPro726LeuHTZTM7 
54ac.2800G>AAla 934 ThrHTZIC5     
55c.2800G>AAla 934 ThrHMZIC5    ([5, 6])
56c.2800G>AAla 934 ThrHTZIC5     
57c.2923C>GLeu 975 ValHTZEC6     
59c.3250C>TArg 1084 TrpHTZNBD2/Cter     
60c.3481C>TPro 1161 SerHTZCter     
61ac.3481C>TPro 1161 SerHTZNBD2/Cter    ([5, 6])
Clinical Features According to the Presence or Absence of ABCB4 Variants

As shown in Table 3, age at onset of symptoms, sex ratio, frequency of either acute (cholangitis or pancreatitis), or chronic complications (cholangitis with or without segmental dilatations of the intrahepatic biliary tree), ICP with or without fetal complications (spontaneous prematurity, fetal distress, stillborn fetus) did not differ significantly between the patients with or without ABCB4 variation.

Table 3. Main Features in LPAC Patients With and Without ABCB4 Sequence Variants
 With Variant n = 79Without Variant n = 77 
  1. Intrahepatic hyperechoic material: microlithiasis and multiple “twinkling” artifacts on standard and color-Doppler ultrasound examination. Radiological features: on magnetic resonance cholangiography and/or endoscopic radiologic cholangiopancreatography. BD dilatations: bile duct dilatations with macroscopic stones. CBD stones: common bile duct with stones. Acute and chronic biliary complications defined as recurrent cholangitis or pancreatitis. ICP: intrahepatic cholestasis of pregnancy; NS: not significant.

Type of sequence variation (%)   
Age at onset of symptoms (years)32 ± 1232 ± 11NS
Sex ratio (% females)7063NS
LPAC diagnostic criteria   
Age <40 yrs (%)7677NS
Symptoms recurrence post cholecystectomy (%)6668NS
Intrahepatic hyperechoic material (%)8884NS
Radiological features   
Intrahepatic biliary tree   
– Mild-to-moderate unifocal BD dilatations (%)119NS
– Severe multifocal BD dilatations (%)86NS
Extrahepatic biliary tree   
– Gallbladder stones (%)9596NS
– CBD stones (%)5762NS
Biliary complications (n)4549 
Acute (%)3951NS
Chronic (%)1813 
Pregnancy (n)4419 
ICP (%)5242NS
Fetal complications (%)1421 
Genotype-Phenotype Relationships in Patients With ABCB4 Sequence Gene Variation

Overall, 70% of the patients with an altered genotype were women (P < 0.001); the mean age at the onset of symptoms was 38.7 years for men and 29.1 years for women (P < 0.003).

Age at the onset of symptoms differed also according to the type of variant and gender. Truncating variations were associated with an earlier onset of symptoms as compared to missense variations (26.5 versus 33.9 years; P < 0.003). Males with a truncating variant were younger (31 ± 12 years) than those with missense variant (40 ± 13 years); likewise, females with a truncating variant were younger (26 ±6 years) than those with a missense variant (40 ± 13 years) (P < 0.001).

There was no significant association between truncating sequence variations and severity of either acute or chronic biliary complications (severe biliary complications defined as acute pancreatitis, recurrent cholangitis, segmental spindle-shape dilatation of the biliary tree filled with gallstones): odds ratio (OR) = 0.8 (95% confidence interval [CI] 0.3-3.7, P = 0.8). These complications were more frequent in men (71% versus 45%, P = 0.05, OR 2.9, 95% CI 1.0-9.6), that in women, independently of age at onset of symptoms and type of variant.

About half of the women who had pregnancy experienced ICP. The frequency and severity of ICP did not differ in patients with missense (44%) and truncating variant (69%) (P = 0.2).

In patients without an ABCB4 detectable variant the clinical characteristics were similar to those observed in patients with gene variation. Of note, in a subset of patients the phospholipid/bile acid ratio measured in hepatic bile (ratio of control gallbladder bile >25%) did not differ between the two groups: 11%, range 4%-16% (n = 7) versus 12%, range 1.4%-16% (n = 8) in patients with and without the ABCB4 variant, respectively.

In the overall cohort, biliary cirrhosis was detected in only two patients. Both patients had a missense heterozygous variant (location and nucleotide changes: c.523A>G and c.959C>T). Intrahepatic cholangiocarcinoma leading to death was observed in a noncirrhosis female patient with a heterozygous splicing mutation (c.1005+5 G>A).

All the patients received ursodeoxycholic acid (UDCA) (8-10 mg/kg/day) as the mainstay treatment after the diagnosis had been made. All the patients with severe chronic biliary complications had sphincterotomy. Patients with symptomatic intrahepatic bile duct dilatations filled with gallstones had repeated endoscopic procedures to remove the stones. All the patients with or without detectable variant and free of intrahepatic bile duct dilatations with gallstones became asymptomatic up to now. The only exception was a patient who did not tolerate UDCA because of bile acid-induced watery diarrhea.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References

Among patients presenting with symptomatic cholelithiasis, three main features defined the syndromatic phenotype termed LPAC: recurrence of biliary symptoms after cholecystectomy, intrahepatic lithiasis, and age <40 years. The results of the present study may be summarized as follows: (1) half of the patients with the LPAC phenotype have detectable sequence variations of the ABCB4 gene, most of them being heterozygous missense. The clinical features of the syndrome, the high prevalence in women, were similar in patients with or without ABCB4 variants; (2) LPAC syndrome is more prevalent in female patients and frequently associated with ICP; (3) the onset of symptoms in female and male patients with a truncating variant occurred earlier in life than in those with a missense variant. However, the occurrence of severe manifestations remained variant-independent; (4) patients without macroscopic gallstones associated with intrahepatic bile duct dilatations became asymptomatic under UDCA treatment; (5) The occurrence of biliary cirrhosis and intrahepatic cholangiocarcinoma was observed but was rare.

Despite very similar clinical features, half of the patients did not harbor ABCB4 alteration. The screening method used in ABCB4 analysis did not include the promoter or other potential regulatory regions of the gene and did not allow for the detection of DNA rearrangements. Synonymous single nucleotide polymorphisms (SNPs) located in coding regions, although seemingly translationally silent, could also have a profound influence on alternative splicing and could lead to exon skipping or aberrant splicing. Alternatively, defects in other regions of the genes or in other genes leading to biliary phospholipid secretion disruption or underlying susceptibility to cholelithiasis might be involved. In this context, high-resolution gene dosage methodologies were used recently in 43 negative LPAC patients for heterozygous point or short insertion/deletion mutations. A partial or complete heterozygous deletion was detected in 7% of them.[23]

The present results highlight the strong association of LPAC with or without ABCB4 gene sequence variation with ICP. It is assumed that the prevalence of ICP in Europe is around 2% and ∼15% of ICP are associated with ABCB4 deficiency.[11] In our cohort, half of the patients who were pregnant developed the symptoms of both syndromes. Several explanations may be proposed for the association of these two phenotypic traits. During pregnancy biliary sludge develops in approximately one-third of the women. By the time of delivery 10% of women exhibit gallstones on ultrasonography examination and approximately one-third of those having gallstones are symptomatic.[24, 25] The prevalence of cholelithiasis is higher in ICP patients than in the normal population. Symptoms of cholelithiasis are found in up to 22% of the patients presenting with severe forms of ICP.[26] Evidence has been provided to indicate that ICP might result from either ABCB11 defect or FXR dysfunction resulting from gene mutation or inhibition induced by high levels of progesterone sulfate metabolites.[27, 28] ABCB4 as ABCB11 expression being under the control of FXR, it may be expected that FXR-reduced activity would promote defective bile acids and phospholipid secretion that could lead to ICP or LPAC or both.

From a clinical standpoint this series of patients indicates that the LPAC syndrome, while apparently resolving in a majority of patients under UDCA treatment, poses serious medical issues in about one-third of them, either because of recurrence of symptoms often necessitating repeated endoscopic procedures and even major liver surgery or because of prematurity and fetal distress associated with ICP. Only one case of cholangiocarcinoma was observed in our series, while in hepatolithiasis from East Asian countries that share many features of LPAC syndrome, this complication does not seem uncommon.[21] Further observational studies in patients with LPAC and cholangiocarcinoma therefore needs attention in the future. Because of the unpredictable course of the disease, we recommend that ABCB4 genotyping should be used to confirm the diagnosis and should allow familial screening. We also recommend that first-degree relatives harboring the variant of the proband should have liver ultrasonography and be informed of the strong association of LPAC and ICP. In patients without any alterations of ABCB4 gene, counseling is obviously difficult. We advise the family that the disease probably has a genetic background and that liver ultrasonography is desirable to disclose intrahepatic microlithiasis, particularly in case of pregnancy.

Prevention of occurrence and recurrence of stones is a major therapeutic issue in patients with LPAC. Currently, UDCA is systematically used because of its efficacy, as suggested in the present study. Up-regulation of ABCB4 by using in particular FXR agonists has to be assessed. Additional genetic studies using new tools that allow the systematic interrogation of the entire genome at high resolution are also obviously required to decipher the genetic abnormalities in ABCB4-negative patients and the modifier genes or genetic events that could account for the phenotypic variability of the syndrome.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References

The authors thank Professor Lionel Arrive for the imaging studies and Nathalie Laurent for genotyping of the patients.

Author Contributions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References

R.P.: study concept, acquisition and interpretation of data, patient follow-up, drafting; O.R.: acquisition and interpretation of data, patient follow-up; P.Y.B.: statistical analysis; Y.C., C.C., O.C.: acquisition of data and patient follow-up; VB, C.H.: gene analysis, interpretation of data and review.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Author Contributions
  8. References
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