Low phospholipid-associated cholelithiasis (LPAC) is a rare genetic variation of the hepatobiliary transporter adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) gene that presents with recurrent intrahepatic gallstones affecting young adults. The condition is treated with ursodeoxycholic acid rather than cholecystectomy and is associated with a number of other potential complications, thus early diagnosis is essential to avoid unnecessary surgical intervention and provide proper follow-up care. However, a high index of suspicion is required. We present a classic case of LPAC which was missed and led to unnecessary cholecystectomy.
A 43-year-old Hispanic woman was referred for evaluation of elevation of liver enzymes after pregnancy. She first presented in 2015 with right upper quadrant abdominal pain and elevated liver chemistries showing alanine aminotransferase (ALT) 522 IU/L, aspartate aminotransferase (AST) 108 IU/L, and alkaline phosphatase (ALP) 217 IU/L, with normal total bilirubin. Magnetic resonance cholangiopancreatography and subsequent endoscopic ultrasound were both unrevealing. She was told she probably passed a stone despite having had a cholecystectomy at age 25. Her liver enzymes spontaneously improved to AST 19 IU/L, ALT 38 IU/L, and ALP 77 IU/L.
This patient had had 3 previous pregnancies resulting in stillbirths, and during her fourth pregnancy, she developed intense pruritus and was again noticed to have elevated liver enzymes, with AST 104 IU/L, ALT 302 IU/L, and ALP 362 IU/L. Serum bile acid level was elevated at 34.2 umol/L (normal value: 4.7–24.5 μmol/L), leading to a diagnosis of intrahepatic cholestasis of pregnancy (ICP) and treatment with ursodeoxycholic acid (UDCA) 300 mg twice a day. She delivered a healthy baby uneventfully at 36 weeks of gestation. At 6 months postpartum, her liver enzymes remained elevated, with AST 69 IU/L, ALT 132 IU/L, and ALP 220 IU/L despite resolution of itching. She was advised to continue on UDCA, with progressive improvement and near normalization of liver chemistries (AST 21 IU/L, ALT 39 IU/L, and ALP 103 IU/L). However, the patient reportedly was nonadherent to therapy and again developed intermittent right upper quadrant pain that necessitated emergency room visits over the next few years. Her liver computed tomography and magnetic resonance imaging showed no biliary or renal stones. She was again told to have passed biliary stones and was advised to restart UDCA.
Her chronic liver disease workup to rule out autoimmune, viral, and metabolic liver diseases showed positive antismooth muscle antibody at 22 units (normal value: 0–20 units), negative viral hepatitis B and C serologies, negative antinuclear and antimitochondrial antibodies, with normal ferritin, alpha 1 antitrypsin, and ceruloplasmin levels; a liver biopsy showed nonspecific findings including ceroid-laden macrophages, without chronic cholestasis, steatosis, or fibrosis. At this point, the patient was referred to us. She denied using over-the-counter products or herbal supplements and did not drink alcohol or use any illicit drugs. Of note, her father had cholelithiasis leading to cholecystectomy at young age. Her only medication was UDCA 300 mg twice a day, and her latest liver enzymes were completely normal. Physical examination showed a mildly obese woman with no stigmata of chronic liver disease. The patient denied any abdominal pain, pruritus, or fatigue during the clinic visit. Genetic predisposition to recurrent intrahepatic microlithiasis was considered; thus, molecular genetic testing for hepatobiliary transporter genes was performed, revealing a heterozygous mutation in the ABCB4 gene (c.1768C>T, p.Arg590*). She was diagnosed with low phospholipid-associated cholelithiasis (LPAC) syndrome. She was referred for genetic counseling and advised to continue UDCA therapy indefinitely.
We present a woman who had cholecystectomy at young age, suffered with recurrent episodes of right upper quadrant pain associated with liver chemistries abnormalities, and who also developed ICP. This clinical presentation was highly suggestive of an inherited form of hepatocellular cholestasis, later confirmed by finding an ABCB4 mutation.
A genetic variation in hepatobiliary transporter of the ABCB4 gene leads to multidrug resistance protein 3 (MDR3) deficiency.1 A deficiency in MDR3 can lead to cholestasis and gallstone formation as seen in LPAC.1 LPAC syndrome, also known as gallbladder disease 1, first described by Rosmorduc et al in 2001, is a rare genetic form of intrahepatic cholelithiasis affecting young adults because of mutations in the ABCB4 gene on chromosome 7q21 encoding the phospholipid transporter of MDR3.2,3 MDR3 is needed for phospholipid secretion, specifically phosphatidylcholine, into bile to mix with bile salts and form a micelle that protects the biliary epithelium from the toxic effects of bile salts. The deficiency leads to low phospholipid concentration and impaired solubilization of biliary cholesterol that precipitates in the form of cholesterol crystals in canaliculi and intrahepatic bile ducts, leading to intrahepatic gallstone formation.3
More than 500 mutations have been described in ABCB4 gene, and clinical presentation can be very heterogeneous and lead to misdiagnosis. Heterozygous or monoallelic variants are more common and account for the attenuated presentations of cholestatic syndromes such as ICP, drug-induced liver injury, and LPAC.3–5 In contrast, the homozygous, or biallelic variants correlate with a more severe loss of MDR3 function and the classic PFIC3 presentation, with jaundice, pruritus, hepatosplenomegaly, cirrhosis, portal hypertension, and growth/mental retardation occurring in early childhood.3,5,6
In a large case-control study in France, it was estimated that LPAC represents approximately 1% of symptomatic cholelithiasis in adults admitted to nonacademic healthcare centers for symptomatic gallstone disease.7 Women are affected more than men, with a ratio of 3:1.8 The most common presentation of LPAC is biliary colic that leads to cholecystectomy at an early age. It has been suggested that the biliary symptoms are likely caused by cholesterol crystal deposition and bile duct inflammation, not related to the gallstones.8 Aside from recurrent biliary colic pain, LPAC syndrome can also lead to pancreatitis, cholangitis, and cholecystitis, just as in common gallstone disease.9
Clinical features suggestive of this LPAC include (i) the onset of symptoms at a young age, usually less than 40 years old, (ii) recurrence of biliary symptoms after cholecystectomy, (ii) presence of intrahepatic sludge or microlithiasis, (iv) a positive family history of gallstones and intrahepatic cholestasis of pregnancy, and (v) a low phospholipid concentration in bile.1,10 This condition should be considered if 2 of the first 3 features are present becaue the analysis of bile composition to detect low phospholipid concentration is not routinely performed in clinical practice.9 Once considered, genetic testing for ABCB4 gene mutations should be pursued to confirm the diagnosis and for familial screening.8 Patients and first-degree relatives with the genetic mutation should have liver ultrasonography and frequent monitoring because the disease has an unpredictable course with reports of development of secondary sclerosing cholangitis, cholangiocarcinoma, and biliary cirrhosis in patients with chronic cholestasis and inflammation.9,10 First-degree relatives and patients should also be informed of the strong association between LPAC and ICP.
Early diagnosis of LPAC syndrome is crucial because the management of this condition is different from that of common gallstone disease. Cholecystectomy as the first strategy in this condition is not recommended as a dramatic reduction in symptoms, and complications has been widely observed in response to UDCA therapy.7 UDCA has been shown to up-regulate the protein expression at the canalicular membrane stimulating the hepatobiliary secretion of bile acids, protecting cholangiocytes against the toxicity of endogenous hydrophobic bile acids and increasing the pool of protective hydrophilic bile acids leading to improve liver biochemistry and improvement of cholestatic symptoms.11 Long-term UDCA therapy may be initiated early to prevent the occurrence or recurrence of this syndrome and its severe complications.
In summary, we report LPAC syndrome presenting with recurrent biliary pain and abnormal liver enzymes despite cholecystectomy at a young age, previous diagnosis of intrahepatic cholestasis of pregnancy, symptoms responsive to UDCA therapy, and positive genetic testing for ABCB4 mutation. Appropriate diagnosis is of utmost importance because this inherited condition is associated with several chronic complications and requires medical management and long-term monitoring.
Author contributions: AM Sy, D. Mosquera, and C. Levy all provided substantial contributions to the conception or design of work and were involved in the drafting and final approval of the version to be published. They agree to be accountable for all aspects of the work. C. Levy is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
1. Wittenburg H. 12 hepatobiliary transport and gallstone formation hepatobiliary transport in health and disease. In: Dieter Häussinger, Verena Keitel and Ralf Kubitz. De Gruyter: Berlin, Boston, 2012, pp 195–206.
2. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001;120(6):1459–67.
3. Sticova E, Jirsa M. ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol. 2020;19(2):126–33.
4. MDR3 Deficiency–NORD (National Organization for Rare Disorders) (rarediseases.org
). Accessed July 02, 2020.
5. Nayagam JS, Foskett P, Strautnieks S, et al. Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol Commun. 2022;6(10):2654–64.
6. Poupon R, Barbu V, Chamouard P, Wendum D, Rosmorduc O, Housset C. Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3. Liver Int. 2010;30(2):327–31.
7. Dong C, Condat B, Picon-Coste M, et al. Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities. JHEP Rep. 2021;3(2):100201.
8. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: Association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis. 2007;2(1):29.
9. Gille N, Karila-Cohen P, Goujon G, et al. Low phospholipid-associated cholelithiasis syndrome: A rare cause of acute pancreatitis that should not be neglected. World J Hepatol. 2020;12(6):312–22.
10. Poupon R, Rosmorduc O, Boëlle PY, et al. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: A study of 156 consecutive patients. Hepatology. 2013;58(3):1105–10.
11. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–31.