ABCB4 mutation ID’d as cause of woman’s recurrent cholestasis
Case highlights need to consider genetic testing when cause is unclear
A young woman in the U.S. who experienced recurrent cholestasis was later found, with the help of genetic testing, to have a mutation in the ABCB4 gene — one that’s been linked to some forms of cholestasis.
In a report detailing the woman’s “challenging diagnostic case,” the researchers suggested that disease characteristics consistent with ABCB4 mutations “should be considered when facing cholestasis of unclear etiology,” or cause.
Further, the team noted that when the cause of recurrent cholestasis is unclear, doctors should look to genetic testing for mutations in this gene to either rule it in or out as playing a role. The researchers stressed that early diagnosis of recurrent cholestasis and treatment with ursodeoxycholic acid can help prevent liver damage and more serious complications in patients.
“This study … [reminds] clinicians to consider early genetic testing when the diagnosis is unclear,” the team wrote.
The case study, “Unveiling the Genetic Culprit: A Diagnostic Dilemma of Recurrent Cholestasis With Intrahepatic Stones,” was published in the ACG Case Reports Journal.
Patient first showed symptoms as teen, had gallbladder removed
Cholestasis occurs when the digestive fluid bile doesn’t flow well from the liver to the intestines. The slowed or stalled bile flow causes bile acids, the main components of bile, to build up to toxic levels in the liver and leak into circulation, leading to a range of symptoms.
When cholestasis develops during pregnancy, it’s called intrahepatic cholestasis of pregnancy, or ICP. In this case, the woman’s symptoms recurred with a first pregnancy.
While it’s rare, genetic mutations can cause or increase the risk of cholestasis. In particular, mutations in the ABCB4 gene, which codes for a protein that helps neutralize bile acids to prevent them from damaging the ducts (tubes) that transport bile, have been linked to some forms of cholestasis.
These include progressive familial intrahepatic cholestasis, which is marked by symptoms typically arising in infancy, and ICP, in which cholestasis is associated with hormonal changes in the later stages of pregnancy.
Now, a team of researchers in Ohio described the case of a young woman in whom a mutation in the ABCB4 gene was found to be the likely cause of her recurrent cholestasis.
She first sought hospital treatment when she was 17 years old due to two days of right-sided abdominal pain. The teen had a history of obesity, and lab tests showed elevated levels of liver enzymes in the blood — an indication of liver damage. An abdominal ultrasound done at the time also showed gallstones, but no inflammation in the gallbladder.
Gallstones are hard deposits of bile compounds that can form in the gallbladder, where bile is stored until it’s needed for digestion; these gallstones can become stuck in the bile ducts, causing pain and sometimes requiring treatment.
The teen’s condition improved with supportive treatment, and later she had her gallbladder removed. During surgery, a blocked bile duct was cleared with endoscopic retrograde cholangiopancreatography (ERCP), which combines X-ray images and an endoscope — a long, flexible tube with a tiny camera on its end — to look into, and manipulate, the bile ducts.
Examination of the removed gallbladder showed eosinophilic cholecystitis, a rare condition characterized by a collection of a type of inflammatory cells called eosinophils.
At her one-month follow-up, she felt fine but still had elevated liver enzymes. Imaging showed mild liver stiffness and slight bile duct irregularities but no major blockages.
After further lab tests excluded other possible infectious and autoimmune conditions, the girl underwent an MRI scan months later, which showed liver volume loss and bile duct changes, suggesting cholangiopathy, or damage to the bile ducts. A liver biopsy showed mild inflammation but no fat buildup, scarring, or major damage to the bile ducts.
At this point, “she was unfortunately lost to follow-up,” the researchers wrote.
Genetic testing after symptoms recurred reveals ABCB4 mutation
Three years after her first symptoms, the young woman became pregnant and her liver enzymes worsened. She had a miscarriage, but fetus and pregnancy tissue were not completely expelled, per the report.
The woman became pregnant again shortly after and had another increase of liver enzymes, leading doctors to suspect ICP. Further scans suggested bile duct dilation within the liver due to possible narrowing of bile ducts, and another liver biopsy showed possible bile duct blockage.
An ERCP suggested the presence of a bile stone in a bile duct within the liver, which could not be easily reached for removal.
Because the cause of cholestasis remained unclear, the doctors ordered genetic testing, which revealed an ABCB4 gene mutation.
Her condition “aligned best with GBD1 (gallbladder disease 1), also known as LPAC (low phospholipid cholelithiasis),” which has been associated with ABCB4 mutations, the team wrote.
With early consideration of genetic testing and management with UDCA [ursodeoxycholic acid], the development of [liver scarring] in patients with ABCB4 mutations may be slowed or halted.
In people with GBD1/LPAC, symptoms usually start between childhood and early adulthood and may include gallstones, bile stones in the liver, and jaundice, or a yellowing of the skin and whites of the eyes. Also, symptoms may recur after gallbladder removal and worsen with pregnancy, the team noted.
The patient was started on ursodeoxycholic acid, known as UCDA, which eased her symptoms, which had included itching and jaundice. The young woman was advised against future pregnancies.
“Three independent factors have been found to be predictive of an ABCB4 mutation: age less than 40 years, recurrence after [gallbladder removal], and [bile deposits or stones within the liver],” the researchers wrote. “Our case included all 3 of these features.”
GBD1/LPAC “is often missed and a high degree of suspicion especially in the context of the intrahepatic stones and ICP should prompt genetic workup,” the team concluded. “With early consideration of genetic testing and management with UDCA, the development of [liver scarring] in patients with ABCB4 mutations may be slowed or halted.”
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