New ABCB4 mutation deemed cause of PFIC3 in 2 unrelated girls
Girls from neighboring Asian countries had similar symptoms
A new ABCB4 gene mutation was the likely cause of progressive familial intrahepatic cholestasis type 3 (PFIC3) in two unrelated Southeast Asian girls, a study reported.
The girls were from neighboring countries in Southeast Asia and had similar clinical presentations that progressed to liver failure within the first decade of life.
“With improved understanding of the gene variants involved in PFIC-3, we can more effectively and accurately anticipate morbidity, mortality, and need for transplant, as well as provide tailored and refined genetic counseling to patients and their families,” the researchers wrote.
The study, “A novel genetic variant associated with progressive familial intrahepatic cholestasis type 3: A case series,” was published in the Journal of Pediatric Gastroenterology and Nutrition.
PFIC3 linked to gene mutations
PFIC is an umbrella term for rare genetic liver diseases that occur when liver cells have problems producing or secreting bile, a digestive fluid. In healthy people, bile is produced in the liver and then flows through a series of bile ducts into the intestines, where it helps digest fatty molecules.
In PFIC patients, however, bile flow is slowed or stalled inside the liver, a phenomenon known as intrahepatic cholestasis. Bile then builds up, causing liver damage that can ultimately result in cirrhosis, or irreversible liver scarring, and organ failure.
PFIC patients will experience symptoms early in life, including jaundice (yellowing of the skin and whites of the eyes), itching, and dark urine.
PFIC type 3 is caused by mutations in the ABCB4 gene, which provides instructions for making a protein called MDR3. In PFIC3 patients, the MDR3 protein has decreased or absent functioning, which impairs the body’s ability to neutralize bile salts and prevent damage to bile duct cells. Typically, the disease is more severe when a child inherits the same ABCB4 mutation from both parents.
“Treatment generally involves medical management of associated symptoms and clinical sequelae, but liver transplantation may be required if symptoms are [resistant] to medical management or if there is progression to [liver failure],” the researchers wrote. They described the cases of two unrelated girls of Southeast Asian descent who carried a new ABCB4 mutation that was the likely cause of their PFIC3.
One, a six-year-old, arrived at a Tennessee emergency department with jaundice, an enlarged liver and spleen, and mild ascites, or buildup of fluid in the abdomen — all signs of potential liver damage. She also had low oxygen levels.
The girl was originally from Myanmar, and her symptoms started when she was 9 months old. At 5, she was living in Malaysia when an abdominal ultrasound scan showed lesions in the liver and spleen and a blood clot in the portal vein, which transports blood from the intestines to the liver.
A liver biopsy at the time showed cirrhosis, and further tests revealed esophageal varices, or enlarged veins in the tube that connects the throat and stomach, which are typically associated with serious liver disease. Her ascites was treated with medications meant to reduce fluid buildup in the body.
In the U.S., lab work showed high levels of liver enzymes and other markers of liver damage. A liver biopsy confirmed cirrhosis. Comprehensive genetic testing showed a new ABCB4 mutation in both copies of the gene — c.779T>C — that was deemed the likely cause of her condition, confirming a PFIC3 diagnosis.
Ultimately, the girl received a liver transplant and was “doing well,” according to the researchers.
The U.S.-based researchers then contacted the genetic laboratory that did the testing to see if the mutation had been previously detected. The laboratory connected them to a medical team in Thailand caring for a girl with the same rare ABCB4 mutation.
Genetic testing makes collaboration ‘critical’
The second girl had also inherited the c.779T>C mutation from both her mother and father. She had been adopted at 3 months, and her family history was unclear.
She came to the hepatology clinic in Thailand at 16 months due to discolored skin, problems with blood clotting, and high levels of liver enzymes. At that time, potential causes of chronic liver disease, including forms of hepatitis, or liver inflammation, were excluded.
At 2, she had jaundice and an enlarged liver. A liver biopsy three years later revealed liver cirrhosis, moderate cholestasis, and bile duct abnormalities. By age 10, the last follow-up, the girl had been intermittently hospitalized for bacterial infections, bleeding in the upper gastrointestinal tract, malnutrition, and other complications. A “lack of caregiver and financial support” meant she was not a candidate for a liver transplant, and she was “receiving palliative care in Thailand,” the researchers wrote.
“Both children had … findings of mixed portal [vein] inflammation and abnormal bile ducts which are consistent with other reports of PFIC-3, although MDR3 staining was not performed,” the team wrote. “As genetic testing becomes more common, collaboration with testing laboratories who may have significant unpublished data is also critical,” they concluded.
About the Author
