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New biomarker to diagnose life-threatening liver disease in children

Researchers have identified a protein present at high levels in blood from infants with biliary atresia that may enable early and accurate detection of this potentially deadly disease. Biliary atresia is a serious liver disease that occurs during the first few months of life. In this disease, bile ducts that drain from the liver, delivering bile acids to the intestine, become inflamed and scarred, leading to a back-up of bile into the liver. This back-up can result in liver damage, as evidenced by jaundice, or the yellowing of the skin and eyes. If not treated with surgery or liver transplantation, biliary atresia can lead to liver failure and is ultimately fatal in these infants. Although a rare disease, biliary atresia remains the most common form of severe liver disease in children and the leading cause for pediatric liver transplantation. While its causes are not fully understood, both inherited and environmental factors appear to play a role in disease development. Early diagnosis and treatment are critically important for ensuring the best outcomes for infants with biliary atresia, but often diagnosis is delayed because jaundice in infants is fairly common, resulting from a number of conditions that affect bile flow. Researchers set forth to identify a clinically useful biomarker for diagnosing biliary atresia by analyzing proteins present in samples from infants enrolled in the NIDDK-supported Childhood Liver Disease Research Network (ChiLDReN). By comparing blood samples from infants with biliary atresia to those from infants with other forms of impaired bile flow, they found that a number of proteins were elevated in infants with biliary atresia. One of these proteins in particular, called matrix metalloproteinase-7 (MMP-7), was able to best distinguish the biliary atresia samples from the others, especially when combined with another marker of impaired bile flow called γ-glutamyltranspeptidase. Exploring MMP-7’s potential role in biliary atresia development, they found it is produced by the cells lining the bile ducts outside the liver. While MMP-7 levels were not associated with the degree of liver damage in infants with biliary atresia, tests in a mouse model of biliary atresia showed that the protein was released into the blood upon bile duct injury. The investigators also found that MMP-7 inhibitors protected against bile duct obstruction and liver damage in the mouse biliary atresia model. These findings suggest that MMP-7 is not only a promising candidate as a much-needed biomarker for improving early diagnosis of biliary atresia, but also likely plays a role in disease development and may be a therapeutic target. Future studies will be required to confirm MMP-7’s utility as a diagnostic tool, to test its usefulness for monitoring disease progression long-term—after interventions in infancy—and to pave the way for possible treatment trials of MMP-7 inhibitors in humans.

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