New biomarkers may help detect pregnancy-linked liver complication
Blood levels of protein, metabolite also can ID severity of ICP, per study
Levels of the metabolite palmitic acid and the protein ACSL1 in the bloodstream can accurately detect the presence and severity of intrahepatic cholestasis of pregnancy (ICP), the most common pregnancy-related liver complication, according to a new study by researchers in China.
Metabolites are small molecules produced during metabolism — the body’s process for converting food, drugs, chemicals, and other substances into the energy and materials needed for life. ACSL1 is also involved in energy metabolism.
In addition to their diagnostic potential, high levels of palmitic acid and ACSL1 were associated with more severe ICP, as well as a younger newborn age at delivery, and lower newborn birth weight, the data showed.
“These findings suggest that [blood] palmitic acid and ACSL1 not only serve as potential diagnostic biomarkers but also correlate with disease severity and adverse [around-birth] outcomes in ICP,” the researchers wrote.
The study, “Integrated proteomic and metabolomic analysis reveals lipid metabolic dysregulation and ferroptosis as potential drivers of placental dysfunction in intrahepatic cholestasis of pregnancy,” was published in the journal Molecular and Cell Biology of Lipids.
ICP is a pregnancy-related form of cholestasis, a condition in which the flow of the digestive fluid bile from the liver is slowed or blocked. The researchers noted that “the placenta plays a pivotal role in ICP, as symptom resolution and biochemical normalization occur rapidly after placental delivery.”
ICP can cause health problems for both mother and unborn baby
Although ICP typically resolves soon after birth, it can cause health problems for both the mother and her unborn baby. For the expectant mother, it can lead to maternal bleeding and gestational diabetes, or high blood sugar during pregnancy. Among infants, it can cause premature birth, meaning the baby is born before 37 weeks of pregnancy, and stillbirth.
While elevated blood levels of bile acids, bile’s main components, “remains the sole laboratory marker for ICP, its diagnostic accuracy is suboptimal,” the researchers wrote, adding that there is, therefore, a “need for more reliable, sensitive, and specific biomarkers.”
To that end, the research team set out to identify new ICP biomarkers by first examining the levels of all proteins and metabolites in the placenta of a rat model of induced ICP. These levels were compared with those of healthy rats. The findings were then validated in placental and blood samples from pregnant women with ICP versus healthy pregnant women.
Initial tests revealed that levels of 1,527 proteins and 221 metabolites were significantly altered in the placentas of pregnant rats with ICP compared with healthy pregnant rats.
By integrating these datasets, the researchers identified two shared underlying processes: degradation and biosynthesis of fatty acids, a type of fatty molecule. This suggested that “disturbances in [fat] metabolism may contribute to the molecular alterations associated with ICP,” the team wrote.
Two molecules — the metabolite palmitic acid and the protein ACSL1 — were then identified as key components of both metabolic pathways. Further analyses showed that these molecules were significantly elevated in placental samples from both ICP rat models and pregnant women with ICP, when compared with samples from their healthy counterparts.
Likewise, both palmitic acid and ACSL1 levels were significantly higher in the blood of pregnant women with ICP compared with those without ICP. Higher blood levels of ACSL1 and palmitic acid were significantly associated with higher levels of each other, as well as of bile acids.
In addition, elevated blood levels of these two molecules were significantly linked to a shorter gestational age at delivery and a lower newborn birth weight. Both palmitic acid and ACSL1 levels were markedly higher in the blood of pregnant women with severe ICP than in mild cases.
These findings suggested that these two molecules could be used as biomarkers both ICP and its severity.
Both biomarkers showed high accuracy in lab testing
The diagnostic accuracy of these potential biomarkers was assessed by the area under the curve, or AUC, which measures a model’s ability to distinguish between two groups — in this case, with or without ICP. AUC values range from zero to one, with higher numbers indicating better discriminative performance.
The AUC for distinguishing pregnant women with ICP from those without was 0.794 for palmitic acid alone, 0.825 for ACSL1 alone, and 0.894 for palmitic acid, ACSL1, and TBA levels combined.
Regarding ICP severity, the AUC for distinguishing women with severe disease from those with mild disease was 0.769 for palmitic acid alone, 0.904 for ACSL1 alone, and 0.94 for palmitic acid and ACSL1 combined. The highest AUC of 0.982 was obtained for the combination of palmitic acid, ACSL1, and bile acids. In comparison, the AUC for bile acids alone was 0.916.
These findings highlighted “the altered [production] of palmitic acid and ACSL1 in ICP patients and demonstrated their potential diagnostic value,” the researchers wrote, adding that “ACSL1 and palmitic acid, particularly when combined with [bile acids], offer superior clinical utility for distinguishing mild from severe ICP.”
According to the researchers, a “combined biomarker analysis improves diagnostic accuracy for ICP.”
Lastly, additional experiments revealed a novel link between altered fat metabolism in ICP and ferroptosis, an iron-dependent form of cell death marked by the buildup of potentially damaging fatty molecules called lipid peroxides.
The data suggested that “dysregulated [fat] metabolism and ferroptosis may act in concert to drive placental injury in ICP, pointing to ferroptosis as a novel mechanistic contributor to disease [development],” the team wrote.
“Future studies will aim to expand both animal experiments and clinical [patient groups] to enhance the reliability and translational relevance of the results,” the researchers concluded.
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