Peroxisomes receptor agonists
An important regulator in bile acid homeostasis is the alpha and delta isoforms of the peroxisome proliferator-activated receptor (PPARα, PPARδ). The function of PPARα is that it promotes bile acid excretion and lowers inflammation by acting on nuclear transcription factors. A well known agonist are fibrates and in the clinical trials, there was a significant biochemical response in most patients. A combination therapy with bezafibrate showed remarkable biochemical improvement, with 67% of patients normalizing their alkaline phosphatase levels. Another study of 48 patients with PBC found a combination of bezafibrate and UDCA showed a decrease of alkaline phosphatase in all patients. Further, the study found those treated had a marked relief in pruritus.However, fibrates are associated with a number of adverse effects including arthritis, leg edema, polydipsia, and myalgias. Elevations of creatinine and creatinine phosphokinase were also found over a long term use. Farnesoid X-receptor agonist
A new novel treatment option is the farnesoid X receptor is responsible for regulating bile acid homeostasis. An agonist of this nuclear hormone receptor is seen as a possible treatment as it can downregulate bile acid synthesis and reabsorption. Further the farnesoid X receptor is partly responsible for lipid and glucose homeostasis, as well as pathogen recognition. An agonist for the farnesoid X receptor can therefore lead to an anti-cholestatic environment to minimize the effect of toxic bile acids on the liver. A candidate agonist for the farnesoid X receptor is obeticholic acid with experiments showing it has very strong affinity.
These signs and symptoms resolve on their own shortly after delivery, though they may reappar in subsequent pregnancies for 45-70% of women. In the treatment of ICP, current evidence suggests ursodeoxycholic acid (UDCA), a minor secondary bile acid in humans, is the most effective drug for reducing pruritus and improving liver function.The etiology of ICP is multifactorial and likely involves hormonal, genetic, and environmental factors. Several observations suggest estrogen plays a major role: ICP begins in the third trimester, when estrogen levels are highest, resolves after estrogen levels return to normal post-delivery, and occurs with higher incidence in multiple pregnancies, where estrogen levels are more elevated than usual. Although estrogens exact pathomechanism in ICP remains unclear, several explanations have been offered. Estrogen may induce a decrease in the fluidity of the hepatic sinusoidal membrane, leading to a decrease in the activity of basolateral Na+/K+-ATPase. A weaker Na+ gradient results in diminished sodium-dependent uptake of bile acids from venous blood into hepatocytes by the sodium/bile acid cotransporter. More recent evidence suggests that estrogen promotes cholestasis via its metabolite estradiol-17-β-D-glucuronide (E2). E2 secreted into the canaliculi by MRP2 was found to repress the transcription of bile salt export pump (BSEP), the apical ABC transporter responsible for exporting monoanionic conjugated bile acids from hepatocytes into bile canaliculi. E2 was also found to upregulate miR-148a, which represses expression of the pregnane X receptor (PXR).