may also occur. to manage this, doses of vitamin a, d, e, and k are recommended to retain appropriate vitamin levels. cholestatic liver disease can impact lipids, and possibly lead to dyslipidemia, which may present a risk for coronary artery disease. statins and fibrates are generally used as lipid lowering therapy to treat patients with cholestatic liver disease. for intrahepatic cholestasis in pregnant women, s-adenosylmethionine has proven to be an effective treatment. dexamethasone is a viable treatment in regards to the symptom of intensive itching. research directions primary sclerosing cholangitis (psc) is one of the most common cholestatic liver diseases, yet treatment options remain limited. treatment for primary biliary cholangitis (pbc) is often done with ursodeoxycholic acid (udca) and with no other suitable alternative, it poses a problem for those that are not responsive to (udca). however, with advancing technology in the molecular biochemistry field and higher understanding of bile acid regulation, novel pharmacological treatments have been considered. for patients with primary biliary cholangitis, current guidelines recommend about 13–15 mg/kg of ursodeoxycholic acid as a first line treatment. this drug stimulates biliary bicarbonate secretion, improves survival without having to resort to a liver transplantation, and is very well tolerated— making it an ideal treatment. however, around 40% of patients with primary biliary cholangitis are not responsive to udca. obeticholic acid has been approved by the us food and drug administration for pbc in 2016 after experiments found beneficial improvements for the liver in half of patients with inadequate response to udca. primary sclerosing cholangitis is a challenging liver disease as treatment options are limited. there is still uncertainty about the efficacy of ursodeoxycholic acid for psc and researchers offer conflicting recommendations. one study found udca had improved biochemical functions but did lower the rate for death or transplant-free survival. 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. a worry though is despite benefits in the biochemical pathways, pruritus was more intense and prevalent than the placebo. a titration strategy may help to mitigate pruritus, but fda approval for obeticholic acid is currently unlikely. in fact, in february 2018, the fda gave a black box warning for oca. a recent study did find that if the drug is given with udca, the incidence for cirrhosis and liver transplants decreases. another target that is being looked into is the all-trans retinoic acid (atra), an activator for the retinoid x receptor. in vitro and animal studies found atra had lowered the amount of bile acid and decreased hepatic inflammation. 24-norursodeoxycholic acid a recent scientific breakthrough for cholestasis that has allowed us to evaluate a new treatment option is that a hydrophilic environment and bicarbonate production protects hepatocytes from bile acid. the novel agent norudca (24-norursodeoxycholic acid) can be passively absorbed by cholangiocytes. this leads to bicarbonate production and an environment that is less toxic. mouse models have found promising results with norudca with the drug showing antiproliferative and anti-inflammatory properties. a recent clinical trial found norudca had significant dose-dependent reductions for alp levels. this makes norudca a viable possibility to look into as it clearly plays a significant role in the treatment of cholestasis. immunomodulatory treatments in pbc, the liver is filled with t cells and b cells that contribute to a worsening condition. therefore, some treatments are looking into targeting the antigens of these immune cells. the monoclonal antibody rituximab targets the cd20 antigen on the b cells, and is already used in a wide array of other rheumatologic diseases. in an open-label study, six patients that were unresponsive to udca had improvement in alp levels after rituximab infusions. however, the efficacy of rituximab is still uncertain, and awaits further studies and trials. pbc can also lead to higher levels of interleukin 12 and interleukin 23. this was what motivated researches to look at the viability of ustekinumab, a monoclonal antibody targeted against interleukin 12 and 23. an experiment found though it did not significantly improve serum alp levels. the researchers were further even criticized for placing patients at risk by allowing them to move to advanced disease stages where immunomodulatory therapies may not even be an option. gut microbiome in several chronic liver diseases, the gut microbiome, which regulates both the innate and adaptive immune systems, is implicated. this can result in abnormal immunological development and an accumulation of primary bile acids. using this information a bile-acid–intestinal-microbiota–cholestasis triangle is thought to be involved in the pathogenesis of pbc and psc. after all, bile acids do modulate the gut microbiota; a disturbance here can result in development and progression of cholestasis. this information has prompted researchers into manipulating the microbiota via antibiotics and probiotics for new treatment options. some antibiotics examined for psc include vancomycin, which has extensively studied and reviewed. the usage of the drug is found along with a significant decrease in alp levels, although the long term clinical benefit is unknown. as biochemistry technology becomes more advanced, promising targets have appeared, prompting numerous studies and trials to evaluate the feasibility. fibrates, fxr agonists, and norudca are all innovative therapies for cholestasis.