vitamin-d-2 and Cholestasis

Topics: Bile Ducts, Intrahepatic; Cholestasis; Cholestyramine Resin; Drainage; Ergocalciferols; Humans; Vitamin E; Vitamin K

Vitamin D deficiency in patients with cholestasis is due to impaired intestinal vitamin D absorption, which results from decreased intestinal bile acid concentration. Patients with cholestasis usually do not achieve optimal vitamin D status when a treatment regimen for children without cholestasis is used. However, data on high-dose vitamin D treatment in patients with cholestasis are limited.. This study is a prospective study that included pediatric patients with cholestasis (serum direct bilirubin > 1 mg/dL) who had vitamin D deficiency (serum 25-hydroxyvitamin D, 25-OHD, < 20 ng/mL). In Phase 1, single-day oral loading of 300,000 IU (or 600,000 IU if weight ≥ 20 kg) of vitamin D2 was administered, followed by an additional loading if serum 25-OHD < 30 ng/mL, and 4-week continuation of treatment using a vitamin D2 dose calculated based on the increment of 25-OHD after first loading. In Phase 2, oral vitamin D2 (200,000 IU/day) was administered for 12 days, followed by 400,000 IU/day of vitamin D2 orally for another 8 weeks if serum 25-OHD < 30 ng/mL.. Phase 1: Seven patients were enrolled. Three out of seven patients had a moderate increase in serum 25-OHD after loading (up to 20.3-27.2 ng/mL). These patients had conditions with partially preserved bile flow. The remaining four patients, who had biliary atresia with failed or no Kasai operation, had low increments of serum 25-OHD. Phase 2: Eleven patients were enrolled. Eight out of 11 patients had a moderate increase in serum 25-OHD after 200,000 IU/day of vitamin D2 for 12 days. Serum 25-OHD continued increasing after administering 400,000 IU/day of vitamin D2 for another 8 weeks, with maximal serum 25-OHD of 15.7-22.8 ng/mL.. Very high doses of vitamin D2 (200,000 and 400,000 IU/day) partly overcame poor intestinal vitamin D absorption and resulted in moderate increases in serum 25-OHD in pediatric patients with cholestasis, particularly when cholestasis was caused by uncorrectable bile duct obstruction.

Topics: Child; Cholestasis; Ergocalciferols; Humans; Prospective Studies; Vitamin D; Vitamin D Deficiency; Vitamins

Clinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear.. Mice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis.. Paricalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-β-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527.. Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway.

Topics: Animals; Bile Ducts; Cellular Senescence; Cholestasis; Epithelium; Ergocalciferols; Liver; Mice; Oxidative Stress; Sirtuin 1

Mounting clinical evidence has revealed that the vitamin D receptor (VDR) is associated with cholestatic liver injury, although the functions of VDR in this condition remain largely unexplored. Here, we investigated the effects of VDR activation on bile duct ligation (BDL) mice, and the underlying mechanisms were further investigated. A low-calcemic VDR agonist, paricalcitol (PAL, 200 ng/kg), was intraperitoneally injected into BDL mice every other day for 5 days or 28 days. Liver histology, liver function indicators, cholangiocyte proliferation, fibrosis scores, and inflammation were evaluated. Mice treated with PAL were rescued from the decreased survival rate induced by BDL and liver damage was reduced. Mechanistically, PAL promoted cholangiocyte proliferation, which was likely conducive to proliferating bile duct maturation and increased branching of bile ducts. PAL treatment also increased the expression of Yes-associated protein (YAP) and its target protein epithelial cell adhesion molecule (EpCam) and decreased the level of inactive cytoplasmic phosphorylated YAP. YAP knockdown abrogated PAL-induced primary bile duct epithelial cell proliferation, confirmed with YAP inhibitor administration. In addition, BDL-induced liver fibrosis and inflammatory cell infiltration were reduced by PAL treatment at both day 5 and day 28 post-BDL. In conclusion, VDR activation mitigates cholestatic liver injury by promoting adaptive bile duct remodeling through cholangiocytic YAP upregulation. Because PAL is an approved clinical drug, it may be useful for treatment of cholestatic liver disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Animals; Bile Ducts; Cholestasis; Ergocalciferols; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Receptors, Calcitriol; YAP-Signaling Proteins

Oral high-dose repletion vitamin D therapy, also known as stoss therapy, can be effective in the treatment of nutritional vitamin D deficiency rickets in infants and young children without liver disease and in patients with cystic fibrosis. There is no literature about this approach in infants with new-onset cholestasis.. This was a retrospective chart review of infants with cholestasis from March 2010 to March 2012 at a pediatric tertiary care center. Four cases satisfied the inclusion criteria, and were described in detail.. All of the patients received oral high-dose repletion therapy with ergocalciferol (vitamin D2) 300,000 IU daily for 2 to 3 days. Follow-up vitamin D levels approximately 4 weeks later showed failure to achieve sufficiency levels (>20 ng/dL) in any patient.. Unlike infants without liver disease, use of oral high-dose repletion therapy may not be adequate as treatment of vitamin D deficiency in the setting of cholestasis.

Topics: Administration, Oral; alpha 1-Antitrypsin Deficiency; Biliary Atresia; Cholestasis; Ergocalciferols; Female; Humans; Infant; Male; Retrospective Studies; Tertiary Care Centers; Treatment Failure; Vitamin D; Vitamin D Deficiency

Twenty-nine patients with chronic liver disease, nine of whom had symptoms suggesting bone disease, were studied by bone histology. Nine had osteomalacia; six associated with cholestatic liver disease and three with primarily hepatocellular disease. Two of these had clinical and biochemical features of cholestasis for at least a year and the other had alcoholic cirrhosis associated with severe malnutrition. Excluding the latter patient, histological osteomalacia was significantly associated with presence and duration of cholestasis. Plasma 25-hydroxyvitamin D was low and fasting urine hydroxyproline/creatinine ratio was high in all patients with osteomalacia but were abnormal also in some patients who did not have histological osteomalacia. Serum calcium, phosphate, alkaline phosphatase, vitamin D-binding protein and radiology were unhelpful in many patients with osteomalacia. Vitamin D-deficiency correlated significantly with deficiency of other fat-soluble vitamins and those patients with rachitic levels of plasma 25-hydroxyvitamin D showed no seasonal variation, suggesting a combination of malabsorption of vitamin D and reduced sunlight exposure. We suggest that patients with chronic liver disease with cholestasis for at least a year are at risk from osteomalacia and that those likely to have this complication may be identified by plasma 25-hydroxyvitamin D and/or fasting urine hydroxyproline/creatinine ratio measurements. The diagnosis can only be made with certainty by bone biopsy.

Topics: 25-Hydroxyvitamin D 2; Adolescent; Adult; Aged; Cholestasis; Chronic Disease; Ergocalciferols; Humans; Liver Diseases; Middle Aged; Osteomalacia; Risk; Seasons; Vitamin D Deficiency

To study the effects of acute and chronic cholestasis on vitamin D metabolism we investigated six cases of acute extrahepatic obstructive jaundice and eight cases of primary biliary cirrhosis (PBC) (three supplemented with vitamin D). Plasma 25-hydroxyvitamin D (25OHD) was low in the patients with PBC unsupplemented with vitamin D but normal in obstructive jaundice. None of the patients with PBC showed radiological or histological evidence of osteomalacia. In PBC, dietary intake of vitamin D was low but response to ultra-violet irradiation of the skin was normal even in those with a considerably raised serum bilirubin. Patients with PBC or obstructive jaundice had low levels of 25 hydroxyvitamin D binding protein which correlated with the serum albumin. The half-life of intravenously injected (3)H vitamin D(3) ((3)HD(3)) and the subsequent production of (3)H 25OHD were normal in all the patients with obstructive jaundice and in most with PBC. The two patients with PBC who produced less (3)H 25OHD than expected were receiving vitamin D supplements. The urinary tritium ((3)H) excretion after the injection of (3)HD(3) correlated with the serum bilirubin. After the injection of (3)H 25OHD(3) the urinary excretion of (3)H was minimal and did not correlate with the serum bilirubin, suggesting that the radioactivity appearing in the urine after the (3)H vitamin D(3) injection was associated with vitamin D metabolites other than 25OHD. Factors contributing to the low plasma 25OHD in primary biliary cirrhosis may be a low dietary intake of vitamin D, inadequate exposure to ultra-violet light, and a tendency to urinary wastage of vitamin D metabolites.

Topics: Acute Disease; Adult; Aged; Cholecalciferol; Cholestasis; Cholestasis, Extrahepatic; Chronic Disease; Ergocalciferols; Female; Half-Life; Humans; Hydroxycholecalciferols; Liver Cirrhosis, Biliary; Male; Middle Aged; Ultraviolet Therapy; Vitamin D

Twenty of 32 patients with either chronic cholestatic or hepatocellular liver disease had bone pain or recent fractures. On bone biopsy five patients had normal bone, 15 had osteomalacia, five had osteoporosis, and seven had a combination of osteomalacia and osteoporosis. In the presence of osteoporosis, osteomalacia was minimal or absent. There was no biochemical, radiological, or histological evidence of excess parathyroid activity. No significant correlations were demonstrated between the plasma and urinary biochemical findings and the presence of either osteoporosis or osteomalacia and bone biopsy was essential for correct diagnosis. There was no statistical relationship between low serum 25-hydroxy vitamin D values and the presence of osteomalacia. Bone disease was not prevented by regular intramuscular vitamin D2, although biochemical changes were improved. Drugs such as corticosteroids and cholestyramine may be important aetiological factors in hepatic osteodystrophy.

Topics: Adult; Bone and Bones; Cholestasis; Chronic Disease; Ergocalciferols; Female; Humans; Hydroxycholecalciferols; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Osteomalacia; Osteoporosis; Parathyroid Glands