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Intrahepatic cholestasis of pregnancy: from an obstetrician point of view

Abdelhafez MMA, Ahmed KAM, Than WW, Baharuddin DMP, Kadir F, Jeffree S, et al.

J Obstet Gynaecol, 2022 Oct;42(7):2550-2557.
PMID: 35666947 DOI: 10.1080/01443615.2022.2081801

Intrahepatic cholestasis of pregnancy (ICP) is the commonest among the specific dermatoses of pregnancy. The disease is characterised by intense pruritus and specifically by elevated bile acid levels and owing to the rarity of data published in this context, the disease carries a great challenge in both diagnosis and management. The disease is associated with significant maternal as well as perinatal adverse effects, hence, this article aims at improving the knowledge of the women's health carers with the up-to-date and evidence-based, whenever possible, recommendations while managing patients with ICP.

Matched MeSH terms: Ursodeoxycholic Acid/adverse effects
Fulltext Advancements in nano drug delivery systems: a challenge for biofilms in respiratory diseases

Dua K, de Jesus Andreoli Pinto T, Chellappan DK, Gupta G, Bebawy M, Hansbro PM

Panminerva Med, 2018 03;60(1):35-36.
PMID: 29370678 DOI: 10.23736/S0031-0808.18.03402-X
Matched MeSH terms: Ursodeoxycholic Acid/chemistry
Fulltext Ursodeoxycholic acid upregulates ERK and Akt in the protection of cardiomyocytes against CoCl2

Hanafi NI, Mohamed AS, Md Noor J, Abdu N, Hasani H, Siran R, et al.

Genet. Mol. Res., 2016 Jun 17;15(2).
PMID: 27323195 DOI: 10.4238/gmr.15028150

Ursodeoxycholic acid (UDCA) is used to treat liver diseases and demonstrates cardioprotective effects. Accumulation of the plasma membrane sphingolipid sphingomyelin in the heart can lead to atherosclerosis and coronary artery disease. Sphingomyelinases (SMases) break down sphingomyelin, producing ceramide, and inhibition of SMases activity can promote cell survival. We hypothesized that UDCA regulates activation of ERK and Akt survival signaling pathways and SMases in protecting cardiac cells against hypoxia. Neonatal cardiomyocytes were isolated from 0- to 2-day-old Sprague Dawley rats, and given 100 μM CoCl2, 150 μM H2O2, or placed in a hypoxia chamber for 24 h. The ameliorative effects of 100-μM UDCA treatment for 12 h were then assessed using MTS, QuantiGene Plex (for Smpd1 and Smpd2), and SMase assays, beating rate assessment, and western blotting (for ERK and Akt). Data were analyzed by the paired Student t-tests and one-way analyses of variance. Cell viability decreased significantly after H2O2 (85%), CoCl2 (50%), and hypoxia chamber (52%) treatments compared to the untreated control (100%). UDCA significantly counteracted the effects of chamber- and CoCl2- induced hypoxia on viability and beating rate. However, no significant differences were observed in acid SMase gene and protein expression between the untreated, CoCl2, and UDCA-CoCl2 groups. In contrast, neutral SMase gene and protein expression did significantly differ between the latter two groups. ERK and Akt phosphorylation was higher in hypoxic cardiomyocytes treated with UDCA than those given CoCl2 alone. In conclusion, UDCA regulates the activation of survival signaling proteins and SMases in neonatal rat cardiomyocytes during hypoxia.

Matched MeSH terms: Ursodeoxycholic Acid/pharmacology*
Fulltext Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis

Adeyemi O, Alvarez-Laviada A, Schultz F, Ibrahim E, Trauner M, Williamson C, et al.

PLoS One, 2017;12(9):e0183167.
PMID: 28934223 DOI: 10.1371/journal.pone.0183167

BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing and development of reentrant arrhythmias, although the cellular mechanism is still being elucidated.
METHODS: High-resolution fluorescent optical mapping of electrical activity and electrocardiogram measurements were used to characterize effects of UDCA on one-day-old neonatal and adult female Langendorff-perfused rat hearts. ICP was modelled by perfusion of taurocholic acid (TC, 400μM). Whole-cell calcium currents were recorded from neonatal rat and human fetal cardiomyocytes.
RESULTS: TC significantly prolonged the PR interval by 11.0±3.5% (P<0.05) and slowed ventricular conduction velocity (CV) by 38.9±5.1% (P<0.05) exclusively in neonatal and not in maternal hearts. A similar CV decline was observed with the selective T-type calcium current (ICa,T) blocker mibefradil 1μM (23.0±6.2%, P<0.05), but not with the L-type calcium current (ICa,L) blocker nifedipine 1μM (6.9±6.6%, NS). The sodium channel blocker lidocaine (30μM) reduced CV by 60.4±4.5% (P<0.05). UDCA co-treatment was protective against CV slowing induced by TC and mibefradil, but not against lidocaine. UDCA prevented the TC-induced reduction in the ICa,T density in both isolated human fetal (-10.2±1.5 versus -5.5±0.9 pA/pF, P<0.05) and neonatal rat ventricular myocytes (-22.3±1.1 versus -9.6±0.8 pA/pF, P<0.0001), whereas UDCA had limited efficacy on the ICa,L.
CONCLUSION: Our findings demonstrate that ICa,T plays a significant role in ICP-associated fetal cardiac conduction slowing and arrhythmogenesis, and is an important component of the fetus-specific anti-arrhythmic activity of UDCA.

Matched MeSH terms: Ursodeoxycholic Acid/pharmacology*
Fulltext Presence of anti-mitochondrial antibodies and elevated serum immunoglobulin G levels: is this primary biliary cirrhosis-autoimmune hepatitis overlap syndrome?

Muttaqillah NA, Abdul Wahab A, Ding CH, Mohammad M, Biswas S, Rahman MM

EXCLI J, 2015;14:175-8.
PMID: 26648811 DOI: 10.17179/excli2014-660

Primary biliary cirrhosis in combination with autoimmune hepatitis has been termed "overlap syndrome", but its diagnosis is challenging. We report a case of a 43-year-old lady who presented with a six-month history of jaundice and pruritus. She subsequently developed gum bleeds. Laboratory investigations revealed hypochromic microcytic anemia, abnormal coagulation profiles, elevated serum alanine transferase and alkaline phosphatase levels, and raised serum IgG and IgM levels. Her serum was also positive for anti-nuclear and anti-mitochondrial antibodies. The findings from her abdominal CT scan were suggestive of early liver cirrhosis and the histopathological examination results of her liver biopsy were consistent with primary biliary cirrhosis. The patient was treated with ursodeoxycholic acid and her liver function test parameters normalized after six months.

Matched MeSH terms: Ursodeoxycholic Acid
Ulcerative colitis with concomitant primary sclerosing cholangitis

Mohamed AK, Seow CE

Med J Malaysia, 2020 11;75(6):756-758.
PMID: 33219195

Primary sclerosing cholangitis (PSC) is the most common liver disease and known hepatobiliary complication of ulcerative colitis (UC). Concomitant PSC in UC is associated with increased risk of rapid progression of primary sclerosing cholangitis, and malignancy including colon carcinoma as well as hepatobiliary carcinoma. We report a case of a 26-year-old woman who was diagnosed as ulcerative colitis during her second pregnancy. Her liver function test showed a significant elevation of alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) with other parameters being within normal range. A clinical suspicion of primary sclerosing cholangitis was then made. Magnetic resonance cholangiopancreticography (MRCP) revealed beaded appearance of the right and left intrahepatic ducts with focal narrowing seen at the ducts, suggestive of primary sclerosing cholangitis. She was subsequently started on oral Ursodeoxycholic acid (UDCA) with improvement in her liver function test within 3 weeks of initiation of treatment.

Matched MeSH terms: Ursodeoxycholic Acid
Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Mohamed AS, Hanafi NI, Sheikh Abdul Kadir SH, Md Noor J, Abdul Hamid Hasani N, Ab Rahim S, et al.

Cell Biochem Funct, 2017 Oct;35(7):453-463.
PMID: 29027248 DOI: 10.1002/cbf.3303

In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca2+ ]i ), and sphingosine-1-phosphate (S1P)-receptor via Gαi -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca2+ ]i , and S1P-Gαi -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl2 ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gαi inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl2 on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl2 -induced [Ca2+ ]i dynamic alteration. Pharmacological inhibition of the Gαi -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl2 detrimental effects, except for cell viability and [Ca2+ ]i . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl2 effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl2 -induced [Ca2+ ]i dynamic changes. We conclude that UDCA cardioprotection against CoCl2 -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gαi -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl2 -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.

Matched MeSH terms: Ursodeoxycholic Acid/pharmacology*
Fulltext Heart and bile acids - Clinical consequences of altered bile acid metabolism

Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, Williamson C

Biochim Biophys Acta Mol Basis Dis, 2018 04;1864(4 Pt B):1345-1355.
PMID: 29317337 DOI: 10.1016/j.bbadis.2017.12.039

Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids.

Matched MeSH terms: Ursodeoxycholic Acid/pharmacology; Ursodeoxycholic Acid/therapeutic use