https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61933-4.pdf

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.22906

Primary Biliary Cirrhosis

https://www.journal-of-hepatology.eu/article/S0168-8278(17)30186-1/pdf

EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.30145

Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases.

Monocarboxylate transporter (MCT) isoforms 1-4 catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane, whereas MCT8 and MCT10 are thyroid hormone and aromatic amino acid transporters, respectively. The importance of MCTs is becoming increasingly evident as their extensive physiological and pathological roles are revealed. MCTs 1-4 play essential metabolic roles in most tissues with their distinct properties, expression profile, and subcellular localization matching the particular metabolic needs of a tissue. Important metabolic roles include energy metabolism in the brain, skeletal muscle, heart, tumor cells, and T-lymphocyte activation, gluconeogenesis in the liver and kidney, spermatogenesis, bowel metabolism of short-chain fatty acids, and drug transport. MCT8 is essential for thyroid hormone transport across the blood-brain barrier. Genetic perturbation of MCT function may be involved in disease states such as pancreatic β-cell malfunction (inappropriate MCT1 expression), chronic fatigue syndromes (impairment of muscle MCT function), and psychomotor retardation (MCT8 mutation). MCT expression can be regulated at both the transcriptional and post-transcriptional levels. Of particular importance is the upregulation of muscle MCT1 expression in response to training and MCT4 expression in response to hypoxia. The latter is mediated by hypoxia inducible factor 1α and often observed in tumor cells that rely almost entirely on glycolysis for their energy provision. The recent discovery of potent and specific MCT1 inhibitors that prevent proliferation of T-lymphocytes confirms that MCTs may be promising pharmacological targets including for cancer chemotherapy.

https://iubmb.onlinelibrary.wiley.com/doi/epdf/10.1002/iub.572

The monocarboxylate transporter family—Role and regulation

BACKGROUND AND AIMS Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided. METHODS We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease. RESULTS There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52–68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38–4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34–3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31–10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease. CONCLUSIONS These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.

https://gut.bmj.com/content/gutjnl/48/3/397.full.pdf

HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility.

28 an international study evaluating the farnesoid x receptor agonist obeticholic acid as monotherapy in pbc

Objectives: many patients with primary biliary cirrhosis present for the first time aged over 65, but it is unclear whether the disease is different in older patients. We have examined presentation and mortality in relation to age at which primary biliary cirrhosis was first suspected clinically. Design: we identified 1023 patients from our regional primary biliary cirrhosis database with definite or probable primary biliary cirrhosis (689 definite); 397 (39%) presented aged $65. Definite primary biliary cirrhosis was defined as a positive antimitochondrial antibody titre $1/40, abnormal liver enzymes and compatible/diagnostic histology; probable as the presence of two of these indications. Results: there was no difference in presenting clinical features between the older and younger groups. Older patients were significantly less likely than younger to have had liver biopsy (50% vs 78%; P < 0:001). The 1023 patients had been followed for 8561 patient years. Follow-up was shorter (5.9 6 4 vs 9.8 6 5.5 years; P < 0:001) in the older group because of higher cumulative mortality (59% vs 33%; P < 0:001). Liver-related deaths were significantly commoner in the older group (18% vs 13%; P < 0:05). The mortality ratio for liver deaths (liver deaths per year of follow-up) was 2.4 times higher in the older group (0.031 vs 0.013). Conclusions: patients with primary biliary cirrhosis who are over and under 65 have similar features on presentation. The annual risk of liver death is 2.4 times higher in those presenting over 65, reaffirming the importance of age as an independent prognostic factor in an unselected primary biliary cirrhosis population.

Presentation and mortality of primary biliary cirrhosis in older patients.

Early assessment of safety and efficacy of tropifexor, a potent non bile-acid FXR agonist, in patients with primary biliary cholangitis: An interim analysis of an ongoing phase 2 study

Clarity: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Lopixibat Chloride (Formerly Lum001), a Novel Apical Sodium-Dependent Bile Acid Transporter Inhibitor, in the Treatment of Primary Biliary Cirrhosis Associated with Itching

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