Circulating MicroRNAs as a marker for liver injury in human immunodeficiency virus patients

Abstract

Human immunodeficiency virus (HIV) and hepatitis virus coinfection amplify and accelerate hepatic injury. MicroRNAs (miRNAs) are small regulatory RNAs suggested as biomarkers for liver injury. We analyzed the circulating levels of miRNAs in HIV patients with regard to the extent and etiology of liver injury. Total RNA was extracted from 335 serum samples of HIV patients and 22 healthy control participants using Qiazol. Comprehensive polymerase chain reaction (PCR) array analyses (768 miRNA) were performed in serum samples of eight HIV, eight HIV/HCV (hepatitis C virus), six HCV patients, and three healthy controls. Reverse transcription (RT)‐PCR measured levels of miRNA‐122, miRNA‐22, and miRNA‐34a in serum samples of 335 patients and 19 healthy control participants. Liver injury and fibrosis in these patients were defined using aspartate aminotransferase (AST) levels, fibrosis‐4 (FIB‐4) index and AST‐to‐platelet ratio index (APRI) score. The miRNA pattern of HIV/HCV samples showed altered expression of 57 and 33 miRNA compared to HCV and HIV infection, respectively. miRNA‐122, miRNA‐22, and miRNA‐34a were highly up‐regulated in HIV/HCV patients. Analyzing the entire cohort, these miRNAs were correlated with liver function tests and were independent predictors of liver injury (AST >2 × ULN). miRNA‐122 and miRNA‐22 were associated with relevant fibrosis (FIB‐4 >1.45; APRI >1). Circulating levels of miRNA‐122 were independent predictors for relevant fibrosis in HIV patients. Interestingly, miRNA‐122 and miRNA‐34a levels were higher in HIV/HCV patients, miRNA‐22 levels were highest in HIV/HBV patients, and circulating levels of miRNA‐34a correlated positively with illicit drug use and ethanol consumption. Conclusion: Circulating miRNA‐122, miRNA‐22, and miRNA‐34a correlates with the etiology of liver injury in HIV patients. These biomarkers not only mirror different mechanisms of hepatic injury, but also are independent predictors of liver injury in HIV patients. (Hepatology 2015;61:46–55)

Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation

“…For example, intracellular levels of miRNAs and/or levels of secretion may fluctuate at different stages of rejection, which may complicate interpretation of the data. For example, circulating liver-specific miRNA-122 is dramatically up-regulated during liver injury [69,70,71,72,73], but significantly down-regulated during late-stage hepatic cirrhosis [75] and hepatocellular carcinoma [76,77], due to intracellular down-regulation of miRNA production. Therefore, levels of certain circulating organ-specific miRNAs may be significantly up-regulated during acute rejection, but significantly down-regulated during chronic or late rejection.…”

“…In recent years, a large number of reports have been published indicating that circulating miR-122 can be applied as a non-invasive biomarker for a wide spectrum of clinical liver-specific diseases, including hepatic virus infections [61,62,63,64,65,66,67,68], liver injury [69,70,71,72,73], hepatic cirrhosis [74,75], and hepatocellular carcinoma [65,76,77] (reviewed in [60]). By reviewing the published papers, we have summarized the information, and it suggests that circulating miR-122 is the most frequent biomarker for liver disease (Figure 2).…”

“…Other circulating hepatic-abundant miRNAs could also serve as biomarkers for liver disease, such as miR-22 [71,78], miR-125b [64,65,68,79], miR-99a [65,68,80] and miR-192 [72,74,76,77] (Figure 2). It is worth noting that a panel of circulating miRNAs may enhance specificity and sensitivity [76,80], in which both liver-specific miRNAs and liver-abundant miRNAs might indicate a specific type of liver disease or dysfunction.…”

Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

“…RNA was isolated from samples using the Qiazol reagent as instructed by the manufacturer (Qiagen, Hilden, Germany) (Trebicka et al, 2013;Anadol et al, 2015). The following assays provided by Applied Biosystems (Foster City, USA) were used: ACTA2 (αSMA, Hs00426835_g1), COL1A1 (Hs00164004_m1), Src (Rn01418228_m1) PDGFRB (Hs01019589_m1), RHOA (for human; Hs01051295-m1), and RhoA (for rat; Rn04219609_m1).…”

miRNAs Expression Profiling, An Exploratory Method for Revealing First-Hand Biomarkers to Predict Disease Progression

“…As for example, circulating liver-specific miRNA-122 was found to be up-regulated on liver injury [28,32,33]; whereas, significantly down-regulated during late-stage hepatic cirrhosis [34] and hepatocellular carcinoma [35] due to intracellular down-regulation of miRNA production. Therefore, levels of certain circulating miRNAs may be significantly up-regulated during acute phases, or down-regulated thereafter.…”