Liver function declines with increased age

Cieslak, Kasia P.; Baur, O; Verheij, Joanne; Bennink, Roelof J.; Gulik, Thomas M. van

doi:10.1016/j.hpb.2016.05.011

Cited by 79 publications

(61 citation statements)

References 26 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such studies confirmed that like chromosomal alterations also base substitution mutations accumulate with age in human brain (8,9), intestine and liver (4).Due to its high metabolic and detoxification activity liver is more likely to be adversely affected by various damaging agents than most other organs. In humans this may cause agerelated loss of function, most notably a severe reduction in metabolic capacity and multiple pathologies, including fatty liver disease, cirrhosis, hepatitis, infections and cancer (10,11). To test if somatic mutations occur with a high frequency and accumulate rapidly with age we performed WGS on single primary hepatocytes from human donors varying in age between 5 months and 77 years of age.…”

mentioning

confidence: 99%

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Brazhnik

Sun

Alani

et al. 2019

Preprint

View full text Add to dashboard Cite

Accumulating somatic mutations have been implicated in age-related cellular degeneration and death. Because of their random nature and low abundance, somatic mutations are difficult to detect except in single cells or clonal lineages. Here we show that in single hepatocytes from human liver, an organ normally exposed to high levels of genotoxic stress, somatic mutation frequencies are high and increase substantially with age. Significantly lower mutation frequencies were observed in liver stem cells and organoids derived from them. These results could explain the increased age-related incidence of liver disease in humans and stress the importance of stem cells in maintaining genome integrity.Genome integrity is critically important for cellular function. Evidence has accumulated that loss of genome integrity and the increasingly frequent appearance of various forms of genome instability, from chromosomal aneuploidy to base substitution mutations, is a hallmark of aging (1, 2). However, somatic mutations occur de novo across cells and tissues and are of low abundance. Hence, thus far, of all mutation types only chromosomal alterations could readily be studied directly during in vivo aging using cytogenetic methods (3). More recently it has become possible to also study low-abundant somatic mutations by whole genome sequencing (WGS) of single cells or clones derived from single cells (4-7). Such studies confirmed that like chromosomal alterations also base substitution mutations accumulate with age in human brain (8,9), intestine and liver (4).Due to its high metabolic and detoxification activity liver is more likely to be adversely affected by various damaging agents than most other organs. In humans this may cause agerelated loss of function, most notably a severe reduction in metabolic capacity and multiple pathologies, including fatty liver disease, cirrhosis, hepatitis, infections and cancer (10,11). To test if somatic mutations occur with a high frequency and accumulate rapidly with age we performed WGS on single primary hepatocytes from human donors varying in age between 5 months and 77 years of age. These cells were isolated from healthy human individuals shortly after death through perfusion of whole donor livers (Lonza Walkersville Inc.). Cell viability was higher than 80% and, after staining with Hoechst, hepatocytes were isolated via FACS into individual PCR tubes as diploid single cells (Fig. S1). In total we sequenced 4 single hepatocytes and bulk genomic liver DNA for each of eight human donors (Table S1). Each cell was subjected to our recently developed procedure for whole genome amplification (WGA) and sequencing (5,6). Somatic single nucleotide variants (SNVs) in single cells were identified relative to bulk genomic DNAs at a depth of ≥ 20X using a combination of VarScan2, MuTect2 and Haplotypecaller software with certain modifications (Methods , Table S2). Overlapping mutations, revealed by all three analytical tools, were exclusively considered for further analysis.After adjusting for genomic ...

show abstract

mentioning

confidence: 99%

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Brazhnik

Sun

Alani

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Apart from the influence of life expectancy, elderly patients with HCC are generally characterized by age-related deterioration of liver function and higher incidences of comorbidities, which are related to higher perioperative risk. [ 8 31 ] Considering these characteristics, the advantages of RFA over SR, such as minimal invasiveness, less blood loss, lower perioperative risk, and fewer deteriorative effects on liver function, must not be overlooked. [ 13 24 32 ] In addition, tumor diameter ≤3 cm is deemed as a favorable prognostic factor for both OS and LCSS, and several studies have proved that RFA can provide comparable survival rates to SR for selected patients with HCC with single tumors ≤3 cm in diameter, if a patient's performance status, tumor location, and underlying liver function are considered.…”

Section: Discussionmentioning

confidence: 99%

“…However, as a unique group, elderly patients with HCC are generally characterized by age-related deterioration of liver function and higher incidences of comorbidities. [ 8 ] Therefore, RFA has been established as the most common alternative treatment for elderly patients with small HCC because of its excellent antitumor effect and its advantage of less invasiveness, lower perioperative risk, and fewer deteriorative effects on liver function than SR.[ 9 ] Nevertheless, RFA has a significant drawback of limited ablative margins, which is associated with high risk of marginal recurrence. [ 10 ] With advancement of surgical techniques and perioperative management, feasibility, safety, and effectiveness of SR for selected elderly patients with early-stage HCC have been widely identified in the past decade.…”

Section: Introductionmentioning

confidence: 99%

Radiofrequency ablation versus surgical resection in elderly patients with early-stage hepatocellular carcinoma in the era of organ shortage

Ding

Liao

et al. 2018

Saudi J Gastroenterol

View full text Add to dashboard Cite

Background/Aims:To compare the survival benefits of surgical resection (SR) with those of radiofrequency ablation (RFA) in elderly patients (≥65 years) with single hepatocellular carcinoma (HCC) ≤5 cm.Patients and Methods:Using the Surveillance, Epidemiology, and End Results database, a total of 461 patients who underwent SR and 575 patients who underwent RFA were enrolled from 2004 to 2012. Overall survival (OS) and liver-cancer-specific survival (LCSS) comparisons were conducted between the two groups before and after propensity score matching (PSM).Results:Elderly patients with early-stage HCC had a lower rate of utilization of liver transplantation, and they were more likely to receive SR or RFA as their first-line treatment compared with younger patients (P < 0.05). In the whole cohort, the SR group had significantly better OS [RFA, hazard ratio (HR) = 1.680 (1.390, 2.031), P < 0.001] and LCSS (RFA, HR = 1.658 (1.327, 2.070), P < 0.001) than the RFA group. After PSM, the improved survival in the SR group was further confirmed (all P < 0.001). In the subgroup analyses, according to patients' age (65–75, >75 years) and tumor size (≤3.0, 3.1–5.0 cm), the SR group still presented better OS and LCSS than the RFA group (all P < 0.05), except for those older than 75 years with tumors ≤3.0 cm (all P > 0.05), both before and after PSM.Conclusion:Treatment strategies for elderly patients (≥65 years) with single HCC ≤5 cm should emphasize SR as the primary therapy, while RFA can be an alternative to SR for those >75 years with single HCC ≤3 cm.

show abstract

“…Xie et al [ 27 ] found that the mortality of HBV related liver failure increased markedly with increasing age ≥ 35 years in males and ≥ 55 years in females. In patients with chronic liver disease, liver function deteriorates with age and the regenerative capacity of the liver declines [ 28 ]. The older patients are more easily combined with complications because of low immunity.…”

Section: Discussionmentioning

confidence: 99%

Prognostic nomogram for acute-on-chronic hepatitis B liver failure

et al. 2017

View full text Add to dashboard Cite

Background & AimsTo establish an effective prognostic nomogram for acute-on-chronic hepatitis B liver failure (ACHBLF).Materials and MethodsThe nomogram was based on clinical data of 203 ACHBLF patients who admitted to the First Affiliated Hospital of Fujian Medical University from 2009 to 2014. The area under the receiver-operating characteristic curve (AUC) and calibration curve were carried out to verify the predictive accuracy ability of the nomogram. The result was validated in internal and external validation cohorts. Kaplan-Meier survival curve was used in survival analysis.ResultsWe developed a new prognostic nomogram to predict 3-month mortality based on risk factors selected by multivariate analysis. This nomogram consisted three independent factors: age, liver to abdominal area ratio (LAAR) and model for end-stage liver disease (MELD) score. The AUC of this nomogram for survival prediction was 0.877 (95% CI 0.831–0.923), which was higher than that of MELD score, MELD-Na and Child-Turcotte-Pugh (CTP). Good agreement of calibration plot for the probability of survival at 3-month was shown between the prediction by nomogram and actual observation. These results were supported by internal and external validation studies.ConclusionsThe ACHBLF nomogram could predict the short-term survival for ACHBLF patients.

show abstract

Liver function declines with increased age

Abstract: This study shows that liver function deteriorates with age. Since the regenerative capacity of the liver correlates with liver function, this finding should be taken into account when assessing surgical risk in patients considered for major liver resection.

Cited by 79 publications

References 26 publications

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver

Radiofrequency ablation versus surgical resection in elderly patients with early-stage hepatocellular carcinoma in the era of organ shortage

Prognostic nomogram for acute-on-chronic hepatitis B liver failure

Contact Info

Product

Resources

About