Monday

Dynamic length changes of telomeres and their nuclear organization in chronic myeloid leukemia

Cancers (Basel). 2013 Aug 22;5(3):1086-102. doi: 10.3390/cancers5031086.

 

Samassekou O.

Source

Manitoba Institute of Cell Biology, Cancer Care Manitoba, Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada. samasseo@cc.umanitoba.ca.

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression

Wednesday

Serum Transaminase Levels in Boys With Duchenne and Becker Muscular Dystrophy

OBJECTIVE: Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels are commonly used as biochemical indicators of hepatocellular injury but can also detect occult muscle disease. High concomitant serum creatine phosphokinase (CPK) levels can point to muscle as the source of high transaminase levels. Nevertheless, clinicians may be reluctant to attribute high transaminase levels to muscle.

METHODS: Study patients were boys with a genetic or biopsy-confirmed dystrophinopathy whose concomitant serum CPK, ALT, and AST levels were measured.

RESULTS: We report 82 enzyme data sets from 46 patients with Duchenne muscular dystrophy (DMD) and 9 with Becker muscular dystrophy. Our results show a linear relationship between serum CPK and serum ALT and AST and a logarithmic relationship between serum enzyme levels and age for boys with DMD. We developed a mathematical model to predict serum ALT and AST levels when the serum CPK level and age are known. For 6 boys, initial failure to consider muscle as a cause of high transaminase levels led to delay of diagnosis and extensive testing for hepatic dysfunction. A second group of 4 boys with known DMD were investigated for liver disease after high transaminase levels were detected. Serum transaminase levels were highest in ambulant boys with DMD, whose levels reached 1220 U/L (ALT) (22.6 times higher than upper-limit normal levels) and 801 U/L (AST) (12.3 times higher than upper-limit normal levels).

CONCLUSIONS: By recognizing muscle as a potential source of serum transaminase levels, clinicians can avoid unnecessary and invasive procedures, expedite clinical diagnosis, and avoid unnecessary cessation of concomitant drug therapy.

Monday

Serum Transaminase Levels in Boys With Duchenne and Becker Muscular Dystrophy

OBJECTIVE Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels are commonly used as biochemical indicators of hepatocellular injury but can also detect occult muscle disease. High concomitant serum creatine phosphokinase (CPK) levels can point to muscle as the source of high transaminase levels. Nevertheless, clinicians may be reluctant to attribute high transaminase levels to muscle.

METHODS Study patients were boys with a genetic or biopsy-confirmed dystrophinopathy whose concomitant serum CPK, ALT, and AST levels were measured.

RESULTS We report 82 enzyme data sets from 46 patients with Duchenne muscular dystrophy (DMD) and 9 with Becker muscular dystrophy. Our results show a linear relationship between serum CPK and serum ALT and AST and a logarithmic relationship between serum enzyme levels and age for boys with DMD. We developed a mathematical model to predict serum ALT and AST levels when the serum CPK level and age are known. For 6 boys, initial failure to consider muscle as a cause of high transaminase levels led to delay of diagnosis and extensive testing for hepatic dysfunction. A second group of 4 boys with known DMD were investigated for liver disease after high transaminase levels were detected. Serum transaminase levels were highest in ambulant boys with DMD, whose levels reached 1220 U/L (ALT) (22.6 times higher than upper-limit normal levels) and 801 U/L (AST) (12.3 times higher than upper-limit normal levels).

CONCLUSIONS By recognizing muscle as a potential source of serum transaminase levels, clinicians can avoid unnecessary and invasive procedures, expedite clinical diagnosis, and avoid unnecessary cessation of concomitant drug therapy.

Hugh J. McMillan, MD, MSca, Matt Gregas, PhDb, Basil T. Darras, MDa, Peter B. Kang, MDa

a Department of Neurology and
b Clinical Research Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Wednesday

The Association of Alanine Transaminase With Aging, Frailty, and Mortality

The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53–2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45–5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging

THERE are several reasons why blood tests of liver function and injury might be associated with age and mortality in older people. First, nonalcoholic fatty liver disease (NAFLD) secondary to obesity is associated with increased mortality and morbidity (1), and in modern societies, overweight and obesity tend to become more prevalent in older people (2). In fact, NAFLD is now one of the most common liver diseases in the Western world, directly as a consequence of the obesity epidemic. One of the key clinical markers of fatty liver is raised blood activity of alanine transaminase (ALT), which is an enzyme released from damaged hepatocytes (1). Yet, there has been at least one report suggesting that ALT decreases with old age (3). The relationship between ALT and obesity in older people and the implication for survival in older people remain unclear.
Furthermore, many studies have reported that the metabolic and detoxification functions of the liver are decreased in old age, although this is controversial (4–6). Because of the role of the liver in regulating systemic metabolism and protecting the body from circulating endogenous and exogenous toxins, any age-related change in liver function has implications for age-related conditions and diseases. Despite the potential significance of liver function in aging, the impact of old age on blood markers of liver injury and liver disease including ALT, gamma-glutamyl transferase (GGT), and bilirubin have not been established in old age, particularly in very elderly people. On the other hand, albumin, which is synthesized by the liver, has been investigated widely. Low albumin is associated with aging, frailty, and reduced survival (7–10), although this might reflect systemic inflammation rather than impaired hepatic function (7,10).
For these reasons, we hypothesized that blood liver function tests will be associated with age and subsequent mortality in older people. In particular, we focused on ALT as a marker of general liver injury and more specifically as a marker of fatty liver, which is associated with obesity. As part of this process, we also describe the changes in liver function tests and body composition in elderly men.


In conclusion, low circulating ALT activity was found to be associated with aging and frailty in old men and to be a predictor of their subsequent survival. The effect of ALT on mortality was mediated via its association with frailty and aging. ALT may be a useful biomarker for aging and frailty and should be considered for future studies, especially because the decrease in ALT with age and frailty was greater than that seen with albumin. However, it must be acknowledged that the mechanisms for the associations that we have reported here remain unclear.

This work was supported by the Australian National Health and Medical Research Council (NHMRC Project Grant No. 301916 and 512364), the Ageing and Alzheimer’s Research Foundation, and the Medical Foundation of the University of Sydney.

Alanine Aminotransferase, Metabolic Syndrome, and Cardiovascular Disease: A Missing Link?

Chia-Chi Wang MD1 and Jia-Horng Kao MD, PhD2

1Department of Hepatology, Buddhist Tzu Chi General Hospital, Taipei Branch and School of Medicine, Tzu Chi University, Hualien, Taiwan
2Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan

published to the editor:
We read with great interest the article by Olynyk et al. (1). In this population-based cohort study, whether elevated alanine aminotransferase (ALT) concentration could predict metabolic syndrome (MS) or cardiovascular disease (CVD) was investigated. Olynyk et al. found a strong association between baseline ALT concentration and MS, independent of insulin resistance. However, serum ALT levels did not seem to contribute to the risk of CVD. Although their results provided additional data to this area of active investigation, several issues deserve further discussion.

First, previous studies have shown similar findings regarding the relationship between serum ALT activity and MS. However, the lack of association of serum ALT levels with the risk of CVD was contradictory to recent reports. In the Hoorn study on an elderly population, a positive association between serum ALT and coronary heart disease events was observed even after adjustment for the components of MS and traditional risk factors (2). In another 20-year follow-up study, higher ALT levels were significantly associated with incident CVD in age-/gender-adjusted models, but this association was attenuated on multivariable adjustment (3). These discrepant findings may be attributed to the more stringent definition of incident CVD, younger participants, or to shorter follow-up period. In this study by Olynyk et al., incident CVD events were ascertained only from hospital admission or death records. However, CVD such as angina pectoris could possibly have been diagnosed and treated by primary care physicians without admission. Therefore, incident CVD events might be underestimated in this study.

Second, nonalcoholic fatty liver disease has been recognized as the hepatic manifestation of MS, by which the risk of CVD could be predicted. On the basis of time to development, CVD may be a later manifestation of MS compared with nonalcoholic fatty liver disease. Therefore, it is possible to show positive results among these parameters in case larger or elderly populations, longer follow-up periods, or more sensitive tests to define the risk of CVD could be adopted in future studies. In a cross-sectional analysis using the Framingham risk score to estimate the 10-year risk of coronary heart disease (4), elevated serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption was found to be associated with increased calculated risk of coronary heart disease.

In summary, serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption serves not only as a marker of nonalcoholic fatty liver disease but also as a possible predictor of MS and CVD (5).

1.Olynyk JK, Knuiman MW, Divitini ML et al. Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population. Am J Gastroenterol 2009;104:1715–1722. | Article | PubMed | ChemPort |
2.Schindhelm RK, Dekker JM, Nijpels G et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007;191:391–396. | Article | PubMed | ChemPort |
3.Goessling W, Massaro JM, Vasan RS et al. Aminotransferase levels and 20-year risk of metabolic syndrome, diabetes, and cardiovascular disease. Gastroenterology 2008;135:1935–1944. | Article | PubMed | ChemPort |
4.Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006;43:1145–1151. | Article | PubMed | ChemPort |
5.Wang CC, Lin SK, Tseng YF et al. Elevation of serum aminotransferase activity increases risk of carotid atherosclerosis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2009;24:1411–1416. | Article | PubMed | ChemPort |

Tuesday

Hepatic enzymes have a role in the diagnosis of hepatic injury after blunt abdominal trauma

Injury, Volume 40, Issue 9, Pages 978-983
K. Tan, S. Bang, A. Vijayan, M. Chiu

Introduction: Delayed diagnosis of patients with severe liver injuries is associated with an adverse outcome. As computed tomographic (CT) scan is not always available in the management of blunt abdominal trauma worldwide, the present study was undertaken to determine the accuracy of selected haematological markers in predicting the presence of hepatic injury and its severity after blunt abdominal trauma.

Methods: A retrospective review of all patients with blunt abdominal trauma presented to our institution over a 3-year period was performed. Patients were excluded if they suffered penetrating injuries, died in the emergency department or if the required blood tests were not performed within 24h of the accident. The grading of the hepatic injury was verified using CT scans or surgical findings.

ResultsNinety-nine patients with blunt abdominal trauma had the required blood tests performed and were included in the study. The median injury severity score was 24 (range 4–75). Fifty-five patients had hepatic injuries, of which 47.3% were minor (Grades I and II) while 52.7% had major hepatic injuries (Grades III–V). There were no patients with Grade VI injuries.

A raised Alanine Transaminase (ALT)(sGPT) was strongly associated with presence of hepatic injuries (OR, 109.8; 95% CI, 25.81–466.9). This relation was also seen in patients with raised AST>2 times (OR, 21.33; 95% CI, 7.27–62.65). This difference was not seen in both bilirubin and ALP.

Alanine Transaminase ALT>2 times normal was associated with major hepatic injuries (OR, 7.15; 95% CI, 1.38–37.14; p=0.012) while patients with simultaneous raised AST>2 times and ALT>2 times had a stronger association for major hepatic injuries (OR, 8.44; 95% CI, 1.64–43.47).

Conclusion: Abnormal transaminases levels are associated with hepatic injuries after blunt abdominal trauma. Patients with (GPT) ALT and (GOT) AST>2 times normal should be assumed to possess major hepatic trauma and managed accordingly. Patients with normal ALT, AST and LDH are unlikely to have major liver injuries.

Thursday

Alanine aminotransferase, gamma-glutamyltransferase (GGT) and all-cause mortality: results from a population-based Danish twins study alanine aminotra

Fraser A, Thinggaard M, Christensen K, Lawlor DA.
Department of Social Medicine, MRC Centre for Causal Analysis in Translational Epidemiology, University of Bristol, Bristol BS8 2BN, UK.

Alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) are widely used markers of liver disease. Several population-based cohort studies have found associations of these liver enzymes with all-cause mortality. None of these studies controlled for genetic variation as well as fetal and early life exposure, whether environmental or genetic. Methods: We studied the associations of ALT and GGT with all-cause mortality using data for 686 twins (73-94 years old) included in the Longitudinal Study of Aging Danish Twins.

Results: An increase in 1 logged U/L of GGT was associated with a 15% increase in the hazard ratio (HR) for mortality [95% confidence interval (CI) 0.99, 1.32] but there was no strong evidence of an association of ALT with all-cause mortality (HR=1.07, 95% CI 0.82, 1.40) when controlling for potential confounders. In this analysis, the study population was treated as individuals, with similarities between twins accounted for by using robust standard errors.

However, an intrapair analysis in which the proportion of twin pairs in which the twin with the higher level of ALT or GGT died first was compared with 50% (expected under the null hypothesis), found no strong evidence that higher ALT or GGT was associated with earlier death within twin pairs; the results were consistent in both monozygotic and dizygotic twins.

Conclusions: gamma-glutamyltransferase but not ALT predicts mortality among older Danish twins when using traditional methods for controlling for potential confounders and existing diabetes and cardiovascular disease. Environmental developmental origins may explain the association, but larger twin studies are required to replicate our findings