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 |

New approaches in the therapy of hepatitis C in dialysis patients

Patients with renal disease are at increased risk of acquiring hepatitis C virus (HCV) infection because of their frequent exposure to blood from transfusions or exposure to HCV-contaminated medical equipment during hemodialysis.

The prevalence of anti-HCV antibodies among hemodialysis patients varies between 5-10% in the developed world, and 10-70% in developing countries. Acute hepatitis C is often mild and associated with few, if any symptoms. The major complication of acute HCV infection is chronic hepatitis, which occurs in up to 80% of the cases, the long-term outcome being cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma.

Interferon alpha (IFN-alpha) has shown activity against HCV. Twenty four to 48 week course of therapy with interferon could lead to a sustained loss of HCV RNA, normalization of alanine aminotrasferase (ALT) levels, and resolution of the liver disease. Sustained viral response was achieved in approximately half of the treated patients. Therapy with interferon was associated with a number of adverse events such as: "flu-like" symptoms, neurological, gastrointestinal symptoms, anemia, fatigue, thrombocytopenia, leucopenia. A major advance in therapy came with the addition of ribavirin to interferon therapy. Peginterferon-alpha-2a (40KD) is a new 'pegylated' subcutaneous formulation of interferon-alpha-2a, that was developed to improve the pharmacokinetic profile and therapeutic efficacy of interferon-alpha-2a. In our study, fourteen hemodialysis patients with chronic hepatitis C received 135 microg PEG-IFN alpha-2a subcutaneously, once a week, after dialysis session for a period of 48 weeks.

In the intention-to-treat analysis, sustained viral response was present in 36% of the patients (five out of fourteen patients) at the end of the follow up period. The biochemical response with normalization of serum ALT levels during the treatment was observed in all treated patients (83 +/- 20.1 U/L at base line vs. 23.4 +/- 4.6 U/L after the 48 weeks; p < 0.01). At present, therapy for hepatitis C should be considered in hemodialysis patients with significant liver disease, minimal other co morbidities, and a reasonable likelihood of prolonged survival or if renal transplantation is planned.

Sikole A, Dzekova P, Asani A, Amitov V, Selim G, Gelev S, Polenakovic M.
University Clinic of Nephrology, Skopje, R. Macedonia