Future Virology
Serum Carnitine Level and Its Associated Factors in Patients With Chronic Viral Hepatitis
Azin Nassiri, Simin Dashti-Khavidaki, Hossein Khalili*, Mohsen Nassiri-Toosi, Alireza AbdollahiDisclosures
Future Virology. 2014;9(4):373-383.
Discussion Only
Full Text Available @ Medscape
Carnitine is a nonessential amino acid, but an essential cofactor,[6] responsible for transferring long-chain free fatty acid through mitochondrial membranes.[7] The acyl moiety transferred into mitochondria matrix, goes under β-oxidation and ATP production.[53] Without a sufficient source of carnitine, ATP production through β-oxidation fails, resulting in lower energy available for the cells. In our study, serum level of carnitine was significantly lower in patients with chronic hepatitis compared with healthy individuals.
Several mechanisms have been proposed for carnitine deficiency in patients with viral chronic hepatitis. Appetite loss, which is a common complaint in patients with chronic hepatitis, is responsible for reduced dietary intake of carnitine and its precursors' amino acids from the food resources. This theory is supported by results of the present study. A significant positive correlation was founded between the carnitine serum level and carnitine dietary intake. In addition, viral particles in hepatocytes may interfere with the physiological synthetic pathway of carnitine from its precursors. Since the last step of carnitine synthesis (butyrobetaine hydroxylation), happens almost exclusively in the liver,[53,54] a decrease in hepatic function following viral infection, may lead to a decrease in serum carnitine level.[45] However, level of serum albumin and PT, representing as two indicators of liver biosynthesis function, were not disturbed in our patients. Comparing PT between the patients with and without carnitine deficiency was surprising. Patients with carnitine sufficiency had longer PT. Antithrombotic activity and reduced levels of CRP and plasma fibrinogen (Factor I) have been reported for carnitine. PT, as an indicator for activity of Factor I, II, V, VII and X, increased in patients with higher level of carnitine.[55,56]
In the current study, although carnitine deficiency was common in both patients with chronic hepatitis B or C infection, a more severe form of deficiency was detected in patients with chronic hepatitis B infection. This finding may be due to different responses of the immune system to the viral infections. Assembling and secretion of hepatitis C virus is the same as for the LDL pathway, and this virus can escape the adaptive immune system. In other hand, HBV is completely detected by the immune system.[57,58] Having an important role in immunomodulation, carnitine is consumed by the immune system cells to clear HBV.[59,60] It has been shown that carnitine deficiency may play a role in persistence of HBV infection. Increases in Th1-mediated cytokine production, resulted in a strict control on viral replication, whereas Th2-mediated cytokine production contributed to persistence of the virus.[61,62] HBV antigens tend to eliminate Th1 cells by Fas–FasL-mediated mechanisms, putting Th2 cells in charge of cytokine production.[63] Carnitine has shown promising effects on reducing Fas–FasL-related apoptosis, which in turn increased Th1 cell count and, consequently, better control of HBV infection.[64]
Even small numbers of the cirrhotic patients in our study, higher level of serum carnitine in this population was detected. This may be due to hepatocyte damage and following release of intra-hepatocyte carnitine into the bloodstream.[20] Reduction in carnitine clearance following kidney damage is another possible mechanism that may change serum carnitine levels in cirrhotic patients.[65] In most patients with advanced liver diseases, kidney function is disturbed to some extent.[66] In our study there was a positive but not significant correlation between the level of serum carnitine and serum creatinine. In the study by Krahenbuhl et al., the authors also reported a positive association between serum carnitine and serum creatinine.[48] However the level of serum creatinine was the same between the healthy control group (with normal carnitine level) and the cirrhotic patients (with high carnitine levels). Third, increase in carnitine synthesis in sites other than the liver may be another factor that cause elevated carnitine levels in chronic hepatitis. The first step for biosynthesis of carnitine is methylation of lysil, which is naturally in protein bound to skeletal muscles,[67] and should be released by proteolysis.[53,54] As a result, increased muscle turnover, provides new resources for lysine and can increase carnitine synthesis. Increased skeletal muscle turnover was reported in patients with advanced liver diseases.[68,69]
There are few studies with respect of evaluating serum carnitine status in patients with viral hepatitis; nonetheless, the results of these studies are very conflicting, and in some cases are even controversial. In the most recent study in 2010, by Anty et al. serum carnitine level has been evaluated in patients with chronic hepatitis C.[36] In agreement with our findings, lower serum carnitine level in these patients compared with normal subjects was reported. The exact pathological mechanism of such deficiency was not investigated, but the authors proposed that the presence of the virus in hepatocytes disturbs synthetic capacity of the liver, resulting in low serum level of carnitine.
The other study by Malaguarnera et al. supported this finding as well. In the mentioned study, serum carnitine level was measured before and after therapy with IFN-α. Serum carnitine level, which was low prior to therapy, was elevated but did not reach the normal level after treatment.[70]
Owing to the important effect of carnitine in energy production, it is proposed that deficiency of this substance may play a key role in developing fatigue. Based on this theory, Kurastune et al. evaluated serum level of carnitine in various diseases with the common manifestation of fatigue. Significant decrease in serum carnitine levels in patients with chronic fatigue syndrome and chronic hepatitis C, but not in other diseases, was detected.[37]
These findings were in contrary with the results of a study by Eskandari et al..[20] In patients with chronic viral hepatitis type B and C, they showed an elevated level of serum carnitine in comparison with the healthy control group. They proposed that the leakage of intracellular carnitine from damaged hepatocyes into the bloodstream was responsible for this elevation. The leakage results in lower level of active carnitine within the cells and subsequently decreases β-oxidation of the free fatty acids, and causes an increase in serum triglyceride level.[20] We also detected a reverse correlation between serum concentrations of carnitine and triglyceride in patients with chronic hepatitis and the level of TG was significantly higher in carnitine-deficient patients. One underestimated issue in Eskandari's study was that it was not specified whether participants suffered from liver cirrhosis or not, since the stage of the liver disease has a crucial impact on the serum level of carnitine.[48]
Kranhenbul et al. evaluated serum carnitine level in cirrhotic and noncirrhotic liver diseases.[48] They found that serum carnitine level in noncirrhotic patients and the healthy controls was the same and in cirrhotic patients was 29% higher than the control group. They did not evaluate serum carnitine level in different subgroups of cirrhosis (e.g., viral hepatitis, autoimmune hepatitis and cryptogenic cirrhosis).[71] This finding supported the results of two other studies by Amodio et al. [72] and Palombo et al.,[73] in which the reported serum levels for carnitine were higher in end-stage liver diseases with different causes. In our study, cirrhotic patients compared with noncirrhotic patients had a higher level of serum carnitine but l-carnitine level was still lower than that of the healthy controls.
In addition to the stage of the liver disease, it is proposed that the duration of viral infection has an important effect on serum carnitine level. All of the patients included in our study had chronic viral hepatitis and at least 6 months had elapsed after infection. Serum carnitine level seems to be much different in acute phase of hepatitis. In the study of Kuratsune et al., acute hepatitis was induced in mice by galactosamine administration.[37] Following induction of acute hepatitis, serum carnitine level was significantly higher in comparison with the level of control group.
Although number of patients suffering from liver cirrhosis was small (22 out of 86 patients) in our study, but serum carnitine level was significantly higher in cirrhotic than noncirrhotic patients. As mentioned above, several studies confirmed that cirrhosis can significantly alter serum carnitine concentration; as a result, further studies regarding Iranian cirrhotic patients must be carried to make a conclusion. Another important issue is that we evaluated the total serum carnitine. Carnitine is present in bloodstream as two different forms; free carnitine (without an attached acyl group) and esterified carntitine (which is attached to an acyl group with carbon chain of various lengths).[53] The ratio of these two different forms of this compound is a reflection of hepatic acylation, which is important in fatty acid oxidation.[74] In hepatic diseases, levels of acyl-carnitine, free carnitine and total carnitine tend to alter differently and even in opposite patterns. This difference should be noted in future studies. Also, due to our small sample size we could not subdivide patients according to their treatment regimen and duration of therapy. Also carnitine dietary intake was calculated through estimations and differences in cooking methods can alter the amount of carnitine in foods dramatically.
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