Hyper-Homocysteinemia : A Potential Indicator of Acute Pancreatitis

AP (AP) is a common disease that features auto-digestion of the pancreas, and is the second highest cause of total hospital stays, the largest contributor to aggregate costs, and the fifth leading cause of in-hospital deaths [1-4]. Furthermore, patients with pancreatitis reportedly bear higher risk of developing pancreatic cancer [5,6]. Biliary disease and excessive alcohol consumption are the most common reasons for AP, but acute and chronic recurrent pancreatitis have also been reported in patients with varieties of concurrent metabolic disorders involving hyperlipidaemias, branched-chain amino acid degradation, homocystinuria, haemolytic, acute intermittent porphyria and several amino acid transporter defects [7]. For instance, hyperlipidaemia is one of the most common causes of AP, and triglyceride (TG) levels above 11.3 mmol/L (1000 mg/dl) are generally considered to put patients at high risks of developing pancreatitis [8,9]. Elevated plasma homocysteine concentrations had been reported to involve the development of arterial thrombosis and atherosclerosis [10]. Based on this point, high homocysteine levels may also be one cause of AP, endothelial dysfunction and impaired microvascular circulation. However, to date, little research was focused on the relationship between plasma homocysteine concentrations and AP [11,12]. Hence, we began our studies on the relationship between plasma homocysteine concentrations and AP and possibilities of the synergistic effect of plasma homocysteine levels and triglyceride levels on the occurrence of AP.


Introduction
AP (AP) is a common disease that features auto-digestion of the pancreas, and is the second highest cause of total hospital stays, the largest contributor to aggregate costs, and the fifth leading cause of in-hospital deaths [1][2][3][4]. Furthermore, patients with pancreatitis reportedly bear higher risk of developing pancreatic cancer [5,6]. Biliary disease and excessive alcohol consumption are the most common reasons for AP, but acute and chronic recurrent pancreatitis have also been reported in patients with varieties of concurrent metabolic disorders involving hyperlipidaemias, branched-chain amino acid degradation, homocystinuria, haemolytic, acute intermittent porphyria and several amino acid transporter defects [7]. For instance, hyperlipidaemia is one of the most common causes of AP, and triglyceride (TG) levels above 11.3 mmol/L (1000 mg/dl) are generally considered to put patients at high risks of developing pancreatitis [8,9]. Elevated plasma homocysteine concentrations had been reported to involve the development of arterial thrombosis and atherosclerosis [10]. Based on this point, high homocysteine levels may also be one cause of AP, endothelial dysfunction and impaired microvascular circulation. However, to date, little research was focused on the relationship between plasma homocysteine concentrations and AP [11,12]. Hence, we began our studies on the relationship between plasma homocysteine concentrations and AP and possibilities of the synergistic effect of plasma homocysteine levels and triglyceride levels on the occurrence of AP.

Subjects
Patients who met at least two of the three following clinical standards were diagnosed as AP bearers: abdominal pain; serum amylase above the upper reference limit of more than 3 times; positive ultrasonography or computed tomography scan. 160 patients (103 men, 57 women) diagnosed with AP in Henan Provincial People's Hospital, Henan Province, China, were recruited for this study. The study was approved by the ethical committees of Henan Provincial People's Hospital. Informed consents were obtained from all patients.

Methods
Information such as the tobacco habits and alcohol consumption of each individual was obtained from the records in the hospital or by faceto-face interviews. Blood samples of all the patients were taken within 24 hours after admission to the hospital. Serum levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and homocysteine were measured on an automatic biochemical analyzer (AU5400, Olympus Optical Co, Sizuoka, Japan). The patients were divided into two groups (Group 1 and Group 2) based their serum homocysteine concentration levels. Patients with high plasma homocysteine concentrations (C>15 µmol/L) were classified as Group 1 (50 men, 25 women), while the rest with normal plasma homocysteine concentrations (5 µmol/L ≤ C ≤ 15 µmol/L) were identified as Group 2 (53 men, 32 women). The clinical characteristics of Group 1 and 2 were shown in Table 1. Differences between groups were analyzed using Student's t test for continuous data and chi-square test for categorical data. The differences were regarded significant if the P value did not exceed 0.05. All analysis was performed using SPSS 19.0.

The association between hyper-homocysteinemia and AP
The results were shown in Table 1. Among all the 160 patients with AP, 75 patients (46.9%, Group 1) which made up a very high percentage were identified with increased plasma homocysteine levels. There were no significant differences of age, BMI, smoking or/and drinking status, serum HDL-C and LDL-C levels between the two groups.

The association between hyper-homocyteinemia and hyper-TG
Notably, the patients in Group 1 (bearing higher plasma homocysteine levels) had lower serum TG and TC levels compared with patients in Group 2 (bearing normal plasma homocysteine levels), with P=0.038 and P=0.046 respectively. In the contrast, there were more patients in Group 2 bearing hyper-TG and hyper-TC than in Group 1 (65.9%vs 52.0%, and 35.3%vs 25.3% respectively), despite that the differences were not large(P=0.079 and P=0.23 respectively).

Discussion
Among the 160 patients with AP, 59.4% of patients (95 persons) got hyper-TG, which was consistent with the previous research that people with hyper-TG were at high risk of getting AP [8,9,13]. And 46.9% of patients (75 persons) had higher plasma homocysteine levels, which, very possibly, indicated that higher plasma homocysteine levels could also increase the risks of suffering AP. This kind of association was rarely deeply studied and reported. Previously, Girish reported that chronic pancreatitis was associated, to some extent, with hyperhomocysteinemia, and that low folate levels maybe a key role in this derangement [12]. Yuzbasioglu reported that patients with AP had higher plasma homocysteine levels than subjects without AP [11]. The discovery in our studies that 46.9% of involved patients got hyperhomocysteinemia, was really consistent with the previous reports, and further demonstrated that a high level of plasma homocysteine is a risk factor for AP. And this high level of plasma homocysteine should be paid enough attention in the prevention of AP.
Moreover, we found that hyper-homocysteinemia and hyper-TG had no observed synergistic effects in patients with AP. Patients with hyper-homocysteinemia generally had lower TG and TC levels than those with normal homocysteine levels. According to some early reports [12,14], 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and low folate levels were supposed to be the main mechanism behind the up regulation of hyper-homocysteinemia in AP. Based on the mechanism, proper folate supplementation is helpful to lower homocysteine levels, resulting in the prevention of AP. And further confirmation of this hypothesis needs more studies to be done in the future.