Regular daily drinking is more likely to result in liver damage than intermittent drinking. The longer this pattern is maintained, the more likely it is that alcoholic hepatitis, and subsequently cirrhosis, will develop[ ¹]. In patients with cirrhosis, the incidence of esophageal varices increases by nearly 5% per year, and the rate of progression from small to large varices is approximately 5%-10% per year[ ^{2 3}]. Bleeding from esophageal varices is common among patients with cirrhosis. Bleeding from varices may occur in 15%-68% of patients with varices[ ⁴]. Variceal hemorrhaging is associated with a high mortality and with high hospital costs[ ⁵]. Both, beta-blockers and endoscopic procedures, have been established as effective preventive modalities for variceal hemorrhage[ ^{5 6}]. Therefore, the early detection of esophageal varices is critical for the effective prevention of variceal hemorrhage[ ⁷]. Adding an accurate serum marker for hepatic fibrosis to the model may improve the diagnostic accuracy in predicting esophageal varices without performing liver biopsy. Moreover, developing an accurate non-invasive diagnostic model might also decrease the costs for the prevention of hemorrhaging from varices[ ⁷].

Twenty-five patients (56.8%) had esophageal varices, and 19 (43.2%) had no varice (Figure 1). A univariate analysis revealed a significant difference between patients with and without esophageal varices with regard to age and type IV collagen levels (Table 1 and Figure 2).

These two variables that were significantly linked to the presence of esophageal varices in the univariate analysis, and a factor previously reported[ ¹¹], age, PT, and type IV collagen, were assessed by multivariate analysis. A logistic regression analysis identified type IV collagen as the only independent variable predictive for esophageal varices ( P = 0.017) (Table 2). Whenever the type IV collagen level raised every 150 ng/mL, the odds ratio of esophageal varices doubled.

Figure 3 shows the positive predictive values at each cut off point of type IV collagen. The positive predictive value of esophageal varices with a type IV collagen value > 900 ng/mL ( n = 6) was 100%.

Finally, the area under the curve (AUC) of type IV collagen as determined by ROC for predicting the presence of esophageal varices was 0.78 (Figure 4).

A rupture of esophageal varices is the most frequent complication of portal hypertension, occurring in one third of all cirrhotic patients, and is associated with a high mortality[ ^{12 13}]. The mortality rate from variceal bleeding is about 20% when patients are treated optimally in a hospital[ ¹⁴]. However, an appreciable proportion of patients with variceal bleeding die before reaching the hospital[ ¹⁵]. Numerous studies have shown that the prevention of UGI bleeding and early detection of esophageal varices reduces mortality, morbidity, and health care costs[ ¹⁶]. Nevertheless, Suzuki et al demanded further studies to determine which strategies are the most beneficial to patients and society in terms of preventing and treating esophageal varices, in a recent article[ ⁷]. We thus examined potential esophageal varice prediction factors for SAD on a medical checkup level.

In this study, a non-invasive marker for hepatic fibrosis (type IV collagen) had a high diagnostic accuracy for the detection of esophageal varices. The combination of abdominal ultrasound scan and this marker correctly identified, at a high rate, patients with esophageal varices. These examinations can be conducted on a medical checkup level, so we considered this approach to be of considerable diagnostic value.

A previous report showed the type IV collagen concentration was the most accurate in correctly identifying patients with severe histologic alcoholic hepatitis. At a cut-off of 150 ng/mL, type IV collagen was 89% sensitive and 77% specific[ ¹⁷]. First, patient sorting was conducted via the abdominal ultrasound test in this study. The alcoholic patients with splenomegaly and/or withering of the right liver lobe participated in this study. In these 44 patients, the value of type IV collagen was > 150 ng/mL in all specimens. As a result, when suspecting SAD, we thought it very meaningful to add the abdominal ultrasound test to the characteristics under evaluation.

In a previous report, Geoffroy and colleagues demonstrated that the independent factors of prothrombin index, alkaline phosphatase activity, and hyaluronate level predicted the presence of esophageal varices[ ¹¹]. Nevertheless, their proposed model included two age-dependent serum markers, hyaluronate and alkaline phosphatase, both of which rise in serum with aging[ ¹⁸]. We therefore added only the prothrombin index as an examination item. Moreover, another report demonstrated a rise in amino-terminal procollagen III peptide (PIIINP) following alcohol withdrawal that is likely to be caused by intact PIIINP[ ¹⁹]. We thus decided not to include this fibrosis marker as an examination item at the time of hospitalization. Finally, we elected to add GTP and collagen type IV as examination items.

The serum concentration of laminin and type IV collagen have been reported to be increased in patients with alcoholic hepatitis and to correlate with the degree of inflammation[ ²⁰– ²⁶]. In our study, logistic regression identified type IV collagen as the only independent variable predictive for esophageal varices. While based on the findings of these studies, laminin may be predictive for esophageal varices. However, the use of such testing is not covered by the national health insurance program in Japan, so we decided to exclude laminin from this study. We therefore hope that further study of esophageal varices in other countries will help to elucidate and confirm the predictive potential of laminin.

Antler et al found that in younger patients, the most common bleeding sites are those associated with alcoholism (esophageal varices, Mallory-Weiss tears, and hemorrhagic gastritis), accounting for 40%-60% of lesions in patients less than 55 years-of-age[ ²⁷]. Another report demonstrated that younger patients had a trend toward more variceal bleeds ( P = 0.39)[ ²⁸]. In our research, there was a positive correlation of esophageal varices with younger age ( P > 0.05). We think that younger alcoholic patients with high fibrosis markers should be evaluated by GI endoscopy.