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Abstract
Background:
The direct/total (d/t) bilirubin ratio can be used to distinguish the causes of jaundice in many patients who have increased levels of direct and indirect bilirubin. However, the reference range of the d/t ratio has not been established, hindering its clinical usefulness. This study assessed the clinical usefulness of the d/t ratio.
Methods:
Paired total bilirubin and direct bilirubin tests (N=4,357) of cholestasis, hemolytic anemia, and neonatal jaundice were evaluated. Regression analyses were performed between total bilirubin and direct bilirubin, and between total bilirubin and the d/t ratio for each disease. Theoretical correlation models were established and used to compare the regression analyses data.
Results:
The theoretical model and regression equation between total bilirubin and direct bilirubin displayed linear correlations for all three cholestatic diseases. The model and regression equation between total bilirubin and the d/t ratio showed reciprocal curve correlations for the cholestatic diseases. When the total bilirubin concentration exceeded approximately 10 mg/dL, the rate of change of the d/t ratio decreased and converged to a constant value between 0.7 and 0.9.
Conclusions:
If the total bilirubin concentration exceeds 10 mg/dL, cholestatic diseases can be diagnosed if the d/t ratio is more than 0.7. However, if the total bilirubin concentration is lower than 10 mg/dL, cholestatic diseases should be considered even if the d/t ratio is lower than 0.7. Therefore, use of the d/t ratio with total bilirubin could prove to be valuable in clinical settings.
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Fig. 1.
Correlations between total bilirubin and direct bilirubin concentrations (A) and between total bilirubin concentration and d/t ratio (B) in patients with cholestasis.
Fig. 2.
Theoretical correlations between total bilirubin and direct bilirubin concentrations (A) and between total bilirubin concentration and d/t ratio (B) in cholestasis.
Fig. 3.
Correlations between total bilirubin and direct bilirubin concentrations in patients with hemolytic anemia (A) and neonatal jaundice (B), and between total bilirubin concentration and d/t ratio in patients with hemolytic anemia (C) and neonatal jaundice (D).
Fig. 4.
Theoretical correlations between total bilirubin and direct bilirubin concentrations (A) and between total bilirubin concentration and d/t ratio (B) in hemolytic anemia and neonatal jaundice.
Table 1.
Characteristics of patients with cholestasis, hemolytic anemia, and neonatal jaundice
| Disease | Number of cases | Age, year∗ | Total bilirubin | Direct bilirubin | Indirect bilirubin | d/t ratio† |
|---|---|---|---|---|---|---|
| (Male/Female) | (mg/dL)† | (mg/dL)† | (mg/dL)† | |||
| Cholestasis | 4,302 (2,876/1,426) | 53.72±13.66 | 5.3, 8.1 | 3.3, 6.2 | 1.9, 2.0 | 0.63, 0.25 |
| Intrahepatic cholestasis | 3,553 (2,432/1,121) | 52.25±12.75 | 5.2, 7.8 | 3.1, 5.8 | 2.0, 2.0 | 0.60, 0.26 |
| Hepatitis | 1,128 (732/396) | 47.36±15.08 | 5.8, 8.5 | 3.8, 7.1 | 1.8, 2.1 | 0.68, 0.24 |
| Acute hepatitis | 333 (176/157) | 39.42±14.50 | 5.8, 7.0 | 4.2, 6.2 | 1.6, 1.3 | 0.73, 0.18 |
| Chronic hepatitis | 795 (556/239) | 50.68±14.03 | 5.8, 8.9 | 3.7, 7.3 | 2.0, 2.5 | 0.64, 0.27 |
| Cirrhosis | 1,857 (1,403/454) | 53.01±11.09 | 4.7, 6.8 | 2.6, 4.7 | 1.9, 1.9 | 0.57, 0.26 |
| Alcoholic cirrhosis | 1,015 (914/101) | 50.62±10.30 | 4.5, 6.8 | 2.5, 4.7 | 1.9, 2.0 | 0.56, 0.24 |
| Non-alcoholic cirrhosis | 842 (489/353) | 55.90±11.32 | 5.0, 6.7 | 2.7, 4.7 | 2.0, 1.7 | 0.57, 0.27 |
| Hepatocellular carcinoma | 568 (297/271) | 59.49±7.89 | 6.2, 9.8 | 3.5, 7.0 | 2.3, 2.7 | 0.60, 0.24 |
| Extrahepatic cholestasis | 749 (444/305) | 60.69±15.56 | 5.5, 9.6 | 4.0, 7.5 | 1.7, 1.8 | 0.71, 0.19 |
| Hemolytic anemia | 28 (8/20) | 52.71±25.77 | 2.5, 3.3 | 0.5, 0.4 | 2.0, 2.9 | 0.18, 0.09 |
| Neonatal jaundice | 27 (12/15) | 0±0 | 10.5, 5.1 | 0.6, 0.1 | 9.9, 5.1 | 0.06, 0.04 |
Table 2.
Regression analysis of correlation between total bilirubin and direct bilirubin concentrations Table 3. Regres
| Disease | y=ax-b∗ | ||
|---|---|---|---|
| a (95% CI) | b (95% CI) | r | |
| Cholestasis | 0.766 (0.761–0.771) | 0.754 (0.693–0.814) | 0.977 |
| Intrahepatic cholestasis | 0.757 (0.751–0.762) | 0.784 (0.716–0.851) | 0.977 |
| Hepatitis | 0.735 (0.725–0.744) | 0.373 (0.250–0.496) | 0.985 |
| Acute hepatitis | 0.851 (0.836–0.866) | 0.666 (0.508–0.824) | 0.987 |
| Chronic hepatitis | 0.716 (0.705–0.727) | 0.470 (0.326–0.614) | 0.978 |
| Cirrhosis | 0.764 (0.756–0.772) | 0.938 (0.847–1.030) | 0.974 |
| Alcoholic cirrhosis | 0.767 (0.757–0.778) | 0.986 (0.863–1.109) | 0.976 |
| Non-alcoholic cirrhosis | 0.760 (0.747–0.772) | 0.878 (0.741–1.016) | 0.972 |
| Hepatocellular carcinoma | 0.771 (0.760–0.783) | 1.029 (0.866–1.191) | 0.975 |
| Extrahepatic cholestasis | 0.814 (0.804–0.823) | 0.667 (0.548–0.785) | 0.986 |
| Hemolytic anemia | 0.066 (0.041–0.091) | -0.289 (-0.425–-0.153) | 0.733 |
| Neonatal jaundice | 0.017 (0.005–0.029) | -0.446 (-0.589–-0.303) | 0.493 |
Table 3.
Regression analysis of correlation between total bilirubin concentration and d/t ratio analysis of correlation between total bilirubin concentrati
| Disease |
y=-b/x+a∗ |
||
|---|---|---|---|
| a | b | r2 | |
| Cholestasis | 0.757 | 0.710 | 0.318 |
| Intrahepatic cholestasis | 0.741 | 0.695 | 0.315 |
| Hepatitis | 0.783 | 0.722 | 0.311 |
| Acute hepatitis | 0.838 | 0.600 | 0.302 |
| Chronic hepatitis | 0.755 | 0.748 | 0.342 |
| Cirrhosis | 0.716 | 0.664 | 0.300 |
| Alcoholic cirrhosis | 0.704 | 0.610 | 0.283 |
| Non-alcoholic cirrhosis | 0.731 | 0.737 | 0.324 |
| Hepatocellular cirrhosis | 0.725 | 0.680 | 0.368 |
| Extrahepatic cholestasis | 0.826 | 0.744 | 0.359 |
| Hemolytic anemia | 0.154 | -0.055 | 0.105 |
| Neonatal jaundice | 0.049 | -0.145 | 0.309 |
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