Background
Methods
Study design and study cohorts
Provocative tests
Fasting test
Rifampin provocative test
Statistical analysis
Results
Parameters |
Group A
Patients with Gilbert syndrome (n = 83) |
Group B
Patients with GS and eradicated HCV (n = 18) | Controls (n = 100) | P value |
---|---|---|---|---|
Age (years) mean ± SD (range) | 28.1 ± 8.6 (18–39) | 34.3 ± 9.5 (21–42) | 31 ± 10.1 (21–42) | Group A vs. B: 0.0058 Group A vs Control: 0.1532 Group B vs control: 0.0285* |
Male/Female | 57/26 | 15/3 | 58/42 | Group A vs. B: 0.2621 Group A vs Control: 0.1670 Group B vs. control: 0.0631 |
Parental consanguinity: n (%) | 45 (54.217) | 9 (50) | 21 (21) | Group A vs. B: 0.7964 Group A vs Control: < 0.0001** Group B vs. control: < 0.0001** |
Cigarette smoking; n (%) | 6 (7.228) | 4 (22.222) | 26 (26) | Group A vs. B: 0.0750 Group A vs Control: 0.0008 Group B vs. control: 1.0000 |
BMI (kg/cm2) mean ± SD (range) | 23.4184 ± 2.36 (18.6–26.7) | 23.095 ± 2.9 (23–27) | 25.5 ± 3.94 (19.8–27.4) | Group A vs. B: 0.6149 Group A vs control: < 0.0001** Group B vs. control: 0.0150* |
Characteristics of the enrolled GS cases
Parameters |
Group A
Patients with Gilbert syndrome (n = 83) |
Group B
Patients with GS and eradicated HCV (n = 18) | Controls (n = 100) | P value |
---|---|---|---|---|
Jaundice episodes: number (percent) | 83 (100) | 18 (100) | 0 | Group A vs B: 1.000 |
Frequency of jaundice episodes per year. N (%) | ||||
▪ 1–5 | 57 (68.674) | 10 (55.56) | 0 | Group A vs B: 1.0000 |
• 6–10 | 20 (24.096) | 5 (27.76) | 0 | Group A vs B: 1.0000 |
• > 10 | 6 (7.229) | 3 (16.67) | 0 | Group A vs B: 0.7111 |
Mean duration of individual jaundice episode (mean ± SD) days | 19.832 ± 14. | 21.1832 ± 15.68 | 0 | Group A vs B: 0.7219 |
Other symptoms/signs during hyperbilribunemia attacks in GS subjects and control subjects; n (%) | ||||
Fatigue: number (%) | 36 (43.37) | 4 (22.22) | 2(2) | Group A vs. B: 0.1163 Group A vs controls: < 0.0001** Group B vs controls: < 0.0001** |
Abdominal pain: number (%) | 21 (25.3) | 8 (44.44) | 3 (3) | Group A vs. B: 0.1490 Group A vs controls: < 0.0001** Group B vs controls: < 0.0001** |
Dyspepsia: number (%) | 19 (22.89) | 7 (38.89) | 2 (2) | Group A vs. B: 0.2321 Group A vs controls: < 0.0001** Group B vs controls: < 0.0001** |
Bloating; number (%) | 17 (20.48) | 9 (50) | 10(10) | Group A vs. B: 0.0159* Group A ys. Controls: 0.0595* Group B vs. controls: 0.002* |
Loss of appetite: number (%) | 10 (12.048) | 2 (11.111) | 13 (13) | Group A vs. B:0.6125 Group A ys. Controls: 1.0000 Group B vs. controls: 1.0000 |
Comorbid conditions | ||||
• Diabetes mellitus (Type 1) | 4 (4.82) | 0 | 0 | Group A vs B: 1.0000 |
• Diabetes mellitus (Type 2) | 2 (2.41) | (11.11) | 0 | Group A vs B: 0.1449 |
• Hypertension | 1 (1.2) | 2 (11.11) | 0 | Group A vs B: 0.0811 |
• Rheumatoid arthritis | 2 (2.41) | 0 | 0 | Group A vs B: 1.0000 |
• Rheumatic heart valve disease | 1 (1.2) | 0 | 0 | Group A vs B: 1.0000 |
Food intolerances and allergies: Celiac/lactose intolerance/food allergies | 9 (10.84) | 1 (5.56) | 3 (3) | Group A vs B: 0.6859 Group A vs. controls: 0.0391* Group B vs. controls: 0.4890 |
Factors associated with attacks of clinical jaundice n (%) | ||||
Prolonged fasting > 12 h/Ramadan fasting | 60 (72.289) | 14 (77.78) | 0 | Group A vs. B: 0.7736 |
Heavy physical exercise | 25 (30.120) | 4 (22.22) | 0 | Group A vs. B: 0.5788 |
Menstrual abnormalities in women | 7 (8.43) | 3 (16.67) | 0 | Group A vs. B: 0.3779 |
Pregnancy (in 8 women) | 8/8 (100) | 0 | 10 (10) | |
Cesarean delivery | 4 (4.82) | 0 | 0 | Group A vs. B: 1.0000 |
Systemic infections | 21 (25.301) | 9 (50) | 0 | Group A vs. B: 0.0486* |
Surgery | 27 (32.530) | 2 (11.11) | 0 | Group A vs. B: 0.0873 |
Diets reported as potentially related to jaundice episodes; n (%) | ||||
Drugs (N;%) | ||||
-Paracetamol | 2 (2.4) | 1 (22.22) | 0 | Group A vs. B: 0.6186 |
-Antibiotics(amoxicillin/clavulanate; ofloxacin) | 7 (8.434) | 2 (11.11) | Group A vs. B: 0.0500* | |
-Direct acting anti-viral agents | 0 | 7 (38.889) | 0 | Group A vs. B: 0.6600 |
-Diclofenac | 3 (3.6) | 1 (16.67) | 0 | Group A vs. B: 0.1493 |
-Oral hypoglycemic drugs | 1 (1.2) | 0 | 0 | Group A vs. B: 0.3261 |
-Anti-hypertensive drugs | 0 | 0 | 0 | Group A vs. B: 0.1782 |
Diets reported as potentially related to jaundice episodes; n (%) | ||||
High animal proteins rich/ Fat rich diets | 4 (4.82) | 0 | 0 |
Gilbert syndrome characteristics in women
Comorbidities with GS
Biochemical and nutritional data
Parameters |
Group A
Patients with Gilbert syndrome (n = 83) |
Group B
Patients with GS and eradicated HCV (n = 18) | Controls (n = 100) | P value |
---|---|---|---|---|
Mean liver function tests in between jaundice episodes | ||||
Total Bilirubin (mg/dL) Mean ± SD (range) | 0.42 ± 0.4 (0.3–1.1) | 0.61 ± 0.5 (0.5–1.2) | 0.38 ± 0.3 (0.1–1.2) | Group A vs. Controls: 0.4410 Group B vs. controls: 0.0087* Group A vs. B: 0.0842 |
Unconjugated Bilirubin (mg/dL) Mean ± SD (range) | 0.21 ± 0.27 (0.1–0.38) | 0.41 ± 0.29 (0.2–0.41) | 0.17 ± 0.19 (0.1–0.38) | Group A vs. Controls: 0.2425 Group B vs. controls: 0.0096* Group A vs. B: 0.1628 |
ALT (U/L) Mean ± SD (range) | 20.16 ± 4.83 (18–28) | 24.06 ± 6.18 (19–37) | 19.86 ± 6.31 (17–36) | Group A vs. Controls: 0.7220 Group B vs. controls: 0.0102* Group A vs. B: 0.0038* |
AST (U/L) Mean ± SD (range) | 23.18 ± 4.83 (17.14–38.5) | 24.72 ± 6.82 (21.63–38.24) | 22.15 ± 4.06 (17.3–32.63) | Group A vs. Controls: 0.1188 Group B vs. controls: 0.0301* Group A vs. B: 0.4770 |
Alkaline Phosphatase (U/L) Mean ± SD (range) | 80.36 ± 10.85 (75.81–106.17) | 91.04 ± 10.74 (80.38–114) | 81.16 ± 19.27 (7.45–91.5) | Group A vs. Controls: 0.7369 Group B vs. controls: 0.0001** Group A vs. B: 0.0003* |
Total Protein (g/L) Mean ± SD (range) | 77.26 ± 5.39 (71.37–83.97) | 76.95 ± 4.85 (70–82.96) | 77.84 ± 5.83 (72.74–84.67) | Group A vs. Controls: 0.4891 Group B vs. controls: 0.5429 Group A vs. B: 0.8225 |
Albumin (g/dl) Mean ± SD (range) | 4.1 ± 0.53 (3.6–5.4) | 3.99 ± 0.61 (3.46–5.2) | 4.2 ± 0.75 (3.76–5.5) | Group A vs. Controls: 0.3085 Group B vs. Controls: 0.2643 Group A vs. B: 0.4391 |
Mean liver function tests during jaundice episodes | ||||
Total Bilirubin (mg/dl) Mean ± SD (range) | 3.56 ± 1.82 (1.46–5.7) | 4.23 ± 2.01 (2.04–7.97) | 0.41 ± 0.31 (0.3–1.4) | Group A vs. B: 0.1677 Group A ys. Controls: < 0.0001 Group B vs. controls: < 0.0001 |
Unconjugated Bilirubin (mg/dl) Mean ± SD (range) | 2.07 ± 0.96 (1.7–3.6) | 3.03 ± 1.08 (1.9–2.06) | 0.37 ± 0.11 (0.1 to 0.6) | Group A vs. B: 0.0001** Group A ys. Controls: < 0.0001 Group B vs. controls: < 0.0001 |
ALT (U/L) Mean ± SD (range) | 25.59 ± 5.23 (19–39) | 29.51 ± 8.06(23–39) | 27.4 ± 4.5 (18–36) | Group A vs. B: 0.0110* Group A ys. Controls: 0.0083 Group B vs. controls: 0.1360 |
AST (U/L) Mean ± SD (range) | 27.8 ± 5.4 (22–35) | 27.59 ± 6.14 (19–37) | 29.4 ± 4.7 (20–37) | Group A vs. B: 0.6308 Group A ys. Controls: 0.16 Group B vs. controls: 0.1589 |
Alkaline Phosphatase (U/L) Mean ± SD (range) | 84.2 ± 15.9 (77–123) | 86.25 ± 17.37 (75–131) | 85.9 ± 14.36 (45–97) | Group A vs. B: 0.6267 Group A ys. Controls: 0.4488 Group B vs. controls: 0.9268 |
Total Proteins (g/L) Mean ± SD (range) | 74.81 ± 4.7 (71.65–82.9) | 71.21 ± 3.9 (6.259–81.85) | 73.63 ± 4.41 (71.25–80.2) | Group A vs. B: 0.0026* Group A ys. Controls: 0.2096 Group B vs. controls: 0.0510 |
Serum Albumin (g/dl) Mean ± SD (range) | 4.1 ± 0.61 (3.7–5.5) | 3.89 ± 0.47 (3.5–5.3) | 4.2 ± 0.59 (4.0–5.45) | Group A vs. B: 0.1729 Group A ys. Controls: 0.2625 Group B vs. controls: 0.0371* |
Hemoglobin, lipids and vitamins during jaundice episode | ||||
Hemoglobin (gm/dl); mean ± SD | 13.31 ± 1.97 (11.83–13.74) | 12.19 ± 1.38 (12.16–14.14) | 13.61 ± 2.01 (12.77–15.37) | Group A vs. B: 0.5414 Group A ys. controls 0.3140 Group B vs. controls: 0.226 |
Cholesterol (mg/dL) Mean ± SD (range) | 169.85 ± 23.74 (132.72–175.92) | 171.52 ± 27.84 (145.73–185.-14) | 175.02 ± 20.14 (142.61–194.98) | Group A vs. B: 0.7909 Group A ys. controls: 0.112 Group B vs. controls: 0.526 |
Triglycerides (mg/dL) Mean ± SD (range) | 139.37 ± 24.72 (127.29–240.84) | 140.13 ± 31.52 (136.4–151.81) | 142.817 ± 20.38 (136.87–159.74) | Group A vs. B: 0.9111 Group A ys. controls: 0.302 Group B vs. controls: 0.639 |
Low-density lipoprotein cholesterol (LDL-C) (mg/dL) Mean ± SD (range) | 68.12 ± 22.81 (48.98–78.81) | 70.32 ± 21.66 (54.26–76.82) | 75.85 ± 22.87 (58.62–103.84) | Group A vs. B: 0.709 Group A ys. controls: 0.023* Group B vs. controls: 0.999 |
High-density lipoprotein cholesterol (HDL-C) (mg/dL) Mean ± SD (range) | 54.41 ± 12.72 (45.12–52.83) | 57.92 ± 13.42 (40.18–64.08) | 56.71 ± 13.85 (52.52–67.17) | Group A vs. controls: 0.300 Group A ys. controls: 0.247 Group B vs. controls: 0.733 |
aVitamin B12 (pg/ml); mean ± SD (95% CI for the mean) | 638. 21 ± 142.15 (507.17 to 769.25) | 649. 17 ± 163.42 (467.90 to 730.44) | 654.71 ± 195.82 (615.86 to 793.57) | Group A vs. B: 0.7733 Group A ys. controls: 0.52 Group B vs. controls: 0.91 |
b25-hydroxy-vitamin D3 (ng/mL); mean ± SD; (95% CI for the mean) | 21.25 ± 15.89 (18.78 to 35.72) | 20.72 ± 11.39 (17.05 to 45.39) | 45.82 ± 17.38 (38.37 to 49.27) | Group A vs. B: 0.89 Group A ys. controls: < 0.0001 ** Group B vs. controls: < 0.0001** |
cFolic acid (ng/mL); mean ± SD (95% CI for the mean) | 16.53 ± 3.63 (13.95 to 15.1) | 15.93 ± 2.51 (14.38 to 16.67) | 18.36 ± 3.16 (17.33 to 20.1) | Group A ys. B: 0.4073 Group A vs. controls: < 0.0002** Group B vs. controls: < 0.0001** |
Health related quality of life assessment
Scores (norm)* | Subjects with Gilbert Syndrome) (101 subjects; n = 83 with GS and 18 with GS and treated HCV) | Control subjects (n = 100) | P value | ||
---|---|---|---|---|---|
During jaundice episode | In between jaundice episodes | During jaundice episode | In between jaundice episodes | ||
SF-6D preference | 0.72 ± 0.12 | 0.77 ± 0.12 | 0. ± 0.11 | < 0.0001** | 0.278 |
SF-36v2
| |||||
PF | 82.5 ± 7.35 | 89.952 ± 2.41 | 90.10 ± 2.40 | 0.0001** | 0.051 |
RP | 90.19 ± 4.2 | 89.19 ± 4.2 | 90. ± 1.4 | 0.06 | 0.81 |
BP | 81.3 ± 3.5 | 83.03 ± 2.8 | 82.63 ± 6.36 | 0.07 | 0.56 |
GH | 49.27 ± 14.5 | 52.64 ± 10.3 | 53.24 ± 9.11 | 0.02 * | 0.66 |
VT | 55.34 ± 4.61 | 59.81 ± 4.18 | 60.35 ± 3.617 | 0.0001** | 0.33 |
SF | 87.16 ± 9.73 | 92.74 ± 15.2 | 92.47 ± 14.9 | 0.0031** | 0.9 |
RE | 80.61 ± 7.24 | 88.39 ± 5.21 | 88.53 ± 8.56 | < 0.0001** | 0.88 |
MH | 71.9 ± 3.6 | 72.6 ± 3.04 | 72.10 ± 4.3 | 0.38 | 0.71 |
PCS | 45.00 ± 12.9 | 47.927 ± 9.21 | 48.81 ± 8.7 | 0.02 | 0.48 |
MCS | 49.81 ± 3.9 | 49.71 ± 3.82 | 50.87 ± 4.31 | 0.07 | 0.07 |
CLDQ
| |||||
AS | 5.48 ± 1.83 | 6.2 ± 1.64 | 6.23 ± 1.55 | 0.012* | 0.58 |
FA | 4.80 ± 1.25 | 5.37 ± 1.36 | 5.72 ± 1.03 | < 0.0001** | 0.04* |
SS | 5.02 ± 0.82 | 5.712 ± 1.224 | 5.82 ± 1.0 | < 0.0001 ** | 0.47 |
AC | 5.87 ± 1.84 | 6.25 ± 1.33 | 6.55 ± 1.41 | 0.004 ** | 0.12 |
EF | 5.231 ± 1.74 | 5.73 ± 1.41 | 5.84 ± 1.43 | 0.007 * | 0.59 |
WO | 5.41 ± 1.26 | 5.83 ± 1.54 | 5.90 ± 1.632 | 0.02* | 0.72 |
Overall | 5.32 ± 1.36 | 5.82 ± 0.89 | 5.92 ± 1.63 | 0.006** | 0.64 |
UGT1A1 alleles and genotype frequencies
Gene polymorphism | Allele status | Total | Individuals with recurrent episodes of overt jaundice (GS: n = 83) | Individuals with GS and eradicated HCV (n = 18) | Control subjects (n = 100) |
---|---|---|---|---|---|
UGT1A1*6
| |||||
SNP 211G > A; (n,%) | −/− | 189 | 80 (96.386) | 12 (66.667) | 97 (97) |
*6/− | 10 | 2 (2.409) | 5 (27.778) | 3 (3) | |
*6/*6 | 1 | 0 | 1 (5.555) | 0 | |
UGT1A1*27
| |||||
SNP 686C > A; (n,%) | −/− | 199 | 81 (97.59) | 18 (100) | 100 (100) |
*27/− | 2 | 2(2.409) | 0 | 0 | |
*27/*27 | 0 | 0 | 0 | 0 | |
UGT1A1*28
| |||||
TA repeat A(TA)7TAA; (n,%) | −/− | 100 | 0 | 0 | 100 |
*28/− | 3 | 2 (2.409) | 1(5.555) | 0 | |
*28/*28 | 98 | 81(97.59) | 17 (94.444) | 0 | |
UGT1A1*60
| |||||
SNP -3263 T > A | −/− | 189 | 71 | 13 | 95 |
*60/− | 13 | 5 | 3 | 5 | |
*60/*60 | 9 | 7 | 2 | 0 |
Risk factors associated with overt clinical jaundice attacks
Variables | Odds ratio | CI (95%) | P value |
---|---|---|---|
Fasting > 12 h | 1.973 | 1.24–2.76 | 0.002** |
Low calories weight losing plans | 2.275 | 1.10–4.68 | 0.026* |
Fat rich diets | 1.417 | 0.93–2.14 | 0.099 |
Intensive physical exercise and sports | 2.737 | 1.12–6.69 | 0.027* |
Menorrhagia or metrorrhagia or dysmenorrhea | 2.898 | 1.05–7.95 | 0.0318* |
Pregnancy | 4.746 | 1.65–13.64 | 0.004** |
Vaginal delivery | 2.335 | 0.79–6.84 | 0.122 |
Caesarian delivery | 2.110 | 1.07–4.16 | 0.031** |
Surgery under general anesthesia | 4.139 | 1.96–8.71 | < 0.001** |
Systemic infections | 2.174 | 1.387–2.861 | 0.0413* |