Prevalence and risk factors of lymphatic dysfunction in cirrhosis patients with refractory ascites: An often unconsidered mechanism

Table 1 Clinical and laboratory characteristics of study population at baseline, n (%)

Parameters	n = 155
Age in yr, mean ± SD	49.0 ± 13.1
Male	119 (77.0)
Etiology of cirrhosis
Alcohol	58 (37.4)
Hepatitis B	23 (14.8)
Hepatitis C	7 (4.5)
NASH	55 (35.4)
Others	14 (9.0)
Duration of RA in mo, median (range)	5 (-48)
MELD scores, median (range)	18.1 ± 8.6, 17(6-42)
Child-Pugh score, mean ± SD	10.3 ± 1.8
Diabetes mellitus	27 (17.4)
Hypertension	12 (7.7)
Corrected body mass index in kg/m2, mean ± SD	20.25 ± 3.40
Obesity	16 (10.3)
Chronic kidney disease	9 (5.8)
Serum total bilirubin in mg/dL, median (range)	2.7 (0.3-28.5)
Serum AST, median (range) U/L	60 (18-672)
Serum ALT, median (range) U/L	32 (4-250)
Serum total protein, mean ± SD mg/dL	5.8 ± 0.7
Serum albumin, mean ± SD mg/dL	2.5 ± 0.5
Hypoproteinemia	42 (27.0%)
INR, median (range)	1.6 (0.4-6.7)
Serum sodium, mean ± SD meq/L	130.0 ± 6.5
Serum potassium, mean ± SD meq/L	4.07 ± 2.40
Serum urea in mg/dL, median (range)	34 (12-191)
Creatinine in mg/dL, median (range)	0.9 (0.3-3.7)
Hemoglobin in g/dL, mean ± SD	8.8 (4.2-65.0)
Total leukocyte count as /cmm, median (range)	6130 (1750-34300)
Lymphocytopenia	72 (46.5)
Esophageal varices
None	3 (1.9)
Small grade	92 (59.4)
Large grade	60 (38.0)
PHG
Mild	118 (76.0)
Severe	35 (22.6)
PHD	31 (20.0)
Ascitic fluid analysis
Cell count as /µL, median (range)	100 (0-11200)
Protein median in gm/dL, median (range)	1.1 (0.1-3.5)
ADA in U/L, median (range)	10 (1-33)
Triglycerides in mg/dL, median (range)	19.5 (0-224.0)
SAAG, median (range)	2.0 (1.2-4.0)

ADA: Adenosine deaminase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; cmm: Cubic millimeter; INR: International normalized ratio; MELD: Model for end-stage liver disease; NASH: Non-alcoholic steatohepatitis; PHG: Portal hypertensive gastropathy; PHD: Portal hypertensive duodenopathy; RA: Refractory ascites; SAAG: Serum ascites albumin gradient.

Table 2 Comparison of clinical and laboratory characteristics of patients with and without clinically evident lymphatic dysfunction (Univariate analysis)

Parameters	LD present, n = 69	LD absent, n = 86	P value
Age in yr, mean ± SD	52.0 ± 13.8	47.8 ± 12.3	0.040
Male, n (%)	56 (81.2%)	63 (73.3%)	0.320
Etiology of cirrhosis, n (%)			0.050
Alcohol	22 (31.8%)	36 (41.8%)
Hepatitis	14 (20.2%)	9 (10.4%)
Hepatitis C	01 (1.4%)	6 (7.0%)
NASH	28 (40.5%)	27 (31.3%)
Others	04 (5.7%)	10 (11.6%)
Duration of RA in mo, median (range)	06 (5-48)	4 (3-36)	0.020
MELD scores, median (range)	18 (7-42)	14 (6-38)	0.003
Child-Pugh score, mean ± SD	10 ± 1.9	9.9 ± 1.6	0.001
Diabetes mellitus, n (%)	15 (21.7%)	12 (14.0%)	0.280
Hypertension, n (%)	06 (8.7%)	6 (7.0%)	0.760
Corrected BMI in kg/m2, mean ± SD	22.2 ± 2.3	20.8 ± 4.6	0.060
Obesity, n (%)	11 (16.0%)	5 (5.8%)	0.030
Chronic kidney disease, n (%)	4 (5.8%)	5 (5.8%)	1.000
Serum total bilirubin in mg/dL, median (range)	3.6 (0.3-28.5)	2.1 (0.4-26.4)	0.040
Serum AST in U/L, median (range)	67 (18-672)	56 (22-238)	0.010
Serum ALT in U/L, median (range)	34 (4-250)	30 (7-202)	0.020
Serum total protein in mg/dL, mean ± SD	5.6 ± 0.6	6.0 ± 0.8	0.001
Severe hypoproteinemia, n (%)	29 (42.0%)	13 (15.1%)	< 0.001
Albumin in mg/dL, mean ± SD	2.4 ± 0.5	2.6 ± 0.5	0.005
INR, median (range)	1.8 (0.8-3.8)	1.5 (0.4-6.7)	0.007
Serum sodium in meq/L, mean ± SD	128.0 ± 7.2	131.0 ± 5.5	0.001
Serum potassium in meq/L, mean ± SD	4.2 ± 1.2	3.9 ± 2.4	0.130
Serum urea, median (range) mg/dL	42 (12-191)	31 (12-188)	0.060
Creatinine in mg/dL, median (range)	1.0 (0.4-2.9)	0.9 (0.3-3.7)	0.160
Hemoglobin in g/dL, mean ± SD	8.6 (5.3-12.3)	8.8 (4.2-15)	0.360
Total leukocyte count as /cmm, median (range)	7000 (1750-34300)	5550 (2050-12680)	0.960
Lymphocytopenia, n (%)	49 (79.0%)	23 (26.7%)	< 0.001
Combined lymphocytopenia and hypoproteinemia, n (%)	21 (30.4%)	2 (2.3%)	< 0.001
Esophageal varices, n (%)			0.610
None	02 (2.9%)	1 (1.2%)
Small grade	40 (58.0%)	52 (60.5%)
Large grade	27 (39.1%)	33 (38.4%)
PHG, n (%)			0.025
Mild	46 (66.7%)	72 (84.0%)
Severe	21 (30.4%)	14 (16.0%)
PHD, n (%)	22 (31.8%)	9 (10.4%)
Ascitic fluid analysis
Cell count as /µL, median (range)	150 (0-3500)	100 (0-1120)	0.970
Protein in gm/dL, median (range)	0.9 (0.1-2.5)	1.1 (0.6-3.5)	0.370
ADA in U/L, median (range)	8.5 (1.0-33.0)	11.0 (2.0-30.0)	0.200
Triglycerides in mg/dL, median (range)	23 (2-224)	18 (0-64)	0.070
SAAG, median (range)	1.8 (1.2-4.0)	2.1 (1.2-3.5)	0.390
Lower limb cellulitis	7 (10.0%)	0	0.003

ADA: Adenosine deaminase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; BMI: Body mass index; cmm: Cubic millimeter; INR: International normalized ratio; LD: Lymphatic dysfunction; MELD: Model for end-stage liver disease; NASH: Non-alcoholic steatohepatitis; PHG: Portal hypertensive gastropathy; PHD: Portal hypertensive duodenopathy; RA: Refractory ascites; SAAG: Serum ascites albumin gradient.

Table 3 Multivariate regression analysis for determining independent associations of lymphatic dysfunction in cirrhosis patients with refractory ascites

Parameters	P value	OR	95%CI
Obesity	0.027	4.2	1.1-15.2
Lymphocytopenia	< 0.001	6.2	2.9-13.2
Hypoproteinemia	0.003	3.7	1.5-8.8

95%CI: 95% Confidence interval; OR: Odds ratio.

Table 4 Multivariate analysis for determining independent associations of lymphedema

Parameters	P value	OR	95%CI
Age	0.002	1.06	1.02-1.10
Child-Pugh score	0.005	1.82	1.19-2.79
Obesity	0.012	6.33	1.49-26.90
Hypoproteinemia	0.001	7.10	2.44-20.70
Lymphocytopenia	0.011	3.55	1.34-9.38

95%CI: 95% Confidence interval; OR: Odds ratio.