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Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation
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https://doi.org/10.1016/j.hpb.2019.08.008
ORIGINAL ARTICLE
Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation Takeo Toshima1, Tomoharu Yoshizumi1, Shoichi Inokuchi1, Yukiko Kosai-Fujimoto1, Takeshi Kurihara1, Shohei Yoshiya1, Yohei Mano1, Kazuki Takeishi1, Shinji Itoh1, Noboru Harada1, Toru Ikegami1, Yuji Soejima1, Mototsugu Shimokawa2, Yoshihiko Maehara1 & Masaki Mori1 1
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and 2Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
Abstract Background: Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors. Methods: Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively. Results: Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P < 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for postLDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well. Conclusions: Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component. Received 14 February 2019; accepted 12 August 2019
Correspondence Takeo Toshima, Department of Surgery and Science, Graduate School of Medicine, Kyushu University, 31-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: [email protected]
Introduction For more than two decades, liver transplantation (LT) has been accepted as the most effective treatment for end-stage liver disease.1 The 5- and 10-year survival rates after LT are 70– 80%, and a mortality rate over 60% is reported to be unrelated to liver function.2 Complications following LT significantly affect the quality of life in long-term survival and metabolic syndrome (MS) is now the most common longterm complication after LT and has been increasing recently with an incidence of 50 –60%.2,3 Additionally, MS is an established risk factor for atherosclerosis and cardiovascular disease, which result in high mortality, increased 4-fold by the presence of MS.
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Several retrospective studies, many of which report on small numbers of patients, have shown a prevalence of MS after deceased donor liver transplantation (DDLT).2–4 However, the actual risk factors for each MS component after living donor liver transplantation (LDLT) remain to be established. Besides, some risk factors such as certain aspects of living donor related factors (age, gender, graft volume) and immunosuppression (particularly the use of calcineurin inhibitors and corticosteroids) should be investigated. Therefore, the aim of this study was to clarify the prevalence of and risk factors for MS components such as hypertension, diabetes mellitus, and dyslipidemia after LDLT and to identify the predictors for each MS component including characteristics of living donors.
© 2019 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Materials and methods Patient characteristics A total of 522 adult patients who underwent LDLT at Kyushu University Hospital (Fukuoka, Japan) from January 1998 through December 2015 were enrolled in the study. Among these, 461 recipients whose data were obtained in detail from the medical records were retrospectively analyzed. The etiology of liver diseases included acute liver failure (n = 61) and liver cirrhosis due to hepatitis C (n = 183), primary biliary cholangitis (n = 66), hepatitis B (n = 41), alcohol abuse (n = 26), primary sclerosing cholangitis (n = 17), nonalcoholic steatohepatitis (n = 12), and others (n = 55). Graft types included left lobe with caudate lobe graft (n = 265), right lobe graft without the middle hepatic vein (n = 190), and posterior segment graft (n = 6), by the selection criteria as previously described.5–7 The median age in our study population was 53 (18–74) years, with a male preponderance (n = 216, 46.9%). The median Model for EndStage Liver Disease (MELD) score was 15.7 (1–54) points and nearly half the patients had hepatocellular carcinoma (HCC) at the time of LDLT (n = 203, 44.0%). All LDLTs were performed after obtaining full informed consent from all patients and approval by the Liver Transplantation Committee of Kyushu University. The study protocol conformed to the ethical guidelines of the 1975 Helsinki Declaration and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board of ethics committee. Surgery and postoperative management The graft harvesting technique, recipient surgery, and perioperative management of recipients, including immunosuppression regimens, have been previously described.5,8,9 Simultaneous splenectomy was performed in 271 recipients (58.8%) to decrease portal vein pressure10 and 18 recipients underwent splenectomy before LDLT. Since 2001, duct-to-duct anastomosis has been preferred to Roux-en-Y hepaticojejunostomy for bile duct reconstruction and was performed over a 2.0 mm C-tube with intermittent 6-0 PDS-II sutures (Ethicon Inc., Somerville, NJ, USA).11 Immunosuppression was initiated with a protocol based on either tacrolimus (Prograf; Astellas Pharma Inc., Tokyo, Japan) or cyclosporine A (Neoral; Novartis Pharma K.K., Tokyo, Japan), with steroid and/or mycophenolate mofetil (MMF; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan).12 Tacrolimus was used in 285 recipients (61.8%) and cyclosporine A in 176 recipients (38.2%). The target trough level for tacrolimus was set at 10 ng/ ml for 3 months after LDLT, followed by 5–10 ng/ml thereafter. The target trough level for cyclosporine A was set at 250 ng/ml for 3 months after LDLT, followed by 150–200 ng/ml thereafter. Methylprednisolone was initiated on the day of LDLT, then tapered and converted to prednisolone 7 days after LDLT. Prednisolone treatment was tapered and discontinued 6 months
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after LDLT. MMF was used in 368 recipients (79.8%) and was started at 1000 mg/day on the day after LDLT, then tapered and discontinued by 6 months after LDLT. Trough levels were not measured for MMF. All patients had monthly follow-ups at least 6 months after surgery to check the trough of calcineurin inhibitors and routine blood chemistry test including fast glucose, triglyceride, and low-density lipoprotein. After that, as the patient condition got stable, the follow-up period extended up to every 3 months.10,12 The median follow-up period was 2763 days (1282 days and 4142 days were the 25th and 75th percentiles, respectively). Definition of MS components: hypertension, diabetes mellitus, and dyslipidemia Three MS components, hypertension, diabetes mellitus, and dyslipidemia, were defined using the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria,13,14 with a modification (Table 1). According to the consensus report15 for the practical extensions to the NCEP ATP III criteria, hypertension, diabetes mellitus, and dyslipidemia were considered present if recorded as a medical diagnosis, or if the patient was on pharmacological therapy for any of these conditions both pre- and post-LDLT.2,16 In particular, regarding the diagnosis for hypertension, after excluding the other diseases that cause hypertension (eg. pheochromocytoma), we clinically diagnosed patients with blood pressure measured at least twice in the hospital or blood pressure at home consistently over 130/85. In addition, because values of serum high-density lipoprotein were not available in the past data, serum total cholesterol 200 mg/dl was adopted to define dyslipidemia instead, as suggested by the supplementary notes in the NCEP ATP III criteria.13 Details pertaining to the onset and progression of these chronic conditions were also captured in the data-collection process. Statistical analysis All statistical analyses were performed with JMP statistical software version 13 (SAS Institute Inc., Cary, NC, USA). Continuous variables were expressed as mean ± standard deviation and compared using the unpaired t-test.17 McNemar test was used to compare the correlated categorical values and Chi squared test for the non-correlated categorical values. Multivariate analyses were performed with logistic regression model and the odds ratio (OR) was calculated for an increment of 1 unit for continuous variables.18 P values < 0.05 were considered significant.
Results Prevalence of hypertension, diabetes mellitus, and dyslipidemia The prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3% (n = 43), 16.5% (n = 76), and 7.2% (n = 33) before LDLT to 44.9% (n = 207),
© 2019 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 1 MS component by modified NCEP ATP III criteria and the prevalence
MS component
Definition
P value
LDLT Pre (%)
Post (%)
Hypertension
BP 130/85 mmHg or pharmacologic treatment
43 (9.3)
207 (44.9)
0.000
Diabetes mellitus
Fasting serum glucose 110 mg/dL or pharmacologic treatment
76 (16.5)
209 (45.3)
0.000
Dyslipidemia
Serum triglyceride 150 mg/dL or serum total cholesterol 200 mg/dL or pharmacologic treatment
33 (7.2)
234 (50.8)
0.000
ATP, Adult Treatment Panel; BP, blood pressure; LDLT, living donor liver transplant; MS, metabolic syndrome; NCEP, National Cholesterol Education Program.
45.3% (n = 209), and 50.8% (n = 234) after LDLT, respectively (Table 1).
recipient weight ratio (GRWR) (0.78 ± 0.17 vs. 0.81 ± 0.18, P = 0.039) (Table 4).
Risk factors for post-LDLT hypertension Post-LDLT hypertension was significantly associated with older age of the recipient (56.4 ± 9.0 vs. 50.3 ± 12.5 years, P < 0.001), the high rate of HCV as etiology (52.7% vs. 29.1%, P = 0.001), low MELD score (15.0 ± 6.9 vs. 16.3 ± 8.2 pts, P = 0.042), presence of HCC (56.0% vs. 34.3%, P < 0.001), high rate of cyclosporine use (50.7% vs. 28.0%, P < 0.001), heavy dry weight (61.4 ± 11.2 vs. 59.0 ± 10.7 kg, P = 0.022), high dry body mass index (BMI) (23.8 ± 3.4 vs. 22.7 ± 3.2 kg/m2, P < 0.001), presence of pre-LDLT hypertension (20.8% vs. 0.4%, P < 0.001), absence of pre-LDLT dyslipidemia (3.9% vs. 9.8%, P = 0.011), younger donor age (35.1 ± 10.6 vs. 38.1 ± 11.1, P = 0.003), male donor (67.6% vs. 57.9%, P = 0.031) (Table 2). There were no significant differences in surgery-related factors between the two groups.
Predictors for post-LDLT hypertension, diabetes mellitus, and dyslipidemia by multivariate analysis Table 5 shows each predictor for post-LDLT hypertension, diabetes mellitus, and dyslipidemia. Multivariate logistic regression analysis was performed using the data excluding the presence of each pre-LDLT MS component. The three factors, cyclosporine use (OR 2.086, 95% CI 1.376–3.161, P = 0.001), recipient age (per year, OR 1.036, 95% CI 1.014–1.058, P = 0.001), and dry BMI (per kg/m2, OR 1.072, 95% CI 1.008–1.139, P = 0.026) were independent risk factors for post-LDLT hypertension. Besides, three factors, male recipient (OR 2.471, 95% CI 1.565–3.901, P < 0.001), recipient age (per year, OR 1.039, 95% CI 1.014–1.065, P = 0.002), and donor BMI (per kg/m2, OR 1.124, 95% CI 1.025–1.232, P = 0.012) were independent risk factors for post-LDLT diabetes mellitus. Final, four factors, cyclosporine use (OR 2.015, 95% CI 1.338–3.034, P = 0.001), prolonged prednisolone use (OR 1.928, 95% CI 1.261–2.947, P = 0.002), recipient age (per year, OR 1.019, 95% CI 1.001–1.038, P = 0.037), and GRWR (per %, OR 0.316, 95% CI 0.105–0.945, P = 0.037) were independent risk factors for postLDLT dyslipidemia (Table 5).
Risk factors for post-LDLT diabetes mellitus Post-LDLT diabetes mellitus was significantly associated with older recipient age (54.7 ± 9.6 vs. 51.6 ± 12.7 years, P = 0.004), male recipient (58.9% vs. 36.9%, P < 0.001), the high rate of HCV as etiology (48.3% vs. 32.5%, P = 0.002), low MELD score (14.7 ± 7.1 vs. 16.5 ± 7.9 pts, P = 0.011), presence of HCC (53.6% vs. 36.1%, P = 0.001), heavy dry weight (62.3 ± 10.7 vs. 58.3 ± 10.8 kg, P < 0.001) and high dry BMI (23.6 ± 3.4 vs. 22.9 ± 3.3 kg/m2, P = 0.023), pre-LDLT diabetes mellitus (35.9% vs. 0.4%, P < 0.001), male donor (68.4% vs. 57.1%, P = 0.013), high donor BMI (22.4 ± 2.6 vs. 21.8 ± 2.7 kg/m2, P = 0.023), high portal vein pressure (PVP) level at closure (16.6 ± 3.9 vs. 15.7 ± 3.5, P = 0.016), absence of splenectomy during liver transplant surgery (57.4% vs. 67.1%, P = 0.033) (Table 3). Risk factors for post-LDLT dyslipidemia Post-LDLT dyslipidemia was significantly associated with older recipient age (54.6 ± 9.9 vs. 51.4 ± 12.8 years, P = 0.003), the high rate of HCV as etiology (45.3% vs. 33.9%, P = 0.004), high rate of cyclosporine use (47.0% vs. 29.1%, P < 0.001), prednisolone use 6 months (42.7% vs. 33.9%, P = 0.032), pre-LDLT dyslipidemia (13.7% vs. 0.4%, P < 0.001), and low graft-
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Discussion This is the first large study to investigate the clinical risk factors for each MS component such as hypertension, diabetes mellitus, and dyslipidemia after LDLT including characteristics related to the living donors and surgical factors. According to multivariate analysis, not only the recipient factors (cyclosporine use, prolonged prednisolone use, age, male gender, and high BMI) but also the donor factors (high BMI and low GRWR) were independently associated with each targeted post-LDLT MS component. Pre-LT MS and each of the three components, have emerged as increasingly prevalent conditions among candidates for LT, and post-LT MS also applies.2 Some studies have demonstrated preand post-DDLT MS in Western populations,2,19 but the applicability of such findings to an Asian population remains unclear
© 2019 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 2 Risk factors for post-LDLT hypertension
Variables (n [ 461)
Post-LDLT hypertension No (n [ 254)
Yes (n [ 207)
P value
Recipient Age (years)
50.3 ± 12.5
56.4 ± 9.0
0.000
Gender (male, %)
121 (47.6)
95 (45.9)
0.709
HCV
74 (29.1)
109 (52.7)
PBC
41 (16.2)
25 (12.1)
ALF
39 (15.4)
22 (10.6)
HBV
27 (10.6)
14 (6.8)
Alcohol
17 (6.7)
9 (4.3)
PSC
13 (5.1)
4 (1.9)
NASH
9 (3.5)
3 (1.5)
Others
34 (13.4)
21 (10.1)
16.3 ± 8.2
15.0 ± 6.9
Etiology (%)
MELD (points)
0.001
0.042
HCC (%)
87 (34.3)
116 (56.0)
0.000
ABO incompatibility (%)
21 (8.3)
16 (7.7)
0.832
Calcineurin inhibitor (CyA, %)
71 (28.0)
105 (50.7)
0.000
Prednisolone use (6 months, %)
104 (40.9)
73 (35.3)
0.212
MMF use for induction (%)
196 (77.5)
172 (83.1)
0.132
Follow-up duration (days)
2649 ± 1687
2903 ± 1725
0.112
0.000
Metabolic variables Dry BMI (kg/m2)
22.7 ± 3.2
23.8 ± 3.4
Pre-LDLT hypertension (%)
1 (0.4)
43 (20.8)
0.000
Pre-LDLT diabetes mellitus (%)
37 (14.6)
39 (18.8)
0.220
Pre-LDLT dyslipidemia (%)
25 (9.8)
8 (3.9)
0.011
Age (years)
38.1 ± 11.1
35.1 ± 10.6
0.003
Gender (male, %)
147 (57.9)
140 (67.6)
0.031
BMI (kg/m2)
22.0 ± 2.5
22.1 ± 2.8
0.666
Graft (Right lobe, %)
102 (40.2)
88 (42.5)
0.610
GRWR (%)
0.80 ± 0.18
0.79 ± 0.18
0.862
PVP at laparotomy (mmHg)
24.8 ± 5.9
24.5 ± 6.2
0.674
PVP at closure (mmHg)
16.0 ± 3.8
16.2 ± 3.6
0.652
Living Donor variables
Surgery variables
Cold ischemic time (min)
116.9 ± 97.4
118.8 ± 61.2
0.842
Warm ischemic time (min)
41.6 ± 12.4
41.4 ± 10.9
0.856
Splenectomy (%)
155 (61.0)
134 (64.7)
0.412
Operative blood loss (10L)
33 (13.3)
33 (16.1)
0.393
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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© 2019 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 3 Risk factors for post-LDLT diabetes mellitus
Variables (n [ 461)
Post-LDLT diabetes mellitus No (n [ 252)
Yes (n [ 209)
P value
Recipient Age (years)
51.6 ± 12.7
54.7 ± 9.6
0.004
Gender (male, %)
93 (36.9)
123 (58.9)
0.000
HCV
82 (32.5)
101 (48.3)
PBC
49 (19.4)
17 (8.1)
Etiology (%)
0.002
ALF
34 (13.5)
27 (12.9)
HBV
21 (8.3)
20 (9.6)
Alcohol
15 (6.0)
11 (5.3)
PSC
13 (5.2)
4 (1.9)
NASH
6 (2.4)
6 (2.9)
Others
32 (12.7)
23 (11.0)
16.5 ± 7.9
14.7 ± 7.1
MELD (points)
0.011
HCC (%)
91 (36.1)
112 (53.6)
0.001
ABO incompatibility (%)
21 (8.3)
16 (7.7)
0.790
Calcineurin inhibitor (CyA, %)
99 (39.3)
77 (36.8)
0.591
Prednisolone use (6 months, %)
107 (42.5)
70 (33.5)
0.055
MMF use for induction (%)
207 (82.5)
161 (77.0)
0.147
Follow-up duration (days)
2676 ± 1684
2867 ± 1733
0.230
Metabolic variables Dry BMI (kg/m2)
22.9 ± 3.3
23.6 ± 3.4
0.012
Pre-LDLT hypertension (%)
23 (9.1)
20 (9.6)
0.871
Pre-LDLT diabetes mellitus (%)
1 (0.4)
75 (35.9)
0.000
Pre-LDLT dyslipidemia (%)
20 (7.9)
13 (6.2)
0.475
Age (years)
37.4 ± 11.0
36.0 ± 10.9
0.185
Gender (male, %)
144 (57.1)
143 (68.4)
0.013
BMI (kg/m2)
21.8 ± 2.7
22.4 ± 2.6
0.023
Graft (Right lobe, %)
104 (41.3)
86 (41.2)
0.979
GRWR (%)
0.80 ± 0.19
0.78 ± 0.16
0.160
PVP at laparotomy (mmHg)
24.7 ± 6.0
24.5 ± 5.9
0.774
PVP at closure (mmHg)
15.7 ± 3.5
16.6 ± 3.9
0.016
Cold ischemic time (min)
116.2 ± 63.6
120.1 ± 107.3
0.696
Warm ischemic time (min)
42.2 ± 12.4
40.6 ± 10.8
0.147
Splenectomy (%)
169 (67.1)
120 (57.4)
0.033
Operative blood loss (10L)
31 (12.5)
35 (16.7)
0.178
Living Donor variables
Surgery variables
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 4 Risk factors for post-LDLT dyslipidemia
Variables (n [ 461)
Post-LDLT dyslipidemia No (n [ 227)
Yes (n [ 234)
P value
Recipient Age (years)
51.4 ± 12.8
54.6 ± 9.9
0.003
Gender (male, %)
111 (48.9)
105 (44.9)
0.386
HCV
77 (33.9)
106 (45.3)
PBC
25 (11.0)
41 (17.5)
Etiology (%)
0.004
ALF
37 (16.3)
24 (10.2)
HBV
28 (12.3)
13 (5.6)
Alcohol
15 (6.6)
11 (4.7)
PSC
6 (2.7)
11 (4.7)
NASH
6 (2.7)
6 (2.6)
Others
33 (14.5)
22 (9.4)
16.3 ± 8.3
15.1 ± 6.9
0.105
MELD (points) HCC (%)
95 (41.9)
108 (46.2)
0.352
ABO incompatibility (%)
19 (8.4)
18 (7.7)
0.790
Calcineurin inhibitor (CyA, %)
66 (29.1)
110 (47.0)
0.000
Prednisolone use (6 months, %)
77 (33.9)
100 (42.7)
0.032
MMF use for induction (%)
174 (77.0)
194 (82.9)
0.113
Follow-up duration (days)
2715 ± 1822
2809 ± 1591
0.551
Metabolic variables Dry BMI (kg/m2)
23.0 ± 3.4
23.4 ± 3.3
0.240
Pre-LDLT hypertension (%)
17 (7.5)
26 (11.1)
0.180
Pre-LDLT diabetes mellitus (%)
33 (14.5)
43 (18.4)
0.266
Pre-LDLT dyslipidemia (%)
1 (0.4)
32 (13.7)
0.000
Age (years)
37.3 ± 11.3
36.2 ± 10.6
0.320
Gender (male, %)
145 (63.9)
142 (60.7)
0.480
BMI (kg/m2)
22.2 ± 2.8
21.9 ± 2.5
0.304
Graft (Right lobe, %)
102 (44.9)
88 (37.6)
0.110
GRWR (%)
0.81 ± 0.18
0.78 ± 0.17
0.035
PVP at laparotomy (mmHg)
24.3 ± 6.2
24.9 ± 5.8
0.417
PVP at closure (mmHg)
15.9 ± 3.7
16.3 ± 3.7
0.222
Living Donor variables
Surgery variables
Cold ischemic time (min)
127.2 ± 101.0
109.5 ± 63.5
0.071
Warm ischemic time (min)
42.4 ± 12.6
40.7 ± 10.8
0.119
Splenectomy (%)
133 (58.6)
156 (66.7)
0.073
Operative blood loss (10L)
33 (14.8)
33 (14.3)
0.877
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 5 Predictors for post-LDLT hypertension, diabetes mellitus, and dyslipidemia by multivariate logistic regression analysis
Variables (n [ 461)
Multivariate analysis OR
95% CI
P value
Calcineurin inhibitor (CyA vs. TAC)
2.086
1.376–3.161
0.001
Recipient age (/years)
1.036
1.014–1.058
0.001
Hypertension
2
Dry BMI (/kg/m )
1.072
1.008–1.139
0.026
Pre-LDLT dyslipidemia (Yes vs. No)
0.481
0.196–1.180
0.099
Etiology: HCV (vs. others)
1.461
0.916–2.328
0.112
Donor gender (male vs. female)
1.353
0.886–2.066
0.161
Donor age (/years)
0.989
0.970–1.008
0.245
HCC (Yes vs. No)
1.146
0.702–1.872
0.586
MELD (/pts)
0.992
0.963–1.022
0.616
Recipient gender (male vs. female)
2.471
1.565–3.901
0.000
Recipient age (/years)
1.039
1.014–1.065
0.002
Diabetes mellitus
2
Donor BMI (/kg/m )
1.124
1.025–1.232
0.012
Splenectomy (Yes vs. No)
0.617
0.381–0.998
0.050
PVP at closure (/mmHg)
1.054
0.993–1.118
0.084
Dry BMI (/kg/m2)
1.040
0.974–1.110
0.241
MELD (/pts)
0.982
0.947–1.017
0.301
Donor gender (male vs. female)
1.241
0.781–1.971
0.361
Etiology: HCV (vs. others)
1.165
0.710–1.912
0.546
HCC (Yes vs. No)
1.147
0.676–1.946
0.612
2.015
1.338–3.034
0.001
Dyslipidemia Calcineurin inhibitor (CyA vs. TAC) Prednisolone use (6 months, Yes vs. No)
1.928
1.261–2.947
0.002
Recipient age (/years)
1.019
1.001–1.038
0.037
GRWR (/%)
0.316
0.105–0.945
0.037
Etiology: HCV (vs. others)
1.470
0.942–2.293
0.089
BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; OR, odds ratio; PVP, portal vein pressure; SLW, standard liver weight; TAC, tacrolimus. Bold character when P value < 0.05.
and these studies involved only small numbers of patients. According to the World Health Organization Expert Consultation, there are certain differences in physical constitution, such as BMI or the ratio of body fat as well as health risks between European and Japanese populations.20 In a population of 90 Singaporeans, Tan HL et al.3 reported that each of the pre-LT MS components and the use of certain immunosuppressants were also related to the development of post-LT MS, who are similar in physical attributes to the Japanese. The prevalence of the three post-LDLT metabolic diseases in our study stands at nearly half the patients (45%–60%), similar not only to the Singaporean study but also to most reports on Western populations.2,14,19 In healthy adults or patients with diseases not involving the liver, there is a difference in the prevalence of MS between Asian and European populations20; however, in cirrhotic patients with severe
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impairment of liver function, there may be similar prevalence. This is consistent with the fact that liver metabolism uniformly decreases and the prevalence of MS and its components increase as the liver function worsens, and these conditions might be independent of physical constitution.21 Aside from the presence of each pre-LDLT MS component, we identified new associations that are significant—those of older recipient age for post-LDLT each of all MS component, male recipient for post-LDLT diabetes mellitus, and high BMI for post-LDLT hypertension. In a meta-analysis of post-DDLT MS,21 three of 10 studies evaluating age as a risk factor for post-LT MS found that age was a significant risk factor with ORs of 1.04–1.05.22–24 Furthermore, two studies also evaluated gender as a risk factor for MS23,24 with, and meta-analyses confirmed this finding with OR of 1.26 (95% CI, 0.87–1.83).21 In addition,
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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obesity was also evaluated as a predictor of MS with an OR of 2.44 (95% CI, 1.48–4.03).21 Our novel findings, the points of which were different from DDLT cohort, were that the living donor-related factors such as high BMI for post-LDLT diabetes mellitus and low GRWR for post-LDLT dyslipidemia were independently associated with the prevalence of post-LT components. Further studies are needed to clarify the relationships among these factors, especially in LDLT candidates in the future. Regarding immunosuppressive medication, cyclosporine vs. tacrolimus use was found to be significantly associated with postLDLT hypertension and dyslipidemia in the present LDLT cohort. Ladevaia M et al.25 also reported that cyclosporine was associated with an increased risk of MS compared to tacrolimus, as we found. In contrast, seven studies did not find a significant correlation,21 and regarding the duration of calcineurin inhibitors used, a dose-dependent association with post-LDLT metabolic diseases could have been indicated as well.3 At this time, precise evaluation of the importance of calcineurin inhibitors may be difficult to evaluate, because most recipients receive either tacrolimus or cyclosporine. Therefore, there are practically no controls, if development of MS in patients receiving cyclosporine equaled the development of MS in patients receiving tacrolimus. However, cyclosporine is biologically reported to predispose patients to dyslipidemia and hypertension,26 and modifications to the immunosuppression regimen have been attempted to minimize the use of calcineurin inhibitors associated with MS components or to switch cyclosporine to tacrolimus could be initiated in the long-term management in these patients.2 The largest recurring association of post-LDLT metabolic diseases in the present research is also the presence of each preexisting component. These MS components before LDLT constitute a high-risk group to which interventions need to be targeted. For nonpharmacological treatment for MS after LT, AlNowaylati AR et al.27 demonstrated the possibility of combining LT with bariatric surgical procedures such as sleeve gastrectomy for obese patients to achieve effective weight loss and resolution of MS after LDLT. However, the death of a few patients because of multiple-organ dysfunction syndrome was observed in the study. Therefore, the timing, indications, and type of bariatric surgery to be applied in these obese patients remains largely controversial. In any case, patients with characteristics established as having independent associations before LDLT or other predictors need to be strictly followed after surgery and early intervention with pharmacological treatment applied, if necessary. Given that the risk factors for cardiac or cerebral events after LDLT are unclear, we might firstly have to elucidate the risk factors for these critical complications, and after that perioperative early intervention may be much effective to prevent these complications. As the risk factors for post-LDLT hypertension, pre-LDLT dyslipidemia, that has been sometimes reported as biomarker
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of the deterioration of arteriosclerosis,28 was not significant risk factor by multivariate logistic regression analysis. This might suggest that in patients after liver transplantation the three factors, such as cyclosporine use, older age of recipient, and recipients’ high BMI, is much more important to cause post-LDLT hypertension than dyslipidemia. For post-LDLT diabetes mellitus, three factors, male recipient, older age of recipient, and donor’s high BMI were independent risk factors. In particular, given that donor’s high BMI indicate obese donor, this might have the potential graft-related diabetes mellitus. There was no report about the graft-related diabetes mellitus in the setting of liver transplantation. Further accumulation of the corresponding cases should be needed to elucidate these relationships. In addition, four factors, such as cyclosporine use, prolonged prednisolone use, older age of recipient, and low GRWR levels were independent risk factors for post-LDLT dyslipidemia. Considering that low GRWR levels means low graft function which is also related to lipid metabolism,29 it might be very effective to select rather large graft to prevent post-LDLT dyslipidemia if possible. A major limitation of our study is its retrospective nature, which limits the ability to establish causal relationships between post-LDLT metabolic outcomes and related factors. We did not extrapolate to investigate the impact on long-term cardiovascular events and survival found in liver transplant populations, as has been done in some recent reports.24,30 We believe that the presence of post-LDLT MS components is a clinically significant issue, especially when the long-term outlook and survival of patients after LT are improving, meaning that more patients will live to see the effects of MS or its components after LDLT. Therefore, we are in the process of reviewing our results, focusing on cardiac evaluation in the postoperative course. In conclusion, not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component and these novel findings were different from DDLT cohort. Further alert verification for morbidity and mortality including cardiovascular prevalence is needed in the future.
Authorship T. Toshima participating in the writing of the manuscript. T. Yoshizumi participated in the study conception and the study design. S. Inokuchi, Y. Kosai-Fujimoto, T. Kurihara, S. Yoshiya, Y. Mano, and K. Takeishi participated in data acquisition. T. Toshima, S. Itoh, N. Harada, and M.Shimokawa participated in statistical data analysis and interpretation. T. Ikegami, T. Yoshizumi, Y. Soejima, and Y. Maehara participated in the review of the manuscript. M. Mori participated in the review of the manuscript and final approval.
© 2019 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Acknowledgements We thank Andrea Baird, MD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
12. Toshima T, Ikegami T, Kimura K, Harimoto N, Yamashita Y, Yoshizumi T
Conflicts of interest The authors declare no conflicts of interest.
13. Expert Panel on Detection E, Treatment of High Blood Cholesterol in A.
et al. (2014) Application of postoperative Model for End-Stage Liver Disease scoring system for evaluating liver graft function after living donor liver transplantation. Transplant Proc 46:81–86. (2001) Executive summary of the third report of the national cholesterol education Program (NCEP) Expert Panel on detection, evaluation, and
Funding sources This study was supported by the following four grants: the Program for Basic
treatment of high blood cholesterol in adults (adult treatment Panel III).
and Clinical Research on Hepatitis, from the Japan Agency for Medical
14. Garcia-Pajares F, Penas-Herrero I, Sanchez-Ocana R, Torrres-Yuste R,
JAMA 285):2486–2497.
Research and Development, AMED (Numbers 18fk0210023h0002 and
Cimavilla-Roman M, Carbajo-Lopez A et al. (2016) Metabolic syndrome
17fk0210305h0003) and JSPS KAKENHI, a Grant-in-Aid from the Ministry of
after liver transplantation: five-year prevalence and risk factors. Trans-
Health, Labor and Welfare, Japan (Numbers JP-16K10577 and JP16H06432).
plant Proc 48:3010–3012. 15. Alberti KG, Zimmet P, Shaw J. (2006) Metabolic syndrome–a new
The funding sources had no role in the collection, analysis, or interpretation of the data, or in the decision to submit the article for publication.
world-wide definition. A consensus statement from the international diabetes federation. Diabet Med 23:469–480. 16. Watt KD, Charlton MR. (2010) Metabolic syndrome and liver trans-
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
https://doi.org/10.1016/j.hpb.2019.08.008
ORIGINAL ARTICLE
Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation Takeo Toshima1, Tomoharu Yoshizumi1, Shoichi Inokuchi1, Yukiko Kosai-Fujimoto1, Takeshi Kurihara1, Shohei Yoshiya1, Yohei Mano1, Kazuki Takeishi1, Shinji Itoh1, Noboru Harada1, Toru Ikegami1, Yuji Soejima1, Mototsugu Shimokawa2, Yoshihiko Maehara1 & Masaki Mori1 1
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, and 2Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
Abstract Background: Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors. Methods: Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively. Results: Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P < 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for postLDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well. Conclusions: Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component. Received 14 February 2019; accepted 12 August 2019
Correspondence Takeo Toshima, Department of Surgery and Science, Graduate School of Medicine, Kyushu University, 31-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: [email protected]
Introduction For more than two decades, liver transplantation (LT) has been accepted as the most effective treatment for end-stage liver disease.1 The 5- and 10-year survival rates after LT are 70– 80%, and a mortality rate over 60% is reported to be unrelated to liver function.2 Complications following LT significantly affect the quality of life in long-term survival and metabolic syndrome (MS) is now the most common longterm complication after LT and has been increasing recently with an incidence of 50 –60%.2,3 Additionally, MS is an established risk factor for atherosclerosis and cardiovascular disease, which result in high mortality, increased 4-fold by the presence of MS.
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Several retrospective studies, many of which report on small numbers of patients, have shown a prevalence of MS after deceased donor liver transplantation (DDLT).2–4 However, the actual risk factors for each MS component after living donor liver transplantation (LDLT) remain to be established. Besides, some risk factors such as certain aspects of living donor related factors (age, gender, graft volume) and immunosuppression (particularly the use of calcineurin inhibitors and corticosteroids) should be investigated. Therefore, the aim of this study was to clarify the prevalence of and risk factors for MS components such as hypertension, diabetes mellitus, and dyslipidemia after LDLT and to identify the predictors for each MS component including characteristics of living donors.
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Materials and methods Patient characteristics A total of 522 adult patients who underwent LDLT at Kyushu University Hospital (Fukuoka, Japan) from January 1998 through December 2015 were enrolled in the study. Among these, 461 recipients whose data were obtained in detail from the medical records were retrospectively analyzed. The etiology of liver diseases included acute liver failure (n = 61) and liver cirrhosis due to hepatitis C (n = 183), primary biliary cholangitis (n = 66), hepatitis B (n = 41), alcohol abuse (n = 26), primary sclerosing cholangitis (n = 17), nonalcoholic steatohepatitis (n = 12), and others (n = 55). Graft types included left lobe with caudate lobe graft (n = 265), right lobe graft without the middle hepatic vein (n = 190), and posterior segment graft (n = 6), by the selection criteria as previously described.5–7 The median age in our study population was 53 (18–74) years, with a male preponderance (n = 216, 46.9%). The median Model for EndStage Liver Disease (MELD) score was 15.7 (1–54) points and nearly half the patients had hepatocellular carcinoma (HCC) at the time of LDLT (n = 203, 44.0%). All LDLTs were performed after obtaining full informed consent from all patients and approval by the Liver Transplantation Committee of Kyushu University. The study protocol conformed to the ethical guidelines of the 1975 Helsinki Declaration and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board of ethics committee. Surgery and postoperative management The graft harvesting technique, recipient surgery, and perioperative management of recipients, including immunosuppression regimens, have been previously described.5,8,9 Simultaneous splenectomy was performed in 271 recipients (58.8%) to decrease portal vein pressure10 and 18 recipients underwent splenectomy before LDLT. Since 2001, duct-to-duct anastomosis has been preferred to Roux-en-Y hepaticojejunostomy for bile duct reconstruction and was performed over a 2.0 mm C-tube with intermittent 6-0 PDS-II sutures (Ethicon Inc., Somerville, NJ, USA).11 Immunosuppression was initiated with a protocol based on either tacrolimus (Prograf; Astellas Pharma Inc., Tokyo, Japan) or cyclosporine A (Neoral; Novartis Pharma K.K., Tokyo, Japan), with steroid and/or mycophenolate mofetil (MMF; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan).12 Tacrolimus was used in 285 recipients (61.8%) and cyclosporine A in 176 recipients (38.2%). The target trough level for tacrolimus was set at 10 ng/ ml for 3 months after LDLT, followed by 5–10 ng/ml thereafter. The target trough level for cyclosporine A was set at 250 ng/ml for 3 months after LDLT, followed by 150–200 ng/ml thereafter. Methylprednisolone was initiated on the day of LDLT, then tapered and converted to prednisolone 7 days after LDLT. Prednisolone treatment was tapered and discontinued 6 months
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after LDLT. MMF was used in 368 recipients (79.8%) and was started at 1000 mg/day on the day after LDLT, then tapered and discontinued by 6 months after LDLT. Trough levels were not measured for MMF. All patients had monthly follow-ups at least 6 months after surgery to check the trough of calcineurin inhibitors and routine blood chemistry test including fast glucose, triglyceride, and low-density lipoprotein. After that, as the patient condition got stable, the follow-up period extended up to every 3 months.10,12 The median follow-up period was 2763 days (1282 days and 4142 days were the 25th and 75th percentiles, respectively). Definition of MS components: hypertension, diabetes mellitus, and dyslipidemia Three MS components, hypertension, diabetes mellitus, and dyslipidemia, were defined using the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria,13,14 with a modification (Table 1). According to the consensus report15 for the practical extensions to the NCEP ATP III criteria, hypertension, diabetes mellitus, and dyslipidemia were considered present if recorded as a medical diagnosis, or if the patient was on pharmacological therapy for any of these conditions both pre- and post-LDLT.2,16 In particular, regarding the diagnosis for hypertension, after excluding the other diseases that cause hypertension (eg. pheochromocytoma), we clinically diagnosed patients with blood pressure measured at least twice in the hospital or blood pressure at home consistently over 130/85. In addition, because values of serum high-density lipoprotein were not available in the past data, serum total cholesterol 200 mg/dl was adopted to define dyslipidemia instead, as suggested by the supplementary notes in the NCEP ATP III criteria.13 Details pertaining to the onset and progression of these chronic conditions were also captured in the data-collection process. Statistical analysis All statistical analyses were performed with JMP statistical software version 13 (SAS Institute Inc., Cary, NC, USA). Continuous variables were expressed as mean ± standard deviation and compared using the unpaired t-test.17 McNemar test was used to compare the correlated categorical values and Chi squared test for the non-correlated categorical values. Multivariate analyses were performed with logistic regression model and the odds ratio (OR) was calculated for an increment of 1 unit for continuous variables.18 P values < 0.05 were considered significant.
Results Prevalence of hypertension, diabetes mellitus, and dyslipidemia The prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3% (n = 43), 16.5% (n = 76), and 7.2% (n = 33) before LDLT to 44.9% (n = 207),
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 1 MS component by modified NCEP ATP III criteria and the prevalence
MS component
Definition
P value
LDLT Pre (%)
Post (%)
Hypertension
BP 130/85 mmHg or pharmacologic treatment
43 (9.3)
207 (44.9)
0.000
Diabetes mellitus
Fasting serum glucose 110 mg/dL or pharmacologic treatment
76 (16.5)
209 (45.3)
0.000
Dyslipidemia
Serum triglyceride 150 mg/dL or serum total cholesterol 200 mg/dL or pharmacologic treatment
33 (7.2)
234 (50.8)
0.000
ATP, Adult Treatment Panel; BP, blood pressure; LDLT, living donor liver transplant; MS, metabolic syndrome; NCEP, National Cholesterol Education Program.
45.3% (n = 209), and 50.8% (n = 234) after LDLT, respectively (Table 1).
recipient weight ratio (GRWR) (0.78 ± 0.17 vs. 0.81 ± 0.18, P = 0.039) (Table 4).
Risk factors for post-LDLT hypertension Post-LDLT hypertension was significantly associated with older age of the recipient (56.4 ± 9.0 vs. 50.3 ± 12.5 years, P < 0.001), the high rate of HCV as etiology (52.7% vs. 29.1%, P = 0.001), low MELD score (15.0 ± 6.9 vs. 16.3 ± 8.2 pts, P = 0.042), presence of HCC (56.0% vs. 34.3%, P < 0.001), high rate of cyclosporine use (50.7% vs. 28.0%, P < 0.001), heavy dry weight (61.4 ± 11.2 vs. 59.0 ± 10.7 kg, P = 0.022), high dry body mass index (BMI) (23.8 ± 3.4 vs. 22.7 ± 3.2 kg/m2, P < 0.001), presence of pre-LDLT hypertension (20.8% vs. 0.4%, P < 0.001), absence of pre-LDLT dyslipidemia (3.9% vs. 9.8%, P = 0.011), younger donor age (35.1 ± 10.6 vs. 38.1 ± 11.1, P = 0.003), male donor (67.6% vs. 57.9%, P = 0.031) (Table 2). There were no significant differences in surgery-related factors between the two groups.
Predictors for post-LDLT hypertension, diabetes mellitus, and dyslipidemia by multivariate analysis Table 5 shows each predictor for post-LDLT hypertension, diabetes mellitus, and dyslipidemia. Multivariate logistic regression analysis was performed using the data excluding the presence of each pre-LDLT MS component. The three factors, cyclosporine use (OR 2.086, 95% CI 1.376–3.161, P = 0.001), recipient age (per year, OR 1.036, 95% CI 1.014–1.058, P = 0.001), and dry BMI (per kg/m2, OR 1.072, 95% CI 1.008–1.139, P = 0.026) were independent risk factors for post-LDLT hypertension. Besides, three factors, male recipient (OR 2.471, 95% CI 1.565–3.901, P < 0.001), recipient age (per year, OR 1.039, 95% CI 1.014–1.065, P = 0.002), and donor BMI (per kg/m2, OR 1.124, 95% CI 1.025–1.232, P = 0.012) were independent risk factors for post-LDLT diabetes mellitus. Final, four factors, cyclosporine use (OR 2.015, 95% CI 1.338–3.034, P = 0.001), prolonged prednisolone use (OR 1.928, 95% CI 1.261–2.947, P = 0.002), recipient age (per year, OR 1.019, 95% CI 1.001–1.038, P = 0.037), and GRWR (per %, OR 0.316, 95% CI 0.105–0.945, P = 0.037) were independent risk factors for postLDLT dyslipidemia (Table 5).
Risk factors for post-LDLT diabetes mellitus Post-LDLT diabetes mellitus was significantly associated with older recipient age (54.7 ± 9.6 vs. 51.6 ± 12.7 years, P = 0.004), male recipient (58.9% vs. 36.9%, P < 0.001), the high rate of HCV as etiology (48.3% vs. 32.5%, P = 0.002), low MELD score (14.7 ± 7.1 vs. 16.5 ± 7.9 pts, P = 0.011), presence of HCC (53.6% vs. 36.1%, P = 0.001), heavy dry weight (62.3 ± 10.7 vs. 58.3 ± 10.8 kg, P < 0.001) and high dry BMI (23.6 ± 3.4 vs. 22.9 ± 3.3 kg/m2, P = 0.023), pre-LDLT diabetes mellitus (35.9% vs. 0.4%, P < 0.001), male donor (68.4% vs. 57.1%, P = 0.013), high donor BMI (22.4 ± 2.6 vs. 21.8 ± 2.7 kg/m2, P = 0.023), high portal vein pressure (PVP) level at closure (16.6 ± 3.9 vs. 15.7 ± 3.5, P = 0.016), absence of splenectomy during liver transplant surgery (57.4% vs. 67.1%, P = 0.033) (Table 3). Risk factors for post-LDLT dyslipidemia Post-LDLT dyslipidemia was significantly associated with older recipient age (54.6 ± 9.9 vs. 51.4 ± 12.8 years, P = 0.003), the high rate of HCV as etiology (45.3% vs. 33.9%, P = 0.004), high rate of cyclosporine use (47.0% vs. 29.1%, P < 0.001), prednisolone use 6 months (42.7% vs. 33.9%, P = 0.032), pre-LDLT dyslipidemia (13.7% vs. 0.4%, P < 0.001), and low graft-
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Discussion This is the first large study to investigate the clinical risk factors for each MS component such as hypertension, diabetes mellitus, and dyslipidemia after LDLT including characteristics related to the living donors and surgical factors. According to multivariate analysis, not only the recipient factors (cyclosporine use, prolonged prednisolone use, age, male gender, and high BMI) but also the donor factors (high BMI and low GRWR) were independently associated with each targeted post-LDLT MS component. Pre-LT MS and each of the three components, have emerged as increasingly prevalent conditions among candidates for LT, and post-LT MS also applies.2 Some studies have demonstrated preand post-DDLT MS in Western populations,2,19 but the applicability of such findings to an Asian population remains unclear
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Table 2 Risk factors for post-LDLT hypertension
Variables (n [ 461)
Post-LDLT hypertension No (n [ 254)
Yes (n [ 207)
P value
Recipient Age (years)
50.3 ± 12.5
56.4 ± 9.0
0.000
Gender (male, %)
121 (47.6)
95 (45.9)
0.709
HCV
74 (29.1)
109 (52.7)
PBC
41 (16.2)
25 (12.1)
ALF
39 (15.4)
22 (10.6)
HBV
27 (10.6)
14 (6.8)
Alcohol
17 (6.7)
9 (4.3)
PSC
13 (5.1)
4 (1.9)
NASH
9 (3.5)
3 (1.5)
Others
34 (13.4)
21 (10.1)
16.3 ± 8.2
15.0 ± 6.9
Etiology (%)
MELD (points)
0.001
0.042
HCC (%)
87 (34.3)
116 (56.0)
0.000
ABO incompatibility (%)
21 (8.3)
16 (7.7)
0.832
Calcineurin inhibitor (CyA, %)
71 (28.0)
105 (50.7)
0.000
Prednisolone use (6 months, %)
104 (40.9)
73 (35.3)
0.212
MMF use for induction (%)
196 (77.5)
172 (83.1)
0.132
Follow-up duration (days)
2649 ± 1687
2903 ± 1725
0.112
0.000
Metabolic variables Dry BMI (kg/m2)
22.7 ± 3.2
23.8 ± 3.4
Pre-LDLT hypertension (%)
1 (0.4)
43 (20.8)
0.000
Pre-LDLT diabetes mellitus (%)
37 (14.6)
39 (18.8)
0.220
Pre-LDLT dyslipidemia (%)
25 (9.8)
8 (3.9)
0.011
Age (years)
38.1 ± 11.1
35.1 ± 10.6
0.003
Gender (male, %)
147 (57.9)
140 (67.6)
0.031
BMI (kg/m2)
22.0 ± 2.5
22.1 ± 2.8
0.666
Graft (Right lobe, %)
102 (40.2)
88 (42.5)
0.610
GRWR (%)
0.80 ± 0.18
0.79 ± 0.18
0.862
PVP at laparotomy (mmHg)
24.8 ± 5.9
24.5 ± 6.2
0.674
PVP at closure (mmHg)
16.0 ± 3.8
16.2 ± 3.6
0.652
Living Donor variables
Surgery variables
Cold ischemic time (min)
116.9 ± 97.4
118.8 ± 61.2
0.842
Warm ischemic time (min)
41.6 ± 12.4
41.4 ± 10.9
0.856
Splenectomy (%)
155 (61.0)
134 (64.7)
0.412
Operative blood loss (10L)
33 (13.3)
33 (16.1)
0.393
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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Table 3 Risk factors for post-LDLT diabetes mellitus
Variables (n [ 461)
Post-LDLT diabetes mellitus No (n [ 252)
Yes (n [ 209)
P value
Recipient Age (years)
51.6 ± 12.7
54.7 ± 9.6
0.004
Gender (male, %)
93 (36.9)
123 (58.9)
0.000
HCV
82 (32.5)
101 (48.3)
PBC
49 (19.4)
17 (8.1)
Etiology (%)
0.002
ALF
34 (13.5)
27 (12.9)
HBV
21 (8.3)
20 (9.6)
Alcohol
15 (6.0)
11 (5.3)
PSC
13 (5.2)
4 (1.9)
NASH
6 (2.4)
6 (2.9)
Others
32 (12.7)
23 (11.0)
16.5 ± 7.9
14.7 ± 7.1
MELD (points)
0.011
HCC (%)
91 (36.1)
112 (53.6)
0.001
ABO incompatibility (%)
21 (8.3)
16 (7.7)
0.790
Calcineurin inhibitor (CyA, %)
99 (39.3)
77 (36.8)
0.591
Prednisolone use (6 months, %)
107 (42.5)
70 (33.5)
0.055
MMF use for induction (%)
207 (82.5)
161 (77.0)
0.147
Follow-up duration (days)
2676 ± 1684
2867 ± 1733
0.230
Metabolic variables Dry BMI (kg/m2)
22.9 ± 3.3
23.6 ± 3.4
0.012
Pre-LDLT hypertension (%)
23 (9.1)
20 (9.6)
0.871
Pre-LDLT diabetes mellitus (%)
1 (0.4)
75 (35.9)
0.000
Pre-LDLT dyslipidemia (%)
20 (7.9)
13 (6.2)
0.475
Age (years)
37.4 ± 11.0
36.0 ± 10.9
0.185
Gender (male, %)
144 (57.1)
143 (68.4)
0.013
BMI (kg/m2)
21.8 ± 2.7
22.4 ± 2.6
0.023
Graft (Right lobe, %)
104 (41.3)
86 (41.2)
0.979
GRWR (%)
0.80 ± 0.19
0.78 ± 0.16
0.160
PVP at laparotomy (mmHg)
24.7 ± 6.0
24.5 ± 5.9
0.774
PVP at closure (mmHg)
15.7 ± 3.5
16.6 ± 3.9
0.016
Cold ischemic time (min)
116.2 ± 63.6
120.1 ± 107.3
0.696
Warm ischemic time (min)
42.2 ± 12.4
40.6 ± 10.8
0.147
Splenectomy (%)
169 (67.1)
120 (57.4)
0.033
Operative blood loss (10L)
31 (12.5)
35 (16.7)
0.178
Living Donor variables
Surgery variables
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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Table 4 Risk factors for post-LDLT dyslipidemia
Variables (n [ 461)
Post-LDLT dyslipidemia No (n [ 227)
Yes (n [ 234)
P value
Recipient Age (years)
51.4 ± 12.8
54.6 ± 9.9
0.003
Gender (male, %)
111 (48.9)
105 (44.9)
0.386
HCV
77 (33.9)
106 (45.3)
PBC
25 (11.0)
41 (17.5)
Etiology (%)
0.004
ALF
37 (16.3)
24 (10.2)
HBV
28 (12.3)
13 (5.6)
Alcohol
15 (6.6)
11 (4.7)
PSC
6 (2.7)
11 (4.7)
NASH
6 (2.7)
6 (2.6)
Others
33 (14.5)
22 (9.4)
16.3 ± 8.3
15.1 ± 6.9
0.105
MELD (points) HCC (%)
95 (41.9)
108 (46.2)
0.352
ABO incompatibility (%)
19 (8.4)
18 (7.7)
0.790
Calcineurin inhibitor (CyA, %)
66 (29.1)
110 (47.0)
0.000
Prednisolone use (6 months, %)
77 (33.9)
100 (42.7)
0.032
MMF use for induction (%)
174 (77.0)
194 (82.9)
0.113
Follow-up duration (days)
2715 ± 1822
2809 ± 1591
0.551
Metabolic variables Dry BMI (kg/m2)
23.0 ± 3.4
23.4 ± 3.3
0.240
Pre-LDLT hypertension (%)
17 (7.5)
26 (11.1)
0.180
Pre-LDLT diabetes mellitus (%)
33 (14.5)
43 (18.4)
0.266
Pre-LDLT dyslipidemia (%)
1 (0.4)
32 (13.7)
0.000
Age (years)
37.3 ± 11.3
36.2 ± 10.6
0.320
Gender (male, %)
145 (63.9)
142 (60.7)
0.480
BMI (kg/m2)
22.2 ± 2.8
21.9 ± 2.5
0.304
Graft (Right lobe, %)
102 (44.9)
88 (37.6)
0.110
GRWR (%)
0.81 ± 0.18
0.78 ± 0.17
0.035
PVP at laparotomy (mmHg)
24.3 ± 6.2
24.9 ± 5.8
0.417
PVP at closure (mmHg)
15.9 ± 3.7
16.3 ± 3.7
0.222
Living Donor variables
Surgery variables
Cold ischemic time (min)
127.2 ± 101.0
109.5 ± 63.5
0.071
Warm ischemic time (min)
42.4 ± 12.6
40.7 ± 10.8
0.119
Splenectomy (%)
133 (58.6)
156 (66.7)
0.073
Operative blood loss (10L)
33 (14.8)
33 (14.3)
0.877
ALF, acute liver failure; BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; GW, graft weight; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; PVP, portal vein pressure; SLW, standard liver weight. Bold character when P value < 0.05.
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Table 5 Predictors for post-LDLT hypertension, diabetes mellitus, and dyslipidemia by multivariate logistic regression analysis
Variables (n [ 461)
Multivariate analysis OR
95% CI
P value
Calcineurin inhibitor (CyA vs. TAC)
2.086
1.376–3.161
0.001
Recipient age (/years)
1.036
1.014–1.058
0.001
Hypertension
2
Dry BMI (/kg/m )
1.072
1.008–1.139
0.026
Pre-LDLT dyslipidemia (Yes vs. No)
0.481
0.196–1.180
0.099
Etiology: HCV (vs. others)
1.461
0.916–2.328
0.112
Donor gender (male vs. female)
1.353
0.886–2.066
0.161
Donor age (/years)
0.989
0.970–1.008
0.245
HCC (Yes vs. No)
1.146
0.702–1.872
0.586
MELD (/pts)
0.992
0.963–1.022
0.616
Recipient gender (male vs. female)
2.471
1.565–3.901
0.000
Recipient age (/years)
1.039
1.014–1.065
0.002
Diabetes mellitus
2
Donor BMI (/kg/m )
1.124
1.025–1.232
0.012
Splenectomy (Yes vs. No)
0.617
0.381–0.998
0.050
PVP at closure (/mmHg)
1.054
0.993–1.118
0.084
Dry BMI (/kg/m2)
1.040
0.974–1.110
0.241
MELD (/pts)
0.982
0.947–1.017
0.301
Donor gender (male vs. female)
1.241
0.781–1.971
0.361
Etiology: HCV (vs. others)
1.165
0.710–1.912
0.546
HCC (Yes vs. No)
1.147
0.676–1.946
0.612
2.015
1.338–3.034
0.001
Dyslipidemia Calcineurin inhibitor (CyA vs. TAC) Prednisolone use (6 months, Yes vs. No)
1.928
1.261–2.947
0.002
Recipient age (/years)
1.019
1.001–1.038
0.037
GRWR (/%)
0.316
0.105–0.945
0.037
Etiology: HCV (vs. others)
1.470
0.942–2.293
0.089
BMI, body mass index; CyA, Cyclosporine; GRWR, graft-recipient weight ratio; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; OR, odds ratio; PVP, portal vein pressure; SLW, standard liver weight; TAC, tacrolimus. Bold character when P value < 0.05.
and these studies involved only small numbers of patients. According to the World Health Organization Expert Consultation, there are certain differences in physical constitution, such as BMI or the ratio of body fat as well as health risks between European and Japanese populations.20 In a population of 90 Singaporeans, Tan HL et al.3 reported that each of the pre-LT MS components and the use of certain immunosuppressants were also related to the development of post-LT MS, who are similar in physical attributes to the Japanese. The prevalence of the three post-LDLT metabolic diseases in our study stands at nearly half the patients (45%–60%), similar not only to the Singaporean study but also to most reports on Western populations.2,14,19 In healthy adults or patients with diseases not involving the liver, there is a difference in the prevalence of MS between Asian and European populations20; however, in cirrhotic patients with severe
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impairment of liver function, there may be similar prevalence. This is consistent with the fact that liver metabolism uniformly decreases and the prevalence of MS and its components increase as the liver function worsens, and these conditions might be independent of physical constitution.21 Aside from the presence of each pre-LDLT MS component, we identified new associations that are significant—those of older recipient age for post-LDLT each of all MS component, male recipient for post-LDLT diabetes mellitus, and high BMI for post-LDLT hypertension. In a meta-analysis of post-DDLT MS,21 three of 10 studies evaluating age as a risk factor for post-LT MS found that age was a significant risk factor with ORs of 1.04–1.05.22–24 Furthermore, two studies also evaluated gender as a risk factor for MS23,24 with, and meta-analyses confirmed this finding with OR of 1.26 (95% CI, 0.87–1.83).21 In addition,
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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obesity was also evaluated as a predictor of MS with an OR of 2.44 (95% CI, 1.48–4.03).21 Our novel findings, the points of which were different from DDLT cohort, were that the living donor-related factors such as high BMI for post-LDLT diabetes mellitus and low GRWR for post-LDLT dyslipidemia were independently associated with the prevalence of post-LT components. Further studies are needed to clarify the relationships among these factors, especially in LDLT candidates in the future. Regarding immunosuppressive medication, cyclosporine vs. tacrolimus use was found to be significantly associated with postLDLT hypertension and dyslipidemia in the present LDLT cohort. Ladevaia M et al.25 also reported that cyclosporine was associated with an increased risk of MS compared to tacrolimus, as we found. In contrast, seven studies did not find a significant correlation,21 and regarding the duration of calcineurin inhibitors used, a dose-dependent association with post-LDLT metabolic diseases could have been indicated as well.3 At this time, precise evaluation of the importance of calcineurin inhibitors may be difficult to evaluate, because most recipients receive either tacrolimus or cyclosporine. Therefore, there are practically no controls, if development of MS in patients receiving cyclosporine equaled the development of MS in patients receiving tacrolimus. However, cyclosporine is biologically reported to predispose patients to dyslipidemia and hypertension,26 and modifications to the immunosuppression regimen have been attempted to minimize the use of calcineurin inhibitors associated with MS components or to switch cyclosporine to tacrolimus could be initiated in the long-term management in these patients.2 The largest recurring association of post-LDLT metabolic diseases in the present research is also the presence of each preexisting component. These MS components before LDLT constitute a high-risk group to which interventions need to be targeted. For nonpharmacological treatment for MS after LT, AlNowaylati AR et al.27 demonstrated the possibility of combining LT with bariatric surgical procedures such as sleeve gastrectomy for obese patients to achieve effective weight loss and resolution of MS after LDLT. However, the death of a few patients because of multiple-organ dysfunction syndrome was observed in the study. Therefore, the timing, indications, and type of bariatric surgery to be applied in these obese patients remains largely controversial. In any case, patients with characteristics established as having independent associations before LDLT or other predictors need to be strictly followed after surgery and early intervention with pharmacological treatment applied, if necessary. Given that the risk factors for cardiac or cerebral events after LDLT are unclear, we might firstly have to elucidate the risk factors for these critical complications, and after that perioperative early intervention may be much effective to prevent these complications. As the risk factors for post-LDLT hypertension, pre-LDLT dyslipidemia, that has been sometimes reported as biomarker
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of the deterioration of arteriosclerosis,28 was not significant risk factor by multivariate logistic regression analysis. This might suggest that in patients after liver transplantation the three factors, such as cyclosporine use, older age of recipient, and recipients’ high BMI, is much more important to cause post-LDLT hypertension than dyslipidemia. For post-LDLT diabetes mellitus, three factors, male recipient, older age of recipient, and donor’s high BMI were independent risk factors. In particular, given that donor’s high BMI indicate obese donor, this might have the potential graft-related diabetes mellitus. There was no report about the graft-related diabetes mellitus in the setting of liver transplantation. Further accumulation of the corresponding cases should be needed to elucidate these relationships. In addition, four factors, such as cyclosporine use, prolonged prednisolone use, older age of recipient, and low GRWR levels were independent risk factors for post-LDLT dyslipidemia. Considering that low GRWR levels means low graft function which is also related to lipid metabolism,29 it might be very effective to select rather large graft to prevent post-LDLT dyslipidemia if possible. A major limitation of our study is its retrospective nature, which limits the ability to establish causal relationships between post-LDLT metabolic outcomes and related factors. We did not extrapolate to investigate the impact on long-term cardiovascular events and survival found in liver transplant populations, as has been done in some recent reports.24,30 We believe that the presence of post-LDLT MS components is a clinically significant issue, especially when the long-term outlook and survival of patients after LT are improving, meaning that more patients will live to see the effects of MS or its components after LDLT. Therefore, we are in the process of reviewing our results, focusing on cardiac evaluation in the postoperative course. In conclusion, not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component and these novel findings were different from DDLT cohort. Further alert verification for morbidity and mortality including cardiovascular prevalence is needed in the future.
Authorship T. Toshima participating in the writing of the manuscript. T. Yoshizumi participated in the study conception and the study design. S. Inokuchi, Y. Kosai-Fujimoto, T. Kurihara, S. Yoshiya, Y. Mano, and K. Takeishi participated in data acquisition. T. Toshima, S. Itoh, N. Harada, and M.Shimokawa participated in statistical data analysis and interpretation. T. Ikegami, T. Yoshizumi, Y. Soejima, and Y. Maehara participated in the review of the manuscript. M. Mori participated in the review of the manuscript and final approval.
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Please cite this article as: Toshima Tet al., Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation, HPB, https://doi.org/10.1016/j.hpb.2019.08.008
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Acknowledgements We thank Andrea Baird, MD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
12. Toshima T, Ikegami T, Kimura K, Harimoto N, Yamashita Y, Yoshizumi T
Conflicts of interest The authors declare no conflicts of interest.
13. Expert Panel on Detection E, Treatment of High Blood Cholesterol in A.
et al. (2014) Application of postoperative Model for End-Stage Liver Disease scoring system for evaluating liver graft function after living donor liver transplantation. Transplant Proc 46:81–86. (2001) Executive summary of the third report of the national cholesterol education Program (NCEP) Expert Panel on detection, evaluation, and
Funding sources This study was supported by the following four grants: the Program for Basic
treatment of high blood cholesterol in adults (adult treatment Panel III).
and Clinical Research on Hepatitis, from the Japan Agency for Medical
14. Garcia-Pajares F, Penas-Herrero I, Sanchez-Ocana R, Torrres-Yuste R,
JAMA 285):2486–2497.
Research and Development, AMED (Numbers 18fk0210023h0002 and
Cimavilla-Roman M, Carbajo-Lopez A et al. (2016) Metabolic syndrome
17fk0210305h0003) and JSPS KAKENHI, a Grant-in-Aid from the Ministry of
after liver transplantation: five-year prevalence and risk factors. Trans-
Health, Labor and Welfare, Japan (Numbers JP-16K10577 and JP16H06432).
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The funding sources had no role in the collection, analysis, or interpretation of the data, or in the decision to submit the article for publication.
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Appendix A. Supplementary data
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