characteristics and perioperative changes of nutritional parameters in patients undergoing living...

Characteristics and perioperative changes of nutritional parameters in patients undergoing

living donor liver transplantation（生体肝移植患者における栄養学的パラメーターの特徴と周術期変化に関する検討 )Ahmed Hammad

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation

Department of Surgery, Graduate School of Medicine, Kyoto University

Protein-energy malnutrition is common in patients with end-stage liver diseases including decompensated liver cirrhosis (LC) requiring liver transplantation (LT).

Derangements of nutritional/metabolic parameters are common in those patients.

Pre-transplant low skeletal muscle mass (SMM) is an independent risk factor for death after living donor LT (LDLT).

2

Background

Kaido T et al. Am J Transplant 2013

Merli M et al. Liver Int. 2010

O’brien A et al. Gastroenterology 2006

3

Patients with LC frequently receive branched-chain amino acid

(BCAA) to delay reduction of hepatic reserve.

A successful LT would be sufficient to correct the disturbed

amino acid-nitrogen imbalance in LC.

Short- and long-term changes in nutritional/metabolic parameters

could reflect adequacy of the graft mass to provide sufficient

metabolic and synthetic functions for the recipient.

Background

Kawamura E et al. Liver Transplant 2009

Sanchez AJ et al. Liver Transplant 2006

Tietge UG et al. Transplant Int 2003

Pre-LT nutritional status Correlation with skeletal muscle mass The effect of pre-admission BCAA administration Perioperative changes of nutritional parameters The impact of graft size remain unclear.

4

BackgroundHowever,

To clarify pre-LT nutritional status in patients undergoing LDLT

To examine the effect of pre-admission BCAA treatment

To clarify perioperative changes of nutritional parameters

To analyze the impact of graft size on the post-LT changes

5

Aims

Analysis

1. Pre-transplant nutritional status

2. Perioperative changes

3. Impact of graft size

Primary adult-to-adult LDLT February 2008 ～ August 2012 Who could undergo body composition analysis (BIA)

8

Patients

N=129

Pre-transplant nutritional status

1) Pre-LT levels

2) Correlation of Zn with other parameters

3) The effect of BCAA treatment

4) Risk factor analysis (mortality, bacteremia)

Analyzed parameters

・ Zinc (Zn)・ Prealbumin (PA)・ Total lymphocyte count (TLC)

・ Ammonia (NH3)

・ Tyrosine (Tyr)・ BCAA-to-Tyr ratio (BTR)

・ Branched chain amino acids

(BCAA)・ Skeletal muscle mass (SMM)

Nutritional Metabolic

NH3 (94.1±16.8 µg/dL)

Tyr (138.6±12.1 µmol/L)

Zn (44.4±12.6 µg/dL)

PA (6.8±2.5 mg/dL)

TLC (855.3±207.3 /µL)

BCAA (397.2±56 µmol/L)

BTR (3.1±0.5)

SMM (92% of the standard)

Pre-LT levels

13

Zn Zn deficiency are common in decompensated LC due to decreased

absorption and diuretic-induced increased urinary excretion.

Zn supplementation was found to improve glucose intolerance and decrease NH3 levels in these patients.

Zn is increasingly utilized for the liver regenerative process.

Sanchez AJ et al, Liver Transplant 2006

Pescovitz MD et al, Clin Transplant 2006

Stickel F et al. Nutr Rev 2008

Zn is crucial for LC

Pre-LT Zn level(μg/dL)

Median 39 μg/dL

88%

Normal range

Age ・ Gender

<50 ≥500

10

20

30

40

50

60

70

y

Age

Male Female0

10

20

30

40

50

60

70

Gender

P = 0.433P = 0.741

(μg/dL) (μg/dL)

Zn Zn

y

Original disease(μg/dL)

ALF Metabolic Other HBV/HCV+HCC BA HBV/HCV Alcholic-LC Cholestatic 0

10

20

30

40

50

60

70

Acute liver failure

P = 0.008 1-way ANOVA

Zn

Autoimmunehepatitis

Metabolicliver

diseases

Hepatocellular carcinoma

Biliary Atresia

HBV/HCV AlcoholicLC

PBC/PSC

† PBC/PSC: Primary Biliary Cholangitis/ Primary Sclerosing Cholangitis; HBV/HCV: Viral hepatitis B, C.

Child-Pugh

(μg/dL)

A B C0

10

20

30

40

50

60

70

P = 0.003

P < 0.001

1-way ANOVA

Zn

MELD score(μg/dL)

<20 ≥200

10

20

30

40

50

60

70P = 0.142

Zn

MELD; Model for End-stage Liver Disease


1) Pre-LT levels




PA, NH3

PA NH3

BCAA, TyrBCAA Tyr

SMM

P = 0.594

（ μg/dL ）r = - 0.087


1) Pre-LT levels




BCAA treatment BCAA treatment was given for several months before admission.

BCAA were introduced at the discretion of the attending physician

before referral of a potential recipient for LDLT.

Either in the form of 1 to 2 packets of BCAA-enriched nutrient mixture

(Aminoleban EN®; Otsuka Pharmaceutical Co., Tokyo, Japan) per day or

3 packets of BCAA granules (Livact®; Ajinomoto Pharma Co., Tokyo,

Japan) per day.

Preadmission BCAA treatment

BCAA (+)

BCAA (-)

N=66

N=63

Retrospective cohort study

Patients Characteristics BCAA+ BCAA- (n=66) (n=63)

Donor age (years) 43.7 ± 10.6 44.4 ± 11.3 0.465

Recipient age at transplantation (years) 52.2 ± 11.1 47.0 ± 14.4 0.148

Gender (male/female) 33/33 30/33 0.861

Body mass index on admission (Kg/m2) 23.0 ± 4.3 21.6 ± 4.4 0.153

Underlying disease

HCC with viral hepatitis 22 14 0.168

Viral hepatitis B/C related cirrhosis 15 17 0.684

Cholestatic diseases (PBC/PSC) 12 12 0.899

Biliary atresis post Kasai 3 5 0.486

Alcoholic cirrhosis 4 3 0.745

Metabolic disease 2 3 0.675

Non-alcoholic Steatohepatitis 2 2 0.962

Autoimmune hepatitis 2 1 0.587

Others 4 6 0.534

ABO compatibility 0.057

identical/compatible 42 50

incompatible 24 13

Preoperative Child-Pugh classification (A/B, C) 20/46 31/32 0.366

Preoperative MELD score 18.3 ± 6.9 20.5 ± 8.2 0.754

P

† PBC/PSC: Primary Biliary Cirrhosis/ Primary Sclerosing Cholangitis, HCC: Hepatocellular Carcinoma.

Variable BCAA+ BCAA-

(n=66) (n=63)

Zinc (µg/dL) 42.5 ± 10.2 44.2 ± 11.2 0.834

Prealbumin (mg/dL) 7.9 ± 2.1 5.2 ± 2.1 0.004

BCAA (µmol/L) 401.3 ± 48.2 392.7 ± 49.5 0.421

Tyrosine (µmol/L) 124.7 ± 12.4 149.2 ± 13.1 <0.001

BTR 3.7 ± 0.3 3.0 ± 0.3 0.007

Total lymphocyte count 893.3 ± 213.1 841.9 ± 215.6 0.781

Ammonia (µg/dL) 93.1 ± 17.3 96.5 ± 15.3 0.560

Skeletal muscle mass (%) 96.8 ± 13.4 92.7 ± 12.5 0.143

Nutritional/metabolic parameters on admission

P


1) Pre-LT levels




Variables

Recipient ageDonor ageSexOriginal diseaseABO blood typeChild-Pugh classificationMELD score

Pretransplant Zn PA BCAA Tyr BTR TLC NH3

Preadmission BCAA Treatment

GRWRGraftOperative timeOperative blood loss

Patient factors Nutrition factors Surgical factors

Post-transplantmortality

Univariate analysis

Variable 90-day OS P Recipient Age (y)

<60 (n=88) 86%

0.283

≥60 (n=41) 91%

Donor Age (y) <50 (n=93)

91%

0.335

≥50 (n=36) 85%

Sex Male (n=63)

91%

0.143

Female (n=66) 83%

Original disease HCC (n=36)

81%

0.144

Non-HCC (n=93) 90%

ABO blood type Compatible (n=92)

90%

0.087

Incompatible (n=37) 81%

Child-Pugh A, B (n=51)

91%

0.227

C (n=78) 84%

MELD score <20 (n=69)

92%

0.069

≥20 (n=50) 81%

GRWR <0.8% (n=36) 89% 0.426

≥0.8% (n=93) 91%

Operative time (h) <12 (n=30) 89% 0.090 ≥12 (n=99) 83%

Operative blood loss (L) <10 (n=88) 92% 0.079 ≥10 (n=41) 81%

Cont’d Variable 90-day OS PPre-LT zinc level (µg/dL) <39 (n=58) 84% 0.634

≥39 (n=71) 88% Pre-LT prealbumin level (mg/dL) <5.4 (n=64) 83% 0.343

≥5.4 (n=65) 90% Pre-LT BCAA level (µmol/L) <375.2 (n=62) 81% 0.476

≥375.2 (n=67) 85% Pre-LT BTR <2.92 (n=60) 85% 0.786

≥2.92 (n=69) 87% Pre-LT tyrosine (µmol/L) <131.7 (n=63) 89% 0.100

≥131.7 (n=66) 85% Pre-LT total lymphocyte count (/µL) <700 (n=61) 85% 0.698

≥700 (n=68) 87%

Pre-LT ammonia level (µg/dL) <87 (n=61) 90% 0.500 ≥87 (n=68) 85%

Preadmission BCAA treatment with (n=66) 91% 0.329 absent (n=63) 86%

Univariate analysis

Variable BCAA+ (n=66) BCAA- (n=63) P

Graft type 0.259

Left lobe graft 27 32

Right lobe including a posterior segment graft 39 31

Graft weight (gm) 541.1 ± 153.5 493.5 ± 113.2 0.754

Surgical duration (min) 914.0 ± 127.0 957.0 ± 167.0 0.544

Intra-operative blood loss (ml) 9556.0 ± 3544.0 9256.0 ± 3334.0 0.964

Intra-operative erythrocyte transfusion 20.9 ± 10.6 21.3 ± 10.5 0.132

Surgical variables

Post-transplantbacteremia

Bacteremia Isolation of bacteria (other than common skin contaminants) from a

single blood culture within 90 days of LT in the presence of symptoms

or signs of infection.

Bacteremia by common skin contaminants was considered only when

organism isolated from 2 individual blood cultures accompanied by

clinical signs of infection.

Definition

Univariate analysis

Variable Bacteremia P Recipient Age (y)

<60 (n=88) 47%

0.063

≥60 (n=41) 29%

Donor Age (y) <50 (n=93)

38%

0.200

≥50 (n=36) 50%

Sex Male (n=63)

41%

0.967

Female (n=66) 41%

Original disease HCC (n=36)

42%

0.933

Non-HCC (n=93) 41%

ABO blood type Compatible (n=92)

38%

0.268

Incompatible (n=37) 49%

Child-Pugh

A, B (n=51) 24%

0.001

C (n=78) 53%

MELD score

<20 (n=69) 48%

0.397

≥20 (n=50) 40%

GRWR <0.8% (n=36) 42% 0.933

≥0.8% (n=93) 41%

Operative time (h) <12 (n=30) 43% 0.755 ≥12 (n=99) 40%

Operative blood loss (L) <10 (n=88) 33% 0.010 ≥10 (n=41) 57%

Cont’d Variable Bacteremia PPre-LT zinc level (µg/dL) <39 (n=58) 41% 0.951

≥39 (n=71) 41% Pre-LT prealbumin level (mg/dL) <5.4 (n=64) 41% 0.916

≥5.4 (n=65) 42% Pre-LT BCAA level (µmol/L) <375.2 (n=62) 42% 0.850

≥375.2 (n=67) 40% Pre-LT BTR <2.92 (n=60) 42% 0.900

≥2.92 (n=69) 41% Pre-LT tyrosine (µmol/L) <131.7 (n=63) 37% 0.229

≥131.7 (n=66) 47% Pre-LT total lymphocyte count (/µL) <700 (n=61) 54% 0.004

≥700 (n=68) 29%

Pre-LT ammonia level (µg/dL) <87 (n=61) 33% 0.070 ≥87 (n=68) 49%

Preadmission BCAA treatment with (n=66) 30% 0.011 absent (n=63) 52%

Univariate analysis

Variable Odds ratio 95% CI P

Child-Pugh class C 7.322 1.600-29.996 0.012

Preoperative low TLC ( < 700/µL) 5.434 1.313-20.133 0.027

Operative blood loss ≥ 10L 4.230 1.373-16.763 0.039

Absence of preadmission BCAA treatment 2.942 1.644-8.643 0.040

Multivariate analysis of factors affecting post-LT bacteremia

† CI, confidence

interval.

Variable Odds ratio 95% CI P-Value

40

Summary 1 Significant pre-transplant hypozinocemia was seen in ESLDs and

correlated to the deterioration of LC.

Higher PA, BTR and lower Tyr were found upon preadmission BCAA

treatment.

Low pre-transplant TLC and absence of preadmission BCAA treatment

were independent risk factors for post-transplant bacteremia .

Analysis




Primary adult-to-adult LDLT Between February 2008 and August 2012

42

Patients

N=208

Zn, PA, Ammonia, TLC, BCAA, Tyr, BTR

Parameters

51

Comparison of early postoperative levels

Patients who died w/in 1 month

N=149

N=18

Patients who were alive 1 year

52

Parameter POD Patients died w/in 1m (n=18) Patients alive 1y (n=149) P

Zn 5th

7th37.3 ± 9.343.1 ± 8.3

45.6 ± 8.3 51.9 ± 9.2

0.0390.016

TLC5th

7th

14th

405.9 ± 191.1 300.0 ± 110.1 420.0 ± 164.1

583.4 ± 181.1 655.3 ± 175.1 670.9 ± 176.1

0.025<0.0010.036

TYR

2-3th

5th

7th

14th

112.4 ± 35.9 148.6 ± 33.8

123.1 ± 34.7 110.4 ± 37.9

84.5 ± 35.1 69.4 ± 34.9 80.6 ± 33.9 80.4 ± 36.4

0.006<0.0010.0030.020

BTR

2-3th

5th

7th

14th

21th

3.2 ± 0.7 3.0 ± 0.8 2.6 ± 0.7 3.5 ± 0.8 2.5 ± 0.5

3.9 ± 0.7 4.4 ± 0.94.6 ± 1.1 4.7 ± 1.1 4.6 ± 0.9

0.025<0.001<0.0010.0440.012

NH3

5th

7th

14th

21th

28th

100.2 ± 30.3 109.8 ± 36.7 96.4 ± 35.7 100.8 ± 36.1 121.3 ± 36.0

61.5 ± 19.2 51.2 ± 20.0 40.9 ± 18.1 47.1 ± 16.3 46.1 ± 16.4

0.043<0.001<0.0010.006

<0.001

53

Summary 2 Pre-transplant high NH3 and Tyr, low BTR, Zn and BCAA levels

normalized within the first 2 weeks post-transplant.

In contrast, TLC normalized in 2-3 months and PA took one year to

normalize.

Worse Lower early postoperative Zn, TLC and BTR levels while higher

TYR and NH3 levels were seen in early mortalities compared to

recipients alive 1 year post-LT.

Analysis




Analysis

Graft-to-recipient weight ratio (GRWR)

Graft size

Graft-to-recipient weight ratio (GRWR)

GRWR ≥ 0.8

GRWR < 0.8

N=141

N=67

Retrospective longitudinal study

† PBC/PSC: Primary Biliary Cirrhosis/ Primary Sclerosing Cholangitis; NASH: Non-alcoholic Steatohepatitis; HCC: Hepatocellular Carcinoma

Variable GRWR ≥ 0.8% (n = 141) GRWR < 0.8% (n = 67) P

Donor age (years) 43.4 ± 11.9 41.0 ± 10.9 0.206Recipient age at transplantation (years) 51.3 ± 12.5 48.9 ± 14.6 0.249Gender (male/female) 65/76 33/34 0.766BMI on admission (Kg/m2) 22.9 ± 4.3 23.8 ± 4.7 0.171Underlying disease 0.543 HCC on top of viral hepatitis B or C 35 17

Viral hepatitis B/C-related cirrhosis 34 12 PBC/PSC 23 11 Acute liver failure 9 6

Biliary atresia after Kasai operation 8 6

Alcoholic cirrhosis 7 4 Metabolic diseases 4 3 NASH 5 2 Autoimmune hepatitis 3 1

Other indications 13 5

Variable GRWR ≥ 0.8% (n = 141) GRWR < 0.8% (n = 67) P

ABO compatibility 0.346 identical/compatible 98 42 incompatible 43 25Pre-operative CTP class 0.754 A/B,C 48/93 21/46Pre-operative MELD score

19.8 ± 8.5 21.7 ± 10.5 0.174

Baseline levels of parametersZn (µg/dL) 44.9 ± 10.5 46.4 ± 12.4 0.594PA (mg/dL) 6.8 ± 2.3 7.3 ± 2.9 0.535BCAA (µmol/L) 388.7 ± 49.9 402.7 ± 60.2 0.380Tyr (µmol/L) 145.3 ± 13.3 151.5 ± 12.6 0.602BTR 3.4 ± 0.5 3.5 ± 0.4 0.964TLC (/µL) 852.3 ± 216.6 886.6 ± 213 0.781

NH3 (µg/dL) 98.6 ± 15.5 97 ± 17.7 0.849

59

Surgical variablesVariable GRWR ≥ 0.8% (n = 141) GRWR < 0.8% (n = 67) P

Graft type <0.001

Left lobe 48 52

Right Lobe including posterior segment graft

93* 15

Graft weight (gm) 571.1 ± 163.6 427.5 ± 114.5 <0.001

Surgical duration (min) 919 ± 138 987 ± 181 0.348

Blood loss (ml) 9598 ± 3155 9769 ± 3190 0.915

Intra-operative erythrocyte transfusion (U) 20.9 ± 10.6 20.8 ± 12.6 0.740

Cold ischemia time (min) 57.3 ± 17.2 82.4 ± 13.1 0.641

Warm ischemia time (min) 39.9 ± 12.1 46.9 ± 17.3 0.387

Peri-transplant changes of the parameters according to preoperative CTP

Department of HBP and Transplant Surgery, Kyoto University

Baseline preoperative zinc and prealbumin levels were significantly higher, whereas those of tyrosine and ammonia were significantly lower in the group with Child-Pugh class A than in the group with class C (P < 0.001, P < 0.001, P = 0.039, and P = 0.026, respectively).

Preoperative zinc and prealbumin levels were significantly higher in the group with class A than in the group with class B (P = 0.041 and P < 0.001, respectively).

None of the other parameters significantly differed among the three groups at any post-transplant time point examined.

Peri-transplant changes of the parameters in ALF recipients and other recipients


Preoperative baseline levels of ammonia, tyrosine and prealbumin were significantly higher, whereas that of BTR was significantly lower in the group with ALF compared to the group without ALF (P = 0.028, P = 0.01, P = 0.002 and P < 0.001), respectively.

Perioperative levels of all other parameters did not significantly differ between the groups at all analyzed post-transplant time points.

Peri-transplant changes of the parameters in ABO-incompatible vs.

ABO-compatible recipients


Levels of zinc, prealbumin, BCAA, tyrosine, BTR and ammonia did not significantly differ between the two groups at any time point.

However, TLC was significantly lower in the ABO-incompatible group than the compatible group during the first three post-operative weeks (POD 2/3, 5, and w1 and w3, P < 0.001; w2, P = 0.006), and remained low, although the difference was not significant.

pre-opera-

tive

2-3 days 5 days 1 week 2 weeks 3 weeks 4 weeks 2 months 3 months 6 months 1 year0

500

1000

1500

2000

2500

3000

*** ***

LDLT

*****

ABO-incompatible

***

ABO-compatible

Time after LDLT

TLC

( /µL

)

Reference normal rangeReference normal rangeReference normal range

( ** P< 0.01, *** P< 0.001 ) vs. ABO-incompatible


pre-op-erative


20

40

60

80

100

120

140

***

Reference normal range

LDLT

GRWR<0.7

0.7<GRWR≤0.8

GRWR≥0.8

Time after LDLT

Amm

onia

(µg/

dL)

** P< 0.01 vs. GRWR≥ 0.8%

Peri-transplant changes of ammonia according to GRWR < 0.7% vs. between 0.7% and 0.8% vs. ≥ 0.8%


pre-oper-ative


20

40

60

80

100

120

140

160

**


LDLT

GRWR<0.7

0.7<GRWR≤0.8

GRWR≥0.8

Time after LDLT

Tyro

sine

(µm

ol/L

)

*** P< 0.001 vs. GRWR≥ 0.8%

Peri-transplant changes of tyrosine according to GRWR < 0.7% vs. between 0.7% and 0.8% vs. ≥ 0.8%


pre-op-erative


1

2

3

4

5

6

7

8

9

***

***✲✲ ✲ ✲


***

LDLT

****** **

GRWR<0.7

0.7<GRWR≤0.8

GRWR≥0.8

Time after LDLT

BTR

(µm

ol/L

)

( ** P< 0.01 , *** P< 0.001 ) vs. GRWR< 0.7% ）

(✲ P<0.05, ✲✲ P<0.01) vs. (0.7%≤ GRWR<0.8%)

Peri-transplant changes of BTR according to GRWR < 0.7% vs. between 0.7% and 0.8% vs. ≥ 0.8%


74

Summary 3

• Nutritional parameters including Zn, PA, BCAA and TLC

recovered irrespective of graft size.

• In contrast, accelerated recovery of metabolic parameters

including NH3, Tyr and BTR levels was seen with larger-sized

grafts especially early after LT.

Preadmission BCAA treatment could ameliorate

preoperative amino acid imbalance and the incidence of

post-transplant bacteremia.

Graft size had little impact on the recovery of

nutritional/metabolic parameters except NH3 and Tyr levels.

75

Conclusion 1


Impact of preoperative quality and quantity of skeletal muscle on outcomes

after living donor liver transplantation


Muscle mass

Strength

Sarcopenia

Function

and

or

Cruz-Jentoft AJ et al. Age Ageing 2010


Kaido T, et al. Am J Transplant 2013

low

Normal/high

47

77

21

55

11

27

No. at risk

P < 0.001


QualityMass Strength

Sarcopenia


High Low

Muscle steatosis

Quality of Muscle


To investigate the impact of preoperative quality and quantity of skeletal muscle on outcomes after LDLT

Aims


Retrospective study


Patients

N = 200• Adult-to-adult LDLT• Jan 2008 ～ Oct 2013• Who could undergo preoperative plain CT


Musclemass

Evaluation for sarcopenia

PMI

IMACMusclequality

Department of HBP and Transplant Surgery, Kyoto University Hamaguchi Y, et al. Liver Transpl 2014

PMI(psoas muscle mass index)

at the umbilical level

cross-sectional areas of psoas muscles (cm2) / height2 (m2)



Hamaguchi Y, et al. Liver Transpl 2014

IMAC(intramuscular adipose tissue content)

CT values of multifidus muscles / CT values of subcutaneous fat


IMAC = -0.491

Higher IMAC Lower quality

IMAC = -0.097

IMAC


1. Differences in IMAC and PMI b/w males and females

2. Relationship b/w IMAC and various parameters

3. Survival rates classified according to IMAC and PMI

4. Risk factors for poor outcomes after LDLT

Assessment






Results


Males Females

-1.0

-0.5

0.0

0.5IM

AC


IMAC

P < 0.001

Significant higher in females


Males Females0

2

4

6

8

10

12PM

I

(cm2/m2)


PMI

P < 0.001

Significant higher in males






Results


• Age• Sex• Total lymphocyte count (TLC)• Prealbumin• BCAA/tyrosine ratio (BTR)• Zinc• PMI• Child-Pugh classification• MELD score

Parameters


malesPatient age PMI

P = 0.025 P = 0.021

Relationship with IMAC


femalesPatient age BTR

P < 0.001 P = 0.013

(BCAA-Tyrosine ratio)



MELD score

P = 0.257

Child- Pugh

P = 0.649

males



P = 0.148

Child- Pugh

P = 0.203

females


MELD score






Results


ROC curves : IMAC

Cut-off values-0.375 -0.216

AUC=0.689 AUC=0.693

males females


ROC curves : PMI

AUC=0.621 AUC=0.688

males females

Cut-off values6.868 4.117


Overall Survival : IMAC



Overall Survival : PMI







Results


Variables 1-yr OS P-value

Recipient age (y) <50 (n = 71)≥50 (n = 129)

70%78% 0.250

Donor age (y) <50 (n = 120)≥50 (n = 80)

79%70% 0.106

Sex Male (n = 95)Female (n = 105)

76%74% 0.721

Original diseaseHCC (n = 67)

HBV or HCV- LC (n = 38)PBC or PSC (n = 34)

others (n = 61)

79%76%59%80%

0.271

ABO blood type compatible (n = 140)Incompatible (n = 60)

77%72% 0.227

MELD score <20 (n = 125)≥20 (n = 75)

78%71% 0.270

Child-Pugh A, B (n = 75)C (n = 125)

80%73% 0.391

Univariate analysis


Variables 1-yr OS P-value

Operative time <12h (n = 50)≥12h (n = 150)

80%74% 0.522

Operative blood loss <10L (n = 140)≥10L (n = 60)

74%80% 0.227

GRWR <0.8% (n = 60)≥0.8% (n = 140)

80%74% 0.388

Graft Right (n = 107)Left (n = 93)

79%71% 0.085

Pretransplant IMAC High (n = 90)Normal (n = 110)

62%86% <0.001

Pretransplant PMI Low (n = 88)Normal (n = 112)

64%85% <0.001

Univariate analysis



Variable Odds ratio 95% CI P-Value

Left lobe graft

Pretransplant high IMAC

1.614

3.898

0.840 – 3.127

2.025 – 7.757

0.151

<0.001

Variable Odds ratio 95% CI P-ValueLeft lobe graft

Pretransplant low PMI

1.532

3.635

0.797– 2.960

1.896 – 7.174

0.200

<0.001

Multivariate analysis



Prospective study


P < 0.001

Sarcopenia in LDLT

Low muscle mass → Low OS

Kaido et al. Am J Transplant 2013


New selection criteria

Jan 2013 ～


1. Walk by oneself2. …3. …

+Nutritional therapy

Rehabilitation

New selection criteria(Excluding acute liver failure)


Perioperative nutritional therapy

1. Pre-ope BCAA enriched formula

2. Late evening snack (LES)

3. Zinc supplement4. Synbiotics

5. Immunonutrition

6. Pre-ope oral rehydration therapy

7. Early enteral nutrition with whey


N = 55

Patients

• Adult-to-adult LDLT• Jan 2013 ～ Dec 2014


Overall Survival1-y94%

2013 ～


P = 0.008

2013 ～1994 ～ 2012

New criteria

Previous

criteria

Overall Survival

(n = 764)


<90% of standard

muscle mass

Kaido T et al. Am J Transplant 2013Chen LK et al. JAMDA 2014

Muscle mass

Grip strengthMale 　

<26kgFemale 　

<18kg

Musclestrengthand

Definition of sarcopenia


1-y94%

2013 ～

Overall survival

All patients who died within 1 year after LDLT had preoperative sarcopenia


Preoperative quality as well as quantity of skeletal muscle was closely involved with post-transplant mortality

Conclusion 2

New selection criteria considering sarcopenia markedly improved outcomes after LDLT

LDLT


Preoperative intramuscular adipose tissue content is a novel prognostic predictor after hepatectomy

for hepatocellular carcinoma


To investigate the impact of sarcopenia on outcomes after

hepatectomy for HCC

Aims


Patients

N = 477• April 2005 ～ August 2014• Preoperative plain CT was available


Musclemass

Evaluation for sarcopenia

PMI

IMACMusclequality

Department of HBP and Transplant Surgery, Kyoto University Hamaguchi Y, et al. Liver Transpl 2014

PMI(psoas muscle mass index)


cross-sectional areas of psoas muscles (cm2) / height2 (m2)




IMAC(intramuscular adipose tissue content)

CT values of multifidus muscles / CT values of subcutaneous fat


IMAC = -0.491

Higher IMAC Lower quality

IMAC = -0.097

IMAC


1. IMAC and PMI in males and females


3. Survival rates according to IMAC and PMI

4. Risk factors for after hepatectomy for HCC

Assessment


Results






IMAC

P < 0.001

Males Females

-1.0

-0.5

0.0

0.5IM

AC

Significant higher in females

Department of HBP and Transplant Surgery, Kyoto UniversityMales Females

0

2

4

6

8

10

12PM

I(cm2/m2)

PMI

P < 0.001

Significant higher in males


Results






Parameters

• Patient age• BMI• PMI• Platelet count• Albumin• Total bilirubin• ICG R15• Child-Pugh classification• Liver histology

• Tumor size• AFP• DCP• Number of tumors• Microvascular

invasion• Differentiation of HCC• TNM stage


MaleAge


Female

20 40 60 80 100-1.0

-0.5

0.0

0.5

patient age (years)

IMA

C

20 40 60 80 100-1.0

-0.5

0.0

0.5

patient age (years)IM

AC

r = 0.535r = 0.368


BMI


10 20 30 40-1.0

-0.5

0.0

0.5

BMI (kg/m2)

IMA

C

10 20 30 40-1.0

-0.5

0.0

0.5

BMI (kg/m2)IM

AC

r = 0.413r = 0.322

Male Female


Results






Cut-off values


0 20 40 60 80 1000

20

40

60

80

100

100% - Specificity%

Sens

itivi

ty%

0 20 40 60 80 1000

20

40

60

80

100

100% - Specificity%

Sens

itivi

ty%

Cut-off values-0.324 -0.138

AUC=0.687 AUC=0.651

ROC curves: IMAC

Male Female


Cut-off values6.089 4.020

ROC curves: PMI

0 20 40 60 80 1000

20

40

60

80

100

100% - Specificity%

Sens

itivi

ty%

0 20 40 60 80 1000

20

40

60

80

100

100% - Specificity%

Sens

itivi

ty%

AUC=0.548 AUC=0.523

Male Female


P < 0.001

Hamaguchi Y, et al. JHBPSci 2015

Overall Survival : IMAC


P = 0.001


Recurrence-free Survival : IMAC


P = 0.318


Overall Survival : PMI


P = 0.747


Recurrence-free Survival : PMI


Results






Parameters• Patient age• Sex• Etiology of HCC• Previous treatment• Platelet count• ICG R15• Child-Pugh classification• AFP• DCP• Liver histology• Tumor size

• Number of tumors• Microvascular invasion• Differentiation of HCC• TNM stage• Surgical procedure• Operative blood loss• BMI• IMAC• PMI


Risk factors for death

Variable Hazard ratio 95% CI P-Value

AFP ≥ 20 ng/dl 1.552 1.110-2.184 0.010

TNM stage III or IV 2.096 1.360-3.241 0.001

Preoperative High IMAC 2.942 2.117-4.136 <0.001



Variable Hazard ratio 95% CI P-Value

Liver fibrosis or cirrhosis 1.464 1.133-1.892 0.004

Tumor size ≥ 5cm 1.412 1.044-1.909 0.025

Multiple tumors 1.357 1.002-1.827 0.048

Microvascular invasion 1.491 1.081-2.044 0.015

TNM stage III or IV 1.799 1.285-2.522 0.001

Preoperative high IMAC 1.542 1.206-1.971 0.001

Risk factors for rec



Conclusion 3

Preoperative quality, not quantity, of skeletal muscle was closely correlated with poor outcomes after hepatectomy

In HCC


Impact of preoperative quality as well as quantity of skeletal muscle on survival after resection of

pancreatic cancer


Low skeletal muscle mass (muscle volume) predicts morbidity and mortality in patients undergoing digestive surgery. Peng P, et al: J Gastrointest Surg. 2012 Aug;16(8):1478-86. Kaido T, et al: Am J Transplant. 2013 Jun;13(6):1549-56. Harimoto N, et al: Br J Surg. 2013 Oct;100(11):1523-30.　

However, the impact of quality as well as quantity of skeletal muscle on outcomes after resection of pancreatic cancer is unclear.

This study investigated the impact of preoperative quantity and quality of skeletal muscle on survival in patients undergoing resection of pancreatic / biliary cancer.

Background and aims


Patients and data collection

Pancreatic cancer: N=230 (Operated between 2004 - 2013 in Kyoto University)

Clinical and pathological data was collected including tumor characteristics and postoperative mortality.


Assessment of skeletal muscle massPMI 　 (Psoas muscle index) (cm2/m2)

= The cross-sectional areas of bilateral psoas muscle/ Height2

Englesbe et al. J Am Coll Surg. 2010 Aug;211(2):271-8.


IMAC 　 (Intra Muscular Adipose tissue Content) = CT value of bilateral multifidus muscle/ CT value of subcutaneous fat

Assessment of skeletal muscle quality

Kitajima et al. J Gastroenterol Hepatol. 2013 Sep;28(9):1507-14.


Clinical characteristics of patientswith pancreatic cancer

　Low PMI

n=64Normal PMI

n=166 P value

CEA (ng/ml); mean±SD 5.2±0.7 4.1±0.4 0.162

CA19-9 (U/ml); mean±SD 335.6±79.0 228.3±49.0 0.249

Tumor size (cm); mean±SD 3.1±1.2 2.9±1.3 0.407

Tumor differentiation (Well+Moderately / Poorly) 55 / 9 142 / 24 0.939

Stage (UICC) (Ia / Ib / IIa / IIb / III / IV) 1 / 0 / 15 / 45 / 1 / 24 / 8 / 62 / 84 / 2 / 6 0.102

Type of operation (PD / DP / TP) 43 / 19 / 2 112 / 47 / 7 0.918

R0 / R1-2 resection 57 / 7 133 / 33 0.109

Postoperative complications (Grade≧3 ） (%) 6 (9.4) 9 (5.4) 0.277

Neo-adjuvant chemotherapy (%) 7 (10.9) 17 (10.2) 0.877

Adjuvant chemotherapy 　 (%) 40 (62.5) 133 (80.1) 0.006


Clinical characteristics of patientswith pancreatic cancer

　High IMAC

n=142Normal IMAC

n=88 P value

CEA (ng/ml); mean±SD 4.9±0.4 3.7±0.5 0.105

CA19-9 (U/ml); mean±SD 266.5±53.2 244.7±67.5 0.801

Tumor size (cm); mean±SD 3.1±1.3 2.7±1.2 0.043

Tumor differentiation (Well+Moderately / Poorly) 123 / 19 74 / 19 0.595

Stage (UICC) (Ia / Ib / IIa / IIb / III / IV) 3 / 4 / 45 / 87 / 1 / 22 / 4 / 32 / 42 / 2 / 6 0.146

Type of operation (PD / DP / TP) 99 / 36 / 7 56 / 30 / 2 0.256

R0 / R1-2 resection 120 / 22 70 / 18 0.335

Postoperative complications (Grade≧3 ） (%) 11 (7.8) 4 (4.6) 0.339

Neo-adjuvant chemotherapy (%) 12 (8.5) 12 (13.6) 0.211

Adjuvant chemotherapy 　 (%) 96 (67.6) 77 (87.5) <0.001


OS and RFS after pancreatic resectionNormal PMI vs Low PMI

P<0.001

0 20 40 60 80 100 1200

20

40

60

80

100

Months after operationO

vera

ll su

rviv

al ra

te (%

)

0 20 40 60 80 100 1200

20

40

60

80

100

Months after operation

Recu

rren

ce-fr

ee su

rviv

al ra

te (%

)

Normal PMI

Low PMIP<0.001

Low PMI

Normal PMIOS

RFS


High IMAC

Normal IMAC

P<0.001

0 20 40 60 80 100 1200

20

40

60

80

100

Months after operationO

vera

ll su

rviv

al ra

te (%

)

High IMAC

Normal IMAC

P=0.010

0 20 40 60 80 100 1200

20

40

60

80

100

Months after operation

Recu

rren

ce-fr

ee su

rviv

al ra

te (%

)

OS and RFS after pancreatic resectionNormal IMAC vs High IMAC

OS

RFS


Prognostic factors for OS after pancreatic resection

　　 Variable Univariate 　　 Multivariate 　

　Hazard ratio

(95% CI)P

value 　Hazard ratio (95% CI)

Pvalue

Low PMI 2.347 (1.658-3.296) <0.001 　1.999 (1.372-2.895) <0.001

High IMAC 2.337 (1.617-3.453) <0.001 2.527 (1.658-3.922) <0.001

Age (>70) 1.410 (0.999-1.973) 0.051 　1.092 (0.736-1.612) 0.661

Male sex 1.362 (0.977-1.909) 0.069 1.633 (1.117-2.399) 0.011

mGPS 2 (vs 0,1) 2.705 (0.827-6.478) 0.092 　1.729 (0.497-4.635) 0.353

PNI (<45) 1.570 (1.038-2.309) 0.033 1.073 (0.675-1.650) 0.759

CA19-9 (>200 U/ml) 1.797 (1.258-2.535) 0.002 1.012 (0.661-1.530) 0.957

Tumor size (>2.0cm) 1.696 (1.152-2.572) 0.007 1.010 (0.659-1.583) 0.963

Poorly differentiated 1.529 (0.924-2.398) 0.095 1.909 (1.090-3.199) 0.025

ne 2,3 (vs 0,1) 1.761 (1.254-2.492) 0.001 1.360 (0.919-2.022) 0.124

Nodal metastasis 2.041 (1.437-2.943) <0.001 1.567 (1.064-2.341) 0.023

R1/2 (vs R0) 1.575 (1.007-2.373) 0.047 2.070 (1.259-3.324) 0.005

PD+TP (vs. DP) 1.443 (0.998-2.136) 0.051 1.446 (0.968-2.203) 0.072

Adjuvant chemotherapy (-) (vs +) 1.530 (1.033-2.214) 　 0.034 　1.793 (1.143-2.779) 0.012


Prognostic factors for RFS after pancreatic resection

　 Variable Univariate 　　 Multivariate 　

　Hazard ratio

(95% CI)P

value 　Hazard ratio (95% CI)

Pvalue

Low PMI 1.799 (1.291-2.478) <0.001 　1.520 (1.073-2.131) 0.019

High IMAC 1.492 (1.088-2.068) 0.013 1.604 (1.128-2.301) 0.008

Male sex 1.303 (0.960-1.775) 0.090 1.215 (0.853-1.733) 0.280

NLR (>4) 1.457 (0.962-2.134) 0.074 　1.320 (0.845-2.003) 0.216

PNI (<45) 1.485 (1.021-2.113) 0.039 1.125 (0.754-1.643) 0.556

CA19-9 (>200 U/ml) 2.106 (1.519-2.890) <0.001 1.365 (0.946-1.952) 0.096

Tumor size (>2.0cm) 1.599 (1.117-2.347) 0.010 1.069 (0.728-1.604) 0.739

ne 2,3 (vs 0,1) 1.640 (1.204-2.241) 0.002 1.055 (0.745-1.494) 0.763

Nodal metastasis 2.366 (1.706-3.326) <0.001 1.919 (1.332-2.801) <0.001

R1/2 (vs R0) 1.976 (1.331-2.852) 0.001 　2.123 (1.387-3.173) <0.001


Conclusion 4

Preoperative quality as well as quantity of skeletal muscle was closely related to postoperative

survival in patients undergoing resection of

pancreatic cancer

characteristics and perioperative changes of nutritional parameters in patients undergoing living...

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