Delayed referral for liver transplant evaluation worsens outcomes in chronic liver disease patients requiring inpatient transplant evaluation

Table 1 Baseline and demographics, %

Characteristic	Delayed referral (n = 78)	Early referral (n = 82)	P value
Portion of sample	49	51	-
Age (yr)	59 (10)	57 (9)	0.19
Distance to center (miles)	43.0 [20.5–59.5]	43.5 [19.3–67.3]	0.74
Time since diagnosis (mo)	30 [12.3–60]	11 [3.75–55.5]	< 0.01
Gender			0.59
Female	39.7	43.9
Male	60.3	56.1
Race			0.49
Asian	1.3	3.7
Black or African American	1.3	1.2
Other/Unknown	17.9	12.2
White	79.5	82.9
Ethnicity			0.11
Hispanic/other	19.2	9.8
Non-Hispanic	80.8	90.1
Etiology			0.88
Autoimmune	5.1	4.9
Alcohol	43.6	53.7
Cryptogenic/cholestatic	5.1	6.1
Genetic	7.7	4.9
Hepatitis C	11.5	9.8
NASH	26.9	20.7
Blood type			0.36
A	37.2	27.2
B	16.7	19.8
AB	1.3	4.9
O	44.9	48.1

Demographic and clinical data for delayed referral (left) versus early referral (right) patients undergoing inpatient liver transplant evaluation. Data reported as percentages of total group for categorical data; as average (standard deviation) for normally distributed continuous data, and as median [IQR] for non-normally distributed continuous data. NASH: Non-alcoholic steatohepatitis.

Table 2 Liver transplant evaluation data, %

	Delayed	Early	P value
Transferred to center	48.7	51.2	0.75
MELD-Na (points)	27.2 (7)	27.0 (9)	0.87
TIPS placed	15.4	7.3	0.22
ICU stay	51.3	43.9	0.35
ICU d (#)	10 (9)	8 (7)	0.44
Pressor support	34.6	26.8	0.29
Declined for LT listing	17.9	15.9	0.72
Reasons declined
Psychosocial	30.0	12.5	0.38
Medical	20.0	25.0
Death	30.0	12.5
Other	20.0	50.0
Decompensations
Ascites	94.9	96.3	0.65
Jaundice	64.1	72.0	0.29
EVB	21.8	24.4	0.70
HE	70.7	70.5	0.98
HRS	59.8	62.8	0.69
HHT	21.8	14.6	0.24
SBP	21.8	18.3	0.58
ACLF grade
Grade 1	34.6	42.7	0.56
Grade 2	50.0	42.7
Grade 3	15.4	14.6
ACLF bilirubin
< 15 mg/dL	82.1	76.8	0.28
15-25 mg/dL	9.0	17.1
> 25 mg/dL	9.0	6.1
ACLF INR
< 1.8	62.8	62.2	0.78
1.8-2.5	28.2	25.6
> 2.5	9	12.2
ACLF lactate
< 1.5 mmol/L	73.1	80.5	0.16
1.5-2.5 mmol/L	15.4	6.1
> 2.5 mmol/L	11.5	13.4
ACLF creatinine
< 0.7 mg/dL	7.3	7.3	0.64
0.7-1.5 mg/dL	32.9	32.9
> 1.5 mg/dL	52.6	59.8

Clinical data from index admission and liver transplant evaluation. Data reported as percentages of group for categorical data; as average (standard deviation) for normally distributed continuous data. Comparisons were made using students T tests and comparison of proportions test. ACLF: Acute on chronic liver failure; LT: Liver transplant; ICU: Intensive care unit; MELD: Model for end stage liver disease; TIPS: Trans-jugular intrahepatic portosystemic shunt; EVB: Esophagogastric variceal bleeding; HRS: Hepatorenal syndrome; HHT: Hepatic hydrothorax; SBP: Spontaneous bacterial peritonitis; LTE: Liver transplant evaluation; INR: International normalized ratio; HE: Hepatic encephalopathy.

Table 3 Pre-transplant clinical and demographic factors, %

	Delayed	Early	P value
Education			0.14
Highschool or less	62.6	50.7
College degree or more	14.7	23.4
Substance use
Smoking history	55.1	57.3	0.15
Drinking history	62.8	74.3	0.12
Sobriety period			< 0.01
< 6 mo	22.4	59.0
6 mo – 2 yrs	53.0	26.2
> 2 yrs	23.6	14.8
Psychosocial factors
Depression history	39.7	28.0	0.12
Trauma history	9.0	2.4	0.07
Public insurance	50.0	50.0	1.00
Non-English first language	20.5	13.6	0.24
Lives with family	78.2	80.2	0.75
Married/stable partner	67.5	52.4	0.05
Unstable housing	6.4	4.9	0.68
Military service history	3.8	8.6	0.21
Worked within 1 mo	7.7	22.2	<0.01
Worked within 1 yr	24.4	49.4	<0.01
Clinical care
Outpatient GI documentation	83.3	78.0%
Ascites on diuretics	90.7	90.3	0.94
Ascites with regular paracentesis	32.0	25.0	0.35
On lactulose/rifaximin	85.0	90.5	0.39
Midodrine	42.9	46.0	0.81
Regular labs	n = 59	n = 40
Low albumin	89.8	77.5	0.09
High ALT/AST	93.2	87.5	0.31
High INR	84.7	72.5	0.14
Prior decompensations
Ascites	96.2	87.8	0.05
Jaundice	66.7	68.3	0.83
Variceal bleed	35.9	29.3	0.37
Hepatic encephalopathy	78.2	64.2	0.06
Hepatorenal syndrome	35.9	31.7	0.58
Hepatic hydrothorax	11.5	9.8	0.72
Spontaneous bacterial peritonitis	21.8	24.4	0.68

Comparison of psychosocial and clinical data from prior to liver transplant evaluation (LTE) in patients with delayed compared to early LTE. Psychiatric comorbidities including depression and trauma occurred more in delayed LTE. Working history was strongly associated with timely referral. Data reported as percentages of group for categorical data; as average (standard deviation) for normally distributed continuous data. Comparisons were made using students T tests and comparison of proportions test. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GI: Gastrointestinal; INR: International normalized ratio.

Table 4 Predictors of transplant

	Initial multivariate regression				Backward logistic regression
	Wald	P value	OR	95%CI	Wald	P value	OR	95%CI
Age (yr)	3.45	0.06	0.94	0.9-1.0	4.62	0.03	0.95	0.9-1.0
Education (HS)	2.41	0.12	1.49	0.9-2.5	-	-	-	-
ICU stay (+)	1.12	0.29	0.38	0.1-2.3	-	-	-	-
ACLF grade (G3)	2.67	0.10	2.76	0.8-9.3	4.75	0.03	2.13	1.1-4.2
MELD (points)	0.58	0.45	1.07	0.9-1.3	-	-	-	-
Creatinine (mg/dL)	0.08	0.78	0.90	0.4-1.9	-	-	-	-
Sodium (mmol/L)	1.28	0.26	0.90	0.8-1.0	-	-	-	-
Bilirubin (mg/dL)	1.06	0.30	1.05	1.1-1.1	-	-	-	-
INR	1.28	0.26	0.42	0.1-1.9	-	-	-	-
WBC (×109/L)	0.03	0.86	0.99	0.8-1.2	-	-	-	-
Hematocrit (%)	1.34	0.25	0.94	0.9-1.0	-	-	-	-
Platelets (×109/L)	1.73	0.19	0.99	1.0-1.0	5.50	0.02	0.99	1.0-1.0
N-L ratio	3.65	0.06	0.89	0.8-1.0	5.15	0.02	0.90	0.8-1.0
Albumin (g/dL)	6.79	< 0.01	3.58	1.4-9.4	9.04	< 0.01	3.32	1.5-7.3
Malnutrition (+)	0.30	0.59	1.39	0.4-4.6	-	-	-	-
Cardiac dx (+)	0.06	0.82	0.83	0.2-3.9	-	-	-	-
Sex (Male)	7.29	< 0.01	14.8	2.1-105	3.02	0.08	2.38	0.9-6.3
Race (White)	1.24	0.27	0.42	0.1-1.9	-	-	-	-
Depression (+)	4.17	0.04	4.24	1.1-17	-	-	-	-
Time since dx (mo)	2.44	0.12	1.01	1.0-1.0	2.69	0.10	1.01	1.0-1.0
Pressor need (+)	0.28	0.60	0.56	0.1-4.8	-	-	-	-
Height (cm)	2.37	0.12	0.94	0.9-1.0	-	-	-	-
Weight (kg)	1.22	0.27	0.99	1.0-1.0	4.72	0.03	0.98	1.0-1.0
Transferred (+)	0.00	1.0	1.00	0.3-3.5	-	-	-	-
Refer to LTE (d)	0.04	0.85	1.00	1.0-1.0	-	-	-	-
Delayed referral (+)	2.67	0.10	0.32	0.1-1.2	3.51	0.06	0.40	0.2-1.0
Decompensations (#)	0.11	0.73	0.91	0.5-1.6	-	-	-	-
Etiology (ETOH)	0.00	0.98	1.00	0.7-1.5	-	-	-	-
TIPS (+)	1.36	0.24	0.52	0.2-1.6	-	-	-	-
Blood type (A)	2.50	0.11	0.62	0.3-1.1	2.71	0.01	0.65	0.4-1.1
Constant	3.26	0.07	5000	-	0.745	0.38	6.54	-

Multivariable logistic model with backward logistic regression to identify predictors of receiving transplant in patients undergoing inpatient liver transplant evaluation (LTE). Starting with 30 potential variables that may predict hepatic encephalopathy, backward regression identified 10 potential independent predictors for transplant including age, ACLF grade, platelets, N-L ratio, serum albumin, sex, time since diagnosis, weight blood type, and having a delayed LTE. Regression complete din SPSS using backward regression conditional model; probability to enter 0.05 and probability to remove 0.10. Units recorded in parenthesis for continuous variables; reference variable recorded in parenthesis for categorical variables where “+” indicates the variable is present in the patient. ACLF: Acute on chronic liver failure; ICU: Intensive care unit; WBC: White blood cell count; MELD: Model for end stage liver disease; INR: International normalized ratio; N-L ratio: Neutrophil to lymphocyte ratio; dx: Diagnosis; TIPS: Trans-jugular intrahepatic portosystemic shunt.

Table 5 Predictors of death

	Initial multivariate regression				Backward logistic regression
	Wald	P value	OR	95%CI	Wald	P value	OR	95%CI
Age (yrs)	5.51	0.02	1.12	1.0-1.2	6.24	0.01	1.10	1.0-1.1
Education (HS)	0.72	0.40	0.75	0.4-1.5	-	-	-	-
ICU stay (+)	0.03	0.86	0.84	0.1-5.8	-	-	-	-
ACLF grade (G3)	0.06	0.81	1.19	0.3-4.9	-	-	-	-
MELD (points)	4.58	0.03	0.73	0.5-1.0	-	-	-	-
Creatinine (mg/dL)	2.85	0.09	2.46	0.9-7.0	-	-	-	-
Sodium (mmol/L)	5.25	0.02	0.82	0.7-1.0	-	-	-	-
Bilirubin (mg/dL)	0.04	0.84	0.99	0.9-1.1	-	-	-	-
INR	3.06	0.08	8.85	0.8-101	-	-	-	-
WBC (×109/L)	0.02	0.88	1.02	0.8-1.3	-	-	-	-
Hematocrit (%)	1.57	0.21	1.11	0.9-1.3	2.67	0.10	1.09	1.0-1.2
Platelets (×109/L)	0.09	0.76	1.00	1.0-1.0	-	-	-	-
N-L ratio	5.90	0.02	1.22	1.0-1.4	5.47	0.02	1.11	1.0-1.2
Albumin (g/dL)	5.07	0.02	0.18	0.0-0.8	2.67	0.10	0.49	0.2-1.2
Malnutrition (+)	0.04	0.85	0.84	0.1-5.1	-	-	-	-
Cardiac dx (+)	1.71	0.19	3.53	0.5-23	-	-	-	-
Sex (Male)	4.43	0.04	0.08	0.0-0.8	-	-	-	-
Race (White)	1.06	0.30	0.32	0.0-2.8	-	-	-	-
Depression (+)	1.72	0.19	3.07	0.6-16	-	-	-	-
Time since dx (mo)	5.84	0.02	0.97	1.0-1.0	3.52	0.06	0.99	1.0-1.0
Pressor need (+)	0.36	0.55	0.44	0.0-6.5	-	-	-	-
Height (cm)	4.04	0.05	1.13	1.0-1.3	-	-	-	-
Weight (kg)	3.83	0.05	1.04	1.0-1.1	7.01	< 0.01	1.02	1.0-1.0
Transferred (+)	1.53	0.22	0.36	0.1-1.8	-	-	-	-
Refer to LTE (d)	0.65	0.42	0.99	1.0-1.0	-	-	-	-
Delayed referral (+)	6.75	0.01	8.40	1.7- 42	7.27	< 0.01	4.51	1.5-14
Decompensations (#)	3.61	0.06	2.08	1.0-4.4	6.33	0.01	1.49	1.1-2.0
Etiology (ETOH)	1.22	0.27	1.30	0.8-2.1	-	-	-	-
Blood type (A)	4.98	0.03	3.01	1.1-7.9	-	-	-	-
TIPS (+)	0.44	0.51	1.45	0.5-4.4	-	-	-	-
Constant	0.09	0.76	0.02	-	0.75	0.38	6.54	-

Multivariable logistic model with backward logistic regression to identify predictors of receiving transplant in patients undergoing inpatient liver transplant evaluation (LTE). Starting with 30 potential variables that may predict hepatic encephalopathy, backward regression identified 8 potential independent predictors for transplant including age, Hematocrit, N-L ratio, serum albumin, sex, time since diagnosis, weight, number of decompensations, and having a delayed LTE. Regression complete din SPSS using backward regression conditional model; probability to enter 0.05 and probability to remove 0.10. Units recorded in parenthesis for continuous variables; reference variable recorded in parenthesis for categorical variables where “+” indicates the variable is present in the patient. ACLF: Acute on chronic liver failure; ICU: Intensive care unit; WBC: White blood cell count; MELD: Model for end stage liver disease; INR: International normalized ratio; N-L ratio: Neutrophil to lymphocyte ratio; dx: Diagnosis; TIPS: Trans-jugular intrahepatic portosystemic shunt.