Abstract
Background:
Complications of patients with liver disease generally occurs as the consequence of advanced fibrosis and portal hypertension. Non-invasive tools to predict the complications may allow for better risk-stratification and medical management in patients with cirrhosis. The goals of this study are to determine the utility of CT-scan based liver and spleen volume measurement in association with complications and outcomes in patients with cirrhosis.
Methods:
Baseline demographic and clinical characteristics of 556 cirrhotic patients who underwent CT scan of the abdomen between January 1-June 30,2009 were reviewed. Liver and spleen volume were measured using semi-automated interactive software and compared to 47 healthy controls. The association between liver and spleen volume and complications of cirrhosis was determined. Independent predictors of survival were analyzed with Cox regression model.
Results:
Patients with cirrhosis had significantly lower total and functional liver volume, larger total and functional spleen volume, and significantly lower total liver to spleen volume ratio when compared to controls. Liver volume, spleen volume, and liver to spleen volume ratio were significantly altered in patients with decompensated stage. Patients with hepatic encephalopathy had significantly lower total liver volume and spleen size was associated with the presence of esophageal varices. Cirrhotic patients who underwent liver transplantation had significantly lower total liver volume and larger total spleen volume. However, spleen volume was not an independent predictor for mortality.
Conclusion:
Baseline liver and spleen volume and its ratio are significantly altered in patients with cirrhosis. Spleen volume is also associated with the presence of esophageal varices.
Keywords: spleen volume, cirrhosis, esophageal varices
Background
Liver cirrhosis, the advanced stage of hepatic fibrosis, may result in serious complications including hepatic encephalopathy, thrombocytopenia, ascites, and esophageal or gastric varices secondary to portal hypertension.1,2 These complications, known as decompensated stage, are associated with high mortality3 Recognizing and understanding the various complications of decompensated cirrhosis may lead to better risk-stratification and improve clinical outcomes.
Liver biopsy is the gold standard to diagnose and evaluate the severity of fibrosis in cirrhosis.4 Given the invasive nature of the procedure with bleeding and other procedure-related complications, non-invasive tests to screen for the presence of advanced fibrosis have been utilized to prognosticate or predict the likelihood of complications in patients with decompensated cirrhosis. Fibrosis-4 (FIB-4) is a non-invasive test based on the patient’s age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count. Its level is associated with the severity of fibrosis in cirrhosis patients.5 Transient elastography is a tool to determine underlying fibrosis in patients with liver disease. It requires equipment and is operator dependent6.
Imaging modalities such as computed tomography (CT) have been able to identify factors related to complications secondary to cirrhosis.7 The use of platelet count with total liver volume, right liver volume (RLV) and spleen volume (SV) has been shown to be correlated with Child-Pugh class and of the presence of esophageal varices.8–11 Spleen stiffness is associated with the size of esophageal varices.12,13 The ratio of liver to spleen ratio is an indicative of cirrhosis progression and a predictor of complications in patients after hepatectomy and those with primary biliary cholangitis14.15 However, common to most of these studies is a small study sample preventing analysis of the various etiologies of cirrhosis and absence in the analysis examining the prognostic significance of spleen volume in patients with cirrhosis.
The objectives of our study are 1) to compare liver and spleen volume as well as its ratio in patients with cirrhosis to body-weight matched controls, 2) to determine if there is an association between spleen volume or liver to spleen volume ratio with the complications secondary to portal hypertension, and 3) to assess if spleen volume is a prognostic indicator for mortality and long-term outcomes in patients with cirrhosis.
Methods
Study cohort
CT scan imaging of 568 patients with cirrhosis and no known history of hepatocellular carcinoma who received their clinical care at Liver clinic, Indiana University between January 1-June 30, 2009 were retrospectively identified. CT scan was performed as part of hepatocellular carcinoma surveillance.Baseline characteristics, clinical course of liver disease (presence of absence of hepatic encephalopathy, esophageal varices, or ascites), laboratory tests (within 2 weeks from the date of CT scan), upper endoscopy results, Child-Pugh classification, and MELD scores were extracted from medical records. Of these, 12 patients were excluded due to missing information on baseline labs or baseline body weight. A total of 556 patients constituted the study cohort. We also identified 47 healthy controls with age-, gender-, and BMI-matched to those with cirrhosis. The schematic diagram of patient selection is shown in Supplementary Figure 1. The study was approved by the Institutional Review Board at the Indiana University Purdue University Indianapolis (IUPUI).
CT scan-based liver (LV) and spleen volume (SV) measurement
Liver volume (LV) measurement was performed as previously described11. Spleen volume (SV) measurement was determined using the semi-automated interactive software “IntelliSpace Portal Liver Analysis application” (Philips Medical Systems, Best, The Netherland). Manual placement of the location of the spleen was conducted allowing the software to identify spleen contour and volume (Supplementary Figure 2). Functional spleen volume was measured by subtracting total spleen volume from the volume of splenic vessels. The measurement was completed independently by MT and MP. The association of the volume measurement for both readers was shown in Supplementary Figure 3, with calculated Pearson correlation coefficient at 0.97 and Spearman Correlation at 0.97.
Statistical analysis
Mean, standard deviation (SD) and frequencies (percentages) were characterized from the data set. Analyses were conducted utilizing SAS software version 9.4 (SAS Institute, Cary, NC). Chi-square test, Student t test, or analysis of variance (ANOVA) was used. The evaluation of independent predictors for mortality was conducted using Cox proportional hazards model. P-value less than 0.05 was considered statistically significant.
Results
Baseline characteristics of study population
Baseline clinical characteristics of our study cohorts are presented in Table 1. According to the study design, there was no differences in age, gender, race, and BMI between both groups. Patients with cirrhosis had a significantly higher level of creatinine (1.1 vs 0.9 mg/dl, p=0.001), alanine aminotransferase (ALT) (54.1 vs 22.5 IU/L, p=<0.0001), aspartate aminotransferase (AST) (78.0 vs 20.7 IU/L, p=<0.001), alkaline phosphatase (ALP) (132.4 vs 83.5 IU/L, p=<0.001), and a lower albumin (3.0 vs 4.1 g/dl, p=<0.001).
Table 1:
Baseline characteristics, laboratory values, and liver volume measurements in controls and patients with cirrhosis
| Variables | Controls (N=47) | Cirrhosis (N=556) | p-value |
|---|---|---|---|
| Age (Yrs) | 52.2±7.5 | 55.8±10.1 | 0.71 |
| Gender (Men, n %) | 23 (49%) | 339 (61%) | 0.10 |
| Race (Whites, n %) | 41 (87%) | 500 (89%) | 0.71 |
| Body weight (Kg) | 85.0±18.4 | 87.1±21.3 | 0.46 |
| Height (cm) | 170.5±12.2 | 170.7±13.0 | 0.92 |
| Body mass index (kg/m2) | 29.6±6.8 | 30.2±11.0 | 0.59 |
| White blood cell counts (×103/mm3) | 10.3±4.5 | 5.8±3.4 | <0.0001 |
| Hemoglobin (g/dl) | 13.6±1.8 | 12.5±5.9 | 0.002 |
| Platelet counts (×103/mm3) | 276.4±101.2 | 111.1±77.2 | <0.0001 |
| Blood urea nitrogen (mg/dl) | 13.4±5.8 | 15.0±12.5 | 0.10 |
| Creatinine (mg/dl) | 0.9±0.2 | 1.1±1.5 | 0.0001 |
| Total bilirubin (mg/dl) | 1.5±5.8 | 2.6±3.3 | 0.21 |
| Alanine aminotransferase (ALT, U/L) | 22.5±15.6 | 54.1±87.0 | <0.0001 |
| Aspartate aminotransferase (AST, U/L) | 20.7±10.7 | 78.0±108.7 | <0.0001 |
| Alkaline phosphatase (ALP, U/L) | 83.5±30.8 | 132.4±108.4 | <0.0001 |
| Albumin (g/dl) | 4.1±0.4 | 3.0±0.7 | <0.0001 |
| Total protein (g/dl) | 7.3±0.6 | 7.1±3.2 | 0.34 |
| International normalized ratio (INR) | 1.1±0.7 | 1.7±6.9 | 0.06 |
| MELD scores | N/A | 11.6±7.0 | <0.0001 |
| Total liver volume (TLV, cm3) | 1789.5±421.1 | 1639.8±594.5 | 0.02 |
| Functional liver volume (FLV, cm3) | 1728.4±413.4 | 1589.4±579.8 | 0.03 |
| Portal vein volume (PVV, cm3) | 33.5±18.8 | 29.1±29.7 | 0.15 |
| Segment 1 volume (cm3) | 40.2±20.6 | 46.0±47.9 | 0.11 |
| Segment 2 volume (cm3) | 214.9±78.7 | 257.7±189.8 | 0.002 |
| Segment 3 volume (cm3) | 124.1±80.6 | 184.0±139.5 | <0.0001 |
| Segment 4 volume (cm3) | 293.2±101.6 | 249.2±155.6 | 0.0006 |
| Segment 5 volume (cm3) | 296.0±118.5 | 230.3±140.9 | 0.0007 |
| Segment 6 volume (cm3) | 177.3±92.5 | 167.4±164.8 | 0.51 |
| Segment 7 volume (cm3) | 272.8±99.6 | 250.7±126.4 | 0.15 |
| Segment 8 volume (cm3) | 310.3±104.7 | 231.2±103.5 | <0.0001 |
| Total spleen volume (cm3) | 218.3±105.4 | 796.2±508.5 | <0.0001 |
| Functional spleen volume (cm3) | 214.0±102.0 | 771.4±493.6 | <0.0001 |
| Total liver to spleen ratio | 9.98±5.2 | 3.15±3.1 | <0.0001 |
| Functional liver to spleen ratio | 9.77±5.0 | 3.16±3.2 | <0.0001 |
Liver to spleen volume ratio and spleen volume in patients with cirrhosis stratified by etiologies
Patients with cirrhosis were noted to have a significantly lower liver to spleen volume ratio when compared to controls (3.15 vs 9.98, p<0.0001) (Table 1). When we considered this ratio based on the etiologies of underlying cirrhosis, we found that non-alcoholic steatohepatitis (NASH) patients had significantly lower liver to spleen volume ratio (2.17) compared to that for patients with hepatitis C (3.2), alcoholic cirrhosis (3.5), and hepatitis C and alcohol (3.3) (Table 2). Patients with cirrhosis had significantly larger spleen compared to controls (796.2 cm3 vs 218.3 cm3, p=<0.0001) (Table 1). When we calculated the spleen volume stratified by etiologies of underlying liver disease, we found that NASH patients had the largest splenic size (934.5 cm3) (Table 2).
Table 2.
Liver volumes stratified by underlying etiologies of cirrhosis
| Variables | Hepatitis C (N=138) | Alcohol (N=84) | Hepatitis C+alcohol (N=59) | NASH (N=69) | p-value |
|---|---|---|---|---|---|
| Total liver volume (TLV, cm3) | 1668.3±507.4 | 1593.7±634.3 | 1758.5±585.3 | 1566.9±560.9 | 0.20 |
| Functional liver volume (FLV, cm3) | 1606.6±510.1 | 1556.5±609.7 | 1710.2±570.9 | 1542.0±523.7 | 0.29 |
| TLV:BW (cm3:kg) | 19.3±5.9 | 19.6±7.8 | 20.3±1.4 | 18.4±14.2 | 0.63 |
| FLV:BW (cm3:kg) | 18.6±5.8 | 19.2±7.5 | 19.8±6.4 | 18.1±13.7 | 0.66 |
| Segment 1 (cm3) | 50.5±52.2 | 46.4±46.5 | 45.2±38.5 | 50.1±47.7 | 0.86 |
| Segment 2 (cm3) | 280.9±312.2 | 222.6±91.0 | 279.1±131.8 | 245.4±121.3 | 0.20 |
| Segment 3 (cm3) | 204.6±177.7 | 156.6±107.0 | 190.5±126.8 | 178.4±129.6 | 0.11 |
| Segment 4 (cm3) | 235.5±123.4 | 250.2±131.4 | 297.4±232.3 | 261.4±140.6 | 0.07 |
| Segment 5 (cm3) | 232.6±130.6 | 232.4±134.3 | 239.3±115.6 | 222.6±125.3 | 0.90 |
| Segment 6 (cm3) | 179.6±133.0 | 179.7±258.6 | 160.9±97.2 | 138.9±79.8 | 0.32 |
| Segment 7 (cm3) | 247.0±97.9 | 261.4±152.5 | 266.7±106.2 | 227.1±94.0 | 0.17 |
| Segment 8 (cm3) | 234.3±97.1 | 216.0±112.9 | 251.2±119.0 | 211.3±82.0 | 0.09 |
| Total spleen volume (cm3) | 789.4±517.5 | 647.1±350.0 | 856.4±621.6 | 934.5±471.5 | 0.003 |
| Functional spleen volume (cm3) | 764.5±500.1 | 628.6±341.8 | 830.4±603.7 | 908.8±458.1 | 0.003 |
| Total liver to spleen ratio | 3.2±2.5 | 3.5±3.8 | 3.3±2.4 | 2.17±1.5 | 0.01 |
| Functional liver to spleen ratio | 3.2±2.5 | 3.5±3.7 | 3.3±2.4 | 2.15±1.5 | 0.01 |
Liver to spleen volume ratio and spleen volume in patients with cirrhosis stratified by compensatory stages
We determined the differences in the liver to spleen volume ratio and spleen volume in compensated (Child –Pugh Class A) and decompensated (Child-Pugh Class B and C) patients (Table 3). As expected, we found that patients with decompensated stage had significantly lower level of hemoglobin (12.0 vs. 13.4 g/dl, p=0.001) and platelets (104.7 vs. 122.1 cells/mm3, p=0.007) compared to those with compensated stage. Patients in decompensated stage had higher MELD scores (13.4 vs. 8.4, p<0.0001).
Table 3:
Baseline characteristics, laboratory values, and liver and spleen volume measurements stratified by Child Pugh Classification.
| Variables | Compensated stage Child Class A (N=202) | Decompensated stage Child Class B and C (N=354) | p-value |
|---|---|---|---|
| Age (Yrs) | 56.4±10.4 | 55.5±9.9 | 0.35 |
| Body weight (Kg) | 85.4±19.2 | 88.0±22.3 | 0.14 |
| Height (cm) | 169.7±13.1 | 171.3±12.9 | 0.17 |
| Body mass index (kg/m2) | 29.4±6.3 | 30.6±12.9 | 0.11 |
| White blood cell counts (×103/mm3) | 5.6±3.5 | 5.8±3.2 | 0.37 |
| Hemoglobin (g/dl) | 13.4±6.2 | 12.0±7.0 | 0.001 |
| Platelet counts (×103/mm3) | 122.1±66.6 | 104.7±82.1 | 0.007 |
| Blood urea nitrogen (mg/dl) | 14.5±8.8 | 15.3±14.2 | 0.42 |
| Creatinine (mg/dl) | 1.2±1.5 | 1.1±1.4 | 0.25 |
| Total bilirubin (mg/dl) | 1.2±0.5 | 3.4±3.9 | <0.0001 |
| Alanine aminotransferase (ALT, U/L) | 48.4±44.7 | 57.3±103.8 | 0.16 |
| Aspartate aminotransferase (AST, U/L) | 55.2±45.2 | 91.1±130.4 | <0.001 |
| Alkaline phosphatase (ALP, U/L) | 110.9±70.7 | 145.0±123.7 | <0.0001 |
| Albumin (g/dl) | 3.6±0.5 | 2.7±0.5 | <0.0001 |
| Total protein (g/dl) | 7.6±5.2 | 6.8±0.9 | 0.02 |
| International normalized ratio (INR) | 1.2±0.1 | 1.9±0.45 | 0.06 |
| MELD scores | 8.4±5.0 | 13.4±7.3 | <0.0001 |
| Total liver volume (TLV, cm3) | 1754.0±562.3 | 1574.7±603.2 | 0.0005 |
| Functional liver volume (FLV, cm3) | 1676.9±573.4 | 1539.5±578.2 | 0.007 |
| Segment 1 volume (cm3) | 48.2±47.5 | 44.7±48.0 | 0.41 |
| Segment 2 volume (cm3) | 271.4±266.8 | 249.8±126.0 | 0.28 |
| Segment 3 volume (cm3) | 209.0±175.4 | 169.8±112.2 | 0.004 |
| Segment 4 volume (cm3) | 262.2±150.9 | 241.7±158.0 | 0.13 |
| Segment 5 volume (cm3) | 255.6±170.5 | 216.1±119.0 | 0.004 |
| Segment 6 volume (cm3) | 177.6±109.1 | 161.6±189.8 | 0.20 |
| Segment 7 volume (cm3) | 263.7±112.8 | 243.4±133.0 | 0.058 |
| Segment 8 volume (cm3) | 242.7±100.0 | 224.5±105.0 | 0.04 |
| Total volume:body weight (cm3:kg) | 21.1±7.1 | 18.7±9.3 | 0.0009 |
| functional volume:body weight (cm3:kg) | 20.2±7.1 | 18.3±8.9 | 0.007 |
| Segment 1:BW (cm3/kg) | 0.6±0.6 | 0.5±0.5 | 0.26 |
| Segment 2:BW (cm3/kg) | 3.2±2.5 | 2.9±1.9 | 0.33 |
| Segment 3:BW (cm3/kg) | 2.5±2.1 | 2.1±1.7 | 0.008 |
| Segment 4:BW (cm3/kg) | 3.2±1.9 | 2.8±2.1 | 0.07 |
| Segment 5:BW (cm3/kg) | 3.1±2.0 | 2.6±1.6 | 0.003 |
| Segment 6:BW (cm3/kg) | 2.1±1.3 | 1.9±2.0 | 0.11 |
| Segment 7:BW (cm3/kg) | 3.2±1.5 | 2.9±1.7 | 0.03 |
| Segment 8:BW (cm3/kg) | 2.0±1.2 | 2.6±1.3 | 0.02 |
| Total spleen volume (cm3) | 676.0±440.7 | 864.8±531.9 | <0.0001 |
| Functional spleen volume (cm3) | 655.3±427.8 | 837.6±516.5 | <0.0001 |
| Total spleen volume:BW (cm3/kg) | 7.9±5.0 | 10.3±7.6 | <0.0001 |
| Functional spleen volume:BW (cm3/kg) | 7.6±4.9 | 9.9±7.3 | <0.0001 |
| Total liver to spleen ratio | 4.0±2.9 | 2.7±3.2 | <0.0001 |
| Functional liver to spleen ratio | 3.9±2.8 | 2.7±3.2 | <0.0001 |
Patients with decompensated stage had significantly lower liver volume (1574.7 vs. 1754 cm3, p=0.0005). The detailed information of liver volume by hepatic segment is shown in Table 3. Patients with decompensated stage had a larger spleen size with the average volume of 864.8 cm3 compared to that of 676.0 cm3 for those with compensated stage (p<0.0001). The liver to spleen volume ratio was significantly lower in patients with decompensated stage (2.7 vs. 4.0, p<0.0001). The complete information for liver to spleen volume ratio and spleen volume stratified by each Child-Pugh class is shown in Supplementary Table 1.
Liver to spleen volume ratio and spleen volume in association with the complications from portal hypertension
We next determined if liver to spleen volume ratio and spleen volume are associated with the complications of portal hypertension, hepatic encephalopathy, esophageal varices, and ascites (Table 4). For hepatic encephalopathy (HE), we found that those with history of HE had significantly lower total liver volume (1509 vs. 1695 cm3, p=0.002) and functional liver volume (1481 vs. 1638 cm3, p=0.007) compared to those without history of HE. We did not observe the differences between total liver and functional liver volume between those with and without esophageal varices or ascites (Table 4). There was no difference in spleen volume in patients with and without history of HE or ascites. However, patients with history of esophageal varices had significantly larger total spleen volume (893 vs. 683 cm3, p<0.0001) and functional spleen volume (661.4 vs. 868.2 cm3, p<0.0001). Interesting, we found significant differences in the liver to spleen volume ratio in patients with and without history of ascites (2.7 vs. 3.5, p=0.01).
Table 4.
Liver and spleen volumes stratified by baseline complications of portal hypertensions*
| Variables | Hepatic encephalopathy | Esophageal varices | Ascites | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Yes (N = 120) | No (N= 274) | p-value | Yes (N=142) | No (N=248) | p-value | Yes (N=89) | No (N=285) | p-value | |
| Liver volume without bodyweight adjustment | |||||||||
| Total liver volume (TLV, cm3) | 1509.9±515.7 | 1695.0±617.7 | 0.002 | 1622.3±564.3 | 1651.1±614.3 | 0.63 | 1598.3±564.3 | 1665.8±591.7 | 0.33 |
| Functional liver volume (FLV, cm3) | 1481.4±488.6 | 1638.4±604.9 | 0.007 | 1580.4±548.6 | 1599.4±595.0 | 0.74 | 1550.9±553.0 | 1617.2±571.4 | 0.32 |
| Segment 1 (cm3) | 44.9±41.1 | 51.6±45.5 | 0.17 | 48.2±42.0 | 50.8±51.4 | 0.60 | 42.8±40.4 | 52.4±50.2 | 0.07 |
| Segment 2 (cm3) | 253.9±130.5 | 263.0±237.2 | 0.62 | 256.9±111.3 | 262.3±251.8 | 0.77 | 245.0±122.7 | 259.2±231.2 | 0.45 |
| Segment 3 (cm3) | 158.5±99.6 | 192.5±161.4 | 0.01 | 173.9±113.6 | 186.8±162.8 | 0.36 | 170.3±113.8 | 189.2±152.8 | 0.21 |
| Segment 4 (cm3) | 234.1±170.0 | 270.2±147.0 | 0.04 | 250.0±137.5 | 264.8±165.2 | 0.34 | 253.9±128.3 | 257.8±158.8 | 0.81 |
| Segment 5 (cm3) | 209.7±117.5 | 241.6±161.5 | 0.02 | 226.6±140.1 | 234.5±155.0 | 0.60 | 236.3±148.8 | 232.8±154.1 | 0.84 |
| Segment 6 (cm3) | 150.6±132.6 | 173.5±170.4 | 0.15 | 167.3±207.9 | 167.1±125.8 | 0.98 | 140.6±103.2 | 179.6±174.4 | 0.01 |
| Segment 7 (cm3) | 232.5±93.9 | 246.6±130.3 | 0.22 | 233.5±110.8 | 248.6±125.5 | 0.22 | 235.8±113.5 | 251.9±124.0 | 0.25 |
| Segment 8 (cm3) | 216.5±103.5 | 227.7±106.1 | 0.32 | 217.1±106.0 | 229.3±105.3 | 0.27 | 227.5±103.2 | 228.3±107.1 | 0.95 |
| Liver volume with bodyweight adjustment | |||||||||
| TLV:BW (cm3:kg) | 17.8±7.0 | 20.7±9.9 | 0.0009 | 19.3±6.8 | 20.3±10.4 | 0.25 | 20.5±13.2 | 19.3±7.2 | 0.40 |
| FLV:BW (cm3:kg) | 17.5±6.8 | 20.0±9.6 | 0.002 | 18.8±6.5 | 19.6±10.1 | 0.32 | 19.9±12.8 | 18.7±6.9 | 0.41 |
| Segment 1:BW (cm3/kg) | 0.5±0.4 | 0.6±0.6 | 0.04 | 0.6±0.5 | 0.6±0.6 | 0.38 | 0.5±0.5 | 0.6±0.6 | 0.26 |
| Segment 2:BW (cm3/kg) | 3.0±1.9 | 3.2±2.6 | 0.51 | 3.1±1.5 | 3.2±2.8 | 0.66 | 3.2±2.6 | 3.0±2.2 | 0.51 |
| Segment 3:BW (cm3/kg) | 1.9±1.4 | 2.4±2.2 | 0.01 | 2.1±1.4 | 2.3±2.3 | 0.22 | 2.3±2.4 | 2.2±1.8 | 0.79 |
| Segment 4:BW (cm3/kg) | 2.7±1.9 | 3.3±2.1 | 0.005 | 3.0±1.8 | 3.2±2.2 | 0.26 | 3.3±2.4 | 3.0±1.9 | 0.35 |
| Segment 5:BW (cm3/kg) | 2.4±1.3 | 2.9±2.0 | 0.005 | 2.7±1.6 | 2.9±2.0 | 0.36 | 3.0±2.3 | 2.7±1.7 | 0.22 |
| Segment 6:BW (cm3/kg) | 1.8±1.8 | 2.1±1.8 | 0.149 | 1.9±1.9 | 2.1±1.8 | 0.47 | 1.8±1.5 | 2.1±1.8 | 0.11 |
| Segment 7:BW (cm3/kg) | 2.8±1.2 | 3.0±1.9 | 0.07 | 2.8±1.3 | 3.1±1.9 | 0.07 | 3.0±2.0 | 2.9±1.5 | 0.66 |
| Segment 8:BW (cm3/kg) | 2.5±1.1 | 2.7±1.4 | 0.07 | 2.5±1.2 | 2.8±1.5 | 0.10 | 2.8±1.6 | 2.6±1.3 | 0.31 |
| Spleen volume with and without body weight adjustment | |||||||||
| Total spleen volume (cm3) | 800.5±481.5 | 754.5±522.4 | 0.39 | 893.9±521.2 | 683.7±457.1 | <0.0001 | 813.8±503.7 | 764.9±515.1 | 0.42 |
| Functional spleen volume (cm3) | 777.7±469.5 | 730.8±505.7 | 0.37 | 868.2±509.0 | 661.4±440.2 | <0.0001 | 788.5±487.5 | 742.4±501.0 | 0.44 |
| Total spleen volume:BW (cm3/kg) | 9.1±5.3 | 9.1±7.6 | 0.91 | 10.4±5.9 | 8.2±7.4 | 0.001 | 10.5±10.5 | 8.6±5.6 | 0.09 |
| Functional spleen volume:BW (cm3/kg) | 8.9±5.1 | 8.8±7.4 | 0.88 | 10.1±5.7 | 8.0±7.2 | 0.001 | 10.2±10.1 | 8.3±5.4 | 0.10 |
| Total liver to spleen ratio | 3.0±4.3 | 3.5±3.2 | 0.22 | 2.4±1.5 | 3.9±4.2 | 0.26 | 2.7±1.9 | 3.5±3.9 | 0.01 |
| Functional liver to spleen ratio | 3.0±4.3 | 3.5±3.1 | 0.29 | 2.4±1.5 | 3.9±4.2 | <0.0001 | 2.7±1.9 | 3.5±3.9 | 0.008 |
only reported cases with available data on the complications of portal hypertension
Liver to spleen volume ratio and spleen volume and outcomes in patients with cirrhosis
During the median follow up period of 3.1 years, 111 underwent liver transplantation and 126 died. Patients who underwent liver transplantation were younger (53.4 vs. 55.7 yrs, p=0.03) than those who were alive. For those who were transplanted, they had significantly lower total liver volume (1514.8 vs. 1736.4 cm3, p=0.0004), lower functional liver volume (1482 vs. 1676 cm3, p=0.001), and larger total spleen volume (946.9 vs. 778.9 cm3, p=0.008)(Table 5). Total liver to spleen volume ratio was also significantly lower in those who underwent liver transplantation (2.2 vs. 3.3, p<0.001)(Table 5). We also performed Cox proportional hazard model and found that only age (p=0.006) and MELD scores (p=<0.0001), but not the splenic volume, were independently associated with mortality. Detailed information on the liver and spleen volume in association with the outcomes is shown in Supplementary Table 2.
Table 5:
Baseline characteristics, laboratory values, and liver volume measurements stratified by outcomes during follow up.
| Variables | Alive (N=319) | Transplanted (N=111) | p-value |
|---|---|---|---|
| Age (Yrs) | 55.7±10.1 | 53.4±10.0 | 0.03 |
| Body weight (Kg) | 87.2±20.5 | 88.7±19.8 | 0.50 |
| Height (cm) | 170.2±13.6 | 172.6±14.0 | 0.11 |
| Body mass index (kg/m2) | 30.6±13.0 | 30.1±8.5 | 0.67 |
| White blood cell counts (×103/mm3) | 5.7±3.0 | 5.2±4.1 | 0.24 |
| Hemoglobin (g/dl) | 12.6±3.0 | 12.0±2.4 | 0.04 |
| Platelet counts (×103/mm3) | 120.5±84.5 | 88.6±44.4 | <0.0001 |
| Creatinine (mg/dl) | 1.1±1.4 | 1.0±0.9 | 0.18 |
| Total bilirubin (mg/dl) | 2.2±3.0 | 2.6±1.9 | 0.14 |
| Alanine aminotransferase (ALT, U/L) | 56.2±106.7 | 53.6±63.4 | 0.76 |
| Aspartate aminotransferase (AST, U/L) | 77.2±134.2 | 78.5±71.8 | 0.89 |
| Alkaline phosphatase (ALP, U/L) | 125.1±96.1 | 142.7±92.7 | 0.09 |
| Albumin (g/dl) | 3.1±0.6 | 3.0±0.7 | |
| Total protein (g/dl) | 7.2±4.2 | 7.0±0.9 | 0.26 |
| International normalized ratio (INR) | 1.3±0.8 | 2.9±15.3 | 0.28 |
| MELD scores | 10.4±6.0 | 12.2±7.1 | 0.01 |
| Total liver volume (TLV, cm3) | 1736.4±610.4 | 1514.8±534.0 | 0.0004 |
| Functional liver volume (FLV, cm3) | 1676.4±602.6 | 1482.9±490.0 | 0.001 |
| Segment 1 volume (cm3) | 45.9±49.1 | 42.0±42.4 | 0.43 |
| Segment 2 volume (cm3) | 257.5±126.0 | 278.2±336.4 | 0.52 |
| Segment 3 volume (cm3) | 201.9±157.0 | 162.7±104.1 | 0.003 |
| Segment 4 volume (cm3) | 261.0±153.0 | 235.4±126.3 | 0.08 |
| Segment 5 volume (cm3) | 248.1±155.6 | 206.5±118.0 | 0.004 |
| Segment 6 volume (cm3) | 175.2±146.8 | 147.8±97.4 | 0.02 |
| Segment 7 volume (cm3) | 268.4±136.7 | 226.6±104.6 | 0.001 |
| Segment 8 volume (cm3) | 245.2±105.1 | 216.8±100.9 | 0.01 |
| Total volume:body weight (cm3:kg) | 20.7±9.2 | 17.7±7.7 | 0.0009 |
| functional volume:body weight (cm3:kg) | 20.0±9.1 | 17.3±7.2 | 0.002 |
| Segment 1:BW (cm3/kg) | 0.5±0.6 | 0.5±0.5 | 0.41 |
| Segment 2:BW (cm3/kg) | 3.1±1.9 | 3.2±3.1 | 0.74 |
| Segment 3:BW (cm3/kg) | 2.4±2.2 | 1.9±1.3 | 0.001 |
| Segment 4:BW (cm3/kg) | 3.1±2.1 | 2.7±1.7 | 0.04 |
| Segment 5:BW (cm3/kg) | 2.9±1.9 | 2.4±1.5 | 0.004 |
| Segment 6:BW (cm3/kg) | 2.1±1.6 | 1.7±1.3 | 0.04 |
| Segment 7:BW (cm3/kg) | 3.2±1.7 | 2.7±1.4 | 0.002 |
| Segment 8:BW (cm3/kg) | 2.9±1.3 | 2.5±1.3 | 0.01 |
| Total spleen volume (cm3) | 778.9 | 946.9±594.6 | 0.008 |
| Functional spleen volume (cm3) | 754.6 | 916.2±576.7 | 0.008 |
| Total spleen volume:BW (cm3/kg) | 9.3±7.6 | 10.8±6.5 | 0.05 |
| Functional spleen volume:BW (cm3/kg) | 9.0±7.4 | 10.4±6.3 | 0.05 |
| Total liver to spleen ratio | 3.3±2.9 | 2.2±1.5 | <0.001 |
| Functional liver to spleen ratio | 3.3±2.9 | 2.2±1.5 | <0.001 |
Discussion
In this study, we found that patients with cirrhosis had significantly lower total and functional liver volume, larger total and functional spleen volume, and as a consequence, a significantly lower total liver to spleen volume ratio when compared to healthy controls. While we did not find the association between total liver volume and underlying etiologies of cirrhosis, we observed that NASH patients had the largest spleen size compared to those with liver diseases from other etiologies. Liver volume, spleen volume, and liver to spleen volume ratio were significantly altered in patients with decompensated stage. Patients with HE had significantly lower total liver volume and spleen size was associated with the presence of esophageal varices. Lastly, we found cirrhotic patients who underwent liver transplantation had significantly lower total liver volume, lower functional liver volume, and larger total spleen volume. However, spleen volume was not an independent predictor for mortality.
The complications secondary to underlying chronic liver diseases occur as a consequence of underlying fibrosis. While the gold standard to quantity the severity of underlying fibrosis requires liver biopsy, the potential complications associated with the procedure prohibits its routine use in clinical practice. At present, there are several non-invasive biological tests, such as FIB-4, AST to platelet ratio index, or enhanced liver fibrosis test to assess the severity of liver fibrosis in those with chronic liver disease6. Transient elastography to measure the liver stiffness is increasingly used as a noninvasive tool for fibrosis assessment6. Patients with advanced liver disease or cirrhosis generally undergo radiographic imaging such as CT scan for hepatocellular carcinoma surveillance. Given the readily available semi-automated interactive software, we set out this study to determine if the measurement of liver and spleen volume will be useful as an indirect indicator for the care of patients with cirrhosis. Liver volume has been used as a pre-operative assessment and risk stratification for patients undergoing hepatic resection. Baseline liver volume is associated with post-operative morbidity and mortality16. We found that liver volume of patients with cirrhosis was significantly lower than that of normal healthy controls. It is known that splenomegaly as a consequence of portal hypertension is common in patients with cirrhosis; the observation which is confirmed in our study with the measurement of a total spleen volume. Of importance, the size of liver and spleen is associated with specific complications of portal hypertension. We found that liver size is associated with the presence of hepatic encephalopathy while the spleen volume is associated with the presence of esophageal varices. Our finding confirmed the previous observation that splenomegaly detected by CT scan or by physical examination is an independent predictor of large esophageal varices17. Recently, a composite score based on the presence of acute upper gastrointestinal bleeding, ascites, and platelet counts, known as Liaoning score, was developed and validated as a predicting tool of esophageal varices in patients with cirrhosis18,19. This scoring system is based on readily available clinical and laboratory data with the good diagnostic performance for esophageal varices18,19. We attempted to determine the diagnostic ability of spleen volume with that of Liaoning score; unfortunately, our data did not capture the presence of acute bleeding status. Future studies to explore several non-invasive tools based on clinical, laboratory, and radiographic data should be explored. We previously reported the important role of liver volume and mortality of patients with cirrhosis11. However, it did not appear that the spleen volume has any prognostic significance on mortality in these patients. A recent study using CT-based value by measuring liver to abdominal area ratio (LAAR) was reported in 128 cirrhotic patients with Child-Pugh Class B or C20. This ratio is effective for predicting the in-hospital mortality20. It will be of interest to determine if using the combination parameters as reported in our study when compared to LAAR will improve the prognostic outcomes in these patients.
The strengths of our study are the large sample size with prospective follow up data on the outcomes. We also acknowledged the limitation on the nature of the retrospective study design and lack of validation cohort in our study. While we found that patients with NASH had the largest spleen size compared to those with cirrhosis from other etiologies, it is important to note that we did not account for the severity of underlying cirrhosis and it is plausible that NASH patients had more advanced disease. Nonetheless, we believe that our results are clinically relevant on the utilization of liver to spleen volume ratio and spleen volume in patients with cirrhosis.
In conclusion, baseline liver and spleen volume and its ratio are significantly altered in patients with cirrhosis. Spleen volume is also associated with the presence of esophageal varices. Our results suggest that the measurement of such values may be beneficial specifically to cirrhotic patients who have clinically indicated indication for CT radiographic examination of the liver. If externally validated, these values may be useful to be considered as part of radiographic report in such patients.
Supplementary Material
Funding
SL is supported in part by VA Merit Award 1I01CX000361
List of abbreviations:
- ANOVA
analysis of variance
- ALT
alanine aminotransferase
- AST
aspartate aminotransferase
- BMI
body mass index
- CT
computed tomography
- HCC
hepatocellular carcinoma
- MELD
Model for end stage liver disease
- NASH
non-alcoholic steatohepatitis
- RLV
right liver volume
- SD
Standard deviation
- SV
Splenic volume
Footnotes
Ethics approval and consent to participate
The study is approved by the Institutional Review Board at Indiana University School of Medicine which abides by the guidance of the Declaration of Helsinki. This was a minimal risk study and consent requirements waived as a result. IRB number 1503966995
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to confidentiality of human research data from our institution, but are available from the corresponding author on reasonable request.
Competing interest
The authors declare that they have no competing interests.
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