Spleen Stiffness in Patients With Cirrhosis In

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Spleen Stiffness in Patients With Cirrhosisin Predicting Esophageal Varices

Praveen Sharma et al.

Department of Gastroenterology and Hepatology,Sir Ganga Ram Hospital , New Delhi , India .

The American Journal of GASTROENTEROLOGY


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INTRODUCTION

Portal hypertension (PHT) and development of esophagealvarices (EV) are one of the major complications of livercirrhosis.

Bleeding from EV is a life-threatening event with 10 20 % Current guidelines recommend that all cirrhotic patients

should undergo screening endoscopy at diagnosis to identifypatients with varices .

Splenomegaly is a common finding in patients with cirrhosis

and noncirrhotic PHT, and is commonly ascribed because ofblood congestion, increased portal pressure, augmentedresistance to splenic vein outfl ow, and increased angiogenesisand fi brogenesis .

These changes of spleen stiff ness (SS) can be quantifi ed bytransient elasto graphy (TE) .


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For the diagnosis of liver fibrosis and its complications,

one needs an ideal noninvasive method with gooddiagnostic accuracy,which will be easy to perform andwill be easily reproducible,and its correlation withhepatic venous pressure gradient (HVPG) being the goldstandard for the diagnosis of PHT.

Platelet count to spleen diameter ratio (PSR) less than909 is one of the several parameters proposed for thenoninvasive prediction of EV .

the study by Kim et al. evaluated liver stiff ness (LS) measurement spleen diameter to platelet ratio score

(LSPS = LS Measurement spleen diameter/ platelet count) in

patients with cirrhosis due to hepatitis B, and theyconcluded that LSPS > 6.5 is a reliable predictor for EVbleeding.


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Several studies have shown that measurement of LS by TE

(using FibroScan) may represent a rapid and noninvasive method for predicting the presence of clinically signifi cant or severe PHT; however, LS correlates poorly at higher HVPG and did not show any diff erentiation in diff erent grades of EV . Recently, Colecchia et al. ( 5 ) showed that SS and LS were more accurate than other noninvasive parameters in identifying

patients with EV and diff erent degrees of PHT. Similar were the results of Stefanescu et al. ( 4 ), who concluded that SS in liver cirrhosis patients could predict the presence, but not the grade, of EV. In our previous study in patients with extrahepatic PHT we had shown that SS is higher in

patients who had EV bleed than those in nonbleeders . The aim of this study was to evaluate the utility of SS in predicting the presence of EV and

comparing it with other noninvasive tests (LSPS and PSR) in evaluating EV


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METHODS


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Patients and study design Between September 2011 and March 2012, a total of 270 patients (aged 18 70 years) with cirrhosis were consecutively included in the study. Th e diagnosis of cirrhosis was based on clinical, biochemical, imaging (ultrasound and computed imaging), and liver biopsy wherever needed. Patients were excluded if they had moderate to severe ascites, active alcohol intake (any amount)

within last 4 weeks, or had acute or chronic liver failure as per the Asian Pacifi c Association for the Study of the Liver guidelines ( 15 ), had hepatocellular carcinoma or any space-occupying lesion in the liver, had portal vein thrombosis, biliary obstruction, and cardiac failure, or were not willing for inclusion in the study. Of 270 patients, 70 were excluded (moderate to tense

ascites, n = 40; hepatocellular carcinoma with portal vein thrombosis, n = 8; hepatitis B reactivation, n = 12; active alcohol intake, n = 10).


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All patients underwent TE of the liver and spleen for the assessment of LS and SS. All patients were evaluated by upper endoscopy for assessing EV as per the AASLD guidelines ( 16 ).

Investigators (VK, PT) who did endoscopy were unaware of the FibroScan (Echosens, Paris, France) value. In case of any doubt regarding the subjectivity of diagnosing the size of EV, another senior-most author s (AA) opinion was taken and a decision was made accordingly. For patients who were on endoscopic band ligation for either primary or secondary prophylaxis of esophageal variceal bleed, the fi rst endoscopy fi ndings were recorded for analyzing the data. All patients had variceal bleed pre-TE


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measurement. Routine biochemical parameters were recorded for every patient, which included complete hemogram, platelet count, international normalized ratio, aspartate aminotransferases,

alanine aminotransferases, albumin, bilirubin, serum creatinine, and relevant workup for the evaluation of etiology of liver disease. All patients also underwent ultrasonography for the liver and spleen diameter. Patients who gave consent for HVPG also underwent HVPG within 1 week of measuring of LS and SS. Th e study protocol was completed within 1 week in all patients. Th e operator (PS) had long-term experience in TE measurements as well as in ultrasonographic examination of the abdomen, and has done more than a thousand TE measurements. Th e nature of the study was explained to all patients and written consent was obtained from all patients. Th e study is in accordance with the

principles of the Declaration of Helsinki.


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Upper gastrointestinal endoscopy

All patients underwent upper endoscopy, using afl exible video

gastroscope. EVs were graded according to theirsize as small

( < 5 mm) or large varices ( > 5 mm) ( 16 ).


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Measurement of HVPG Aft er an overnight fast, HVPG was measured using

a standard procedure. Measurements were made in triplicate,and the mean

of three readings was taken in each case. If therewas a diff erence

of more than 1 mm Hg between the readings, all thereadings were repeated. HVPG was obtained as the diff erence

between wedge and free hepatic venous pressure ( 17 ).


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LS and SS measurement by FibroScan

Aft er an overnight fasting, patients underwent a complete upper

abdomen ultrasound examination. Same day aft er patients had

their breakfast, TE was performed in morning hours using the

FibroScan apparatus (Echosens), which consists of a 5-MHz

ultrasound transducer probe mounted on the axis of a vibrator.

We did not look for any diurnal variation in LS and SS in this study, as all the measurements were carried out in morning

hours only. Th e tip of the t ransducer (M-probe) was covered

with a drop of gel and placed perpendicularly in the intercostal

space, with the patient lying in dorsal decubitus position with

the right arm in the maximal abduction. Under control, in time

motion and in A-mode, the operator chose a liver portion within

the right liver lobe, at least 6-cm thick and free of large vascular

structures, and the gallbladder. Stiff ness was measured on a cylinder

of hepatic tissue of 1 cm of diameter and 2 4 cm of length.

For assessing the SS the patient was in supine position with his

left arm in maximum abduction and by placing the transducer in the left intercostal spaces, usually on the posterior axillary line

or directly over the palpable spleen just below the costal space.

We used ultrasonography to depict the spleen parenchyma, to

choose the right place for SS measurement, and to measure

the spleen diameter (long axis). A median value of 10 successful

acquisitions, expressed in kPa, was kept as a representative

of the LS and SS measurements. Th e LS and SS measurement

failure was recorded when no value was obtained aft er at least10 shots. Th e results were considered unreliable in the following

circumstances: valid shots fewer than 10, success rate < 60 % , or

interquartile range / LS >30 % ( 12 ).


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Blood tests, imaging, and biochemical examinations Aft er overnight fasting, patients venous blood was taken and analyzed for routine liver function tests and hematologic parameters

by conventional methods, and evaluation of viral markers like hepatitis B and hepatic C were carried out. Ultrasound for the abdomen and computed tomography for the liver and spleen size, along with Doppler study for abdominal vessels and liver biopsy, if needed, were also performed. All patients underwent UGIE for the evaluation of varices. Th e PSR and LSPS were calculated according to the formula LS spleen diameter / platelet count, for each patient ( 6,8 ).


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Statistical analysis Th e statistical analysis was performed using the SPSS soft ware version 15.0 (SPSS, Chicago, IL). Th e continuous variables were presented as median values and range (minimum and maximum

values). Data were compared using the Mann Whitney U -test and the 2 -test for continuous and categorical variables, respectively. Th e relationships between the parameters were characterized using the Spearman s correlation coeffi cients. Th e diagnostic performance of LS and SS was assessed using sensitivity (Se), specifi city (Sp), positive predictive value (PPV), negative predictive value (NPV), accuracy, likelihood ratios,

and receiver operating characteristic (ROC) curves. Multivariate predictors were determined for EVs by multiple regression binary logistic with forward conditional elimination to examine covariate eff ects of each, and calculate the odds ratio and their 95 % confi dence interval.P -values less than 0.05 were considered statistically signifi cant.


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RESULTS Of the 200 patients enrolled in this study, 26 (13 % ) had an inconclusive SS and / or LS measurement (defi ned as failure (no valid measurement) and unreliable results (valid measurement

< 10 or interquartile range > 30 % of median value, or success rate < 60 % )), and were excluded from the study. Of these 26 patients, in 12 patients both LS and SS measurements failed because of a high body mass index with a median of 34 kg / m 2 , even when using an XL probe. In another 10 patients SS was not measurable (no valid measurements obtained), because the spleen was not enlarged or because of the interposition of the lung or colonic gas, and in 4 patients SS could be measured but had high interquartile range ( > 30 % ). All patients with cirrhosis underwent UGIE for screening of EV.


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Of 174 patients, etiology of cirrhosis were because of alcohol ( n = 77, 44.3 % ), hepatitis B ( n = 23, 13.2 % ), hepatitis C ( n = 29, 16.7 % ), and cryptogenic ( n = 45, 25.9 % ). One hundred

and twenty-four (71 % ) patients had EV (small, n = 46; large, n = 78). Of 26 patients who were excluded from the study, 19 had EV (small, n = 14; large, n = 5). The baseline characteristics of 174 patients are shown in Table 1 . There was significant difference in hemoglobulin, total leucocytes count, platelet count, Child Turcotte Pugh score, and spleen diameter in patients with EV compared with those without EV ( Table 1 ). However, we did not find any difference in the Child Turcotte Pugh score (7.78 1.8vs. 7.6 1.8,P = 0.70) in patients with variceal bleed ( n = 46) compared with those without variceal bleed ( n = 78).


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Assessment of EVs in liver cirrhosis patients by noninvasive tests

All patients gave consent for biochemical tests, ultrasound of the abdomen, and TE, and underwent LS, SS, LSPS, and PSRmeasurements. Th e median time of getting these tests done in

patients with variceal bleed was 6 days (3 10 days). Th ere was

signifi cant diff erence in median LS (51.4 vs. 23.9 kPa,P = 0.001),

SS (54 vs. 32 kPa,P = 0.001), LSPS (6.1 vs. 2.5, P = 0.001), and PSR (812 vs. 1,165,P = 0.001) between patients with EV vs. those without

EV ( Table 2 and Figure 1 ). We categorized the patients based

on alcoholic ( n = 77) and nonalcoholic ( n = 107) patients. Th ere

was a signifi cant diff erence (P < 0.001) between patients with

varices and those without varices in both the categories (alcoholic:

LS, 51.5 kPa (18 75) vs. 21.8 kPa (15 59.3); SS, 53 kPa (12 75) vs. 29 kPa (12 65); LSPS, 6.6 (1.5 21.0) vs. 2.7 (1.06 10.0); PSR 812.5

(178.9 2,193.5) vs. 1,193.7 (333.3 2,314.8); and nonalcoholic:

LS, 51.4 kPa (15 75) vs. 24.1 kPa (16 34); SS, 55 kPa (32 75) vs.

34 kPa (14.9 58); LSPS, 5.96 (1.4 17.8) vs. 2.1 (1.2 6.4), and PSR 808.9 (333.3 1,798.3) vs. 1,108.3 (392 2,047).

On multivariate analysis, taking into account all variables

(hemoglobulin level, total leucocytes count, platelet count,

spleen diameter, Child Turcotte Pugh score, LS, SS, LSPS and

PSR) associated with the presence of EV, only LS (Exp (B) 1.09

(1.028 1.157),P = 0.004) and SS (Exp (B) 1.127 (1.056 1.202), P = 0.0001) were predictive of EVs.


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LS and SS measurements LS higher than 27.3 kPa and the area under the ROC curve being 0.908 (0.861 0.956) had Se (91%), Sp (72%), PPV (89%), NPV (76 % ), and diagnostic accuracy (86 % ) in predicting the presence

of EV. However, LS could not diff erentiate patients with small varices vs. large varices (53 kPa vs. 45.3 kPa,P = 0.57), nor it could diff erentiate patients who had variceal bleed vs. those who never had variceal bleed (52.6 kPa vs. 51.4 kPa,P = 0.94; Tables 2 and 3 , and Figure 2 ). Similarly, SS having a cutoff value of 40.8 kPa with the area under the ROC being 0.898 (0.842 0.954) had Se (94 % ),

Sp (76 % ), PPV (91 % ), NPV (84 % ), and diagnostic accuracy (86 % ) for predicting the presence of EV. SS was signifi cantly higher in patients who had large varices (56 kPa vs. 49 kPa, P = 0.001) and variceal bleed (58 kPa vs. 50.2 kPa, P = 0.001; Table 4 and Figure 2 ). Having a cutoff value of 54.5 kPa and the area under the ROC curve of 0.819 (0.750 0.888,P = 0.001),


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SS could predict bleeder with Se of 76 % and Sp of 73 % . Combining the two LS + SS (27.3 kPa + 40.8 kPa) had Se ( 90 % ), Sp (90 % ), PPV (96 % ), NPV (79 % ), and diagnostic accuracy (90 % ; Table 4 ).

LSPS measurement cutoff value 3.09 with area under ROC curve being 0.867 (0.809 0.926) had Se and Sp of 89 % and 76 % , respectively, for predicting the presence of EV. We did not fi nd any diff erence in the LSPS value in patients who had variceal bleed vs. those who

did not (7.1 vs. 5.7,P = 044). Similarly, the LSPS value was not signifi cantly diff erent in patients with large vs. small EV (6.5 vs. 5.6,P = 0.24; Tables 3 and 4 ). Th e

PSR cutoff value of 1,023.2 with area under ROC curve of 0.752 (0.669 0.835) had a diagnostic accuracy of 74 % in predicting the presence of EV. When we took the cutoff value of 909 or less, we found Se of 64 % , Sp of 76 % , PPV of 87 % , NPV of 46 % , and diagnostic accuracy of 68 % in predicting EV. PSR showed signifi cant correlation with SS ( n = 174, r = 0.370, P = 0.001), LS ( n = 174, r = 0.207, P = 0.006), HVPG ( n = 52, r = 0.270, P = 0.05), and LSPS ( n = 174, r = 0.675, P = 0.001).


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HVPG and its correlation with noninvasive parameters

HVPG was measured in a subgroup of patients who gave

consent for it. Only 52 (30 % ) of 174 patients underwent

HVPG. Of 52 patients who underwent HVPG, 15 (29 % ) had

small varices and 37 (71 % ) had large varices. None of the

patients without EV underwent HVPG. Median HVPG was signifi cantly higher in patients with large EV compared with patients with small EV (19 mm Hg vs. 15 mm Hg,P = 0.001) and

it was signifi cantly higher in bleeder compared with nonbleeder (19.5 mm Hg vs. 15 mm Hg,P = 0.001). Th e median time of

getting HVPG done in patients with variceal bleed was 7 days

(5 14 days).

HVPG showed correlation with SS ( r = 0.433, P = 0.001), LSPS

( r = 0.335, P = 0.01), and PSR ( r = 0.270, P = 0.05), but not with

LS ( r = 0.178, P = 0.20), when we took all patients ( n = 174). When

we included only those patients ( n = 52) who had HVPG, LS, SS,

LSPS, and PSR done, HVPG showed correlation with only SS

( r = 0.433, P = 0.001) and LSPS ( r = 0.335, P = 0.01), but not with

LS ( r = 0.178, P = 0.207) and PSR ( r = 0.270, P = 0.05). However,

at higher HVPG ( 19 mm Hg) seen in 24 patients (large varices,

n = 20; small, n = 4), SS did not show any correlation with HVPG ( r = 0.05, P = 0.816).


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DISCUSSION


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Spleen Stiffness in Patients With Cirrhosis In