correlation of splenic arfi with endoscopic findings of ...

“CORRELATION OF SPLENIC ARFI WITH ENDOSCOPIC

FINDINGS OF ESOPHAGEAL VARICES IN

CHRONIC LIVER PARENCHYMAL DISEASE”

DISSERTATION SUBMITTED TO

THE TAMIL NADU Dr. M.G.R MEDICAL UNIVERSITY, CHENNAI

IN PARTIAL FULFILLMENT OF THE REGULATIONS FOR THE

AWARD OF DEGREE OF M.D IN RADIODIAGNOSIS.

BY

DR. MUTHUSUBRAMANIAN.R

GUIDE: DR. RAJA KUMAR.R

DEPARTMENT OF RADIOLOGY

PSG INSTITUTE OF MEDICAL SCIENCES AND RESEARCH

PEELAMEDU, COIMBATORE – 641004

TAMILNADU, INDIA








BY




PSG INSTITUTE OF MEDICAL SCIENCES AND RESEARCH


TAMILNADU, INDIA








BY




PSG INSTITIUTE OF MEDICAL SCIENCES AND RESEASRCH


TAMILNADU, INDIA

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “CORRELATION OF

SPLENIC ARFI WITH ENDOSCOPIC FINDINGS OF ESOPHAGEAL

VARICES IN CHRONIC LIVER PARENCHYMAL DISEASE” is the

bonafide original work of Dr. Muthusubramanian.R in the department

of Radiodiagnosis, PSG Institute of Medical Sciences and Research,

Coimbatore in partial fulfillment of the regulations for the award of

degree of M.D in Radiodiagnosis.

Signature of the guide

Dr. Raja Kumar.R, D.M.R.D., D.N.B

Associate professor,

Department of Radiodiagnosis,

PSGIMSR,

COIMBATORE.

CERTIFICATE

PSG INSTITIUTE OF MEDICAL SCIENCES

AND RESEASRCH, COIMBATORE

This is to certify that the dissertation entitled “CORRELATION OF

SPLENIC ARFI WITH ENDOSCOPIC FINDINGS OF ESOPHAGEAL

VARICES IN CHRONIC LIVER PARENCHYMAL DISEASE” is the

bonafide original work of Dr. Muthusubramanian.R in the department


Coimbatore in partial fulfillment of the regulations for the award of

degree of M.D in Radiodiagnosis.

Dr. Devanand .B, Dr. Ramalingam .S

Professor and HOD, Principal, Department of Radiodiagnosis, PSG IMS & R, PSG IMS & R, Coimbatore.

Coimbatore.

Place: Coimbatore

Date: 16.10.17

DECLARATION

I, Dr. Muthusubramanian .R solemnly declare that the

dissertation titled “CORRELATION OF SPLENIC ARFI WITH

ENDOSCOPIC FINDINGS OF ESOPHAGEAL VARICES IN CHRONIC

LIVER PARENCHYMAL DISEASE” was done by me at the department


Coimbatore during the period from December 2015 to September 2017

under the guidance and supervision of Dr. Raja Kumar .R, Associate

Professor, Department of Radio Diagnosis, PSG Institute of Medical

Sciences and Research, Coimbatore. This dissertation is submitted to the

Tamilnadu Dr.M.G.R. Medical University towards the partial fulfillment

of the requirement for the award of M.D. Degree in Radiodiagnosis.

I have not submitted this dissertation on any previous occasion to

any University for the award of any degree.

Place: Coimbatore Dr.Muthusubramanian .R

Date: 16.10.2017

ACKNOWLEDGEMENT Foremost, I would like to express my sincere gratitude to my professor and HOD

Dr. Devanand .B and my guide Dr. Raja Kumar .R for their ever friendly co-

operation which was present throughout the preparation of this work. This work

would not have been possible without their guidance, support and encouragement,

they were always been a key inspiration to me.

I would like to thank Dr. Ramalingam .S, Principal of PSG Institute of Medical

Sciences and Research for providing me with this opportunity and resources to

accomplish my research work.

I would like to thank and express my sincere gratitude to Dr. Devanand .B, HOD,

Prof Dr. Elango .N and Dr. Maheshwaran .V, Assistant Professor for providing me

the motivation, guidance in completing my research work and helping me with the

statistical analysis. They were very supportive right from the beginning to the final

stages of my research work and helping me battle minor indifferences and

providing me with valuable practical tips which were extremely helpful in

completing the work.

I would like to extend my heartfelt thanks to Dr. Venkatakrishnan .L, Professor

and Head, Department of Medical Gastroenterology and Dr. Krishnaveni .J,

Professor, Department of Medical Gastroenterology for helping me in providing

endoscopic findings and making consensus decisions on few challenging cases.

I would like to thank my fellow postgraduates and my dear friends for their

immense help and support during the entire period of my study and for making my

college life unforgettable.

My special thanks to my friend Dr. Karthikeyan for helping me in statistics and in

framing and formulating my thesis. He have helped me in various aspects of the

study and have aided me in completion of my thesis work.

Last, but not least, I would like to express my heartfelt gratitude to all the patients

who had participated in this study. Finally my sincere thanks and gratitude to the

associate professors, assistant professors, senior residents, staff and office people

for their immense support for carrying out and completing this work.

I dedicate this whole dissertation and all years of hard work to my Family and God

Almighty.

PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled


FINDINGS OF ESOPHAGEAL VARICES IN CHRONIC

LIVER PARENCHYMAL DISEASE” of the candidate

Dr. Muthusubramanian .R with registration number 201518102 for

the award of M.D degree in the branch of Radiodiagnosis.

I personally verified the urkund.com website for the purpose of

Plagiarism check. I found that the uploaded thesis file contains

introduction to conclusion pages and result shows 1 % of plagiarism in

the dissertation.

Signature of the guide

Dr. Raja Kumar.R, D.M.R.D., D.N.B

Associate professor,

Department of Radiodiagnosis,

PSGIMSR,

COIMBATORE.

TABLE OF CONTENTS

S. NO CONTENT PAGE NO

1 INTRODUCTION 1

2 AIMS OF THE STUDY 3

3 OBJECTIVES OF THE STUDY 4

4 MATERIALS AND METHODS 5

5 REVIEW OF LITERATURE 15

6 OBSERVATION AND RESULTS 52

7 DISCUSSION 88

8 SUMMARY 95

9 CONCLUSION 98

10 LIMITATIONS 99

11 BIBLIOGRAPHY

12 IMAGES

13 ANNEXURES

14 MASTER CHART

ABBREVIATIONS

2D TWO DIMENSIONAL

3D THREE DIMENSIONAL

ALD ALCOHOLIC LIVER DISEASE

ALT ALANINE AMINOTRANFERASE

AP ANTERO-POSTERIOR DIAMETER

ARFI ACOUSTIC RADIATION FORCE IMPLUSE

AST ASPARTATE AMINOTEANSFERASE

AUROC AREA UNDER RECEIVER OPERATING CHARACTERISTICS

CC CRANIOCAUDAL LENGTH

CVVHD CONTINUOUS VENO-VENOUS HEMODIALYSIS

EVs ESOPHAGEAL VARICES

HBV HEPATITIS B VIRUS

HCV HEPATITIS C VIRUS

HVPG HEPATIC VENOUS PRESSURE GRADIENT

Hz HERTZ

ABBREVIATIONS

INR INTERNATIONAL NORMALIZED RATIO

kPa KILOPASCALS

ln NATURAL LOGARITHM

LS LIVER STIFFNESS

m/s METERS PER SECOND

MELD MODEL FOR END STAGE LIVER DISEASE

mg/dL MILLIGRAMS PER DECILITER

MRI MAGNETIC RESONANCE IMAGING

ms MILLISECONDS

NAFLD NON ALCOHOLIC FATTY LIVER DISEASE

PHT PORTAL HYPERTENSION

PSR PLATELET COUNT / SPLEEN LENGTH RATIO

pSWE POINT SHEAR WAVE ELASTOGRAPHY

PVD PORTAL VEIN DIAMETER

ROC RECEIVER OPERATING CHARACTERISTICS

ABBREVIATIONS

ROI REGION OF INTEREST

SD STANDARD DEVIATION

SS SPLEEN STIFFNESS

SW SHEAR WAVES

SWE SHEAR WAVE ELASTOGRAPHY

SWV SHEAR WAVE VELOCITY

TE TRANSIENT ELASTOGRAPHY

TR TRANSVERSE DIAMETER

UGI UPPER GASTROINTESTINA TRACT

UGI SCOPY UPPER GASTROINTESTINAL ENDOSCOPY

USG ULTRASONOGRAPHY

VTI VIRTUAL TOUCH IMAGING

VTQ VIRTUAL TOUCH QUANTIFICATION

WHO WORLD HEALTH ORGANISATION

μl MICROLITER

LIST OF FIGURES

FIGURE 1 ELASTOGRAPHY TECHNIQUE FOR LS

FIGURE 2 STRATIFIED RANDOM SAMPLING METHOD

FIGURE 3 ELASTOGRAPHY TECHNIQUE FOR SS

FIGURE 4 SPLENIC ARTERY AND ITS BRANCHES

FIGURE 5 VASCULAR ANATOMY OF SPLENIC VEIN

FIGURE 6 SCHEMATIC REPRESENTATION OF ANATOMIC CLASSIFICATION OF PHT

FIGURE 7 NORMAL PORTAL VENOUS ANATOMY

FIGURE 8 NORMAL VENOUS FLOW THROUGH PORTAL & SYSTEMIC CIRCULATION

FIGURE 9 REDIRECTION OF FLOW THROUGH THE LEFT GASTRIC VEIN IN PHT

FIGURE 10 DIFFERENT ELASTOGRAHY TECHNIQUES

FIGURE 11 CURRENTLY AVAILABLE ULTRASOUND ELASTOGRAPHY TECHNIQUES

FIGURE 12 DIAGRAMATIC ILLUSTRATION OF FIBROSCAN

FIGURE 13 FIBRO SCAN IMAGES IN NORMAL & CIRRHOTIC PATIENTS

FIGURE 14 DIAGRAMTIC ILLUSTRATION OF ARFI IMAGING

FIGURE 15 LIVER ARFI IN NORMAL & CIRRHOTIC PATIENT

FIGURE 16 SUPERSONIC SHEAR IMAGING IN NORMAL & CIRRHOTIC PATIENT

FIGURE 17 SIEMENS ACUSON S 2000 AND ACUSON S 3000

LIST OF FIGURES

FIGURE 18 LIVER MEASUREMENT, LIVER ARFI, SPLEEN MEASUREMENT AND SPLEEN ARFI FINDINGS IN CIRHHOTIC PATIENT WITH GRADE III ESOPHAGEAL VARICES IN UGISCOPY

FIGURE 19

FIGURE 20

FIGURE 21 SPLEEN ARFI FINDINGS IN CIRHHOTIC PATIENT WITH GRADE II ESOPHAGEAL VARICES IN UGISCOPY FIGURE 22

FIGURE 23 SPLEEN MEASUREMENT AND SPLEEN ARFI FINDINGS IN CIRHHOTIC PATIENT WITH ABSENT ESOPHAGEAL VARICES IN UGISCOPY FIGURE 24

LIST OF TABLES

TABLE 1 SEX DISTRIBUTION IN CIRRHOTICS WITH EVs

TABLE 2 SEX DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

TABLE 3 ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITH EVs

TABLE 4 ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

TABLE 5 CHILD PUGH CLASS IN CIRRHOTICS WITH EVs

TABLE 6 CHILD PUGH CLASS IN CIRRHOTICS WITHOUT EVs

TABLE 7 MELD SCORE IN CIRRHOTICS WITH EVs

TABLE 8 MELD SCORE IN CIRRHOTICS WITHOUT EVs

TABLE 9 PLATELET COUNT IN CIRRHOTICS WITH EVs

TABLE 10 PLATELET COUNT IN CIRRHOTICS WITHOUT EVs

TABLE 11 AST / ALT RATIO IN CIRRHOTICS WITH EVs

TABLE 12 AST / ALT RATIO IN CIRRHOTICS WITHOUT EVs

TABLE 13 PVD IN CIRRHOTICS WITH EVS

TABLE 14 PVD IN CIRRHOTICS WITHOUT EVS

TABLE 15 PV FLOW VELOCITY IN CIRRHOTICS WITH EVs

LIST OF TABLES

TABLE 16 PV FLOW VELOCITY IN CIRRHOTICS WITHOUT EVs

TABLE 17 SPLEEN LENGTH IN CIRRHOTICS WITH EVS

TABLE 18 SPLEEN LENGTH IN CIRRHOTICS WITHOUT EVS

TABLE 19 PSR IN CIRRHOTICS WITH EVs

TABLE 20 PSR IN CIRRHOTICS WITHOUT EVs

TABLE 21 LIVER ARFI IN CIRRHOTICS WITH EVs

TABLE 22 LIVER ARFI IN CIRRHOTICS WITHOUT EVs

TABLE 23 SPLEEN ARFI IN CIRRHOTICS WITH EVs

TABLE 24 SPLEEN ARFI IN CIRRHOTICS WITHOUT EVs

TABLE 25 GRADES OF EVs IN CIRRHOTICS WITH EVs

TABLE 26 SIGNIFICANCE OF CLINICAL AND LABORATORY PREDICTORS BETWEEN CIRRHOTICS WITH EVs AND WITHOUT EVs

TABLE 27 SIGNIFICANCE OF RADIOLOGICAL PREDICTORS BETWEEN CIRRHOTICS WITH EVs & WITHOUT EVs

TABLE 28 SIGNIFICANCE OF CLINICAL AND LABORATORY PREDICTORS BETWEEN LOW GRADE EVs AND HIGH GRADE EVs

TABLE 29 SIGNIFICANCE OF RADIOLOGICAL PREDICTORS BETWEEN LOW GRADE EVs AND HIGH GRADE EVs

LIST OF GRAPHS

GRAPH 1 SEX DISTRIBUTION IN CIRRHOTICS WITH EVs

GRAPH 2 SEX DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

GRAPH 3 ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITH EVs

GRAPH 4 ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

GRAPH 5 CHILD PUGH CLASS IN CIRRHOTICS WITH EVs

GRAPH 6 CHILD PUGH CLASS IN CIRRHOTICS WITHOUT EVs

GRAPH 7 MELD SCORE IN CIRRHOTICS WITH EVs

GRAPH 8 MELD SCORE IN CIRRHOTICS WITHOUT EVs

GRAPH 9 PLATELET COUNT IN CIRRHOTICS WITH EVs

GRAPH 10 PLATELET COUNT IN CIRRHOTICS WITHOUT EVs

GRAPH 11 AST / ALT RATIO IN CIRRHOTICS WITH EVs

GRAPH 12 AST / ALT RATIO IN CIRRHOTICS WITHOUT EVs

GRAPH 13 PVD IN CIRRHOTICS WITH EVS

GRAPH 14 PVD IN CIRRHOTICS WITHOUT EVS

GRAPH 15 PV FLOW VELOCITY IN CIRRHOTICS WITH EVs

LIST OF GRAPHS

GRAPH 16 PV FLOW VELOCITY IN CIRRHOTICS WITHOUT EVs

GRAPH 17 SPLEEN LENGTH IN CIRRHOTICS WITH EVS

GRAPH 18 SPLEEN LENGTH IN CIRRHOTICS WITHOUT EVS

GRAPH 19 PSR IN CIRRHOTICS WITH EVs

GRAPH 20 PSR IN CIRRHOTICS WITHOUT EVs

GRAPH 21 LIVER ARFI IN CIRRHOTICS WITH EVs

GRAPH 22 LIVER ARFI IN CIRRHOTICS WITHOUT EVs

GRAPH 23 SPLEEN ARFI IN CIRRHOTICS WITH EVs

GRAPH 24 SPLEEN ARFI IN CIRRHOTICS WITHOUT EVs

GRAPH 25 GRADES OF EVs IN CIRRHOTICS WITH EVs

GRAPH 26 ROC ANALYSIS: MELD IN EVs DETECTION

GRAPH 27 ROC ANALYSIS: PLATELET COUNT IN EVs DETECTION

GRAPH 28 ROC ANALYSIS: SPLEEN SIZE IN EVs DETECTION

GRAPH 29 ROC ANALYSIS: PSR IN EVs DETECTION

GRAPH 30 ROC ANALYSIS: SPLEEN ARFI IN EVs DETECTION

GRAPH 31 ROC ANALYSIS: SPLEEN ARFI IN DELINEATING LOW GRADE AND HIGH GRADE EVs

INTRODUCTION

Diversity of chronic liver insults leads to a common endpoint as cirrhosis.

Cirrhosis is pathologically characterized by extensive fibrosis, regenerative

nodules and distortion of hepatic parenchymal architecture [1]. Alcoholism and

viral hepatitis have been the most common etiologies leading to cirrhosis, however

nonalcoholic fatty liver disease is showing increase in trend in recent years.

Complications of cirrhosis shows heterogeneity which can be categorized as portal

hypertension related and portal hypertension unrelated complications. Common

portal hypertension related complications are development of esophageal varices

and variceal bleeding, spontaneous bacterial peritonitis, hepato-renal syndrome,

porto-pulmonary hypertension and hepato-pulmonary syndrome [2]. Esophageal

varices have been documented the second most common cause of upper

gastrointestinal tract bleed which leads to significant amount of mortality and

morbidity. Till date, invasive upper gastrointestinal endoscopy (UGI scopy)

remains the mainstay for the detection and grading of esophageal varices [3]. In

addition to diagnostic advantage, UGI scopy facilitates rendering treatment options

such as band ligation and sclerotherapy. Despite its diagnostic and therapeutic

utility, UGI scopy as an invasive procedure has its inherent complications such as

bleeding, perforation, infection and cardio-respiratory complications related to

sedation [4]. With current advances in the field of Ultrasonography, estimation of

elasticity of the tissue is made possible with Elastography. It is an ultrasonographic

analogue of manual palpation, based on the principle that pathology changes the

stiffness of the tissue. Shear Wave Elastography (SWE) is a technique of

elastography that uses “shear wave” generated within tissue secondary to the

acoustic push, the so called Acoustic Radiation Force Impluse (ARFI). In this

technique as no external compression is required and as a push impulse can be

directed anywhere, it is possible to attain a fine elastogram of entire pancreas.

Additionally, quantification of elasticity of particular region of interest based on

shear wave velocity (SWV) is possible [5]. Elasticity of the spleen will be decreased

in cirrhosis due to portal venous congestion and hyperplasia of splenic tissue;

hence the splenic stiffness will be increased. Portal venous congestion ensues in

the formation of porto-systemic collateral network. Esophageal varices are formed

due to blood pooling in the varicoid submucosal veins due to shunting of blood

from left gastric vein to azygos vein and superior vena cava via para esophageal

and esophageal veins [6]. Screening UGI scopy is recommended in all cirrhotic

patients in accordance with recent guidelines and primary prophylaxis against

variceal hemorrhage is called for, if indicated [7]. Implementing these guidelines is

confronted with cost, complications and invasiveness of UGI scopy. Henceforth, it

necessitates accurate and noninvasive methods for detecting and grading the

severity of esophageal varices.

AIMS OF THE STUDY

To evaluate splenic ARFI as a noninvasive tool for detection of esophageal

varices in chronic liver parenchymal disease

To assess the utility of splenic ARFI in differentiating low grade and high

grade esophageal varices

OBJECTIVES OF THE STUDY

PRIMARY OBJECTIVE:

To determine the utility of splenic ARFI as a non-invasive predictor of

esophageal varices

SECONDARY OBJECTIVE:

To evaluate the efficiency of splenic ARFI in delineating low grade and high

grade esophageal varices

To correlate the ability of splenic ARFI vs other proposed noninvasive

predictors in detection of esophageal varices

MATERIALS AND METHODS

STUDY DESIGN : Prospective case control study

STUDY PERIOD : January 2016 to February 2017

STUDY PLACE : Department of Radiodiagnosis, PSG Institute of Medical

Sciences and Research, Peelamedu, Coimbatore

SOURCE OF DATA : The present study comprised of patients presenting with

clinical / radiological features of chronic liver

parenchymal disease who underwent screening UGI

scopy for detection of esophageal varices

SAMPLE SIZE : Total of 100 patients with clinical / radiological features

of chronic liver parenchymal disease were included in

this study

STUDY DESIGN

SELECTION CRITERIA:

INCLUSION CRITERIA FOR PATIENTS:

Age >18 years

Patients with clinical / radiological features of chronic liver disease

Underwent screening UGI scopy for detection of esophageal varices

EXCLUSION CRITERIA FOR PATIENTS:

Age <18 years

Presence of focal liver / spleen lesions

Did not undergo screening UGI scopy

Presence of portal vein thrombosis

Extra hepatic portal vein obstruction

Pregnant women

Presenting with acute variceal bleed

Terminally ill patients

Mentally challenged

Had underwent endoscopic variceal ligation / sclerotherapy in past

ETHICAL CLEARANCE:

Prior to the commencement of the study, ethical clearance was obtained from

Institutional Human Ethical Committee, PSG Institute of Medical Sciences and

Research, Peelamedu, Coimbatore.

INFORMED CONSENT:

The selected patients were briefed about the nature of the study in the regional

language and written informed consent was obtained from them.

DATA COLLECTION:

Consecutive patients who had been diagnosed as chronic liver parenchymal

disease, based on either clinical or radiological grounds, fulfilling the requisites of

selection criteria were included in this study. Screening UGI scopy had been

considered the standard tool for the detection of esophageal varices in cirrhotics in

our institution. Total of 50 consecutive patients with endoscopic findings of

esophageal varices and 50 consecutive patients with endoscopic findings of absent

esophageal varices were included in this study. Patients were interviewed for

demographic data such as age & sex, followed by brief explanation about

elastography procedure and informed consent of the patients to undergo the

procedure was obtained. B-mode ultrasound is performed for the patients, followed

by elastography of spleen and liver and outcome variables were recorded in the

predesigned proforma. Retrospective search of clinical and laboratory data for all

the patients was done with the assistance of hospital information system and

necessary outcome variables which had been analyzed within one month of date of

elastography procedure were also recorded. Clinical and laboratory parameters

analyzed were Child-Pugh class, MELD score, etiology of cirrhosis, platelet count,

AST/ALT ratio and PSR (Platelet count / Spleen length Ratio).

B-MODE ULTRASONOGRAPHY TECHNIQUE:

B mode ultrasonography was performed with Siemens Acuson S2000TM / Siemens

Acuson S3000 TM ultrasound systems with 6C1 / 4C1 curvilinear transducer with

patient in supine position. Following variables were evaluated:

Liver size at midclavicular line

Portal vein diameter at the level of porta hepatis

Maximum velocity of portal vein

Spleen size (maximum cephalo-caudal length)

ELASTOGRAPHY TECHNIQUE:

PRINCIPLES OF ARFI:

It was performed with Siemens Acuson S2000TM / Siemens Acuson S3000 TM

ultrasound systems with ARFI enabled 6C1 / 4C1 curvilinear transducer. Shear

Wave Elastography (SWE) is a technique of elastography that uses “shear wave”

generated within tissue secondary to the acoustic push, the so called “Acoustic

Radiation Force Impluse” (ARFI). ARFI has two Virtual touch TM implementations

by Siemens Virtual Touch TM Quantification (VTQ) and Virtual Touch TM Imaging

(VTI). VTI obtains grey scale maps representing the 'hardness' or 'softness' of the

tissue on a grey scale map. VTQ shows the stiffness of target tissue within the ROI

digitally by measuring shear wave velocity (SWV), thus providing a quantitative,

objective, reproducible and comparable value. Spleen stiffness (SS) and liver

stiffness (LS) were assessed by means of shear wave elastography (ARFI - VTQ).

On performing VTQ, the tissue within the region of interest (ROI) identified on B

mode is excited mechanically using acoustic pulses for a short duration (<1ms) in

turn producing localized displacement of the tissue (1-10 micron) without any

external compression. Localized tissue displacement will generate acoustic shear

waves (SW). Data regarding the acoustic shear waves (SW) which are generated,

propagated and received are then framed into a function of Young’s modulus[8,9,10].

Values of this function represents the Shear wave velocity (m/s) which is the

measure of peak displacement, which is directly proportional to the tissue stiffness.

LIVER ARFI TECHNIQUE:

For the LS evaluation, patient was lying in left lateral decubitus position and

assessment was done in right lobe of liver by intercostal approach. In breath hold

position, region of interest measuring 10mm in depth and 5mm in width is placed

>1 cm below the level of liver capsule, in parenchyma devoid of visible blood

vessels and biliary channels and ARFI evaluation was done (Figure 1). 5 ARFI

values for each segment (V, VI, VII and VIII) in right lobe of liver were obtained.

Mean and median of total 20 ARFI measurements was automatically calculated

and expressed in meters per second (m/s). Only mean ARFI values are considered

for analysis. Henceforth, liver ARFI in this text represents mean liver ARFI.

FIGURE 1: ELASTOGRAPHY TECHNIQUE FOR LS

SPLEEN ARFI TECHNIQUE:

For the SS evaluation, patient was lying in right lateral decubitus position and

assessment was done by intercostal approach. In order to cover uniformly the

spleen, we adopted the stratified random sampling method used in the previous

studies (11) (Figure 2). Spleen will be subdivided into cranial external(1), cranial

central(2), cranial internal(1), intermediate external(1), intermediate central(1),

intermediate internal(1), caudal external(1), caudal central(1) and caudal internal

(1) segments. Numbers in the parenthesis represents the number of ARFI values

obtained in each segment. In breath hold position, region of interest measuring

10mm in depth and 5mm in width was placed in parenchyma devoid of visible

blood vessels and >1 cm below the level of spleen capsule and ARFI evaluation

was done (Figure 3). Total of 10 successful measurements were be obtained for

each patient. In patients with morbid obesity and massive ascites, assessment of

deep seated (>8 cm from skin) splenic parenchyma cannot be assessed, due to

depth restriction of ARFI. In such cases, total of 10 ARFI values were obtained

from the accessible splenic parenchyma. Mean and median of ARFI values were

automatically calculated and expressed in meters per second (m/s). Only mean

ARFI values are considered for analysis. From this point forward, liver ARFI in

this text represents mean liver ARFI.

FIGURE 2: STRATIFIED RANDOM SAMPLING METHOD [11]

FIGURE 3: ELASTOGRAPHY TECHNIQUE FOR SS

STATISTICAL ANALYSIS:

The data obtained was coded and entered in Microsoft Excel Spreadsheet. Data

was analyzed using SPSS version 20.0 statistical software. Categorical variables

were expressed as percentages and the comparative analysis was done using chi-

square test or Fischer exact test. Continuous variables were expressed as mean ±

standard deviation (SD) and the comparative analysis was done by independent

sample ‘t’ test. The receiver operating characteristics (ROC) curve was plotted and

the area under the curve was determined to the cut off points for statistically

significant variables. A probability value (p value) of less than or equal to 0.05 at

95% confidence interval was considered as statistically significant.

REVIEW OF LITERATURE

EMBRYOLOGY OF SPLEEN:

Spleen is one of the important organ of hematological and reticulo-endothelial

systems. It begins to develop in utero by fifth week of gestation. Mesenchymal cell

mass in mesogastrium coalesce together to form spleen. As the development

progresses, with intestinal rotation, greater curvature of stomach rotates to the left

and the spleen is carried along with it into the left upper quadrant [12].

MORPHOLOGICAL ANATOMY OF SPLEEN:

It is a wedge shaped organ, situated in the left hypochondrial niche formed by

stomach, diaphragm, chest wall, left kidney and phrenico-colic ligament. It is a

highly vascular organ with varying size and weight from person to person. Average

adult splenic dimensions are 12.5, 7.5 and 2.5cms. (CC, TR, AP respectively).

Morphologically, spleen has two poles (superior & inferior), three borders and two

surfaces. It is surrounded by thin capsule. Peritoneum completely covers the

spleen, except for the hilum, where splenic vessels and nerve pass through and

serves as attachment site for supporting ligaments (Gastrosplenic and

Splenorenal).[13]

VASCULAR ANATOMY OF SPLEEN:

Splenic artery, a branch of coeliac trunk, supplies oxygenated blood to the spleen,

parts of stomach and pancreas. It divides into superior and inferior terminal

branches, near the splenic hilum, which further subdivides in their course into four

to six intrasplenic segmental branches (Figure 4) [14]. Splenic vein is formed at the

level of splenic hilum, draining majorly from spleen and in part from stomach and

pancreas. It runs along the course of splenic artery and confluences with superior

mesenteric vein, behind the neck of pancreas to form portal vein. Inferior

mesenteric vein drains into splenic vein, before its confluence with superior

mesenteric vein (Figure 5) [15].

FIGURE 4: SPLENIC ARTERY AND ITS BRANCHES

FIGURE 5: VASCULAR ANATOMY OF SPLENIC VEIN

CIRRHOSIS:

Liver is an important vital organ, located in the right upper quadrant extending into

epigastrium. It has dual blood supply from portal vein (80%) and hepatic artery

(20%). Spectrum of liver pathologies ranges from steatosis (fatty deposits),

hepatitis (inflammation), fibrosis (scarring) and cirrhosis. Cirrhosis or Chronic

liver parenchymal disease is a condition where inflammation followed by scarring

spreads through liver gradually and irreversibly disrupts its shape and function,

thereby causing permanent cell damage which in time progresses to liver failure in

the absence of or despite timely intervention [16]. The term ‘cirrhosis’ is derived

from the Greek word ‘kirrhos’ to denote ‘orange yellow’ [17]. This term ‘kirrhos’

was first used by Laennec (1891) in a brief footnote to his treatise

De auscultation mediate [18]. According to World Health Organization (WHO)

working party (1978) cirrhosis is defined as “A diffuse process characterized by

fibrosis and the conversion of normal liver architectures into structurally abnormal

nodules” [19]. Hepatitis refers to inflammation of liver parenchyma secondary to

any insult associated with influx of acute or chronic inflammatory cells. Cirrhosis

is diffuse, fibrosing, nodular progressive disease leading to disruption of entire

normal liver architecture [20]. Progression of long standing persistent liver injury

leads to cirrhosis. The pathophysiological mechanism of this injury varies, but the

common pathway remains a persistent wound healing progressing to fibrosis of

liver parenchyma [21].

EPIDEMIOLOGY & ETIOLOGY:

Cirrhosis affects 0.1% of European population, which corresponds to 14-26 new

cases per 100,000 inhabitants and an estimated 170,000 deaths per year [22]. Very

few data is available on the prevalence and incidence of cirrhosis in India. Previous

studies have shown that, mean age of diagnosis is 60 years with male

preponderance at male : female ratio of 1.3:4 [23].

Alcoholic Liver Disease (ALD) and Non Alcoholic Fatty Liver Disease (NAFLD)

are the major contributing factors for cirrhosis in developed countries while viral

hepatitis is identified as the major etiology of cirrhosis in developing

countries[24,25]. Patients with ALD have relatively high mortality rates compared to

patients with cirrhosis from other etiologies [26]. Diversity of liver insults leading to

cirrhosis are identified and can be enumerated as follows.

Etiologies of hepatic cirrhosis [20,21,27]

Most common causes:

Alcohol (60-70%)

Biliary obstruction (5-10%)

Primary or secondary biliary cirrhosis

Chronic hepatitis B or C (10%)

Hemochromatosis (5-10%)

NAFLD (10%)

Less common causes:

Autoimmune chronic hepatitis

Drugs and toxins

Metabolic disorders (Wilson’s disease)

Idiopathic / Miscellaneous (Sarcoidosis)

Infection (Schistosomiasis, Brucellosis)

Vascular (Veno-occlusive disease, Heart failure)

PROGNOSTICATION OF CIRRHOSIS:

Cirrhosis is described as the most common cause of portal hypertension [28].

Prognostication is very important for decision making in the clinical setting. Two

scoring systems are widely used: Child-Pugh’s system and MELD system.

CHILD PUGH’S SCORING SYSTEM [28,29,30]

MELD SCORING SYSTEM [31]

MELD SCORE COMPONENTS, CALCULATION & MORTALITY PREDICTION

Serum bilirubin (mg/dL)

Serum creatinine (mg/dL)

INR

MELD=3.8 [ln serum bilirubin (mg/dL)]+11.2 [Ln INR]+9.6 [ln serum

creatinine (mg/dL)]+6.4

*If a patient has had two or more hemodialysis treatments or 24 h of

CVVHD in the week prior to the time of the scoring, creatinine will be set to

4 mg/dL

MELD score Mortality in 3 months (%)

< 9 1.9

10 – 19 6.0

20 – 29 19.6

30 – 39 52.6

> 40 71.3

INR: International normalized ratio

MELD: Model for end-stage liver disease

COMPLICATIONS OF CIRRHOSIS:

They contribute to significant morbidity and mortality of patients with cirrhosis

and can be broadly categorized as follows [32]:

PORTAL HYPERTENSION RELATED

o Esophageal variceal bleeding

o Hepato-renal syndrome

o Hepato-pulmonary syndrome

o Porto-pulmonary hypertension

o Spontaneous bacterial peritonitis

PORTAL HYPERTENSION UNRELATED

o Hepatocellular carcinoma

o Hepatic encephalopathy

o Hepatic osteodystrophy

o Hepatic sarcopenia

o Immune dysfunction and sepsis

PORTAL HYPERTENSION (PHT):

Dual blood supply to liver from low pressure portal venous circulation (80%) and

high pressure hepatic arterial circulation (20%) enters hepatic lobule at portal triad

and gets mixed in hepatic sinusoids. Sinusoids opens into the hepatic central vein

which further drains into hepatic veins and inferior vena cava [33]. Cirrhosis,

characterized by fibrosis and architectural distortion, ensues in increased vascular

resistance to portal flow which starts the chain of events leading to portal

hypertension. By definition, PHT represents increased pressure in the portal

venous system of about >10mmHg. Common clinical manifestations are

splenomegaly, ascites and gastrointestinal bleeding [34]. Apart from cirrhosis,

various other pathologies can lead to the development of PHT. Based on the

anatomical location, they are classified as pre-hepatic, intrahepatic and post-

hepatic (Figure 6).

CLASSIFICATION OF PORTAL HYPERTENSION: [33]

Prehepatic

Portal vein thrombosis – independent of cause

Splenic vein thrombosis

Splenic arterio-venous fistula

Intrahepatic

Presinusoidal

Chronic HBV / HCV

Sarcoidosis

Tuberculosis

Wilson’s disease

Hemochromatosis

Amyloidosis

Idiopathic portal hypertension

Benign and malignant neoplasms

Sinusoidal

Liver cirrhosis – independent of etiology

Acute viral or alcoholic hepatitis

Acute fatty liver of pregnancy

Post sinusoidal

Veno-occlusive disease

Alcoholic hyaline sclerosis of central veins

Extrahepatic

Budd Chiari disease, Inferior vena cava occlusion

Cardiac disease: Chronic right ventricular failure

FIGURE 6: SCHEMATIC REPRESENTATION OF ANATOMIC

CLASSIFICATION OF PHT [33]

ESOPHAGEAL VARICES (EVs):

Esophageal varices comprise one of the major complications of cirrhosis. They are

basically porto-systemic collaterals that form as a consequence of portal

hypertension usually in the lower esophageal submucosal layers. Disruption and

bleed of these EVs is associated with high mortality. Variceal bleeding alone

accounts for up to 30% cases of upper gastrointestinal (UGI) bleed [35].

EPIDEMIOLOGY:

Esophageal varices are present in 50% of patients with liver cirrhosis.

Approximately 15% cirrhotics have denovo worsening of varices annually which

manifests as a sudden UGI bleed in about a third of patients causing significant

morbidity and mortality [36]. The frequency of EVs varies between 30% to 70% in

cirrhotics, and 9 to 36 % in patients with high risk varices. Annual rate of

development of EVs in cirrhotics is 5 to 8%. However the risk of bleeding is only 1

to 2% in large varices. Approximately 4 to 30% of patients with small varices will

develop large varices annually leading to an increased risk of bleeding.

Approximately 30% of patients with cirrhosis have EVs at diagnosis and reaches to

90% after 10 years. Variceal hemorrhage is identified as the common occurring

consequence of cirrhosis causing fatalities [35].

PATHOPHYSIOLOGY:

In 1841, Raciborski put forth that collaterals could develop in cases of PHT

between portal and caval system via the short gastric veins, hemorrhoidal veins and

veins in the abdominal wall [37]. The raised pressure difference between systemic

and portal circulation (HVPG) is directly responsible for the development of

esophageal varices [38,39]. Portal vein with excess pressure diverts up to 90% of its

blood flow through the porto-systemic collaterals back to the heart decompressing

itself and causing enlargement of these vessels in the process. Gastro-esophageal

junction is the most common site for development of varices, which are more

prone to bleed due to their submucosal location[38,39,40]. Inflow to gastro-esophageal

varices occurs through left gastric vein and short gastric veins. (Figure 7,8,9)

FIGURE 7: NORMAL PORTAL VENOUS ANATOMY [41]

FIGURE 8: NORMAL VENOUS FLOW THROUGH PORTAL & SYSTEMIC CIRCULATION[41]

FIGURE 9: REDIRECTION OF FLOW THROUGH THE LEFT GASTRIC VEIN IN PHT [41]

DETECTION OF VARICES:

UGI scopy remains the gold standard diagnostic tool for detection of esophageal

varices worldwide. According to consensus, cirrhotic patients need regular

screening for esophageal varices by UGI scopy. If initial UGI scopy is negative for

varices, repeat examination should be scheduled in two to three years. If small

varices are detected at initial imaging, follow up is indicated in one to two

years[42,43]. Grading of EVs is subjective. Criteria for standardization of esophageal

varices have been studied extensively. Various classification systems have been

postulated for categorizing EVs: Japanese Research Society for Portal

Hypertension, Baveno V and Paquet.

PAQUET CLASSIFICATION OF ESOPHAGEAL VARICES: [44]

GRADES OF EVs ENDOSCOPIC FINDINGS

GRADE 0 Absence of esophageal varices

GRADE 1 Microcapillars at OG junction or distal esophagus

GRADE 2 1 or 2 small varices in distal esophagus

GRADE 3 Medium varices

GRADE 4 Large varices in any part of esophagus

Mortality from liver cirrhosis related complications have shown a declining trend

in the developed countries, probably due to early detection and appropriate

management of complications. Though UGI scopy remains as a first line

diagnostic tool in detection of EVs, health care providers should keep in mind

about the intrinsic complications of this invasive procedure.

ELASTOGRAPHY:

Elastography is an Ultrasonographic (USG) analogue of manual palpation, based

on the principle that pathology changes the stiffness of the tissue. It measures the

elastic property of the tissues. It is implemented in clinical US and MR systems.

This technique does not measure stiffness directly, instead indirectly by measuring

the speed of shear waves propagating in the tissue of interest.

PRINCIPLES OF ELASTOGRAPHY:

Basic principle of elastography is that speed of shear waves depends on the

stiffness of the tissues. Shear waves travel faster in stiff tissues and slower in soft

tissues. For the estimation of tissue stiffness, various elastography techniques have

been developed and they may be classified according to the source, duration of

tissue formation and the modality used for tracking. Depending on the technique,

various stiffness parameters may be reported. Most commonly reported stiffness

parameters and corresponding units are shear wave speed in meters per second

(m/s), magnitude of complex shear modulus in kilopascals (kPa) and the young

elastic modulus in kilopascals. Two methods have been devised to study this

phenomenon, which are the strain elastography and the shear wave elastography

(Figures 10 and 11).

FIGURE 10: DIFFERENT ELASTOGRAHY TECHNIQUES

The mechanical properties of the tissue assessed by elastography is associated with

the elastic restoring forces acting against type of deformation (shape change)

knows as “shear”. Deformation may be represented in an elastogram or as a local

measurement, in one of the three ways:

1. Tissue displacement may be detected and displayed directly known as

Acoustic Radiation Force Impulse(ARFI) Imaging

2. Tissue strain may be calculated and displayed, producing strain elastogram

3. In the dynamic elastography only, propagation of shear waves are recorded,

which are used to calculate either a) regional speed values (without making

images) referred as Transient Elastography (TE) and point shear wave

elastography (pSWE) or b) images of their speed referred to as shear wave

elastography (SWE) which includes 2D SWE and 3D SWE.

FIGURE 11: CURRENTLY AVAILABLE ULTRASOUND

ELASTOGRAPHY TECHNIQUES [45]

STATIC OR QUASISTATIC ELASTOGRAPHY:

In static elastography technique, stress is applied manual compression of tissues

whereas in quasistatic type, the transmitted physiological vibrations of the heart or

blood vessels act as stress. Static and quasistatic elastography have limited

applications in liver fibrosis. Example: eSie Touch in Siemens Healthcare.

DYNAMIC ELASTOGRAPHY:

It is also referred as shear wave imaging. By tracking shear waves propagating

through the media, it has the ability to assess stiffness and stiffness related

parameters. It works on basic principle that shear waves travel faster in stiff tissues

and slower in soft tissues. Stiffness of the tissues can be inferred, by measuring

shear wave speed within the tissues. Different techniques employs different range

of wave frequencies, hence stiffness related parameters obtained with various

techniques are not comparable. Example: Point shear wave elastography – Virual

Touch Quantification in Siemens.

TYPES OF WAVES IN ELASTOGRAPHY:

Waves which travel inside body organs can be categorized into two types namely

Compression waves and Shear waves. In compression waves, tissues move back

and forth in a direction parallel to wave propagation. Magnitude of compression

waves measures up to 1500m/s. Since, compression eaves propagate so rapidly,

they cannot be assessed accurately by current imaging techniques. Therefore,

present elastography techniques are based on shear waves. Shear waves propagate

at the magnitude of 1-10m/s with the direction of tissue motion perpendicular to

the wave propagation.

WAVE GENERATION:

Shear waves may be generated by applying mechanical vibration to the surface of

the body or focusing acoustic radiation force impulses inside the region of interest.

Few elastography techniques utilizes the former method of shear wave generation,

whereas others use the later. Former technique, utilizes the vibrator which

typically oscillates perpendicular to the body surface at a precisely controlled

frequency. Compression waves are generated and directed towards the body

surface, part of its energy is converted to shear waves by the process of “mode

conversion” (46). By this technique, precise control of shear wave frequency can be

obtained and associated energy absorption by tissue is minimal, but adequacy of

waves delivered into region of interest is not sufficient. Whereas later technique

employs focused acoustic compression pulses into the region of interest, part of its

energy is absorbed and released in the form of shear waves [47]. By this technique

wave delivery into area of interest more efficient than mechanic vibration

techniques. On contrary, ARFI is associated with higher power output, greater

energy absorption and difficulty in controlling shear wave frequency.

MECHANICAL PROPERTIES AND PARAMETERS:

Current clinically available techniques report the shear-wave speed, the magnitude

if complex shear modulus, or the Young modulus. The modulus parameters are

often referred to as “stiffness” in medical elastography literature. Two such

parameters are elasticity and viscosity. Elasticity is the mechanical property of a

material that tends to return to its original shape after a deformation. Viscosity

refers to the ability of the material to resist rapid movement or deformation.

Biologic tissues are considered to have both properties. (Viscoelastic)

TYPES OF DYNAMIC ELASTOGRAPHY:

Current techniques in dynamic elastography, use transient shear wave excitations

at a frequency of 50-400Hz [48,49,50].

ONE DIMENSIONAL TRANSIENT ELASTOGRAPHY:

FibroScan (Echosens) was the first commercially available shear wave

measurement technique based on the concept of transient elastography. A single

element piston like ultrasound transducer mounted on a vibrating actuator

generates a transient vibration of short duration (<30ms) at a frequency of 50Hz[51].

The mechanical impulse generates a shear wave that propagates symmetrically

with respect to the axis of the single element transducer [48,51,52,53,54,55]. The

displacements induced by shear wave are tracked using ultrasonic eaves emitted

and received at very high frequency (6 kHz) by single element transducer. In

addition to shear wave, compression is also by mechanical impulse but do not

interfere with the shear wave measurements, because of its high speed it

propagates beyond the region of interest at which shear waves are tracked.

This technique provides M-mode and A-mode graphs, instead of an anatomic

image, to locate the optimal measurement point. The shear wave propagation graph

is displayed after each acquisition. The acquired data is used to evaluate the shear

wave speed in the region of interest. The results are converted to Young modulus

and reported in kilopascals (Figures 12 and 13).

ADVANTAGES:

Inexpensive, highly portable and widely available

Independently validated worldwide

Easy to learn and rapid to perform

Highly standardized measurements

Less inter observer variability

Low power output

LIMITATIONS:

Obese patients

Narrow intercostal space

Ascites

No anatomical image – sampling variability in monitoring over time

FIGURE 12: DIAGRAMATIC ILLUSTRATION OF FIBROSCAN [56]

FIGURE 13: FIBRO SCAN IMAGES IN NORMAL & CIRRHOTIC PATIENTS [57]

NORMAL

CIRRHOSIS

POINT SHEAR WAVE ELASTOGRAPHY:

It is based on high frequency spheric compression wave (Acoustic Radiation Force

Impulse or Acoustic Push Pulse) focused on a spot [47], which is then absorbed as

acoustic energy. It causes expansion of expansion of tissues [58], which creates

shear waves perpendicular to the ultrasound beam axis [59]. Displacement produced

by push pulse is recorded by 2D ultrasound probe using series of tracking pulses

and shear wave speed values are calculated. There are several implementations of

point shear wave elastography and can be integrated into current scanners by

adding the necessary hardware (transducers and electronic components) and

software (shear wave tracking algorithms). In commercial availability, Acuson

S2000TM and Acuson S3000TM (Siemens Healthcare), are used for qualitative and

quantitative assessment of point shear wave elastography. With the quantitative

technique (Virtual Touch Quantification, Siemens Healthcare), a rectangular

region of interest box measuring 10 x 5mm is placed on a B mode image. A

transient shear wave is generated within the region. The shear wave is tracked and

its speed is measured within the region of interest, expressed in meters per second,

at a range of 0.5-5m/s in abdominal applications [60] (Figures 14 and 15).

FIGURE 14: DIAGRAMTIC ILLUSTRATION OF ARFI IMAGING [56]

FIGURE 15: LIVER ARFI IN NORMAL & CIRRHOTIC PATIENT [57]

NORMAL

CIRRHOSIS

ADVANTAGES:

Allows the operator to evaluate specific region of interest

Same region of interest can be monitored on serial follow up

Can be performed in obese patients and in the presence of

LIMITATIONS:

More expertise

Experienced radiologist is needed to perform the procedure

Less validated worldwide

High energy absorption by tissues

SHEAR WAVE ELASTOGRAPHY:

Supersonic Shear Imaging technique (Aixplorer) combines a cone shaped

quasiplanar wave front and an ultrafast imaging technique to track shear wave

displacements across an entire imaging plane [61](Figure 16). An acoustic radiation

force is focused at successively greater depths on an axial line to produce multiple

sequential spheric wave fronts. These interfere constructively to create a Mach

cone of high displacement magnitudes than that of individual wave fronts. By

analogy with supersonic planes, Mach cone is produced because the rate of

sequential wave front production is greater than the speed of the resulting shear

waves. In commercial implementation of shear wave elastography, several Mach

cones are produced at different lateral positions of the image. An ultra-high frame

rate (up to 15000 images per second) is used to scan the entire imaging plane in

one acquisition with high temporal resolution [49]. Combination of Mach cone

generation and fast imaging allows real time generation of elastogram. The results

are reported as meters per second or converted to the young modulus in

kilopascals.

ADVANTAGES:

Quantitative elastogram

Reduces sampling variability

LIMITATIONS:

Less commercially available

High cost of the equipment

FIGURE 16: SUPERSONIC SHEAR IMAGING IN NORMAL & CIRRHOTIC PATIENT [57]

NORMAL

CIRRHOSIS

NONINVASIVE DETECTION OF ESOPHAGEAL VARICES:

Variceal bleeding is the most lethal complication of cirrhosis and accounts for 20%

to 35% mortality. Recent search is in the development of prophylactic measures for

variceal bleeding, thereby improving patient’s prognosis and reducing the costs of

hospitalization [62]. American and European guidelines for primary prophylaxis of

esophageal variceal bleeding have been established and recommends screening

UGI scopy for all cirrhotic patients [63,64]. However, these guidelines imposes

onerous financial expenditure and intrinsic risks of the invasive procedure.

Previous studies on non-invasive clinical and radiological parameters for the

detection of esophageal varices have thrown light on this context, thereby reducing

the number of invasive UGI scopy for the screening of EVs in cirrhotics. Previous

studies in the literature showed differing results on the ability of these variables in

detecting esophageal varices.

CLINICAL PREDICTORS:

Clinical parameters evaluated in the recent studies were Child Pugh class, MELD

score, Platelet count and AST/ALT ratio.

RADIOLOGICAL PREDICTORS:

Radiological parameters assessed in the previous studies were liver size, spleen

size, portal vein diameter and flow velocity, PSR, liver and spleen ARFI.

CLINICAL PREDICTORS:

CHILD PUGH CLASS:

Cirrhotic patients categorized as Child-Pugh class B or C have high predilection

(x3 times) towards detection of esophageal varices or large esophageal varices in

comparison to Child-Pugh class A cirrhotics, was inferred by Zaman et al [65]. In a

prospective study of 299 patients newly diagnosed with chronic liver disease done

by Cherian et al (66) reported that three non-endoscopic predictors namely Child-

Pugh class, low platelet count and spleen diameter. On multivariate analysis, they

deduced that Child-Pugh class B or C, platelet count of <90,000 per μl and spleen

diameter of >160 mm were strong predictors in of large EVs.

MELD SCORE:

De Mattos et al inferred that there is conspicuous association of esophageal varices

with MELD score, platelet count, spleen diameter, platelet count/spleen diameter

ratio on univariate analysis(p<0.05)[67]. Striking association between esophageal

varices and MELD Score was revealed by Tafarel et al [68]. In a prospective study

of 51 patients by Chandail VS et al [69] deduced that MELD score is a reliable

noninvasive predictor of esophageal varices in cirrhotics and with cut off of 15.91

it can certainly differentiate cirrhotics with vs without esophageal varices with

maximum sensitivity, specificity and positive predictive value.

PLATELET COUNT:

Portal hypertension induced splenomegaly may lead to thrombocytopenia, in part

due to platelet sequestration. Literature search unwinds the large number of studies

performed in the assessment of correlation between platelet count and esophageal

varices [65,70,71,72]. Though low-platelet count is frequently considered as valid

laboratory parameter in predicting the presence of esophageal varices and large

esophageal varices in cirrhotics, but there is a broad variation in the cut-off level of

platelets ranging from 68,000 to 160,000 per μl with specificities ranging from 36–

73% and sensitivities from 71–90% and. Selection bias is likely to interpret for

much of this variation, with the most of the studies being retrospective and

constitutes heterogeneous patients cohorts resulting in both selection and spectrum

bias.

In contrary, Qamar et al [73], in their longitudinal study on 213 patients with chronic

liver disease with portal hypertension without EVs found that median of platelet

count at the time of occurrence of esophageal varices was 91,000. Although, no

reliable cut off value of platelet count could be depicted that precisely predicted the

presence of EVs (AUROC: 0.63). Thence, they deduced that platelet count is a

fallible noninvasive marker for detection of esophageal varices in cirrhotics.

AST/ALT RATIO:

AST/ALT ratio was proved useful in the prediction of cirrhosis. By natural

extension studies had been performed to assess its utility as a non-invasive marker

in the prediction of esophageal varices.

Nyblom et al [74], in their retrospective study inferred that AST/ALT ratios were

significantly higher in patients with varices when compared to those without (ratio:

1.8 versus 1.0).

Castera et al [75], in their prospective study, found that AST/ALT ratio significantly

differentiates cirrhotics with vs without EVs with cut off value > 1.12 with

sensitivity of 47.8%, specificity of 87%, PPV 42.3%, and NPV 89.2%, and an

AUROC of 0.69. Further in this study, a different cut-off of ≥1.0 demonstrated a

sensitivity of 68%, specificity of 89%, PPV 77%, and NPV 83%, with an AUROC

of 0.83 (0.72–0.94) for prediction of EVs. For the detection of large EVs, it

demonstrated a sensitivity of 68%, specificity of 77%, PPV of 41%, and NPV of

92%, and AUROC of 0.79 (0.64–0.94). Comprehensively, AST/ALT ratio

precisely classified 81% patients for the detection of EVs and 76% of patients with

large EVs.

In contrary, Kraja et al [76] in their prospective study of 199 patients found that no

significant association exists between AST/ALT ratio and the presence of

esophageal varices.

RADIOLOGICAL PREDICTORS:

Radiologic parameters such as portal vein diameter, portal blood velocity and

congestion index, spleen size, flow pattern in the hepatic veins, and the presence of

abdominal portosystemic collaterals are previously thought to have prognostic

significance but all with poor sensitivity and specificity. Radiological parameters

evaluated in the recent literature were portal vein diameter & flow velocity, spleen

length, platelet count – Spleen length ratio (PSR), liver stiffness and splenic

stiffness. Previous studies in the literature inferred varying results on the capability

of these radiological markers in detecting esophageal varices.

PORTAL VEIN DIAMETER (PVD):

Two studies, by Schepis et al [77] and Cottone et al [78], proved that PVD can be

considered as an independent radiological marker for prediction of the presence of

EVs vs without EVs in cirrhotics. Schepis et al [77] found PVD of 13.82 ± 2.1 mm,

amongst patients with esophageal varices, and 12.33 ± 2.04 mm amongst patients

without esophageal varices. In their studies, they found that PVD ≥ 13 mm had

100% sensitivity in predicting the presence of EVs.

Sarwar et al [79], postulated that PVD > 11 mm is independently associated with the

presence of EVs. Fook Hong et al [80], deduced a portal vein diameter of 1.15 ±

0.24 cm in cirrhotics with EVs and 1.05 ± 0.26 cm in cirrhotics without EVs.

PORTAL VEIN FLOW VELOCITY:

Diminished portal flow volume is associated with poor liver function tests and

PHT in cirrhotics and it might predict variceal bleeding [81], although there is

disagreement[82]. Dib et al [83] found that portal vein flow velocity can be

considered as non-invasive marker in detection of EVs with cut off value of

<12cm/sec at which maximum sensitivity and specificity were obtained.

SPLEEN LENGTH:

Chalasani et al [84] and Sudha Rain et al [85] proved that splenomegaly is a reliable

predictor of EVs in cirrhotics. Kumar et al [86] inferred that spleen diameter of >140

mm and portal vein diameter of >13 mm are reliable noninvasive radiological

markers of EVs in cirrhotics.

In another study, by Tarzamini et al [87] postulated that spleen diameter as

independent predictor of EVs with cut off value of more than 157 mm.

Thomopoulos et al [88] found that spleen length can be regarded as significant

predictor of EVs with cut off value of 13.5 cm which has 95% sensitivity and

37% specificity.

Sharma and Agarwal [89], in their study found that clinically palpable spleen

showed significant association with high grade varices, although they did not

measure the ultra-sonographic length of spleen. Mandal et al [90] postulated that

splenomegaly and portal vein diameter are reliable predictors of variceal

hemorrhage and also inferred that grading of EVs also correlate with splenic size

and portal vein diameter. In their study, average splenic size and portal vein

diameter in high grade varices were 14.43 ± 0.86 mm and 15.36 ± 2.14 cm

respectively.

PLATELET COUNT – SPLEEN LENGTH RATIO (PSR):

It is calculated by dividing the platelet number/mm3 by the maximum spleen length

in mm as estimated by abdominal ultrasound. In 2003, Giannini et al [91], proved

that PSR, spleen diameter and platelet count are significantly different among

cirrhotic patients with and without EVs. They found that PSR cut off value of 909

had 100% negative predictive value for the diagnosis of EVs.

In another study, González-Ojeda et al [92], proved that PSR is a reliable

noninvasive parameter to detect EVs independent of the grade with cutoff value of

≤ 884.3 which showed sensitivity of 84% and specificity of 70%.

In contrary, Chawla et al [93], found the inability PSR as an independent predictor

of EVs in cirrhotics.

LIVER STIFFNESS:

Elastographic methods of measuring liver stiffness has attracted enormous

attention in the last decade. Transient elastography (TE, FibroScan, Echosens,

France) is a noninvasive technique which was proved to be capable of assessing

hepatic fibrosis in patients with chronic liver diseases. Beyond its utility in

assessment and grading of hepatic fibrosis, it has been comprehensively studied in

the recent years, evaluating its ability to predict EVs in cirrhotics. Some variability

was observed in the results but in most studies showing a negative predictive value

of above 90%[94,95]. Nonetheless, these studies were highly heterogeneous and

thereby defining threshold value is difficult enough that TE could not be practiced

to triage the patients needing and not needing UGI scopy.

Liver stiffness measured by ARFI elastography may non-invasively predict the

presence or absence of clinically significant esophageal varices. Parvez, M.D.

Nadeem et al [96], found that ARFI values were significantly higher in cirrhotic

patients with clinically significant EVs as compared to cirrhotic patients without

significant EVs (3.63 ± 0.30 vs 2.01 ± 0.08, P < 0.001) and it has positive

correlation with the grade of EVs (r = 0.78, P < 0.043). They also found that ARFI

value of <2.0 m/s (≤grade 2 fibrosis) has high prediction towards the absence of

large EVs.

Morishita et al [97], found that liver ARFI value increased with grades of EVs

(p<0.001). The ARFI value for high-risk EVs was significantly higher than that

for low-risk EVs (p < 0.001). The optimal cutoff value of ARFI for EV presence

was 2.05 m/s with good sensitivity (83 %), specificity (76 %), PPV (78 %), and

NPV (81 %), and that for high-risk EVs was 2.39 m/s with good sensitivity

(81 %), specificity (82 %), PPV (69 %), and NPV (89 %).

SPLEEN STIFFNESS: Determination of spleen stiffness can be done with transient elastography, using

the presumed hypothesis that splenomegaly resulting from portal hypertension

causes changes in the density of spleen tissues. Stefanescu et at [98], studied of 135

cirrhotic patients and 51 non cirrhotic individual and postulated that spleen

stiffness can be used as a non-invasive marker to detect esophageal varices, as the

values were significantly higher in cirrhotics than noncirrhotics and in patients

with EVs compared to those without. They determined the cut off value as 52.5kPa

which had better diagnostic accuracy.

In a study of 17 compensated cirrhotic patients, by Talwalkar et al [99], proposed

that MR Elastographic spleen stiffness can be used to predict the presence of

esophageal varices reliably with the mean cut off value of >10.5kPa.

Xiao-Ping et al [100], inferred that inferred that significantly higher values are seen

in cirrhotics with EVs in comparison to those without. They determined the cut off

value of spleen ARFI as 3.16 m/s varices (AUROC = 0.83) can reliably

differentiates these two groups, thereby validating spleen ARFI as a non-invasive

marker for EVs in cirrhotics. Although, no significant association was determined

between liver ARFI and the presence of EVs.

Likely, Takuma et al [101], deduced the utility of spleen ARFI as initial non-invasive

screening test for the prediction of EVs in cirrhotics with cut off spleen stiffness of

3.18 m/s. Moreover, they also determined that spleen ARFI showed significant

correlation with severity of esophageal varices. Cutoff value of 3.30 m/s identified

patients with high grade EVs with a 99.4% negative predictive value and 98.9%

sensitivity. The presence of high grade EVs can be reliably ruled out with cut off

SS values of <3.3 m/s in patients with chronic liver parenchymal disease.

In contrary, Rifia et al [102], proved that spleen elastography is inferior to liver

elastography for the detection of portal hypertension.

OBSERVATION AND RESULTS

This prospective case control study was conducted at PSG institute of Medical

Sciences and Research, Peelamedu, Coimbatore from January 2016 to February

2017. A total of 100 patients with chronic liver disease (50 patients with EVs and

50 patients without EVs) were enrolled in this study. The data obtained was

analyzed between two groups: Cirrhotics with EVs vs Cirrhotics without EVs.

Mean age of patients in Cirrhotics with EVs group is 47.9 years (Range: 20 – 85

years) and in Cirrhotics without EVs group is 48.3 years (Range: 28 – 82 years).

All the patients in both groups had coarse echotexture of liver in B mode

ultrasound and surface nodularity is present in 48 patients (96%) in EVs group and

44 patients (88%) in without EVs group. Final results were interpreted in tables

and /or illustrative graphs as follows. Values expressed as A (B %), represents

actual numbers as A and percentage as B% within each group.

TABLE 1: SEX DISTRIBUTION IN CIRRHOTICS WITH EVs

SEX DISTRIBUTION (N=50)

NUMBER PERCENTAGE

MALE 36 72

FEMALE 14 28

TOTAL 50 100

GRAPH 1: SEX DISTRIBUTION IN CIRRHOTICS WITH EVs

In the present study, cirrhotics with EVs group comprised of 36 males (72%) and

14 females (28%) with male to female ratio of 2.57:1.

TABLE 2: SEX DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

SEX DISTRIBUTION (N=50)

NUMBER PERCENTAGE

MALE 38 76

FEMALE 12 24

TOTAL 50 100

GRAPH 2: SEX DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

In the present study, cirrhotics without EVs group comprised of 38 males (76%)

and 12 females (24%) with male to female ratio of 3.16:1.

TABLE 3: ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITH EVs

ETIOLOGY DISTRIBUTION (N=50)

NUMBER PERCENTAGE

ALCOHOL 37 74

NAFLD 6 12

AUTOIMMUNE 6 12

METABOLIC 1 2

TOTAL 50 100

GRAPH 3: ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITH EVs

In our study, in cirrhotics with EVs group, etiologies were alcohol (74%),

NAFLD(12%), autoimmune (12%) and metabolic (1%).

TABLE 4: ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

ETIOLOGY DISTRIBUTION (N=50)

NUMBER PERCENTAGE

ALCOHOL 35 70

NAFLD 6 12

AUTOIMMUNE 9 18

TOTAL 50 100

GRAPH 4: ETIOLOGY DISTRIBUTION IN CIRRHOTICS WITHOUT EVs

In our study, in cirrhotics without EVs group, etiologies were alcohol in 35

patients(70%), NAFLD in 9 patients (18%) and autoimmune in 6 patients (12%).

TABLE 5: CHILD PUGH CLASS IN CIRRHOTICS WITH EVs

CHILD PUGH CLASS

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

A 8 16

B 13 26

C 29 58

TOTAL 50 100

GRAPH 5: CHILD PUGH CLASS IN CIRRHOTICS WITH EVs

In the present study, in cirrhotics with EVs group, 8 patients (16%) belongs to

Child Pugh A class, 13 patients (26%) belongs to Child Pugh B class and 29

patients (58%) belongs to Child Pugh C class.

TABLE 6: CHILD PUGH CLASS IN CIRRHOTICS WITHOUT EVs

CHILD PUGH CLASS

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

A 7 14

B 16 32

C 27 54

TOTAL 50 100

GRAPH 6: CHILD PUGH CLASS IN CIRRHOTICS WITHOUT EVs

In the present study, in cirrhotics without EVs group, 7 patients (14%) belongs to

Child Pugh A class, 16 patients (32%) belongs to Child Pugh B class and 27

patients(54%) belongs to Child Pugh C class.

TABLE 7: MELD SCORE IN CIRRHOTICS WITH EVs

MELD SCORE DISTRIBUTION (N=50)

NUMBER PERCENTAGE

> 25 34 68

16-25 12 24

0-15 4 8

TOTAL 50 100

GRAPH 7: MELD SCORE IN CIRRHOTICS WITH EVs

Our study showed in cirrhotics with EVs group, MELD scores were > 25 in 34

patients (68%), 16-25 in 12 patients (24%) and 0-15 in 4 patients (8%).

TABLE 8: MELD SCORE IN CIRRHOTICS WITHOUT EVs

MELD SCORE DISTRIBUTION (N=50)

NUMBER PERCENTAGE

> 25 27 54

16-25 20 40

0-15 3 6

TOTAL 50 100

GRAPH 8: MELD SCORE IN CIRRHOTICS WITHOUT EVs

Our study showed in cirrhotics without EVs group, MELD scores were > 25 in 27

patients (54%), 16-25 in 20 patients (40%) and 0-15 in 3 patients (6%).

TABLE 9: PLATELET COUNT IN CIRRHOTICS WITH EVs

PLATELET COUNT DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 90000 33 66

>90000 17 34

TOTAL 50 100

GRAPH 9: PLATELET COUNT IN CIRRHOTICS WITH EVs

In the present study, in cirrhotics with EVs group 33 patients (66%) have platelet

count ≤ 90000 per µl and 17 patients (34%) have platelet count > 90000 per µl.

TABLE 10: PLATELET COUNT IN CIRRHOTICS WITHOUT EVs

PLATELET COUNT DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 90000 6 12

>90000 44 88

TOTAL 50 100

GRAPH 10: PLATELET COUNT IN CIRRHOTICS WITHOUT EVs

In the present study, in cirrhotics without EVs group 6 patients (12%) have platelet

count ≤ 90000 per µl and 44 patients (88%) have platelet count > 90000 per µl.

TABLE 11: AST/ALT RATIO IN CIRRHOTICS WITH EVs

AST/ALT RATIO DISTRIBUTION (N=50)

NUMBER PERCENTAGE

> 3 14 28

2 TO 3 14 28

1 TO 2 22 44

TOTAL 50 100

GRAPH 11: AST/ALT RATIO IN CIRRHOTICS WITH EVs

Our study showed in cirrhotics with EVs group, AST/ALT ratio was > 3 in 14

patients (28%), 2 to 3 in 14 patients (28%) and 1 to 2 in 22 patients (44%).

TABLE 12: AST/ALT RATIO IN CIRRHOTICS WITHOUT EVs

AST/ALT RATIO DISTRIBUTION (N=50)

NUMBER PERCENTAGE

> 3 16 32

2 TO 3 17 34

1 TO 2 17 34

TOTAL 50 100

GRAPH 12: AST/ALT RATIO IN CIRRHOTICS WITHOUT EVs

Our study showed in cirrhotics without EVs group, AST/ALT ratio was > 3 in 16

patients (32%), 2 to 3 in 17 patients (34%) and 1 to 2 in 17 patients (34%).

TABLE 13: PORTAL VEIN DIAMETER IN CIRRHOTICS WITH EVs

PORTAL VEIN DIAMETER

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≥ 13mm 29 58

< 13mm 21 42

TOTAL 50 100

GRAPH 13: PORTAL VEIN DIAMETER IN CIRRHOTICS WITH EVs

In the current study, in cirrhotics with EVs group 29 patients (58%) have portal

vein diameter ≥ 13mm and 21 patients (42%) have portal vein diameter < 13mm.

TABLE 14: PORTAL VEIN DIAMETER IN CIRRHOTICS WITHOUT EVs

PORTAL VEIN DIAMETER

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≥ 13mm 25 50

< 13mm 25 50

TOTAL 50 100

GRAPH 14: PVD IN CIRRHOTICS WITHOUT EVs

In the current study, in cirrhotics without EVs group 25 patients (50%) have portal

vein diameter ≥ 13mm and 25 patients (50%) have portal vein diameter < 13mm.

TABLE 15: PV FLOW VELOCITY IN CIRRHOTICS WITH EVs

PORTAL VEIN FLOW VELOCITY

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 12 cm/sec 5 10

>12 cm/sec 45 90

TOTAL 50 100

GRAPH 15: PV FLOW VELOCITY IN CIRRHOTICS WITH EVs

In this study, in cirrhotics with EVs group, portal vein flow velocity was ≤ 12

cm/sec in 5 patients (10%) and portal vein flow velocity was > 12 cm/sec in 45

patients (90%).

TABLE 16: PV FLOW VELOCITY IN CIRRHOTICS WITHOUT EVs

PORTAL VEIN FLOW VELOCITY

DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 12 cm/sec 2 4

>12 cm/sec 48 96

TOTAL 50 100

GRAPH 16: PV FLOW VELOCITY IN CIRRHOTICS WITHOUT EVs

In this study, in cirrhotics without EVs group, portal vein flow velocity was ≤ 12

cm/sec in 2 patients (4%) and portal vein flow velocity was > 12 cm/sec in 45

patients (90%).

TABLE 17: SPLEEN LENGTH IN CIRRHOTICS WITH EVs

SPLEEN LENGTH DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 140 mm 24 48

> 140 mm 26 52

TOTAL 50 100

GRAPH 17: SPLEEN LENGTH IN CIRRHOTICS WITH EVs

Our study showed that in cirrhotics with EVs group, 24 patients (48%) had spleen

length of ≤ 140 mm and 26 patients (52%) had spleen length of > 140mm.

TABLE 18: SPLEEN DIAMETER IN CIRRHOTICS WITHOUT EVs

SPLEEN LENGTH DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 140 mm 25 50

> 140 mm 25 50

TOTAL 50 100

GRAPH 18: SPLEEN DIAMETER IN CIRRHOTICS WITHOUT EVs

Our study showed that in cirrhotics without EVs group, 25 patients (50%) had

spleen length of ≤ 140 mm and 25 patients (50%) had spleen length of > 140mm.

TABLE 19: PSR IN CIRRHOTICS WITH EVs

PSR DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 884 43 86

> 884 7 14

TOTAL 50 100

GRAPH 19: PSR IN CIRRHOTICS WITH EVs

In the current study, in cirrhotics with EVs group, 43 patients (86%) have PSR

values ≤ 884 and 7 patients (14%) have PSR values > 884.

TABLE 20: PSR IN CIRRHOTICS WITHOUT EVs

PSR DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≤ 884 7 14

> 884 43 86

TOTAL 50 100

GRAPH 20: PSR IN CIRRHOTICS WITHOUT EVs

In the current study, in cirrhotics without EVs group, 7 patients (14%) have PSR

values ≤ 884 and 43 patients (86%) have PSR values > 884.

TABLE 21: LIVER ARFI IN CIRRHOTICS WITH EVs

LIVER ARFI DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≥ 2 m/s 44 88

< 2 m/s 6 12

TOTAL 50 100

GRAPH 21: LIVER ARFI IN CIRRHOTICS WITH EVs

In this study, in cirrhotics with EVs group, Liver ARFI values were ≥ 2 m/s in 44

patients (88%) and Liver ARFI values were < 2 m/s in 6 patients (12%)

TABLE 22: LIVER ARFI IN CIRRHOTICS WITHOUT EVs

LIVER ARFI DISTRIBUTION (N=50)

NUMBER PERCENTAGE

≥ 2 m/s 44 88

< 2 m/s 6 12

TOTAL 50 100

GRAPH 22: LIVER ARFI IN CIRRHOTICS WITHOUT EVs

In this study, in cirrhotics without EVs group, Liver ARFI values were ≥ 2 m/s in

44 patients (88%) and Liver ARFI values were < 2 m/s in 6 patients (12%)

TABLE 23: SPLEEN ARFI IN CIRRHOTICS WITH EVs

SPLEEN ARFI DISTRIBUTION (N=50)

NUMBER PERCENTAGE

< 3.18 4 8

≥ 3.18 m/s 46 92

TOTAL 50 100

GRAPH 23: SPLEEN ARFI IN CIRRHOTICS WITH EVs


ARFI values of ≥ 3.18m/s and 4 patients (8%) had ARFI values of < 3.18m/s.

TABLE 24: SPLEEN ARFI IN CIRRHOTICS WITHOUT EVs

SPLEEN ARFI DISTRIBUTION (N=50)

NUMBER PERCENTAGE

< 3.18 46 92

≥ 3.18 m/s 4 8

TOTAL 50 100

GRAPH 24: SPLEEN ARFI IN CIRRHOTICS WITHOUT EVs


ARFI values of ≥ 3.18m/s and 46 patients (92%) had ARFI values of < 3.18m/s.

TABLE 25: GRADES OF EVs IN CIRRHOTICS WITH EVs GROUP

GRADES OF EVs DISTRIBUTION (N=50)

NUMBER PERCENTAGE

LOW GRADE 23 46

HIGH GRADE 27 54

TOTAL 50 100

GRAPH 25: GRADES OF EVs IN CIRRHOTICS WITH EVs GROUP

In this study, we divided cirrhotics with EVs group into two subgroups – Low

grade (Grade I &II) and High grade (Grade III & IV). 27 patients (54%) had high

grade EVs and 23 patients (46%) had low grade EVs.

TABLE 26: SIGNIFICANCE OF CLINICAL AND LABORATORY

PREDICTORS BETWEEN CIRRHOTICS WITH EVs AND WITHOUT EVs

PREDICTORS

INDEPENDENT ‘t’ TEST

EVs MEAN ± SD

WITHOUT EVs MEAN ± SD P value

AGE 47.94 ± 13.20 48.38 ± 12.40 0.864

MELD 28.80 ± 9.48 25.56 ± 5.96 0.043*

PLATELET COUNT 83940.00 134580.00 0.000*

AST/ALT RATIO 2.59 ± 1.27 2.72 ± 0.93 0.571

CHISQUARE TEST

SEX 72% MALES 28% FEMALES

76% MALES 24% FEMALES 0.648

ETIOLOGY 74% ALCOHOL

12% NAFLD 12% AUTOIMMUNE

2% METABOLIC

70% ALCOHOL 18% NAFLD

12% AUTOIMMUNE 0.647

CHILD 16% A 26% B 58% C

14% A 32% B 54% C

0.799

* P= < 0.05 IS STATISTICALLY SIGNIFICANT

MELD and Platelet count showed statistical significance between two

groups

TABLE 27: SIGNIFICANCE OF RADIOLOGICAL PREDICTORS

BETWEEN CIRRHOTICS WITH EVs AND WITHOUT EVs

PREDICTORS


EVs MEAN ± SD

WITHOUT EVs MEAN ± SD P value

LIVER SIZE 140.50 ± 20.97 138.36 ± 19.62 0.599

PVD 12.54 ± 2.46 12.28 ± 2.06 0.569

PV FLOW VELOCITY 18.91 ± 6.23 20.28 ± 4.56 0.216

SPLEEN SIZE 147.54 ± 26.5 138.66 ± 16.90 0.049*

PSR 588.52 ± 274.58 972.86 ± 177.99 0.000*

LIVER ARFI 3.03 ± 0.78 2.92 ± 0.69 0.458

SPLEEN ARFI 3.33 ± 0.23 2.99 ± 0.17 0.000*


Spleen size, PSR and spleen ARFI showed statistical significance between

cirrhotics with EVs and cirrhotics without EVs groups

TABLE 28: SIGNIFICANCE OF CLINICAL AND LABORATORY

PREDICTORS BETWEEN LOW GRADE EVs AND HIGH GRADE EVs

PREDICTORS


LOW GRADE MEAN ± SD

HIGH GRADE MEAN ± SD P value

AGE 49.26 ± 13.02 46.81 ± 13.50 0.519

MELD 29.09 ± 10.03 28.56 ± 9.17 0.846

PLATELET COUNT 89217.39 79444.44 0.383

AST/ALT RATIO 2.90 ± 1.64 2.33 ± 0.79 0.115

CHISQUARE TEST

SEX 83% MALES 17% FEMALES

63% MALES 37% FEMALES 0.123

ETIOLOGY 78% ALCOHOL

13% NAFLD 9% AUTOIMMUNE

70% ALCOHOL 11% NAFLD

15% AUTOIMMUNE 4% METABOLIC

0.710

CHILD 22% A 30% B 48% C

11% A 22% B 67% C

0.375


Neither of clinical or laboratory predictors showed statistical significance

TABLE 29: SIGNIFICANCE OF RADIOLOGICAL PREDICTORS

BETWEEN LOW GRADE EVs AND HIGH GRADE EVs

PREDICTORS


LOW GRADE MEAN ± SD

HIGH GRADE MEAN ± SD P value

LIVER SIZE 144.91 ± 23.39 136.74 ± 18.27 0.172

PVD 12.22 ± 2.33 12.81 ± 2.58 0.399

PV FLOW VELOCITY 18.69 ± 7.09 19.10 ± 5.52 0.819

SPLEEN SIZE 140.70 ± 31.17 153.37 ± 20.60 0.092

PSR 651.63 ± 223.87 534.75 ± 305.22 0.135

LIVER ARFI 2.99 ± 0.65 3.07 ± 0.90 0.698

SPLEEN ARFI 3.22 ± 0.36 3.42 ± 0.28 0.001*


Spleen ARFI solely independently shows statistical significance between

low grade EVs and high grade EVs subgroups

GRAPH 26: ROC ANALYSIS: MELD IN EVs DETECTION

PREDICTOR CUT OFF AUROC SENSITIVITY SPECIFICITY

MELD ≥ 26.5 0.601 64% 58%

In the present study, ROC analysis of MELD in detecting EVs showed maximum

area under the curve of 0.601 at cutoff of ≥ 26.5 with sensitivity of 64% and

specificity of 58%.

GRAPH 27: ROC ANALYSIS: PLATELET COUNT IN EVs DETECTION


PLATELET COUNT ≤ 115000 0.863 86% 84%

ROC analysis of platelet count in detecting EVs in our study showed maximum

area under the curve of 0.863 at cutoff of ≤ 115000 with sensitivity of 86% and

specificity of 84%.

GRAPH 28: ROC ANALYSIS: SPLEEN SIZE IN EVs DETECTION


SPLEEN SIZE ≥ 148.50 0.581 50% 72%

In the present study, ROC analysis of spleen size in detecting EVs inferred a cut

off of ≥ 148.50 with maximum area under the curve of 0.581 with specificity of

72% and sensitivity of 50%.

GRAPH 29: ROC ANALYSIS: PSR IN EVs DETECTION


PSR ≤ 868.07 0.893 86% 86%

In the current study, ROC analysis of PSR in detecting EVs depicted a cutoff of

≤868.07 with maximum area under the curve of 0.893 at cutoff of with sensitivity

of 86% and specificity of 86%.

GRAPH 30: ROC ANALYSIS: SPLEEN ARFI IN EVs DETECTION


SPLEEN ARFI ≥ 3.16 0.906 94% 92%

ROC analysis of spleen ARFI in detecting EVs in this study showed maximum

area under the curve of 0.906 at a cutoff of ≥ 3.16 with maximum sensitivity of

94% and specificity of 92%.

GRAPH 31: ROC ANALYSIS: SPLENIC ARFI IN DELINEATING

HIGH GRADE AND LOW GRADE EVs


SPLEEN ARFI ≥ 3.29 0.874 85% 100%

In the current study, ROC analysis of spleen ARFI in delineating high grade and

low grade EVs depicted a cutoff of ≥ 3.29 with maximum area under the curve of

0.874 at cutoff of with sensitivity of 85% and specificity of 100%

DISCUSSION

Recent guidelines endorse that endoscopic screening should be done for all

cirrhotic patients at the time of diagnosis to recognize those at high risk of bleeding

and possibly to benefit from primary prophylaxis [7]. Implementation of these

guidelines imposes huge burden on UGIscopy units and frequent testing over time

can decrease the compliance of patient. Moreover, UGIscopy is not always feasible

in peripheral centers. By noninvasive prediction of the presence of EVs, one can

recommend the appropriate category of patients to undergo invasive UGI scopy,

thereby reducing unnecessary endoscopic examinations and burden on endoscopy

units. Previous studies have correlated various radiological and laboratory

parameters either alone or in combination with the presence or absence of EVs in

cirrhotics. Although, the efficiency of parameters or combination of parameters

reported in each study differ amongst them, due to the heterogeneous nature of the

studies. Good predictive value of several non-endoscopic variables for the presence

or absence of EVs have been documented by many previous studies, but the data is

limited from our part of the country. This study was performed to assess the

effectiveness of various clinical, laboratory and radiological parameters, in reliably

detecting the existence of EVs and high grade EVs in cirrhotic patients.

In the present study, there is no significant association of demographic parameters

between the two study groups. Mean age of patients in varices group is 47.4 ± 13.2

years and in group without varices is 48.3 ± 12.4 years (p = 0.864). Varices group

is constituted by 36(72%) males and 14(28%) females and group without varices

constituted 38(76%) males and 12(24%) females (p = 0.648).

Previous studies by Zaman et al [65] and Cherian et al [66], showed that Child Pugh

class B or C cirrhotic patients, as compared to class A cirrhotics, have high

propensity towards the detection of EVs on UGI scopy. In contrary, our study

inferred no significant association between Child Pugh class and the presence of

EVs (p = 0.799).

In addition, we assessed MELD scores and found significant affiliation with

presence of EVs, in congruence to the results of previous studies by De Mattos et

al [67] , Tafarel et al [68] and Chandail VS et al [69]. We derived a cut off of ≥ 26.5

(AUROC: 0.601) with 64% sensitivity and 58% specificity. The cut off value is

relatively higher when compared to the previous study by Chandail VS et al, who

postulated that cut off of 15.91 can certainly predict the presence of EVs. Very

shallow specificity and sensitivity of MELD in detection of EVs provokes its

debatable utility.

Our findings were consistent with previous studies by Garcia-Tsao et al [70], Pilette

et al [71] and Chalasani et al [72]. In this study, we revealed that platelet count is a

self-determining factor for the prediction of EVs, as patients with EVs showed

higher mean (83940 per μl) of platelet count in comparison to patients without EVs

(p=0.000). We also derived a cutoff point of ≤ 115000 per μl (AUROC: 0.863),

with 86% sensitivity and 84% specificity for the detection of EVs in cirrhotics.

Unlike Qamar et al [73], who postulated that platelet count is a fallible noninvasive

marker for detection of EVs.

In agreement with Kraja et al [76], AST/ALT ratio didn’t show significant

difference between the two groups, suggesting its incompetency in the prediction

of EVs in cirrhotics (p= 0.571). However this finding was in contrast to previous

studies done by Nyblom et al [74] and Castera et al [75] which inferred that

AST/ALT ratio is significantly higher in cirrhotic patients with EVs than without

EVs.

On ultrasound examination, size of the liver in midclavicular line in EVs group

was 140 ± 20mm and in without EVs group was 138 ± 19mm. No significant

difference in the size of liver between the two groups is observed from this study

(p= 0.599).

Our findings were in contradiction with previous studies by Schepis et al (77) and

Cottone et al (78), who postulated that PVD with cutoff of PVD ≥ 13 mm had 100%

sensitivity in predicting the presence of EVs. Likely, Sarwar et al (79) and Fook

Hong et al (80) reported that PVD as independent radiological marker in prediction

of EVs. However, our study showed no significant variation in portal vein diameter

between cirrhotic patients with EVs and without EVs (p= 0.569).

Present study deduced that mean of portal vein flow velocity in cirrhotics with EVs

group is 18.91 ± 6.2 cm/sec and in without EVs group is 20.28 ± 2.5 cm/sec. No

significant difference in portal vein flow velocity was derived between these two

groups (p= 0.216). This finding is in contrary to previous study by Dib et al (83)

who postulated that portal vein flow velocity with cutoff of <12 cm/sec, reliably

depicts the presence of esophageal varices with maximum sensitivity and

specificity.

Our findings were consistent with previous studies by Chalasani et al (84), Sudha

Rain et al (85), Kumar et al (86), Thomopoulos et al (88), Sharma and Agarwal (89),

Mandal et al (90) and Tarzamini et al (87), who proved splenomegaly as an

independent predictor of esophageal varices. Kumar et al (86) derived a cutoff of

>140mm and Tarzamini et al (87) inferred a cutoff of >157mm for effective utility

of spleen length as a noninvasive predictor of EVs. In this study, we found that

mean length of spleen in cirrhotics with EVs was 147.54 ± 26mm and that of

without EVs was 138.66 ± 16mm, which showed significant variation between

these two groups (p= 0.049). In addition, we acquired a cutoff of ≥ 148.50mm

(AUROC: 0.581) with sensitivity of 50% and specificity of 72%. The cutoff

obtained in this study was midway between the cutoffs derived by Kumar et al (86)

and Tarzamini et al (87). However, low sensitivity of cut off obtained in this study,

imposes questionable consideration on the utility of spleen length in the prediction

of EVs.

Earlier studies by Giannini et al (91) in 2003, postulated that PSR, spleen diameter

and platelet count showed significant variation among cirrhotic patients with and

without EVs. They depicted cut off value of 909 with 100% negative predictive

value. This finding was supported by González-Ojeda et al (92) who proved that

PSR was an independent noninvasive parameter to detect EVs, independent of the

grade with cutoff value of ≤ 884.3 with 84% sensitivity and 70% specificity. In

endorsement with these studies, the present study also showed significant

difference in PSR between cirrhotic patients with EVs and without EVs (p= 0.000).

Mean of PSR in group with EVs was 588.52 and in group without EVs was

972.86. We acquired a cutoff of ≤ 868.07(AUROC: 0.893) with sensitivity of 86%

and specificity of 86%, which can be reliably employed for non-invasive detection

of EVs. Unlike Chawla et al (93) who postulated the PSR is not a reliable

noninvasive predictor of EVs in cirrhotics.

Our study in contradiction to previous studies by Nadeem et al [96] and Morishita et

al [97], inferred that there is no significant difference in liver stiffness measured by

elastography between cirrhotics with EVs and cirrhotics without EVs (p= 0.458).

Morishita et al [97] postulated the optimal liver ARFI cutoffs of 2.05m/s and

2.39m/s for the presence of EVs and detection of high risk EVs respectively.

In agreement with Takuma et al [101], our study also showed significant difference

in the values of spleen stiffness measured by ARFI between cirrhotics with EVs

and without EVs (p= 0.000). We acquired the optimal cutoff of ≥ 3.16m/s

(AUROC: 0.906) with sensitivity of 94% and specificity of 92%, thereby

validating spleen ARFI as a non-invasive radiological marker for the presence of

EVs in cirrhotics. Spleen ARFI cutoff of ≥ 3.16m/s obtained in the present study is

identical to cutoff of ≥ 3.16m/s acquired by Xiao-Ping et al [100] and in close

approximation with the cutoff of ≥ 3.18m/s reported by Takuma et al [101]. Our

findings are in contrary to the previous study by Rifia et al [102], which postulated

that spleen elastography is inferior to liver elastography in the prediction of

esophageal varices.

Amongst the noninvasive parameters which showed significant difference between

cirrhotics with EVs and without EVs, spleen ARFI had the highest sensitivity and

specificity for the detection of EVs. Henceforth, spleen ARFI can be regarded as

an independent noninvasive predictor of EVs in cirrhotics.

In the present study, we furthermore evaluated the utility of the above discussed

noninvasive clinical, laboratory and radiological parameters in the detection of

high grade EVs in cirrhotics. We divided the group of cirrhotics with EVs into two

subgroups – Low grade EVs (Grades I and II) and High grade EVs (Grades III and

IV). Of all the noninvasive parameters analyzed, spleen ARFI exclusively showed

significant difference between the two subgroups (p= 0.001). We derived the

optimal cutoff of ≥ 3.29m/s (AUROC: 0.874) with sensitivity of 85% and

specificity of 100%, which is in very close approximation with spleen ARFI cutoff

of ≥ 3.30m/s obtained by Takuma et al (101). Thereby substantiating spleen ARFI as

a non-invasive radiological marker for the presence of high grade EVs in

cirrhotics. In other words, the presence of high grade EVs can be reliably ruled out

with the spleen ARFI cutoff of < 3.29m/s in patients with chronic liver

parenchymal disease.

Although a recent meta-analysis based on a pooled analysis of 12 studies with

significant heterogeneity postulated that spleen ARFI measurement might be

suboptimal for the diagnosis of esophageal varices. Subgroup analysis exhibited

that the diagnostic performance of spleen ARFI was better in studies from Asia

than in those from Western countries perhaps due to variations in habitus and body

size [103]. Our study added a positive result for the utility of spleen ARFI to detect

esophageal varices in cirrhotic Indian population.

SUMMARY

Cirrhosis is the end point of diverse chronic liver insults. Esophageal varices is one

amongst the complication of cirrhosis related to portal hypertension, which leads to

significant morbidity and mortality due to variceal bleeding. In the past few

decades, UGI scopy has been the gold standard diagnostic modality being

practiced for the detection of esophageal varices in cirrhotics in accordance to the

recommended guidelines. Besides reliable diagnostic performance of UGI scopy, it

has been regarded as primary therapeutic tool for the prophylaxis of variceal

bleeding. However, UGI scopy as an invasive procedure has its intrinsic

complications and practicing it as the screening modality in cirrhotics imposes

heavy burden on endoscopy units and poor patient compliance. Various

noninvasive clinical, laboratory and radiological predictors of esophageal varices

had been postulated in the previous studies, very sparse from our part of the

country, with differing results and inference. ARFI elastography is the novel

ultrasonography technique which assess the elasticity of tissues of interest. It is

considered as the radiological analogue of manual palpation. Elasticity of spleen

was hypothesized to be reduced in portal hypertension due to increased splenic

influx, thereby increasing the density of splenic parenchyma. Hence, this study was

performed to assess the utility of spleen ARFI as a non-invasive tool for the

prediction of EVs and in the delineation of high grade vs low grade EVs.

This study included total of 100 chronic liver parenchymal disease patients

diagnosed based on clinical or radiological grounds. After routine UGI scopy

screening for EVs for cirrhotics in our hospital, we included 50 cirrhotic patients

with EVs and 50 cirrhotic patients without EVs as two groups in this study. B

mode ultrasonography and elastography assessment of liver and spleen have been

done for these patients. Clinical and laboratory data of the patients was obtained

from retrospective search on hospital information system. Statistical analysis of

various clinical, laboratory and radiological parameters for the noninvasive

detection of EVs and in delineating low grade EVs vs high grade EVs was done.

Spleen ARFI showed significant correlation between cirrhotics with EVs and

without EVs groups. We found that cut off of ≥ 3.16 m/s (AUROC: 0.906)

precisely detects EVs with sensitivity of 94% and specificity of 92%. Furthermore,

spleen ARFI significantly correlates with severity of EVs. The optimal cut off of

≥ 3.29 m/s (AUROC: 0.874) can confidentially differentiate low grade vs high

grade varices in cirrhotics with sensitivity of 85% and specificity of 100%.

MELD, Platelet count, Spleen length and PSR are the other noninvasive

parameters in this study which showed significant relationship with the presence of

EVs. Platelet count cutoff of ≤ 115000 (AUROC: 0.863) with sensitivity of 86%

and specificity of 84% may reliably predict the presence of EVs in cirrhotics but

have poor ability to differentiate the severity of esophageal varices. Similar trend

in predictability is seen in PSR with cutoff of ≤ 868.07(AUROC: 0.893) with 86 %

sensitivity & 86% specificity, spleen length with cutoff of ≥ 148.50mm (AUROC:

0.581) with 50% sensitivity & 72% specificity and MELD with cut off of ≥ 26.5

(AUROC: 0.601) with 64% sensitivity and 58% specificity. Other parameters such

as liver stiffness, portal vein diameter, flow velocity, Child Pugh class and

AST/ALT ratio, which have been postulated in literature as possible noninvasive

predictors of EVs, didn’t show significant utility in detection EVs in cirrhotics in

this study. Besides spleen ARFI, neither of the clinical, laboratory and radiological

parameters showed statistical significance in differentiating low grade vs high

grade EVs.

CONCLUSION

Based on the results of this study, it may be inferred that, spleen stiffness

measured by ARFI can be identified as a noninvasive tool in the detection of

EVs with high diagnostic accuracy.

Amongst the noninvasive parameters analyzed in this study, spleen ARFI

exclusively showed highest sensitivity and specificity in the detection of

EVs and high grade EVs.

Henceforth, spleen ARFI can be used as a noninvasive tool in the detection

of esophageal varices and high grade esophageal varices with the cut off of ≥

3.16 m/s and ≥ 3.29m/s respectively with high diagnostic accuracy in

cirrhotic patients.

In other words, it hypothesizes that when spleen ARFI values reaches the

threshold cut-off level in cirrhotics, UGIscopy is warranted to evaluate

appropriate pharmacological or endoscopic intervention, thereby reducing

burden on endoscopy units and reducing the numbers of unnecessary

endoscopies. This strategy is of particular practicality in terms of patient

convenience and compliance, because regular ultrasonographic surveillance

for hepatoma is recommended for cirrhotics and ARFI elastography can be

concurrently performed besides routine B-mode imaging. Further validation

in a large-scale, prospective and long-term study is warranted.

LIMITATIONS OF THE STUDY

Only few patients with grade IV EVs were been included in this study. It is

due to the lower prevalence of grade IV EVs, as in part by the practice of

generous prophylactic & therapeutic measures which heralds the progression

of severity of low grade EVs

Terminally ill patients are not included in this study, as they are incapable of

breath hold, which is mandate for the assessment of ARFI

It is a single center study

Inter observer variability is not assessed in this study

Future studies on this context should focus on multicenter design with evaluation

of equipment of various manufacturers and assessment of inter observer variability.

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IMAGES

A

B

FIGURE 17 A, B: SIEMENS ACUSON S 2000 AND SIEMENS ACUSON

S3000 USG SYSTEMS USED FOR THIS STUDY

A

B

FIGURE 18 A, B: 54 year old female patient with chronic liver parenchymal

disease. A) Demonstrating measurement of liver size at mid clavicular line. B)

Demonstrating the placement of ROI in segment V of liver, which is devoid of

visible blood vessels.

C

D

FIGURE 18 C, D: Same patient as in Figure 18 A, B. C) Demonstrating the

placement of ROI in segment VI of liver, D) Demonstrating the placement of

ROI in segment VII of liver.

A

B

FIGURE 19 A, B: Same patient as in Figure 18 A,B. A) Demonstrating the

measurement maximum cephalo-caudal length of spleen, B) Illustrating the

placement of ROI in caudal segment of spleen.

C

D

FIGURE 19 C, D: Same patient as in Figure 18 A, B. C) Illustrating the

placement of ROI in intermediate segment of spleen, D) Illustrating the

placement of ROI in cranial segment of spleen.

A

B

FIGURE 20 A, B: Same patient as in Figure 18 A,B. A) Illustrating the

automatic mean (3.30 m/s) and median calculation, B) Demonsatrating the

presence of Grade III esophageal varices in UGI scopy.

A

B

FIGURE 21 A, B: 45 year old male patient with chronic liver parenchymal

disease. A) Demonstrating the placement of ROI in caudal segment of spleen,

B) Demonsatrating the placement of ROI in intermediate segment of spleen.

CC

D

FIGURE 21 C, D: Same patient as in Figure 21A, B. C) Demonstrating the

placement of ROI in intermediate segment of spleen, D) Illustrating the

placement of ROI in cranial segment of spleen

A

B

FIGURE 22 A, B: Same patient as in Figure 21A, B. A) Demonstrating the

automated calculation of mean (3.17 m/s) and median, B) Illustrating the

presence of Grade II esophageal varices in UGI scopy.

A

B

FIGURE 23 A, B: 50 year old male patient with chronic liver parenchymal

disease. A) Demonstrating the measurement of maximum cephalo-caudal

length of spleen, B) Demonsatrating the placement of ROI in caudal segment

of spleen.

C

D

FIGURE 23 C, D: Same patient as in figure 23 A, B. C) Demonstrating the

placement of ROI in intermediate segment of spleen, D) Demonsatrating the

placement of ROI in caudal external segment of spleen.

A

B

FIGURE 24 A, B: Same patient as in figure 23 A, B. A) Demonstrating the

placement of ROI in caudal internal segment of spleen, B) Demonsatrating the

automated calculation of mean (3.08 m/s) and median. No esophageal varices

detected in this patient in UGI scopy.

150 | P a g e

151 | P a g e

152 | P a g e

153 | P a g e

154 | P a g e

155 | P a g e

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