“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
“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
“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 INSTITIUTE OF MEDICAL SCIENCES AND RESEASRCH PEELAMEDU, COIMBATORE – 641004
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 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.
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 of Radiodiagnosis, PSG Institute of Medical Sciences and Research, 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
“CORRELATION OF SPLENIC ARFI WITH ENDOSCOPIC 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]
FIGURE8: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]
FIGURE13: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
FIGURE16: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
