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Ultrasound in diagnosis of liver cirrhosis: How accurate is it? (An evidence-based review)
Siti SarahFaculty of Medicine University of Indonesia
AbstractBackground: Diagnosis of cirrhosis in chronic liver diseases is crucial for prognostic and management of the course of the disease. Ultrasonography (US) is a noninvasive and inexpensive procedure for diagnosis of parenchymal disease of liver. In a low-resources setting, a simple, low-cost and accurate method should be occupied in daily clinical practice. Therefore, the diagnostic values of this method should be comprehensively evaluated.
Aim: To compare the diagnostic values of US exam in diagnosing liver cirrhosis compared with liver biopsy.
Methods: The search on the Cochrane Library® and PubMed® was conducted with the keywords of “liver cirrhosis OR liver fibrosis” AND “ultrasound” OR “US examination”. We used diagnostic appraisal questions developed by Centre of Evidence-Based Medicine (CEBM), University of Oxford.
Result: Analysis of 4 studies involving 1082 patients with various chronic liver disease was conducted finding at the liver cirrhosis diagnostic values. Sensitifity(Se), specificity (Sp), Positive Predictive Value (PPV), and Negative Predictive Value (NPV) of US examination in prediciting liver cirrhosis were varied considering the US parameters used, respectively 33-76%, 44-97%, 12-70%, and 86-95%. US scoring system used for US parameters was resulted in best diagnostic values compared with use of other single parameters.
Conlcusion: US examination had a wide range of diagnostic value depends on the parameters used in each studies. US examination could be occupied as a first line radiological examination to predict liver cirrhosis due to its simple, low-cost, and accurate profile
Keywords: Ultrasound, liver cirrhosis, accuracy, chronic liver disease
Background
Liver cirrhosis is considered as an end stage condition of chronic hepatitis virus B or
C infection.Error: Reference source not found It causes a parenchymal damage of
liver that secondarily lead to the systemic adverse effects due to the decreased
function of liver. Therefore, accurate diagnosis of cirrhosis in chronic liver diseases, is
crucial for prognostic and management of the course of the disease.Error: Reference
source not found
Histopathology examination of fibrosis and cirrhosis remains acknowledged as a gold
standard diagnostic tool. However, biopsy is invasive and cannot be used repeatedly
in order to monitor the progress of the disease. Moreover, it may produce false
negative results in approximately 30% of cases.Error: Reference source not found
Therefore, the noninvasive, reliable, and accurate methods were needed to be
developed.
Ultrasonography (US) is a noninvasive and inexpensive procedure for diagnosis of
parenchymal disease of liver.Error: Reference source not found However, correlation
between US and histologic diagnosis has not been fully studied in large series of
patients. Several attempts had been conducted to improve the accuracies of US
examination. The widely ranging technology from a conventional- to high-
technology devices were devloped i.e grey-scale US, Doppler sonographyError:
Reference source not found, Transient Elastography (TE), real Time Elastography
(RTE), Acoustic Radiation Force Impulse Imaging (ARFI) and more recently Shear
Wave Elastography (SWE).Error: Reference source not found
These modalities had been widely studied in several studies and resulted in promising
result.Error: Reference source not found However, to incorporate a modality in a
routine clinical practice, a comprehensive review and resources assessment should be
conducted. In a low-resources setting, a simple, low-cost and accurate method should
be occupied in daily clinical practice. Spleen length, portal velocity, liver surface,
liver length, liver parenchym, hepatic vessels, spleen index were evaluated using US
examination to establish the diagnosis of cirrhosis in a number of studies. Error:
Reference source not found Moreover, recent studies focused in assessing the
degreeError: Reference source not found and causesError: Reference source not found
of the disease.
We conducted a critical review on several diagnostic studies to compare the
accuracies of US exam in diagnosing liver cirrhosis with the gold standard
assessment. In this review we used liver biopsy as a gold standard to provide the
sensitivity and specificity value of each parameters in US examination.
Methods
Clinical question
Is conventional methods of ultrasound examination accurate as a diagnostic tool in
liver cirrhosis patient?
P (patients) : Patients with liver cirrhosis
I (intervention) : Conventional methods of ultrasound examination
C (comparison) : Liver Biopsy
O (objective) : Liver cirrhosis
METHODS
Search strategy
The search on the Cochrane Library® and PubMed® was conducted on January 11th
2015 with the keywords of “liver cirrhosis OR liver fibrosis” AND “ultrasound” OR
“US examination”. Reference lists of relevant articles were searched for other
possibly relevant studies (figure 1).
Figure 1. Searching Flow
Selection
After achieving the result, a first selection was done by screening the study title and
abstract. Studies that not used liver biopsy as comparison and studies with other
languages than english were excluded. (Fig. 1 ). Five articles were available as full
text, and four of them proceed into our appraisal study.
(liver cirrhosis OR liver fibrosis ) AND (ultrasound OR US examination) AND (liver biopsy)
(liver cirrhosis OR liver fibrosis ) AND (ultrasound OR US examination) AND (liver biopsy)
Pubmed: 231Pubmed: 231
1212 00
66
full-text availablefull-text available
55
reading full-textreading full-text
useful: 4 articlesuseful: 4 articles
Type: title/abstract, Filters: English,
Human
Type: title/abstract, Filters: English,
Human
Exclusion Criteria
Liver biopsy not as gold standardDouble publicationKorean language
Exclusion Criteria
Liver biopsy not as gold standardDouble publicationKorean language
Cochrane: 45Cochrane: 45
screening title and abstractscreening title and abstract
Critical appraisal
Appraisal of four diagnostic studies involving 1082 patients with various chronic liver
disease was conducted finding at the diagnostic values (sensitifity, specificity, PPV,
NPV) of US examination in diagnosing liver cirrhosis. We used diagnostic appraisal
questions developed by Centre of Evidence-Based Medicine (CEBM), University of
Oxford (available at: http://www.cebm.net/critical-appraisal/).
Result
We appraised 4 diagnostic studies to assess the diagnostic accuracies of ultrasound
examination to diagnose liver cirrhosis. The total of subjects is 1082 patients with
chronic liver disease. However, the ultrasound parameters used among studies were
varied.
Table 1. Critical Appraisal Result of 4 diagnostic studies
No Study No. of subject
Ultrasound Parameters
Cut-off value
Validity Result Applic-ability
TotalScore
1 2 34
4 (Sn)
5 (Sp)
6(PPV)
7 (NPV)
8
1. Lee, et al (2010)
203 Surface nodularity
- + + + 33.33 97.01 70.59 87.10 + 7/8
2. Wang, et al (2009)
312 US score 7 + + +
74.0 86.0 55.0 93.0 + 7/8
3. Shen, et al (2006)
324 length of spleen
12.1 cm
+ + + 60.0 75.3 19.8 94.8 + 5//8
diameter of spleen vein
8 mm 60.0 78.1 22.0 95.0
diameter of portal vein
12 mm
76.7 44.6 12.4 94.9
4. Aube, et al(1999)
243 11 variables (global accuracy)
- + + + ? ? 79.0 86.0 + 6/8
1, representative patients; 2 reference standard; 3, blind & independent; 4, sensitivity; 5, specificity; 6, positive predictive value; 7, negative predictive value; 8 detail methods to permit replication;US, ultrasound; +, adequate; −, inadequate; ?, unknown, no information given’. Every item was scored based on diagnostic study appraisal questions developed by CEBM (available at: http://www.cebm.net/critical-appraisal/)
Lee, et al conducted a diagnostic study included 203 chronic viral hepatitis patients
who underwent liver biopsy. They assessed ultrasonographic findings, including
surface nodularity, parenchyma echogenecity, and spleen size. Using multivariate
analysis, surface nodularity was the only US paramaters that had >95% specificity,
with the PPV and NPV were respectively 70.59% and 87.10%. Echogenicity and
spleen size were not correlated with the diagnosis of liver cirrhosis determined by
liver biopsy. Error: Reference source not found
Three-hundred and twenty patients with chronic hepatitis B (HBV) or hepatitis C
virus (HCV) infections, with indications for liver biopsy, were prospectively enrolled
in a study conducted by Wang, et al to compare the accuracy between FibroScan®
and US examination in predicting fibrosis score. US scoring system, including
assessment of liver surface, liver parenchyma, hepatic vessels and spleen
index, was developed to evaluate the degree of hepatic fibrosis. Primarily they
found that of FibroScan® is significantly superior to US in the prediction of all HCV-
related fibrosis scores. In addition, they stated that among all patients (inlcuding
HBV-and HCV-infected patients) the area under the curve (AUC) were 0.832 (95%CI
0.775-0.879) and 0.929 (95%CI 0.886 – 0.960), for respectively FibroScan® and US
examination.Error: Reference source not found
The liver cirrhosis diagnosis in 324 patients was evaluated by both needle biopsy and
ultrasonography in a study conducted by Shen, et al. Among the quantitative
parameters, cut-off value of spleen length (12.1 cm) had a sensitivity of 0.600 and a
specificity of 0.753 for diagnosis of liver cirrhosis. The diameters of spleen (8 mm)
and portal vein (12 mm) had a diagnostic sensitivity of 0.600 and 0.767, and a
diagnostic specificity of 0.781 and 0.446, respectively. Error: Reference source not
found
Aube studied the diagnostic accuracy of ultrasonography for cirrhosis or fibrosis.
Among 243 patients, they found that the diagnostic accuracy of ultrasound was 84%
using spleen length and portal velocity as the US parameters. Finally, they conluded
that cirrhosis can be correctly diagnosed in 82-88% of patients with chronic liver
disease using a few ultrasonographic signs.Error: Reference source not found
On Lee, et al found that value of true positive, false positive, false negative and true
negative are 22, 16, 19 and 151. So, if sensitivity, specificity, PPV and NPV are
calculated on 2x2 table :
+ -
USG + 22 16 38
USG - 19 151 170
41 167 208
from the table above, if the value of the sensitivity, specificity, PPV, NPV,
prevalence, LR +, LR -, pretest odds, post test odds and post-test probability are
calculated will get results 54% (the proportion of people with disease who have a
positive test are 54%), 10% (the proportion of people free of disease who have a
negative test), 58% (the probability that a person with a positive test results has, or
will get the disease are 58% ), 89% (a numerical value of the proportion of individuals
with a negative test results who are free of the target condition are 89%), 20% (the
proportion of a population that is affected by the disease at a specific time are 20%),
0,6 (the probability of a person who has a disease testing positive divided by the
probability of a person who does not have the disease testing positive is 0,6. So it can
be concluded that the study of Lee likelihood ratio of 0.6 is not too supportive
sensitivity), LR - 4,9 (with a value of 4.9 it can be concluded that the specificity of the
US to the exclusion of liver cirrhosis in screening are pretty good), pretest odds 0,26
(The odds that the patient has the target disorder before the test is carried out is not
good enough), post-test odds 0,14 (The odds that the patient has the target disorder
after the test is carried out is not good enough), and post-test probability 12% (The
proportion of people with the target disorder in the population at risk at a specific time
or time interval is 12% and that is not good enough). These results it can be concluded
that ultrasound in the study of Lee, et al is not too good for screening but to be false
positive results is very small.
On Aube, et al found that value of true positive, false positive, false negative and true
negative are 93, 25, 18 and 107. So, if sensitivity, specificity, PPV and NPV are
calculated on 2x2 table :
+ -
USG + 93 25 118
USG - 18 107 125
111 132 243
from the table above, if the value of the sensitivity, specificity, PPV, NPV,
prevalence, LR +, LR -, pretest odds, post test odds and post-test probability are
calculated will get results 84% (the proportion of people with disease who have a
positive test are 84%), 19% (the proportion of people free of disease who have a
negative test), 79% (the probability that a person with a positive test results has, or
will get the disease are 79%), 86% (a numerical value of the proportion of individuals
with a negative test results who are free of the target condition are 86%), 45% (the
proportion of a population that is affected by the disease at a specific time are 45%),
1,03 (the probability of a person who has a disease testing positive divided by the
probability of a person who does not have the disease testing positive is 0,6. So it can
be concluded that the study of Lee likelihood ratio of 0.6 is not too supportive
sensitivity), LR - 0,9 (with a value of 4.9 it can be concluded that the specificity of the
US to the exclusion of liver cirrhosis in screening are not good enough), pretest odds
0,82 (The odds that the patient has the target disorder before the test is carried out is
not good enough), post-test odds 0,84 (The odds that the patient has the target
disorder after the test is carried out is good), and post-test probability 46% (The
proportion of people with the target disorder in the population at risk at a specific time
or time interval is 46% and that is not good enough). These results it can be concluded
that ultrasound in the study of Lee, et al is good for diagnosed cirrhosis but not good
for screening but to be false positive results is very small.
On Wang, et al found that value of true positive, false positive, false negative and true
negative are 48, 41, 17 and 226. So, if sensitivity, specificity, PPV and NPV are
calculated on 2x2 table :
+ -
USG + 48 41 89
USG - 17 226 243
65 267 332
from the table above, if the value of the sensitivity, specificity, PPV, NPV,
prevalence, LR +, LR -, pretest odds, post test odds and post-test probability are
calculated will get results 74% (the proportion of people with disease who have a
positive test are 74%), 15% (the proportion of people free of disease who have a
negative test), 54% (the probability that a person with a positive test results has, or
will get the disease are 54%), 93% (a numerical value of the proportion of individuals
with a negative test results who are free of the target condition are 93%), 20% (the
proportion of a population that is affected by the disease at a specific time are 20%),
0,87 (the probability of a person who has a disease testing positive divided by the
probability of a person who does not have the disease testing positive is 0,87. So it
can be concluded that the study of Wang likelihood ratio of 0.87 is not too supportive
sensitivity), LR - 1,71 (with a value of 1,71 it can be concluded that the specificity of
the US to the exclusion of liver cirrhosis in screening are not good enough), pretest
odds 0,24 (The odds that the patient has the target disorder before the test is carried
out is good enough), post-test odds 0,21 (The odds that the patient has the target
disorder after the test is carried out is not good enough), and post-test probability 17%
(The proportion of people with the target disorder in the population at risk at a
specific time or time interval is 17% and that is not good enough). These results it can
be concluded that ultrasound in the study of Wang, et al is good for diagnosed
cirrhosis but not good for screening but to be false positive results is very small.
On Shen, et al found that value of true positive, false positive, false negative and true
negative are 13, 66, 6 and 236. So, if sensitivity, specificity, PPV and NPV are
calculated on 2x2 table :
+ -
USG + 13 66 79
USG - 9 236 242
22 302 324
from the table above, if the value of the sensitivity, specificity, PPV, NPV,
prevalence, LR +, LR -, pretest odds, post test odds and post-test probability are
calculated will get results 59% (the proportion of people with disease who have a
positive test are 59%), 22% (the proportion of people free of disease who have a
negative test), 16% (the probability that a person with a positive test results has, or
will get the disease are 16% ), 98% (a numerical value of the proportion of individuals
with a negative test results who are free of the target condition are 98%), 7% (the
proportion of a population that is affected by the disease at a specific time are 7%),
0,75 (the probability of a person who has a disease testing positive divided by the
probability of a person who does not have the disease testing positive is 0,75. So it
can be concluded that the study of Lee likelihood ratio of 0.6 is not too supportive
sensitivity), LR - 1,9 (with a value of 1.9 it can be concluded that the specificity of the
US to the exclusion of liver cirrhosis in screening are not good enough), pretest odds
0,07 (The odds that the patient has the target disorder before the test is carried out is
good enough), post-test odds 0,05 (The odds that the patient has the target disorder
after the test is carried out is not good enough), and post-test probability 5% (The
proportion of people with the target disorder in the population at risk at a specific time
or time interval is 5% and that is not good enough). These results it can be concluded
that ultrasound in the study of Shen, et al is not good enough for diagnosed cirrhosis,
bad for screening but to be false positive results is very small.
Discussion
Four diagnostic studies were assessed to determine the accuracies of ultrasound
examination to diagnose liver cirrhosis. The total of subject is 1082 patients diagnosed
with chronic liver disease, including alcoholic liver disease, hepatitis B and hepatitis
C. However, the ultrasound parameters used among studies were varied, from a single
parematers to the combined parameters including several anatomical indices. Surface
nodularity,length of spleen, diameter of spleen vein, and diameter of portal vein were
mostly used as parameters among studies included in this review.
We found all studies had conducted a valid study regarding to the methods they used.
Four studies enrolled patients who were consecutively admitted to the hospital
so that selection bias is minimized. In addition, US scans were performed by 1
to 4 hepatologists who were experienced with medical ultrasound
examinations. The US was performed within the same day or at least at the
same week with the liver biopsy, therefore the results would not be
significantly differed between examinations.
Overall studies show moderate to good accuracies of US examination to predict liver
biopsy. However the sensitivity was found to be more than 70% if the diameter of
portal vein or combination of scores were used as the US parameters. The specificity
of surface nodularuty and US scores to predict liver cirrhosis were respectively 97%
and 86%. All studies shown a good NPV of US examination, it was ranging from
86% to 95%. These values was comparable to other methods of diagnostic. Thierry
found that the specificity/senitifity was for FibroTest® 0.87/0.41, liver stiffness
measurement (LSM) 0.93/0.39, alanine aminotramsferase (ALT) 0.78/ 0.08 and
biopsy 0.95/0.51 (Table 2).Error: Reference source not found On our literature
searching, laparoscopy had the best specificity to diagnose liver cirrhosis, which
approximately 99%.Error: Reference source not found Eventhough several diagnostic
studies declared that several methods could avoid liver biopsy in clinical
practiceError: Reference source not found, in our institution liver biopsy remains a
gold standard tool for liver cirrhosis.
Table 2. Comparison of several diagnostic values for liver cirrhosis diagnosis Error: Reference source not foundLSM, liver stiffness measurement; ALT, alanine aminotramsferase
Examination Sensitifity SpecificityUltrasound 33% - 76% 44 – 97%FibroTest® 41% 87%LSM 39% 93%ALT 8% 78%Tranisent elastography 53.5% 98.6%Magnetic elastography 74.4% 98.6 %Laparoscopy 68% 98%Biopsy 51% 95%
Conclusion
In this review we found the sensitifity, specificity, PPV, and NPV of ultrasound
examination in predicting liver cirrhosis were respectively 33-76%, 44-97%, 12-70%,
and 86-95%. In conclusion, ultrasound examination had a wide range of diagnostic
value depends on the US parameteres used. US scoring system used for US
parameters was resulted in best diagnostic values compared with the use of other
single parameters.
Recommendation
US examination could be occupied as a first line radiological examination to predict
liver cirrhosis due to its simple, low-cost and accurate profiles.
ReferencesError: Reference source not found
Aube, et al
+ -
USG + 93 25 118
USG - 18 107 125
111 132 243
Sensitivity : a/a+c = 93/111 = 0,837 = 84%
Specificity : b/b+d = 25/132 = 0,189 = 19%
PPV : a/a+b = 93/118 = 0,778 = 78%
NPV : d/c+d = 107/125 = 0,856 = 86%
Prevalence : (a+c)/(a+b+c+d) = 111/243 = 0,45 = 45%
LR + = Sn/(1-Sp) = 0,837/1-0,189 = 0,837/0,811 = 1,032
LR - = (1-Sn)/Sp = 1-0,837/0,189 = 0,862
Pretest Odds = Prevalence/(1-Prevalence) = 0,45/1-0,45 = 0,45/0,55 = 0,818
Post-Test Odds =Pretest odds x LR = 0,818 x 1,032 = 0,844
Post-Test Probability = Post-Test Odds/1+Post-test Odds = 0,844/1,844 = 0,457 = 46%
Wang, et al
+ -
USG + 48 41 89
USG - 17 226 243
65 267 332
Sensitivity : a/a+c = 48/65 = 0,738 = 74%
Specificity : b/b+d = 41/267 = 0,153 = 15%
PPV : a/a+b = 48/89 = 0,54 = 54%
NPV : d/c+d = 226/243 = 0,930 = 93%
Prevalence : (a+c)/(a+b+c+d) = 111/243 = 0,45 = 45%
LR + = Sn/(1-Sp) = 0,837/1-0,189 = 0,837/0,811 = 1,032
LR - = (1-Sn)/Sp = 1-0,837/0,189 = 0,862
Pretest Odds = Prevalence/(1-Prevalence) = 0,45/1-0,45 = 0,45/0,55 = 0,818
Post-Test Odds =Pretest odds x LR = 0,818 x 1,032 = 0,844
Post-Test Probability = Post-Test Odds/1+Post-test Odds = 0,844/1,844 = 0,457 = 46%
Shen, et al
+ -
USG + 13 66 79
USG - 9 236 242
22 302 324
Sensitivity : a/a+c = 13/22 = 0,59 = 59%
Specificity : b/b+d = 66/302 = 0,218 = 22%
PPV : a/a+b = 13/79 = 0,164 = 16%
NPV : d/c+d = 236/242 = 0,975 = 98%
Prevalence : (a+c)/(a+b+c+d) = 22/324 = 0,067 = 7%
LR + = Sn/(1-Sp) = 0,59/1-0,218 = 0,59/0,782 = 0,75
LR - = (1-Sn)/Sp = 1-0,59/0,218 = 0,41/0,218 = 1,880
Pretest Odds = Prevalence/(1-Prevalence) = 0,067/1-0,067 = 0,067/0,933 = 0,071
Post-Test Odds = Pretest odds x LR = 0,071 x 0,75 = 0,053
Post-Test Probability = Post-Test Odds/1+Post-test Odds = 0,053/1,053 = 0,050 = 5%