2.4 Liver histology evaluation
Each patient received an echo-guided percutaneous liver biopsy from the right hepatic lobe by using a 16-gauge Bard Max-core biopsy instrument. The sampling tissues were stained with H&E and reticulin silver. The degree of liver necroinflammation was calculated by Histology Activity Index scores. The degree of liver fibrosis was staged by modified Knodell histology index. Histology was reported by 3 pathologists, all of whom had no knowledge of the clinical characteristics of the study subjects. Compensated cirrhosis was defined as bridging fibrosis and cirrhosis, that is, modified Knodell score of 3 or 4.
2.5 Statistical analysis
The continuous variables were summarized as appropriate in terms of mean and standard deviation or median and interquartile range, and the categorical variables were summarized in terms of frequency and percentage. The categorical variables were compared by chi-squared or Fisher exact tests, whereas the continuous variables were compared with the Student's t test. The diagnostic accuracy of ultrasound was assessed by the area under the receiver operating characteristic curves using liver biopsy as a reference. The area under the ROC curve (AUROC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratio for ultrasound examination were computed. All statistical analyses were performed by STATA version 11.0.
3.1 Characteristics of the patients
The inclusion and exclusion of potential subjects for this study are depicted in Figure 1. Among 2055 screened CHC patients, 1738 (84.6%) were subsequently included. The characteristics of the patients are shown in Table 1. The mean age was 52.5 years, 53.1% of the patients were male, 46.7% of the patients were genotype 1, 48.6% of the patients were genotype 2, the mean necroinflammation score was 7.3, the median aspartate aminotransferase (AST) level was 91 IU/L, the median alanine-aminotransferase (ALT) level was 133 IU/L, 315 (18.12%) of the patients had a fibrosis score of 3, 433 (24.91%) of the patients had cirrhosis, and 283 (16.28%) of the patients had ultrasound-identified cirrhosis.
3.2 Comparison of patients with or without compensated cirrhosis
A comparison of the patients with or without compensated cirrhosis is shown in Table 2. In comparison to those without compensated cirrhosis, those with compensated cirrhosis were older, had higher body mass index (BMI) scores, had higher necroinflammation scores, had higher AST and ALT levels, and included higher proportions of patients who were female, genotype 1, had thrombocytopenia, and had ultrasound-identified cirrhosis.
3.3 Diagnostic accuracy of ultrasound in identifying compensated cirrhosis
Of the 748 patients with compensated cirrhosis, 494 (66%) were negative for ultrasound-identified cirrhosis (i.e., the ultrasound yielded false-negative results); on the other hand, 29 (2.9%) of the 990 patients without compensated cirrhosis were positive for ultrasound-identified cirrhosis (i.e., the ultrasound yielded false-positive results). Using ultrasound-identified cirrhosis to diagnose compensated cirrhosis, the sensitivity was 34.0%, the specificity was 97.1%, the PPV was 89.8%, the NPV was 66.1%, the positive likelihood ratio was 11.6, the negative likelihood ratio was 0.68, and the AUROC was 0.66.
3.4 Ultrasound signs of portal hypertension
Ultrasound-identified cirrhosis was noted in 283 patients in our study, and splenomegaly was noted in 106 patients (37.5%).
In this study, ultrasound was found to be highly specific in diagnosing compensated cirrhosis, with a specificity of 97.1%. However, the sensitivity was low (34.0%). Therefore, the ultrasound findings were sufficiently specific to allow a diagnostic confirmatory strategy, indicating that a positive result can “rule in” compensated cirrhosis; on the contrary, the sensitivity of ultrasound was too low to support a screening diagnostic strategy, indicating that a negative result cannot rule out compensated cirrhosis.
Previous prospective studies used ultrasound-identified liver surface nodularity as a predictor of compensated cirrhosis in CHC patients, with low sensitivity (53% and 73%, respectively) and high specificity (91% and 90%, respectively), results which are compatible to those for this study.[11,12]
It is widely accepted that nodular liver surface can be used to diagnose cirrhosis. A recent study reported that mammillated caudate lobe, gallbladder scalloping, and inferior vena cava scalloping are three novel signs that improve the accuracy of ultrasound in diagnosing liver cirrhosis. Remarkable advances have been made in cardiovascular medical image.[15–17]
According to the American Association for the Study of Liver Diseases (AASLD) guideline, splenomegaly taken alone is a sensitive, but nonspecific, sign of portal hypertension. The presence of portocollateral vessels or a reversal of flow within the portal system is 100% specific for clinically significant portal hypertension (CSPH). Several sonographic signs of portal hypertension have been described, such as the reduction of portal vein velocity and dilatation of portal vein.[20,21] Ultrasound-identified cirrhosis was noted in 283 patients in our study, and splenomegaly was noted in 106 patients (37.5%). Therefore, 106 patients (37.5%) had possible portal hypertension in this study. However, we did not routinely record sonographic signs of portal hypertension regarding portal vein and portocollateral vessels. In this study, only ultrasound signs for assessing hepatic parenchyma were used, whereas signs of CSPH were not included. According to the AASLD guideline recommendation, patients with compensated cirrhosis should be substaged into those with mild portal hypertension and those with CSPH. The presence of portocollateral vessels or a reversal of flow within the portal system are 100% specific (pathognomonic) signs of portal hypertension, such that liver cirrhosis can be diagnosed without liver biopsy with these signs.  However, using this non-invasive criteria to diagnose liver cirrhosis could have led to the under diagnosis of liver cirrhosis in those without CSPH.
Distinguishing between a stage of fibrosis 3 or 4 is also important for choosing type and duration of DAAs. According to the EASL guideline,  patients with cirrhosis (F4) must be identified, as their treatment regimen must be adjusted. Three kinds of ultrasound-based elastography for prediction of F3 (bridging fibrosis) and F4 (cirrhosis) were mentioned in the EASL guideline.  These ultrasound-based elastography including TE, [22–24] acoustic radiation force impulse imaging (ARFI) and 2D-shear wave elastography (2D-SWE). Overall diagnostic performances of these ultrasound-based elastography were excellent with the AUROC > 0.90 for prediction of F4.[22–26] In our study, ultrasound is highly specific in diagnosing compensated cirrhosis (≥F3) in CHC patients. However, the sensitivity is low (34.0%) The sensitivity of these ultrasound-based elastography in diagnosing compensated cirrhosis (≥F3) is high (range from 72∼90%).[22,25,26]
Theses ultrasound-based elastography techniques have been fully described. According to the EASL guideline, TE have several advantages:
- most widely used technique,
- good reproducibility,
- good performance for cirrhosis, and
- easy to learn, can be performed by a technician after minimal training.
ARFI have several advantages:
- It can be implemented on a regular ultrasound machine,
- higher applicability than TE (e.g., obesity and ascites),
- the location of region of interest (ROI) can be chosen by the operator, and
- good performance for cirrhosis.
2D-SWE has several advantages:
- It can be implemented on a regular ultrasound machine,
- the location of ROI can be chosen by the operator,
- good performance for cirrhosis, and
- good applicability.
The major strength of this study is that it included a large cohort of treatment-naïve patients, because several studies have shown that liver histology may improve even among nonresponders to interferon-based therapy.[28–30] Most importantly, we used ultrasound to evaluate hepatic parenchyma alone. The use of this simple technique in our study is not time consuming and more feasible for daily clinical practice. We acknowledge, however, that there are limitations to this study. First, it was a retrospective study. Second, it included patients from a medical center, 43% of whom had compensated cirrhosis on histology and none of whom had prior antiviral treatment. As such, whether our results can be generalized to community-based practices in which patients may have milder disease or to patients who have failed prior interferon therapy remains to be determined. Third, our study did not involve a central pathologist for the interpretation of liver histology. There were interobserver discrepancies in the assessments of hepatic fibrosis.
In conclusion, ultrasound is insensitive but highly specific for the detection of compensated cirrhosis in CHC patients in real world clinical practice. Assessment of the compensated cirrhosis by ultrasound-based elastography is not required in CHC patients with ultrasound-identified cirrhosis. The sensitivity of ultrasound-based elastography in diagnosing compensated cirrhosis is high.[22,25,26] Thus, we suggest ultrasound-based elastography in CHC patients without ultrasound-identified cirrhosis.
Conceptualization: Yi-Hao Yen.
Data curation: Yi-Hao Yen.
Formal analysis: Yi-Hao Yen.
Funding acquisition: Yi-Hao Yen.
Investigation: Yi-Hao Yen.
Methodology: Yi-Hao Yen.
Project administration: Yi-Hao Yen.
Resources: Yi-Hao Yen.
Supervision: Fang-Ying Kuo, Chien-Hung Chen, Tsung-Hui Hu, Sheng-Nan Lu, Jing-Houng Wang, Chao-Hung Hung.
Writing – original draft: Yi-Hao Yen.
Tsung-Hui Hu orcid: 0000-0002-9172-1967.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
chronic hepatitis C; compensated cirrhosis; ultrasound