Introduction
Fibrosis is the hallmark of liver damage. It is the single most important predictor
of outcomes in patients with underling liver disease. Historically, severity of fibrosis
has been defined by percutaneous liver biopsies. Because of their invasive nature,
such biopsies have been replaced by laboratory and imaging noninvasive markers of
fibrosis. Although these tools are helpful in identifying patients with advanced fibrosis,
they are limited in their ability to estimate fibrosis severity in patients with intermediate
amounts of liver damage. Nevertheless, liver biopsy remains an important tool in selection
of individuals [1]
[2]
[3].
Endoscopic ultrasound-guided liver biopsy (EUS-LB) is an emerging procedure that offers
an alternative to conventional percutaneous and transjugular liver biopsy approaches
[4]
[5]. EUS-guided liver biopsy has been shown to be efficacious in diagnosing both malignant
and parenchymal liver disease. The safety and efficacy of EUS-LB in liver sampling
and confirming histopathological diagnosis has been evaluated in a number of studies
[6]
[7]
[8]. EUS has also demonstrated great ability in further characterization and staging
of a previously detected lesion, which can impact disease management [9]
[10]
[11]
[12].
When parenchymal liver disease is unexplained by imaging or laboratory testing, EUS
offers the advantage of avoiding sampling error, which is usually an issue with the
conventional PC method because both the right and left lobes of the liver can be sampled
during EUS. EUS-LB has also proven to provide excellent histologic specimens with
regards to barometers of adequacy of histological yield specimen size, specimen length
and complete portal tracts (CPT). By allowing simultaneous, live endoscopic and endosonographic
visualization, accidental injury to adjacent blood vessels and/or organs is more easily
avoided [13]
[14]
[15].
Newer flexible core needles have made it possible to obtain core parenchymal tissue.
We previously demonstrated that EUS-modified LB (EUS-MLB), as described below, is
a safe and effective method of obtaining adequate liver tissue [7]. Samples obtained using EUS-MLB in that study met the minimum measurement requirements
that have been set by liver society organizations for CPT and specimen length [13].
In this study, we compared two types of core needles: Franseen tip fork-tip. Given
the differences in their designs, we hypothesized that liver parenchymal yield, too,
would differ. Thus, we sought to compare the histological yield of the two needles
and the adverse events (AEs) associated with each needle type.
Patients and methods
We retrospectively studied 420 patients with unexplained abnormal liver-associated
tests who were referred to two tertiary medical centers (both medical centers being
in Florida) for evaluation with EUS. All the patients were referred for evaluation
of the pancreas and biliary tree in the setting of unexplained elevated liver enzymes.
The first 210 consecutive patients underwent EUS-MLB using a fork-tip needle, 165
of whom were also included in the previously published study. The next 210 patients
underwent EUS-MLB using the Franseen tip needle. The decision to perform EUS-guided
MLB was made by the endoscopist at the time of the procedure. EUS-guided liver biopsy
was performed during the same session once pancreatobiliary pathology was excluded.
The EUS-MLB procedure was performed by one of two advanced endoscopists (JN, EP),
both with substantial experience in endoscopic ultrasound. The two endoscopists reviewed
all the imaging and pertinent clinical data before performing the procedures. Institutional
review board approval was obtained.
Technique
EUS-modified liver biopsy sampling
In all procedures, monitored anesthesia care or general anesthesia was administered
at the discretion of the certified anesthesia provider and cardiorespiratory monitoring
was done by an anesthesiologist or a certified registered nurse anesthetist. A complete
EUS examination for the primary procedure indication was performed. A standard linear-array
echoendoscope was utilized to perform echoendoscopy. In addition, a complete EUS evaluation
of the visualized liver and upper abdominal region was done to rule out varices or tumor.
EUS-MLB was performed once biliary and pancreatic pathology had been excluded. It
was done using a novel, commercially available 19-gauge needle (Sharkcore or Acquire).
The needle was primed with saline solution. The left lobe of the liver was accessed
by the transgastric route and the right lobe by the transduodenal route. Under direct
EUS guidance, the liver was punctured such that 7 cm of the needle was within the
liver parenchyma. Next maximal (20 mL) suction was applied via a syringe.
The needle was then slowly withdrawn 3 cm back or if saline is displaced into the
syringe then suction is turned off. With EUS guidance, large vessels can be avoided
using Doppler imaging.
Wet suction or a saline prime needle was used to indicate tissue acquisition into
the bore of the needle by displacing the saline solution into the syringe; this would
notify the endoscopist to turn off the suction.
Core biopsies were immediately placed into formalin. The endoscopist personally separated
the blood clots from the specimen and embedded paraffin in one container. This was
followed by tissue block staining with hematoxylin and eosin. Additional immunohistochemistry
was performed as needed per pathology. Experienced gastrointestinal pathologists examined
the samples and evaluated for the outcome parameters mentioned below ([Fig. 1]).
Fig. 1 Live view of parenchymal tissue obtained via EUS.
Patients were monitored in the endoscopy suite for at least 30 minutes to 1 hour following
the procedure. Those who developed pain after the procedure were observed for a longer
period of time. All patients were contacted by phone 48 hours after the procedure.
Furthermore, patients were seen in clinic 2 weeks and 4 weeks after the procedure
to assess for any AEs. A 1-hour recovery time after the EUS-MLB is sufficient in almost
all cases [7].
Technical success was defined as successful completion of all the steps of the EUS-modified
liver biopsy sampling as outlined in the technique section above from the beginning
of the EUS exam to completion of the tissue acquisition process. Clinical success
was defined as successful tissue acquisition without AEs.
AEs were defined as any deviation from the anticipated intra-procedure and post-procedural
course. AEs included but were not limited to bleeding, perforation, infection, bile
leak, pneumothorax, and anesthesia-related events. Patients were followed for 2 weeks
to 4 weeks to monitor for AEs.
Outcome parameters measured included total specimen length (TSL), intact specimen
length, and complete portal tracts (CPTs), and rate of AEs. Furthermore, the ability
of each needle to distinguish the different fibrosis scores was compared. Patient
biopsies were divided according to their corresponding fibrosis scores: F0–F2 were
compared alone and F3–F4 were compared separately.
Statistical analysis
Descriptive statistics were used to illustrate categorical and continuous variables.
The ISL, TSL and CPTs were measured. Both Levene’s and Bonett’s tests were used to
compare the variances between needle type and TSL, ISL, and CPT means. Equal Variance
was only found for mean CPT. The findings of unequal variance required the use of
Welch’s T test and Games-Howell pairwise comparisons for TSL and ISL groups. Tukey
and Fisher pairwise comparisons were used to compare needle type and CPT. One-way
ANOVA was used to compare TSL, ISL and CPT groups between both needle types. P < 0.05 was considered statistically significant. Post hoc power analyses for overall
needle comparison, fibrosis score 0–2 (ISL, TSL, CPT) and fibrosis score 3 to 4 (ISL,
TSL, CPT) were completed.
Results
This was a retrospective study of 420 patients who underwent EUS-MLB at two medical
centers between 2015 and 2018 for evaluation of pancreatic biliary pathology in the
setting of unexplained elevated liver enzymes. The majority of patients were women
(238/420). Mean age (SD) in both the fork-tip and Franseen groups was 52 (15.63).
The patients were divided into two groups. The first group consisted of 210 patients
who had undergone EUS-MLB using a 19-gauge fork-tip needle consecutively. The second
group included 210 patients who underwent EUS-MLB using a 19 Franseen tip needle.
The two groups were compared in terms of outcomes and histological yield.
The Franseen and fork-tip needle-types were used in 210 patients each, equating to
420 EUS-guided parenchymal biopsies in total. Each patient underwent two passes using
the same needle type. Two hundred ninety-four patients (70 %) who received EUS-MLB
had a history of viral hepatitis (96 patients) and fatty liver (198 patients). The
other 126 patients (30 %) did not have any history of liver disease. Ninety-two patients
(22 %) reported alcohol use. Fibrosis scores, mean TSL, ISL, and CPT were compared
as well as the percentages diagnosed with nonalcoholic fatty liver disease, viral
hepatitis, and autoimmune conditions.
Needle type comparison for TSL, ISL, and CPT first occurred with inclusion of all
patient types. Then patients were divided based on their corresponding fibrosis score
for subsequent comparison of both needles for each one of the barometers of specimen
adequacy.
Total specimen length
The mean (SD) TSL was statistically significant longer for fork-tip (N = 210) than
for Franseen needles (N = 210) (5.99 cm [2.07] and 6.52 cm [2.56], respectively) (P = 0.02).
Mean (SD) TSL was 6.173 cm (2.03) and 6.232 cm (2.51) between the fork-tip (N = 81)
and Franseen (N = 74) needles, respectively, for patients noted to have a histologic
fibrosis score between 0 and 2 (P = 0.87) ([Table 1]). Mean TSL for fork-tip (N = 27) (6.97 cm [1.78]) and Franseen (N = 52) (6.94 cm
[2.80]) for patients with fibrosis scores of 3 or 4 was also similar (P =–0.94).
Table 1
Comparison of outcomes between two needles.
|
Fork-tip needle
|
Franseen needle
|
P value
|
|
Overall
|
|
|
Mean TSL (SD) (cm)
|
6.0 (2.07)
|
6.5 (2.56)
|
0.02
|
|
Mean ISL (SD) (cm)
|
2.7 (1.14)
|
3.1 (1.39)
|
0.01
|
|
Mean CPT (SD)
|
19.5 (8.55)
|
24.0 (8.81)
|
< 0.01
|
|
F0–2
|
|
|
Mean TSL (SD) (cm)
|
6.17 (2.03)
|
6.23 (2.51)
|
0.23
|
|
Mean ISL (SD) (cm)
|
2.64 (1.21)
|
2.92 (1.31)
|
0.87
|
|
Mean CPT (SD)
|
18.20 (6.64)
|
24.18 (8.95)
|
< 0.01
|
|
F3–4
|
|
|
Mean TSL (SD) (cm)
|
6.97 (1.78)
|
6.94 (2.79)
|
0.94
|
|
Mean ISL (SD) (cm)
|
3.00 (0.92)
|
3.33 (1.44)
|
0.23
|
|
Mean CPT (SD)
|
19.81 (7.09)
|
25.27 (8.96)
|
< 0.01
|
SD, standard deviation; TSL, total specimen length; ISL intact specimen length; CPT,
complete portal tracts
Post hoc power analysis revealed a power score of 58 % for overall comparison between
fork-tip and Franseen needle types. This highlights that in future studies with larger
sample sizes, the possibility of larger differences between groups may occur.
A power score of 3.6 % was calculated for the fibrosis score 0 to 2 group. A power
score of 3.0 % was also found for the fibrosis score 3 to 4 group. The results of
the power analysis indicate the need for larger sample sizes for comparison of fibrosis
groups to improve detection of differences.
Intact specimen length
Comparison of ISL between fork-tip (N = 210) and Franseen (N = 210) needles in all
patients showed a statistically significant difference (P = 0.01) between means (fork-tip 2.67 cm, Franseen 3.10 cm).
Patients noted to have a histological fibrosis score between 0 and 2, had a mean ISL
of 2.64 cm and 2.92 cm using the fork-tip (N = 81) and Franseen (N = 76) needles,
respectively (P = 0.17). Patients falling into fibrosis scores of 3 to 4 did not have a statistically
significant difference (P = 0.23) in the mean ISL between fork-tip (N = 27) (3.00 cm) and Franseen (N = 52)
(3.33 cm) ([Table 1]).
Post hoc power analysis revealed a score of 92.6 %. This indicates a sufficiently
large sample size was used in the comparison of means between groups.
Power analysis calculated a power of 28.5 % for fibrosis scores between 0 and 2. A
power score of 22.9 % was also found for the fibrosis scores between 3 and 4. The
results of the power analysis indicate the need for larger sample sizes for comparison
of fibrosis groups to improve detection of differences.
Complete portal tracts
More CPTs could be obtained with the Franseen needle than with the Fork-tip needle,
which aids the pathologist in making a more accurate diagnosis during biopsy analysis.
There was a statistically significantly greater number of CPTs noted with Franseen
(N = 210) as compared to fork-tip (N = 210) needles (mean 24.05 vs 19.55, respectively)
(P < 0.01).
The mean CPT was 18.198 and 24.18 between the fork-tip (N = 81) and Franseen (N = 76)
needles, respectively, in patients with fibrosis scores between 0 and 2. This difference
was statistically significant (P < 0.01). For patients with fibrosis scores of 3 to 4 did, a statistically significant
difference (P < 0.01) was seen in the mean CPT between fork-tip (N = 27) (19.81) and Franseen (N = 52)
(25.27) ([Table 1]).
Post hoc power analysis revealed a score of 100 % for the overall comparison between
needle types, indicating an adequate sample size was used in the comparison of means
between groups. A power score of 99.7 % was calculated for patients with fibrosis
scores 0 to 2. The power score was 84.1 % for those with fibrosis scores 0 to 3, which
also demonstrates a satisfactory sample size.
Adverse events
The number of AEs were comparable between both needle types. EUS-liver biopsy utilizing
the fork-tip needle was associated with abdominal pain in 35 patients (17 %) immediately
post-procedure. Two patients required intravenous (IV) narcotic administration (hydromorphone
0.25 mg IVP every 2 hours as needed for pain) for a total of .5 mg and 1 mg in each
patient, respectively. In addition, subcapsular hematomas developed in one patients
(0.5 %). The hematoma measured 2.5 cm by 3.5 cm on abdominal computed tomography.
The patient was admitted overnight for pain control and received 1 unit of packed
red blood cell transfusion. The hematoma resolved on follow-up abdominal imaging 1
month later.
Four patients (2.0 %) developed abdominal pain following the biopsy when using the
Franseen needle, which resolved in all of them after IV narcotic administration. Bile
leak occurred in one patient (0.4 %) patient ([Table 2]).
Table 2
Baseline characteristics and demographic data according to needle type.
|
Franseen
|
Fork-tip
|
|
Male %
|
44
|
43
|
|
Age (SD)
|
52 (7.9)
|
52 (16.6)
|
|
Mean TSL (cm)(SD)
|
6.5 (2.6)
|
6.0 (2.1)
|
|
Mean ISL (cm)(SD)
|
3.1 (1.3)
|
2.7 (1.1)
|
|
Mean CPT (SD)
|
24 (8.8)
|
19.5 (8.5)
|
|
Major AE
|
0
|
1
|
|
% Diagnosed NASH
|
61
|
50
|
|
% Diagnosed viral hepatitis
|
10
|
19
|
|
% Diagnosed autoimmune
|
0.5
|
2
|
|
% Alcohol use
|
23
|
21
|
|
Mean BMI (SD)
|
32.2 (15.2)
|
29.6 (7.4)
|
|
Mean platelet count
|
221
|
203
|
|
Mean INR
|
1.4
|
1.1
|
SD, standard deviation; TSL, total specimen length; ISL, intact specimen length; CPT,
complete portal tracts; NASH, nonalcoholic steatohepatitis; BMI, body mass index;
INR, international normalized ratio
Discussion
The technique of EUS-LB has evolved. The first core needle used to obtain core biopsy
specimen was the Quick-Core (Cook Medical Inc, Bloomington, Indiana, United States)
by means of a spring-loaded trucut mechanism [16]. We recently published an article on use of 19-gauge needles in obtaining parenchymal
cores with a modified one-pass, one actuation wet suction technique. One hundred sixty
five of the patients included in this study were also included in the previously published
study [7]. Since then multiple studies have shown the utility of 19G and 22G core needles
in EUS-MLB. The Acquire needle’s design consisting of the three-point heel allows
maximum tissue capture and minimal fragmentation. On the other hand, the Sharkcore
needle design consists of six distal cutting edges, which facilitates obtaining cohesive
units of tissue with preserved cell architecture [4].
Using a modified one-pass, one-actuation wet suction technique, both needles met 100 %
American Association for the Study of Liver Dieases specimen adequacy (> 11 CPT or
TSL > 2.5 cm). For patients with fibrosis scores of 1 to 2, the Franseen needles were
capable of retrieving more CPTs. The difference persisted in patients with fibrosis
scores of 3 to 4 as the Franseen needle was also able to obtain more CPTs. For all
fibrosis scores, there was no difference in the needles in terms of TSL and ISL. Overall
comparison including all patient types showed that the Franseen needle was able to
obtain a larger TSL and ISL and more CPTs ([Fig. 2], [Fig. 3]).
Fig. 2 Mean intact specimen length (ISL) and total specimen length (TSL) comparison with
inclusion of all patient types.
Fig. 3 Comparison with inclusion of all patient types between the two needles in terms of
complete portal tracts (CPT).
In a recent meta-analysis published by Mohan et al., 437 patients who had undergone
EUS-LB were studied [4]. The yield was 93.9 % and the AE rate was 2.3 %, proving the safety and efficacy
of EUS-LB. A subgroup analysis compared the outcomes based on the type of biopsy needle.
The AE rate was found to be lower with the 19-gauge FNA needle when compared with
core biopsy needles and the diagnostic yield was also higher. On further subgroup
analysis, the rate of diagnostic yield was not statistically significantly different
between the 19-gauge FNA needle and core needles. The FNA needle had a significantly
lower rate of insufficient specimens than core biopsy needles (QuickCore and ProCore)
[4].
In terms of AEs, the rates were comparable between both groups in our study. In our
experience, bleeding as a complication of EUS-MLB is a rare occurrence. Only one patient
developed a subcapsular hematoma, which eventually resolved. With EUS-MLB, a 1-hour
period after the procedure is usually sufficient for pain to subside [7]. Unlike with PC liver biopsy, the fact that patients undergoing EUS are usually
sedated eliminates problems with patient cooperation, which would otherwise raise
the risk of bleeding. The 1 hour proved to be sufficient to achieve pain relief according
to the meta-analysis by Mohan et al [17]. In the 437 patients who underwent EUS-MLB included in the meta-analysis, the pooled
rate of AEs with EUS-guided LB was 2.3 %. Sub-analysis showed that the rate of AEs,
including pain, with the 19-gauge FNA needle was not significantly different than
the rate of AEs with other biopsy needles.
To the best of our knowledge, this cohort of 420 patients is the largest study evaluating
endoscopic ultrasound for obtaining liver samples using core needles. Previous studies
have compared 19G fine-needle aspiration (FNA) with 19G fine-needle biopsy (FNB),
or 19G FNA needle with a 22G core needle (SharkCore) [18]
[19]. Comparing the 19G FNA versus 19G FNB, the core needle demonstrated superiority
in regard to all measures of liver biopsy [19]. Comparing the 19G FNA to 22G core, the 22G had higher rates of tissue fragmentation
which lead to lower tissue adequacy rates compared to 19G FNA [18]. Dewitt et al compared two 19G core needles in 85 patients and demonstrated superior
ability of FNB compared to Tru-Cut biopsy needle in terms of prevalence of diagnostic
histology, TSL, and CPT [20]. In a recent study by Hasan MK et al, efficacy and safety of 22-G EUS-FNB for performing
EUS-MLB was evaluated. Forty patients were included in the study and in 100 % of them,
a 22-G needle was able to provide sufficient unfragmented core tissue with 100 % histological
diagnosis of parenchymal liver disease [21]. Our current study with 420 patients is the first head-to-head study of its size
to compare different two kinds of core needles for obtaining tissue in evaluation
of parenchymal liver disease.
Our study has several important limitations. First, the results are limited by its
retrospective nature. However, the biopsies were contemporaneously related and done
at two different institutions. Another limitation is that the results (technical success,
CPT, tissue length) may not generalizable to all endoscopists. EUS-MLB is a technically
demanding procedure and preference should be given to placing it in the hands of expert
endoscopists at tertiary medical centers where there is high volume and more familiarity
with EUS-MLB so as to be able to replicate findings reported in this study and recent
literature. Nevertheless, the results highlight the overall safety and efficacy using
one cohort evaluated.
Conclusion
In conclusion, our results indicate a difference between the needles in terms of TSL,
ISL and CPT. However, histological yield was not affected and both needles were able
to provide sufficient tissue for histological analysis in all patients regardless
of fibrosis score. However, since the Franseen tip obtains more specimen, EUS procedures
performed with it may be reduced to only one pass, therefore, possibly reducing complications
and procedure times. There is a need for randomized clinical trials to establish the superiority of one
needle over the other. Moreover, the yield from EUS-MLB will also likely increase
as the technique for the procedure is further perfected with continued research and
technological innovation. Wider application of EUS-MLB outside the scope of tertiary
medical centers with advanced endoscopy services will also contribute to perfecting
the technique and its histological yield.
