Radiological methods:
Ultrasound in evaluation of CFHBI:
Ultrasound (US) is a relatively inexpensive and widely available tool to
assess the liver. The initial role of US was established in a
single-center study involving a cohort of 106 children with CF followed
for approximately 10 years. In this study, a heterogeneous echogenic
pattern on liver US was utilized to evaluate children at risk for aCFLD
(defined as a nodular liver in US) with or without portal hypertension58. The authors demonstrated that children with CF
with a heterogeneous echogenic appearance had a 5.2-fold increased
incidence of a nodular appearance and a 6.1-fold increased incidence of
portal hypertension compared with participants with a normal echogenic
pattern 58. These results were confirmed by the
Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF (PUSH
study) which showed the heterogenous pattern had 9.5 times increased
incidence of the nodular pattern when compared to participants with
normal liver appearance over a six-year period 59.
In addition to showing an association between a heterogenous US pattern
and the development of a nodular pattern on US, the PUSH study also
demonstrated significant differences between US groups (normal,
heterogenous, homogenous and nodular) for spleen size, and non-invasive
hepatic markers depicting the ability of a research ultrasound in the
evaluation of CFHBI and aCFLD 44. FIB-4, GPR, and APRI
were significantly increased, and platelets decreased in participants
with a heterogeneous pattern when compared with PwCF with a normal liver
appearance 60. In another study with longitudinal
follow up, the same group of PUSH study investigators noted that in
approximately 6.3 years of average follow-up, six participants with
nodular liver appearance developed esophageal varices, two had bleeding
related to varices, and two had liver transplants 61.
The control population had no liver-related adverse events highlighting
the feasibility of research US in discriminating the progression of
aCFLD from the individuals with normal liver appearance.
While the data regarding US in CF is encouraging, there remain
significant clinical concerns. US lacks the ability to detect early
stages of aCFLD reliably and a normal US does not preclude significant
liver fibrosis 12. Another major limitation is a high
percentage of interpretation variabilities (both intra- and
interobserver) between sonologists specifically in clinical settings12, an important point to note given the PUSH study
was conducted by trained and experienced radiologist within a research
protocol. US is likely best utilized clinically to compliment serum
biomarkers. This is highlighted by the proposed algorithm by Sellars et
al integrating conventional liver indices to guide when to perform a
liver ultrasound (US). They utilized GGT as an initial screening test
and further utilized APRI and GPR to determine when an abdominal
ultrasound is needed 27. This is supported by the
final PUSH multivariate analysis showing that the combination of initial
US pattern, age and GPR produced the best AUC in predicting the
development of a Nodular US 60.
Elastography in evaluating CFHBI:
With progressive fibrosis, the stiffness of the liver increases with
decreasing elasticity which can be utilized for screening using several
elastography techniques 38. A high cutoff for LSM
increases the specificity of diagnosis (ruling in) advanced liver
fibrosis and conversely a low cut-off provides a relatively higher
sensitivity for the evaluation of early stages of (minimal or no)
fibrosis. Common radiological methods include vibration-controlled
transient elastography (TE), ultrasound-guided elastography such as
point shear wave elastography (SWE) or 2D-shear wave elastography, and
magnetic resonance elastography (MRE) have been studied.
TE (FibroScan®) has been utilized in the early evaluation and monitoring
of liver fibrosis in both children and adults with CF39-42 Lewindon et al demonstrated that liver stiffness
measured by TE was significantly higher in children with CFHBI (10.7
kPa, SD 2.4) when compared with children without CFHBI (4.6, SD 0.1) and
healthy control population (4.1 kPa, SD 0.1)41. Using
5.5 kPa as a screening cut-off for CFHBI, the liver stiffness
measurement (LSM) identified children with CFHBI with an AUROC of 0.82,
70% sensitivity and 82% specificity (P <0.0001). A higher
cutoff of 8.7 kPa improved the specificity of the diagnosis and
differentiated children with aCFLD (diagnosis of aCFLD based on
ultrasound findings or by liver biopsy, stages F3-F4) vs patients with
early fibrosis (stages F1-F2), with an AUROC, 0.87; 75% sensitivity,
100% specificity 41. Also, the combined utility of
APRI and LSM identified children with CFHBI with higher diagnostic
accuracy (AUROC of 0.89, 87% sensitivity, and 74% specificity). Also,
the combination of APRI and LSM improved the differentiation of patients
with severe fibrosis vs mild fibrosis 41. Lam and
colleagues did a meta-analysis by pooling results from six studies (605
participants) and demonstrated an ideal cut-off for LSM by TE and APRI
as ≥5.95 kPa and ≥0.329 respectively 62 The
sensitivity, specificity, and AUROC were 55%, 87%, 0.76 and 52%,
93%, and 0.84 for LSM and APRI respectively. When both parameters were
combined, the sensitivity, specificity, PPV, and NPV were 43%, 99%,
92%, and 87% with a diagnostic odds ratio of 75.
Although encouraging, LSM by TE suffers from poor intra- and
interindividual variation. The poor repeatability of TE was highlighted
by Rowland and colleagues in healthy children (normal range of LSM was
as 2.88–6.52 kPa) across various age categories 63. A
difference of >1kPa between paired measurements was noted
in approximately 26% of the participants 63.
Therefore well agreed standard cut-off values for TE in the evaluation
of CFHBI are urgent needed.
Calvopina and colleagues demonstrated that LSM by supersonic SWE showed
good diagnostic accuracy in children with CFHBI 64.
LSM was significantly higher in CFHBI (8.1 kPa, IQR = 6.7–11.9) versus
without liver involvement (6.2 kPa, IQR = 5.6–7.0; P <
0.0001) and control population (5.3 kPa, IQR=4.9–5.8; P <
0.0001) 64. The diagnostic accuracy improved when
supersonic SWE was combined with APRI.
In a single-center study, both TE using FibroScan® and
point SWE (Virtual TouchTM Quantification) were
compared in children with CF for their repeatability and reproducibility34. The performance of both techniques was good and
investigators concluded that either one of the two methods can be
utilized for evaluating CFHBI 34. However, the
intraclass correlation was superior for TE than SWE for both intra- and
interobserver agreements 28. Unlike TE, the LSM
measurements between studies may not be comparable in difference studies
involving SWE as the results may vary based on the technology utilized
(point SWE vs 2D-SWE, probe and frequency (6Hz vs 9 Hz) differences, and
availability of different commercial brands 65.
MRE is the most accurate elastographic technique but its availability is
limited to research settings in tertiary care centers. MRE is expensive
and also poses technical challenges in young children, people with
severe obesity, and advanced lung disease 66. In a
single-center prospective study involving 55 percipients, all three (TE,
SWE, and MRE) elastography modalities were compared67. PwCF aged 6-18 years were included and based on US
findings, participants were grouped into three groups (aCFLD,
heterogenous increased echogenicity, and normal/homogeneous
echogenicity). All tests were done on the same day. LSM on all
elastography methods was significantly higher compared to the other two
groups. TE and SWE were highly correlated (r=0.9) and concordant in
identifying aCFLD (Cohen’s k=0.84) while MRE was moderately correlated
and concordant with TE (r=0.41; k=36) and SWE (r=0.5; k=0.50)67. Even though these elastography techniques have
shown good reliability in the evaluation of early diagnosis of
significant liver fibrosis, their effect on longitudinal monitoring of
disease progression is lacking, and further studies are awaited1.
Spleen elastography:
Increased spleen stiffness measured by elastography methods has been
utilized in both children and adults with advanced liver disease and may
help to predict the severity of portal hypertension68,69. In a single-center study involving children,
higher swear wave velocity was noted in CF than in control population.70. But no differences in swear wave velocity were
noted in CF children with or without liver involvement and further
studies are needed to explore its utilization in the early stages of
aCFLD 70.
Radiological methods conclusions:
Greyscale US is often clinically utilized in evaluation of aCFLD due to
wide availability and relatively low cost. However, it lacks the
sensitivity to detect early stages of aCFLD reliably and also has high
percentage of interpretation variabilities (both intra- and
interobserver) among radiologists. US-based elastographies (TE and SWE)
are relatively readily available, technically easier to perform, and
cost effective. LSM obtained by various elastography techniques (TE,
SWE, and MRE) are modality-dependent, and cannot be compared directly to
one another. Also, these radiological tests are best utilized to
complement the serum biomarkers in the evaluation of CFHBI. Finally,
spleen elastography may be advantageous to evaluate portal hypertension,
with or without cirrhosis, but its availability is limited and
additional CF-specific studies are needed.
Genetics in the evaluation of CFHBI :
While CFHBI has been associated with pancreatic insufficiency, history
of meconium ileus and CFRD, no clear genotype association has been
established 7. While some studies have shown F508del
homozygosity was associated with aCFLD, it is unclear if that reflects
the frequency of the mutation rather a true risk factor. It is generally
believed that severe mutations (class 1-3) are associated with aCFLD71, but given the relatively low incidence rate among
patients with two severe mutations, it has long been believed that
additional genetic modifiers contribute to aCFLD.
To date, only the SERPINA1 Z allele has been associated with the
development of aCFLD 72,73, but only accounts for a
small portion of those with aCFLD. However, SERPINA1 has since been
shown to be an independent risk factor for advanced liver disease in a
number of chronic liver conditions 74, and thus
unlikely to be a CF-specific modifier. In silico modeling has also
supported the idea that additional genetic modifiers beyond SERPINA1 Z
may contribute to the development of aCFLD 75Currently, both the PUSH study team and researchers for the CF
Foundation are conducting studies to better understand the role of
genetic modifiers in CFLD (Clinical Trials NCT01144507 and NCT00804583).
Genetic modifiers conclusion:
To date, only the SERPINA1 Z allele has been associated with aCFLD but
only accounts for a small portion of the population, and is unlikely to
be CF-specific. Additional work is underway to better understand the
potential genetic modifiers associated with CFHBI and aCFLD.