Baveno VII proposed liver stiffness measurement (LSM)/platelet count (PLT)-based criteria (‘ruled out,’ LSM ≤15 kPa plus PLT ≥150 G/L; ‘ruled in’: LSM ≥25 kPa) for clinically significant portal ...hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). However, a substantial proportion of patients remains ‘unclassified.’
Patients with evidence of cACLD (LSM ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital 2004 to 2021 (derivation 2004–2016, n = 221; validation 2017–2021, n = 81) were included. The performance of noninvasive tests (NITs) including von Willebrand factor antigen to PLT ratio (VITRO) for the detection of CSPH (HVPG ≥10 mmHg) were evaluated.
Overall, viral hepatitis was the predominant (50.7%) etiology, followed by alcoholic liver disease (15.2%) and nonalcoholic steatohepatitis (13.2%); CSPH prevalence was 62.3%. In the derivation cohort, 45.7% were ‘unclassified’ according to Baveno VII criteria; in this group, VITRO showed an excellent diagnostic performance for the detection of CSPH (area under the receiver operating curve, 0.909; 95% confidence interval, 0.823–0.965). VITRO ≤1.5 and ≥2.5 ruled out (sensitivity, 97.7%; negative predictive value, 97.5%) and ruled in (specificity, 94.7%; positive predictive value, 91.2%), respectively, CSPH in patients who were ‘unclassifiable’ by Baveno VII criteria. The application of a sequential Baveno VII-VITRO algorithm reallocated 73% and 70% of ‘unclassified’ patients to the ‘ruled in’ and ‘ruled out’ group, respectively, while maintaining high sensitivity and negative predictive value and specificity and positive predictive value in the derivation and validation cohort, respectively. No patient allocated to the ‘CSPH ruled out’ group by the Baveno VII-VITRO algorithm developed decompensation within 5 years, whereas 5-year decompensation rates were negligible (4%) and substantial (23.9%) among ‘unclassified’ and ‘CSPH ruled in’ patients, respectively.
The sequential application of VITRO in patients with cACLD who were ‘unclassifiable’ with regard to CSPH by Baveno VII criteria substantially decreased the number of ‘unclassifiable’ patients to <15% and refined prognostication.
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Background
Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant portal hypertension (CSPH). This study assesses different features of CSPH and their distinct ...prognostic impact regarding decompensation and survival in patients with PBC.
Methods
Patients with PBC were identified during a database query of our digital patient reporting system.
Results
A total of 333 PBC patients (mean age 54.3 years, 86.8% females, median follow-up 5.8 years) were retrospectively assessed and 127 (38.1%) showed features of CSPH: 63 (18.9%) developed varices, 98 (29.4%) splenomegaly, 62 (18.6%) ascites and 20 (15.7%) experienced acute variceal bleeding. Splenomegaly, portosystemic collaterals and esophageal varices were associated with an increased 5-year (5Y) risk of decompensation (15.0%, 17.8% and 20.9%, respectively). Patients without advanced chronic liver disease (ACLD) had a similar 5Y-transplant free survival (TFS) (96.6%) compared to patients with compensated ACLD (cACLD) but without CSPH (96.9%). On the contrary, PBC patients with cACLD and CSPH (57.4%) or decompensated ACLD (dACLD) (36.4%) had significantly decreased 5Y survival rates. The combination of LSM < 15 kPa and platelets ≥ 150G/L indicated a negligible risk for decompensation (5Y 0.0%) and for mortality (5Y 0.0%). Overall, 44 (13.2%) patients died, with 18 (40.9%) deaths attributed to CSPH-related complications.
Conclusion
In PBC, features of CSPH may occur early and indicate an increased risk for subsequent decompensation and mortality. Hence, regular screening and on-time treatment for CSPH is crucial. Combining LSM and platelets serves as a valuable preliminary assessment, as LSM < 15 kPa and platelets ≥ 150G/L indicate an excellent long-term outcome.
Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the ...subsequent survival in patients with decompensated alcohol-related cirrhosis.
The rate of recompensation was evaluated in patients with decompensated alcohol-related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function.
Two hundred and four abstinent patients with decompensated alcohol-related cirrhosis (age: 57.2 IQR:50.1-63.7 years; 75.0% male; median MELD: 15 IQR:11-19) and a median HVPG of 20 (IQR:18-24) mmHg were included. During a median follow-up of 24.4 (IQR:10.9-50.4) months, 37 patients (18.1%) achieved abstinence-induced recompensation. Lower baseline HVPG, lower Child-Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver-related mortality (adjusted HR: 0.091 95% CI: 0.012-0.677; p = .019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 95% CI: 0.084-1.878; p = .245), yet this finding did not reach statistical significance and requires further investigation.
Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG-characterised patients with decompensated alcohol-related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver-related mortality.
We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 ...decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.
The folding trajectory of solute carrier 6 (SLC6) family members is of interest because point mutations result in misfolding and thus cause clinically relevant phenotypes in people. Here we examined ...the contribution of the C terminus in supporting folding of the serotonin transporter (SERT; SLC6A4). Our working hypothesis posited that the amphipathic nature of the C-terminal α-helix (Thr603–Thr613) was important for folding of SERT. Accordingly, we disrupted the hydrophobic moment of the α-helix by replacing Phe604, Ile608, or Ile612 by Gln. The bulk of the resulting mutants SERT-F604Q, SERT-I608Q, and SERT-I612Q were retained in the endoplasmic reticulum, but their residual delivery to the cell surface still depended on SEC24C. This indicates that the amphipathic nature of the C-terminal α-helix was dispensable to endoplasmic reticulum export. The folding trajectory of SERT is thought to proceed through the inward facing conformation. Consistent with this conjecture, cell surface expression of the misfolded mutants was restored by (i) introducing second site suppressor mutations, which trap SERT in the inward facing state, or (ii) by the pharmacochaperone noribogaine, which binds to the inward facing conformation. Finally, mutation of Glu615 at the end of the C-terminal α-helix to Lys reduced surface expression of SERT-E615K. A charge reversal mutation in intracellular loop 1 restored surface expression of SERT-R152E/E615K to wild type levels. These observations support a mechanistic model where the C-terminal amphipathic helix is stabilized by an intramolecular salt bridge between residues Glu615 and Arg152. This interaction acts as a pivot in the conformational search associated with folding of SERT.
Background: The C terminus of the serotonin transporter (SERT) is required for folding.
Results: Replacing C-terminal residues (Phe604, Ile608, and Ile612 by Gln and Glu615 by Lys) caused misfolding of SERT. A charge reversal (R152E) rescued SERT-E615K.
Conclusion: An amphipathic C-terminal helix interacts with the first intracellular loop to facilitate folding of SERT.
Significance: These data provide insights into the folding trajectory of SERT and related transporters.
Objectives
Porto-sinusoidal vascular disorder (PSVD) is a recently defined vascular liver disease. Since diagnosis remains challenging, we aimed to evaluate radiological features that are distinct ...between PSVD and cirrhosis.
Methods
Clinical, laboratory, and radiological parameters (CT/MRI) of patients with histologically-confirmed PSVD vs. cirrhosis vs. non-cirrhotic parenchymal liver disease were retrospectively evaluated.
Results
Sixty-three PSVD, 155 cirrhosis, and 41 non-cirrhotic patients were included. As compared to cirrhosis, PSVD patients were younger and had lower HVPG, liver stiffness, and MELD. Routine clinical and imaging findings indicative of portal hypertension were similarly common. Intrahepatic portal tract abnormalities (49% vs. 15%;
p
< 0.001), FNH-like lesions (30% vs. 1%;
p
< 0.001), and abnormal liver morphology defined as peripheral parenchymal atrophy and compensatory hypertrophy of central segments (32% vs. 7%;
p
< 0.001) were significantly more common in PSVD patients. Hypertrophy of segment I (70% vs. 84%;
p
= 0.019), atrophy of segment IV (24% vs. 47%;
p
= 0.001), and nodular liver surface (22% vs. 89%;
p
< 0.001) were more common in patients with cirrhosis. In patients with gadoxetic acid–enhanced MRI, we identified the distinct imaging feature of “periportal hyperintensity” in the hepatobiliary phase (HBP) in 42% of patients with PSVD (14/33) vs. 1% in cirrhosis (1/95) vs. 0% in non-cirrhotic controls (0/41);
p
< 0.001).
Conclusions
Diagnosis of PSVD must be considered in younger patients presenting with clinical features of portal hypertension, portal tract abnormalities, and FNH-like lesions on CT/MRI. ‘Periportal hyperintensity’ in the HBP of gadoxetic acid–enhanced MRI was identified as a specific radiological feature of PSVD.
Key Points
• Cross-sectional imaging can provide essential information to identify patients with porto-sinusoidal vascular disorder (PSVD).
• Intrahepatic portal tract abnormalities, FNH-like lesions, and abnormal liver morphology are common in PSVD patients.
• Periportal hyperintensity on the hepatobiliary phase of gadoxetic acid–enhanced MRI seems to be specific for patients with PSVD.
To explore the epidemiology and clinical course of hepatitis A virus (HAV) infections at the Vienna General Hospital. We retrospectively identified patients who were tested positive for HAV-IgM at ...the Vienna General Hospital form Q1/2008 to Q3/2018. Our definition of severe HAV infection was AST and/or ALT > 5 × above the upper limit of normal (ULN); and liver dysfunction as (i) hepatic encephalopathy or ammonia > 100 μmol/L, (ii) coagulopathy with INR > 1.5, or (iii) jaundice with bilirubin > 5 mg/dL. A total of 578 HAV-IgM (+) were identified, including 31 (5.4%) and 38 (6.6%) without and with liver dysfunction, respectively. A proportional increase in severe HAV cases with and without liver dysfunction occurred in 2016/2017 with (21.5% (vs. 8.0% in the years before;
p
< 0.001). Thirty-seven (53.6%) patients with severe HAV were hospitalized, 6 (9%) required ICU support, and one patient received liver transplantation within 30 days. Patients with severe HAV and liver dysfunction were more often male (60.5 vs. 43.1%,
p
= 0.055) and younger (31.5 vs. 63 years,
p
< 0.001) as compared with other HAV-IgM (+) cases. The observed increase of severe HAV infections in Vienna in 2017 among young males, coincided with a multinational HAV outbreak among MSM. Our data suggests a higher likelihood of severe courses of hepatitis A in MSM. Vaccination against HAV should be recommended for risk groups.
Objectives
To examine inter- and intra-observer agreement for four simple hepatobiliary phase (HBP)–based scores on gadoxetic acid (GA)–enhanced MRI and their correlation with liver function in ...patients with mixed chronic liver disease (CLD).
Methods
This single-center, retrospective study included 287 patients (62% male, 38% female, mean age 53.5 ± 13.7 years) with mixed CLD (20.9% hepatitis C, 19.2% alcoholic liver disease, 8% hepatitis B) who underwent GA-enhanced MRI of the liver for clinical care between 2010 and 2015. Relative liver enhancement (RLE), contrast uptake index (CUI), hepatic uptake index (HUI), and liver-to-spleen contrast index (LSI) were calculated by two radiologists independently using unenhanced and GA-enhanced HPB (obtained 20 min after GA administration) images; 50 patients selected at random were reviewed twice by one reader to assess intra-observer reliability. Agreement was assessed by intraclass correlation coefficient (ICC). The albumin-bilirubin (ALBI) score, the model of end-stage liver disease (MELD), and the Child-Turcotte-Pugh (CTP) score were calculated as standards of reference for hepatic function.
Results
Intra-observer ICCs ranged from 0.814 (0.668–0.896) for CUI to 0.969 (0.945–0.983) for RLE. Inter-observer ICCs ranged from 0.777 (0.605–0.874) for HUI to 0.979 (0.963–0.988) for RLE. All HBP-based scores correlated significantly (all
p
< 0.001) with the ALBI, MELD, and CTP scores and were able to discriminate patients with a MELD score ≥ 15 versus ≤ 14, with area under the curve values ranging from 0.760 for RLE to 0.782 for HUI.
Conclusion
GA-enhanced, MRI-derived, HBP-based parameters showed excellent inter- and intra-observer agreement. All HBP-based parameters correlated with clinical and laboratory scores of hepatic dysfunction, with no significant differences between each other.
Key Points
• Radiological parameters that quantify the hepatic uptake of gadoxetic acid are highly reproducible.
• These parameters can be used interchangeably because they correlate with each other and with scores of hepatic dysfunction.
• Assessment of these parameters may be helpful in monitoring disease progression.
Background
Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD).
...Methods
Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (
n
= 249). Serum biomarkers of BT (lipopolysaccharide LPS, lipoteichoic acid LTA, bacterial DNA bactDNA), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (
n
= 7 ACLD,
n
= 4 controls) were analyzed by flow cytometry.
Results
Patients had a median HVPG of 18 (12–21) mmHg and 56% had decompensated ACLD. LPS (0.04 0.02–0.06 vs. 0.64 0.30–1.06 EU/mL), LTA (4.53 3.58–5.97 vs. 43.2 23.2–109 pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (
n
= 40;
p
< 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman’s
r
s
= 0.523,
p
< 0.001/
r
s
= 0.143,
p
= 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 0.28–0.95 vs. 0.88 0.32–1.31 EU/mL,
p
= 0.001) and TNF-α (15.3 6.31–28.1 vs. 20.9 13.8–32.9 pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased T
H
1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20–26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months.
Conclusion
BT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD.
Clinical trial number
NCT03267615.
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