Indications and results in cholestatic liver disease - PSC, SSC, PBC.

Primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis (SSC), and primary biliary cholangitis (PBC) are impor-tant indications for liver transplantation. An emerging indication for liver transplantation in selected cases is SSC after severe COVID-19 infection. The clinical presenta-tion of these cholestatic diseases is highly heterogeneous - from asymptomatic and mild elevations of liver enzymes to severe disease-specific complications like recurrent cholangitis or severe bone disorder to de-compensated liver cirrhosis. Such disease-specific clinical complications, disease-spe-cific scores, as well as the MELD score, need to be considered when selecting patients for liver transplantation.Copyright © 2023 Dustri-Verlag Dr. K. Feistle.

Temporal changes in patient-reported outcome measures stratified by liver fibrosis severity in large-duct primary sclerosing cholangitis

Background and aims: Patient-reported outcome measures (PROMs) are increasingly used as exploratory end points in clinical trials. The aim of this studywas to evaluate the temporal relationship between health-related quality of life (HrQoL) and liver fibrosis using generic (SF-36) and disease-specific (PSC-PRO) tools. Method: Patients with large-duct PSC were invited to complete HrQoL questionnaires in an outpatient setting at baseline (V1) and follow-up (V2) visits at least 12 months apart. Transient elastography liver stiffness (LS;Echosens, France) measurementswere recorded on the same day. SF-36 and PSC-PRO health domains were scored out of a maximum of 100% and 5, respectively. Mean scores were calculated for each domain with lower SF-36 and higher PSC-PRO scores representing poorer quality of life. Advanced fibrosis (F3-6) was defined based on published cutoff of LS >9.6kPa in PSC. Results: Fifty-five patients (64% male) with median age 45 years (range: 20–77) and median PSC duration 11 years (range: 2–26) attended both study visits. The median time between visits was 417 days (range: 362–582). The mean scores were numerically lower at V2 than V1 in all the SF-36 domains but only three domains showed statistically significant difference: bodily pain (74% vs 83%, p < 0.01), energy/fatigue (47% vs 57%, p < 0.0001), and mental summary score (66% vs 71%, p < 0.001). There were no differences in any of the PSCPRO domains between the visits. When stratified by baseline LS >9.6 kPa threshold (Figure 1), SF-36 physical functioning mean score dropped in the F3-6 group but increased slightly in the F0-2 group (−9.0 ± 17% vs 0.4 ± 21%, p = 0.01). In the PSC-PRO, the emotional impact mean score increased in the F3-6 group but decreased in the F0-2 group (0.6 ± 0.7 vs −0.1 ± 0.5, p < 0.01). Therewere no significant differences in mean scores in the other domains between the visits.(Figure Presented)Conclusion: Therewasworsening of bodily pain, levels of energy and mental health even within a year in patients with large-duct PSC. Patients with advanced fibrosis reported lower physical functioning and higher emotional impact of their disease compared to those without advanced fibrosis. Changes in PROMs are related to liver fibrosis and need to be considered in future antifibrotic drug trials. These findings, however, need to be interpreted in the context of imposed restrictions during the Covid-19 pandemic which may have had a significant psycho-social impact on patients.

Rationale for evaluation of PLN-74809 treatment in participants with primary sclerosing cholangitis in Phase 2a study INTEGRIS-PSC

Background and aims: Transforming growth factor beta (TGF-beta) signalling is a key driver of liver fibrosis. In primary sclerosing cholangitis (PSC), integrins over-expressed on injured cholangiocytes (alpha-v/beta-6) and myofibroblasts (alpha-v/beta-1) regulate TGFbeta activity. PLN-74809 is an oral, once-daily, dual-selective inhibitor of integrins alpha-v/beta-6 and alpha-v/beta-1 in development for the treatment of PSC and idiopathic pulmonary fibrosis. It has shown favourable tolerability in over 280 healthy participants, reduced TGF-beta signalling and achieved high target engagement in human lungs. Pre-clinical evaluation of antifibrotic activity resulting from dual integrin inhibition was performed to support clinical evaluation. Method: PLN-74809 was administered orally for 6 weeks in BALBc. Mdr2-/- mice with established fibrosis. A tool alpha-v/beta-6 and alpha-v/beta-1 inhibitor compound, PLN-75068, was tested therapeutically in a diet-induced mouse model of biliary fibrosis using 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC). Hepatic collagen was quantified by hydroxyproline (OHP) and collagen proportionate area (CPA) and TGF-beta signalling by phosphorylated SMAD3 (pSMAD3) levels. An ex vivo study evaluated the effects of 2-day treatment with PLN-74809 on the expression of profibrotic genes, COL1A1 and COL1A2, in precision-cut liver slices (PCLivS) from tissue explants of participants with biliary fibrosis (n = 2 PSC;n = 2 primary biliary cholangitis [PBC]). A review of available blinded safety data from the enrolling Phase 2a study in participants with PSC was performed (NCT04480840). Results: PLN-74809 dose-dependently reduced OHP (up to ∼30%, p < 0.05), CPA (up to ∼50%, p < 0.05) and pSMAD3 (up to ∼40%, p < 0.001) in the BALBc.Mdr2-/- mouse model, as well as COL1A1 and COL1A2 gene expression (up to ∼30%, p = 0.0789) in PCLivS from tissue explants of participants with PSC and PBC. PLN-75068 reduced OHP (up to ∼20%, p < 0.05) in DDC-injured mice in a dose-dependent manner. PLN-74809waswell tolerated in participants with PSC. Most adverse events (AEs)were mild;nonewere severe. The most common AE was mild headache. One participant experienced serious AEs at least 20 days after the last dose of study drug, deemed not related by the investigator. One participant prematurely discontinued due to COVID-19. PLN-74809 pharmacokinetics in participants with PSC were consistent with those of healthy participants. Conclusion: Pharmacological inhibition of integrins alpha-v/beta-6 and alpha-v/beta-1 demonstrated antifibrotic activity in two models of biliary fibrosis and in PCLivS from participants with PSC or PBC. Available safety findings from participants with PSC enrolled in the ongoing Phase 2a INTEGRIS-PSC study, continue to support the favourable tolerability profile of PLN-74809.

Autoimmune sclerosing cholangitis might be triggered by SARS-CoV-2 infection in a child - a case report.

The spectrum of liver involvement during coronavirus disease 2019 (COVID-19) is broad and mainly includes elevated liver enzymes and cholestasis. Severe acute respiratory syndrome corona- virus-2 (SARS-CoV-2) infection most often leads to a transient moderate increase in liver enzymes that is not accompanied by disturbances in the synthetic function of the liver. However, there is increasing evidence that SARS-CoV-2 infection is associated with the development of autoimmune disorders. The pathogenesis of autoimmune hepatobiliary diseases is not fully understood, taking into account genetic and environmental factors such as viral infections. We present a pediatric case of autoimmune sclerosing cholangitis (ASC), which was diagnosed 2 months after SARS-CoV-2 infection. To the best of our knowledge, ASC potentially triggered by COVID-19 has not been reported in pediatric patients. Further studies are needed to describe the clinical impact of the development of autoimmune liver diseases potentially associated with SARS-CoV-2 infection in pediatric patients. Our observations indicate that children with liver injury potentially caused by COVID-19 require long-term monitoring of liver function parameters.

A case of successful management of adult-onset linear IgA bullous disease with sulfasalazine during the COVID-19 pandemic

Linear IgA bullous disease (LABD) is a rare, acquired, autoimmune, pruritic and blistering skin condition. Dapsone is a first line treatment option, however there are limited options if this fails, or was contraindicated. We present a case of successful management of LABD with sulfasalazine. A 46-year-old white woman with LABD was commenced on high-dose corticosteroids. She failed weaning, and dapsone was contraindicated due to a history of primary sclerosing cholangitis and risk of hepatitis. Following the failure of mycophenolate mofetil, sulfasalazine was trialled, and successfully controlled both the patient's LABD and ulcerative colitis. There is little literature on the use of sulfasalazine in dermatological conditions. We present sulfasalazine as an option for patients who are unable to tolerate classically used treatments for LABD, or in those who have a dual diagnosis, as in this case, allowing for one agent to manage both conditions. Furthermore, the National Institute for Health and Care Excellence (NICE) guidance mentions sulfasalazine as one of the few drugs that can be continued during the COVID-19 pandemic, and its use spared this patient from the significant immunosuppression associated with other treatment modalities.

Good Outcome of Living Donor Liver Transplant in Primary Sclerosing Cholangitis- An Experience From North India

Primary sclerosing cholangitis (PSC) is a cholestatic disorder wherein liver transplant is the definitive treatment for advance stages. However, recurrence of PSC after liver transplant is of concern which can leads to graft failure and may require retransplant. There is limited data on outcomes of living donor liver transplant (LDLT) in PSC. Also, in LDLT as donors are related there is possibility of disease recurrence. So, we conducted this retrospective study to analyse the outcomes of LDLT in PSC at a tertiary liver transplant centre in north India. Methods: We conducted a retrospective analysis of 3213 transplant recipients who underwent LDLT from January 2006 to May 2021. Of these 26 (0.80%) patients has PSC as indication for liver transplantation (PSC=24, PSC/AIH overlaP=2). Data analysis was done to look for baseline demographics, clinical details, transplant outcomes, PSC recurrence and survival. Results: Mean age of study group was 42(±13.8) years and 19 (73.1%) were males. All patients had decompensated cirrhosis at time of transplant. Mean CTP score and MELD score were 9.5(±1.8) and 18.9(±7.1) respectively. 16 patients received modified right lobe graft, 7 extended right lobe graft and 5 patients received left lateral graft. Average graft weight and GRWR were 633.5(IQR 473.5-633.5) grams and 1.23(SD±0.42) respectively. Most common biliary anastomosis was hepaticojejunostomy, done in 19(73.1%) while duct to duct anastomosis was performed in 7(26.9%) patients. Median follow- up was 96(36-123) months. One patient had ulcerative colitis and none had cholangiocarcinoma. Two (7.7%) patients had bile leak during early post-transplant period. Three (11.1%) patients developed graft rejection and managed successfully with steroid pulses. Three patients died during early post-transplant period while 7 deaths occurred during long term follow-up including one death due to COVID-19. Five (19.2%) patients had recurrence of PSC of which 2 patients lost their grafts including one after retransplantation. The overall 1 year and 5-year survival rates were 88.5% and 75% respectively. Conclusion: LDLT can be performed in PSC with good long-term outcomes with a risk of PSC recurrence in about 1/5th patients.

SARS-CoV-2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease.

BACKGROUND/AIMS: In this observational study, we explored the humoral and cellular immune response to SARS-CoV-2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). METHODS: Anti-SARS-CoV-2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID-19 vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of individuals. RESULTS: Previous SARS-CoV-2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike-specific T-cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike-specific T-cell response. CONCLUSION: Patients with AIH show an increased SARS-CoV-2 infection rate as well as an impaired B- and T-cell response to SARS-CoV-2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.

Incidence, characteristics, and outcome of COVID-19 in patients on liver transplant program: a retrospective study in the north of Iran.

The risk of severe coronavirus disease-2019 (COVID-19) disease seems to be higher in individuals with solid organ transplantation. Therefore, the purpose of the present research is to investigate the incidence of COVID-19 and laboratory data and epidemiologic factors in liver transplant recipients and the patients on the waiting list for liver transplantation. In this study, we evaluated the records of patients on the waiting list for liver transplantation and of recipients of a liver transplant. Demographic data, underlying disease, history of drug use and participants' outcomes were collected. The diagnosis of SARS-CoV-2 infection for all patients was confirmed using a nasopharyngeal swab specimen with real-time RT-PCR. During the study period, 172 patients were enrolled, among whom 85 patients (49.4%) were on the waiting list for liver transplantation, and 87 patients (50.6%) were recipients of a liver transplant. Out of them, 10 (5.8%) had a positive result for SARS-CoV-2. Of these patients, 7.05% (6/85) and 4.6% (4/87) of patients on the waiting list and recipients of liver transplants were positive for SARS-CoV-2, respectively. Patients on the waiting list with COVID-19 infection had a higher median of albumin, ALT, AST, TBIL, DBIL, HDL and LDL value. In summary, the incidence of COVID-19 in liver transplant patients was slightly higher. The existence of underlying liver diseases should be well known as one of the poor predictive factors for worse outcomes in patients with COVID-19. So, comparative studies are recommended to identify risk factors for COVID-19 in patients with liver injury.

Promyelocytic Leukemia Antigen Expression: a Histological Marker for Primary Biliary Cholangitis Diagnosis?

BACKGROUND AND OBJECTIVES: Distinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens. METHODS: We evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody. RESULTS: Immunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18. CONCLUSIONS: We postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.