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1.
Gut & Liver ; 02:02, 2022.
Article in English | MEDLINE | ID: covidwho-2155635

ABSTRACT

The impact of the coronavirus disease 2019 (COVID-19) pandemic has been immense, and it continues to have lasting repercussions. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus primarily infects the respiratory system, other organ systems are affected, including the liver. Scientific knowledge on the role of SARS-CoV-2 infection and liver injury has evolved rapidly, with recent data suggesting specific hepatotropism of SARS-CoV-2. Moreover, additional concerns have been raised in regard to long-term liver damage, related to emerging cases of post-COVID-19 cholangiopathy and chronic cholestasis. Great effort has also been focused on studying how specific subpopulations with chronic medical conditions might be disproportionately impacted by COVID-19. One such population includes individuals with chronic liver disease (CLD) and cirrhosis, with an expanding body of research indicating these patients being particularly susceptible to adverse outcomes. In this review, we provide an updated summary on the current pathogenesis and mechanism of liver injury in the setting of SARS-CoV-2 infection, the association between health outcomes and SARS-CoV-2 infection in patients with CLD, and the unique consequences of the COVID-19 pandemic on the routine care of patients with CLD.

2.
Nature ; 2022.
Article in English | PubMed | ID: covidwho-2151057

ABSTRACT

Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE2(1), could represent a new chemoprophylactic approach for COVID-19 complementing vaccination(2,3). However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the road for future clinical trials.

4.
Gastroenterology ; 162(7):S-1284, 2022.
Article in English | EMBASE | ID: covidwho-1967448

ABSTRACT

BACKGROUND: Turmeric (curcumin) is a commonly used over-the-counter herbal product whose uses include diarrhea, arthritis, cancer and even COVID-19. Recently turmeric has been implicated in cases of clinically apparent liver injury with jaundice. The aim of this case series is to describe the clinical, histologic and human leukocyte antigen (HLA) associations of turmeric-associated hepatotoxicity as seen in the U.S. Drug Induced Liver Injury Network (DILIN) Prospective Study. METHODS: All adjudicated cases enrolled in DILIN between 2003-2020 with turmeric as an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were collected and analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing. RESULTS: Of 1697 cases of drug-induced liver injury judged to be definite, highly likely or probable (high confidence), nine (0.5%) were attributed to turmeric, all of which were enrolled since 2012, and 6 since 2017 (Figure). The 9 cases included 7 women, 8 whites, with a mean age of 51 years (range, 35-62 years) and BMI 25 kg/m2 (range, 15-40). Seven patients used alcohol, but none to excess, and none had underlying liver disease. Turmeric was used for an average of 102 days before onset of injury (range, 30-425 days). Initial mean ALT was 1179 U/L (range, 328-2245), ALP 211 U/L (41-441), total bilirubin 5.9 mg/dL (1.2-10.8), and INR 1.0 (0.9-1.2). Six patients developed jaundice, and serum bilirubin peaked at 9.6 mg/dL (0.8-26), and INR 2.3 (1.0- 9.7). Liver injury was hepatocellular in 8 patients (mean R = 22). Five patients had elevated antinuclear antibody (ANA) titer and two anti-smooth muscle (ASM) antibody, but none were treated with corticosteroids. Liver biopsy in 5 patients showed portal and lobular mixed inflammatory infiltrates with lymphocytes and eosinophils typical of drug-induced liver injury. Five patients were hospitalized, and one patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products analyzed;3 also contained piperine (black pepper), and none contained green tea. Of 7 patients with HLA typing available, 4 carried HLA-B*35:01, a class I HLA allele previously implicated in both green tea and Polygonum multiflorum hepatotoxicity. CONCLUSION: Liver injury due to turmeric appears to be increasing, perhaps, reflecting usage patterns or increased combination with black pepper, which increases its absorption. Turmeric liver injury, similar to that caused by other polyphenolic herbal products, is typically hepatocellular, with a latency of 1 to 6 months, and is linked to HLA-B*35:01. While most cases are self-limited, the injury can be severe and result in death or liver transplantation.

5.
Gastroenterology ; 162(7):S-1248, 2022.
Article in English | EMBASE | ID: covidwho-1967431

ABSTRACT

commonly worldwide but their effectiveness in participants with cirrhosis is unknown. We explored the effectiveness of vaccination with the Janssen Ad.26.COV2.S compared to the mRNA Pfizer BNT162b2 or Moderna 1273-mRNA vaccine in participants with cirrhosis. Method: This was a test-negative case control study among participants with cirrhosis. This study design is widely used in evaluations of vaccine effectiveness and has the advantage of minimizing biases associated with access to vaccination or health care. Cases were those who were SARS CoV2 PCR positive, controls were those who tested negative during the study period between March 15, 2021 and October 3, 2021. Participants who did not undergo SARS CoV2 PCR testing, who had COVID-19 before the study period, or received a liver transplant, were excluded. COVID-19 was classified based on individual chart review using the National Institute of Health (NIH) COVID-19 severity scale as asymptomatic, mild, moderate, severe or critical illness. Propensity score matching was used to match test positive cases and test negative controls. The propensity score of having COVID-19 were derived from a logistic regression that adjusted for the participant's sex, age, date of testing, race/ethnicity, location, alcohol as the etiology of liver disease, body mass index (BMI), diabetes mellitus, current tobacco use, current alcohol use, co-morbidities, and the Child Turcotte Pugh score. Multinomial logistic regression models were fit for COVID-19, to assess the adjusted effect from vaccination with either the Ad.26.COV2.S or the mRNA-1273 or BNT162b2 vaccines. Results: A total of 955 cases and 955 matched controls were included in the study population. The two groups were well matched to all baseline characteristics. The Ad.26.COV2.S vaccine had an effectiveness of 64% against COVID-19 (adjusted Odds Ratio [aOR] 0.36, 95% CI 0.20-0.62, p=0.005). Effectiveness was lowest with asymptomatic illness (aOR 0.42, 0.18-0.73, p=0.03), and higher against mild (aOR 0.36, 0.15-0.63, p= 0.006), moderate (aOR 0.33, 0.14-0.49, p=0.002) and severe/critical (aOR 0.24, 0.08-0.83, p=0.04) COVID-19. In the same period, mRNA vaccines had a 73% effectiveness against overall COVID-19 (aOR 0.27, 0.19-0.37, p<0.0001), progressively higher from asymptomatic (aOR 0.38, 0.23-0.59, p=0.0004) to mild (aOR 0.29, 0.18-0.42, p<0.0001), moderate (aOR 0.27, 0.18-0.36, p<0.0001), and severe or critical illness (aOR 0.17, 0.06-0.32, p<0.0001). There were no statistically significant differences between the viral vector and mRNA vaccines. Conclusion: In participants with cirrhosis, the Ad.26.COV2.S demonstrated a 64% effectiveness against COVID-19, and a 74% effectiveness against severe or critical COVID-19, similar to that associated with mRNA vaccines. (Figure Presented)

7.
Hepatology ; 74(SUPPL 1):846A, 2021.
Article in English | EMBASE | ID: covidwho-1508772

ABSTRACT

Background: Liver transplant is an important curative option for select patients with hepatocellular carcinoma (HCC). The acuity circles-based allocation in February 2021 and a change setting model for end stage liver disease (MELD) exception points for HCC to the regional median MELD minus three, have the potential to create a difference in transplant opportunity for HCC patients despite having the same disease. We analyzed the effect of allocation changes on deceased donor liver transplant (DDLTs) for HCC in various regions of the US. Methods: Characteristics of HCC and non-HCC DDLTs in the year before (2/4/2019-2/3/2020) and after (2/4/2020-2/4/2021) introduction of the acuity circle policy were assessed using the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database. Based on the median national MELD at transplant of 28, OPTN regions were stratified into low (≤28) and high (>28) MELD regions. We performed chi-squared proportional testing to compare differences in transplant volumes in both eras. Results: In the pre-acuity circle era there were 6699 DDLTs performed compared to 6660 DDLTs in the post-acuity circle area era (-0.6%). The 0.6% decrease in the number of DDLTs was driven entirely by a decrease in DDLTs for HCC (1529 to 1351;-11.6%) (Figure 1). There was a reduction in the absolute numbers of HCC transplants performed in most regions. There were statistically significant decreases in regions 2 (-37.8%, p<0.001) and 4 (-28.3%, p=0.001) and a numerical decrease in region 11 (-20.3% p=0.088), all low MELD regions. Conversely, there were absolute increases in DDLTs for HCC in region 9 (+17.6%, p=0.388), region 1 (+3.0%, p=0.875), and region 5 (+1.6%, p=0.811), all high MELD regions. To assess if the reduction in HCC transplants was attributable to the COVID-19 pandemic, we examined changes in the proportion of all DDLT being performed for HCC. Similar to the changes in the absolute number of DDLTs, the overall percentage of DDLTs performed for HCC decreased after the new allocation system nationally (22.8% to 20.3%) with statistically significant decreases in regions 2 (26.5% to 18.3%, p<0.001) and 4 (27.8% to 20.5%, p=0.001). Conclusion: After introduction of new organ allocation policies in early 2020, there were large shifts in regional sharing of organs and statistically significant decreases in DDLT for HCC both nationally and in low MELD regions. The COVID-19 pandemic-related changes are unlikely to account for disproportionate decreases in HCC transplants. Ongoing investigation of these trends are needed to ensure that HCC patients are not unfairly disadvantaged because of geographic differences in score allocation for the same disease.

8.
Hepatology ; 74(SUPPL 1):318A, 2021.
Article in English | EMBASE | ID: covidwho-1508693

ABSTRACT

Background: Despite recent advances, the management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. Modifying the expression of the SARS-CoV-2 entry receptor ACE2 could prevent viral infection and limit disease progression. Here, we identify that ACE2 expression is controlled by the transcription factor farnesoid X receptor (FXR) and demonstrate that ACE2 downregulation through FXR antagonism, using approved drugs, such as ursodeoxycholic acid (UDCA), could represent a novel therapeutic strategy to complement current approaches. Methods: Primary cholangiocyte, pulmonary and intestinal organoids were propagated using established protocols. Marker expression was assessed using singlecell RNA sequencing, QPCR, immunofluorescence and flow cytometry. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Viral load was measured via QPCR. Human livers not used for transplantation were perfused ex-situ using the metra (OrganOx) normothermic perfusion device. Serum ACE2 activity was measured with commercial kits. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching. Results: FXR activation directly upregulated ACE2 transcription in organoids from COVID19 affected tissues, including the biliary, gastrointestinal and respiratory systems. Conversely, FXR antagonism with z-guggulsterone or UDCA, had the opposite effect. Importantly, both drugs reduced susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. Furthermore, systemic administration of UDCA in human organs perfused ex-situ downregulated ACE2 and reduced SARS-CoV-2 infection ex-vivo. Oral UDCA rapidly reduced serum ACE2 in vivo. Registry data showed a correlation between UDCA administration and better clinical outcomes in COVID19 patients, including hospitalisation, ICU admission, mechanical ventilation and death. Conclusion: We discovered FXR as a novel therapeutic target against SARS-CoV-2 and we identified approved FXR inhibitors which could be repurposed to potentially treat COVID19, paving the road for future clinical trials to validate these results.

9.
Hepatology ; 74(SUPPL 1):327A-328A, 2021.
Article in English | EMBASE | ID: covidwho-1508685

ABSTRACT

Background: A number of factors can inform ICU escalation decisions, including the likelihood of survival and patient co-morbidities. This study examined prior liver transplant (LT) recipients and patients with chronic liver disease (CLD) diagnosed with SARS-CoV-2, and compared the rate of ICU admission and decline amongst those who were sick enough to require ICU care. Methods: Patient data from 12 March 2020 to 6 May 2021 was extracted using two international reporting registries (SECURE-Liver and COVID-Hep). Patients had a history of LT or CLD, laboratory-confirmed SARS-CoV-2, and were deemed ill enough to require ICU care. Patients were either admitted to the ICU, or declined admission due to inadequate capacity or because ICU escalation was deemed inappropriate. We compared patient characteristics by ICU decline, and compared ICU decline rates by LT and CLD categories with unadjusted and multivariable logistic regression. Results: 173 LT recipients were admitted to the hospital with SARS-CoV-2 (transplant year 1986-2020, median age 63, 74% male), and 66 (38.2%) were deemed unwell enough to require ICU care. Among those sick enough to require ICU care, 55 (83.3%) were admitted to the ICU and 11 (16.7%) were declined admission. Compared to those admitted to the ICU, patients declined ICU admission were significantly older (median 69 yrs vs 62 yrs, p=0.01) but otherwise similar in other characteristics. ICU decline rates in prior LT recipients (16.7%) were similar to patients with non-cirrhotic CLD (16.1%, p=0.96), but substantially lower than patients with Child A cirrhosis (31.8%, p=0.03), Child B cirrhosis (37.1%, p=0.006) and Child C cirrhosis (38.7%, p=0.004). Differences in ICU decline between LT recipients and Child B or C cirrhosis remained statistically significant after adjustment for age, sex and major co-morbidities. Among patients admitted to the ICU, mortality was higher in LT recipients compared to non-cirrhotic CLD (OR 0.31, 95% CI 0.14-0.71) but lower in LT recipients compared to Child C cirrhosis (OR 3.85, 95% CI 1.47-10.11) after adjustment for age, sex and co-morbidities (see Figure 1). Conclusion: ICU decline was less likely in LT recipients compared to patients with decompensated cirrhosis. LT recipients may be seen as gaining more benefit from ICU care, given the higher mortality amongst patients with decompensated cirrhosis. This is in line with prior data showing decompensated cirrhosis is a predictor of higher mortality in patients with SARS-CoV-2. Moreover, large investment of resources in LT recipients may make them more likely to be admitted to the ICU.

10.
Gut ; 70(SUPPL 3):A4, 2021.
Article in English | EMBASE | ID: covidwho-1467707

ABSTRACT

Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.

12.
Hepatology ; 72(1 SUPPL):420A, 2020.
Article in English | EMBASE | ID: covidwho-986108

ABSTRACT

Background: Smartphone applications are on the rise;yet it is unclear whether liver transplant (LT) recipients would use or benefit from this technology. We aimed to understand baseline smartphone practices and identify preferences for an app-based intervention to guide the development of the LiveRightTM Transplant app among LT recipients Methods: Twenty in-depth, in-person interviews were conducted from 2019-2020 among adults 3 to 6 months after LT at the University of North Carolina We evaluated baseline use of smartphone technology, as well as acceptability of and preferences for a LT app Interviews were conducted by trained qualitative experts and analyzed in an iterative fashion using a thematic content approach to identify relevant themes Coded transcripts were analyzed using Dedoose qualitative software Results: Among 20 LT recipients, median age was 61 years (range 28-68);65% were male;60% Caucasian;40% underwent LT for non-alcoholic fatty liver disease, 20% for viral hepatitis, and 10% for alcohol-associated liver disease Patients lived 76 miles (range 14-270) from the hospital A majority (90%) of patients owned smartphones In addition to calls, text, and email, smartphone users engaged in social media including Facebook (55%), sought information through search engines (50%), and played games or watched videos (30%) on their phones Most (65%) used EPIC MyChart to communicate with the transplant team and set phone alarms for medication reminders A majority (80%) were interested in a LT app that enabled: 1) anonymous and secure ways to connect with other LT recipients, 2) logging biometric data, 3) medication reminders including real time updates of dosages, 4) virtual communication with the medical team (after hours or early in post-LT recovery when difficult to travel to clinic), and 5) vetted educational materials especially on medication side effects/symptoms, diet, and physical activity (Figure 1) Conclusion: LT recipients want a smartphone app to aid in their recovery Most important to them is connecting with other LT recipients for peer support, educational resources related to expectations, symptoms and medication side effects, and easy options to log biometric data to be shared with their transplant team With the advent of COVID-19, using smartphone interventions will be critical to improving transplant outcomes These data informed the development of the LiveRightTM app with pilot testing underway. (Table Presented).

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