LTSI Consensus Guidelines: Preoperative Pulmonary Evaluation in Adult Liver Transplant Recipients.

The relationship between chronic liver disease and respiratory symptoms and hypoxia is well recognized. Over the last century, three pulmonary complications specific to chronic liver disease (CLD) have been characterized: hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. Apart from that coexisting pulmonary disease like chronic obstructive lung disease and interstitial lung disease also complicate the outcomes after liver transplantation (LT). Assessment for evaluation of underlying pulmonary disorders is essential to improve outcomes in patients with CLD, posted for LT. This consensus guideline of the Liver Transplant Society of India (LTSI) provides a comprehensive review of pulmonary issues in CLD, related and unrelated to underlying liver disease and gives recommendations for pulmonary screening in specific clinical scenarios in adults with chronic liver disease planned for LT. This document also aims to standardize the strategies for preoperative evaluation of these pulmonary issues in this subset of patients. Proposed recommendations were based on selected single case reports, small series, registries, databases, and expert opinion. The paucity of randomized, controlled trials in either of these disorders was noted. Additionally, this review will highlight the lacunae in our current evaluation strategy, challenges faced, and will provide direction to potentially useful futuristic preoperative evaluation strategies.

Scientific debrief: cirrhosis

Globally, hepatitis C (26%), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from nonalcoholic fatty liver disease (8%) is small but increasing. Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acuteon-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure, Cardiovascular alterations including portal hypertension trigger the formation of portocaval shunts and varices. Systemic under filling and arterial hypotension is compensated by vasoconstriction but might decline into a state of aggravated portal hypertension and cirrhotic cardiomyopathy, leading to a hyperdynamic state, microvascular dysfunction and reduced organ perfusion culminating in decompensation. The immune system is dysfunctional showing a contrary co-existence of immune paralysis and immune overstimulation leading to secondary infections and inflammatory response syndrome aggravating cardiovascular alterations but also initiating tissue injury and metabolic alteration. This transition from compensated to decompensated cirrhosis is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF. Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV). In the majority of patients, systemic inflammation is a major driver of progression from compensated to decompensated cirrhosis. Once the first episode of AD develops, systemic inflammation follows a chronic course, with transient periods of aggravation due to proinflammatory precipitants or bursts of bacterial translocation resulting in repeated episodes of AD. The multistate model describing the clinical outcomes of decompensated cirrhosis has been well validated. State 3 is defined by the occurrence of variceal bleeding alone, state 4 by any single non-bleeding event, state 5 by any 2 or more events and the late decompensate state by any event with organ failures either with or without ACLF. 5-year mortality across states from 3 to 5 is in the order of, respectively: 20%, 30%, 88%. With late decompensation mortality ranges between 60 and 80% at 1 year. Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. Aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, management of hepatic encephalopathy (HE), ascites, hepatorenal syndrome, non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue, and reduce the risk of hepatocellular carcinoma. New disease-modifying agents are expected to be identified in the next few years by systematic drug repurposing and the development of novel molecules currently undergoing pre-clinical or early clinical testing. COVID-19 continues to pose a significant healthcare challenge throughout the world. Comorbidities including diabetes and hypertension are associated with a significantly higher mortality risk. Cirrhosis is associated with an increased risk of all-cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection, such as shielding and prioritisation of vaccination.

Check Point SOS! A Case of Cemiplimab-Associated Sinusoidal Obstruction Syndrome

Introduction: Hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), is a clinical syndrome characterized by hepatomegaly, right-upper quadrant pain, and ascites that occurs most commonly in the setting of high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT). The diagnosis can be confirmed on biopsy. Cemiplimab is an immune checkpoint inhibitor recently approved for the treatment of cutaneous squamous cell carcinoma. There are currently no known reports of immune checkpoint inhibitor-related VOD/SOS. Case Description/Methods: A 58-year-old female with a history of locally advanced basal cell carcinoma of the left eye treated with six months of Cemipilimab presented with ascites. On admission, labs were notable for a total bilirubin of 1.2, mildly elevated liver function tests, alkaline phosphatase 884, and international normalized ratio 2.1. A diagnostic tap revealed a high SAAG ascites that was negative for infection. A comprehensive serological workup for viral, metabolic and autoimmune causes was unrevealing. A transjugular liver biopsy demonstrated a hepatic venous pressure gradient of 18mmHg, nodular regenerative hyperplasia (NRH), and portal venopathy. The patient was discharged on steroids but returned one month later for recurrent ascites and worsening bilirubin to 12.6 (direct 7.3);COVID PCR was negative. A full rheumatologic and vasculitis workup was unremarkable. Repeat biopsy (Figure 1) demonstrated moderate NRH changes, prominent central vein sclerosis with fibrous obliteration, signs of SOS/ VOD and central venulitis with fibrotic changes with sinusoidal portal hypertension. Discussion(s): VOD occurs most often with hematopoietic stem cell transplantation, and chemotherapeutic agents. Here we present the first case of checkpoint inhibitor-induced VOD/SOS. Despite discontinuation of the offending agent and a trial of steroids, the patient's clinical course continued to deteriorate. She eventually developed refractory ascites and portosystemic encephalopathy. She was deemed not a candidate for liver transplant given her underlying malignancy. She was transitioned to home hospice before further treatment, such as Defibrotide could have been pursued. VOD associated with immune checkpoint inhibition should be considered in the differential of patients who develop new onset liver dysfunction and ascites while receiving these medications (Figure Presented).

Investigating the correlation between COVID-19 and the progression of chronic liver disease.

INTRODUCTION: The novel coronavirus disease 2019 has thrown light on various heterogeneous afflictions of newly emerging viruses on the human body. Early reports demonstrated direct effect of novel coronavirus on the liver, but subsequently, this did not stand up to validation. The SARS-CoV-2 virus affects the liver differentially; in healthy compared to those with preexisting liver disease. AREAS COVERED: This exhaustive paper reviews the current, literature on mechanisms by which COVID-19 affects the healthy liver and those with preexisting liver disease such as alcohol-related and nonalcoholic fatty liver, autoimmune liver disease, chronic liver disease and cirrhosis, hepatocellular carcinoma, viral hepatitis, and liver transplant recipients, with special mention on drug-and herb-induced liver injury with COVID-19 therapies. Search methodology: the review (Dec. 2022 - Jan. 2023) is based on PubMed (NLM) search using the keyword 'COVID' with supplementary searches using 'fibrosis;' 'liver;' 'cirrhosis;' 'CLD;' 'NAFLD;' 'NASH;' 'hepatocellular carcinoma;' 'hepatitis;' 'fatty liver;' 'alcohol;' 'viral;' 'transplant;' and 'liver failure.' EXPERT OPINION: Direct liver tropism of SARS-CoV-2 does not cause liver damage. Adverse events following infection depend on the severity of liver disease, the severity of COVID-19, and other risk factors such as metabolic syndrome and older age. Alcohol-related liver disease independently predicts adverse outcomes.

Safety and immunogenicity of booster dose in patients with chronic liver disease

Background/Aims: Several studies showed that patients with liver cirrhosis have an immune dysregulation leading to poor immunological response to vaccination. However, in literature there are few data about the response to SARS-CoV-2 vaccination in patients with chronic liver disease (CLD). Aims of the study are (is) the evaluation of safety and immunogenicity of booster dose in patients with CLD. Methods: From September 2021 to April 2022, all consecutive outpatients with CLD who completed the primary vaccination course and the booster dose for anti-SARS-CoV-2 vaccination were enrolled. Blood samples were collected 12-16 weeks after second dose and after booster dose. Collected samples were analyzed for detecting anti-Spike protein IgG using LIAISON TrimericS IgG chemiluminescent assay (Diasorin, Italy). Results: We enrolled 340 patients (187 Males, mean age:64.32±17.34years). Stratified by the presence of cirrhosis, 249 had CLD and 91 were cirrhotic whose 57 (62.24%) had portal hypertension. At the end of the primary vaccination course, 60 patients (17.65%) did not develop a protective antibody titer, with no statistically significant differences between the two groups (19.7% in cirrhotic vs 16.8% in non-cirrhotic;p=0.076). The majority of them (53/60 patients;88.3%) developed a protective titer after booster dose, without differences between cirrhotics and non-cirrhotics (p=0.089). At multivariate analysis, factors associated with a higher humoral response after booster dose were young age (p=0.0098);porto-sinusoidal vascular disorder (p=0.005), none or a single comorbidity rather than two or more (p=0.05) and Spikevax booster dose compared with Comirnaty (p=0.001). Moreover, the antibody titer is inversely related to age (p=0.000). Conclusions: In a large cohort of patients with CLD booster dose of anti-Sars-CoV-2 vaccine has an excellent immunogenicity and leads to an adequate antibody response even in those who had not produced a protective titer after the primary vaccination course. Cirrhosis is not associated with a reduced humoral response.

Spike-specific humoral and cellular immune responses after COVID-19 mRNA vaccination in patients with cirrhosis: A prospective single center study.

BACKGROUND AND AIMS: COVID-19 mRNA vaccines were approved to prevent severe forms of the disease, but their immunogenicity and safety in cirrhosis is poorly known. METHOD: In this prospective single-center study enrolling patients with cirrhosis undergoing COVID-19 vaccination (BNT162b2 and mRNA-1273), we assessed humoral and cellular responses vs healthy controls, the incidence of breakthrough infections and adverse events (AEs). Antibodies against spike- and nucleocapsid-protein (anti-S and anti-N) and Spike-specific T-cells responses were quantified at baseline, 21 days after the first and second doses and during follow-up. RESULTS: 182 cirrhotics (85% SARS-CoV-2-naïve) and 38 controls were enrolled. After 2 doses of vaccine, anti-S titres were significantly lower in cirrhotics vs controls [1,751 (0.4-25,000) U/mL vs 4,523 (259-25,000) U/mL, p=0.012] and in SARS-CoV-2-naïve vs previously infected cirrhotics [999 (0.4-17,329) U/mL vs 7,500 (12.5-25,000) U/mL, (p<0.001)]. T-cell responses in cirrhotics were similar to controls, although with different kinetics. In SARS-CoV-2-naïve cirrhotics, HCC, Child-Pugh B/C and BNT162b2 were independent predictors of low response. Neither unexpected nor severe AEs emerged. During follow-up, 2% turned SARS-CoV-2 positive, all asymptomatic. CONCLUSION: Humoral response to COVID-19 vaccines appeared suboptimal in patients with cirrhosis, particularly in SARS-CoV-2-naïve decompensated cirrhotics, although cellular response appeared preserved, and low breakthrough infections rate was registered.

Impact of COVID-19 on endoscopic follow-up of gastroesophageal varices.

Background: Portal hypertension is considered as a major complication of liver cirrhosis. Endoscopy plays a main role in managing of gastrointestinal complications of portal hypertension. Endoscopists are at increased risk for COVID-19 infection because upper gastrointestinal (GI) endoscopy is a high-risk aerosol-generating procedure and may be a potential route for COVID-19. Objectives: To compare the outcome between cirrhotic patients who underwent classic regular endoscopic variceal ligation after primary bleeding episode every 2-4 weeks, and those presented during the era of COVID-19 and their follow-up were postponed 2 months later. Methods: This retrospective study included cross-matched 238 cirrhotic patients with portal hypertension presented with upper GI bleeding, 112 cirrhotic patients presented during the era of COVID19 (group A) underwent endoscopic variceal ligation, another session after 2 weeks and their subsequent follow-up was postponed 2 months later, and 126 cirrhotic patients as control (group B) underwent regular endoscopic variceal band ligation after primary bleeding episode every 2-4 weeks. Results: Eradication of varices was achieved in 32% of cases in group A, and 46% in group was not any statistically significant (p > 0.05); also, there was no any statistical significant difference between both groups regarding occurrence of rebleeding, post endoscopic symptoms, and mortality rate (p > 0.05). Conclusion: Band ligation and injection of esophageal and gastric vary every 2 months were as effective and safe as doing it every 2 to 4 weeks after primary bleeding episode for further studies and validation.

NHS GRAMPIAN REVIEW OF NEW GUIDANCE FOR VARICEAL SCREENING

Introduction Covid-19 pandemic caused significant disruption to elective endoscopy services nationally. This paved way to endoscopy minimised management pathways for patients with liver cirrhosis. Standard pathway pre-COVID19 was as set out in Baveno VI consensus guidelines and involved variceal screening endoscopy for all patients with clinically significant portal hypertension. We adopted the new pathway as suggested by the national clinical forum, endorsed by the Scottish Government, which proposes the use of Carvedilol in patients with clinically significant portal hypertension and endoscopy reserved for patients who are intolerant of carvedilol or have contraindications to beta-blocker use. The rationale behind new guidance is the improvement in survival with Carvedilol and its efficacy in reducing hepatic venous pressure gradient and preventing decompensation. The recent Baveno VII consensus also suggests patients established on Carvedilol therapy do not need endoscopy as it is unlikely to change clinical management. We aim to assess the impact of applying the new guidance on the variceal screening/surveillance endoscopy waiting list. Methods 243 patients were identified on our variceal endoscopy waiting list who were due an endoscopy between 2019 and 2024. Patients on variceal banding programme have been excluded from this analysis. Data collected included their Childs Pugh score, fibroscan score, medications, platelet count and previous endoscopy results if applicable. Patients were then categorised into three groups. 1. Clinical monitoring of blood tests and fibroscan yearly without endoscopy 2. Carvedilol therapy indicated 3. To continue with endoscopic screening. Results 26/243 (10.6%) patients were removed from the waiting list with plan for yearly monitoring. 10/243 (4%) patients were to continue with endoscopic screening due to Carvedilol intolerance. 207 patients met the criteria to commence Carvedilol without the need for endoscopy. Therefore, 207/233 (88%) patients could be removed from the waiting list by applying the new guidance. This would free up approximately 29 endoscopy lists which can be utilised to address other areas within gastroenterology and hepatology service with longer waiting times. Conclusions The impact on variceal endoscopy waiting times by adopting the new guidance is significant. It provides opportunity to utilise the resources more effectively. From patient's perspective, endoscopy is an invasive procedure and anxiety provoking to some patients resulting in failure to attend endoscopy appointments. As the requirement for endoscopy is considerably low, the new guidance may be more acceptable to patients who prefer to avoid endoscopy. Patient compliance and tolerance to Carvedilol will be recorded prospectively to assess the overall impact on the service.

Seronegative Full-House Immune Complex Glomerulonephritis Post-mRNA COVID-19 Vaccination

Immunization with COVID-19 mRNA vaccines has been associated with new-onset and relapse of glomerulonephritis (GN)1,2. We present a case of new onset, seronegative, full-house immune-complex GN after mRNA COVID-19 vaccination. A 24-year-old male with history of idiopathic portal vein thrombosis in childhood, portal hypertension post splenorenal shunt and splenectomy 5 years prior presented with 9 weeks of progressive edema, ascites, and foamy urine. His symptoms started then worsened after his 1st and 2nd doses of the mRNA- 1273 COVID-19 vaccination (Moderna). Cr peaked at 3.04mg/dl (baseline 0.7) and UPCR at 50.52 g/g. Serum albumin 0.9 g/dl. Complements were low. ANA and anti-DS DNA were negative as were other serologies. Infectious work up was also negative. Kidney biopsy showed membranoproliferative pattern of injury on light microscopy with one fibrocellular crescent and without IFTA. IF revealed “full house” staining and EM showed severe subepithelial deposits with subendothelial and mesangial deposits. No tubuloreticular inclusions were present (Figure 1). The patient received cyclophosphamide 750 mg and high dose steroids. One month after treatment, Cr improved to 0.92 and proteinuria fell to 6.05g/g. Complements returned to normal. The high potency of mRNA COVID-19 vaccine can induce a robust immune response which may incite or unmask GNs2. Our patient had a rapid and robust response to immunosuppression. Seronegative full-house immune complex GN may occur after receiving mRNA SARS-CoV-2 vaccination and nephrologists should be aware of potential association. Prompt recognition and treatment may lead to favorable outcomes. (Figure Presented)

A newly diagnosed Budd-Chiari Syndrome with thrombotic thrombocytopenia after BTN162b2 vaccination

Objectives: Worldwide, Pfizer/BioNTech (BTN162b2) mRNA vaccine is now under massive use to be protected from COVID-19, although it may cause thrombotic thrombocytopenia in rare cases. Budd-Chiari syndrome (BCS) is a rare condition and is defined as the obstruction of hepatic venous outflow. Materials and Methods: A 34-year-old woman who was vaccinated with first dose of BTN162b2 6 weeks ago newly developed ascites, liver dysfunction, and thrombocytopenia. Results: Contrast-enhanced CT scan, doppler ultrasound, and hepatic venography showed complete obstruction of three major hepatic veins without membranous structure and without any collaterals, causing portal hypertension and liver dysfunction. Percutaneous liver biopsy showed diffusion dilation of sinusoids with extensive hepatocyte dropout, although there was no portal inflammation or fibrosis. The patient was treated with anticoagulants and intravenous immunoglobulin. After 6 weeks of anticoagulation, hepatic venous outflow became well detectable by doppler ultrasonography and ascites disappeared. Conclusion: This is a rare case of acute BCS with thrombotic thrombocytopenia after BNT162b2 mRNA vaccination.

HEPATO-PULMONARY SYNDROME: LOOK CLOSELY OR YOU MIGHT MISS IT

CASE: A Hispanic-speaking 63-year-old lady presented with left shoulder pain and dyspnea since two weeks. Past history was significant for cirrhosis due to autoimmune hepatitis and portal hypertension diagnosed 1.5 years prior. Upon further questioning, she revealed that she had exertional dyspnea for 2 years, which got progressively worse after her COVID-19 infection, 14 months prior. On initial exam, her hemoglobin levels were unchanged with previous. Troponin and BNP levels were unremarkable. CT Pulmonary Embolus scan and shoulder X-ray were negative. However, her SpO2 which was 90% on lying flat, fell to 84% on walking and she was admitted for further workup. On exam, she had a loud S2, spider angioma, and clubbing. ABG showed an alveolar-arterial oxygen gradient of 54.7 mm and PO2 of 61.7 mm. A contrastenhanced transthoracic echo with saline showed significant shunting with dilated pulmonary veins. Upon close inspection, she had a small right to left intracardiac shunt through an incidental PFO and a rather large intrapulmonary shunt. This was confirmed on trans-esophageal echo. Right heart catheterization showed a high cardiac index (5.3 L/min) suggestive of a high-output state, as typically seen with cirrhosis. It also revealed increased right-sided oxygen saturations, confirming the presence of a significant left to right shunt. Finally, pulmonary CT angiography was negative for AVMs. These findings were congruent with hepato-pulmonary syndrome (HPS) and based on her presenting symptoms she was referred to hepatology for consideration of liver transplantation. IMPACT/DISCUSSION: HPS is characterized by abnormal oxygenation due to intrapulmonary vascular dilations (IPVD) in the setting of advanced liver disease. Diagnosis needs an elevated A-a gradient (≥ 15mm or ≥ 20 mm if >64 years). IPVDs may not be seen on CT scans and are optimally detected on CE-TTE. The delayed appearance of injected microbubbles in the left heart, 3 or more cardiac cycles after visualization in the right heart signifies abnormally dilated pulmonary capillaries which don't trap the bubbles. TTE can help differentiate intracardiac and intrapulmonary shunts, by revealing the source of the microbubbles entering into the left atrium (across the atrial septum vs pulmonary veins). Shunting classically causes platypnea-orthodexia (worsening dyspnea on standing or sitting, alleviated by lying down). Alterations in lung parenchyma due to COVID-19 could have increased the flow through intrapulmonary AVMs and contributed to the worsening of symptoms. Management of HPS is supportive. Liver transplantation improves survival. CONCLUSION: Evaluation and management of HPS involves multiple modalities of testing and specialists in gastroenterology, cardiac imaging, interventional cardiology, interventional radiology, and transplant surgery. The diagnosis of HPS should escalate referral to a liver transplant center. Engaging medical interpreters can help elicit more detailed history and improve clinical outcomes.

Practical management of esophageal varices in the context of SARS-CoV-2 (COVID-19): the Alberta protocol.

The challenges of managing varices during the COVID-19 pandemic are reviewed, and a treatment algorithm is presented to best manage patients with advanced liver disease during periods of limited access to endoscopy.

Correlation of Portal Vein Diameter as a Reflection of Portal Hypertension With Clinical and Laboratory Parameters in Chronic Liver Disease

Chronic liver disease (CLD) patients develop portal hypertension which lead to complications like splenomegaly, ascites and esophageal varices. Portal hypertension is defined as hepatic venous pressure gradient more than 5mmHg, being invasive it is difficult to measure. Some studies show that increased portal vein diameter (PVD) on ultrasonography correlate with oesophageal varices and can indicate portal hypertension. Studies correlating PVD with other complications of portal hypertension like ascites and spleen size are lacking. Aim of this study was to correlate portal vein diameter with ascites, spleen size, thrombocytopenia and prognostic markers like Child-Turcotte Pugh (CTP) score and Model for End stage Liver Disease (MELD) score in Chronic liver disease patients. MATERIAL: This was a cross-sectional observational study of patients with Chronic liver disease conducted at tertiary care teaching hospital. All patient underwent clinical history, examination, blood testing and ultrasonography. Data collected was analysed by using statistical tests. OBSERVATION: Out of 97 CLD patients taken in study, the mean age of patients was 47.39 ± 12.64 year and majority were male (75.3%). Most common etiological factor was alcohol (in 53.7%). On clinical examination, 55.7% patients had pallor, 54.6% had icterus. Chest radiograph shows pleural effusion in 14.4% patients. Mean portal vein diameter was found to be 12.31 ± 2.71mm. Correlation coefficient of portal vein diameter with spleen size was 0.3 with p value of 0.004 suggesting a positive correlation. Parameters like thrombocytopenia, CTP score and MELD score correlation coefficient was -0.2(p-value: 0.066), 0.1(p value: 0.463) and 0.0(p-value: 0.725) respectively. The mean of PVD(mm) in ascites group was 12.43 and non ascites group was 11.92. Strength of association was 0.08 (Point Biserial correlation) indicating no association. CONCLUSION: Portal vein diameter had positive correlation with spleen size which is statistically significant in our study. No significant correlation was observed between PVD with ascites, thrombocytopenia, CTP score and MELD score. © Journal of the Association of Physicians of India 2011.

Liver dysfunction in the patient with COVID-19. (Pautas nacionales para la atenci..n de pacientes adultos con COVID-19.) [Spanish]

In all patients diagnosed with COVID-19, they must evaluate the existence of previous liver disease and consider that, if it exists, it is an element of poor prognosis. In Uruguay, according to the MSP Epidemiological Report of 3/10/20, 9 of 529 deceased patients had previous liver disease as comorbidity (1.7%). In patients with hepatic dirrhosis, immunosuppression due to prolonged treatment with high doses of corticosteroids can favor the development of spontaneous bacterial peritonitis and variceal bleeding due to increased portal hypertension. According to numerous published works, 2% to 11% of patients with COVID-19 had underlying chronic liver disease. Hepatogram abnormalities to monitor in the clinical context include elevated TGO and TGP enzymes as an expression of hepatocyte injury;the elevation of lactate dehydrogenase (LDH) is also characteristic but its wide distribution in the organism is an expression of endothelial injury and hypoperfusion of various tissues, particularly muscle, not only liver.

Critically Ill COVID-19 Patient with Chronic Liver Disease - Insights into a Comprehensive Liver Intensive Care.

The novel coronavirus-related coronavirus disease 2019 (COVID-19) pandemic has been relentless in disrupting and overwhelming healthcare the world over. Clinical outcomes of COVID-19 in patients with chronic comorbidities, especially in those with metabolic syndrome, are well documented. Chronic liver disease and cirrhosis patients are a special sub-group, among whom the management of COVID-19 is challenging. Understanding the pathophysiology of COVID-19 in patients with cirrhosis and portal hypertension improves our identification of at-risk patients for disease progression that will further help compartmentalize generalized and specialized treatment options in this special patient group. In this exhaustive review, we critically review the impact of COVID-19 on the liver and in chronic liver disease and cirrhosis patients. We further discuss common features associated with the pathophysiology of COVID-19 and cirrhosis, based on the renin-angiotensin system and deliberate current literature on guidelines for the treatment of COVID-19 and extrapolate the same to the cirrhosis population to provide a concise and stepwise, evidence-based management for cirrhosis patients with severe and critical COVID-19. There are no specific management guidelines for cirrhosis patients with COVID-19 and current recommendations for treatment are as per guidelines for general population. Nevertheless, specific issues like avoiding corticosteroids in decompensated patients with variceal bleeding, suspected sepsis, high grade hepatic encephalopathy and acute kidney injury, use of early mechanical ventilation strategies in those with severe ascites and hepatopulmonary syndrome, avoidance of remdesivir in advanced liver disease, and application of liver-specific severity scores for prognostication and identification of futility need to be highlighted.

Cirrhosis-Associated RAS-Inflammation-Coagulation Axis Anomalies: Parallels to Severe COVID-19.

(1) Background: Cirrhotic patients have an increased risk for severe COVID-19. We investigated the renin-angiotensin-aldosterone system (RAS), parameters of endothelial dysfunction, inflammation, and coagulation/fibrinolysis in cirrhotic patients and in COVID-19 patients. (2) Methods: 127 prospectively characterized cirrhotic patients (CIRR), along with nine patients with mild COVID-19 (mild-COVID), 11 patients with COVID-19 acute respiratory distress syndrome (ARDS; ARDS-COVID), and 10 healthy subjects (HS) were included in the study. Portal hypertension (PH) in cirrhotic patients was characterized by hepatic venous pressure gradient (HVPG). (3) Results: With increased liver disease severity (Child-Pugh stage A vs. B vs. C) and compared to HS, CIRR patients exhibited higher RAS activity (angiotensin-converting enzyme (ACE), renin, aldosterone), endothelial dysfunction (von Willebrand-factor (VWF) antigen), inflammation (C-reactive protein (CRP), interleukin-6 (IL-6)), and a disturbed coagulation/fibrinolysis profile (prothrombin fragment F1,2, D-dimer, plasminogen activity, antiplasmin activity). Increased RAS activity (renin), endothelial dysfunction (vWF), coagulation parameters (D-dimer, prothrombin fragment F1,2) and inflammation (CRP, IL-6) were significantly altered in COVID patients and followed similar trends from mild-COVID to ARDS-COVID. In CIRR patients, ACE activity was linked to IL-6 (ρ = 0.26; p = 0.003), independently correlated with VWF antigen (aB: 0.10; p = 0.001), and was inversely associated with prothrombin fragment F1,2 (aB: -0.03; p = 0.023) and antiplasmin activity (aB: -0.58; p = 0.006), after adjusting for liver disease severity. (4) Conclusions: The considerable upregulation of the RAS in Child-Pugh B/C cirrhosis is linked to systemic inflammation, endothelial dysfunction, and abnormal coagulation profile. The cirrhosis-associated abnormalities of ACE, IL-6, VWF antigen, and antiplasmin parallel those observed in severe COVID-19.

Predictors of in-hospital Outcomes in Patients With Cirrhosis and Coronavirus Disease-2019.

Background: Coronavirus disease-2019 (COVID-19) cases continue to increase globally. Poor outcomes in patients with COVID-19 and cirrhosis have been reported; predictors of outcome are unclear. The existing data is from the early part of the pandemic when variants of concern (VOC) were not reported. Aims: We aimed to assess the outcomes and predictors in patients with cirrhosis and COVID-19. We also compared the differences in outcomes between the first wave of pandemic and the second wave. Methods: In this retrospective analysis of a prospectively maintained database, data on consecutive cirrhosis patients (n = 221) admitted to the COVID-19 care facility of a tertiary care center in India were evaluated for presentation, the severity of liver disease, the severity of COVID-19, and outcomes. Results: The clinical presentation included: 18 (8.1%) patients had compensated cirrhosis, 139 (62.9%) acute decompensation (AD), and 64 (29.0%) had an acute-on-chronic liver failure (ACLF). Patients with ACLF had more severe COVID-19 infection than those with compensated cirrhosis and AD (54.7% vs. 16.5% and 33.3%, P < 0.001). The overall mortality was 90 (40.7%), the highest among ACLF (72.0%). On multivariate analysis, independent predictors of mortality were high leukocyte count, alkaline phosphatase, creatinine, child class, model for end-stage liver disease (MELD) score, and COVID-19 severity. The second wave had more cases of severe COVID-19 as compared to the first wave, with a similar MELD score and Child score. The overall mortality was similar between the two waves. Conclusion: Patients with COVID-19 and cirrhosis have high mortality (40%), particularly those with ACLF (72%). A higher leukocyte count, creatinine, alkaline phosphatase, Child class, and MELD score are predictors of mortality.