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.

Expert perspectives for the pharmacist on facilitating and improving the use of albumin in cirrhosis.

PURPOSE: Albumin, the most abundant and arguably most important protein in the human body, plays a unique role in decompensated cirrhosis because its structure and function are quantitatively and qualitatively affected. A literature review was performed to provide insights into albumin use. The manuscript was developed using a multidisciplinary approach; 2 hepatologists, a nephrologist, a hospitalist, and a pharmacist, who are all members of or work closely with the Chronic Liver Disease Foundation, collaborated to write this expert perspective review. SUMMARY: Cirrhosis represents the potential end in the spectrum of all chronic liver diseases. Decompensated cirrhosis, defined by the overt manifestation of liver failure (eg, ascites, hepatic encephalopathy, variceal bleeding), is the inflection point associated with increased mortality. Human serum albumin (HSA) infusion serves an important role in the treatment of advanced liver disease. The benefits of HSA administration in patients with cirrhosis are widely accepted, and its use has been advocated by several professional societies. However, inappropriate HSA use can lead to significant adverse patient events. This paper discusses the rationale for the administration of HSA in the treatment of complications of cirrhosis, analyzes the data on the use of HSA in cirrhosis, and streamlines practical recommendations set forth in published guidance. CONCLUSION: Use of HSA in clinical practice needs to be improved. The objective of this paper is to empower pharmacists to facilitate and improve the use of HSA in patients with cirrhosis at their practice sites.

Epidemiology and Disease Burden of Alcohol Associated Liver Disease.

Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.

COVID-19 and hepatorenal syndrome.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease which emerged into a global pandemic. Although it primarily causes respiratory symptoms for affected patients, COVID-19 was shown to have multi-organ manifestations. Elevated liver enzymes appear to be commonly observed during the course of COVID-19, and there have been numerous reports of liver injury secondary to COVID-19 infection. It has been established that patients with pre-existing chronic liver disease (CLD) are more likely to have poorer outcomes following COVID-19 infection compared to those without CLD. Co-morbidities such as diabetes, hypertension, obesity, cardiovascular and chronic kidney disease frequently co-exist in individuals living with CLD, and a substantial population may also live with some degree of frailty. The mechanisms of how COVID-19 induces liver injury have been postulated. Hepatorenal syndrome (HRS) is the occurrence of kidney dysfunction in patients with severe CLD/fulminant liver failure in the absence of another identifiable cause, and is usually a marker of severe decompensated liver disease. Select reports of HRS following acute COVID-19 infection have been presented, although the risk factors and pathophysiological mechanisms leading to HRS in COVID-19 infection or following COVID-19 treatment remain largely unestablished due to the relative lack and novelty of published data. Evidence discussing the management of HRS in high-dependency care and intensive care contexts is only emerging. In this article, we provide an overview on the speculative pathophysiological mechanisms of COVID-19 induced HRS and propose strategies for clinical diagnosis and management to optimize outcomes in this scenario.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

Hepatology Clinical

Compared with conventional practice, ROTEM-guided blood product transfusion resulted in fewer units of platelets (0.22 I vs i 0.66 units per patient, I P i = 0.32) and cryoprecipitate (0.61 I vs i 1.24 units/patient, I P i = 0.26) per patient. Twelve patients used one drug, one patient used two drugs, four patients used three drugs, two patients used four drugs, and one patient used five drugs. B 19 b B Non-cirrhotic, non-hepatitis hepatocellular carcinoma: A case report b B M Gururatsakul b I Department of Gastroenterology and Hepatology, Chulabhorn Hospital, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand;i I Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia i B I Introduction: i b Hepatocellular carcinoma (HCC) generally develops in patients with underlying chronic liver disease, cirrhosis, chronic hepatitis B or chronic hepatitis C virus infections, or non-alcohol-associated steatohepatitis. We aimed to assess COVID-19 vaccination rates in patients with liver disease, comparing them with the general population, to identify if this was a vulnerable patient group who needed particular follow-up. B I Methods: i b We performed a cross-sectional study, collecting COVID-19 vaccination data from patients who had attended an outpatient liver clinic between 1 July 2021 and 30 September 2021. [Extracted from the article] Copyright of Journal of Gastroenterology & Hepatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

SARS-CoV-2 infection in patients with underlying chronic liver disease is associated with significantly greater risk of liver decompensation and acute on chronic liver failure

Objectives: Chronic liver disease (CLD) patients are hypothesized to have greater risks of liver decompensation following SARS-CoV-2 infection. Data evaluating COVID-19 in CLD patients remains sparse. We aim to evaluate whether SARS-CoV-2 infection in CLD patients is associated with increased risks of liver decompensation or acute on chronic liver failure (ACLF). Materials and Methods: Using the Common Data Schema from COVID-19 Research Database, a large U.S. database containing over 72 million linked patients with both electronic health records and claims data, we evaluated CLD patients with (CLD - COVID-19) vs. without COVID-19 (CLD without COVID-19). Patients had minimum 6-months follow-up until censoring event or end of study period (August 31, 2021) to evaluate incident liver decompensation (i.e. ascites, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, liver failure) and incident ACLF (EASL-CLIF definition). Outcomes were evaluated using adjusted multivariate Cox proportional hazards models. Results: Among 923,671 adults with CLD (44.7% women, 12.4% cirrhosis), 3.8% had CLD - COVID-19 and 96.3% had CLD without COVID-19. Over a median follow-up of 242-267 days, when compared to CLD without COVID-19, CLD - COVID-19 patients had significantly greater risk of liver decompensation (HR 1.22, 95% CI 1.13-1.32, p<0.001) and ACLF (HR 1.54, 95% CI 1.17-2.03, p<0.01). Among CLD patients with cirrhosis at baseline, COVID- 19 was similarly associated with higher risk of ACLF (HR 1.66, 95% CI 1.26-2.19, p<0.001). When evaluating individual organ failures in patients with ACLF, CLD - COVID-19 vs. CLD without COVID- 19 was associated with significantly greater risks of cardiovascular failure (HR 4.75, p<0.001), respiratory failure (HR 5.80, p<0.001), and renal failure (HR 3.93, p<0.001). Conclusion: Among a large U.S. cohort evaluating COVID-19 in CLD patients, SARS-CoV-2 infection was associated with significantly greater risks of liver decompensation and ACLF in patients with underlying CLD. The primary drivers of ACLF were the increased risks of cardiovascular failure, respiratory failure, and renal failure associated with COVID-19.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis

Background and aims: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Method: This prospective, open label trial randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8. SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient’s primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30, 000/mm3 on Day 8. Primary outcomewas survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Results: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC>30, 000/ mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval {CI}: 0.57–0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44–0.89];p > 0.05). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and therewere no serious adverse events attributed to pegfilgrastim. Conclusion: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.

IN-HOSPITAL CASE FATALITY RATE DUE TO MODERATE-TO-SEVERE COVID-19 IN PATIENTS WITH CIRRHOSIS: A MULTICENTER COHORT STUDY

Background: The presence of comorbidities has been associated with worse outcomes in patients with SARS-CoV2 virus infection. It has been reported that patients with cirrhosis and COVID-19 showed higher mortality rates than patients without cirrhosis. This study aims to analyze the case fatality rate (CFR) in patients with cirrhosis and COVID-19, as well as the implications that this infection has on the incidence of acute decompensations. Methods: A multicenter prospective cohort study was conducted in 13 COVID-19 centers in Mexico. Patients with cirrhosis and COVID-19 were compared with randomly selected age- and sex-matched controls with COVID-19 without cirrhosis. The characteristics and development of decompensation in patients with cirrhosis were analyzed. Results: A total of 96 patients with cirrhosis and COVID-19 and 193 controls with COVID-19 were studied. Age (56.80 vs. 56.45 years, respectively;P=0.80) and male sex proportion (65.6% vs. 65.6%, respectively;P=0.98) was comparable between the two groups. Patients with cirrhosis and COVID-19 had a higher CFR than patients without cirrhosis (29.2% versus 19.2%, respectively, P=0.05) (Figure 1). There were no differences in the use of invasive mechanical ventilation, vasopressors, or the hospitalization length. The most common decompensations were worsening ascites (43%), encephalopathy (42%), and variceal bleeding (13%). Acute kidney injury occurred in 60% of patients with cirrhosis and 30% fulfill criteria of hepatorenal syndrome. Conclusion: Cirrhosis may impose a significant death risk factor in moderateto- severe COVID-19. Moreover, COVID-19 might be an important trigger of acute decompensation of cirrhosis, which could influence short-term CFR. (Figure Presented)

THE IMPACT OF THE CORONAVIRUS PANDEMIC AND GOVERNMENT LOCKDOWNS ON LIVER DISEASE HOSPITALIZATIONS, INPATIENT MORTALITY, AND LIVER TRANSPLANT SURGERY IN CALIFORNIA: A POPULATION-LEVEL ANALYSIS

Introduction: The COVID-19 pandemic created massive disruptions in established healthcare utilization patterns. The impact of these interruptions in patients with liver diseases including cirrhosis is underreported at a population level. As such, we used a large, state-wide dataset to report inpatient liver disease outcomes during the 2020 Coronavirus pandemic using 2018 and 2019 as comparator years. Methods: Using the all-payer California State Inpatient Dataset for 2018-2020, we explored year-to-year trends, and 2020 month-to-month variations in liver-related (alcoholic liver disease, hepatocellular cancer, cirrhosis and attendant complications including hepatic encephalopathy, variceal bleeding, ascites, spontaneous bacterial peritonitis [SBP], and hepatorenal syndrome) hospitalizations, length of stay, and inpatient mortality (all-cause & viral pneumonia-specific) using joinpoin, linear, and logistic regression models. We also investigated trends in endoscopy utilization for esophageal variceal bleeding and variations in liver transplantation during the pandemic. Results: There was an increase in decompensated cirrhosis hospitalizations (264,008 in 2019 to 272,092 in 2020, p<0.001) and all-cause mortality (11.6% in 2019 to 13.8% in 2020, p<0.001). Alcoholic hepatitis and alcohol-related liver disease hospitalizations also increased in this period (ptrend<0.001) [Fig 1]. The 2020 month-to-month trend analyses showed the lowest hospitalization rates in April, coinciding with the early stages of the pandemic. This was associated with significant trend in mortality for patients with cirrhosis (ptrend<0.001) and alcoholic liver disease (ptrend=0.004) where mortality was highest in December 2020. Viral pneumonia admissions increased from 0.3% (n=940) in 2019 to 6% (n=18,544) of all hospitalizations (p<0.001) and this was associated with a significant increase in respiratory failure and death, 0% in 2019 to 1.8% in 2020 (p<0.001). Sensitivity analysis showed that decompensated cirrhosis accounted for >95% of viral pneumonia deaths in 2020 among all liver disease patients. There was no significant change in rates of liver transplant surgery during the 2020 pandemic (ptrend=0.36). In addition, endoscopic treatment for esophageal variceal bleeding within the first 24 hours of admission was not significantly different between 2019 and 2020 (44% vs 41%, p=0.65), and rates of paracentesis for SBP were also comparable (30% in 2019 vs 30.6% in 2020, p=0.07). Conclusions: The Covid-19 pandemic resulted in significant increases in hospitalization for decompensated cirrhosis and alcohol-related liver disease in California. Patients with decompensated cirrhosis accounted for the majority of viral pneumonia cases and deaths among all liver-related admissions. However, liver transplantation and endoscopy utilization rates were comparable with prepandemic numbers. (Figure Presented) Figure 1: Trends in hospitalization, length of stay, and mortality rates of liver diseases in California from 2018 to 2020(Figure Presented) Figure 2: 2020 month-to-month trends in liver-related hospitalizations and mortality in California State

A Case of MyastheniaGravis and Myositis after Immunotherapy and COVID Vaccine

Objective: To explore triple overlap syndrome and immune effects of COVID-19 vaccination. Background: Neurologic immune related adverse events (nIRAE) are potential complications of Immune Checkpoint Inhibitors (ICI). nIRAE of the Peripheral Nervous System (PNS) can present fulminantly, especially myositis, myasthenia gravis (MG), and overlap syndrome of myositis, MG, and myocarditis. Design/Methods: NA Results: 77-year old male with metastatic melanoma presented to hospital with leg weakness, hoarseness, dyspnea, and ptosis 1 week after first cycle of ipilimumab and nivolumab and 3 days after COVID-19 vaccine. He had bradycardia with heart block, and hepatorenal failure. Exam was remarkable for dysarthria, right eye ptosis, hip flexion weakness 4+/5, without fatigability. Labs showed CK 21,325, Troponin-T 4,888, Aldolase 307, AChR antibody positive, and AntiStriated Muscle Antibody 1:3840. Vital Capacity (VC) was 1.9L and Negative Inspiratory Force (NIF) -20cmH2O. Patient received BiPAP, plasmapheresis, and methylprednisolone 1000mg. After this, he developed fatigability of ocular muscles, voice, and proximal arms;VC dropped to 1.3L. He was diagnosed with triple overlap syndrome, but MG manifested after receiving first dose of high-dose steroids. Heart biopsy showed lymphohystiocytic inflammation. Muscle biopsy showed focal and dispersed lymphomononuclear cell endomysial infiltration. Electromyography demonstrated patchy myositis in lower extremities. Patient completed 3 days of high-dose steroids, 5 days of plasmapheresis, abatacept, and rituximab, followed by slow steroid taper. He did not require intubation despite tenuous respiratory status. Conclusions: nIRAE of the PNS are rare potential complications of immunotherapy, usually presenting by 6 weeks, although overlap syndrome can present hyper-acutely after 1 dose. Our patient presented 1 week after first treatment, perhaps influenced by COVID vaccine. Management of nIRAE is consensus-based, as no standard evidence-based treatment exists. Our patient was successfully treated with plasmapheresis prior to high-dose steroids (obviating steroid-induced myasthenic crisis), abatacept and rituximab. The myasthenic crisis was successfully managed with BiPAP, avoiding intubation, and he ultimately improved.

Decompensated Csirrhosis and COVID 19; Report of Two Cases.

Coronavirus disease 2019 (COVID-19) has turned to be the primary health concern worldwide and for critical patients in particular. Patients with cirrhosis may experience decompensation, as presented in the current case report. An 82-year-old man with cirrhosis was admitted for hepatorenal syndrome, and hemodialysis was initiated. Due to manifestations of COVID-19 in computed tomography (CT), the therapeutic protocols of coronavirus were initiated, and the patient was successfully rehabilitated by COVID-19 treatment and trice-a-week hemodialysis. The other case was a 59-year-old woman with cirrhosis and hematemesis, elevated creatinine, and progressive loss of consciousness. CT scan was compatible with COVID-19 confirmed by Real-time polymerase chain reaction (RT-PCR). Irresponsiveness to medical therapy led to four courses of hemodialysis. Respiratory distress led to intubation, and eventually, the cardiopulmonary arrest occurred, which led to unsuccessful cardiopulmonary resuscitation. Cirrhosis may be decompensated by COVID-19 and lead to fatal outcomes. Despite all the conventional efforts to help the patients survive, prevention from coronavirus infection remains the mainstay for patients with cirrhosis.

A case of neglected hepatorenal dysfunction during the COVID pandemic.

As the world fights with the Coronavirus, most of the hospitals are gearing up for the care of these patients. As most of the attention these days is being given on Coronavirus, the patients suffering from other clinical infections are being neglected. SARS-CoV-2 is being kept as the top differential in patients presenting with fever and respiratory distress. We hereby present a case of patient returning from Indonesia during the pandemic presenting with a history of hepatic, renal dysfunction with fever and cough. Due to the pandemic, the patient's fever and cough outweighed the hepatic and renal dysfunction, and the patient had to undergo dialysis before the final diagnosis of leptospirosis could be made.