Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.

COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms.

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.

Suspension of ulipristal acetate for uterine fibroids during ongoing EMA's review of liver injury risk: Unfortunate timing during the Covid-19 pandemic!

OBJECTIVE: EMA decided that with ulipristal acetate (UPA) treatment for uterine fibroids, should be discontinued due to the associated risk of hepatic failure, We analyzed whether the risk of recurrent symptoms due to fibroids may lead to an increased risk of Covid -19 infection and death, that would exceed the former risk of hepatic failure and transplantation. STUDY DESIGN, SIZE, DURATION: We used a Markov model to generate probabilities. PARTICIPANTS/MATERIALS, SETTING, METHODS: There are currently about 36,250 treated patients in Europe. We estimated bleeding probabilities, while using or discontinuing UPA, which may induce a need of medical or surgical management in symptomatic patients, and increase the risk of acquiring a Covid-19 infection, and die from it. We also estimated the risk of suffering a hepatic failure and hepatic transplantation. MAIN RESULTS AND THE ROLE OF CHANCE: Based on our assumptions, ceasing UPA during a Covid 19 pandemic may be associated with a fatality ratio between 4 and 18, due to the Pandemic, whereas pursuing UPA would be associated with a fatality rate due to the pandemic between 1-2, and an added fatality rate due to hepatic impairment of 1. The added risk of stopping UPA may range between 2 and 15 additional deaths. Our calculations suggest that the decision to stop UPA in the middle of the Covid- 19 pandemic may be untimely, since it may result in an increased risk of Covid-19 infection, due to the recurrence of symptoms and the need for medical and surgical treatment. WIDER IMPLICATIONS OF THE FINDINGS: A decision, like the one EMA took need to be taken in a wider health context of a population, than simply analyzing its role as regulating agent for medications.

Early experience with remdesivir in SARS-CoV-2 pneumonia.

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.

The association of hepatitis B virus screening and antiviral prophylaxis with adverse liver outcomes in Chinese cancer patients undergoing chemotherapy: A retrospective study.

Currently, the association of the initiation time of hepatitis B virus (HBV) screening and antiviral prophylaxis with adverse liver outcomes in cancer patients undergoing chemotherapy remains conflicting.This retrospective study was designed to determine the association of HBV screening and antiviral prophylaxis with adverse liver outcomes, and then proposed optimal management strategies on HBV screening and antiviral prophylaxis.We analyzed the medical data of Chinese cancer patients undergoing chemotherapy between 2000 and 2015. Descriptive statistics and Chi square tests were performed to analyze the basic characteristics of patients. Time-to-event analysis was used to determine incidence, and competing risk analysis was used to determine the hazard ratios (HRs) for outcomes.A total of 12,158 patients (81.1% with solid tumors) were analyzed. Among solid tumors patients, late screening and late antiviral therapy of chronic HBV were associated with higher incidence of hepatitis flare (HR 3.29, 95% confidence interval [CI] 2.26-4.79; HR 6.79, 95% CI 4.42-10.41), hepatic impairment (HR 2.96, 95% CI 2.03-4.32; HR 8.03, 95% CI 4.78-13.48), liver failure (HR 2.19, 95% CI 1.41-3.40; HR 14.81, 95% CI 6.57-33.42), and HBV-related death (HR 3.29, 95% CI 2.26-4.79; HR 8.30, 95% CI 4.95-13.91) in comparison with early screening and early therapy.Early HBV screening and antiviral therapy could reduce the risk of adverse liver outcomes among chronic HBV patients receiving chemotherapy. Hepatitis B surface antibody-positivity was associated with a decreased risk of liver failure and chronic HBV, late screening or late antiviral therapy were predictors of liver failure for patients with anti-tumor therapy. However, it should be applied cautiously into each types of solid tumors and hematologic malignancies because subgroup analysis according to type of cancer was not designed.

A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis.

RATIONALE: Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS: A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES: On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS: Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES: Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS: We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.

Prophylactic antiviral treatment reduces the incidence of liver failure among patients coinfected with Mycobacterium tuberculosis and hepatitis B virus.

BACKGROUND: China has a high prevalence of tuberculosis and hepatitis B virus infection. The purpose of this study was to determine whether HBV coinfection increases the risk of incidence of drug-induced hepatotoxicity among patients on anti-tuberculosis therapy. METHODS: This retrospective study was carried out at the First Affiliated Hospital, School of Medicine, Zhejiang University, from 2013 to 2017. All enrolled patients were confirmed HBsAg-positive for a duration of at least 6 months and coinfected with mycobacterium tuberculosis. RESULTS: A cohort of 90 patients was analyzed. The incidence of liver damage and liver failure was 51.11% (n = 46) and 22.22% (n = 20), respectively. By multivariate analysis, initial albumin <35 g/l (P = 0.004, odds ratio 6.162, 95% confidence interval 1.767-21.486) was an independent risk factor for liver failure, but prophylactic antiviral treatment (P < 0.001, odds ratio 0.033, 95% confidence interval 0.007-0.154) was an independent protective factor for liver failure. Of the 90 patients, 20 developed liver failure, none of the patients with liver failure received prophylactic antiviral therapy, and 6 of those patients died of liver failure. CONCLUSIONS: Prophylactic antiviral treatment reduces the incidence of liver failure in patients coinfected with Mycobacterium tuberculosis and hepatitis B virus; therefore, it is recommended that prophylactic antiviral treatment be administered while receiving anti-tuberculosis treatment in patients coinfected with Mycobacterium tuberculosis and hepatitis B virus.

Hepatotoxicity and virological breakthrough of HCV following treatment with sofosbuvir, daclatasvir, and ribavirin in patients previously treated for tuberculosis.

The prevalence of hepatitis C virus/tuberculosis (HCV/TB) coinfection has not been estimated globally but few studies highlight the risk of hepatotoxicity following TB treatment or HCV treatment. Previously reported data highlights the risk of drug-induced hepatotoxicity associated with three of the first-line anti-TB agents: rifampin, isoniazid, and pyrazinamide specifically in patients coinfected with HIV and HCV. Thus far, direct-acting antiviral (DAA) drug-induced hepatotoxicity has not been reported in the literature but herein, we observed an unusual case of HCV virological breakthrough and hepatoxicity during treatment with DAA drugs in a patient who has previously been successfully treated for TB.

Glecaprevir/pibrentasvir-associated acute liver injury in non-cirrhotic, chronic HCV infection without HBV co-infection.

The combination of glecaprevir and pibrentasvir was recently approved for chronic hepatitis C virus (HCV) infection with recommended treatment duration of 8-12 weeks depending on previous treatments, viral genotype and cirrhosis status. Although liver injury was reported with other protease inhibitors in the presence of cirrhosis or hepatitis B virus (HBV) co-infection, glecaprevir/pibrentasvir treatment is not known to cause liver injury. We report a patient with chronic HCV infection who despite the absence of cirrhosis and HBV co-infection developed acute liver injury that completely resolved after glecaprevir/pibrentasvir withdrawal. Interestingly, sustained HCV virologic response was achieved after only 3 weeks of glecaprevir/pibrentasvir treatment.

Type 3 cytokines in liver fibrosis and liver cancer.

The type 3 cytokines IL-17 and IL-22 play a crucial, well synchronized physiological role in wound healing and repairing tissue damage due to infections or injury at barrier surfaces. These cytokines act on epithelial cells to induce secretion of early immune mediators, recruitment of inflammatory cells to the site of injury, and to trigger tissue repair mechanisms. However, if the damage persists or if these cytokines are dysregulated, then they contribute to a number of inflammatory pathologies, autoimmune conditions and cancer. The liver is a multifunctional organ that plays an essential role in metabolism, detoxification, and immune surveillance. It is also exposed to a variety of pathogens, toxins and injuries. Over the past decade, IL-17 and IL-22 have been implicated in various aspects of liver inflammation. IL-17 is upregulated in chronic liver injury and associated with liver disease progression. In contrast, IL-22 was shown to be hepatoprotective during acute liver injury but exhibited inflammatory effects in other models. Furthermore, IL-22 and IL-17 are both associated with poor prognosis in liver cancer. Finally, the regulatory mechanisms governing the physiological versus the pathological role of these two cytokines during acute and chronic liver injury remain poorly understood. In this review, we will summarize the current state of knowledge about IL-17 and IL-22 in wound healing during acute and chronic liver injury, their contribution to pathogenesis, their regulation, and their role in the transition from advanced liver disease to liver cancer.

Baseline HBV load increases the risk of anti-tuberculous drug-induced hepatitis flares in patients with tuberculosis.

Hepatitis associated anti-tuberculous treatment (HATT) has been a main obstacle in managing patients co-infected with Mycobacterium tuberculosis and hepatitis B virus (HBV). Therefore, we evaluated the factors related to the severity of adverse effects during HATT, especially those associated with liver failure. A retrospective study was carried out at Tongji Hospital from 2007 to 2012. Increases in serum transaminase levels of >3, 5, and 10 times the upper limit of normal (ULN) were used to define liver damage as mild, moderate, and severe, respectively. Patients with elevated total bilirubin (TBil) levels that were more than 10 times the ULN (>171 µmol/L) with or without decreased (<40%) prothrombin activity (PTA) were diagnosed with liver failure. A cohort of 87 patients was analyzed. The incidence of liver damage and liver failure was 59.8% (n=52) and 25.3% (n=22), respectively. The following variables were correlated with the severity of hepatotoxicity: albumin (ALB) levels, PTA, platelet counts (PLT), and the use of antiretroviral therapies (P<0.05). Hypo-proteinemia and antiretroviral therapy were significantly associated with liver failure, and high viral loads were a significant risk factor with an odds ratio (OR) of 2.066. Judicious follow-up of clinical conditions, liver function tests, and coagulation function, especially in patients with high HBV loads and hypoalbuminemia is recommended. It may be advisable to reconsider the use of antiviral drugs failure during the course of anti-tuberculous treatment of HBV infection patients to avoid the occurrence of furious liver failure.

Risk factors for damaged liver function after chemotherapy in hepatitis B virus carriers with non-Hodgkin lymphoma.

The goal of this study was to investigate damaged liver function after chemotherapy in hepatitis B virus (HBV) carriers with non-Hodgkin lymphoma (NHL) and to evaluate risk factors associated with a high risk of damaged liver function. Clinical histories of 134 HBV carriers with NHL who were treated with chemotherapy were obtained and analyzed for the occurrence of damaged liver function and other related high-risk factors. Analysis showed that 76 patients (56.7%) had damaged liver function after chemotherapy: 6 patients (7.9%) had I degree, 17 patients (22.4%) had II degree, 20 patients (26.3%) had III degree, and 33 patients (43.4%) had IV degree damage. After treatment, 18 patients (23.7%) continued to receive chemotherapy according to their original schedule, 39 patients (51.3%) delayed chemotherapy, 16 patients (21.1%) stopped chemotherapy, and 3 patients (3.9%) died. Analysis of a binary multivariate logistic regression model showed that administration of steroids was a high-risk factor for damaged liver function after chemotherapy in NHL patients. The incidence of damaged liver function after chemotherapy is high among HBV carriers with NHL; therefore, administration of steroid chemotherapy is a high-risk factor.

The effectiveness of risk communication regarding drug safety information: a nationwide survey by the Japanese public health insurance claims data.

WHAT IS KNOWN AND OBJECTIVE: We evaluated the effectiveness of warning letters published by the pharmaceutical regulatory agency in Japan on communication of drug safety and risk by quantitative analysis of the national health insurance claims database (NHICD). We then explored what factors may have affected risk communication. METHODS: We measured the implementation rate of the hepatitis virus-monitoring test among methotrexate (MTX)-treated patients; a warning letter had been issued regarding the use of MTX, as it apparently activates the hepatitis virus. Data from the NHICD, which include 99·3% of Japanese residents, were used. A total of 4,933,481 patients with rheumatoid arthritis (RA) (January-June, 2010) were the focus of this study. RESULTS: The implementation rate of the hepatitis virus-monitoring test increased from 1·4% before to 1·8% after the warning letter announcement. Logistic regression analysis suggested that the installation of a drug information management room is one of the important factors affecting risk communication. Further analysis revealed that the hepatitis virus monitoring rates in hospitals without drug information management rooms increased from 2·3% to 4·1% due to the issue of the warning letter. WHAT IS NEW AND CONCLUSION: The warning letter from the regulatory agency plays an important role in risk communication in hospitals without drug information management rooms.

Tuberculosis and hepatic steatosis are prevalent liver pathology findings among HIV-infected patients in South Africa.

Liver disease epidemiology in sub-Saharan Africa has shifted as a result of HIV and the increased use of antiretroviral therapy leading to a need for updated data on common causes of liver disease. We retrospectively reviewed records from all hospitalized patients who had liver biopsy at a single hospital in South Africa from 2001 to 2009 and compared diagnosis by HIV status. During the period of study 262 patients had liver biopsy, 108 (41%) were HIV-infected, 25 (10%) were HIV-sero-negative, and 129 (49%) had unknown or unrecorded HIV status. Overall 81% of biopsies provided additional diagnostic data. Malignancy was the most common finding reported on 56 (21%) biopsies followed by granuloma or TB, hepatic steatosis, and fibrosis or cirrhosis. HIV-infected patients were more likely to have granulomas and steatosis. Half of patients with granulomas were already on TB treatment, suggesting paradoxical reactions or drug induced liver injury may have been important causes of liver inflammation among these patients. We note that TB, paradoxical reactions during TB treatment, possible drug induced liver injury, and hepatic steatosis are important causes of liver pathology among HIV-infected hospitalized patients with unclear etiology of liver disease after initial assessment. Among HIV sero-negative patients, malignancy was the major cause of liver disease. Our findings re-enforce the importance of TB as a diagnosis among HIV-infected individuals.

The impact of HBV or HCV infection in a cohort of HIV-infected pregnant women receiving a nevirapine-based antiretroviral regimen in Malawi.

BACKGROUND: Coinfection with the hepatitis viruses is common in the HIV population in sub-Saharan Africa. The aim of this study was to assess, in a cohort of HIV-infected pregnant women receiving antiretroviral drugs (ARVs), the prevalence of HBV and HCV infections and to determine the impact of these infections on the occurrence of liver toxicity and on the viro-immunological response. METHODS: Women were screened for HBsAg and HCV-RNA before starting, at week 25 of gestational age, an antiretroviral regimen consisting of lamivudine and nevirapine plus either stavudine or zidovudine. Women with CD4+ < 350/mm3 continued ARVs indefinitely, while the other women interrupted treatment 6 months postpartum (end of breastfeeding period). Both groups were followed for 2 years after delivery. Liver function was monitored by alanine aminotransferase (ALT) measurement. The Cox proportional hazards model was used to identify factors associated with the emergence of liver toxicity. RESULTS: A total of 28 women out of the 309 enrolled in the study (9.1%) were coinfected with HBV (n. 27), or HCV (n. 1). During follow-up 125 women (40.4%) developed a grade ≥ 1 ALT elevation, 28 (9.1%) a grade ≥ 2 and 6 (1.9%) an elevation defining grade 3 toxicity. In a multivariate model including age, baseline CD4+ count and hemoglobin level, the presence of either HBV or HCV infection was significantly associated with the development of an ALT increase of any grade (P = 0.035). Moderate or severe liver laboratory toxicity (grade ≥ 2) was more frequent among women with baseline CD4+ > 250/mm3 (P = 0.030). In HBV-infected women a baseline HBV-DNA level above 10,000 IU/ml was significantly associated to the development of liver toxicity of grade ≥ 1 (P = 0.040). Coinfections had no impact on the immunological and virological response to antiretroviral drugs up to 2 years after delivery. CONCLUSIONS: In this cohort of nevirapine-treated women the presence of HBV or HCV was associated only to the development of mild liver toxicity, while the occurrence of moderate or severe hepatoxicity was correlated to a baseline CD4+ count > 250/mm3. No statistically significant effect of the coinfections was observed on the efficacy of antiretroviral therapy.

Drug-induced severe adverse reaction enhanced by human herpes virus-6 reactivation.

Reactivation of certain latent viruses has been linked with a more severe course of drug-induced hypersensitivity reaction (HSR). For example, reactivation of human herpes virus (HHV)-6 is associated with severe organ involvement and a prolonged course of disease. The present study discusses an HSR developed in a previously healthy male exposed to ceftriaxone, doxycycline, vancomycin, and trimethoprim/sulfamethoxazole (co-trimoxazole; TMP/SMX). Initially, the patient presented clinical manifestations of HSR, as well as clinical and laboratory measurements compatible with liver and renal failure. Moreover, the patient presented skin desquamation compatible with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis. During the reaction, it was observed HHV-6 reactivation. The severity of clinical symptoms is correlated with HHV-6 titer, as well as with results of the in vitro lymphocyte toxicity assay (LTA). Serum levels of a large panel of cytokines are compared between the patient, a large population of SJS patients, and a cohort of healthy controls, using data collected by our laboratory over the years. HHV-6 was measured in the cell culture media from lymphocytes incubated with each of the 4 drugs. Moreover, we describe a new assay using cytokines released by patient lymphocytes following in vitro exposure to the incriminated drugs as biomarkers of HSR. Based on LTA results, HHV-6 reactivation and cytokine measurements, we establish that only doxycycline and TMP/SMX were involved in the HSR. As result of this analysis, the patient could continue to use the other 2 antibiotics safely.

[Acute toxic dystrophy of the liver during antituberculosis therapy].

The paper considers a case of acute toxic dystrophy of the liver developing as a manifestation of an idiosyncratic dose-independent unpredictable reaction during standard antituberculosis therapy. The process of liver damage was fulminant with massive diffuse centrilobular necroses, lymphoid-eosinophilic infiltration in the portal tracts, and the development of liver failure.

Nevirapine- and efavirenz-associated hepatotoxicity under programmatic conditions in Kenya and Mozambique.

To describe the frequency, risk factors, and clinical signs and symptoms associated with hepatotoxicity (HT) in patients on nevirapine- or efavirenz-based antiretroviral therapy (ART), we conducted a retrospective cohort analysis of patients attending the ART clinic in Kibera, Kenya, from April 2003 to December 2006 and in Mavalane, Mozambique, from December 2002 to March 2007. Data were collected on 5832 HIV-positive individuals who had initiated nevirapine- or efavirenz-based ART. Median baseline CD4+ count was 125 cells/µL (interquartile range [IQR] 55-196). Over a median follow-up time of 426 (IQR 147-693) days, 124 (2.4%) patients developed HT. Forty-one (54.7%) of 75 patients with grade 3 HT compared with 21 (80.8%) of 26 with grade 4 had associated clinical signs or symptoms (P = 0.018). Four (5.7%) of 124 patients with HT died in the first six months compared with 271 (5.3%) of 5159 patients who did not develop HT (P = 0.315). The proportion of patients developing HT was low and HT was not associated with increased mortality. Clinical signs and symptoms identified 50% of grade 3 HT and most cases of grade 4 HT. This suggests that in settings where alanine aminotransferase measurement is not feasible, nevirapine- and efavirenz-based ART may be given safely without laboratory monitoring.