Elevated Aminotransferase Levels Research Articles

Severe liver dysfunction complicating course of COVID-19 in the critically ill: multifactorial cause or direct viral effect?

BackgroundSARS-CoV-2 caused a pandemic and global threat for human health. Presence of liver injury was commonly reported in patients with coronavirus disease 2019 (COVID-19). However, reports on severe liver dysfunction (SLD) in critically ill with COVID-19 are lacking. We evaluated the occurrence, clinical characteristics and outcome of SLD in critically ill patients with COVID-19.MethodsClinical course and laboratory was analyzed from all patients with confirmed COVID-19 admitted to ICU of the university hospital. SLD was defined as: bilirubin ≥ 2 mg/dl or elevation of aminotransferase levels (> 20-fold ULN).Results72 critically ill patients were identified, 22 (31%) patients developed SLD. Presenting characteristics including age, gender, comorbidities as well as clinical presentation regarding COVID-19 overlapped substantially in both groups. Patients with SLD had more severe respiratory failure (paO2/FiO2: 82 (58–114) vs. 117 (83–155); p < 0.05). Thus, required more frequently mechanical ventilation (95% vs. 64%; p < 0.01), rescue therapies (ECMO) (27% vs. 12%; p = 0.106), vasopressor (95% vs. 72%; p < 0.05) and renal replacement therapy (86% vs. 30%; p < 0.001). Severity of illness was significantly higher (SAPS II: 48 (39–52) vs. 40 (32–45); p < 0.01). Patients with SLD and without presented viremic during ICU stay in 68% and 34%, respectively (p = 0.002). Occurrence of SLD was independently associated with presence of viremia [OR 6.359; 95% CI 1.336–30.253; p < 0.05] and severity of illness (SAPS II) [OR 1.078; 95% CI 1.004–1.157; p < 0.05]. Mortality was high in patients with SLD compared to other patients (68% vs. 16%, p < 0.001). After adjustment for confounders, SLD was independently associated with mortality [HR3.347; 95% CI 1.401–7.999; p < 0.01].ConclusionOne-third of critically ill patients with COVID-19 suffer from SLD, which is associated with high mortality. Occurrence of viremia and severity of illness seem to contribute to occurrence of SLD and underline the multifactorial cause.

An Experimental DUAL Model of Advanced Liver Damage.

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.

Enoxaparin-induced hepatotoxicity: clinical cases and literature review

Low molecular weight heparins, in particular enoxaparin, have a wide range of applications, including prevention and treatment of deep vein thrombosis. The most common adverse effects of these drugs are bleeding and thrombocytopenia, but a clinician should be aware of another less common but not less important adverse effect such as an elevated transaminase level. In 2019, we observed two cases of enoxaparin-induced hepatotoxicity. In the first one, enoxaparin 0.4 ml subcutaneously twice a day was prescribed to a 40-year-old woman as a bridge therapy to discontinue warfarin before elective surgery. In the second case, a 27-year-old man received enoxaparin 0.4 ml subcutaneously twice a day for the prevention of deep vein thrombosis. The elevation of transaminase level for more than 3 times above the norm was noted in both patients which required discontinuation of the drug.

A216 CLINICAL MANIFESTATIONS OF LYSOSOMAL ACID LIPASE DEFICIENCY (LAL-D): THE INTERNATIONAL LAL-D REGISTRY

Abstract Background Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease caused by pathogenic variants in the LIPA gene. Lysosomal accumulation of cholesteryl esters and triglycerides leads to cirrhosis and dyslipidemia across a clinical spectrum, and affect both infants and children/adults. Aims An international registry (NCT01633489; Alexion Pharmaceuticals, Inc.; 2013–ongoing) was established to better understand the natural history of lysosomal acid lipase deficiency (LAL-D) and to evaluate long-term treatment outcomes. Methods Baseline findings for patients enrolled through July 1, 2019 are presented. Of 190 patients enrolled, 35 were excluded from this analysis (LIPA carrier, deceased at enrollment, unconfirmed LAL-D diagnosis); 155 patients with confirmed LAL-D diagnosis were included (12 infants, 143 children/adults). LAL enzyme activity analysis was performed for 145/154 patients (94%) and genetic testing for 128/154 patients (83%). Results Of 105 children/adults with reported LIPA mutations, 39 were homozygous and 34 were compound heterozygous for the common LIPA mutation E8SJM (c.894G&amp;gt;A); 6 infants with reported LIPA mutations were homozygotes and 2 were compound heterozygotes. Of the 155 patients, 62% were &amp;lt;18 years, 52% were male, and 85% were white. Median (range) age at clinical onset was 0.2 years (0.0–0.7) among infants and 6.0 years (0.0–41.3) among 133 children/adults with data; median (range) age at diagnosis was 0.2 years (−0.1 to 1.2) among infants and 10.8 years (0.2–53.6) among 135 children/adults with data. Manifestations that raised suspicion of LAL-D were reported in 149/155 patients. Infants (12 with data) presented predominantly with hepatomegaly (75%), splenomegaly (58%), nausea/vomiting (58%), and diarrhea (50%), and 50% had a known family history of LAL-D. Children/adults (n=143) presented predominantly with elevated alanine aminotransferase levels (67%), hepatomegaly (66%), and elevated aspartate aminotransferase levels (65%). Of 74 children/adults with baseline liver biopsy, 58% had microvesicular steatosis, 16% had micro- and macrovesicular steatosis, and 32% had lobular inflammation. Of the 155 patients, 6% had a medical history of cirrhosis. Analyses exploring the genotype-phenotype relationship will be presented. Conclusions Registry data of &amp;gt;150 LAL-D patients demonstrate early symptom onset, variable clinical manifestations, and a significant diagnostic delay in children/adults. Funding Agencies Alexion Pharmaceuticals, Inc.

Chrysene, a four-ring polycyclic aromatic hydrocarbon, induces hepatotoxicity in mice by activation of the aryl hydrocarbon receptor (AhR)

Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic global environmental pollutants and cause harmful effects on human health. Here, we evaluated adverse effects of chrysene, which is a four-ring PAH and an important member of 16 priority PAHs, on the liver. Chrysene was detected in some common raw and cooked Chinese food samples. Hepatotoxicity including increased relative liver weight, hepatocyte swelling and degeneration, and elevated serum alanine aminotransferase (ALT) levels were observed in chrysene-exposed C57BL/6 mice. Glutamine treatment effectively ameliorated chrysene-induced mice liver injury by decreasing serum ALT levels. Chrysene induced mice hepatic glutathione depletion and oxidative DNA damage with increased 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. Hepatic expression levels of the aryl hydrocarbon receptor (AhR), AhR-related target genes including CYP1A1, CYP1A2 and CYP1B1, and AhR nuclear translocator (ARNT) were significantly increased in chrysene-exposed C57BL/6 mice. Chrysene induced mice hepatic mRNA levels of the nuclear factor erythroid 2–related factor 2 (Nrf2) and Nrf2-mediated phase II detoxifying and antioxidant enzymes including NQO1, UGT1A1, UGT1A6, SULT1A1, GSTm1, GSTm3, Catalase (CAT), GPx1, and SOD2. We found that chrysene had toxic effects including increased relative liver weight and elevated serum ALT levels on AhR+/+ mice but not AhR−/- mice. Chrysene significantly induced hepatic mRNA levels of CYP1A1 and CYP1A2 in AhR+/+ mice but not AhR−/- mice. To our knowledge, this study is the first to demonstrate that hepatotoxicity causes by chrysene is dependent on AhR, and Nrf2 plays an important regulation role in protection against oxidative liver injury induced by chrysene.

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. Preterm neonates (≤37weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. Intravenous acetaminophen at 15mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Scrub typhus-related hepatotoxicity: The Indian scenario.

In Scrunb Typhus, hepatotoxicity is an important, yet understudied, manifestation. We reviewed studies on scrub typhus, published in the last five years (2014-2019), which evaluated its clinico-epidemiological factors in India, and concentrated on its hepatic involvement. Nine studies were found, and no Indian study exclusively evaluated hepatic dysfunction. Thus, comments from a few international studies were also included. We conclude that liver dysfunction in the form of elevated serum transaminase levels is a common manifestation of scrub typhus, which may herald progress to fulminant hepatic failure.

Albendazole-Induced Liver Injury.

Albendazole is an anthelmintic drug used worldwide for prophylactic or curative treatment. Side effects include diarrhea, abdominal pain, elevated levels of hepatic transaminases, dizziness, neutropenia, and alopecia. The main question of the systematic review is if albendazole administration can cause liver injury or liver failure. Two researchers conducted the search on PubMed and the key words used were: "albendazole," "anthelmintic," "drug-induced liver injury," and "acute hepatitis." Two new case reports were included in the systematic review. Literature search concluded in 10 cases listed on PubMed. Another 2 new case reports from our experience are included in the systematic review. Most common symptoms presented are jaundice, anorexia, and vomiting after the single-use of albendazole or long-term usage. All cases presented high levels of transaminases, with remission after stopping the administration of albendazole. The treatment with albendazole was mostly given for liver hydatid cysts or empirically. Albendazole is a prescription-based drug used by most patients without medical advice, without knowing the risk of side effects. The anthelmintic drug may induce liver injury, even in small doses; in result, practitioners and patients should take this information in consideration.

Liver injury predicts overall mortality in severe COVID-19: a prospective multicenter study in Brazil.

Background/purposeThe relationship between liver injury and mortality remains unclear in patients with COVID-19. We aimed to evaluate the prognostic value of aminotransferases levels at hospital admission to predict mortality in patients with COVID-19.Methods and resultsThis prospective study included 406 patients [57% male, aged 56 years] with COVID-19 hospitalized in 26 centers in Brazil. Overall, 36.7% (95% CI 32.1–41.5) presented at admission with severe disease requiring respiratory support. The prevalence of elevated ALT and AST levels at admission [> 2 × ULN] was 14.0% (95% CI 11.0–17.8) and 12.9% (95% CI 10.0–16.6), respectively. Sixty-two patients [15.3% (95% CI 12.1–19.1)] died during hospitalization and the overall mortality rate was 13.4 (10.5–17.2) deaths per 1000 persons-years. The 15-day-overall survival (95% CI) was significantly lower in patients with ALT levels ≥ 2 × ULN compared to those with ALT < 2 × ULN [67.1% (48.4–80.2) vs 83.4% (76.1–88.6), p = 0.001] and in those with AST levels ≥ 2 × ULN compared to those with AST < 2 × ULN [61.5% (44.7–74.6) vs 84.2% (76.5–89.5), p < 0.001]. The presence of elevated aminotransferases levels at hospital admission significantly increased the risk of in-hospital all-cause mortality adjusted for age-and-sex. Those findings were present in the subgroup of critically ill patients already admitted in need of respiratory support (n = 149), but not in patients without that requirement at admission (n = 257).ConclusionsElevated aminotransferases at hospital admission predicted in-hospital all-cause mortality in patients with COVID-19, especially in those with severe disease. Measurement of transaminases levels at hospital admission should be integrated to the care of patients with COVID-19 as an auxiliary strategy to identify patients at higher death risk.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12072-021-10141-6.

Serum Immunoglobulin G Levels Predict Biochemical and Histological Remission of Autoimmune Hepatitis Type 1: A Single-Center Experience and Literature Review.

Autoimmune hepatitis (AIH) is characterized by interface hepatitis, elevated serum alanine aminotransferase and aspartate aminotransferase levels, circulating autoantibodies, and elevated predominantly immunoglobulin G (IgG)levels. The goal in the treatment of autoimmune hepatitis (AIH) is complete disease remission. Here we took advantage of a large cohort of AIH patients to clarify predictors associated with biochemical and histological remission. Of 705 patients with complete follow-up, 569 (80.7%) patientsachieved complete biochemical remission. Lower IgG levels (17.8 vs. 25g/L, p < 0.001) and less liver cirrhosis (19.3% vs. 33.1%, p < 0.001) at diagnosis were observed in these patients. They also had lower serum IgG levels (13 vs. 18.9g/L, p < 0.001) after 3 months of treatment. Histological remission was achieved in 69.4% of 160 patients with complete biochemical remission after 3 years of treatment. Patients with histological remission had lower IgG levels (16.2 vs. 20.1g/L, p = 0.006) and Ishak fibrosis scores (3.4 vs. 4.1, p = 0.010) at diagnosis, and they appeared to achieve biochemical remission more rapidly (1 vs. 3months, p < 0.001). Of note, patients with histological remission had higher frequency of fibrosis regression than those with persisting histological activity (87.5% vs. 60%, p = 0.004). In conclusion, lower serum IgG levels, less fibrosis in liver histology at diagnosis, and rapid response to immunosuppressive therapy are reliable predictors of biochemical and histological remission. Our study underscores the importance of early diagnosis and appropriate treatment.

Risk and Protective Factors Associated with Daytime Sleepiness in Patients Diagnosed with Hepatitis B or Hepatitis C Infection

Background: Poor sleep quality and daytime fatigue are common features of chronic hepatitis. Objectives: To evaluate the association between daytime sleepiness and hepatitis and to identify factors that contribute to daytime sleepiness in patients with hepatitis B and those with hepatitis C. Methods: In this prospective cross-sectional pilot study, outpatients with fatigue who did not receive any treatment for hepatitis were recruited from the Department of Gastroenterology and Hepatology and were classified into 5 groups of hepatitis B, hepatitis C, hepatitis B + C, other hepatitis types, and without hepatitis (controls). Gastroesophageal reflux and daytime sleepiness were determined based on two self-reported questionnaires, and linear and logistic regression analyses were performed. Results: In total 42 subjects had hepatitis B, 62 had hepatitis C, 9 had hepatitis B + C, 4 had other hepatitis types, and 14 had no hepatitis. Of them, 38 (29.01%) had gastroesophageal reflux (GERDQ score ≥ 12), and 13 (9.92%) had daytime sleepiness (ESS score ≥ 8). Hepatitis B patients with gastroesophageal reflux had significantly higher odds of daytime sleepiness [odds ratio (OR) = 12.44, 95% confidence interval (CI) = 1.59 - 261.02]. In hepatitis C patients, hypertension was significantly associated with daytime sleepiness (OR = 15.6, 95% CI = 2.13 - 143.21), while those with taller body height and elevated serum glutamic-oxaloacetic transaminase (GOT) levels had significantly lower odds of daytime sleepiness (body height: OR = 0.81, 95% CI = 0.65 - 0.93; GOT: OR = 0.76, 95% CI = 0.55 - 0.95). Conclusions: Gastroesophageal reflux is a risk factor for daytime sleepiness in hepatitis B patients. In hepatitis C patients, hypertension is a risk factor, while taller body height and elevated serum GOT are protective factors for daytime sleepiness.

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice.

Simple SummaryAspartame is an artificial sweetener used in foods and beverages worldwide to prevent increasing obesity and diabetes mellitus, acting as a tool to help the control of caloric intake. However, its chronic intake is controversial since it has been linked to some adverse effects including oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. Thus, this work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Aspartame generated liver injury and fibrosis. It also decreased the activity of antioxidant enzymes and increased the levels of lipid peroxidation, thus, probably, triggering inflammation and cell death through the induction of protein 53 (p53). Finally, via p53 activation, aspartame inhibited a transcriptional coactivator, the peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a master regulator of glucose and lipid metabolism, probably leading to changes in lipid profile in serum, total lipid accumulation, as well as an impairment in the gluconeogenesis in mouse liver, thus causing hypoglycemia. Therefore, this study provides new insights to understand the mechanisms related to aspartame-linked adverse effects, showing that its intake should be cautioned.Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

A longitudinal observational study in two cats naturally-infected with hepadnavirus

Hepatitis B virus (HBV) is a major cause of liver disease in humans including chronic hepatitis and hepatocellular carcinoma. Domestic cat hepadnavirus (DCH), a novel HBV-like hepadnavirus, was identified in domestic cats in 2018. From 6.5 %–10.8 % of pet cats are viremic for DCH and altered serological markers suggestive of liver damage have been identified in 50 % of DCH-infected cats. DCH DNA has been detected in association with characteristic lesions of chronic hepatitis and with hepatocellular carcinoma in cats, suggesting a possible association. In this study longitudinal molecular screening of cats infected with DCH was performed to determine if DCH can cause chronic infections in cats. Upon re-testing of sera from five DCH-positive animals, 2–10 months after the initial diagnosis, three cats tested negative for DCH on two consecutive occasions using quantitative PCR. Two other cats remained DCH-positive, including an 8-month-old female cat re-tested four months after the initial positive result, and a 9-year-old male cat, which tested positive for DCH on six occasions over an 11-month period. The latter had a history of chronic hepatopathy with jaundice, lethargy and elevated serum alanine transaminase levels (ALT). During the period of observation, DCH titers ranged between 1.64 × 105 and 2.09 × 106 DNA copies/mL and ALT was persistently elevated, suggesting chronic infection. DCH DNA was not detected in oral, conjunctival, preputial and rectal swabs from the two animals collected at several time points. Long-term (chronic) infection would be consistent with the relatively high number of viremic cats identified in epidemiological investigations, with the possible association of DCH with chronic hepatic pathologies and with what described with HBV in human patients.

Prevalence and risk factors of metabolic associated fatty liver disease among people living with HIV in China.

The new definition for metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD), would undoubtedly have significant influence on diagnosis, epidemiology, and new drug research. We investigated the prevalence and risk factors of MAFLD among people living with HIV (PLWH). In this cross-sectional study, transient elastography was performed in PLWH without significant alcohol intake and hepatitis B virus and hepatitis C virus infection. NAFLD was diagnosed as controlled attenuation parameter (CAP)≥248dB/m by transient elastography, and MAFLD was defined according to the 2020 international consensus. Advanced fibrosis was defined as liver stiffness measurement (LSM)≥10kPa. Among the 361 PLWH enrolled, the prevalence of NAFLD and MAFLD were 37.67% and 34.90%, respectively. Compared with the non-MAFLD group, the prevalence of elevated alanine aminotransferase (ALT) level (44.44% vs 16.17%, P<0.001) and advanced fibrosis (19.05% vs 2.55%, P<0.001) were significantly higher in the MAFLD group. A positive correlation between LSM and CAP values was found in the MAFLD group (rs =0.350, P<0.001) but not in the non-MAFLD group. In multivariate analysis, independent risk predictors for MAFLD were higher ALT level (odds ratio [OR] 1.015, 95% confidence interval [CI] 1.003-1.028, P=0.018), higher uric acid (OR 1.005, 95% CI 1.002-1.009, P=0.003), higher total cholesterol (OR 1.406, 95% CI 1.029-1.921, P=0.032), and greater waist-height ratio (OR 1.291, 95% CI 1.196-1.393, P<0.001). A third of PLWH had MAFLD, which was highly accordant with the prevalence of NAFLD. Routine screening for MAFLD is necessary in PLWH.

Cytokine-induced liver injury in coronavirus disease-2019 (COVID-19): untangling the knots.

Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus disease-2019 (COVID-19) infection. The mechanism of liver injury in COVID-19 infection is unclear. However, it has been hypothesized to be a result of direct cytopathic effects of the virus, immune dysfunction and cytokine storm-related multiorgan damage, hypoxia-reperfusion injury and idiosyncratic drug-induced liver injury due to medications used in the management of COVID-19. The favored hypothesis regarding the pathophysiology of liver injury in the setting of COVID-19 is cytokine storm, an aberrant and unabated inflammatory response leading to hyperproduction of cytokines. In the current review, we have summarized the potential pathophysiologic mechanisms of cytokine-induced liver injury based on the reported literature.

Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis

PurposeEndometriosis is a common, chronic gynecological disease that affects women’s fertility potential. Dydrogesterone is an effective and safe drug that is under-utilized due to limited clinical research. The purpose of this evidence mapping is to identify, describe, and analyze the current available evidence regarding dydrogesterone for the treatment of endometriosis.Materials and methodsWe performed a search in electronic databases: Medline, The Cochrane Library, EMBASE, PubMed, CNKI, Wanfang, VIP, and CBM. We also hand-searched google for relevant studies. Our primary outcomes included changes in pain relief including pelvic pain, dysmenorrhea, and dyspareunia. Secondary outcomes included pregnancy rate, frequency of analgesic use, and other reported outcomes according to specific settings in the studies.ResultsOf 377 references screened, 19 studies were included in the data synthesis involving 1709 female participants. Nearly three-quarters were either randomized control trials or clinical control trials. Compared with gestrinone, dydrogesterone relieved dysmenorrhea, increased the pregnancy rate, and reduced the risk of certain adverse events. Compared with GnRH-a, dydrogesterone also lowered the risk of endometriosis recurrence and elevated transaminase levels. Whether there was any difference in efficacy between dydrogesterone and leuprolide acetate, letrozole or traditional Chinese medicine remains unclear due to insufficient data.ConclusionsThe amount and quality of evidence evaluating the effects of dydrogesterone for the treatment of endometriosis is generally very low. Limited evidence suggests that dydrogesterone may have some advantages over gestrinone, GnRH agonists, and other therapeutic interventions in treating endometriosis. However, this conclusion should be interpreted with caution.

Retrospective study of factors associated with progression and remission/regression of diabetic kidney disease-hypomagnesemia was associated with progression and elevated serum alanine aminotransferase levels were associated with remission or regression.

This study was aimed at retrospectively investigating some common clinical factors, including the serum level of magnesium (Mg), associated with progression and remission/regression of diabetic kidney disease (DKD). The subjects were 690 Japanese patients with type 2 diabetes mellitus who were receiving treatment with oral antidiabetic drugs other than SGLT2 inhibitors. Routine clinical data were collected on the first and last day of the observation period. The prognosis of DKD is categorized into four stages according to the Kidney Disease Improving Global Outcomes classification. Progression was defined as transition from any of the lower three risk categories (LR, MIR, HR) at the start of the observation period, to the VHR stage/category at the end of the observation period. Remission/regression was defined as improvement of the risk category by at least one stage from the start to the end of the observation period. Factors associated with progression and regression/remission were investigated using Cox proportional hazards analysis. Furthermore, the factors associated with the annual decrease in eGFR of 5ml/min/1.73m2 or more were examined by logistic regression analysis. Factors associated with transition of urinary protein negative to trace or positive, or transition of negative or trace to positive, were investigated by Cox proportional hazard analysis. The observation period was 2251 ± 1614days. Age (Exp [B] = 1.10, 95% CI; 1.06-1.14; P < 0.01; 1year old), serum Mg (Exp [B] = 0.82, 95% CI; 0.71-0.95; P < 0.01); 0.1mg/dl), and serum HbA1c (Exp [B] = 1.03, 95% CI; 1.01-1.05; P < 0.01: 0.1%) were associated with progression of DKD; on the other hand, serum ALT was associated with the likelihood of remission/regression of DKD (Exp [B] = 1.01, 95% CI; 1.002-1.018; P < 0.05; 1IU/L). The decline in eGFR was associated with higher HbA1c levels, hypomagnesemia, and lower ALT. The new appearance of trace or overt proteinuria was correlated with higher HbA1c levels, advancing age, hypomagnesemia and hypertriglycemia. Our findings confirmed previous reports that advancing age and serum HbA1c levels were associated with an increased risk of progression of DKD. Lower serum Mg concentrations were also found to be associated with a high risk of progression of DKD, and interventional studies are needed to confirm a causal relationship. Elevated HbA1c levels and hypomagnesemia were common factors in the decline in eGFR and the appearance of trace or overt proteinuria. Lower serum ALT levels were associated with the decline in eGFR. Since serum ALT is known to decrease as the renal function deteriorates, serum ALT is considered to be a marker of renal function. The online version contains supplementary material available at 10.1007/s13340-020-00483-1.

Impact of Liver Test Abnormalities and Chronic Liver Disease on the Clinical Outcomes of Patients Hospitalized with COVID-19

Background and Aims: The impact of SARS-CoV-2 infection on the liver and the possibility of chronic liver disease (CLD) as a risk factor for COVID-19 severity is not fully understood. Our goal was to describe clinical outcomes of COVID-19 inpatients regarding the presence of abnormal liver tests and CLD. Methods: A retrospective analysis of patients with SARS-CoV-2 infection, hospitalized in a tertiary center in Portugal, was performed. Studied outcomes were disease and hospitalization length, COVID-19 severity, admission to intensive care unit (ICU) and mortality, analyzed by the presence of abnormal liver tests and CLD. Results: We included 317 inpatients with a mean age of 70.4 years, 50.5% males. COVID-19 severity was moderate to severe in 57.4% and critical in 12.9%. The mean disease length was 37.8 days, the median hospitalization duration 10.0 days and overall mortality 22.8%. At admission, 50.3% showed abnormal liver tests, and 41.5% showed elevated aminotransferase levels, from which 75.4% were mild. Elevated aminotransferase levels at admission were associated with COVID-19 severity (78.7 vs. 63.3%, p = 0.01), ICU admission (13.1 vs. 5.92%, p = 0.034) and increased mortality (25.8 vs. 13.3%, p = 0.007). However, in a subgroup analysis, only aspartate transaminase (AST) was associated with these worse outcomes. Alkaline phosphatase was elevated in 11.4% of the patients and was associated with critical COVID-19 (21.1 vs. 9.92%, p = 0.044) and mortality (20.4 vs. 9.52%, p = 0.025), while 24.6% of the patients showed elevated γ-glutamyl transferase, which was associated with ICU admission (42.3 vs. 22.8%, p = 0.028). Fourteen patients had baseline CLD (4.42%), 3 with liver cirrhosis. Alcohol (n = 6) and nonalcoholic fatty liver disease (n = 6) were the most frequent etiologies. CLD patients had critical COVID-19 in 21.4% (p = 0.237), mean disease length of 36.6 days (p = 0.291), median hospitalization duration of 11.5 days (p = 0.447) and a mortality rate of 28.6% (p = 0.595), which increased to 66.7% among cirrhotic patients (p = 0.176). Conclusions: Liver test abnormalities in COVID-19 patients were frequent but most commonly mild. AST, but not alanine transaminase, was associated with worse clinical outcomes, such as COVID-19 severity and mortality, probably indicating these outcomes were independent of liver injury. A low prevalence of CLD was seen, and a clear impact on COVID-19 outcomes was not seen.

Experiences in outpatient parenteral antimicrobial therapy (OPAT): Barriers and challenges from the front lines.

Outpatient parenteral antimicrobial therapy (OPAT) is now the standard of care for managing patients who no longer need inpatient care but require prolonged intravenous antimicrobial therapy. OPAT increases patient satisfaction, reduces the lengths of hospital stay, lowers emergency department readmission rates, and decreases total healthcare spending. To investigate Virginia Commonwealth University Health System's experience with OPAT and to highlight the obstacles patients and clinicians face when navigating and utilizing this program. We conducted this descriptive study at a large, academic, tertiary-care hospital in Central Virginia. We performed manual reviews of electronic medical records of 602 patient, and we evaluated the records of those receiving OPAT between 2017 and 2020. Reviews included antimicrobial agents, diagnoses requiring OPAT, adverse effects related to antimicrobials, adverse effects related to peripherally inserted central catheters (PICC), readmission rate, discharge destination, and death. We evaluated our program with descriptive statistics. Among 602 patients who received OPAT, most were diagnosed with bacteremia or musculoskeletal infections. Patients were either discharged home or to another healthcare facility, with the former comprising most of the rehospitalizations. Ertapenem and vancomycin were associated with the most adverse drug events among our cohort. Elevated transaminase levels were noted in 23% of patients. The rate of PICC-line adverse events in this study population was 0.05%. Our findings highlight the barriers and challenges that patients and providers face when receiving OPAT, and they can inform efforts to improve patient clinical outcomes.

Outcomes of starting low-dose pazopanib in patients with metastatic renal cell carcinoma who do not meet eligibility criteria for clinical trials

Purpose: Eligibility for clinical trials is very strict and only patients who satisfy various criteria can enter trials. The individual use of pazopanib has not been adequately investigated. An optimal administration regimen for pazopanib in “real-world” patients with metastatic renal cell carcinoma (mRCC) is required. Our purpose was to determine the tolerability and efficacy of first-line pazopanib with a low starting dose in patients with mRCC who were ineligible for clinical trials. Materials and Methods: This study included patients with mRCC who underwent treatment with first-line pazopanib and were previously excluded from clinical trials because they did not meet the inclusion criteria. A 400 mg pazopanib starting dose is used routinely in patients with mRCC; if tolerated, dose escalation up to 800 mg may occur. Results: We identified 18 patients with mRCC who received first-line pazopanib and were previously determined ineligible for clinical trials. Pazopanib dose was escalated in 12 patients (66.6%), to 600 mg/day in 8 patients (44.4%) and to 800 mg/day in 4 patients (22.2%), and was not escalated in 6 patients (33.3%). In 3 patients (16.7%), pazopanib was discontinued owing to intolerability. The most common frequent adverse event was elevated alanine aminotransferase levels in 6 patients (33.3%), followed by a decreased platelet count in 5 patients (27.8%) and anorexia in 5 patients (27.8%). Partial response was seen in 5 patients (27.8%) and stable disease in 10 patients (55.6%); median progression-free survival was 11.9 months (95% confidence interval: 6.3–28.7 months). Conclusion: Our data indicated that a low starting dose of 400 mg pazopanib did not negatively affect treatment tolerability and efficacy in patients with mRCC ineligible for clinical trials. We found that lower starting doses may lead to better results. Additional studies are needed in a larger cohort and longer follow-up to attain authentic outcomes.