Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology

BACKGROUND The coronavirus disease 2019(COVID-19),a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide,was described to be frequently accompanied by extrapulmonary manifestations,including liver dysfunction.Liver dysfunction and elevated liver enzymes were observed in about 53%of COVID-19 patients.AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction.METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed.Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways.The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis,fibrosis,non-alcoholic fatty liver disease(NAFLD),and hepatitis A/B/C.Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR.RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes,DNAJB1,IGF2,EGFR,and HDGF.Concordantly,the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling(liver cirrhosis,Fibrosis,NAFLD,and hepatitis A/B/C).Moreover,we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function,including cytochrome P450 family members,ACAD11,CIDEB,GNMT,and GPAM.Consequently,drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity.In correspondence with the RNA-seq data analysis,we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction.CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling,mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.

Noninvasive imaging of hepatic dysfunction: A state-of-the-art review

Hepatic dysfunction represents a wide spectrum of pathological changes,which can be frequently found in hepatitis,cholestasis,metabolic diseases,and focal liver lesions.As hepatic dysfunction is often clinically silent until advanced stages,there remains an unmet need to identify affected patients at early stages to enable individualized intervention which can improve prognosis.Passive liver function tests include biochemical parameters and clinical grading systems(e.g.,the Child-Pugh score and Model for End-Stage Liver Disease score).Despite widely used and readily available,these approaches provide indirect and limited information regarding hepatic function.Dynamic quantitative tests of liver function are based on clearance capacity tests such as the indocyanine green(ICG)clearance test.However,controversial results have been reported for the ICG clearance test in relation with clinical outcome and the accuracy is easily affected by various factors.Imaging techniques,including ultrasound,computed tomography,and magnetic resonance imaging,allow morphological and functional assessment of the entire hepatobiliary system,hence demonstrating great potential in evaluating hepatic dysfunction noninvasively.In this article,we provide a state-of-the-art summary of noninvasive imaging modalities for hepatic dysfunction assessment along the pathophysiological track,with special emphasis on the imaging modality comparison and selection for each clinical scenario.

Risk factors associated with hepatic dysfunction after Sun's procedure for type A aortic dissection

Background Type A aortic dissection,as a cardiovascular emergency,is best treated with early surgical intervention.With advancements in surgical techniques and perioperative management,the clinical cure rate of surgery has significantly improved.However,the probability of postoperative complications remains high,among which postoperative hepatic dysfunction is one of the common and serious complications affecting prognosis.The purpose of this study was to explore the risk factors associated with postoperative hepatic dysfunction in patients with type A aortic dissection,hoping to identify high-risk patients early,prevent postoperative hepatic dysfunction,and improve patient prognosis.Methods A retrospective analysis was conducted on patients diagnosed with Stanford type A aortic dissection and treated with Sun's procedure at Guangdong Provincial People's Hospital from January 1,2021,to October 1,2022.The Model for End-Stage Liver Disease excluding International Normalized Ratio(MELD-XI)score was used as the evaluation index for postoperative hepatic dysfunction(HD).MELD-XI scores from postoperative day 1 to 7 were collected.Statistical methods were employed to analyze the perioperative clinical data of the two groups of patients.Variables with statistical significance in univariate analysis were included in multivariate logistic regression analysis to identify independent risk factors associated with postoperative HD.Results A total of 241 patients diagnosed with Stanford type A aortic dissection and hospitalized for Sun's procedure treatment were selected using specific inclusion and exclusion criteria.All patients were divided into HD group(MELD-XI score≥12,n=108)and normal group(MELD-XI score<12,n=133),with a postoperative HD incidence rate of 44.81%.There were statistically significant differences(P<0.05)between the two groups in terms of whether the surgery was emergency,gender distribution,preoperative level of white blood cell count,alanine aminotransferase,aspartate aminotransferase,brain natriuretic peptide,high-sensitivity troponin T,and serum creatinine.Statistically significant differences(P<0.05)were also observed in surgical duration,cardiopulmonary bypass time,intraoperative and postoperative 24-hour red blood cell transfusion volume,intraoperative and postoperative 24-hour plasma transfusion volume,and intraoperative bleeding volume.Moreover,patients with postoperative hepatic dysfunction had longer mechanical ventilation time,longer intensive care unit(ICU)and total hospital stay,and higher probabilities of postoperative gastrointestinal bleeding,paraplegia,cerebral complications,re-thoracotomy for hemostasis,reintubation,and extracorporeal membrane oxygenation(ECMO)therapy(P<0.05).The probabilities of acute kidney injury and receiving hemodialysis treatment were also higher(P<0.05).Following multivariate regression analysis,preoperative white blood cell count(OR:1.169,95%CI:1.028-1.329,P=0.017),preoperative serum creat-inine(OR:1.045,95%CI:1.028-1.062,P<0.001),and intraoperative and postoperative 24-hour red blood cell transfusion volume(OR:1.146,95%CI:1.030-1.274,P=0.012)were identified as independent risk factors associated with postoperative hepatic dysfunction in patients with Stanford type A aortic dissection after Sun's procedure.Conclusions In this study,the incidence of postoperative hepatic dysfunction in patients with Stanford type A aortic dissection after Sun's procedure was relatively high,at 44.81%.The independent risk factors associated with postoperative hepatic dysfunction in patients with type A aortic dissection include preoperative white blood cell count,preoperative alanine aminotransferase,and intraoperative and postoperative 24-hour red blood cell transfusion volume.Postoperative hepatic dysfunction significantly affects the prognosis of patients with Stanford type A aortic dissection,increasing the duration of postoperative mechanical ventilation,postoperative hospitalization time,and the probability of postoperative acute kidney injury.

Association of COVID-19 with hepatic metabolic dysfunction

The coronavirus disease 2019(COVID-19)pandemic continues to be a global problem with over 438 million cases reported so far.Although it mostly affects the respiratory system,the involvement of extrapulmonary organs,including the liver,is not uncommon.Since the beginning of the pandemic,metabolic comorbidities,such as obesity,diabetes,hypertension,and dyslipidemia,have been identified as poor prognostic indicators.Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19.The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body.The liver is an important organ with high metabolic activity,and a significant proportion of COVID-19 patients have metabolic comorbidities;thus,this factor could play a key role in orchestrating systemic metabolic changes during infection.Evidence suggests that metabolic dysregulation in COVID-19 has both short-and long-term metabolic implications.Furthermore,COVID-19 has adverse associations with metabolic-associated fatty liver disease.Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism,COVID-19 can have significant implications in patients with advanced chronic liver disease.A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets.In this review,we discuss the current understanding of metabolic dysfunction in COVID-19,focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.

Postoperative hepatic dysfunction risk in patients undergoing surgery for type A aortic dissection:Recent progress

Background Aortic dissection is one of the most complex cardiovascular diseases;type A aortic dissection is more dangerous than type B and requires timely surgical intervention. Hepatic dysfunction is one of the common complications after aortic dissection surgery and is a significant risk factor for poor prognosis. This study aims to discuss and analyze the perioperative risk factors for postoperative hepatic insufficiency after type A dissection surgery. It also aims to provide an important basis for its prevention and treatment.

Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically

AIM: Cardiotonic Pill (CP), an oral herbal medicine that includes Danshen (Salviae Miltiorrhizae), Panax notoginseny and Dyroblanops aromatica gaettn, has been clinically used for vascular diseases such as occlusive vasculitis, coronary diseases, atherosclerosis, and cerebral infarction. The main component, Salviae Miltiorrhizae, has been reported to prevent cerebral and intestinal reperfusion injury. However, little is known about the effect of CP on hepatic microcirculation. Thus, this study aimed to determine whether CP could affect hepatic microvascular dysfunction elicited by gut ischemia/ reperfusion (I/R) in rats fed ethanol chronically. METHODS: Male Wistar rats were pair-fed with a liquid diet containing ethanol or isocaloric control diet for 6 wk. After laparotomy, one lobe of the liver was examined through an inverted intravital microscope. The rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Rhodamine-6G-labeled leukocytes in the sinusoids were observed 90 min after the onset of superior mesenteric artery occlusion. Plasma tumor necrosis factor (TNF)-α and endotoxin levels were measured 1 h after the onset of reperfusion. Plasma alanine aminotransferase (ALT) activities were measured 6 h after the onset of reperfusion. In another set of experiments, CP (0.8 g/kg, intragastrically) was administered 1 and 24 h before the onset of ischemia. RESULTS: In control rats, gut I/R elicited increases in the number of stationary leukocytes, and plasma TNF-α and endotoxin levels and plasma ALT activities. These changes were mitigated by pretreatment with CP. In ethanol-fed rats, the gut I/R-induced increases in the number of stationary leukocytes, plasma endotoxin levels and ALT activities were enhanced. Pretreatment with CP attenuated the enhancement of gut I/R-induced responses by chronic ethanol consumption. CONCLUSION: These results suggest that CP prevents the gut I/R-induced hepatic microvascular dysfunction and hepatocellular injury. A reduction of inflammatory responses such as TNF-α production via reduction of blood endotoxin levels appears to be involved in the mechanisms. Chronic ethanol consumption enhances gut I/R-induced hepatic microvascular and hepatocellular injury. CP also attenuates an enhancement of gut I/R-induced responses by chronic ethanol consumption via the reduction of blood endotoxin levels.

Diagnosis and management of late hepatic allograft dysfunction

Late hepatic allograft dysfunction (LHAD) is common after liver transplantation (LT) and can cause graft failure,retransplantation,or even death.A variety of etiologies including rejection,vascular complications,bile duct complications,recurrent diseases,infections,de novo diseases,neoplasms and drug toxicity can result in LHAD.The recurrent diseases have the potential to become the most serious problems facing LT in the future.It is difficult to differentiate late acute rejection from recurrent viral or autoimmune hepatitis.Accurate diagnosis of the cause of LHAD has therapeutic importance.

Predictive factors for liver dysfunction and failure after hepatectomy:Analysis of 467 patients with hepatocellular carcinoma

Objective： The aim of our study was to analyze hepatic dysfunction and failure after hepatocellular carcinoma （HCC） resection and relationship of clinical and pathological factors. Methods： Clinical and pathological data of 467 HCC patients was retrospectively reviewed, who underwent liver resection from January 2002 to December 2008 in the Affiliated Hospital of Medical College, Qingdao University, and the post-resectional liver dysfunction and failure risk factors were analyzed by univariate and multivariate analysis. Results： The morbidity of post-resectional liver dysfunction and failure was 1.7% and 2.1%. The post-resectional liver dysfunction and failure after HCC hepatectomy into the statistical analysis： univariate analysis revealed preoperative platelet level （〈 100 × 10^9）, serum albumin level （〈 35 g/L）, serum gamma-Glutamyl transferase （〉 64 U/L）, Child-Pugh classification （B）, MELD score （≥ 9）, intraoperative bleeding （-〉 1000 mL）, blood transfusion were positive factors, multivariate analysis （Logistic） revealed that preoperative platelet level （0.983, 95% CI = 0.971-0.995） and intraoperative blood transfusion （3.145, 95% CI = 1.027-12.028） were independent risk factors for post-resectional liver dysfunction and failure. Conclusion： Prevented liver failure and liver dysfunction occurring after liver resection, it is the key to accurate preoperative assessment of liver function and the patient＇s reserved liver functional, precise hepatectomy and reasonable blockage of hepatic inflow.

COVID-19-induced liver injury in infants,children,and adolescents

Coronavirus disease 2019(COVID-19)typically presents with fever and respiratory symptoms in children.Most children develop an asymptomatic and mild illness,with a minority requiring specialist medical care.Gastrointestinal manifestations and liver injury can also occur in children following infection.The mechanisms of liver injury may include infection following direct viral hepatic tissue invasion,immune response,or medication effects.Affected children might develop mild liver dysfunction which has a benign course in most children with no pre-existing liver disease.However,the presence of non-alcoholic fatty liver disease or other pre-existing chronic liver disorders is associated with a higher risk of developing severe COVID-19 illness with poor outcomes.On the other hand,the presence of liver manifestations is associated with the severity of COVID-19 disease and is considered an independent prognostic factor.Respiratory,hemodynamic,and nutritional supportive therapies are the mainstay of management.Vaccination of children at increased risk of developing severe COVID-19 disease is indicated.This review describes the liver manifestations in children with COVID-19,detailing its epidemiology,basic mechanisms,clinical expression,management,and prognosis in those with and without pre-existing liver disease and also children who have had earlier liver transplantation.

An accurate predictor of liver failure and death after hepatectomy:A single institution's experience with 478 consecutive cases

AIM:To establish a reliable definition of postoperative liver failure(PLF)and allow the prediction of outcomes after hepatectomy.METHODS:The clinical data of 478 consecutive patients who underwent hepatectomy were retrospectively analyzed.The examined prognostic factors included the ratio of total bilirubin(TBIL)on postoperative day(POD)X to TBIL on POD 1(TBIL-r1)and the ratio of the international normalized ratio(INR)on POD X to the INR on POD 1(INR-r1)for PODs 3,5 and 7.Student’s t test,theχ2test,logistic regression,survival analysis and receiver operating curve analysis were used to evaluate risk factors and establish the definition of postoperative liver failure(PLF).RESULTS:Fourteen patients(2.9%)died of liver failure within 3 mo of surgery.Significant differences were found between patients who died of liver failure and the remaining patients in terms of TBIL-r1 and INR-r1on PODs 3,5 and 7.The combination of TBIL-r1 and INR-r1 on POD 5 showed strong predictive power for liver failure-related death(sensitivity 92.9%and specificity 90.1%).The hepatic damage score(HDs),which was derived from TBIL-r1 and INR-r1,was used to define the degree of metabolic functional impairment after resection as mild(HDs=0),reversible hepatic"dysfunction"(HDs=1)or fatal hepatic failure(HDs=2).Furthermore,the indocyanine green retention rate at 15 min(ICG-R15)and the number of resected segments(RSs)were identified as independent predictors of the HDs.A linear relationship was found between ICG-R15 and RSs in the HDs=2 group.The regression equation was:RSs=-0.168×ICG-R15+5.625(r2=0.613,F=14.257,P=0.004).CONCLUSION:PLF can be defined by the HDs,which accurately predicts liver failure-related death after liver resection.Furthermore,the ICG-R15 and RSs can be used as selection criteria for hepatectomy.

Coagulopathy in a subtype of choledochal cyst and management strategy

AIM: To evaluated our management algorithm of the coagulopathy. We evaluated our management algorithm of the coagulopathy.

Diabetic patients with COVID-19 need more attention and better glycemic control

BACKGROUND Coronavirus disease 2019 (COVID-19) is a pandemic disease spreading all overthe world and has aroused global concerns. The increasing mortality has revealedits severity. It is important to distinguish severe patients and provide appropriatetreatment and care to prevent damages. Diabetes is reported to be a commoncomorbidity in COVID-19 patients and associated with higher mortality. Weattempted to clarify the relationship between diabetes and COVID-19 patients’severity.AIMTo determine the role of type 2 diabetes in COVID-19 patients.METHODSTo study the relationship between diabetes and COVID-19, we retrospectivelycollected 61 patients’ data from a tertiary medical center in Wuhan. All thepatients were diagnosed with laboratory-confirmed COVID-19 and admitted tothe center from February 13 to March 1, 2020. Patients’ age, sex, laboratory tests,chest computed tomography findings, capillary blood glucose (BG), andtreatments were collected and analyzed. Fisher exact test was used for categoricaldata. Univariate and multivariate logistic regressions were used to explore therelationship between clinical characteristics and patients’ severity.RESULTSIn the 61 patients, the comorbidity of type 2 diabetes, hypertension, and heartdiseases were 24.6% (15 out of 61), 37.7% (23 out of 61), and 11.5% (7 out of 61),respectively. The diabetic group was related to more invasive treatments (P =0.02) and severe status (P = 0.003). In univariate logistic regression, histories ofdiabetes (OR = 7.13, P = 0.003), hypertension (OR = 3.41, P = 0.039), and hepaticdysfunction (OR = 7.69, P = 0.002) were predictors of patients’ severity while heart disease (OR = 4.21, P = 0.083) and large lung involvement (OR = 2.70, P = 0.093)also slightly exacerbated patients’ conditions. In the multivariate analysis,diabetes (OR = 6.29, P = 0.016) and hepatic dysfunction (OR = 5.88, P = 0.018)were risk factors for severe patients. Diabetic patients showed elevated BG in61.7% of preprandial tests and 33.3% of postprandial tests, revealing the limitedcontrol of glycemia in COVID-19 patients.CONCLUSIONA history of type 2 diabetes is correlated with invasive treatments and severestatus. Suboptimal glycemic control and hepatic dysfunction have negative effectson severity status and may lead to the exacerbation of COVID-19 patients.

A Patient with Acute Liver Injury after Sulfamethoxazole/Trimethoprim Treatment for Pyelonephritis

Background: Sulfamethoxazole/Trimethoprim is a commonly used drug in a variety of clinically indicated scenarios, but it is not without side effect. Case-reports have stated that adverse reactions secondary to Sulfamethoxazole/Trimethoprim can present very early in the course of treatment, especially in patients who have a higher predisposition. Thus, the burden is placed on the clinician to be wary of these side effects and be able to recognize them in the correct clinic scenario. Objective: To discuss the risk of developing cholestatic hepatic dysfunction secondary to treatment with sulfamethoxazole/trimethoprim. Methods: We present the history, physical findings, laboratory investigations, and clinical course of a 47-year-old African-American female who developed cholestatic hepatic dysfunction after treatment with sulfamethoxazole/trimethoprim for pyelonephritis. Results: Drug-induced liver injury is a rare complication of sulfamethoxazole/trimethoprim therapy and only 20% of cases are secondary to cholestatic hepatic dysfunction. Our patient, who had been on sulfamethoxazole/trimethoprim for 7 days for pyelonephritis, presented to our hospital with a clinical picture consistent with hepatic injury;her laboratory investigations were noteworthy for an elevated white blood cell count, platelet count, and elevated transaminases, along with alkaline phosphatase levels greater than 2 times the upper limit of normal. Promptly following the discontinuation of sulfamethoxazole/trimethoprim, our patient improved clinically and her liver enzymes down-trended during the course of her hospital stay. She returned to normal at her 4 month follow up, thus confirming the diagnosis of cholestatic hepatic dysfunction secondary to sulfamethoxazole/trimethoprim. Conclusion: Cholestatic hepatic dysfunction is a form of drug-induced liver injury and a rare complication of sulfamethoxazole/trimethoprim treatment. The majority of cases resolve following discontinuation of the offending medication. However, a small percentage of patients may progress to liver failure and ultimately require liver transplantation. Clinicians should be aware of these risks to avoid delaying the discontinuation of sulfamethoxazole/trimethoprim.