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Biomolecules Jan 2023The global outbreak of COVID-19 possesses serious challenges and adverse impacts for patients with progression of chronic liver disease and has become a major threat to... (Review)
Review
The global outbreak of COVID-19 possesses serious challenges and adverse impacts for patients with progression of chronic liver disease and has become a major threat to public health. COVID-19 patients have a high risk of lung injury and multiorgan dysfunction that remains a major challenge to hepatology. COVID-19 patients and those with liver injury exhibit clinical manifestations, including elevation in ALT, AST, GGT, bilirubin, TNF-α, and IL-6 and reduction in the levels of CD4 and CD8. Liver injury in COVID-19 patients is induced through multiple factors, including a direct attack of SARS-CoV-2 on liver hepatocytes, hypoxia reperfusion dysfunction, cytokine release syndrome, drug-induced hepatotoxicity caused by lopinavir and ritonavir, immune-mediated inflammation, renin-angiotensin system, and coagulopathy. Cellular and molecular mechanisms underlying liver dysfunction are not fully understood in severe COVID-19 attacks. High mortality and the development of chronic liver diseases such as cirrhosis, alcoholic liver disease, autoimmune hepatitis, nonalcoholic fatty liver disease, and hepatocellular carcinoma are also associated with patients with liver damage. COVID-19 patients with preexisting or developing liver disease should be managed. They often need hospitalization and medication, especially in conjunction with liver transplants. In the present review, we highlight the attack of SARS-CoV-2 on liver hepatocytes by exploring the cellular and molecular events underlying the pathophysiological mechanisms in COVID-19 patients with liver injury. We also discuss the development of chronic liver diseases during the progression of SARS-CoV-2 replication. Lastly, we explore management principles in COVID-19 patients with liver injury and liver transplantation.
Topics: Humans; COVID-19; SARS-CoV-2; Non-alcoholic Fatty Liver Disease; Liver Neoplasms
PubMed: 36671484
DOI: 10.3390/biom13010099 -
BMJ Open Sep 2021The aim was to elucidate the relationship between liver function and idiopathic pulmonary arterial hypertension (IPAH).
OBJECTIVES
The aim was to elucidate the relationship between liver function and idiopathic pulmonary arterial hypertension (IPAH).
DESIGN AND SETTING
Retrospective, longitudinal study in urban tertiary care centre in Shanghai, China.
PARTICIPANTS
407 IPAH consecutive incident patients age 18-65 years were retrospectively enrolled from January 2008 to December 2018.
OUTCOME MEASUREMENTS
The primary endpoint was all-cause mortality. The cut-off value was determined by receiver operating characteristic curve (ROC), which was validated by Cox proportional hazard model was internally validated by bootstrap analysis and used for survival analysis. The Cox model was (internally) validated and cross-validated areas under the curve (AUC) should be reported.
RESULTS
The prevalence of abnormal liver function tests (LFTs) at baseline was 77.6%. Hyperbilirubinaemia is the most common abnormal biochemical liver test: abnormal total bilirubin (TBIL in 51.6% patients). During the follow-up, 160 patients died. Patients with mixed liver dysfunction have worse prognosis than those with normal LFTs or isolated abnormal bilirubin metabolism. Comparing with patients with hepatocellular injury, the survival of patients with abnormal bilirubin metabolism is lower. Multivariable Cox models revealed a positive association between TBIL, γ-glutamyltransferase (GGT) and mortality showing that each Ig increment in TBIL and GGT was associated with a higher all-cause mortality (TBIL: HR 4. 29 (95% CI 1. 21 to 15. 27), p=0. 02; GGT: HR 2. 76 (95% CI 1. 18 to 6. 45), p=0. 02). A novel formula named Liver Function Predict Index (LFPI) was constructed (LFPI=-0.002*6MWD+1.014*lg GGT+1.458*lg TBIL) to predict prognosis. ROC curve analysis did further identify 2.729 as the best cut-off value for LFPI (AUC 0.75, p<0.001, sensitivity 79%, specificity 70%).
CONCLUSIONS
Liver dysfunction is frequent in IPAH, and characterised by a predominantly cholestatic enzyme profile. LFTs abnormalities are associated with worse survival and LFPI was a new and simple predictor for prognosis of IPAH.
Topics: Adolescent; Adult; Aged; China; Familial Primary Pulmonary Hypertension; Humans; Liver Diseases; Longitudinal Studies; Middle Aged; Prevalence; Prognosis; ROC Curve; Retrospective Studies; Young Adult
PubMed: 34493501
DOI: 10.1136/bmjopen-2020-045165 -
Journal of Hepato-biliary-pancreatic... Jan 2011Liver regeneration is a necessary process that most liver damage depends on for recovery. Regeneration is achieved by a complex interactive network consisting of liver... (Review)
Review
Liver regeneration is a necessary process that most liver damage depends on for recovery. Regeneration is achieved by a complex interactive network consisting of liver cells (hepatocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells, and stem cells) and extrahepatic organs (thyroid gland, adrenal gland, pancreas, duodenum, and autonomous nervous system). The restoration of liver volume depends on hepatocyte proliferation, which includes initiation, proliferation, and termination phases. Hepatocytes are "primed" mainly by Kupffer cells via cytokines (IL-6 and TNF-alpha) and then "proliferation" and "cell growth" of hepatocytes are induced by the stimulations of cytokines and growth factors (HGF and TGF-alpha). Liver regeneration is achieved by cell proliferation and cell growth, where the IL-6/STAT3 and PI3-K/PDK1/Akt pathways play pivotal roles, respectively. IL-6/STAT3 pathway regulates hepatocyte proliferation via cyclin D1/p21 and protects against cell death by upregulating FLIP, Bcl-2, Bcl-xL, Ref1, and MnSOD. PI3-K/PDK1/Akt is known to be responsible for regulation of cell size via its downstream molecules such as mTOR in addition to being known for its survival, anti-apoptotic and anti-oxidative properties. Although the molecular mechanisms of liver regeneration have been actively studied, the mechanisms of liver regeneration must be elucidated and leveraged for the sufficient treatment of liver diseases.
Topics: Animals; Apoptosis; Cell Proliferation; Hepatocytes; Intercellular Signaling Peptides and Proteins; Interleukin-6; Kupffer Cells; Liver; Liver Diseases; Liver Regeneration; Mice; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats; Ribosomal Protein S6 Kinases, 70-kDa; STAT3 Transcription Factor; Signal Transduction
PubMed: 20607568
DOI: 10.1007/s00534-010-0304-2 -
Seminars in Thrombosis and Hemostasis Jul 2015Cirrhosis presents with decreased procoagulant factors as a consequence of the impaired synthetic capacity of the liver. This was taken as evidence to explain the... (Review)
Review
Cirrhosis presents with decreased procoagulant factors as a consequence of the impaired synthetic capacity of the liver. This was taken as evidence to explain the abnormalities of the coagulation tests prothrombin time (PT) and activated partial thromboplastin time (aPTT) and the bleeding events that occur in these patients. It was for long time (and probably is still) common practice to test patients with the PT and to treat those with predefined (but arbitrary) cutoff values with plasma or prohemostatic agents to prevent or stop bleeding. However, anticoagulant factors that contrast the procoagulants are also decreased in cirrhosis. It was therefore postulated that the coagulation balance (i.e., the net result between the action of pro- and anticoagulants) is somewhat rebalanced. Subsequent studies supported this view showing that plasma from cirrhotic patients generates normal amounts of thrombin. In addition, primary hemostasis (i.e., platelet-vessel wall interaction) is rebalanced notwithstanding cirrhosis present with thrombocytopenia. It was shown that increased levels of the adhesive protein von Willebrand factor (a typical feature of cirrhosis) compensate for the low number (function) of platelets. The earlier considerations have been instrumental to help dismantle the old paradigms of cirrhosis as the epitome of the acquired hemorrhagic coagulopathies and the traditional coagulation tests PT and aPTT as suitable predictors of bleeding risk. The demise of the old paradigms and the rise of the new one may have important practical implications for the management of patients with cirrhosis and will be discussed in this chapter.
Topics: Hemorrhage; Hemostasis; Hemostatics; Humans; Liver Cirrhosis; Liver Diseases; Thrombosis
PubMed: 26080306
DOI: 10.1055/s-0035-1550440 -
Frontiers in Immunology 2022To date, evidences with high evidence-level evaluating the association between liver diseases and hidradenitis suppurativa was lacking. Given that inconsistency exists... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To date, evidences with high evidence-level evaluating the association between liver diseases and hidradenitis suppurativa was lacking. Given that inconsistency exists in some of the previous observational studies, evaluating the prevalence of liver diseases in HS patients could potentially serve as a reference of future guidelines for HS comorbidity screening. The aim of the current study was to evaluate potential association between hidradenitis suppurativa and liver diseases and provide integrated evidences.
METHODS
A search in PubMed, Web of Science and Embase based on the syntaxes ''hidradenitis suppurativa'' or ''acne inversa'' with "comorbidities", "liver diseases", "fatty liver" or "hepatitis" was performed. Observational studies evaluating epidemiological association between hidradenitis suppurativa and the risk of all liver diseases, including specific diseases as non-alcoholic fatty liver disease, hepatitis B, hepatitis C were targeted to be extracted in this systematic review and meta-analysis.
RESULTS
Within the initial 702 records, there were finally 8 real-world observational studies extracted. Results suggest that patients with HS are associated with all liver diseases (OR= 1.50; 95% CI, 1.27, 1.76), non-alcoholic fatty liver disease (OR= 1.78; 95% CI, 1.28, 2.48) and hepatitis B (OR=1.48; 95% CI, 1.12, 1.94), but not hepatitis C (OR= 1.27; 95% CI, 0.78, 2.07). HS patients were associated with significantly increased risk of liver diseases, especially the risk of non-alcoholic fatty liver disease and hepatitis B.
CONCLUSIONS
Clinicians should be alert to the clinical relationship while caring people with hidradenitis suppurativa and the screening of liver function should be recommended to HS patients.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022296034.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Comorbidity; Hidradenitis Suppurativa; Hepatitis B; Hepatitis C; Observational Studies as Topic
PubMed: 36591267
DOI: 10.3389/fimmu.2022.959691 -
American Journal of Hematology Dec 2017The prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly...
The prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (<12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed. An abnormal LFT was present in 82/2336 (3.5%) patients at diagnosis and was associated with advanced Rai stage (Rai III-IV) (21% vs. 6%; P < .001), lower hemoglobin (13.1 g/dL vs. 13.9 g/dL; P < .001), and lower platelet count (187 × 109/L vs. 200 × 109/L; P = .03). Additionally, 236 patients with normal LFTs at diagnosis developed acquired liver dysfunction during follow-up. Patients with abnormal LFTs at diagnosis had a shorter OS compared to those with normal LFTs (HR 1.80 95% CI 1.13-2.87; P = .014, adjusted for age, sex, Rai stage, and treatment), although TTFT was not different. Of 52 patients who underwent a liver biopsy, CLL was present in liver tissue in 39/52 (73%) patients, with the portal tracts the most common region involved. Histopathology findings of liver involvement by CLL had limited correlation with choice of CLL therapy. In conclusion, approximately 1 of 25 newly diagnosed CLL patients has abnormal LFTs at diagnosis. Although the TTFT was not different among patients with abnormal LFTs, these patients have a shorter OS compared to those with normal LFTs.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Liver Diseases; Liver Function Tests; Male; Middle Aged; Prevalence; Survival Rate; Treatment Outcome
PubMed: 28940587
DOI: 10.1002/ajh.24915 -
Pediatrics Jan 2022Develop evidence-based criteria for individual organ dysfunction.
CONTEXT
Develop evidence-based criteria for individual organ dysfunction.
OBJECTIVES
Evaluate current evidence and develop contemporary consensus criteria for acute liver dysfunction with associated outcomes in critically ill children.
DATA SOURCES
Electronic searches of PubMed and Embase conducted from January 1992 to January 2020, used medical subject heading terms and text words to characterize acute liver dysfunction and outcomes.
STUDY SELECTION
Studies evaluating critically ill children with acute liver dysfunction, assessed screening tools, and outcomes were included. Studies evaluating adults, infants ≤36 weeks gestational age, or animals or were reviews/commentaries, case series with sample size ≤10, or non-English language studies were excluded.
DATA EXTRACTION
Data were abstracted from each eligible study into a data extraction form along with risk of bias assessment by a task force member.
RESULTS
The systematic review supports criteria for acute liver dysfunction, in the absence of known chronic liver disease, as having onset of symptoms <8 weeks, combined with biochemical evidence of acute liver injury, and liver-based coagulopathy, with hepatic encephalopathy required for an international normalized ratio between 1.5 and 2.0.
LIMITATIONS
Unable to assess acute-on-chronic liver dysfunction, subjective nature of hepatic encephalopathy, relevant articles missed by reviewers.
CONCLUSIONS
Proposed criteria identify an infant, child, or adolescent who has reached a clinical threshold where any of the 3 outcomes (alive with native liver, death, or liver transplant) are possible and should prompt an urgent liaison with a recognized pediatric liver transplant center if liver failure is the principal driver of multiple organ dysfunction.
Topics: Adolescent; Child; Critical Illness; Humans; Infant; Liver Diseases; Multiple Organ Failure; Organ Dysfunction Scores
PubMed: 34970684
DOI: 10.1542/peds.2021-052888I -
Clinical & Developmental Immunology 2013Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction.... (Review)
Review
Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.
Topics: Allografts; Animals; Chemokines; Chronic Disease; Humans; Liver Diseases; Liver Transplantation; Receptors, Chemokine
PubMed: 24382971
DOI: 10.1155/2013/325318 -
World Journal of Gastroenterology May 2015Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is... (Review)
Review
Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.
Topics: Animals; Arginine; Biomarkers; Critical Illness; Humans; Liver; Liver Diseases; Multiple Organ Failure; Prognosis; Risk Factors; Signal Transduction; Up-Regulation
PubMed: 25954086
DOI: 10.3748/wjg.v21.i17.5131 -
Gastroenterology Aug 2012c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis... (Review)
Review
c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis factor and interleukin-1), reactive oxygen species (ROS), pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and metabolic changes. Upon activation, JNK induces multiple biologic events through the transcription factor activator protein-1 and transcription-independent control of effector molecules. JNK isozymes regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis in the liver. The biologic functions of JNK are isoform, cell type, and context dependent. Recent studies using genetically engineered mice showed that loss or hyperactivation of the JNK pathway contributes to the development of inflammation, fibrosis, cancer growth, and metabolic diseases that include obesity, hepatic steatosis, and insulin resistance. We review the functions and pathways of JNK in liver physiology and pathology and discuss findings from preclinical studies with JNK inhibitors.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Biomarkers; Carcinoma, Hepatocellular; Cell Death; Chemical and Drug Induced Liver Injury; Fatty Liver; Humans; JNK Mitogen-Activated Protein Kinases; Liver; Liver Diseases; Liver Neoplasms; Liver Regeneration; Liver Transplantation; MAP Kinase Signaling System; Metabolic Syndrome; Mice; Primary Graft Dysfunction; Protein Kinase Inhibitors
PubMed: 22705006
DOI: 10.1053/j.gastro.2012.06.004