Severity Of Hepatic Fibrosis Research Articles

HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via non-canonical phosphorylation

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. Approach and Results: Herein, we identified Cyclin-dependent kinase like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis and diabetes. Mechanism-wise, CDKL3 directly phosphorylates FoxO1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of HNF4α. HNF4α is inhibited during MASLD, which led to diminished CDKL3 expression. The CDKL3-mediated crosstalk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.

Schistosomicidal Effects of Moringa oleifera Seed Oil Extract on Schistosoma mansoni-Infected Mice.

Schistosomiasis causes severe hepatic fibrosis, making it a global health issue. Moringa oleifera seed oil extract, which had antiparasitic, anti-inflammatory and antioxidant effects, was investigated as an alternative treatment. The 50 mice were divided into control, infected, praziquantel-treated, M. oleifera seed oil extract-treated and combined treatment groups. These treatments were examined for their effects on egg granulomas, hepatic enzymes, total protein, albumin, antioxidant enzymes and pro-inflammatory cytokines. M. oleifera seed oil and/or PZQ significantly reduced egg numbers, granuloma size and liver histopathology. M. oleifera seed oil reduced hepatic enzyme activity, increased total protein and albumin, and increased antioxidant enzyme activity while decreasing malondialdehyde. M. oleifera seed oil reduced the levels of pro-inflammatory cytokines. M. oleifera seed oil may treat schistosomiasis instead of PZQ due to its antifibrotic, immunomodulatory and schistosomicidal properties.

Association between dietary tea consumption and non-alcoholic fatty liver disease: a study based on Mendelian randomisation and National Health and Nutrition Examination Survey (2005-2018) association between tea and non-alcoholic fatty liver disease.

Tea can improve the progression of some metabolic diseases through anti-inflammatory and antioxidant effects, but its impact on non-alcoholic fatty liver disease (NAFLD) is still controversial. The aim of this paper is to identify the relationship between tea and NAFLD by Mendelian randomisation (MR) and complete clinical validation using National Health and Nutrition Examination Survey (NHANES) database. MR used data from Genome Wide Association Study, with inverse-variance weighted (IVW) as principal analytical methods. The reliability of the results was verified by a series of sensitivity and heterogeneity tests. Subsequently, clinical validation was conducted using NHANES (2005-2018), involving 22257 participants, grouped by the type of tea. Green tea drinkers were categorised into four groups (Q1-Q4) by quartiles of green tea intake, from lowest to highest (similar for black tea drinkers and other tea drinkers). Models were constructed by logistic regression to estimate the role of tea consumption (Q1-4) on NAFLD. Finally, using fibrosis-4 index (FIB-4) to evaluate the severity of hepatic fibrosis, the effect of tea consumption (Q1-4) on the degree of hepatic fibrosis was investigated by linear regression. IVW method (OR = 0·43, 95 % CI: 0·21, 0·85, P = 0·01) and weighted median method (OR = 0·35, 95 % CI: 0·14, 0·91, P = 0·03) revealed there was a causal relationship between tea and NAFLD. An array of sensitivity analyses validated the reliability of results. Analysis of NHANES indicated tea drinker present a slightly lower prevalence of NAFLD than non-tea drinker (green tea drinkers: 47·6 %, black tea drinkers: 46·3 %, other tea drinker: 43·2 %, non-tea drinkers: 48·1 %, P < 0·05). After adjusting for confounders, compared with the lowest black tea consumption (Q1), the population with the highest black tea consumption (Q4) was independently related to lower presence of NAFLD (Q4: OR = 0·69, 95 % CI: 0·50, 0·93, P < 0·05), such association remained stable in the overweight subgroup. As further analysed, Q4 also displayed a significant negative correlation with the level of hepatic fibrosis in patients with NAFLD (β = -0·073, 95 % CI: -0·126, -0·020, P < 0·01).Tea reduces the morbidity of NAFLD and ameliorates hepatic fibrosis degree in those already suffering from the disease.

6681 Age and Sex Disparity in NASH and the Potential Role of Estradiol Treatment for NASH

Abstract Disclosure: M. Tripathi: None. S. Sakthivel: None. A. Suzuki: None. B.K. Singh: None. P.M. Yen: None. Introduction: NAFLD (nonalcoholic fatty liver disease) and its more severe form, NASH (nonalcoholic steatohepatitis) are sexually dimorphic conditions that exhibit higher prevalence in men than women during reproductive ages but have similar prevalence after menopause. Reproductive age women are protected from hepatic fibrosis relative to men, although they lose this protection after menopause. These sex differences in NASH have been attributed, at least partly, to different circulating estrogen levels. However, the underlying mechanism(s) is not fully understood. We thus conducted animal experiments to investigate: 1) sex differences in the histologic severity of NASH, necroinflammatory and fibrogenic activities, and other relevant pathways in young and old male and female mice and 2) the effects of estradiol administration on these parameters in old male and female mice to evaluate the therapeutic potential of estradiol in NASH. Methodology: Young/reproductive age (12-weeks old) and old/post-reproductive age female and male (48∼50-weeks weeks old) C57BL/6J mice were fed control chow diet (NCD) or high-fat methionine/choline-deficient (MCD) diet for six weeks to induce NASH. The old mice were administered 200nM 17β-estradiol (physiological) in drinking water. We analyzed serum and hepatic NASH parameters, ER stress, and lysosome-autophagy defects. Results and Conclusion: Among reproductive age mice with NASH, females developed less severe histologic inflammation and fibrosis and decreased gene expression of Il1b, Il6, Tgfb, Col1a1, Ccl2, and Ccl5, and lower hepatic collagen than males. Females with NASH also had less inhibition of hepatic autophagy and lysosomal protein expression than males with NASH. Among old mice, post-reproductive age females fed NCD or MCD exhibited more severe hepatic inflammation and fibrosis and had higher gene expression of inflammatory and fibrogenic markers with comparable autophagic inhibition and lysosomal defects as similar age males. Physiological doses of estradiol significantly reduced hepatic gene expression of inflammatory and fibrogenic markers, ER stress and lysosomal-autophagic defects in post-reproductive age females. In conclusion, similar to clinical NASH, we observed marked sex and age-related differences in the severity of NASH. Furthermore, physiological doses of estradiol treatment improved the hepatic histology, lysosome-autophagy, inflammation, and fibrosis in post-reproductive age female mice with NASH and suggests that estradiol supplementation may decrease or reverse NASH progression in post-menopausal women with NASH. Presentation: 6/2/2024

Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson’s disease

Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson’s disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3–5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD.

Development of a Lipid-encapsulated TGFβRI-siRNA Drug for Liver Fibrosis Induced by Schistosoma mansoni.

Schistosoma mansoni infection leads to chronic schistosomiasis and severe hepatic fibrosis. We designed a liver-targeted lipid nanoparticle (LNP) carrying siRNA against type I TGF-β receptor (TGFβRI) mRNA to treat schistosomiasis-induced liver fibrosis in BALB/c mice. Knockdown of TGFβRI by LNP-siTGFβRI reduced LX-2 cell activation in vitro and alleviated liver fibrosis in S. mansoni-infected mice. αSMA and Col1a1 fibrotic markers in the liver tissues of infected mice were significantly suppressed in the treatment groups. In the serum of the LNP-siTGFβRI-treated groups, cytokines IFNγ, IL-1α, IL-6, IL-12, RANTES (CCL5), and TNFα increased, while GM-CSF, IL-2, IL-4, IL-10, IL-13, and KC (CXCL1) decreased compared to the control. Cell proportions were significantly altered in S. mansoni-infected mice, with increased CD56d NK cells and decreased CD19+ B cells and CD4+ T cells compared to naïve mice. Following LNP-siTGFβRI treatment, CD56d NK cells were downregulated, while B and memory Th cell populations were upregulated. The density of fibrotic regions significantly decreased with LNP-siTGFβRI treatment in a dose-dependent manner, and no systemic toxicity was observed in the major organs. This targeted siRNA delivery strategy effectively reduced granulomatous lesions in schistosomiasis-induced liver fibrosis without detectable side effects.

Sex differences in Murine MASH evoked by a Fructose-Palmitate-Cholesterol-Enriched Diet

Background/AimsMetabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. MethodsFemale and male C57BL/6J mice were fed fructose-palmitate-cholesterol (“FPC-(non-alcoholic steatohepatitis) (NASH)”) diet versus standard chow (SC) for 16 weeks (N=40 mice). At sacrifice, plasma and liver were retrieved, the latter for single nucleus RNA sequencing. Publicly-available data sets of human male and female MASH liver were probed. ResultsThe FPC-NASH diet induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis (p=0.0262), inflammation (p=0.0206), and fibrosis (p<0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the SC diet. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. ConclusionsMolecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female subjects in MAFLD/MASH studies and clinical trials. Impact and ImplicationsDespite the importance of metabolic syndrome-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single nucleus RNA sequencing of liver revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female versus male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female versus male MASH patients. Our findings of dysregulated bile acid metabolism and androgen receptor-related within-sex increases in testosterone in female versus male mice fed fructose-NASH diet versus standard chow diet highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.

Endogenous PGD2 acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis.

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers - an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-β and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-β and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction - an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis.

Capillaria hepatica (syn. Calodium hepaticum) infection and factors influencing infection carriage in rats (Rattus spp.) in Hong Kong

Capillaria hepatica (syn. Calodium hepaticum) (Bancroft, 1893) is a nematode, which colonises the liver of a wide range of hosts including humans. The worldwide prevalence of infection in the genus Rattus can be as high as 100% and the Norway rat (R. norvegicus) and black rat (R. rattus) are considered the main host species. This study is the first to investigate the epidemiology of C. hepatica infection in wild rats trapped in various geographical locations in Hong Kong. Four species of trapped rats were identified, with 65% being R. norvegicus, followed by 30% R. tanezumi (Asian house rat), 4% R. andamanensis (Sikkim rat), and 1% Niviventer huang (South China white-bellied rat). The overall prevalence of C. hepatica infection was 36.7% (81/221) (95% CI 30.4–43.4) and R. norvegicus was the most common rat species trapped during this study, with the highest prevalence of C. hepatica infection. Two risk factors for host infection were skin wounds and geographical region, whilst sex, body weight, stage of development, and presence of ectoparasites were not risk factors for this infection. Gross hepatic lesions were absent in 17% of infected rats and when present, were not pathognomonic for the infection. Infected rats lacked severe hepatic inflammation or fibrosis, indicating that rats tolerate the infection well. Egg production was observed in the livers of 69% of infected rats, which emphasizes their role as reservoirs of this zoonotic parasite. Several infected rats in this study were trapped inside residential buildings, which highlights the zoonotic risk of C. hepatica to humans following the potential ingestion of embryonated eggs from contaminated food, water, or soil.

Induction of hepatic fibrosis in mice with schistosomiasis by extracellular microRNA-30 derived from Schistosoma japonicum eggs.

Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host's immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by S. japonicum contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of S. japonicum secrete miRNA-30, a novel miRNA. In vitro, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges. This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, in vitro, i.e., it significantly increases the fibrogenic factors Col1(α1), Col3(α1), and α-SMA at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, in vivo experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of Col1(α1), Col3(α1), and α-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the in vivo silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, in vivo, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with S. japonica. The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.

Elevated serum HE4 levels as a novel biomarker of disease severity and hepatic fibrosis in autoimmune hepatitis

BackgroundHuman epididymis protein 4 (HE4) has been identified as a biomarker for renal fibrosis. This study aimed to evaluate the role of HE4 in the diagnosis and determination of disease severity and hepatic fibrosis in autoimmune hepatitis (AIH). MethodsSerum HE4 levels were determined via electrochemiluminescence immunoassays in 60 healthy controls and 109 AIH patients (43 without liver cirrhosis and 66 with liver cirrhosis). Liver biopsy was performed on 56 of 109 enrolled patients. We conducted a 5-year follow-up survey of 53 enrolled patients. All continuous variables were reported as median (25th–75th percentile). ResultsSerum HE4 levels were significantly elevated in autoimmune hepatitis with liver cirrhosis (AIH-LC) patients compared with AIH patients and healthy controls [98.60 (74.15–139.08) vs 73.50 (59.88–82.00) vs 48.75 (43.38–52.93) pmol/L, p = 0.004]. The serum HE4 levels showed a positive correlation with the METAVIR scoring system in patients with liver biopsy (r = 0.711, p < 0.001). Serum HE4 levels were significantly elevated in Child–Pugh class C patients compared with Child–Pugh class B patients and Child–Pugh class A patients [106.50 (83.46–151.25) vs 110.00 (73.83–166.75) vs 77.03 (72.35–83.33) pmol/L, p = 0.006]. The diagnostic sensitivity and specificity of serum HE4 for evaluating liver cirrhosis were 69.7 % and 79.07 %, respectively, with a cutoff value of 82.34 pmol/L in enrolled patients. The logistic regression analysis showed that high levels of HE4 (≥82.34 pmol/L) were associated with AIH-LC (OR = 8.751, 95 % CI = 1.412–54.225, p = 0.020). The Kaplan-Meier curves demonstrated that high levels of serum HE4 (≥82.34 pmol/L) were associated with poor outcome (log-rank p = 0.037, HR = 0.372, 95 % CI = 0.146–0.946). ConclusionsSerum HE4 levels were found to be elevated in AIH-LC patients and exhibited a strong correlation with the severity of hepatic fibrosis, thus supporting their potential clinical value as a novel biomarker of disease severity and hepatic fibrosis in AIH.

A Validation Study of Non-invasive Scoring Systems for Assessing Severity of Hepatic Fibrosis in a Cohort of South Indian Patients With Non-alcoholic Fatty Liver Disease

IntroductionLiver biopsy is the gold standard for diagnosing and staging NAFLD. But liver biopsy has its limitations. Non-invasive tests (NITs) eliminate many of the drawbacks of liver biopsy. We did a retrospective observational study to validate the non-alcoholic fatty liver disease Fibrosis Score (NFS score) and Fibrosis Score 4 (FIB-4 index) against the gold standard liver biopsy in a cohort of south Indian patients with NAFLD. Material and MethodsA retrospective observational analytical study of patients who had a liver biopsy with a diagnosis of NAFLD and had all the data for aetiology assessment and NIT calculation within 4 weeks of biopsy were included in the study. On liver biopsy NAFLD was scored as per NIH’s NASH committee (NASH CRN) grading system. NAFLD Fibrosis Score (NFS) and FIB-4 index were calculated and scores more than 0.676 and 2.67 respectively was taken as the cut-off to predict advanced fibrosis. The sensitivity, specificity, positive predictive value, negative predictive value and area under the ROC curve for NFS score and FIB-4 score to diagnose advanced fibrosis were calculated. ResultsA total of 147 patients were included in the study. Of these 56 (38.1%) patients had advanced fibrosis (Stage 3, 4). Patients with advanced fibrosis were more likely to be older and have DM. Patients with advanced fibrosis had lower platelet count, higher AST, lower albumin and higher AST/ALT ratio. The NFS of > 0.676 had a sensitivity of 68% and specificity of 100% and FIB-4 index of >2.67 had a sensitivity of 67% and specificity of 95.6 % in diagnosing advanced fibrosis in our study. ConclusionThe non-invasive scoring systems NAFLD Fibrosis Score (NFS) and FIB-4 index, can be used as a bedside tool for diagnosing Liver fibrosis in NAFLD allowing liver biopsy to be used in a more targeted manner for patients diagnosed with advanced fibrosis on NITs.

A multiple variable index and extracardiac-Fontan associated hepatic fibrosis

BackgroundThe serial follow-up of Fontan-associated liver disease is challenging, as laboratory values are frequently normal, especially with mild to moderate liver disease. ObjectiveWe investigated a composite index's correlation with hepatic biopsy total fibrosis scores in extracardiac Fontan patients. MethodsWe identified extracardiac Fontan patients undergoing cardiac catheterization and transvenous hepatic biopsies between June 2013 and September 2023 and liver shear wave elastography between January 2017 and July 2023. We developed a composite index from the following: 1) elastography values, 2) sex, 3) history of a neonatal aortopulmonary shunt for pulmonary flow obstruction, 4) pacemaker, 5) Fontan duration, 6) bilirubin values, 7) univentricular dysfunction, 8) atrioventricular valvar regurgitation, 9) mean Fontan pressures, and 10) venovenous collaterals presence. We correlated the index with hepatic total fibrosis scores (0–8), the sum of pathology grading (0 to 4) performed for sinusoidal and portal fibrosis. We defined a hepatic total fibrosis score of 0–3 as none to mild and 4–8 as moderate to severe fibrosis. ResultsWe identified 62 patients who underwent 92 transvenous liver biopsies, with 30 patients undergoing 2 biopsies. The average age at biopsy was 15 ± 2 years. We found a strong correlation (rho = 0.8, p = .00001) between liver total fibrosis scores and composite index values. A receiver operating characteristic analysis demonstrated that an index cut-off value of ≥26 predicted a total fibrosis score of ≥4 with a sensitivity of 71 % and a specificity of 75 % (AUC = 0.73, 95 % CI 0.63, 0.83, p = .0001). ConclusionsWe developed a composite index with a moderate predictive ability to discriminate none to mild from moderate to severe hepatic fibrosis. Nevertheless, additional data is needed to assist further validation and determine its clinical utility in the serial follow-up of Fontan associated liver disease.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

New Applications of Contrast-Enhanced Ultrasound for Hepatic Fibrosis and Portal Hypertension

Liver biopsy and measurement of hepatic venous pressure gradient in patients with cirrhosis are the gold standards for estimation of hepatic fibrosis, and they have diagnostic and prognostic value. However, both approaches are invasive and cannot be used repeatedly in clinical practice. Ultrasonography (US) is safe, easy to perform, inexpensive, and yields numerical and accurate results. Contrast-enhanced US (CEUS) using second-generation microbubble ultrasonography agents (USA) is able to show the vascular structure and enhancement pattern of lesions and can be used in the diagnosis of hepatocellular carcinoma (HCC) due to its characteristic neovascularization. Beyond the diagnosis of HCC, functional US indices based on CEUS have been suggested as promising markers for fibrosis and portal hypertension (PH). Although investigations of the reproducibility and long-term prognostic value are needed, CEUS-based indices are promising quantitative non-invasive tests to estimate the severity of hepatic fibrosis and PH. Therefore, in this study, we describe the characteristics of second-generation microbubble USA and the usefulness of CEUS-based indices for hepatic fibrosis and PH.

EUS-directed transgastric ERCP for management of severe hepatic steatosis and fibrosis in a liver transplantation patient with bypass anatomy

EUS-directed transgastric ERCP for management of severe hepatic steatosis and fibrosis in a liver transplantation patient with bypass anatomy

Air pollution associate with advanced hepatic fibrosis among patients with chronic liver disease.

We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti-HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM2.5 ], nitrogen dioxide [NO2 ], ozone [O3 ] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05-4.77; p < 0.001), smoking (OR, 1.79; 95% CI, 1.16-2.74; p = 0.01), age (OR, 1.04; 95% CI, 1.02-1.05; p < 0.001) and PM2.5 (OR, 1.10; 95% CI, 1.05-1.16; p < 0.001). Linear regression analysis revealed that LSM was independently correlated with PM2.5 (β: 0.134; 95% CI: 0.025, 0.243; p = 0.02). There was a dose-dependent relationship between different fibrotic stages and the PM2.5 level (the PM2.5 level in patients with fibrotic stages 0, 1-2 and 3-4: 27.9, 28.4, and 29.3 μg/m3 , respectively; trend p < 0.001). Exposure to PM2.5 , as well as HBV and HCV infections, is associated with advanced liver fibrosis in patients with MAFLD. There was a dose-dependent correlation between PM2.5 levels and the severity of hepatic fibrosis.

Comparison between Intravoxel Incoherent Motion and Splenic Volumetry to Predict Hepatic Fibrosis Staging in Preoperative Patients.

Intravoxel incoherent motion (IVIM) and splenic volumetry (SV) for hepatic fibrosis (HF) prediction have been reported to be effective. Our purpose is to compare the HF prediction of IVIM and SV in 67 patients with pathologically staged HF. SV was divided by body surface area (BSA). IVIM indices, such as slow diffusion-coefficient related to molecular diffusion (D), fast diffusion-coefficient related to perfusion in microvessels (D*), apparent diffusion-coefficient (ADC), and perfusion related diffusion-fraction (f), were calculated by two observers (R1/R2). D (p = 0.718 for R1, p = 0.087 for R2) and D* (p = 0.513, p = 0.708, respectively) showed a poor correlation with HF. ADC (p = 0.034, p = 0.528, respectively) and f (p < 0.001, p = 0.007, respectively) decreased as HF progressed, whereas SV/BSA increased (p = 0.015 for R1). The AUCs of SV/BSA (0.649-0.698 for R1) were higher than those of f (0.575-0.683 for R1 + R2) for severe HF (≥F3-4 and ≥F4), although AUCs of f (0.705-0.790 for R1 + R2) were higher than those of SV/BSA (0.628 for R1) for mild or no HF (≤F0-1). No significant differences to identify HF were observed between IVIM and SV/BSA. SV/BSA allows a higher estimation for evaluating severe HF than IVIM. IVIM is more suitable than SV/BSA for the assessment of mild or no HF.

TMM: A comprehensive CAD system for hepatic fibrosis 5-grade METAVIR staging based on liver MRI.

Precise staging of hepatic fibrosis with MRI is necessary as it can assist precision medicine. Computer aided diagnosis (CAD) system with distinguishing radiomics features and radiologists domain knowledge is expected to obtain 5-grade meta-analysis of histological data in viral hepatitis (METAVIR)staging. This study aims to obtain the precise staging of hepatic fibrosis based on MRI as it predicts the risk of future liver-related morbidity and the need for treatment, monitoring and surveillance. Based on METAVIR score, fibrosis can be divided into five stages. Most previous researches focus on binary classification, such as cirrhosis versus non-cirrhosis, early versus advanced fibrosis, and substantial fibrosis or not. In this paper, a comprehensive CAD system TMM is proposed to precisely class hepatic fibrosis into five stages for precision medicine instead of the common binaryclassification. We propose a novel hepatic fibrosis staging CAD system TMM which includes three modules, Two-level Image Statistical Radiomics Feature (TISRF), Monotonic Error Correcting Output Codes (MECOC) and Monotone Multiclassification with Deep Forest (MMDF). TISRF extracts radiomics features for distinguishing different hepatic fibrosis stages. MECOC is proposed to encode monotonic multiclass by making full use of the progressive severity of hepatic fibrosis and increase the fault tolerance and error correction ability. MMDF combines multiple Deep Forest network to ensure the final five-class classification, which can achieve more precise classification than the common binary classification. The performance of the proposed hepatic fibrosis CAD system is tested on the hepatic data collected from our rabbits models offibrosis. A total of 140 regions of interest (ROI) are selected from MRI T1W of liver fibrosis models in 35 rabbits with F0(n=16), F1(n=28), F2(n=29), F3(n=44) and F4(n=23). The performance is evaluated by five-fold cross-validation. TMM can achieve the highest total accuracy of 72.14% for five fibrosis stages compared with other popular classifications. To make a comprehensive comparison, a binary classification experiment have been carried out. T1WI can obtain precise staging of hepatic fibrosis with the help of comprehensive CAD including radiomics features extraction inspired by radiologists, monotonic multiclass according to the severity of hepatic fibrosis, and deep learningclassification.

Sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus and moderate to severe hepatic fibrosis: A retrospective study

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to decrease hepatic transaminases, steatosis, and in some studies, hepatic fibrosis. However, the safety and efficacy of SGLT2i has not been tested in patients who have moderate to severe hepatic fibrosis. In a retrospective study of sixty patients with moderate to severe hepatic fibrosis (kPa estimated by Fibroscan > 10), SGLT2i were prescribed on top of other oral anti-hyperglycemic medications. The safety and efficacy of SGLT2i were evaluated. Using the Fibroscan, CAP scores (decibel/meter), and liver stiffness measurement (LSM) (kPa, kilopascals) were examined before and after treatment. The mean age of the T2DM patients was 54.7±10.3 years, and the mean duration of T2DM was 8.3±7.1 years. SGLT2i were given from 3 to 36 months. After treatment, a decrease in glycated hemoglobin (HbA1c), and hepatic transaminases (SGOT and SGPT) was recorded. Upon follow up, CAP and kPa scores decreased significantly. Importantly, no adverse drug reaction, such as balanoposthitis, vulvovaginitis, urosepsis, and postural drop in blood pressure, were reported in any patient. In this retrospective cohort study, patient with T2DM and moderate to severe hepatic fibrosis, use of SGLT2i is safe with respect to common adverse effects & may have contributed to improved hepatic profile.