Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that ...associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, ...but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.
We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment.
A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval CI, 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients 29.7%) and the standard-care group (120 of 397 patients 30.2%) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.
In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).
Background & Aims Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Methods Using ...cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA −/− mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells ( IL-17RA −/− to wild-type and IL-17A −/− to wild-type mice) or liver resident cells (wild-type to IL-17RA −/− mice). Results In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells ( GFAPStat3 −/− mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.
Simple and inexpensive non-invasive fibrosis tests are highly needed but have been poorly studied in sub-Saharan Africa.
Using liver histology as a gold standard, we developed a novel index using ...routine laboratory tests to predict significant fibrosis in patients with chronic HBV infection in The Gambia, West Africa. We prospectively assessed the diagnostic accuracy of the novel index, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and Fib-4 in Gambian patients with CHB (training set) and also in French and Senegalese CHB cohorts (validation sets).
Of 135 consecutive treatment-naïve patients with CHB who had liver biopsy, 39% had significant fibrosis (Metavir fibrosis stage ≥F2) and 15% had cirrhosis (F4). In multivariable analysis, gamma-glutamyl transpeptidase (GGT) and platelet count were independent predictors of significant fibrosis. Consequently, GGT-to-platelet ratio (GPR) was developed. In The Gambia, the area under the receiver operating characteristic curve (AUROC) of the GPR was significantly higher than that of APRI and Fib-4 to predict ≥F2, ≥F3 and F4. In Senegal, the AUROC of GPR was significantly better than Fib-4 and APRI for ≥F2 (0.73, 95% CI 0.59 to 0.86) and better than Fib-4 and Fibroscan for ≥F3 (0.93, 0.87 to 0.99). In France, the AUROC of GPR to diagnose ≥F2 (0.72, 95% CI 0.59 to 0.85) and F4 (0.87, 0.76 to 0.98) was equivalent to that of APRI and Fib-4.
The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa. The GPR represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa.
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Nitazoxanide is an FDA-approved antiprotozoal drug. Our previous studies find that nitazoxanide and its metabolite tizoxanide affect AMPK, STAT3, and Smad2/3 signals which are ...involved in the pathogenesis of liver fibrosis, therefore, in the present study, we examined the effect of nitazoxanide on experimental liver fibrosis and elucidated the potential mechanisms. The in vivo experiment results showed that oral nitazoxanide (75, 100 mg·kg−1) significantly improved CCl4- and bile duct ligation-induced liver fibrosis in mice. Oral nitazoxanide activated the inhibited AMPK and inhibited the activated STAT3 in liver tissues from liver fibrosis mice. The in vitro experiment results showed that nitazoxanide and its metabolite tizoxanide activated AMPK and inhibited STAT3 signals in LX-2 cells (human hepatic stellate cells). Nitazoxanide and tizoxanide inhibited cell proliferation and collagen I expression and secretion of LX-2 cells. Nitazoxanide and tizoxanide inhibited transforming growth factor-β1 (TGF-β1)- and IL-6-induced increases of cell proliferation, collagen I expression and secretion, inhibited TGF-β1- and IL-6-induced STAT3 and Smad2/3 activation in LX-2 cells. In mouse primary hepatic stellate cells, nitazoxanide and tizoxanide also activated AMPK, inhibited STAT3 and Smad2/3 activation, inhibited cell proliferation, collagen I expression and secretion. In conclusion, nitazoxanide inhibits liver fibrosis and the underlying mechanisms involve AMPK activation, and STAT3 and Smad2/3 inhibition.
Liver cirrhosis Ginès, Pere; Krag, Aleksander; Abraldes, Juan G ...
The Lancet (British edition),
10/2021, Letnik:
398, Številka:
10308
Journal Article
Recenzirano
Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as obesity, non-alcoholic fatty liver disease, high alcohol consumption, hepatitis B or C infection, ...autoimmune diseases, cholestatic diseases, and iron or copper overload. Cirrhosis develops after a long period of inflammation that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. The disease evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the complications of which often result in hospitalisation, impaired quality of life, and high mortality. Progressive portal hypertension, systemic inflammation, and liver failure drive disease outcomes. The management of liver cirrhosis is centred on the treatment of the causes and complications, and liver transplantation can be required in some cases. In this Seminar, we discuss the disease burden, pathophysiology, and recommendations for the diagnosis and management of cirrhosis and its complications. Future challenges include better screening for early fibrosis or cirrhosis, early identification and reversal of causative factors, and prevention of complications.
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis.Recent data indicate that the termination of ...fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis.Therefore,efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis.Activation of hepatic stellate cells(HSCs)remains a central event in fibrosis,complemented by other sources of matrix-producing cells,including portal fibroblasts,fibrocytes and bone marrow-derived myofibroblasts.These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury.Defining the interaction of different cell types,revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets.Moreover,the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies.This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies.The pathogenesis of liver fibrosis associated with alcoholic liver disease,non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes ...transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP.
Primary HSCs were isolated from C57BL/6 or Smoflox/flox mice; we also performed studies with rat and human myofibroblastic HSCs. We measured changes of glutaminolytic genes during culture-induced primary HSC transdifferentiation. Glutaminolysis was disrupted in cells by glutamine deprivation or pathway inhibitors (bis-2-5-phenylacetamido-1,2,4-thiadiazol-2-yl ethyl sulfide, CB-839, epigallocatechin gallate, and aminooxyacetic acid), and effects on mitochondrial respiration, cell growth and migration, and fibrogenesis were measured. Hedgehog signaling to YAP was disrupted in cells by adenovirus expression of Cre-recombinase or by small hairpin RNA knockdown of YAP. Hedgehog and YAP activity were inhibited by incubation of cells with cyclopamine or verteporfin, and effects on glutaminolysis were measured. Acute and chronic liver fibrosis were induced in mice by intraperitoneal injection of CCl4 or methionine choline-deficient diet. Some mice were then given injections of bis-2-5-phenylacetamido-1,2,4-thiadiazol-2-yl ethyl sulfide to inhibit glutaminolysis, and myofibroblast accumulation was measured. We also performed messenger RNA and immunohistochemical analyses of percutaneous liver biopsies from healthy human and 4 patients with no fibrosis, 6 patients with mild fibrosis, and 3 patients with severe fibrosis.
Expression of genes that regulate glutaminolysis increased during transdifferentiation of primary Q-HSCs into myofibroblastic HSCs, and inhibition of glutaminolysis disrupted transdifferentiation. Blocking glutaminolysis in myofibroblastic HSCs suppressed mitochondrial respiration, cell growth and migration, and fibrogenesis; replenishing glutaminolysis metabolites to these cells restored these activities. Knockout of the hedgehog signaling intermediate smoothened or knockdown of YAP inhibited expression of glutaminase, the rate-limiting enzyme in glutaminolysis. Hedgehog and YAP inhibitors blocked glutaminolysis and suppressed myofibroblastic activities in HSCs. In livers of patients and of mice with acute or chronic fibrosis, glutaminolysis was induced in myofibroblastic HSCs. In mice with liver fibrosis, inhibition of glutaminase blocked accumulation of myofibroblasts and fibrosis progression.
Glutaminolysis controls accumulation of myofibroblast HSCs in mice and might be a therapeutic target for cirrhosis.
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Nonalcoholic fatty liver disease (NAFLD) is a spectrum comprised of isolated steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not ...have NASH and do not carry a significant risk for liver‐related adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high to low prevalence rates is noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition of NASH as an important liver disease, the diagnosis of NASH still requires a liver biopsy that is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, this method suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathological features. A number of noninvasive modalities to diagnose NASH and stage liver fibrosis are being developed. These modalities include predictive models (NAFLD fibrosis score) and serum biomarkers such as enhanced liver fibrosis (ELF). Other tests are based on radiological techniques, such as transient elastography (TE) or magnetic resonance elastography (MRE), which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have area under the curve ranging between 0.76 and 0.90%, with MRE having the best predictive performance. In summary, developing safe and easily accessible noninvasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease, but also to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH. (Hepatology 2018;68:349‐360).
Liver cirrhosis Tsochatzis, Emmanuel A, PhD; Bosch, Jaime, Prof; Burroughs, Andrew K, Prof
The Lancet (British edition),
05/2014, Letnik:
383, Številka:
9930
Journal Article
Recenzirano
Summary Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, ...cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.
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