The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure

BACKGROUND & AIMS Cirrhotic patients with acute decompensation frequently develop acute-on-chronic liver failure (ACLF), which is associated with high mortality rates. Recently, a specific score for these patients has been developed using the CANONIC study database. The aims of this study were to develop and validate the CLIF-C AD score, a specific prognostic score for hospitalised cirrhotic patients with acute decompensation (AD), but without ACLF, and to compare this with the Child-Pugh, MELD, and MELD-Na scores. METHODS The derivation set included 1016 CANONIC study patients without ACLF. Proportional hazards models considering liver transplantation as a competing risk were used to identify score parameters. Estimated coefficients were used as relative weights to compute the CLIF-C ADs. External validation was performed in 225 cirrhotic AD patients. CLIF-C ADs was also tested for sequential use. RESULTS Age, serum sodium, white-cell count, creatinine and INR were selected as the best predictors of mortality. The C-index for prediction of mortality was better for CLIF-C ADs compared with Child-Pugh, MELD, and MELD-Nas at predicting 3- and 12-month mortality in the derivation, internal validation and the external dataset. CLIF-C ADs improved in its ability to predict 3-month mortality using data from days 2, 3-7, and 8-15 (C-index: 0.72, 0.75, and 0.77 respectively). CONCLUSIONS The new CLIF-C ADs is more accurate than other liver scores in predicting prognosis in hospitalised cirrhotic patients without ACLF. CLIF-C ADs therefore may be used to identify a high-risk cohort for intensive management and a low-risk group that may be discharged early.

Physical activity and liver diseases

Regular physical activity beneficially impacts the risk of onset and progression of several chronic diseases. However, research regarding the effects of exercising on chronic liver diseases is relatively recent. Most authors focused on non-alcoholic fatty liver disease (NAFLD), in which increasing clinical and experimental data indicate that skeletal muscle cross-talking to the adipose tissue and the liver regulates intrahepatic fat storage. In this setting physical activity is considered required in combination with calories restriction to allow an effective decrease of intrahepatic lipid component, and despite that evidence is not conclusive, some studies suggest that vigorous activity might be more beneficial than moderate activity to improve NAFLD/NASH. Evidence regarding the effects of exercise on the risk of hepatocellular carcinoma is scarce; some epidemiological studies indicate a lower risk in patients regularly and vigorously exercising. In compensated cirrhosis exercise acutely increases portal pressure, but in longer term it has been proved safe and probably beneficial. Decreased aerobic capacity (VO2) correlates with mortality in patients with decompensated cirrhosis, who are almost invariably sarcopenic. In these patients VO2 is improved by physical activity, which might also reduce the risk of hepatic encephalopathy through an increase in skeletal muscle mass. In solid organ transplantation recipients exercise is able to improve lean mass, muscle strength and as a consequence, aerobic capacity. Few data exist in liver transplant recipients, in whom exercise should be object of future studies given its high potential of providing long-term beneficial effects. Despite evidence is far from complete, physical activity should be seen as an important part of the management of patients with liver disease in order to improve their clinical outcome. This article is protected by copyright. All rights reserved.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared to their pre-treatment values (within 6 six months prior to the start of therapy). All registered platelet count measurements from 24 week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 x10(9) /L (IQR 7-62, p<0.001). In comparison, patients without SVR showed a median decline of 17 x10(9) /L (IQR -5-47, p<0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, p<0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R=-0.41, p<0.001). CONCLUSIONS Among chronic HCV-infected patients with advanced hepatic fibrosis the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. This article is protected by copyright. All rights reserved.

Hepatocellular carcinoma and lifestyles.

The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to non-alcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and non-alcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.

UNLABELLED Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.

Alcoholic Cirrhosis Increases Risk for Autoimmune Diseases: A Nationwide Registry-Based Cohort Study

BACKGROUND & AIMS Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients with alcoholic cirrhosis vs controls in Denmark. METHODS We collected data from nationwide health care registries to identify and follow up all citizens of Denmark diagnosed with alcoholic cirrhosis from 1977 through 2010. Each patient was matched with 5 random individuals from the population (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination). RESULTS Of the 24,679 patients diagnosed with alcoholic cirrhosis, 532 developed an autoimmune disease, yielding an overall increased adjusted incidence rate ratio (aIRR) of 1.36 (95% confidence interval [CI], 1.24-1.50). The strongest associations were with Addison's disease (aIRR, 2.47; 95% CI, 1.04-5.85), inflammatory bowel disease (aIRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate for polymyalgia rheumatica decreased in patients with alcoholic cirrhosis compared with controls (aIRR, 0.47; 95% CI, 0.33-0.67). CONCLUSIONS Based on a nationwide cohort study of patients in Denmark, alcoholic cirrhosis is a risk factor for several autoimmune diseases.

P2X1 regulated IL-22 secretion by innate lymphoid cells is required for efficient liver regeneration.

Paracrine signalling mediated via cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin-22 (IL-22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear if IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy. Here we found that plasma levels of IL-22 and its upstream cytokine IL-23 are highly elevated in patients after major liver resection. In a mouse model of partial hepatectomy, deletion of IL-22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. Using Rag1-/- and Rag2-/- γc-/- mice we show that the main producers of IL-22 post partial hepatectomy are conventional natural killer cells and innate lymphoid cells type 1. Extracellular ATP, a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2 type nucleotide receptors P2X1 and P2Y6 significantly decreased IL-22 secretion ex vivo. In vivo, specific inhibition of P2X1 was associated with decreased IL-22 secretion, elevated liver injury and impaired liver regeneration.

Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men

BACKGROUND AND AIMS Hepatitis C (HCV) is a leading cause of morbidity and mortality in people who live with HIV. In many countries, access to direct acting antiviral agents to treat HCV is restricted to individuals with advanced liver disease (METAVIR stage F3 or F4). Our goal was to estimate the long term impact of deferring HCV treatment for men who have sex with men (MSM) who are coinfected with HIV and often have multiple risk factors for liver disease progression. METHODS We developed an individual-based model of liver disease progression in HIV/HCV coinfected men who have sex with men. We estimated liver-related morbidity and mortality as well as the median time spent with replicating HCV infection when individuals were treated in liver fibrosis stages F0, F1, F2, F3 or F4 on the METAVIR scale. RESULTS The percentage of individuals who died of liver-related complications was 2% if treatment was initiated in F0 or F1. It increased to 3% if treatment was deferred until F2, 7% if it was deferred until F3 and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. CONCLUSIONS Deferring HCV therapy until advanced liver fibrosis is established could increase liver-related morbidity and mortality in HIV/HCV coinfected individuals, and substantially prolong the time individuals spend with replicating HCV infection.

A synthetic biology-based device prevents liver injury in mice

BACKGROUND & AIMS The liver performs a panoply of complex activities coordinating metabolic, immunologic and detoxification processes. Despite the liver's robustness and unique self-regeneration capacity, viral infection, autoimmune disorders, fatty liver disease, alcohol abuse and drug-induced hepatotoxicity contribute to the increasing prevalence of liver failure. Liver injuries impair the clearance of bile acids from the hepatic portal vein which leads to their spill over into the peripheral circulation where they activate the G-protein-coupled bile acid receptor TGR5 to initiate a variety of hepatoprotective processes. METHODS By functionally linking activation of ectopically expressed TGR5 to an artificial promoter controlling transcription of the hepatocyte growth factor (HGF), we created a closed-loop synthetic signalling network that coordinated liver injury-associated serum bile acid levels to expression of HGF in a self-sufficient, reversible and dose-dependent manner. RESULTS After implantation of genetically engineered human cells inside auto-vascularizing, immunoprotective and clinically validated alginate-poly-(L-lysine)-alginate beads into mice, the liver-protection device detected pathologic serum bile acid levels and produced therapeutic HGF levels that protected the animals from acute drug-induced liver failure. CONCLUSIONS Genetically engineered cells containing theranostic gene circuits that dynamically interface with host metabolism may provide novel opportunities for preventive, acute and chronic healthcare. LAY SUMMARY Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage.