Synthesis of acute phase proteins in rats with cirrhosis exposed to lipopolysaccharide

BACKGROUND: In patients with cirrhosis, infection is frequent and a leading cause of death. This is secondary to various immunologic abnormalities in both the innate and the adaptive immune system. However, it remains unclear whether cirrhosis affects the inflammatory systemic component of the innate immunity, 'the acute phase response', mostly effectuated by the liver itself. We hypothesized that rats with cirrhosis raise a reduced acute phase response induced by lipopolysaccharide (LPS). RESULTS: We examined the acute phase response induced by intraperitoneal injection of a low dose of LPS, in sham operated control animals and in rats with liver cirrhosis induced by bile duct ligation (BDL). We measured the serum concentrations of the most important acute phase proteins and their liver tissue gene expressions, assessed by mRNA levels. The BDL-model itself increased the serum concentration of α1-acid glycoprotein (α1AGP) and haptoglobin. LPS was lethal to 25% of the cirrhotic animals and to none of the controls. Twenty-four hours after LPS, the serum concentration of α1AGP and haptoglobin, the mRNA level of these acute phase proteins and of α2-macroglobulin and thiostatin rose to the same level in the animals with cirrhosis and in controls. CONCLUSION: In rats with experimental cirrhosis LPS caused high mortality. In the survivors, the cirrhotic liver still synthesized acute phase proteins as the normal liver, indicating a normal hepatic contribution to this part of the acute phase response

The galactose elimination capacity and mortality in 781 Danish patients with newly-diagnosed liver cirrhosis: a cohort study

<p>Abstract</p> <p>Background</p> <p>Despite its biologic plausibility, the association between liver function and mortality of patients with chronic liver disease is not well supported by data. Therefore, we examined whether the galactose elimination capacity (GEC), a physiological measure of the total metabolic capacity of the liver, was associated with mortality in a large cohort of patients with newly-diagnosed cirrhosis.</p> <p>Methods</p> <p>By combining data from a GEC database with data from healthcare registries we identified cirrhosis patients with a GEC test at the time of cirrhosis diagnosis in 1992–2005. We divided the patients into 10 equal-sized groups according to GEC and calculated all-cause mortality as well as cirrhosis-related and not cirrhosis-related mortality for each group. Cox regression was used to adjust the association between GEC and all-cause mortality for confounding by age, gender and comorbidity, measured by the Charlson comorbidity index.</p> <p>Results</p> <p>We included 781 patients, and 454 (58%) of them died during 2,617 years of follow-up. Among the 75% of patients with a decreased GEC (<1.75 mmol/min), GEC was a strong predictor of 30-day, 1-year, and 5-year mortality, and this could not be explained by confounding (crude hazard ratio for a 0.5 mmol/min GEC increase = 0.74, 95% CI 0.59–0.92; adjusted hazard ratio = 0.64, 95% CI 0.51–0.81). Further analyses showed that the association between GEC and mortality was identical for patients with alcoholic or non-alcoholic cirrhosis etiology, that it also existed among patients with comorbidity, and that GEC was only a predictor of cirrhosis-related mortality. Among the 25% of patients with a GEC in the normal range (≥ 1.75 mmol/min), GEC was only weakly associated with mortality (crude hazard ratio = 0.79, 95% CI 0.59–1.05; adjusted hazard ratio = 0.80, 95% CI 0.60–1.08).</p> <p>Conclusion</p> <p>Among patients with newly-diagnosed cirrhosis and a decreased GEC, the GEC was a strong predictor of short- and long-term all-cause and cirrhosis-related mortality. These findings support the expectation that loss of liver function increases mortality.</p

Presence and consequence of tooth periapical radiolucency in patients with cirrhosis

BACKGROUND: Periapical radiolucency is the radiographic sign of inflammatory bone lesions around the apex of the tooth. We determined the prevalence and predictors of periapical radiolucency in patients with cirrhosis and the association with systemic inflammation status and cirrhosis-related complications. METHODS: A total of 110 cirrhosis patients were consecutively enrolled. Periapical radiolucency was defined as the presence of radiolucency or widening of the periapical periodontal ligament space to more than twice the normal width. Predictors of periapical radiolucency and the association with systemic inflammation markers and cirrhosis-related complications were explored by univariable and multivariable logistic regression analyses. RESULTS: Periapical radiolucency was present in one or more teeth in 46% of the patients. Strong predictors were gross caries (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.43–6.79) and severe periodontitis (OR 3.98, 95% CI 1.04–15.20). Also old age (OR 1.10, 95% CI 1.01–1.19) and smoking (OR 3.24, 95% CI 1.02–17.62) were predictors. However, cirrhosis etiology (alcoholic vs nonalcoholic) or severity (Model of End-Stage Liver Disease score) were not predictors. The patients with periapical radiolucency had higher C-reactive protein (15.8 mg/L vs 8.1 mg/L, P=0.02) and lower albumin contents (25 g/L vs 28 g/L, P=0.04) than those without. Furthermore, the patients with periapical radiolucency had a higher prevalence of cirrhosis-related complications such as ascites, hepatic encephalopathy, and/or variceal bleeding (46% vs 27%, P=0.05). CONCLUSION: Periapical radiolucency is often present as an element of poor oral health status and likely has an adverse clinical significance, which should motivate diagnostic and clinical attention to the findings

Role of ammonia in NAFLD: An unusual suspect

Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body’s only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials