H. Vilstrup

Risk of Venous Thromboembolism in Patients With Liver Disease : A Nationwide Population-Based Case-Control Study

OBJECTIVES:It is known that liver disease can cause an imbalance in the coagulation system, but available data on liver disease and risk of venous thromboembolism are conflicting. We examined the risk of venous thromboembolism in patients hospitalized with liver diseases.METHODS:We conducted a nationwide Danish case–control study of incident cases of venous thromboembolism from 1980 to 2005 using population-based data from the National Registry of Patients, and from the Civil Registration System. We used conditional logistic regression to compute the relative risk of venous thromboembolism in patients with liver disease compared to population controls. We then excluded patients with known malignancy (diagnosed either before or up to 3 months after the venous thromboembolism) or fractures, trauma, surgery, or pregnancy within 90 days before the venous thromboembolism to estimate the risk associated with unprovoked venous thromboembolism.RESULTS:A total of 99,444 patients with venous thromboembolism and 496,872 population controls were included in the study. Patients with liver disease had a clearly increased relative risk of venous thromboembolism, varying from 1.74 (95% CI, 1.54–1.95) for liver cirrhosis to 1.87 (95% CI, 1.73–2.03) for non-cirrhotic liver disease. The risks were higher for deep venous thrombosis compared with pulmonary embolism. In the analysis, restricted to 67,519 patients with unprovoked venous thromboembolism and 308,614 population controls, we found slightly higher relative risks: 2.06 (95% CI, 1.79–2.38) for liver cirrhosis and 2.10 (95% CI, 1.91–2.31) for non-cirrhotic liver disease.CONCLUSIONS:Patients with liver disease have a substantially increased risk of venous thromboembolism.

The nutritional management of hepatic encephalopathy in patients with cirrhosis: International society for hepatic encephalopathy and nitrogen metabolism consensus

Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex‐related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35‐45 kcal/g and 1.2‐1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late‐night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short‐term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE. (Hepatology 2013)

Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF)

BACKGROUND & AIMS In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. METHODS We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n=406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n=301). RESULTS HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n=174) and not associated (n=286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. CONCLUSIONS In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF.

Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity

Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of satavaptan over placebo in delaying ascites formation. Moreover, satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. Conclusion Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.

Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study.

Goals To examine the risk of cancer in patients with fatty liver. Background The relation between liver disease, including fatty liver, and cancer risk is poorly understood. Study Using the population-based National Registry of Patients, we examined the incidence of cancer in 7,326 patients discharged with a diagnosis of fatty liver from a Danish hospital during 1977–1993. Patients with a prior diagnosis of liver cirrhosis were excluded. We identified cancers through the Danish Cancer Registry. The expected number of cancers was estimated from national age-, sex-, and site-specific incidence rates. Results Overall, 523 cancers were diagnosed during 47,594 person-years of follow-up, yielding a 1.7-fold increased risk (95% confidence interval, 1.6–1.9) compared with the Danish general population. The risk of primary liver cancer was markedly elevated in patients with alcoholic as well as nonalcoholic fatty liver with a standardized incidence ratio of 9.5 (95% confidence interval, 5.7–14.8) and 4.4 (95% confidence interval, 1.2–11.4), respectively. Patients with alcoholic fatty liver also had substantially increased risks of several types of cancer associated with alcohol and tobacco use (cancers of the lung, pharynx, larynx, esophagus, and stomach) and a moderately increased risk for cancers of the colon and breast. Among patients with nonalcoholic fatty liver, an increased risk of some alcohol- and tobacco-related cancers was seen, and there was also an increased risk of colon and pancreas cancer. Conclusions Patients discharged with a diagnosis of fatty liver have an increased risk of cancer, in particular liver cancer, most prominently among patients with alcoholic fatty liver.

Plasma clearances of branched-chain amino acids in control subjects and in patients with cirrhosis

In an attempt to clarify the pathogenesis of the decreased branched-chain amino acid (BCAA) plasma concentrations in cirrhosis, the plasma clearances were measured in 7 patients with cirrhosis and in 7 age- and sex-matched control subjects. BCAA were given as prime-continuous infusions. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady state concentration, were low normal in cirrhotics despite hyperinsulinaemia, but different BCAA had different clearances (P less than 0.01). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were lower in cirrhotics (P less than 0.025). The apparent theoretical volumes of distribution of BCAA, assessed by the ratio between the clearance and the concentration decay constant after infusion stop, were on average 67% of the total body weight, and were neither different among the three BCAA, nor between the two groups. The urea nitrogen synthesis rate did not increase significantly, suggesting that most of the infused BCAA nitrogen was taken up in peripheral tissues. The decreased concentration of BCAA in cirrhotics (394 +/- 81 mumol/l (mean +/- SD) in the present series vs 510 +/- 68 in controls; P less than 0.025) is not attributable to changes in plasma clearance. The most likely explanation is decreased afflux of BCAA into plasma.

Increased risk and case fatality rate of pyogenic liver abscess in patients with liver cirrhosis: a nationwide study in Denmark

BACKGROUND Patients with liver cirrhosis are at increased risk of serious bacterial infections carrying a high case fatality rate. Case reports have suggested an association between liver cirrhosis and pyogenic liver abscess. AIMS To estimate the risk and case fatality rate of pyogenic liver abscess in Danish patients with liver cirrhosis compared with the background population. METHODS Identification of all patients with liver cirrhosis and pyogenic liver abscess over a 17 year period in the National Registry of Patients. Information on death was obtained from the Danish Central Person Registry. RESULTS We identified 22 764 patients with liver cirrhosis and 665 patients with pyogenic liver abscess, of whom 21 were cirrhotics and 644 were non-cirrhotics. The crude incidence rate of liver abscess in cirrhotics was 23.3 (95% CI 14.4–35.6) per 100 000 person years. The age adjusted risk of liver abscess was increased 15-fold in patients with cirrhosis compared with the background population. The 30 day case fatality rates in patients with liver abscess and cirrhosis were 38.5% (13.9–68.4) in alcoholic cirrhosis and 62.5% (24.5–91.5) in non-alcoholic cirrhosis compared with 26.9% (23.5–30.5) in liver abscess patients from the background population. After adjustment for sex, age, and comorbidity, the relative risk of death was increased more than fourfold in alcoholic cirrhosis and non-alcoholic cirrhosis compared with the background population. CONCLUSIONS Liver cirrhosis is a strong risk factor for pyogenic liver abscess associated with a poor prognosis.

No oxygen delivery limitation in hepatic encephalopathy

Hepatic encephalopathy is a condition of reduced brain functioning in which both blood flow and brain energy metabolism declined. It is not known whether blood flow or metabolism is the primary limiting factor of brain function in this condition. We used calculations of mitochondrial oxygen tension to choose between cause and effect in three groups of volunteers, including healthy control subjects (HC), patients with cirrhosis of the liver without hepatic encephalopathy (CL), and patients with cirrhosis with acute hepatic encephalopathy. Compared to HC subjects, blood flow and energy metabolism had declined in all gray matter regions of the brain in patients with HE but not significantly in patients with CL. Analysis of flow-metabolism coupling indicated that blood flow declined in HE as a consequence of reduced brain energy metabolism implied by the calculation of increased mitochondrial oxygen tensions that patients with HE were unable to utilize. We ascribe the inability to use the delivered oxygen of patients with HE to a specific inhibition associated with oxidative metabolism in mitochondria.

Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus

Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.

Cirrhosis is Associated with an Increased 30-Day Mortality After Venous Thromboembolism

Objectives:Patients with cirrhosis are at increased risk of venous thromboembolism (VTE), but the impact of cirrhosis on the clinical course following VTE is unclear. In a nationwide cohort study, we examined 30-day mortality among patients with cirrhosis and VTE.Methods:We used Danish population-based health-care databases (1994–2011) to identify patients with incident VTE, i.e., deep venous thrombosis (DVT), pulmonary embolism (PE), and portal vein thrombosis (PVT). Among these, we identified 745 patients with cirrhosis and 3647 patients without cirrhosis (matched on gender, year of birth, calendar year of VTE diagnosis and VTE type). We assessed the 30-day mortality risk among VTE patients with and without cirrhosis, and the mortality rate ratios (MRRs), using an adjusted Cox model with 95% confidence interval. We obtained information on immediate cause of death for patients who died within 30 days after VTE.Results:The 30-day mortality risk for DVT was 7% for patients with cirrhosis and 3% for patients without cirrhosis. Corresponding PE-related mortality risks were 35% and 16%, and PVT-related mortality risks were 19% and 15%, respectively. The adjusted 30-day MRRs were 2.17 (1.24–3.79) for DVT, 1.83 (1.30–2.56) for PE, and 1.30 (0.80–2.13) for PVT. Though overall mortality was higher in patients with cirrhosis than patients without cirrhosis, the proportions of deaths due to PE were similar among patients (25% and 24%, respectively).Conclusions:Cirrhosis is a predictor for increased short-term mortality following VTE, with PE as the most frequent cause of death.