Annette Dam Fialla

Transient and 2-Dimensional Shear-Wave Elastography Provide Comparable Assessment of Alcoholic Liver Fibrosis and Cirrhosis

BACKGROUND & AIMS Alcohol abuse causes half of all deaths from cirrhosis in the West, but few tools are available for noninvasive diagnosis of alcoholic liver disease. We evaluated 2 elastography techniques for diagnosis of alcoholic fibrosis and cirrhosis; liver biopsy with Ishak score and collagen-proportionate area were used as reference. METHODS We performed a prospective study of 199 consecutive patients with ongoing or prior alcohol abuse, but without known liver disease. One group of patients had a high pretest probability of cirrhosis because they were identified at hospital liver clinics (in Southern Denmark). The second, lower-risk group, was recruited from municipal alcohol rehabilitation centers and the Danish national public health portal. All subjects underwent same-day transient elastography (FibroScan), 2-dimensional shear wave elastography (Supersonic Aixplorer), and liver biopsy after an overnight fast. RESULTS Transient elastography and 2-dimensional shear wave elastography identified subjects in each group with significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) with high accuracy (area under the curve ≥0.92). There was no difference in diagnostic accuracy between techniques. The cutoff values for optimal identification of significant fibrosis by transient elastography and 2-dimensional shear wave elastography were 9.6 kPa and 10.2 kPa, and for cirrhosis 19.7 kPa and 16.4 kPa. Negative predictive values were high for both groups, but the positive predictive value for cirrhosis was >66% in the high-risk group vs approximately 50% in the low-risk group. Evidence of alcohol-induced damage to cholangiocytes, but not ongoing alcohol abuse, affected liver stiffness. The collagen-proportionate area correlated with Ishak grades and accurately identified individuals with significant fibrosis and cirrhosis. CONCLUSIONS In a prospective study of individuals at risk for liver fibrosis due to alcohol consumption, we found elastography to be an excellent tool for diagnosing liver fibrosis and for excluding (ruling out rather than ruling in) cirrhosis.

Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis

Patients with cirrhosis and alcoholic hepatitis are often malnourished and have a superimposed stress metabolism, which increases nutritional demands. We performed a systematic review on the effects of nutritional therapy vs. no intervention for patients with cirrhosis or alcoholic hepatitis.

Incidence, etiology and mortality of cirrhosis: a population-based cohort study

Abstract Objective. Knowledge on the prognosis among patients with cirrhosis is mainly based on clinical trials with selected patient groups as well as population-based register studies with suboptimal diagnostic reliability. The aim of the study was to describe incidence, etiology, and mortality of well-validated cirrhotic cases in a population-based cohort at Funen (population 470,000) between 1996 and 2006. Materials and methods. A population-based cohort study with case identification from discharge diagnosis followed by manual validation of patient records with inclusion of cases that fulfilled predefined diagnostic criteria. Results. 4010 possible cases were identified. 1369 patients were included, 67% males, mean age 56.4 years, 75% had cirrhotic complications at entry. Mean follow-up was 3.6 years with a total of 4976 years of follow-up. The incidence was 33/100,000 person-years (95% confidence interval CI 28–40). Stratified for age and sex, the incidence was twice as high for men compared with women in all age groups. The five-year mortality was 62% (95% CI 59–65). A multivariate analysis showed a high mortality associated with male gender (HR 1.24, 95% CI 1.08–1.42), ages above 70 years (HR 2.01 95% CI 1.65–2.47) compared with ages 50–59 years, complications present at diagnosis (HR 1.28, 95% CI 1.09–1.50) and etiology of alcoholic disease or cryptogenic cirrhosis (HR 2.38, 95% CI 1.22–4.67 and 2.26, 95% CI 1.13–4.53). Conclusions. Incidence of cirrhosis is higher among men than among women. High age, male gender, alcoholic cirrhosis, cryptogenic cirrhosis, and complications at the time of diagnosis increased mortality.

Large Variations in Risk of Hepatocellular Carcinoma and Mortality in Treatment Naïve Hepatitis B Patients: Systematic Review with Meta-Analyses

Background The complications to chronic hepatitis B (HBV) include incidence of hepatocellular carcinoma (HCC) and mortality. The risk of these complications may vary in different patient groups. Aim To estimate the incidence and predictors of HCC and in untreated HBV patients. Methods Systematic review with random effects meta-analyses of randomized controlled trials and observational studies. Results are expressed as annual incidence (events per 100 person-years) with 95% confidence intervals. Subgroup and sensitivity analyses of patient and study characteristics were performed to identify common risk factors. Results We included 68 trials and studies with a total of 27,584 patients (264,919 person-years). In total, 1,285 of 26,687 (5%) patients developed HCC and 730 of 12,511 (6%) patients died. The annual incidence was 0.88 (95% CI, 0.76–0.99) for HCC and 1.26 (95% CI, 1.01–1.51) for mortality. Patients with cirrhosis had a higher risk of HCC (incidence 3.16; 95% CI, 2.58–3.74) than patients without cirrhosis (0.10; 95% CI, 0.02–0.18). The risk of dying was also higher for patients with than patients without cirrhosis (4.89; 95% CI, 3.16–6.63; and 0.11; 95% CI, 0.09–0.14). The risk of developing HCC increased with HCV coinfection, older age and inflammatory activity. The country of origin did not clearly predict HCC or mortality estimates. Conclusions Cirrhosis was the strongest predictor of HCC incidence and mortality. Patients with HBV cirrhosis have a 31-fold increased risk of HCC and a 44-fold increased mortality compared to non-cirrhotic patients. The low incidence rates should be taken into account when considering HCC screening in non-cirrhotic patients. Trial Registration Prospero CRD42013004764

Reduced platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis

Abstract Results from previous studies regarding platelet function in liver cirrhosis are discordant. The aim was to investigate platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. We included 27 patients with alcoholic liver cirrhosis and 22 healthy individuals. A recently established flow cytometric approach was used to measure platelet activation and platelet aggregation independent of sample platelet count. Platelet aggregation was further investigated using light transmission aggregometry (LTA) (for platelet count >100 × 109/L). Platelet agonists were adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid, collagen, and collagen-related peptide. Patients had lower median platelet count than healthy individuals, 125 × 109/L (interquartile range [IQR] 90˗185) versus 240 × 109 (IQR 204˗285), p < 0.001. Platelet activation levels in stimulated samples were lower in patients versus healthy individuals, e.g., after collagen-related peptide stimulation, the median percentage of platelets positive for activated glycoprotein IIb/IIIa was 85% (IQR 70–94) in patients versus 97% (IQR 94–99) in healthy individuals, p < 0.001; lower platelet activation capacity being associated with low platelet count and Child–Pugh class B/C cirrhosis. Flow cytometric platelet aggregation was reduced in patients for collagen-related peptide and for adenosine diphosphate, e.g., platelet aggregation (mean ± standard deviation) was 57% ± 4 in patients versus 70% ± 1 in healthy individuals for collagen-related peptide, p = 0.01. Light LTA showed reduced collagen-induced platelet aggregation in some patients compared with healthy individuals. In conclusion, platelet function was reduced in some patients with alcoholic liver cirrhosis and the severity was associated with platelet count and severity of liver cirrhosis.

Internal dysregulation of the renin system in patients with stable liver cirrhosis

Abstract Sodium retention in cirrhosis is associated with changes in the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS), and the glomerular filtration rate (GFR). We hypothesized that in cirrhosis the acute reactions of RAAS and SNS to volume expansion are qualitatively intact, but occurring from elevated baseline levels. Acute cardiovascular, neurohumoral and renal responses to central blood volume changes were studied in cirrhotic patients and healthy controls. In patients, baseline plasma renin concentration (PRC) was elevated 5-fold compared to controls (p < .001); it increased during standing (+144%, p < .001) and remained elevated during subsequent sitting (+118%, p < .001). At baseline, plasma angiotensin II (pANGII) was not elevated significantly (14 ± 2 vs. 9 ± 2 pg/mL) in contrast to plasma aldosterone (pAldo, +160%, p < .001). During orthostatic RAAS activation, the rise in pAngII per unit increase in PRC was 0.04 pg AngII/mIU and 0.48 pg AngII/mIU in patients and controls, respectively (p < .001); similarly, the change in pAldo per unit change in pANGII was 3.6 in patients and 14.5 pg/pg in controls (p < .001). Plasma noradrenaline was elevated in the patients, but the dynamic changes were virtually identical to those of controls. During standing, abrupt decreases in renal blood flow (−63%, p < .001) and GFR (−42% p < .04) occurred only in patients. In conclusion, in stable cirrhosis, static and dynamic dysregulation exists within the RAAS; in the supine position pAngII levels are inappropriately low, and the AngII-mediated regulation of aldosterone secretion is severely impeded. In cirrhotic patients, profound reductions in renal blood flow and GFR occur during standing.

The calcium-activated potassium channel KCa3.1 is an important modulator of hepatic injury

The calcium-activated potassium channel KCa3.1 controls different cellular processes such as proliferation and volume homeostasis. We investigated the role of KCa3.1 in experimental and human liver fibrosis. KCa3.1 gene expression was investigated in healthy and injured human and rodent liver. Effect of genetic depletion and pharmacological inhibition of KCa3.1 was evaluated in mice during carbon tetrachloride induced hepatic fibrogenesis. Transcription, protein expression and localisation of KCa3.1 was analysed by reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Hemodynamic effects of KCa3.1 inhibition were investigated in bile duct-ligated and carbon tetrachloride intoxicated rats. In vitro experiments were performed in rat hepatic stellate cells and hepatocytes. KCa3.1 expression was increased in rodent and human liver fibrosis and was predominantly observed in the hepatocytes. Inhibition of KCa3.1 aggravated liver fibrosis during carbon tetrachloride challenge but did not change hemodynamic parameters in portal hypertensive rats. In vitro, KCa3.1 inhibition leads to increased hepatocyte apoptosis and DNA damage, whereas proliferation of hepatic stellate cells was stimulated by KCa3.1 inhibition. Our data identifies KCa3.1 channels as important modulators in hepatocellular homeostasis. In contrast to previous studies in vitro and other tissues this channel appears to be anti-fibrotic and protective during liver injury.

The role of glucocorticoids in sodium retention in cirrhotic patients: A double blind, randomized, crossover study

Abstract Objective. Cirrhotic patients have an increased ratio of urinary cortisol to cortisone metabolites, indicating decreased renal 11-β-hydroxysteroid dehydrogenase type-2 activity. This suggests that cortisol – by activation of the mineralocorticoid receptor – may contribute to the abnormal sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout interval of 14 days separated the two periods. After a basal period of 36 h, dexamethasone (0.5 mg every 6 h) or placebo was given for two days. Urine was collected for 12 h periods, and the concentrations of sodium, potassium, creatinine, cortisol and cortisol metabolites were determined. Blood samples for hemoglobin, glucose, sodium, potassium, creatinine, aldosterone and cortisol were obtained daily. Results. Dexamethasone treatment decreased S-cortisol 92.3% (82.9–93.4%) (median and range) compared with that in the basal period. Natriuresis (dexamethasone – placebo) increased 55.1 (−26.4–168.7) mmol/day (median and range). No statistically significant differences (dexamethasone – placebo) were found in changes in body weight (0.00 (−0.45–2.20) kg/day), diuresis (0.56 (−0.35–1.43) L/day) or mean arterial pressure (8.33 (−16.0–41.3) mmHg) (median and range) in reference to the preceding 24 h basal period. Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver.