Portal hypertension is the main driver of liver stiffness in advanced liver cirrhosis.

Liver stiffness (LS) is a novel non-invasive parameter widely used in clinical hepatology. LS correlates with liver fibrosis stage in non-cirrhotic patients. In cirrhotic patients it also shows good correlation with Hepatic Venous Pressure Gradient (HVPG). Our aim was to assess the contribution of liver fibrosis and portal hypertension to LS in patients with advanced liver cirrhosis. Eighty-one liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG and LS measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France). Liver collagen content was assessed in the explanted liver as collagen proportionate area (CPA) and hydroxyproline content (HP). The studied cohort included predominantly patients with Child-Pugh class B and C (63/81, 77.8%), minority of patients were Child-Pugh A (18/81, 22.2%). LS showed the best correlation with HVPG (r=0.719, p< 0.001), correlation of LS with CPA (r=0.441, p< 0.001) and HP/Amino Acids (r=0.414, p< 0.001) was weaker. Both variables expressing liver collagen content showed good correlation with each other (r=0.574, p<0.001). Multiple linear regression identified the strongest association between LS and HVPG (p < 0.0001) and weaker association of LS with CPA (p = 0.01883). Stepwise modelling showed minimal increase in r2 after addition of CPA to HVPG (0.5073 vs. 0.5513). The derived formula expressing LS value formation is: LS = 2.48 + (1.29 x HVPG) + (0.26 x CPA). We conclude that LS is determined predominantly by HVPG in patients with advanced liver cirrhosis whereas contribution of liver collagen content is relatively low.

Acute Liver Failure due to Amanita phalloides Poisoning: Therapeutic Approach and Outcome.

INTRODUCTION: Amanita phalloides poisoning is a potentially fatal cause of acute liver failure. The aim of this study was to analyze the impact of initial patients' characteristics and different treatment modalities on the outcome of patients with liver failure caused by Amanita poisoning. MATERIAL AND METHODS: We retrospectively evaluated 23 patients admitted to our center between July 2007 and August 2016. RESULTS: Mean time interval between Amanita phalloides ingestion and the onset of gastrointestinal symptoms was 12.48 ± 9.88 hours and the interval between ingestion and hospital admission 26.26 ± 15.14 hours. The treatment was intiated by oral decontamination using activated charcoal followed by intravenous rehydration and high doses of intravenous N-acetylcysteine and silibinin. Fourteen patients (61%) underwent extracorporeal elimination method. Ten patients had plasmapheresis, 1 patient had hemoperfusion, and 5 patients had fractionated plasma separation and adsorption. Seven patients who met King's College Criteria were listed for urgent liver transplantation; one of them died before transplantation. Six patients underwent liver transplantation; the mean waiting time was 6.5 ± 12.0 days (range, 1-31 days). One patient died 2 months afterward. All 16 patients who did not meet King's College Criteria and received conservative treatment survived. CONCLUSION: Our results documented a good prognostic value of standard King's College Criteria for indication of urgent liver transplantation in acute liver failure caused by Amanita phalloides poisoning. Fractionated plasma separation and adsorption may contribute to low mortality on the waiting list. Intensive care and extracorporeal elimination methods seem to be crucial points of the conservative treatment.

Incidental hepatocellular carcinoma: risk factors and long-term outcome after liver transplantation.

BACKGROUND: Orthotopic liver transplantation (OLT) currently represents the treatment of choice for early hepatocellular carcinoma (HCC). Preoperatively known HCC (pkHCC) is diagnosed via imaging methods before OLT or before HCC is found postoperatively in the liver explant, denoted as incidental HCC (iHCC). The aim of this study was a comprehensive analysis of the post-transplantation survival of patients with iHCC and the identification of risk factors of iHCC occurrence in cirrhotic liver. METHODS: We retrospectively reviewed 33 adult cirrhotic patients with incidentally found HCC, comparing them with 606 tumor-free adult cirrhotic patients with end-stage liver disease (group Ci) who underwent OLT in our center from January 1995 to August 2012. Within the same period, a total of 84 patients underwent transplantation for pkHCC. We compared post-transplantation survivals of iHCC, Ci, and pkHCC patients. In the group of cirrhotic patients (Ci + iHCC), we searched for risk factors of iHCC occurrence. RESULTS: There was no difference in sex, Model for End-Stage Liver Disease score, and time spent on the waiting list in either group. In the multivariate analysis we identified age >57 years (odds ratio [OR], 3.37; 95% confidence interval [CI], 1.75-8.14; P < .001), hepatitis C virus or alcoholic liver disease (OR, 3.89; 95% CI, 1.42-10.7; P < .001), and alpha-fetoprotein level >6.4 µg/L (OR, 6.65; 95% CI, 2.82-15.7; P = .002) to be independent predictors of iHCC occurrence. Both the 1-, 3-, and 5-year overall survival (OS) and the 1-, 3- and 5-year recurrence-free survival (RFS) differed in iHCC patients compared with the Ci group (iHCC: OS 79%, 72%, and 68%, respectively; RFS 79%, 72%, and 63%, respectively; vs Ci: OS = RFS: 93%, 94%, and 87%, respectively; P < .001). CONCLUSIONS: The survival of iHCC patients is worse than in tumor-free cirrhotic patients, but similar to pkHCC patients. The independent risk factors for iHCC occurrence in cirrhotic liver are age, hepatitis C virus, or alcoholic liver disease etiology of liver cirrhosis and alpha-fetoprotein level.

Historical epidemiology of hepatitis C virus (HCV) in selected countries.

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6,358,000 cases in 2008 and Brazil with 2,106,000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden.

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm.

The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.

Urgent liver transplantation for chemotherapy-induced HBV reactivation: a suitable option in patients recently treated for malignant lymphoma.

BACKGROUND: Hepatitis B (HBV) reactivation induced by chemotherapy is a problem currently encountered in the management of malignancies. HBV reactivation occurs particularly in patients who were not checked for HBV status, and therefore have not undergone antiviral prophylaxis. HBV reactivation may ultimately lead to fulminant liver failure (FLF). Liver transplantation (OLT), the only remaining effective treatment option, is generally denied for subjects with a recent history of malignancy. CASE REPORTS: We described retrospectively three cases of FLF caused by HBV reactivation in two men and one woman undergoing rituximab-containing chemotherapy for malignant lymphomas: follicular, diffuse large B-cell and lymphoplasmacytic types. The two men reactivated after eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone and the one woman after 13 cycles of rituximab monotherapy; their hematologic disease was in remission. All three patients were hepatitis B surface antigen (HBsAg)-positive with high HBV DNA levels. Neither man had been screened for HBV before chemotherapy; the woman had been treated with lamivudine (LAM) experiencing an HBV flare-up due to emergence of LAM resistance. All patients fulfilled King's College criteria for urgent OLT upon admission to the transplant center and underwent an urgent OLT. Their hemato-oncologic prognosis was considered to be favorable. All three patients are alive (54, 46, and 37 months post-transplantation), tumor-free and HBsAg negative on a standard HBV prophylaxis regimen: hepatitis B immunoglobulin and LAM + adefovir or tenofovir. CONCLUSIONS: Before chemotherapy appropriate prophylaxis for HBV reactivation should always be administered to at-risk patients. However, if reactivation with FLF occurs, OLT should not be generally denied. The prognosis of the hematologic malignancy should be assessed; OLT should be considered for patients in remission with a favorable long-term prognosis, for our data suggest acceptable survival.

Ontogeny of social behavior of pups of laboratory rats genetically selected for activity level.

In pups of Wistar laboratory rats genetically selected for high (+A) and low (-A) locomotor activity in an open field social behavior was tested in a situation of paired interactions in a novel environment. Tests were performed on postnatal Days 16, 19, 23, and 27. They consisted of four five-minute trials with 50 min, intertrial intervals. Duration of active contacts, passive contacts, mutual grooming, following (chasing), and playful fighting was recorded. In pups of the +A line total duration of all social interactions increased between Days 16 and 23, while in the -A pairs preweaning maximum in most types of social activities was achieved already on Day 16, after this day the time spent in mutual contacts decreased. Analysis of dynamics of social behavior over trials in the -A line showed the tendency to habituate, maximum duration of paired interactions appeared in the first trial contrary to +A groups, in which duration of social contacts tended to increase with repeated trials. In both lines, duration of following responses increased from Day 16 to Day 27. In +A pairs following often led to playful fighting, while in -A pairs fighting was practically absent. The experiment demonstrated that differences between lines +A and -A appeared in those social contacts which required higher energy expenditure and which realized themselves in the larger space of the testing box.

Responses to the change in the environment in pairs of male rats genetically selected for activity level.

Laboratory Wistar strain rats were genetically selected for high (+A) and low (-A) activity level. In thirteen pairs of adult males of the 23rd filial generation reactions to changes in the external environment were studied. The animals were housed in breeding cages four each. Two parallel studies were conducted: in pairs simultaneously placed into a novel environment (NOV), empty cages of the same dimensions as the home cage (HC), in the second, behaviour of the second pair that remained in the HC, after removal of two cage-mates, was tested. Once a minute, for a period of one hour, the type of activity was recorded and noted whether it was an element effected in contact with the partner or without any contact. The animals +A and -A differed in the frequency of various types of activity and immobility, in the ratio between behavioural manifestations shown in or without contact as well as in the response to the type of modified environment. To changes in the situation, whether removed cage-mates from the HC or placed into NOV +A animals reacted with a high wave of environment exploration which gradually habituated. -A rats equally responded with exploration but on a lower level. In +rats we recorded more frequently exploration without contact with the partner in HC and NOV in comparison with -A, more frequent grooming, less immobility in contact and with no contact. Between +A partners there was a greater number of contacts in NOV than in HC whereas in the -A group the incidence of contact did not differ between HC and NOV. ANOVA revealed the influence of factors of genetics and environment and interaction in several behavioural categories. The simple and in time economical method demonstrated the possibility of use for the detection of differences between +A and -A lines even at relatively small changes in the external stimulatory situation.

Spontaneous wheel running in laboratory rats genetically selected for activity level in a novel environment.

Wistar rats were genetically selected for either high (+A) or low (-A) locomotor activity level in a new environment. The response to the novelty was tested in all filial generations at the age between 75-80 days of life. Groups of 15 +A male rats selected from the 11th and 12th generations were placed in the individual cages connected with rotation wheels at the age 149 +/- 9 days. For a period of 32 days, the spontaneous wheel running activity was recorded for the time intervals 0.00-6.00 a.m., 6.00-12.00, 12.00-18.00, and 18.00-24.00 h. The -A group exhibited a generally low level of running activity over the entire experimental period, whereas the time of running in the +A tended to increase. Inside the +A group, homogeneous as to the short- term activity level, there gradually differentiated two sub-groups, one with relatively constant medium values and the other which showed an enormous prolongation of the time spent with running. The +A and -A groups differed also in their daily activity rhythm. Whereas the +A rats reached maximum of their activity between 18-24 h., followed by a rapid decrease in the morning hours, the -A animals showed a tendency to a later onset of night-type activity, and a higher level continued to morning hours.

Influence of amphetamine-induced changes in the behavior of adult "aunts" on development and long term behavioral patterns of rats.

Infant rats of the Wistar strain were kept either with their mother or with both the mother and the "aunt"--an adult virgin female during the suckling period. One group of aunts was injected regularly with amphetamine in the dose of 3 mg/kg b.w. (the AA group), another group with saline (the SA group). Control (CO) pups were reared by their mother only. Both acute and long term consequences of aunt-rearing on behavioral development and growth rate were observed. On Days 25 and 28 the SA pups displayed an increased exploratory activity level and more contacts with the litter-mate in the test of paired interactions when compared with both the AA and CO groups. The lowest frequency of exploratory, of manipulatory and social activities were recorded for the AA pups. In adulthood, both the aunt-reared groups of male rats exhibited higher activity level in a novel environment than the CO males. However, while in the CO and the SA males the activity level tended to habituate over the repeated tests, in the AA it persisted on a high level. The difference among females was not significant. Growth rate was retarded in the AA male and female rats.

Maternal behavior in females of the laboratory rat selected for high and low activity and defecation rates.

Laboratory rats of the Wistar strain were selectively bred for a high or a low level of short-term activity (+A, -A) and defecation (+D, -D) in a novel environment. In lactating females of groups +A-D, +A+D, -A+D and -A-D maternal behavior was tested in situations, differing in complexity and demands of the ability of the females to adapt themselves to a new environment. Most intergroup differences were dependent on the characteristics of their activity, while defecation manifested itself less markedly in maternal behavior. In all tests +A groups showed a higher number of active contacts with the young, and the duration of maternal activities was higher in them when compared with -A females. The results indicated difference in the structure of maternal behavior and in the strategy with which they coped with a new situation. Females -A arranged the scattered pups into a nest more rapidly but they manipulated less with them and retrieved them minimally. In -A more often than in the +A the cycle of maternal behavior was interrupted by the elements of other than maternal programs. On the other hand, females +A gave more attention to each pup, they carried it from place to place for a long time, they tended to rearrange the newly formed nest, maternal program being interrupted less often. The most marked difference appeared between groups +A-D and -A+D.

Behavioural responses of rats to early housing conditions and to protein-energy malnutrition.

Lactating rats were fed either the commercial diet (CO) or the low protein diet which induced symptoms of protein - energy deprivation (PD). They were housed in cages either individually (IH) together with eight offspring or in a large community cage (COM) shared by six dams and 48 youngs. After weaning all rats lived in cages by 4-5 animals. The PD terminated at the age of 49 days. Behaviour was tested on the 10th, 42nd and 150 th days of life. Body weight was recorded during nursing period both in dams and pups, after weaning in male rats. The low protein diet affected both body weight and maternal behaviour of the dams. In PD + IH pups growth as well as behavioural development was retarded. Behavioural alterations persisted even after the PD had been treated. The COM housing improved the body weight in the PD + COM dams, behaviour of both the PD + COM dams ond the pups was less affected than of the PD + IH group. The effect of the early housing was long lasting, manifested itself in elevated exploratory activity and in the decreased emotional responses in both the PD + COM and the CO + COM groups at the age of 42 and 150 days.

Sexual behaviour of female rats subjected to early protein energy malnutrition.

Young rats (left with the mother until weaned) were exposed from birth to the age of 49 days to a low protein (malnutritional) diet. At 80 days the young females were ovariectomized and were subjected to standard long-term treatment with oestradiol and progesterone. The females' sexual behaviour was studied in interaction tests with an intact male. It was evaluated according to a scale of sexual responsiveness comprising copulatory (a lordosis posture) and precopulatory (a presenting posture, hopping, ritualized darting) patterns. All the experimental females displayed a high copulatory readiness and precopulatory behaviour; a tendency to lower sexual responsiveness, interpreted as diminished sensitivity to the given doses of the hormones, was manifested only after their repeated administration. Compared with the control females, the number of experimental animals in which the given doses of the hormones induced complete precopulatory behaviour--ritualized darting--was smaller. The results contrast with findings on the sexual behaviour of males subjected to malnutrition from an early age.