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Background Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. Objectives The aim of the study was to estimate population event rates for NSAID-associated ALFT Methods This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1–2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2–3.9) for ibuprofen, 1.9 (95 % CI 0.8–3.7) for nimesulide, 1.6 (95 % CI 0.6–3.4) for diclofenac and 1.6 (95 % CI 0.3–4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6–4.1) without overdoses and 7.8 (95 % CI 6.8–9.0) including overdoses. Conclusions ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure. Electronic supplementary material The online version of this article (doi:10.1007/s40264-012-0013-7) contains supplementary material, which is available to authorized users.

The relationship between hepatic encephalopathy (HE) and the sleep-wake disturbances exhibited by patients with cirrhosis remains debated. The aim of this study was to examine the usefulness of sleep-wake interview within the context of HE assessment. One-hundred-and-six cirrhotic patients were asked three yes/no questions investigating the presence of difficulty falling asleep, night awakenings and daytime sleepiness. All underwent formal HE assessment, quantitative electroencephalography and standardised psychometry. Fifty-eight were monitored for 8 ± 6 months in relation to the occurrence of HE. Patients complaining of daytime sleepiness (n = 75, 71 %) had slower EEGs than those who did not report it (relative alpha power: 37 ± 19 vs. 48 ± 17 %, p

Awareness of previous hepatic encephalopathy (HE) and compliance with treatment can probably reduce HE recurrence. The aim of this study was to assess the degree of awareness of previous HE and its treatment in a group of cirrhotic patients and their caregivers. Thirty-five cirrhotic patients with a history of HE and their caregivers (n = 31) were enrolled. Patients underwent evaluation of HE (clinical, psychometry and electroencephalography), quality of life (SF36 questionnaire), and awareness of HE/treatment on an ad hoc questionnaire (QAE). Caregivers underwent the QAE plus the Caregiver Burden Inventory. On the day of study, 7 patients were unimpaired, 8 had minimal and 20 low-grade overt HE. Of the patients, 37 % were aware of previous HE, 6 % of being on treatment and 6 % understood treatment effects. Of the caregivers, 48 % were aware of previous HE, 6 % of their relative being on treatment and 6 % understood treatment effects. Significant correlations were observed between neuropsychiatric status/linear HE indices and both the patients' quality of life and the caregivers' burden. In conclusion, HE awareness was poor in both patients and caregivers, most likely in relation to insufficient/inadequate provision of information.

Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 ± 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test—Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child–Pugh score: 18% of patients were Child–Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child–Pugh score. Psychometric performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.

The role of portal-systemic shunting and portal liver hypoperfusion in the pathophysiology of central nervous system dysfunction (CNSD) of cirrhosis is not yet well defined. It is well known that one of the most important collateral vessels (CVs) is a patent paraumbilical vein (PUV), but there is controversy regarding its clinical significance. We have evaluated the relationships between neuropsychological and EEG alterations, ammonia plasma level (NH4), hepatic function, and portal hemodynamics (Doppler Ultrasound) in 95 cirrhotic patients. Patency, diameter, or flow of PUV or the presence of other CVs were not related to an increased prevalence of neuropsychological or EEG abnormalities. Patients with effective portal flow (EPF = portal flow − PUV flow) lower than 692 mL/min (median) had a significantly higher risk of failing the neuropsychological test, or of having an altered EEG. Low EPF and prothrombin time (

The physiological roles of the protease inhibitor SERPINB3 (SB3) are still largely unknown. The study was addressed to assess the biological effects of this serpin in vivo using a SB3 transgenic mouse model. Two colonies of mice (123 transgenic for SB3 and 148 C57BL/6J controls) have been studied. Transgenic (TG) mice showed longer survival than controls and the difference was more remarkable in males than in females (18.5% vs 12.7% life span increase). In TG mice decreased IL-6 in serum and lower p66shc in the liver were observed. In addition, TG males showed higher expression of mTOR in the liver. Liver histology showed age-dependent increase of steatosis and decrease of glycogen storage in both groups and none of the animals developed neoplastic lesions. In conclusion, the gain in life span observed in SB3-transgenic mice could be determined by multiple mechanisms, including the decrease of circulating IL-6 and the modulation of ageing genes in the liver.

Memory dysfunction is reported in cirrhotics. The aim of this paper was to increase insight into memory function of cirrhotic patients without overt hepatic encephalopathy. Eighty-six consecutive cirrhotics without overt hepatic encephalopathy (aged 54±10 yr., mean±s.d.) and 28 controls (52±10 yr.) with comparable education level were enrolled. Seventeen patients were class A, 55 class B, 14 class C according to Child-Pugh classification; 29 had alcoholic cirrhosis. The presence of subclinical signs of central nervous system dysfunction were assessed by Number Connection Test (NCT) and quantified EEG analysis. Memory scanning was evaluated by reaction times (RTs) in the Sternberg paradigm. MANOVA analysis showed that RTs were higher (F1,99=11, p

The prevalence of subclinical hepatic encephalopathy (SHE) varies according to the diagnostic tool used in its detection. Since a standardised approach to the diagnosis of SHE is not yet available, we compared psychometric tests and EEG spectral analysis. On the same day 32 cirrhotic patients without overt hepatic encephalopathy and 18 controls were assessed by psychometric tests, both standard and computerized (CPT), and by EEG spectral analysis (EEG-SA). The CPT, measuring reaction time (Rt) and errors (er), were Font, Choice1, Choice2 and Scan test. The standard psychometric tests were the number connection test (NCT), the Reitan-B test, the Line Tracing Test [for time: LTT(t) and for errors: LTT(er)], and the Symbol Digit test (SD). Both psychometric tests [Reitan-B test, LTT(er) and CPT but Font (Rt) and Choice2 (er)] and EEG-SA parameters [mean dominant frequency (MDF) and theta power (θ%)] significantly correlated (p

Prealbumin plasma level is considered a good index of liver function in liver cirrhosis. However, plasma protein levels depend not only on liver function, but also on amino acid supply which is consequent to nutritional status.In 12 cirrhotics we measured prealbumin plasma levels and the lower limb venous-artero difference of amino acid plasma levels in blood samples taken from femoral vein and femoral artery in post-absorptive conditions considered as a direct index of protein release from peripheral tissues and an indirect index of protein nutritional status.In arterial and in venous plasma amino acid sum was 1.86±0.40 (mean + sd) and 2.00 ± 0.04 mMol/l respectively.Prealbumin plasma levels were found directly correlated with the venousartero difference of amino acid plasma levels (r = 0.57p0.05) and of glutamate + glutamine levels (r = 0.73p0.007).In conclusions, these data suggest that prealbumin plasma levels are linked to amino acid supply from peripheral tissues in cirrhotics.