Transient Elastography Accurately Screens for Compensated Advanced Chronic Liver Disease in Patients With Ongoing or Recent Alcohol Withdrawal.

BACKGROUND & AIMS: Liver stiffness measurement by transient elastography (TE) is a promising method for staging fibrosis in alcohol-related liver disease, but uncertainties remain regarding the influence of alcohol consumption and thus the ideal timing for TE performance. We evaluated the performance of TE compared with liver biopsy to exclude compensated advanced chronic liver disease (cACLD) in patients hospitalized for alcohol detoxification. METHODS: Patients were recruited prospectively at 6 in-patient addiction centers in France. Eligible patients had increased aspartate aminotransferase levels, and no history or signs of overt cirrhosis. TE, histology, and biochemistry measurements were obtained within a median of 6 days after alcohol withdrawal. TE and biochemistry were repeated 1 and 2 months later. RESULTS: The study included 259 patients for per-protocol analysis, of whom 45 (17%) had cACLD. TE identified patients with high accuracy at inclusion and at the 1- and 2-month follow-up evaluation, with area under the curve values of 0.96 (95% CIs, 0.94-0.99), 0.96 (95% CIs, 0.92-0.99), and 0.93 (95% CIs, 0.85-1.00), respectively. In 84% of patients, cACLD was ruled out when liver stiffness was less than 10 kPa (negative predictive value, 99% (95% CIs, 98%-100%)) or ruled in when greater than 25 kPa (positive predictive value, 93% (95% CI, 83%-102%)). Algorithms based on aminotransferase levels and/or bilirubin did not add to the diagnostic performance of TE in this period. Among patients with initial liver stiffness of 10 to 25 kPa, more than half of those with no cACLD showed liver stiffness of less than 10 at 1- and 2-month follow-up testing. CONCLUSIONS: TE performed during the first 2 months after alcohol cessation is an excellent method for excluding alcohol-related cACLD. CLINICAL TRIAL NUMBER: NCT01789008.

Effect of a brief motivational intervention in reducing alcohol consumption in the emergency department: a randomized controlled trial.

BACKGROUND: Introduction to alcohol consumption early in life increases the risk of alcohol dependency and hence motivational interventions are needed in young patients visiting the emergency department (ED). AIM: This study aims to investigate the efficacy of a brief motivational intervention in reducing alcohol consumption among young ED patients. PATIENTS AND METHODS: This was a blind randomized controlled trial with follow-up at 3 months. Patients were stratified on the basis of age and blood alcohol level of 0.5 g/l or more. A total of 263 patients aged 16-24 were randomized, with 132 patients in the brief motivational intervention group and 131 in the control group, with data collection at 3 months. From September 2011 to July 2012, a psychologist performed the brief motivational intervention 5 days after the patients' discharge. A phone call was made at 1 and 2 months. The control group received a self-assessment leaflet. The reduction in consumption was determined on the basis of the number of drinks consumed in the last week prior to the survey. RESULTS: The mean reduction between number of drinks at baseline and number of drinks at 3 months in the control group was 0.3 and that in the intervention group was 0.9. This reduction in alcohol use in the brief motivational intervention group was not significant. The study did not show an association between brief motivational intervention and repeated drunkenness [relative risk (RR): 0.99, 95% confidence interval (CI): 0.79-1.24], alcohol consumption at least once a month (RR: 0.81, 95% CI: 0.31-2.10) and alcohol consumption at least 10 times during the month (RR: 1.1, 95% CI: 0.96-1.26). CONCLUSION: We did not observe a significant decrease in alcohol consumption among the youth. Further studies are needed to confirm the positive impact of a brief motivational intervention in the ED.

Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis.

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc.

Postdetoxification Factors Predicting Alcohol-Related Emergency Room Visits 12 to 24 Months After Discharge: Results from a Prospective Study of Patients with Alcohol Dependence.

BACKGROUND: Relapse is common in patients with alcohol dependence, even after detoxification. The aims of this prospective study were to investigate changes affecting patients during the first 6 months after discharge from hospitalization for detoxification and to determine the influence of these changes on the likelihood of alcohol-related emergency room (ER) visits in the following 18-month period. METHODS: The study included 88 patients hospitalized for participation in a detoxification program in the addiction department of a university hospital in Rennes, France. Alcohol consumption, psychiatric symptoms, and life events were investigated by addiction specialists during hospitalization and 6 months afterward. For each patient, the number of alcohol-related ER visits in the last 6 months was prospectively recorded at the hospital 12, 18, and 24 months after hospitalization. The rate ratios of ER visits as a function of sociodemographic variables and changes observed 6 months after discharge were estimated using Poisson regression with autoregressive errors. RESULTS: Nearly half of the patients (47.7%) had ER visits in the 12- to 24-month period following discharge. The likelihood of ER visits was higher for patients living with friends/parents and for those with aggravated psychiatric symptoms, negative changes in their family life, and who had a medical follow-up in the 6 months after discharge. In contrast, the likelihood of ER visits was lower for patients living with children and those with improved psychiatric morbidity. Alcohol consumption and psychiatric symptoms at baseline had no significant effect. CONCLUSIONS: Monitoring changes in psychiatric symptoms and family life early after a detoxification program may help identify patients who are vulnerable to relapse in the subsequent 18-month period. Systematic screening for these changes as early as possible, in combination with appropriate treatment and the establishment of a social support system, could be fundamental in avoiding further relapses and ER visits.

Non-invasive assessment of liver fibrosis in C282Y homozygous HFE hemochromatosis.

BACKGROUND & AIMS: C282Y homozygotes with serum ferritin (SF) levels >1000 µg/L and/or increased serum transaminase levels are at risk of severe F3/F4 fibrosis. Current practical guidelines recommend liver biopsy in such individuals. This prospective observational cohort study aimed to evaluate non-invasive alternative means such as hyaluronic acid (HA) and transient elastography (TE) for the assessment of severe fibrosis in patients with SF >1000 µg/L or elevated transaminases. METHODS: Between September 2005 and April 2013, 77 patients diagnosed C282Y homozygotes underwent a liver biopsy because of SF >1000 µg/L and/or increased transaminases according to current guidelines, with concomitant TE. All of them had clinical and biological evaluation, including HA measurement in 52 cases. RESULTS: A total of 19.5% of patients had F3-F4 severe fibrosis. HA was higher in patients with severe fibrosis, but did not accurately predict severe fibrosis. TE was significantly higher in patients with severe fibrosis (17.2 vs. 4.9 kPa; P < 0.05) and was able to accurately predict fibrosis stage in 47/61 (77%) patients with valid measurement using a lower threshold of 6.4 kPa and an upper threshold of 13.9 kPa. Efficient assessment of severe fibrosis was not possible in patients with intermediate TE values. CONCLUSION: An algorithm that successively employed SF and TE can accurately classify severe fibrosis in 61% of patients, restricting the need for liver biopsy to the 39% of patients with intermediate or unvalid TE values. This algorithm should be validated in independent cohorts before extended use.

Ferroportin diseases: functional studies, a link between genetic and clinical phenotype.

Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression.

Effect of alcohol consumption on liver stiffness measured by transient elastography.

AIM: To determine the evolution of transient elastography (TE) in patients with alcoholic liver disease according to alcohol cessation or continuation. METHODS: We retrospectively selected in our local database all patients who had two TE between June 2005 and November 2010 with chronic alcohol excessive consumption and excluded those with associated cause of liver disease. TE was performed at least one week apart by senior operator. TE examinations with less than ten successful measures or with an interquartile range above 30% were excluded. We retrospectively reviewed file of all patients to include only patient followed up by trained addictologist and for which definite information on alcohol consumption was available. Concomitant biological parameters [aspartate amino transferase (AST), alanine amino transferase and gamma-glutamyl transpeptidase (GGT)] within 4 wk of initial and final TE were recorded. Putative fibrosis score according to initial and final TE were determined with available cut-off for alcoholic liver disease and hepatitis C. Initial and final putative fibrosis score were compared according to alcohol consumption during follow-up. RESULTS: During the study period 572 patients had TE examination for alcoholic liver disease and 79 of them had at least two examinations. Thirty-seven patients met our criteria with a median follow-up of 32.5 wk. At the end of the study, 13 (35%) were abstinent, and 24 (65%) relapsers. Eight patients had liver biopsy during follow-up. TE decreased significantly during follow-up in 85% of abstinent patients [median (range): -4.9 (-6.1,-1.9)], leading to a modification of the putative fibrosis stage in 28%-71% of patient according to different cut-off value. In relapsers TE increased in 45% and decreased in 54% of patient. There was no statistical difference between initial and final TE in relapsers. In the overall population, using 22.6 kPa as cut-off for cirrhosis, 4 patients had cirrhosis at initial TE and 3 patients had cirrhosis at final TE. Using 19.5 kPa as cut-off for cirrhosis, 7 patients had cirrhosis at initial TE and 5 patients had cirrhosis at final TE. Using 12.5 kPa as cut-off for cirrhosis, 16 patients had cirrhosis at initial TE and 15 patients had cirrhosis at final TE. Evolution of biological data was in accordance with the relapse or abstinent status: abstinence ratio (duration of abstinence/duration follow-up) was correlated with AST ratio (r = -0.465, P = 0.007) and GGT ratio (r = -0.662, P < 0.0001). GGT was correlated with initial (r = 0.488, P = 0.002) and final TE (r = 0.49, P < 0.005). Final TE was correlated with AST (r = 0.362, P < 0.05). Correlation between TE ratio and AST ratio (r = 0.44, P = 0.01) revealed that TE varied proportionally to AST for all patients irrespective of their alcohol status. The same relationship was observed between TE ratio and GGT ratio (r = 0.65, P < 0.0001). Evolution of TE was significantly correlated with the ratio of time of abstinence to observation time (r = -0.387, P = 0.016) and the evolution of liver enzymes. CONCLUSION: TE significantly decreased with abstinence. Results of TE in alcoholic liver disease cannot be interpreted without taking into account alcohol consumption and liver enzymes.

Non-transferrin bound iron: a key role in iron overload and iron toxicity.

BACKGROUND: Besides transferrin iron, which represents the normal form of circulating iron, non-transferrin bound iron (NTBI) has been identified in the plasma of patients with various pathological conditions in which transferrin saturation is significantly elevated. SCOPE OF THE REVIEW: To show that: i) NTBI is present not only during chronic iron overload disorders (hemochromatosis, transfusional iron overload) but also in miscellaneous diseases which are not primarily iron overloaded conditions; ii) this iron species represents a potentially toxic iron form due to its high propensity to induce reactive oxygen species and is responsible for cellular damage not only at the plasma membrane level but also towards different intracellular organelles; iii) the NTBI concept may be expanded to include intracytosolic iron forms which are not linked to ferritin, the major storage protein which exerts, at the cellular level, the same type of protective effect towards the intracellular environment as transferrin in the plasma. MAJOR CONCLUSIONS: Plasma NTBI and especially labile plasma iron determinations represent a new important biological tool since elimination of this toxic iron species is a major therapeutic goal. GENERAL SIGNIFICANCE: The NTBI approach represents an important mechanistic concept for explaining cellular iron excess and toxicity and provides new important biochemical diagnostic tools. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

A multi-disciplinary approach to treating hepatitis C with interferon and ribavirin in alcohol-dependent patients with ongoing abuse.

BACKGROUND & AIMS: Guidelines recommend 6 months of alcohol abstinence before treating hepatitis C (HCV). Abstinence is difficult for alcohol-dependent patients to achieve. This study evaluated HCV treatment in alcoholic patients with ongoing consumption or less than 6 months of abstinence. METHODS: A multidisciplinary management model was built by a liver unit and two centers involved in the care of addict patients. Patients were included in a prospective observational study of treatment with pegylated interferon and ribavirin if they presented alcohol dependence with ongoing intoxication or abstinence of less than 6 months. Pre-therapeutic evaluation and follow-up were multidisciplinary, and addiction care was personalized to patient condition and willingness. Alcohol abstinence or reduction was encouraged but not mandatory. The primary end point was sustained virological response (SVR). Results were compared to a control group of patients matched for genotype, viral load, fibrosis stage, sex, and age. RESULTS: A total of 73 patients treated between 2002 and 2008 were included in the study. Intent to treat analysis showed an SVR in 48% (35/73) of patients versus 49% (36/73) of controls. Low viral load and length of abstinence during treatment were independently associated with SVR. During treatment, 20 (27%) patients were abstinent, 23 (32%) had controlled consumption, and 24 (33%) had excessive consumption. At the end of the follow-up, 22 (30%) patients were durably abstinent. CONCLUSIONS: A multidisciplinary approach allowed HCV treatment in alcohol-dependent patients with a satisfactory SVR rate and positive effects on addiction behavior.

Sex and acquired cofactors determine phenotypes of ferroportin disease.

BACKGROUND & AIMS: Ferroportin disease is characterized by iron overload. It has an autosomal-dominant pattern of inheritance and has been associated with mutations in the SLC40A1 gene, which encodes the cellular iron exporter ferroportin. Since the first description in 2001, about 30 mutations have been reported; the heterogeneity of ferroportin disease phenotypes has led to the hypothesis that the nature of the mutation affects the function of the protein in different ways. We studied genotypes and phenotypes of a large cohort of patients with ferroportin disease. METHODS: We studied clinical, biochemical, imaging, histologic, and genetic data from 70 affected subjects from 33 families with 19 mutations. RESULTS: We found that ferroportin disease, at the time of diagnosis, has limited consequences in the absence of cofactors. Data indicated that transferrin saturation, which correlated with fibrosis and levels of alanine aminotransferase, might be a marker of disease severity. Although the study was performed in a large number of families, we observed incomplete penetrance and no correlation between genotypes and phenotypes. CONCLUSIONS: Members of families with ferroportin disease should be screened for biochemical parameters of iron metabolism as well as genotype to detect silent mutations that might cause disease with acquired or genetic cofactors. Patients should be followed up long term to identify potential complications of the disease.

Fiber evanescent wave spectroscopy using the mid-infrared provides useful fingerprints for metabolic profiling in humans.

Fiber evanescent wave spectroscopy (FEWS) explores the mid-infrared domain, providing information on functional chemical groups represented in the sample. Our goal is to evaluate whether spectral fingerprints obtained by FEWS might orientate clinical diagnosis. Serum samples from normal volunteers and from four groups of patients with metabolic abnormalities are analyzed by FEWS. These groups consist of iron overloaded genetic hemochromatosis (GH), iron depleted GH, cirrhosis, and dysmetabolic hepatosiderosis (DYSH). A partial least squares (PLS) logistic method is used in a training group to create a classification algorithm, thereafter applied to a test group. Patients with cirrhosis or DYSH, two groups exhibiting important metabolic disturbances, are clearly discriminated from control groups with AUROC values of 0.94+/-0.05 and 0.90+/-0.06, and sensibility/specificity of 8684% and 8787%, respectively. When pooling all groups, the PLS method contributes to discriminate controls, cirrhotic, and dysmetabolic patients. Our data demonstrate that metabolic profiling using infrared FEWS is a possible way to investigate metabolic alterations in patients.

Current approach to hemochromatosis.

Iron overload diseases of genetic origin are an ever changing world, due to major advances in genetics and molecular biology. Five major categories are now established: HFE-related or type1 hemochromatosis, frequently found in Caucasians, and four rarer diseases which are type 2 (A and B) hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 (A and B) hemochromatosis (ferroportin disease), and a(hypo)ceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to an impairment of hepcidin synthesis, account for the development of cellular excess in types 1, 2, 3, and 4B hemochromatosis whereas decreased cellular iron egress is involved in the main form of type 4A) hemochromatosis and in aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. The combination of magnetic resonance imaging (for diagnosing visceral iron overload) and of genetic testing has drastically reduced the need for liver biopsy. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases paves the road for innovative therapeutic approaches.

[Genetic iron overload diseases: a deeply changing world]. / Les surcharges génétiques en fer: un monde en pleine mutation.

Iron overload diseases are a quickly and deeply changing world, due to major advances in genetics and molecular biology. Five main entities are concerned: a frequent one, namely HFE-related or type1 haemochromatosis, and four rare or exceptional diseases which are types 2, 3 and 4 haemochromatosis and aceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to hypo-hepcidinemia, account for the development of cellular excess in types 1, 2, 3 haemochromatosis whereas decreased cellular iron egress is the main explanation for type 4 haemochromatosis and aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases open the road for innovative therapeutic approaches.

Redox active plasma iron in C282Y/C282Y hemochromatosis.

Labile plasma iron (LPI) represents the redox active component of non-transferrin-bound iron (NTBI). Its presence in thalassemic patients has been recently reported. The aim of the present study was to quantify LPI in HFE genetic hemochromatosis (GH) and to characterize the mechanisms accounting for its appearance. We studied 159 subjects subdivided into the following groups: (1) 23 with iron overloaded GH; (2) 14 with iron-depleted GH; (3) 26 with dysmetabolic hepatosiderosis; (4) 33 with alcoholic cirrhosis; (5) 63 healthy controls. Both NTBI and LPI were substantially higher in patients with iron-overloaded GH than in those with iron-depleted GH or in healthy controls. LPI was significantly correlated with serum transaminase increase in this group. LPI was elevated in the alcoholic cirrhosis subgroup of severely affected patients. LPI was found essentially when transferrin saturation exceeded 75%, regardless of the etiologic condition. Transferrin saturation above 75% was related to iron overload in GH and to liver failure in alcoholic cirrhosis. LPI is present in C282Y/C282Y hemochromatosis and may be a marker of toxicity due to its potential for catalyzing the generation of reactive oxygen radicals in vivo.

Serum ceruloplasmin and ferroxidase activity are not decreased in hepatic failure related to alcoholic cirrhosis: clinical and pathophysiological implications.

BACKGROUND: A decrease in serum ceruloplasmin (Cp), a protein involved in iron metabolism through its ferroxidase activity, is classically claimed to be observed in severe hepatic failure of non-wilsonian chronic liver disease and therefore to be a confounding factor for the diagnosis of Wilson's disease. Moreover, a simultaneous decrease in ferroxidase activity could be hypothesized as playing a role in the development of the hepatic siderosis frequently observed in advanced chronic liver diseases. The aim of this study was to test the validity of these two statements. METHODS: This study investigated Cp, determined by immunonephelometry, and its ferroxidase 1 activity determined by Erel's method in 33 male patients with severe alcoholic cirrhosis compared with 66 healthy male volunteers, selected on strict criteria. Each patient was age-matched with two controls. Nonparametric tests were used for statistical analysis. RESULTS: The mean values of Cp were significantly higher in cirrhotic patients as compared with control subjects. A significant elevation of Cp was also observed in the subgroup of 11 cirrhotic patients who had normal serum C-reactive protein levels. The mean values of ferroxidase 1 activity were similar to those obtained in control subjects. CONCLUSIONS: Low serum Cp should not be expected in severe hepatic cirrhosis of non-wilsonian origin. Hepatic siderosis in advanced chronic liver disease is likely to be unrelated to decreased ferroxidase activity.

[Endoscopic and pathological aspect of small bowel and colonic involvement in Whipple's disease: a case report]. / Aspect endoscopique et pathologique de l'atteinte intestinale et colique de la maladie de Whipple. A propos d'un cas.

We describe a case of Whipple's disease confirmed by clinical, histological, bacteriological and molecular criteria. The duodenal involvement was associated with the presence of an endoscopic and histological enterocolitis. Final diagnosis of small bowel and colonic involvement by Whipple's disease was confirmed by histology and molecular biology. We review the literature on extra duodenal involvement. We underline the fact that enterocolitis in Whipple's disease is non-specific. We also discuss the other causes of intestinal mucosal infiltration by macrophages.