Pharmacotherapy of alcoholic liver disease in clinical practice.

AIMS: Alcohol is the most commonly used addictive substance and alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide, responsible for 47.9% of all liver chronic deaths. Despite ALD has a significant burden on the health, few therapeutic advances have been made in the last 40 years, particularly in the long-term management of these patients. METHODS: we searched in PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant English language publications focused on long-term therapy of ALD. RESULTS: From the huge literature on this topic, including about 755 studies, 75 were selected as eligible including clinical trials and meta-analysis. CONCLUSIONS: Abstinence remains the cornerstone of ALD therapy but it is also the most difficult therapeutic target to achieve and the risk of recidivism is very high at any time. Several drugs (disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective to prevent alcohol relapse and increase the abstinence, although the psychotherapeutic support remains crucial. Baclofen seems to be effective to improve abstinence, showing an excellent safety and tolerability. ALD is often complicated by a state of malnutrition, which is related to a worst mortality. A nutritional therapy may improve survival in cirrhotic patients, reversing muscle wasting, weight loss and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis are recommended specific drug treatments, including glucocorticoids or pentoxifylline, for the long-term treatment of ALD, specific treatments aimed at stopping the progression of fibrosis are not yet approved, but there are some future perspective in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin and endocannabinoids.

Role of bisphenol A as environmental factor in the promotion of non-alcoholic fatty liver disease: in vitro and clinical study.

BACKGROUND: Bisphenol A is an endocrine disrupting chemical associated with type 2 diabetes mellitus (T2DM), cardiovascular disease and liver enzyme abnormalities. AIM: To evaluate bisphenol A plasma and urine levels in non-alcoholic fatty liver disease (NAFLD) patients compared to healthy subjects. Furthermore, we evaluated, in human HepG2 cells, the effects of exposure to different concentrations of bisphenol A on both oxidative stress induction and cell proliferation. METHODS: We enrolled 60 patients with histological diagnosis of NAFLD with or without T2DM and sixty healthy subjects. In vitro, the proliferation of bisphenol A-exposed HepG2 cells at two different concentrations (0.025 and 0.05 µM) was evaluated, both at high (H-HepG2) and at low (L-HepG2) glucose concentrations for 48 h. Lipoperoxidation was assessed by thiobarbituric acid reactive substances (TBARS) assay. RESULTS: Bisphenol A levels were significantly higher in 60 NAFLD subjects, both in urine and in plasma (P < 0.0001) when compared to controls and, in this group, it appeared to be higher in 30 non-alcoholic steatohepatitis patients compared to 30 simple steatosis subjects (P < 0.05), independently from the presence of T2DM. After a bisphenol A-free diet for 1 month, NAFLD patients showed a significant reduction in bisphenol A circulating levels (P < 0.05), without a significant reduction in urine levels. H-HepG2 cells treated with bisphenol A (0.05 µM) increased proliferation compared to controls at 48 h (P < 0.0001). Bisphenol A increased TBARS levels at 48 h versus controls. CONCLUSIONS: Our study reveals a possible role of bisphenol A as an environmental factor involved in the promotion of NAFLD, particularly in T2DM patients.

The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis.

AIM: The observation of bright liver echo pattern on ultrasound is commonly considered a sign of hepatic steatosis. However, the interference of liver fibrosis on sensitivity and specificity of bright liver echo pattern has caused many to question its effectiveness as a diagnostic tool. The objective of this study was to evaluate the sensitivity, specificity and predictive values of bright liver echo pattern for liver steatosis. PATIENTS AND METHODS: We studied 235 consecutive patients suspected of having liver disease of various aetiologies. Median age was 52 years (range, 17-72 years), and there was a male/female ratio of 1:18. All patients underwent ultrasound examination before liver biopsy and was performed by two operators. The presence or absence of bright liver echo pattern and posterior attenuation or areas with different patterns of fat infiltration were noted. Histologic evaluation was performed and graded by Ishak score. Steatosis was categorised as absent, 0-2%, 3-29% to 30-49% or >50%. RESULTS: Interobserver concordance was high. Bright liver echo pattern was found in 67% of patients with steatosis of any degree and 89% of patients with steatosis of >or=30%. Only three patients without steatosis, who had a low Ishak score, demonstrated bright liver echo pattern on ultrasonography. The sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern for steatosis were 64%, 97%, 96.0% and 65%, respectively. Among the subgroup of patients who had steatosis of >or=30%, the sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern were 91%, 93%, 89% and 94%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of posterior attenuation and/or skip areas associated with bright liver echo pattern for steatosis were 89.7%, 100%, 100% and 92.3%, respectively. Univariate analysis showed bright liver echo pattern to be associated only with steatosis and not with fibrosis. CONCLUSION: We concluded that the presence of bright liver echo pattern is a sign of liver steatosis and that liver fibrosis does not interfere with ultrasound measurements. Posterior attenuation and/or skip areas are closely related to steatosis of >or=30%.

The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: role of endothelial dysfunction.

The non-alcoholic fatty liver disease is considered a predominant hepatopathy worldwide and a component of metabolic syndrome. It represents a risk factor for the development of cardiovascular diseases, independently of the presence of diabetes mellitus, hypertension and obesity. For this reason, nowadays an epidemiological analysis and a research of the causes that correlate non-alcoholic fatty liver disease and cardiovascular pathologies, are extremely useful. There are important epidemiological variations in relation to various geographical areas, and depending on different population groups, the prevalence of this pathology changes. Epidemiological analysis for non-alcoholic fatty liver disease shows its remarkable relevance and diffusion, especially in Western areas; therefore immediate interventions are necessary for its prevention, diagnosis and therapy. Endothelial dysfunction could be the joining link between non-alcoholic fatty liver diseases and cardiovascular disease risk. Indeed, their correlation should be researched in the alterations that metabolic hepatopathies are able to induce on endothelial function and viceversa. For this reason, the scientific community may research new therapeutic strategies for non-alcoholic fatty liver disease, by intervening on the early stage of the pathology and blocking endothelial dysfunction.

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.

AIMS: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD). METHODS: 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead. RESULTS: CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05

Helicobacter pylori infection but not small intestinal bacterial overgrowth may play a pathogenic role in rosacea.

BACKGROUND AND AIMS: Recent studies suggest a potential relationship between rosacea and Helicobacter pylori (H. pylori) infection or small intestinal bacterial overgrowth (SIBO), but there is no firm evidence of an association between rosacea and H. pylori infection or SIBO. We performed a prospective study to assess the prevalence of H. pylori infection and/or SIBO in patients with rosacea and evaluated the effect of H. pylori or SIBO eradication on rosacea. METHODS: We enrolled 90 patients with rosacea from January 2012 to January 2013 and a control group consisting of 90 patients referred to us because of mapping of nevi during the same period. We used the (13)C Urea Breath Test and H. pylori stool antigen (HpSA) test to assess H. pylori infection and the glucose breath test to assess SIBO. Patients infected by H. pylori were treated with clarithromycin-containing sequential therapy. Patients positive for SIBO were treated with rifaximin. RESULTS: We found that 44/90 (48.9%) patients with rosacea and 24/90 (26.7%) control subjects were infected with H. pylori (p = 0.003). Moreover, 9/90 (10%) patients with rosacea and 7/90 (7.8%) subjects in the control group had SIBO (p = 0.6). Within 10 weeks from the end of antibiotic therapy, the skin lesions of rosacea disappeared or decreased markedly in 35/36 (97.2%) patients after eradication of H. pylori and in 3/8 (37.5%) patients who did not eradicate the infection (p < 0.0001). Rosacea skin lesions decreased markedly in 6/7 (85.7%) after eradication of SIBO whereas of the two patients who did not eradicate SIBO, one (50%) showed an improvement in rosacea (p = 0.284). CONCLUSIONS: Prevalence of H. pylori infection was significantly higher in patients with rosacea than control group, whereas SIBO prevalence was comparable between the two groups. Eradication of H. pylori infection led to a significant improvement of skin symptoms in rosacea patients.

[Interstitial pulmonitis due to the cytomegalovirus in an immunocompetent adolescent: treatment with ganciclovir]. / Polmonite interstiziale da citomegalovirus in adolescente immunocompetente: trattamento con il Ganciclovir.

Interstitial pneumonia is the most common disease caused by infection from cytomegalovirus (CMV) in immunodepressed patients, whereas it is a rare complication in immunocompetent patients. With reference to the second group of patients, little literature has been produced as for the therapy to choose when symptoms are serious. We report the case of immunocompetent adolescent with CMV pneumonitis who responded dramatically to therapy with ganciclovir. For a week B. M., a 15-year-old girl, has been showing fever, cough and boring pain at her left thoracic base. When hospitalized, the girl was suffering and dyspneic, cardio-thoracic conditions were bad. Spleen and liver were palpable two fingers far form costal arch. Hematochemical tests showed an increase in phlogosis and transaminase value. Thoracic X-ray was negative, as well as cultures. Among the serological tests high response of anti-CMV IgM was remarkable. Virological blood test confirmed active CMV infection. On the fifth day, a thoracic radiography showed widespread interstitial infiltrates. Treatment with ganciclovir--i.v. 6 mg/kg/day, twice a day for twelve days--has been then adopted. After two day treatment, the girls was apyretic and eupneic. After ten day treatment, thoracic radiography was negative and a great decrease in CMV antigenic response was given by blood tests. No side effect were observed. According to our experience we can say that treatment with ganciclovir may positively shorten the course of pneumonia caused by CMV in immunocompetent patients.

[Evaluation of 3-year ultrasound screening in congenital hip dysplasia. Comparison of clinical examination, risk factors and ultrasonography. Interpretation of Graf type IIA grading and the most suitable age for 1st ultrasonography]. / Valutazione di tre anni di screening ecografico della displasia congenita delle anche. Confronto tra clinica, fattori di rischio ed ecografia. Interpretazione dei quadri IIA di Graf ed età più idonea per l'esecuzione del primo esame ecografico.

2237 infants (1210 females, 1027 males) aged two days-six months were screened by ultrasound for congenital dysplasia of the hip (CDH). 21 infants (0.93%) were detected having CDH by ultrasound examination. We have evaluated the concordance between ultrasonography, clinical examination (Ortolani's examination) and risk factors. Of the 21 infants with CDH, 10 (47.6%) had a positivity of Ortolani's examination, 13 (61.9%) had at least one risk factor, 3 (14.2%) had a negative clinical evaluation and no risk factors. Our data indicates the superiority of ultrasonography as compared with physical examination alone, for the diagnosis of CDH. Infants presenting any risk factors for CDH and/or a positive Ortolani's examination should have an early ultrasound evaluation in order to allow initiation of treatment early on, while in infants with negative clinical findings and no risk factors, it should be postponed to avoid the frequent finding of physiological immaturity of the hip. The finding of a high rate of infants that presented a grade IIA in the Graf's grading system during their first month of life and that evolved favourably in the absence of risk factors, and which required further sonograms, indicates the period between the second and the third month as the most desirable for ultrasound screening of CDH.

Steatohepatitis is associated with diabetes and fibrosis in genotype 1b HCV-related chronic liver disease.

Liver steatosis, diabetes mellitus and hepatitis C virus (HCV) genotype have been implicated in liver fibrosis in HCV-related chronic active hepatitis (CAH). The aim of this study was to evaluate whether steatosis and diabetes were associated with more severe liver fibrosis in patients with genotype 1b HCV-related CAH. One-hundred and eighty patients (98 men, 82 women; age range 17-68 years; median 51) infected with genotype 1b HCV underwent ultrasound examination and liver biopsy because of elevated levels of serum alanine transaminase. Based on liver histology, patients were divided into three steatosis classes: 1 (involving <33% of hepatocytes), 2 (34-66%) and 3 (>66%). Fibrosis was graded with the Ishak score (range: 0-6). Virological and epidemiologic characteristics, biochemical data, body mass index, and apparent duration of disease were recorded. Diabetes was identified according to American Diabetes Association criteria. The median fibrosis grade was 2 (23 patients had liver cirrhosis) in the three steatosis classes, with no significant differences between classes. At multivariate analysis, fibrosis was significantly related to age, alanine transaminase, diabetes, hepatitis B core antibody, steatohepatitis and grading. At binary logistic regression analysis, only diabetes and fibrosis stage were significantly associated with steatohepatitis. Steatosis was not an independent risk factor for liver disease severity in our CAH/genotype 1b HCV-infected patients. Steatohepatitis was associated as well as diabetes and affected the severity of liver fibrosis.

Hepatitis C virus carriers with persistently normal ALT levels: biological peculiarities and update of the natural history of liver disease at 10 years.

Some chronic hepatitis C (CHC) patients exhibit persistently normal alanine aminotransferase (ALT) levels (PNAL). Patients with PNAL experience significantly milder disease. In order to understand the differences between CHC patients with elevated ALT levels compared with those with PNAL better, we compared epidemiological, immunological and histological findings, in particular, the value of proliferating hepatocyte activity (PCNA) between the two groups of patients. We studied 40 chronic hepatitis C virus (HCV) carriers with increased ALT who underwent liver biopsy for histological diagnosis and determination of clinical prognosis, and 24 PNAL patients under follow-up for 10 years. Immunological response to different HCV genomic epitopes was tested in both the control group and in PNAL subjects. PCNA values from liver specimens of all patients as well as liver biopsies of PNAL patients at time points 0 and 5 years were calculated according to Hall et al.Age, sex and body mass index (BMI) were not significantly different between the two groups. The median liver histology stage was significantly higher in HCV carriers vs the PNAL group (2.5, range = 2-6 vs 1.5, range = 1-2; P < 0.01). Among PNAL patients, histological stage was not statistically different at the three time points considered. Interferon (IFN)-gamma production was comparable in the two groups. PCNA was significantly higher in the group with elevated ALT levels vs the PNAL group (8%, range = 4-15%vs 5% range = 3-8%; P < 0.05) and no statistically significant differences were found in PNAL patients at time points 0, 5 and 10 years. This study confirms that progression to cirrhosis is slow or absent in PNAL patients after 10 years of follow-up. Accordingly, the hepatic proliferative activity index is low and seems to be stable over time.

[Pseudohypoparathyroidism. Report of two clinical cases]. / Lo pseudoipoparatiroidismo. Descrizione di due casi clinici.

The cases of two sisters suffering from stature and weight retardation, skeletal changes and phosphocalcic homeostasis are reported. Objective examination and laboratory data suggested a hypothesis of pseudohypoparathyroidism. After three years treatment with vitamin D and thyroxin, the haematochemical parameters normalized.

[A critical review of the problem of children at audiological and phoniatric risk in the first year of life]. / Revisione critica sul problema dei bambini a rischio audiologico e foniatrico nel primo anno di vita.

The "M. L. Marenzi" Centre of Infantile Otophoniatrics, in collaboration with the Department of Neonatal Pathology of the Fatebenefratelli Hospital in Milan, performed longitudinal controls of an audiological and phoniatric type in 252 children. In the present study attention is focused in particular on audiological evaluations made in a group of 71 infants aged from 6-9 months old. During audiological tests the evaluation of auditory capacity and the type of response to acoustic stimulus were taken into account. The behavioural observation of selective attention to sound is a very important index of the maturity of sensorial patterns. The retarded development of response to an acoustic stimulus may indicate future communication disorders. The type of response to acoustic stimulus obtained in 71 infants were compared with those in a further two groups of children: the first comprised 3822 children with no audiological risk, and the second 3755 children at audiological risk according to Feinmeser and Telly's expanded list. This comparison highlighted a significant persistence of an archaic-type response in the group of infants from the Department of Neonatal Pathology. It is therefore essential that these children are examined further from a phoniatric point of view.

Myelokathexis associated with multiple congenital malformations: immunological study on phagocytic cells and lymphocytes.

A 5-year-old boy was first seen at the age of 11 months when he presented with growth retardation, skeletal dysmorphisms and neutropenia. Since then he has remained leukopenic except when he has pulmonary infections with a marked leukocytosis. Despite his neutropenia, marked myeloid hyperplasia was evident on marrow smear examination; many cells showed abnormally hypersegmented nuclei, with unusual shape or pyknotic nuclei. Phagocytic cells showed impaired phagocytosis, candidacidal activity, metabolic burst and chemotaxis. Moreover, the patient's serum generated less chemotactic activity than normal serum. These data indicate a selectively complex defect of the neutrophil during differentiation associated with the presence of an inhibitor of chemotactic factors in the patient's serum.

Immunoactivation by pidotimod in children with recurrent respiratory infections.

The therapeutic activity and safety of pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6), a new synthetic "biological response modifier", were examined in a double-blind, placebo-controlled, multicentre trial in 101 children, including 53 boys and 48 girls aged 2-13 years (mean +/- SD: 4.7 +/- 2.1 years) with a history of recurrent respiratory infections (RRI). Pidotimod (400 mg/day) or placebo were administered orally for 60 consecutive days, followed by a further 60-day follow-up period. The trial was completed by 89.1% of patients. The results indicate that pidotimod has a beneficial effect in children with recurrent respiratory infections: the percentage of patients presenting symptoms affecting the upper and lower airways was significantly lower after treatment with the active drug than after treatment with placebo. Relevant side effects were not reported during the trial. An evaluation of the expression of CD25 (after in vitro stimulation of circulating mononuclear cells with PHA) before and after treatment with the two products revealed a significant increase in CD25+ cells in the group treated with pidotimod but not in the group treated with placebo.