NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

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Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.

http://science.sciencemag.org/content/sci/317/5834/121.full.pdf

Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production

The current manuscript is the second update of the original Practical Guide, published in 2013 [Heidbuchel et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on anticoagulation. Both physicians and patients are becoming more accustomed to the use of these drugs in clinical practice. However, many unresolved questions on how to optimally use these agents in specific clinical situations remain. The European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group identified 20 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 20 topics are as follows i.e., (1) Eligibility for NOACs; (2) Practical start-up and follow-up scheme for patients on NOACs; (3) Ensuring adherence to prescribed oral anticoagulant intake; (4) Switching between anticoagulant regimens; (5) Pharmacokinetics and drug-drug interactions of NOACs; (6) NOACs in patients with chronic kidney or advanced liver disease; (7) How to measure the anticoagulant effect of NOACs; (8) NOAC plasma level measurement: rare indications, precautions, and potential pitfalls; (9) How to deal with dosing errors; (10) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a potential risk of bleeding; (11) Management of bleeding under NOAC therapy; (12) Patients undergoing a planned invasive procedure, surgery or ablation; (13) Patients requiring an urgent surgical intervention; (14) Patients with AF and coronary artery disease; (15) Avoiding confusion with NOAC dosing across indications; (16) Cardioversion in a NOAC-treated patient; (17) AF patients presenting with acute stroke while on NOACs; (18) NOACs in special situations; (19) Anticoagulation in AF patients with a malignancy; and (20) Optimizing dose adjustments of VKA. Additional information and downloads of the text and anticoagulation cards in different languages can be found on an EHRA website (www.NOACforAF.eu).

/pdf/the-2018-european-heart-rhythm-association-practical-guide-4iood3iocz.pdf

The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

https://www.spg.pt/wp-content/uploads/2015/11/2013-ACG_Guideline_CeliacDisease_May_2013.pdf

ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease

Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa2b regimen and the peginterferon alfa-2a regimen. Results Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standarddose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peg interferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for lowdose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon– ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.)

/pdf/peginterferon-alfa-2b-or-alfa-2a-with-ribavirin-for-2nk440xpf1.pdf

Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.

https://iris.unipa.it/bitstream/10447/210246/1/American%20Journal%20Gastroenterology%202012%20107%201898-906.pdf

Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity.

Background Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. Methods We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for 2 weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. Results Forty-four of the 65 children (68 percent) had a response while receiving s...

Intolerance of Cow's Milk and Chronic Constipation in Children

The liver is morphologically and functionally modulated by sex hormones. Long-term use of oral contraceptives (OCs) and anabolic androgenic steroids (AASs) can induce both benign (hemangioma, adenoma, and focal nodular hyperplasia [FNH]) and malignant (hepatocellular carcinoma [HCC]) hepatocellular tumors. Hepatic adenomas (HAs) are rare, benign neoplasms usually occurring in young women, the development and the complications of which have been related to the strength of OCs and the duration of their use. HA incidence has fallen since the introduction of pills containing smaller amounts of estrogens. FNH is a benign lesion, most commonly seen in young women, which is thought to represent a local hyperplastic response of hepatocytes to a vascular abnormality. Because of the female predominance and the young age at onset, a role of female hormones has been suggested. Furthermore, a large proportion of women with FNH (50-75%) are OC users. Liver hemangiomas (LHs) are the most common benign liver tumors and are seen more commonly in young adult females. The female predilection and clinical observations of LH growth under conditions of estrogenic exposure suggest a possible role for estrogen in the pathogenesis of LHs. HCC has become one of the most widespread tumors in the world in recent years, representing the sixth leading cancer and the third most common cause of death from cancer. Apart from liver cirrhosis, numerous other factors responsible for its onset have been proposed: hepatitis infections from virus B (HBV) and C (HCV), alcohol, smoking, and aflatoxin. However, regardless of etiology, chronic liver diseases progress at unequal rates in the two sexes, with the major sequelae, such as cirrhosis and HCC, being more frequent in men than in women. These epidemiological data have prompted researchers to investigate the relationship between sex hormones and liver tumors. The human liver expresses estrogen and androgen receptors and experimentally both androgens and estrogens have been implicated in stimulating hepatocyte proliferation and may act as liver tumor inducers or promoters.

Sex Hormones and Risk of Liver Tumor

Background: Recent reports have suggested that gastroesophageal reflux in pediatric patients may be caused by food allergy. Objective: The aim of our study was to determine the frequency of the association of gastroesophageal reflux with cow's milk protein allergy in patients in the first year of life. Methods: We studied 204 consecutive patients (median age, 6.3 months) who had been diagnosed as having gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa. Results: Clinical history suggested diagnosis of cow's milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus eosinophils) but did not have symptoms indicating cow's milk allergy. The cow's milk-free diet and two successive blind challenges confirmed the diagnosis of cow's milk allergy in 85 of the 204 patients with gastroesophageal reflux. The clinical presentations of the infants with gastroesophageal reflux alone were different, in view of the greater frequency of diarrhea (p Conclusions: Considering the frequency of this association, patients younger than 12 months old with symptoms of gastroesophageal reflux should be carefully examined to determine whether this disorder is primary or caused by cow's milk allergy.

Gastroesophageal reflux and cow's milk allergy in infants: A prospective study

Background: Recent reports have suggested that gastroesophageal reflux in pediatric patients may be caused by food allergy. Objective: The aim of our study was to determine the frequency of the association of gastroesophageal reflux with cow's milk protein allergy in patients in the first year of life. Methods: We studied 204 consecutive patients (median age, 6.3 months) who had been diagnosed as having gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa. Results: Clinical history suggested diagnosis of cow's milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus' eosinophils) but did not have symptoms indicating cow's milk allergy. The cow's milk-free diet and two successive blind challenges confirmed the diagnosis of cow's milk allergy in 85 of the 204 patients with gastroesophageal reflux. The clinical presentations of the infants with gastroesophageal reflux alone were different, in view of the greater frequency of diarrhea (p < 0.0001) and atopic dermatitis (p < 0.0002). In all, gastroesophageal reflux was associated with, and probably caused by cow's milk allergy, in 85 of 204 cases (41.8%). Conclusions: Considering the frequency of this association, patients younger than 12 months old with symptoms of gastroesophageal reflux should be carefully examined to determine whether this disorder is primary or caused by cow's milk allergy. (J ALLERGY CL1N IMMUNOL 1996;97:822-7.)

https://www.jacionline.org/article/S0091-6749(96)80160-6/pdf

Maurizio Soresi

Papers

Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity.

Intolerance of Cow's Milk and Chronic Constipation in Children

Sex Hormones and Risk of Liver Tumor

Gastroesophageal reflux and cow's milk allergy in infants: A prospective study

Immunodeficiency and other clinical immunology Gastroesophageal reflux and .cow's milk allergy in infants: A prospective study