The Intestinal Microbiome and the Metabolic Syndrome-How Its Manipulation May Affect Metabolic-Associated Fatty Liver Disease (MAFLD).

Metabolic-associated fatty liver disease (MAFLD) is now the predominant liver disease worldwide consequent to the epidemic of obesity. The intestinal microbiome (IM), consisting of the bacteria, fungi, archaea, and viruses residing in the gastrointestinal tract, plays an important role in human metabolism and preserving the epithelial barrier function. Disturbances in the IM have been shown to influence the development and progression of MAFLD and play a role in the development of metabolic syndrome (MS). The main treatment for MAFLD involves lifestyle changes, which also influence the IM. Manipulation of the IM by fecal microbial transplantation (FMT) has been approved for the treatment of recurrent Closteroides difficile infection. This may be administered by endoscopic administration from the lower or upper GI tract. Other methods of administration include nasogastric tube, enema, and oral capsules of stool from healthy donors. In this narrative review, we elaborate on the role of the IM in developing MS and MAFLD and on the current experience with IM modulation by FMT on MAFLD.

Manipulation of the intestinal microbiome-a slow journey to primetime.

The gut microbiota has important functions in the regulation of normal body functions. Alterations of the microbiota are being increasingly linked to various disease states. The microbiome has been manipulated via the administration of stool from animals or humans, for more than 1000 years. Currently, fecal microbiota transplantation can be performed via endoscopic administration of fecal matter to the duodenum or colon or via capsules of lyophilized stools. More recently fecal microbial transplantation has been shown to be very effective for recurrent Clostridoides difficile infection (CDI). In addition there is some evidence of efficacy in the metabolic syndrome and its hepatic manifestation, metabolic associated fatty liver disease (MAFLD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). We review the current literature regarding the microbiome and the pathogenesis and treatment of CDI, MAFLD, IBS and IBD.

Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different.

In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.

Treating the Metabolic Syndrome by Fecal Transplantation-Current Status.

The intestinal microbiome (IM) is important for normal gastrointestinal (GI) and other organ systems' functioning. An alteration in the normal IM, dysbiosis, and changes in intestinal motility result in microorganisms' overgrowth and an alteration in intestinal permeability. The gut-brain axis is also of importance in the irritable bowel syndrome (IBS) and associated bowel overgrowth. Secondary to the epidemic of obesity, the metabolic syndrome has become a major health problem. Disturbances in the fecal microbiome are associated with the metabolic syndrome. Metabolic-associated fatty liver disease (MAFLD) is now the current terminology for non-alcoholic fatty liver disease. IM alteration by fecal transplantation is an approved treatment method for recurrent Clostridioides difficile infection. Initially performed by either duodenal infusion or colonoscopy, it is now easily performed by the administration of capsules containing stools. We discuss the intestinal microbiome-its composition, as well as the qualitative changes of microbiome composition leading to inflammation. In addition, we discuss the evidence of the effect of fecal transplantation on the metabolic syndrome and MAFLD, as well as its clinical indications.

Checkpoint Inhibitors and Hepatotoxicity.

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. Tumor cells escape the immune surveillance mechanism, avoiding immune detection and elimination by activating these checkpoints and suppressing the anti-tumor response, thus allowing formation of tumors. Antigenic modulation facilitates masking and contributes to the escape of tumor cells. In addition, there are growing cell promoters, like transforming growth factor ß (TGF-ß), contributing to escape mechanisms. Targeting the immunological escape of malignant cells is the basis of immune oncology. Checkpoint inhibitors, cytokines and their antibodies may enhance the immune system's response to tumors. Currently, immunomodulatory agents have been designed, evaluated in clinical trials and have been approved by both European and United States Drug Agencies. The present review is a reflection of the increasingly important role of the checkpoint inhibitors. Our aim is to review the side effects with the emphasis on hepatic adverse reactions of these novel biological drug interventions.

Liraglutide-Induced Hepatotoxicity.

A 52-year-old woman with a BMI of 31.2 kg/m2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug's mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.

Treatment of Chronic Hepatitis C in the Aged - Does It Impact Life Expectancy? A Decision Analysis.

BACKGROUND AND AIMS: Recent studies have demonstrated that the efficacy of interferon-free direct-acting antiviral agents (DAAs) in patients over 70 is similar to that of younger age groups. Evidence continues to mount that life expectancy (LE) increases with successful treatment of hepatitis C (HCV) patients with advanced fibrosis. The evidence in older people is more limited. Our aim was to estimate the life year (LY) and quality-adjusted life year (QALY) gained by treatment of naïve patients with HCV as a function of patient's age and fibrosis stage. METHODS: We constructed a Markov model of HCV progression toward advanced liver disease. The primary outcome was LY and QALY saved. The model and the sustained virological response of HCV infected subjects treated with a fixed-dose combination of the NS5B polymerase inhibitor Sofosbuvir and the NS5A replication complex inhibitor Ledipasvir were based on the published literature and expert opinion. RESULTS: Generally, both the number of LY gained and QALY gained gradually decreased with advancing age but the rate of decline was slower with more advanced fibrosis stage. For patients with fibrosis stage F1, F2 and F3, LY gained dropped below six months if treated by the age of 55, 65 or 70 years, respectively, while for a patient with fibrosis stage F4, the gain was one LY if treated by the age of 75. The QALY gained for treated over untreated elderly were reasonably high even for those treated at early fibrosis stage. CONCLUSIONS: There is a significant life expectancy benefit to HCV treatment in patients up to age 75 with advanced-stage fibrosis.

Two men with dyspnea, enlarged lymph nodes · Dx?

Systolic heart failure has been previously recognized as a cause of reversible mediastinal lymphadenopathy (MLN). Other causes of MLN include sarcoidosis, various malignancies, pulmonary infections, and occupational lung diseases. There are, however, no reports of MLN in patients with diastolic heart failure.

Perimyocarditis following streptococcal group A infection: from clinical cases to bioinformatics analysis.

BACKGROUND: Streptococcal infection is known to be associated with non-suppurative complications, including rheumatic fever. A less well recognized complication is perimyocarditis. METHODS: We report 4 cases of myocarditis in young males associated with acute streptoccal infection. Following this clinical observation we employed bioinformatic techniques to identify common epitopes between Streptococcus group A and human muscle proteins. We used Blast to search all the proteome (1697 proteins) of the Streptococcus pyogenes M1 GAS against the human proteome of 34,180 proteins. RESULTS: 4 patients with streptococcal A related myocarditis were treated and made a complete recovery. One cardiac protein, ATP2A2 (NP_733765.1)), a cardiac Ca2+ ATPase, shared an epitope with Streptococcus group A and a high probability of being presented on a MHC Class II molecule. CONCLUSION: Streptococcal myocarditis may be a commoner entity than previously appreciated. Bioinformatic techniques have identified a suspected common epitope between the streptococcal proteins and a cardiac Ca2+ ATPase.

[Shared residency training in internal medicine--a need for the 21st century].

The crisis that has enveloped internal medicine over the past decade has resulted in difficulties in attracting the best and brightest graduates to this specialization. Since an increasing number of graduates are female, there is often a conflict between raising a family and completing demanding postgraduate medical training. We suggest that serious consideration be given to part-time training in internal medicine in Israel. This article outlines our proposal and reports experience in other countries that supports the concept of postgraduate training in a part-time position. We suggest that this idea is suited to internal medicine and should be seriously considered by the regulatory authorities.

Splenic embolus: 13 cases from a single medical department.

BACKGROUND: Despite the spleen having a very rich blood supply, there is a paucity of reports of splenic emboli. OBJECTIVES: To investigate the incidence of splenic emboli treated in a single general internal medicine department over the last 3 years. METHODS: We examined the records of a 35 bed internal medicine department in a hospital in the center of Israel. RESULTS: Over a period of 3 years 13 patients admitted to one internal medicine department developed acute abdominal pain and areas of hypoperfusion in the spleen on contrast computed tomography imaging. The patients were treated with anticoagulants, their course was benign and there were no long-term sequelae. CONCLUSIONS: Embolus to the spleen is not rare in an internal medicine department. Diagnosis can be easily made by contrast CT scanning, and treatment with anticoagulants results in a good prognosis.

A cost-effective method for reducing the volume of laboratory tests in a university-associated teaching hospital.

BACKGROUND: Laboratory tests comprise a significant portion of hospital expenditure. Attempts to reduce their use have had mixed results. OBJECTIVE: To investigate the effect of an intervention based on a simple form-based system for ordering laboratory tests by physicians, on both use of laboratory resources and diagnostic accuracy. DESIGN: At Kaplan Medical Center in Rehovot , Israel , there are 4 similar Internal Medicine departments. In one department (C), the new system was initiated, whereas in the other 3 departments (A, B and D), the traditional method of ordering blood tests was continued. The intervention used was a requirement for tests to be specifically requested by residents following unbundling of test panels, with hands-on supervision by a senior physician. In addition, the residents attended a series of lectures on the economic implications of laboratory testing. The intervention study lasted for 3 years. MEASUREMENTS: Total number of tests performed in each department, number of tests per admission and total cost of each test at Medicare reimbursement prices. RESULTS: The number of tests per admission prior to the intervention was 1.91 +/- 0.89; it decreased for each of the next 3 years: 0.76 +/- 0.61, 0.80 +/- 0.62 and 0.78 +/- 0.63 respectively. There was a total decrease of 97,365 tests during the 3-year period, saving 1,914,149 dollars. There was no difference in the readmission rate or in the number of diagnoses of conditions based primarily on blood tests such as hypokalemia or hyponatremia, between department C and the other departments. CONCLUSIONS: The intervention developed here produced significant and sustained reduction of financial savings in the number of laboratory tests ordered, without negatively impacting diagnostic capability or patient care.