The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction

International study of the prevalence and outcomes of infection in intensive care units

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

An official ATS statement: hepatotoxicity of antituberculosis therapy.

The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1746.2007.05207.x

Antituberculosis drug-induced hepatotoxicity: concise up-to-date review.

The role of N-acetylcysteine (NAC), a glutathione (GSH) precursor, was investigated in protection against isoniazid- (INH) and rifampicin- (RIF) induced oxidative hepatic injury in young Wistar rats. The hepatotoxic dose of INH and RIF was 50 mg kg(-1) day(-1) each and the hepatoprotective dose of NAC was 100 mg kg(-1) day(-1). All drugs were administered intraperitoneally (i.p.) in sterile water (4.0 ml kg(-1) day(-1)) over a period of 3 weeks. Status of oxidative/antioxidative profiles was the mechanistic approach to assess the hepatotoxicity and/or hepatoprotection. The oxidative injury in INH-RIF co-exposed animals was closely associated with significant decline of GSH and related thiols, as well as with compromised antioxidant enzyme system. The oxidative stress was further supported by increased lipid peroxidation observed in these animals. The co-administration of NAC prevented the induction of oxidative stress in INH-RIF co-exposed animals. The amelioration of oxidative stress by NAC was faithfully reflected as normal morphology in these animals, except the presence of mild degree of portal triaditis in one animal co-exposed to INH-RIF and NAC. In contrast, the animals co-exposed to INH-RIF alone showed histological lesions which ranged from intralobular inflammation to patchy necrosis. These results suggest that INH-RIF-induced oxidative injury can be prevented by supporting the cellular antioxidant defense mechanism by NAC.

Isoniazid- and rifampicin-induced oxidative hepatic injury : protection by N-acetylcysteine

Small intestinal bacterial overgrowth (SIBO) syndrome is characterized in its florid form by diarrhoea and weight loss The most common underlying factors are dysmotility, small intestinal obstruction, blind or afferent loops Small intestinal bacterial overgrowth can be diagnosed by: 1) culture of jejunum aspirate for bacterial counts, 2) 14C-D-xylose breath testing, 3) non-invasive hydrogen breath testing using glucose or lactulose or 4) 14C-glycocholic acid breath testing The treatment usually consists of the eradication of bacterial overgrowth with repeated course of antimicrobials, correction of associated nutritional deficiencies and, when possible, correction of the underlying predisposing conditions

Small intestinal bacterial overgrowth.

The present article reviews the historical and popular uses of garlic, its antioxidant, haematological, antimicrobial, hepatoprotective and antineoplastic properties and its potential toxicity (from sulfoxide). Garlic has been suggested to affect several cardiovascular risk factors. It has also been shown that garlic and its organic allyl sulfur components are effective inhibitors of the cancer process. Since garlic and its constituents can suppress carcinogen formation, bioactivation and tumour proliferation, it is imperative that biomarkers be established to identify which individuals might benefit most. Garlic powder, aged garlic and garlic oil have demonstrated antiplatelet and anticoagulant effects by interfering with cyclo-oxygenase-mediated thromboxane synthesis. Garlic has also been found to have synergistic effects against Helicobacter pylori with a proton pump inhibitor. The active compound allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages. Freshly prepared garlic homogenate protects against isoniazid+rifampicin-induced liver injury in experimental animal models. Several mechanisms are likely to account for this protection.

/pdf/garlic-in-health-and-disease-4fatdvzf4l.pdf

Garlic in health and disease.

The role of oxidative-stress as a mechanism of hepatotoxicity caused by combination of isoniazid (INH) and Rifampicin (RMP) was investigated in young growing rats. A successful model of hepatotoxicity was produced by giving 50 mg/kg/day each of INH and RMP in two weeks. Liver showed type II hepatocellular changes (microvesicular fat deposition) with mild portal triaditis. The glutathione and related thiols were significantly decreased in both blood and liver tissues with combination of INH and RMP treatment. Superoxide dismutase, glutathione peroxidase, catalase and glutathione-S-transferases with CDNB and DCNB as substrates were decreased in the combination treated group. Glutathione reductase, glutathione-S-transferase with ethacrynic acid as substrate and lipid peroxidation exhibited a significant increase with treatment. The altered profile of antioxidant enzymes with increased lipid peroxidation indicated the enhanced oxidative-stress in combination of INH and RMP treatment. All the findings are faithfully reflected in the blood tissue except superoxide dismutase which showed significant enhancement in this tissue. INH and RMP hepatotoxicity is thus appeared to be mediated through oxidative-stress.

Study of oxidative-stress in isoniazid-rifampicin induced hepatic injury in young rats.

Ulcerative colitis (UC) and Crohn's disease are the types of inflammatory bowel diseases (IBD). UC mainly affects the lining of the large intestine (colon) and rectum. This disease may affect any age group, but it is most prevalent in individuals in the age groups 15-30 and 50-70 yr1. Incidence rate of UC in north India has been reported to be 6.02 cases per 100,000 inhabitants2. Although the aetiology of this inflammatory disorder remains essentially unknown, there have been significant advances in identifying genetic and environmental factors that contribute to its pathogenesis3. Stress and certain food items may trigger symptoms of this disease. It is currently thought that loss of tolerance against indigenous enteric flora is the fundamental event in the pathogenesis of UC4. Amongst the immune-regulatory factors, oxidative stress is one of the major contributing factors involved in the development of the disease and may be secondary to inflammation5. Substantial evidence suggests that chronic intestinal inflammation is associated with enhanced production of reactive oxygen and nitrogen species (ROS/RNS). The overproduction of ROS/RNS and the consequent oxidative stress and redox modulation by antioxidants, e.g. superoxide dismutase (SOD), catalase, reduced glutathione (GSH) have been demonstrated to play a critical role in the pathophysiology of UC in both experimental animals and human subjects6,7. SOD convert the superoxide anion into the easily diffusible and stable metabolite hydrogen peroxide (H2O2) and then catalase acts on H2O2 and neutralizes it into water.

The microbiota is critical for maintaining intestinal homeostasis through activation of innate immune toll like receptors8 and could also play a causal role in the impaired mucosal integrity and repair seen in UC patients. In diseases like IBD, diet is implicated as a contributing factor by having direct effects on host metabolism and/or immune responses. However, recent evidence suggests that diet also influences the composition of the microbiome9. Therefore, it can be assumed that environmental factors including diet can affect the pathogenesis of this disease. Though studies related to oxidative stress in UC have been done in different populations5,6,7, no such study has been reported from India. Therefore, this study was planned to elucidate the role of oxidative stress and antioxidants levels in erythrocytes of UC patients from India.

S. V. Rana

Papers

Isoniazid- and rifampicin-induced oxidative hepatic injury : protection by N-acetylcysteine

Small intestinal bacterial overgrowth.

Garlic in health and disease.

Study of oxidative-stress in isoniazid-rifampicin induced hepatic injury in young rats.

Role of oxidative stress & antioxidant defence in ulcerative colitis patients from north India