Apoptosis and pathogenesis of viral hepatitis C--an update

Hepatitis C virus is a major causative agent of chronic liver disease. Viral genotype, mutations, virus-host interaction, expression of viral proteins and host immune-reaction are important factors in the pathogenesis of HCV infection. Precise pathogenesis and perpetuation of hepatocellular injury in hepatitis C viral infection remain unclear. Proposed mechanisms include direct viropathic effect, the host immune response mediated through cytotoxic T lymphocytes, both viropathic and cytopathic effects, and macrophages/monocytes. Apoptosis occurs both in acute or chronic hepatitis and has been suggested to be mediated through Fas antigen. In HCV infection, Fas expression is up-regulated in the liver cells in line with the severity of liver inflammation. When HCV-specific T cells migrate into hepatocytes and recognize the viral antigen via the T cell receptor, they become activated and express Fas ligand that transduces the apoptotic death signal to Fas-bearing hepatocytes resulting in their destruction. Thus, the Fas system plays an important role in liver cell injury by HCV infection. Possible inducers of apoptosis in hepatitis C include cytokines, especially tumor necrosis factor-alpha (TNF-alpha), released by inflammatory cells, and acting through TNF and other cytokine receptors.     

Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management

The pathogenesis of hepatic encephalopathy (HE) is unknown. Many theories have been proposed. Most established therapies are based on such theories but since no theory has have ever been proved, therapies have to be considered empiric. The spectrum of HE ranges from minimal cerebral functional deficits, which can only be found by sensitive psychometric tests, to coma with signs of decerebration. HE has arbitrarily been divided into stages. A number of precipitating factors are known and the first line of therapy should always be the elimination of these factors. The differential diagnosis includes all states of impaired consciousness and deficits in cerebral function in patients with chronic liver disease, and clinical and biochemical tests to differentiate are indicated. The therapeutic options for HE include: protein restriction only for a limited time in comatous patients; nonabsorbable antibiotics (aminoglycosides), which because of adverse effects are also limited to higher grades of HE: intestinal cleansing which is applicable in all degrees of HE; lactulose, branched chain aminoacids and ornithin aspartate which have been proven to be effective and can be applied long term in patients with lower grades of HE.     

Hepatocellular carcinoma associated with chronic viral hepatitis. Aetiology, diagnosis and treatment

Two major aetiological factors have been definitively incriminated in the pathogenesis of HCC: these are chronic hepatitis and hepatic cirrhosis. Chronic infection with hepatotropic viruses may account for the majority of cases of hepatocellular carcinoma in high incidence areas, and a varying prevalence of human hepatitis B and hepatitis C virus infection appears to determine the differing geographical prevalence of hepatocellular carcinoma in high and low incidence areas of the world. Patients with advanced hepatocellular carcinoma have a grave prognosis. However, at-risk groups have been characterized, and recent advances in hepatic imaging and tumour marker testing have made screening for asymptomatic primary liver cancer feasible. It it not clear, however, whether screening for small hepatocellular carcinoma improves the prognosis. Lipiodol has been shown to serve as a useful vehicle for diagnosis of small, centimetre sized nodules of tumour, and for delivery of cancer chemotherapeutic or radioactive agents to HCC. The combination of early diagnosis, and coupled medical and surgical treatments including targeted lipiodol or monoclonal antibody conjugates and hepatic resection or transplantation may lead to an improved outlook for viral-associated hepatocellular carcinoma.     

Urinary tract infections in childhood: definition, pathogenesis, diagnosis, and management

Urinary tract infections in childhood are defined as significant bacterial growth in urine obtained by bladder catheterization, suprapubic aspiration, or several clean-voided specimens. In infants and young children they may be easily overlooked because of nonspecific symptoms. This leads to an underestimation of their true prevalence. The severity of these infections is a function of the balance between the various host defense mechanisms and the virulence of the microorganism. The assessment of symptomatic infants and children requires a complete radiographic evaluation (renal ultrasound and voiding cystourethrogram), because of the high frequency of anatomic abnormalities, particularly vesicoureteral reflux. The major issues in the management of children with uncomplicated lower urinary tract infections are whether a single dose or short course of therapy is as efficacious as the conventional 7-10 days, and whether asymptomatic bacteriuria requires treatment.     

Review article: the diagnosis and management of alcoholic hepatitis

Background  Alcoholic hepatitis is a severe, cholestatic liver disease occurring in patients with alcohol abuse. Mortality is substantial; however, therapies may improve clinical outcomes.
Aim  To provide an updated review of the epidemiology, diagnosis, staging and treatment of alcoholic hepatitis.
Methods  A MEDLINE literature search was performed to identify pertinent articles. Relevant clinical abstracts were also reviewed.
Results  Severe alcoholic hepatitis occurs in a small fraction of patients who abuse alcohol. The 28-day mortality ranges from 30% to 50% in most series. Diagnosis is generally based on clinical features, with a limited role for liver biopsy. Beneficial treatment options include alcohol abstinence and nutritional therapy. Despite variable results in clinical trials, corticosteroids and pentoxifylline appear to provide moderate survival benefit. Anti-tumour necrosis factor agents and antioxidants have not proven beneficial, and should be limited to clinical trials. Liver transplant is not a frequent option given the active or recent alcohol use.
Conclusions  Severe alcoholic hepatitis is a clinically-diagnosed condition associated with significant mortality. Alcohol abstinence and nutritional therapy have been associated with improved clinical parameters and should be considered in all patients. Corticosteroid therapy and pentoxifylline therapy appear to show moderate survival benefit and should be considered as first-line therapeutic agents.     

Acute exacerbations of chronic bronchitis in elderly patients: pathogenesis, diagnosis and management

Chronic bronchitis (CB) is a disorder that is characterised by chronic mucus production. This disorder is called chronic obstructive pulmonary disease (COPD) when airflow obstruction is present. The majority of patients with COPD, which often goes undiagnosed or inadequately treated in the elderly, have symptoms consistent with CB. The clinical course of CB is usually punctuated by periodic acute exacerbations linked to infections caused by viral and typical or atypical bacterial pathogens. Acute exacerbations of chronic bronchitis (AECB) often lead to a decline in lung function and poor quality of life in association with increased risk of mortality and a significant economic impact on the healthcare system and society because of the direct costs of hospitalisations. In elderly individuals with COPD, co-morbidities play a vital role as determinants of health status and prognosis. Failure to eradicate infecting pathogens contributes to persistence of infection and inflammation that requires repeated courses of therapy and hospitalisation. Stratifying patients with AECB according to symptoms, degree of pulmonary function impairment and risk factors for poor outcome can help clinicians choose empirical antimicrobial chemotherapy regimens that are most likely to result in treatment success. Failure to cover likely pathogens associated with episodes of AECB can lead to lengthy hospital admissions and significant declines in functional status for elderly patients. Fluoroquinolones may provide the best therapeutic option for elderly patients with COPD who have complicated underlying CB but who are sufficiently stable to be treated in the outpatient setting. Optimised treatment for stable outpatients with CB may diminish the frequency of AECB, and effective antimicrobial therapy for AECB episodes can significantly diminish healthcare costs and maintain quality of life in the elderly patient.     

Tuberculosis in neonates and infants: epidemiology, pathogenesis, clinical manifestations, diagnosis, and management issues

Tuberculosis is one of the leading infectious causes of death and as such represents a major global health problem. Infants may develop congenital tuberculosis from an infectious mother or, most commonly, they may acquire postnatal disease by contact with an infectious adult source. Important epidemiologic, pathogenetic, and clinical data regarding the management of infantile disease are reviewed.Diagnostic evaluation includes tuberculin skin tests, chest radiography and other imaging studies, smears and cultures, examination of the cerebrospinal fluid, and polymerase chain reaction, as well as the more recent interferon-gamma assay.Pregnant women with a positive Mantoux skin test but normal chest x-ray should either start chemoprophylaxis during gestation or after delivery depending on the likelihood of being recently infected, their risk of progression to disease, as well as their clinical evidence of disease. Pregnant women with a positive Mantoux skin test and chest x-ray or symptoms indicative of active disease should be treated with non-teratogenic agents during gestation; all household contacts should also be screened. When tuberculosis is suspected around delivery, the mother should be assessed by chest x-ray and sputum smear; separation of mother and offspring is indicated only if the mother is non-adherent to medical treatment, needs to be hospitalized, or when drug-resistant tuberculosis is involved.According to the American Academy of Pediatrics, treatment of latent infection is highly effective with isoniazid administration for 9 months. This regimen may be extended to 12 months for immunocompromised patients. When drug resistance is suspected, combination therapies, which usually consist of isoniazid with rifampin (rifampicin), are administered until the results of susceptibility tests become available. Organisms resistant to isoniazid only may be treated with rifampin alone for a total of 6-9 months.All infants with tuberculosis disease should be started on four agents (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) until drug susceptibility is assessed. For susceptible intrathoracic tuberculosis, isoniazid, rifampin, and pyrazinamide are administered for a total of 2 months, at which point pyrazinamide is withdrawn and the other two agents are continued for another 4-10 months depending on the severity of the disease. The same regimen may be applied in extrapulmonary tuberculosis with the exception of skeletal, miliary, and CNS disease, which require daily administration of isoniazid, rifampin, pyrazinamide, and streptomycin for 1-2 months, followed by isoniazid and rifampin daily or twice weekly for another 10 months. When drug-resistant tuberculosis is suspected, a regimen of isoniazid, rifampin, and pyrazinamide plus either streptomycin or ethambutol should be initially prescribed, until the results of susceptibility tests become available. HIV-seropositive infants with pulmonary tuberculosis should receive isoniazid, rifampin, pyrazinamide, and ethambutol or an aminoglycoside for 2 months, followed by isoniazid and rifampin for a total of at least 12 months.Apart from conventional antimycobacterial agents, novel therapeutic modalities, which stimulate the host immune system such as interleukin-2 (IL-2), IL-12, interferon-gamma, and tumor necrosis factor antagonists have been tested with promising results.     

自身免疫性肝病的治疗药物研究进展

自身免疫性肝病是一组由自身免疫介导的肝脏炎症性疾病,主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎等。近年来,自身免疫性肝病逐渐成为肝病领域的研究热点,其治疗药物的研究也有了新的突破。综述自身免疫性肝病治疗药物的研究进展。

     

Celiac disease in pediatric patients with autoimmune hepatitis: etiology, diagnosis, and management

Celiac disease (CD) is defined as a permanent intolerance to ingested wheat gliadins and other cereal prolamins, occurring in genetically susceptible people. Persistent elevation of serum aminotransferase activity is expression of liver damage related to CD, which occurs in two distinctive forms. The most frequent is a mild asymptomatic liver injury, with a moderate increase of serum aminotransferase activities and a mild inflammatory portal and lobular infiltrate on liver biopsy (celiac hepatitis), reversible on a gluten-free diet (GFD). More rarely, severe and progressive inflammatory liver damage, induced by an autoimmune process and identified as autoimmune hepatitis (AIH), can develop and it is generally unaffected by gluten withdrawal. Surveys that included only pediatric patients report a wide range of prevalence of CD in AIH of 11.5-46% (mean 21.5%). CD and AIH share selected combinations of genes coding for class II human leukocyte antigens, which could explain their coexistence. Increased intestinal permeability and circulation of anti-tissue transglutaminase (tTG) have also been considered as further potential causes of liver damage in CD patients. tTG in the liver and in other extraintestinal tissues could modify other external- or self-antigens and generate different neo-antigens, which are responsible for liver injury in patients with CD. Patients with AIH represent a population at high risk for developing CD; screening for CD should be integrated into the diagnostic routine of all patients with AIH, with or without gastrointestinal manifestations, before starting immunosuppressive treatments. The only currently available treatment for CD is the GFD and the supportive nutritional care for iron, calcium, and vitamin deficiencies. Due to the difficulties of a GFD, in the past decade researchers have become increasingly interested in therapeutic alternatives to continuous or intermittent use of a GFD in patients with CD. Interventions addressed to correct the defect in the intestinal barrier are currently at the most advanced stage of clinical trials. The impact of a GFD on the outcome of AIH is not clear but it seems to be ineffective in the treatment of AIH. The early detection and treatment of CD, however, may prevent progression to end-stage liver failure.