Hepatitis: Rochester, MN

Czaja AJ, Freese DK, Anonymous00040. · Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. · Hepatology. · Pubmed #12143059 No free full text.

This publication has no abstract.

Razonable RR. · Division of Infectious Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · World J Gastroenterol. · Pubmed #18756591 links to  free full text

Abstract: Cytomegalovirus (CMV) is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D+/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4+ and CD8+ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-). However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D+/R- liver transplant recipients. Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being performed comparing the efficacy and safety of maribavir, a novel benzimidazole riboside, and oral ganciclovir as prophylaxis against primary CMV disease in liver transplant recipients. The treatment of CMV disease consists mainly of intravenous (IV) ganciclovir, and if feasible, a reduction in the degree of immunosuppression. A recent controlled clinical trial demonstrated that valganciclovir is as effective and safe as IV ganciclovir for the treatment of CMV disease in solid organ (including liver) transplant recipients. In this article, the author reviews the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

Czaja AJ. · Mayo Clinic, 200 First Street S.W, Rochester, Minnesota 55905, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072441 No free full text.

Abstract: Diagnostic criteria have been codified by the International Autoimmune Hepatitis Group, and a scoring system can quantify the strength of the diagnosis and over-ride the impact of absent or inconsistent features. The absence of a definable etiologic agent and precise diagnostic test, implies that the diagnosis may be missed or misapplied. Centrilobular (zone 3) necrosis may be an early form of autoimmune hepatitis and this pattern can transform to the classical pattern of interface hepatitis. An acute severe or fulminant presentation is possible, and different ethnic groups may have different manifestations and outcomes. Asymptomatic patients at presentation commonly become symptomatic, and treatment decisions must be based on objective features of disease severity and not the presence or absence of symptoms. Concurrent autoimmune diseases are frequent, and they may constitute an autoimmune polyglandular syndrome associated with a single gene mutation. Emerging autoantibodies of possible prognostic value are antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1. HLA DRB1*03, *04, *03-*04, *07, *13 and DQB1*02 are associated with the occurrence, clinical phenotype and outcome of autoimmune hepatitis. Variant syndromes should be suspected if cholestatic features are prominent and conventional treatment is ineffective.

Czaja AJ. · Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072440 No free full text.

Abstract: Autoimmune hepatitis is a consequence of a triggering antigen and genetic factors that favor the presentation of autoantigens, polymorphisms that affect immunocyte activation and durability, cytokine alterations that promote proliferation of liver-infiltrating cytotoxic T cells, and perturbations in the number and function of immune-regulatory cell populations, including T regulatory cells and natural killer T cells. The triggering epitope is probably a short sequence peptide that is common in multiple infectious or toxic agents. Homologies between this epitope and self-antigens (molecular mimicry) may stimulate humoral and cellular responses that are cross-reactive. Sensitized immunocytes extend and perpetuate the inflammation through imprecise targeting of self-antigens that resemble foreign antigens (promiscuous behavior). The occurrence and clinical phenotype of the disease may relate to genetic susceptibility factors that favor protracted exposure to indigenous etiological agents, and these genetic factors can vary in different geographical regions and ethnic groups. The clinical phenotype within a population can be modified further by genetic polymorphisms that are not disease specific and that affect immunocyte activation, differentiation, proliferation and programmed death (apoptosis). Autoimmune hepatitis is a model of autoreactivity that reflects multiple disturbances in the counter-regulatory mechanisms essential for immune homeostasis.

Silveira MG, Lindor KD. · Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072425 No free full text.

Abstract: Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC-AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC-AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.

Sandhu DS, Tharayil VS, Lai JP, Roberts LR. · Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072372 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is frequently diagnosed at advanced stages and has a high mortality rate. With improved survival of patients with cirrhotic liver disease and increased prevalence of chronic hepatitis C viral infections, a rise in the number of HCC cases is being reported worldwide. Early diagnosis and treatment can significantly improve the prognosis of patients with HCC. Although surgical resection is an important potentially curative therapy for liver tumors, in appropriately selected patients, liver transplantation has been shown to achieve excellent survival rates for a solid tumor. Locally ablative and locoregional therapies in the form of percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization and transcatheter arterial radioembolization (TheraSphere) are viable options in patients with unresectable HCC. Unfortunately, the role of systemic therapy has been very limited in the treatment of these patients. Novel treatment options based on an improved understanding of the molecular pathogenesis of HCC are being explored. These targeted molecular therapies are aimed at growth factors and their receptors, intracellular signal transduction and cell cycle control. A substantial improvement in outcomes of intermediate and advanced stage HCC is expected with the advent of these targeted therapies, used in combination with surgical or locoregional therapies. Recent positive results from a large Phase III study of the receptor tyrosine kinase inhibitor, sorafenib, hold great promise in the treatment of HCC.

Rubio-Tapia A, Murray JA. · Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Minerva Med. · Pubmed #19034257 No free full text.

Abstract: Celiac disease is a chronic immune-mediated disorder that may affect several organs. Liver abnormalities are common extraintestinal manifestations of celiac disease. Isolated hypertransaminasemia, with mild or nonspecific histologic changes in the liver biopsy, also known as ''celiac hepatitis'', is the most frequent presentation of liver injury in celiac disease. Both, histologic changes and liver enzymes reverse to normal after treatment with a gluten-free diet in most patients. Celiac disease may also be associated with severe forms of liver disease and/or coexist with other chronic liver disorders (i.e., autoimmune liver diseases). The mechanisms underlying liver injury in celiac disease are poorly understood. Predisposition to autoimmunity by shared genetic factors (i.e., human leukocyte antigen [HLA] genes) as well as the systemic effects of abnormal intestinal permeability, cytokines, autoantibodies, and/or other yet undefined biologic mediators induced by gluten exposure in susceptible persons may play a pathogenic role. The aims of this article are: 1) to review the spectrum of liver injury related to celiac disease and 2) to understand the clinical implications of celiac disease in patients with chronic liver disorders.

Czaja AJ. · Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN 55905, USA. · Minerva Med. · Pubmed #19034254 No free full text.

Abstract: Autoimmune hepatitis has diverse clinical presentations which complicate its diagnosis and adverse outcomes which demand new treatments. The aims of this review are to indicate the progress that has been made in solving these problems and to illuminate the pathway for additional solutions. Prime source and review articles in English were selected through Medline from 1970-2008 and assimilated into a personal library spanning 31 years. Two diagnostic scoring systems with complementary virtues have been developed that are useful in evaluating patients with confusing features. Acute severe and fulminant presentations require prompt corticosteroid therapy, and coincidental bile duct changes and centrilobular zone 3 necrosis on histological examination do not discount the diagnosis. Cholangio-graphic changes may be present in children and adults with the disease, and antibodies to soluble liver antigen have prognostic value. Autoimmune hepatitis must be considered in patients without autoantibodies and with graft dysfunction after liver transplantation. Asymptomatic patients may not require immediate treatment, and the Model of End Stage Liver Disease identifies problematic patients early. Normal liver tests and tissue constitute the optimal end point of treatment, and the first relapse is an indication for long-term azathioprine therapy. Cyclosporine, tacrolimus and mycophenolate mofetil are promising salvage therapies, and budesonide with azathioprine can be used as frontline treatment in select patients. Progress has been made in the diagnosis and treatment of autoimmune hepatitis, but more work must be done. Multicenter clinical trials are essential before the incorporation of new drugs into the treatment algorithm.

Lim YS, Kim WR. · Division of Gastroenterology and Hepatology (PL 6), Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Clin Liver Dis. · Pubmed #18984463 No free full text.

Abstract: Hepatic fibrosis is an integral part in the progression of chronic liver disease, ultimately leading to cirrhosis and hepatocellular carcinoma. Globally, alcohol consumption, hepatitis B (HBV) and hepatitis C (HCV) have been the main causes of cirrhosis. More recently, the increasing prevalence of obesity and the metabolic syndrome has resulted in increasing incidence of cirrhosis secondary to nonalcoholic fatty liver disease (NAFLD), especially in developed countries. Chronic liver disease and cirrhosis are important causes of morbidity and mortality in the world. Moreover, the burden of chronic liver disease is projected to increase, due in part to the increasing prevalence of end-stage liver disease and HCC secondary to NAFLD and HCV.

Poland GA, Ovsyannikova IG, Jacobson RM. · Mayo Clinic College of Medicine, Mayo Vaccine Research Group, Program in TranslationalImmunovirology and Biodefense, Mayo Clinic, Rochester, Minnesota 55905, USA. · Expert Opin Biol Ther. · Pubmed #18847302 No free full text.

Abstract: The next 'golden age' in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.

Czaja AJ. · Mayo Clinic and Mayo Clinic College of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA. · Expert Opin Drug Saf. · Pubmed #18462189 No free full text.

Abstract: BACKGROUND: Prednisone and azathioprine are effective in the treatment of autoimmune hepatitis, but diverse side effects can diminish their net benefit. OBJECTIVES: Describe the frequency and nature of these side effects and propose management strategies to minimize their impact. METHODS: Pertinent articles published from 1970 to 2007 were identified by Medline search and through a personal library. RESULTS: Medication is prematurely discontinued in 13% of patients mainly because of cosmetic changes, cytopenia, or osteopenia. Populations at high risk are the elderly, those with pre-existent co-morbidities, patients with near-zero thiopurine methyltransferase activity, individuals who are treatment-dependent, pregnant women, and asymptomatic patients who are over-treated. CONCLUSIONS: Proper patient selection, effective pre-treatment counseling, preemptive protective measures, realistic treatment objectives, and early identification of problematic patients can reduce complications. Individualized dosing schedules and the emergence of non-steroidal medications are realistic expectations.

Rashtak S, Pittelkow MR. · Department of Dermatology, Mayo Clinic College of edicine, Rochester, MN 55905, USA. · Curr Dir Autoimmun. · Pubmed #18460895 No free full text.

Abstract: Autoimmune diseases present with varied and broad-ranging cutaneous manifestations. Connective tissue disorders have a plethora of skin manifestations such as rheumatoid nodules in rheumatoid arthritis, psoriatic plaques in psoriatic arthritis, acne and pustulosis in SAPHO syndrome, livedo reticularis and ulceration in antiphospholipid antibody syndrome and xerosis in Sjögren syndrome. Cutaneous manifestations of autoimmune vasculitides such as polyarteritis nodosa, Kawasaki disease, Henoch-Schönlein purpura, cryoglobulinemic vasculitis, Behcet disease, Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome range from papules, subcutaneous nodules and livedo reticularis, to palpable purpura, hemorrhagic bulla and ulcerating lesions. Pathological skin manifestations in autoimmune endocrinopathies include pretibial myxedema/dermopathy in Graves' disease, diabetic dermopathy and necrobiosis lipoidica in type I autoimmune diabetes mellitus, candidiasis, ectodermal dysplasia, vitiligo and alopecia areata in APECED and uniform hyperpigmentation of the skin in Addison's disease. Autoimmune gastrointestinal disorders such as inflammatory bowel disease (with erythema nodosum), gluten-sensitive enteropathy (with dermatitis herpetiformis), autoimmune hepatitis and primary biliary cirrhosis (with jaundice and pruritus), hematologic/oncologic disorders such as acute and chronic graft-versus-host disease (with skin manifestations ranging from pruritic maculopapular eruptions and lichen planus-like lesions to generalized scleroderma), and paraneoplastic autoimmune dermatoses are discussed as well.

Czaja AJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Curr Opin Gastroenterol. · Pubmed #18408457 No free full text.

Abstract: PURPOSE OF REVIEW: To review studies that improve the diagnosis and treatment of autoimmune hepatitis and extend understanding of its pathogenic mechanisms. RECENT FINDINGS: Black patients have more advanced disease and poorer outcomes than white patients. Genome-wide DNA microsatellite techniques have identified multiple regions that may confer susceptibility or resistance to the disease. Preferential inactivation of one parentally-derived X chromosome may favor autoreactivity in women. Acute and chronic hepatitis of undetermined cause can respond to corticosteroid therapy and represent autoantibody-negative autoimmune hepatitis. Outcomes can be improved by continuing therapies until resolution of all features and by early identification of problematic patients with the Model for End Stage Liver Disease. Serum levels of B-cell activating factor correlate with laboratory indices of liver injury. Tacrolimus and mycophenolate mofetil are promising therapies for problematic patients, and the antigenic targets of atypical antibodies to liver/kidney microsome may lead to diagnostic tests for de-novo autoimmune hepatitis after liver transplantation. SUMMARY: Ethnic background and genetic predisposition affect the occurrence and outcome of autoimmune hepatitis. Susceptibility and resistance factors across the human genome underscore the genetic complexity of the disease. Outcomes can be improved by better use of current regimens and further evaluation of action-specific immunosuppressive agents.

Czaja AJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Drugs Aging. · Pubmed #18331074 No free full text.

Abstract: Autoimmune hepatitis affects all ages, and it is probably under-diagnosed in the elderly. Patients aged >or= 60 years have a higher frequency of cirrhosis at presentation than adults aged <or= 30 years, and they more commonly have HLA DRB1*04. These findings suggest that host factors affect the clinical phenotype by influencing the antigens that are presented to immunocytes and the nature of the immune response. The elderly may have an indolent progressive disease that is asymptomatic or masked by other concurrent rheumatic conditions. An acute, even fulminant, presentation may reflect de novo disease or a spontaneous exacerbation of a pre-existent chronic process. Centrilobular (zone 3) necrosis may reflect an early histological stage that transforms later to classical interface hepatitis. Diagnostic criteria have been codified, and a scoring system allows systemic assessment of all clinical features and quantifies the strength of the diagnosis. Prednisone in combination with azathioprine is the safest effective initial treatment, and all elderly patients with severe disease should be treated vigorously to full resolution of clinical, laboratory and histological features. Adverse effects of treatment occur mainly with protracted treatment (>18 months) and repeated therapies after relapse. Adjustments in the management strategy are warranted for an incomplete response or a need for re-treatment after relapse. Azathioprine (2 mg/kg/day) should be used as a corticosteroid-sparing, long-term maintenance therapy in these instances. Treatment failure is uncommon in the elderly, and age-related changes in the cellular immune response may attenuate the disease and enhance its response to therapy. Concurrent adjuvant therapies must focus on maintenance of bone density.

Czaja AJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Clin Gastroenterol Hepatol. · Pubmed #18328791 No free full text.

Abstract: Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67-72 in the DRbeta polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRbeta71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRbeta71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-alpha gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor-receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general.

Hay JE. · Division of Gastroenterology and Hepatology, The Mayo Clinic, Rochester, MN, USA. · Hepatology. · Pubmed #18265410 No free full text.

Abstract: Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main categories depending on their association with or without preeclampsia. The preeclampsia-associated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL), and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to preeclampsia. Although still enigmatic, there have been recent interesting advances in understanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and elevated bile acids in the second half of pregnancy, accompanied by high levels of aminotransferases and mild jaundice. Maternal management is symptomatic with ursodeoxycholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)-the HELLP syndrome. Immediate delivery is the only definitive therapy, but many maternal complications can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery are essential for maternal and fetal survival.

Rizza SA, Badley AD. · Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Med Chem. · Pubmed #18220972 No free full text.

Abstract: HIV protease inhibitors are the backbone of HIV therapy. In addition to blocking intracellular HIV protease and dramatically decreasing viral burden, the protease inhibitors also regulate apoptosis. A growing body of data has confirmed the immunomodulatory effects of HIV protease inhibitors which block CD4+ and CD8+ T cell death in models of HIV infection. The mechanism of this apoptosis inhibition is still under active investigation and supported by several proposed hypothesis for how they alter the fate of the cell. More recently, the anti-apoptotic effects of the HIV protease inhibitors has been extended to the non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease, in animal models of sepsis, hepatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

Viswanatha DS, Dogan A. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. · J Clin Pathol. · Pubmed #18042694 No free full text.

Abstract: Hepatitis C virus (HCV) is well known for its aetiological role in chronic non-A, non-B viral hepatitis, liver cirrhosis and hepatocellular carcinoma; in addition, the virus has also been implicated in a number of extra-hepatic "autoimmune" disease manifestations. A causative association between HCV and non-Hodgkin lymphoma (NHL) was postulated relatively recently and has been the subject of intense investigation, as well as some debate. On the strength of epidemiological data, emerging biological investigations and clinical observations, HCV appears to be involved in the pathogenesis of at least a proportion of patients with NHL. Morphologically, HCV-associated lymphomas represent a variety of histological subtypes including marginal zone lymphoma (splenic, nodal and extranodal), small lymphocytic lymphoma/chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma. Remarkably, some HCV-associated NHL appears to be highly responsive to antiviral therapy, providing some clinical evidence for this relationship, as well as the prospect for novel therapeutic intervention.

Rubio-Tapia A, Murray JA. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA. · Hepatology. · Pubmed #17969053 No free full text.

Abstract: Celiac disease is a common (1% prevalence) chronic immune-mediated disorder of the small intestine induced by dietary wheat, barley, and rye. Several hepatic disorders have been described in association with celiac disease. Isolated hypertransaminasemia with nonspecific histologic changes in a liver biopsy is the commonest hepatic presentation of celiac disease. A gluten-free diet normalizes liver enzymes and histologic changes in most patients. Moreover, celiac disease can coexist with autoimmune liver disorders such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. Celiac disease has increasingly been reported with a variety of other liver diseases. Thus, the hepatologist needs to consider celiac disease in the differential of abnormal liver blood tests and to be aware of the clinical implications of this frequent disease in patients with liver disorders. The possible mechanisms of liver injury and those common factors that explain the association of celiac disease with liver disorders are discussed. The aims of this article are (1) to review the spectrum and pathogenesis of liver injury related to celiac disease and (2) to provide direction to those caring for patients with chronic liver diseases regarding the detection and effective treatment of celiac disease.

Iglesias-Gamarra A, Restrepo JF, Matteson EL. · Division of Rheumatology, Mayo Clinic College of Medicine, Southwest, Rochester, MN 55905, USA. · Curr Rheumatol Rep. · Pubmed #17688840 No free full text.

Abstract: Small-vessel vasculitis is a convenient descriptor for a wide range of diseases characterized by vascular inflammation of the venules, capillaries, and/or arterioles with pleomorphic clinical manifestations. The classical clinical phenotype is leukocytoclastic vasculitis with palpable purpura, but manifestations vary widely depending upon the organs involved. Histopathologic examination in leukocytoclastic vasculitis reveals angiocentric segmental inflammation, fibrinoid necrosis, and a neutrophilic infiltrate around the blood vessel walls with erythrocyte extravasation. The etiology of small-vessel vasculitis is unknown in many cases, but in others, drugs, post viral syndromes, malignancy, primary vasculitis such as microscopic polyarteritis, and connective tissue disorders are associated. The diagnosis of small-vessel vasculitis relies on a thorough history and physical examination, as well as relevant antibody testing including antinuclear antibody and antineutrophil cytoplasmic antibody, hepatitis B and C serologies, assessment of complement, immunoglobulins, blood count, serum creatinine, liver function tests, urinalysis, radiographic imaging, and biopsy.

Pungpapong S, Kim WR, Poterucha JJ. · Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Mayo Clin Proc. · Pubmed #17673066 links to  free full text

Abstract: Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.

Björnsson E, Angulo P. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Arch Med Res. · Pubmed #17613353 No free full text.

Abstract: Hepatitis C infection and non-alcohol-related hepatic steatosis are the most common liver diseases worldwide, and both conditions often co-exist in the same patient. Hepatitis C virus (HCV) genotype 3 directly induces development of steatosis, whereas in patients with non-genotype 3 chronic hepatitis C infection, insulin resistance plays a key role in the pathophysiology of steatosis. Insulin resistance and its clinical components including obesity, hyperglycemia, hypertriglyceridemia, increased blood pressure, and low HDL-cholesterol levels are often seen in patients with chronic hepatitis C infection. Both increased adipocity and presence of steatosis may increase the risk of fibrosis progression, and both have been associated with a decreased rate of response to antiviral treatment. Hence, liver steatosis in the setting of HCV infection is a distinct condition with specific clinical and prognostic implications. Accumulating evidence suggests that weight management may lead not only to a decrease in steatosis but also improvement in fibrosis severity. However, further studies are necessary to determine whether weight reduction improves response to antiviral therapy.

Charatcharoenwitthaya P, Lindor KD. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Clin Liver Dis. · Pubmed #17544971 No free full text.

Abstract: During the last decade, the role of radiologic modalities in management of patients who have fatty liver disease has expanded. Ultrasonography has been used as a noninvasive alternative to biopsy for monitoring patients who have hepatic steatosis, but MRI is more appealing than ultrasonography to denote minor changes in hepatic fat content. Distinguishing patients who have non-alcoholic steatohepatitis from steatosis alone has become of clinical importance; however, the differences are not apparent with any radiologic modalities. Several modalities have been developed to noninvasively and accurately quantify hepatic fat content and diagnose steatohepatitis. In the future, radiologic modalities might be used to monitor the natural history of the disease or evaluate therapeutic interventions in patients who have non-alcoholic fatty liver disease.

Vlahakis SR, Bennett SA, Whitehead SN, Badley AD. · Division Infectious Disease, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Apoptosis. · Pubmed #17453162 No free full text.

Abstract: HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8+ T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

Czaja AJ. · Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Minerva Gastroenterol Dietol. · Pubmed #17415344 No free full text.

Abstract: The diagnostic criteria for autoimmune hepatitis have been codified, and a scoring system can quantify the strength of the diagnosis. Centrilobular (zone 3) necrosis signifies acute disease, and severe acute and fulminant presentations of autoimmune hepatitis are recognized. The absence of symptoms at presentation may identify some patients who do not require treatment, but therapeutic decisions must be based on disease activity not symptoms, especially since 26-70% of asymptomatic patients become symptomatic. Elderly patients have more advanced disease at presentation, but they respond well to treatment. Antibodies to soluble liver antigen/liver pancreas, asialoglycoprotein receptor, actin, and liver cytosol type 1 have prognostic value. Molecular mimicry between viral and self-antigens is the likely basis for the autoimmune response. Susceptibility alleles optimize antigen presentation. Polymorphisms influence immunocyte activation, counter-regulatory actions within the cytokine milieu, and apoptotic pathways for hepatocyte and immunocyte death. Perturbations in the populations of T regulatory cells and natural killer T cells disrupt immune homeostasis. Cyclosporine, mycophenolate mofetil, and budesonide afford new treatment opportunities, and molecular interventions at critical pathogenic pathways are feasible, especially within the cytokine network. Confident animal models of the human disease and a collaborative network of clinical investigators are the requisites for progress.