The hedgehog pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hh pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

New Insights About Albumin and Liver Disease.

Decompensated liver cirrhosis has a dismal prognosis, with an overall survival of 2-4 years, which is worse than for many oncological diseases. Albumin is an important tool in the management of patients with cirrhosis, since it decreases for less than half the risk for post-paracentesis cardiocirculatory dysfunction and mortality associated with spontaneous bacterial infection, as well as, it triplicates the response to terlipressin in patients with hepatorenal syndrome. Recently, research on albumin has been a hot topic, with important new insights such as the characterization of the pleiotropic effects of albumin (which surpass its oncotic properties) and the concept of effective albumin concentration. In fact, patients with liver cirrhosis present posttranslational modifications on albumin that compromises its function. Those modified albumin forms were proved to have prognostic value and its knowledge may change the paradigm of albumin treatment. In this review, we critically summarize the latest evidence on the potential benefits of albumin in patients with end-stage liver disease.

Role of Hedgehog Signaling Pathway in NASH.

Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease in the Western world. Although only a minority of patients will ultimately develop end-stage liver disease, it is not yet possible to efficiently predict who will progress and, most importantly, effective treatments are still unavailable. Better understanding of the pathophysiology of this disease is necessary to improve the clinical management of NAFLD patients. Epidemiological data indicate that NAFLD prognosis is determined by an individual's response to lipotoxic injury, rather than either the severity of exposure to lipotoxins, or the intensity of liver injury. The liver responds to injury with a synchronized wound-healing response. When this response is abnormal, it leads to pathological scarring, resulting in progressive fibrosis and cirrhosis, rather than repair. The hedgehog pathway is a crucial player in the wound-healing response. In this review, we summarize the pre-clinical and clinical evidence, which demonstrate the role of hedgehog pathway dysregulation in NAFLD pathogenesis, and the preliminary data that place the hedgehog pathway as a potential target for the treatment of this disease.

Celiac Disease Revisited.

Celiac disease (CD) is a systemic disease triggered by gluten ingestion in genetically predisposed individuals. It manifests primarily as an autoimmune enteropathy associated with specific circulating autoantibodies and a human leukocyte antigen haplotype (HLA-DQ2 or HLA-DQ8). It afflicts roughly 1% of the population, though the majority of patients remain undiagnosed. Diarrhea and malabsorption are classic manifestations of CD; however, both children and adults can be paucisymptomatic and present extraintestinal manifestations such as anemia, osteoporosis, and abnormal liver tests. CD screening is not recommended for the general population, and it should be focused on high-risk groups. CD diagnosis is challenging and relies on serological tests, duodenal histology, and genetic testing. Particularly difficult presentations to manage are seronegative patients, seropositive patients without villus atrophy, and patients who have started a gluten-free diet before the diagnostic workup. The only proven treatment is a lifelong gluten-free diet. We present an in-depth review on the physiopathology and management of CD, with a particular emphasis on diagnostic challenges.

A doença celíaca (DC) é uma doença sistémica desencadeada pela exposição ao glúten em doentes geneticamente susceptíveis. Manifesta-se maioritariamente por uma enteropatia auto-imune associada a auto-anticorpos e aos haplotipos HLA-DQ2 ou HLA-DQ8. A DC afecta aproximadamente 1% da população mundial admitindose, no entanto, que a maioria dos doentes não esteja diagnosticada. As manifestações clássicas de DC são a diarreia e sintomas de malabsorção, no entanto tanto crianças como adultos podem ser pauci-sintomáticos ou apresentar manifestações extra-intestinais incluindo anemia, osteoporose ou alteração das provas hepáticas. O rastreio de base populacional não está recomendado, devendo o foco ser nos grupos de risco para DC. O diagnóstico de DC é um desafio e assenta em três pilares: testes serológicos, histologia duodenal e testes genéticos. Apresentações particularmente difíceis de manejar são os doentes sero-negativos, doentes sero-positivos sem atrofia vilositária e doentes que iniciam dieta sem glúten antes da marcha diagnóstica. O único tratamento com eficácia comprovada é a dieta sem glúten. Apresentamos uma revisão aprofundada da fisiopatologia e manejo da DC, com particular ênfase nos desafios diagnósticos.

Human Herpesvirus 6 Reactivation Associated With Intestinal Pseudo-Obstruction in a Renal Transplant Recipient.

Human herpesvirus 6 infection is common after organ transplant. Generally, infection is asymptomatic or is associated with a mild illness. However, human herpesvirus 6 infection in these patients may as well be life threatening as a result of severe end-stage organ disease. Here, we have reported a case of a severe human herpesvirus 6 infection with cerebral, hepatic, and gastrointestinal involvement, which presented as intestinal pseudo-obstruction. The patient was a renal transplant recipient who was successfully treated with ganciclovir. We also reviewed the literature on human herpesvirus 6 diagnosis and the associated colitis and encephalitis with its infection in solid-organ transplant recipients.

Secondary Sclerosing Cholangitis in Critically Ill Patients: An Underdiagnosed Entity.

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is a recently identified cholestatic liver disease occurring in patients without prior history of hepatobiliary disease, after receiving treatment in the intensive care unit (ICU) in different settings, including cardiothoracic surgery, infection, trauma, and burns. It is a rare entity, being estimated to occur in 1/2,000 patients in an ICU; however, it is a dismal condition, with up to half of the patients dying during the ICU stay and with rapid progression to liver cirrhosis over weeks to months. SSC-CIP should be considered in the differential diagnosis of cholestasis in the ICU, particularly when cholestasis persists after recovery from the critical event. Diagnosis is established with magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography showing dilations and stenoses of the intrahepatic bile ducts as well as biliary casts. No available treatment has been shown to slow the rapid progression of the disease, and liver transplant referral should be considered early after the diagnosis of SSC-CIP. Increased awareness and timely diagnosis are crucial in order to improve the current appalling outcome.

A colangite esclerosante secundária em doentes críticos (CEP-DC) é uma doença colestàtica, identificada recentemente, que ocorre em doentes sem antecedentes de patologia hepato-biliar, após internamento em unidade de cuidados intensivos (UCI) por diferentes indicações, incluindo: cirurgia cárdio-torácica, infeção, trauma e queimaduras. É uma entidade rara, com uma incidência estimada de um em cada 2,000 doentes em UCI. Ainda assim, tratase de uma doença com um muito mau prognóstico, sendo que até metade dos doentes morre durante o internamento na UCI, e apresenta uma rápida progressão para cirrose em semanas a meses. A CEP-DC deve ser considerada no diagnóstico diferencial de colestase em UCI, particularmente se a colestase persistir após a recuperação do evento potencialmente fatal. O diagnóstico é estabelecido através de colangiopancreatografia por ressonância magnética ou colangiopancreatografia retrógrada endoscópica, que revelam estenoses e dilatações difusas dos canais biliares intra-hepáticos e cilindros biliares. Não está disponível uma terapêutica capazde atrasar a rápida progressão da doença e a referenciação para transplantação hepática deve ser considerada logo após o diagnóstico. Para melhorar o mau prognóstico atual, é essencial um maior reconhecimento e diagnóstico precoce.