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1.
Dig Liver Dis ; 2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38220486

RESUMO

BACKGROUND: Fontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD. AIM: Investigate biomarkers correlating with severity of liver biopsy fibrosis in FALD. METHODS: A retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores. RESULTS: Sixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa. CONCLUSIONS: APRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.

2.
Am J Gastroenterol ; 119(2): 287-296, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37543729

RESUMO

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.


Assuntos
Encefalopatia Hepática , Readmissão do Paciente , Humanos , Estudos Prospectivos , Encefalopatia Hepática/epidemiologia , Encefalopatia Hepática/etiologia , Ascite/epidemiologia , Ascite/etiologia , Ascite/terapia , Assistência ao Convalescente , Qualidade de Vida , Alta do Paciente , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Cirrose Hepática/terapia , Fatores de Risco , Estudos Retrospectivos
3.
Dig Endosc ; 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37886793

RESUMO

OBJECTIVES: Endoscopic ultrasound (EUS)-guided injection of cyanoacrylate (CYA) for primary prophylaxis (PP) of gastric varices (GV) is controversial. This study evaluates the safety and efficacy of this intervention. METHODS: Patients treated for PP of GV bleeding by EUS injection of CYA with or without coils were identified. Endoscopic techniques, outcomes, and adverse events (AEs) were reviewed and compared with a group treated for secondary prophylaxis (SP). Patients were followed until: (i) loss to follow-up; (ii) GV bleeding; (iii) interventional radiology or surgery decompression; (iv) liver transplant; or (v) death or comfort care. RESULTS: One hundred and nineteen patients (61 men; mean 59 ± 12 years) underwent EUS for PP (n = 24) or SP (n = 95). The PP group was treated with CYA alone (n = 18) or with coils (n = 4). Eight (33%) mild (n = 6) or moderate (n = 2) AEs and no index GV bleeding occurred during a mean of 6.1 ± 5.9 months follow-up. Repeat EUS in 22 (92%) PP patients showed 7 (32%) residual GVs, which were retreated with CYA alone (n = 6) or with coils (n = 1). Two (29%) mild (n = 1) or moderate (n = 1) AEs occurred after repeat EUS and 1/22 (5%) index GV bleed occurred during a mean 23 ± 25 months follow-up. Compared to the SP group, the PP group had lower Model for End-stage Liver Disease (MELD) score (P = 0.03), fewer GV stigmata (P < 0.001), required less CYA (P = 0.019) during index EUS, and had a longer time between index and surveillance EUS (P = 0.014). The incidence of AEs and GV bleeding between the two groups were similar. CONCLUSION: Posttreatment GV bleeding and AEs are similar following EUS-guided primary and secondary GV prophylaxis.

4.
Gastrointest Endosc ; 98(5): 843-847, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37385550

RESUMO

BACKGROUND AND AIMS: The use of EUS for peristomal varices (PV) is limited to case reports. METHODS: Patients who underwent EUS-guided treatment of PV with cyanoacrylate (CYA) and/or coils between April 2013 and December 2019 were identified. All patients had failed previous therapies or had comorbidities precluding other options. Endoscopic technique, adverse events (AEs), recurrent bleeding, and repeat interventions were assessed. RESULTS: Twenty patients (12 men; median age, 62 years [interquartile range {IQR}, 54.8-69.5]) underwent initial EUS-guided PV injection of CYA for secondary (n = 19) or primary (n = 1) prophylaxis. Within 30 days, AEs occurred in 11 patients (55%), of which 8 were mild. During a median 2.5 months (IQR, 2-8.5) of follow-up, confirmed (n = 6) or suspected (n = 2) PV bleeding recurred; 5 of 8 recurrences were retreated with CYA and/or coils without AEs. After retreatment, PV bleeding recurred in 2 patients a median of 6 months (IQR, 6-30) later. CONCLUSIONS: EUS appears to be a safe and promising technique for treatment of PV.

5.
PLoS One ; 12(11): e0185813, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29095942

RESUMO

AIM: Serum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials. METHODS: Serum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists. RESULTS: In the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD. CONCLUSION: Serum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.


Assuntos
Proteínas de Grupo de Alta Mobilidade/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia , Adulto , Criança , Estudos Transversais , Humanos , Índice de Gravidade de Doença
6.
J Biol Chem ; 292(34): 14050-14065, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28710282

RESUMO

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.


Assuntos
Proteínas de Transporte/metabolismo , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Resposta a Proteínas não Dobradas , Proteínas Adaptadoras de Transdução de Sinal , Proteína 5 Relacionada à Autofagia/antagonistas & inibidores , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Biomarcadores/metabolismo , Biópsia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Progressão da Doença , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/patologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Fígado/imunologia , Fígado/patologia , Fígado/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transporte Proteico , Interferência de RNA , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Proteínas de Transporte Vesicular/metabolismo , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
7.
J Investig Med High Impact Case Rep ; 4(4): 2324709616683721, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28203570

RESUMO

Primary gastrointestinal (GI) lymphoma is a heterogeneous disease with varied clinical presentations. The stomach is the most common GI site and accounts for 70% to 75% of GI lymphomas. We present a patient with gastric diffuse large B cell lymphoma (DLBCL) who presented with significant weight loss, early satiety, and multifocal ulcerated gastric lesions. Esophagoduodenoscopy should be performed in patients presenting with warning symptoms as in our case. Diagnosis is usually made by endoscopic biopsies. Multiple treatment modalities including surgery, radiotherapy, and chemotherapy have been used. Advancements in endoscopic and pathologic technology decrease turnaround time for diagnosis and treatment initiation, thus reducing the need for surgery. Health care providers should maintain a high level of suspicion and consider gastric DLBCL as part of the differential diagnosis, especially in those with warning symptoms such as weight loss and early satiety with abnormal endoscopic findings.

8.
Dig Dis Sci ; 60(12): 3642-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26195313

RESUMO

BACKGROUND AND AIM: Hepatocyte apoptosis or necrosis from accumulation of bile salts may play an important role in the disease progression of primary sclerosing cholangitis (PSC). The aim of the current study was to measure serum markers of hepatocyte apoptosis (cytokeratin-18 fragments--K18) and necrosis (high-mobility group protein B1--HMGB1) in adults with PSC and examine the relationship with disease severity. METHODS: We measured serum levels of K18 and HMGB1 in well-phenotyped PSC (N = 37) and 39 control subjects (N = 39). Severity of PSC was assessed biochemically, histologically, and PSC Mayo risk score. Quantification of hepatocyte apoptosis was performed using TUNEL assay. RESULTS: The mean age of the study cohort was 49.7 ± 13.3 years and comprised of 67% men and 93% Caucasian. Serum K18 levels were significantly higher in the PSC patients compared to control (217.4 ± 78.1 vs. 157.0 ± 58.2 U/L, p = 0.001). However, HMGB1 levels were not different between the two groups (5.38 ± 2.99 vs. 6.28 ± 2.85 ng/mL, p = 0.15). Within the PSC group, K18 levels significantly correlated with AST (r = 0.5, p = 0.002), alkaline phosphatase (r = 0.5, p = 0.001), total bilirubin (r = 0.61, p ≤ 0.001), and albumin (r = -0.4, p = 0.02). Serum K18 levels also correlated with the level of apoptosis present on the liver biopsy (r = 0.8, p ≤ 0.001) and Mayo risk score (r = 0.4, p = 0.015). CONCLUSION: Serum K18 but not HMGB1 levels were increased in PSC and associated with severity of underlying liver disease and the degree of hepatocyte apoptosis.


Assuntos
Colangite Esclerosante/sangue , Colangite Esclerosante/patologia , Proteína HMGB1/sangue , Hepatócitos/patologia , Queratina-18/sangue , Adulto , Apoptose , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose/sangue , Necrose/metabolismo
9.
PLoS One ; 10(5): e0124173, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25978364

RESUMO

BACKGROUND: Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. METHODS: Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. RESULTS: The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. CONCLUSIONS: This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Cirrose Hepática/diagnóstico , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colesterol/efeitos adversos , Gorduras na Dieta/efeitos adversos , Modelos Animais de Doenças , Feminino , Frutose/efeitos adversos , Cirrose Hepática/etiologia , Suínos , Porco Miniatura
10.
Mol Biol Cell ; 26(12): 2190-204, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25904325

RESUMO

Free fatty acid induction of inflammation and cell death is an important feature of nonalcoholic steatohepatitis (NASH) and has been associated with disruption of the endoplasmic reticulum and activation of the unfolded protein response (UPR). After chronic UPR activation, the transcription factor CHOP (GADD153/DDIT3) triggers cell death; however, the mechanisms linking the UPR or CHOP to hepatoceullular injury and inflammation in the pathogenesis of NASH are not well understood. Using HepG2 and primary human hepatocytes, we found that CHOP induces cell death and inflammatory responses after saturated free fatty acid exposure by activating NF-κB through a pathway involving IRAK2 expression, resulting in secretion of cytokines IL-8 and TNFα directly from hepatocytes. TNFα facilitates hepatocyte death upon exposure to saturated free fatty acids, and secretion of both IL-8 and TNFα contribute to inflammation. Of interest, CHOP/NF-κB signaling is not conserved in primary rodent hepatocytes. Our studies suggest that CHOP plays a vital role in the pathophysiology of NASH by induction of secreted factors that trigger inflammation and hepatocellular death via a signaling pathway specific to human hepatocytes.


Assuntos
NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Fator de Transcrição CHOP/metabolismo , Animais , Apoptose , Estresse do Retículo Endoplasmático , Humanos , Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais
13.
Clin Gastroenterol Hepatol ; 12(12): 2121-30.e1-2, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24846279

RESUMO

BACKGROUND & AIMS: Cross-sectional studies have associated serum levels of the keratin 18 (K18) fragment with histologic features of liver in individuals with nonalcoholic fatty liver disease (NAFLD). We investigated the relationship between changes in serum levels of K18 and changes in liver histology in adults and children with NAFLD. METHODS: We measured levels of K18 in stored serum samples collected at baseline and various time points from 231 adults with nonalcoholic steatohepatitis and 152 children with NAFLD who participated in 2 separate prospective randomized clinical trials. Liver biopsy specimens collected at baseline and week 96 were reviewed centrally. RESULTS: There were greater decreases in serum levels of K18 in adults with histologic improvement at week 96 than in those without histologic improvement at week 16 (decrease, 193 ± 293 vs 139 ± 467 U/L; P < .001), week 48 (decrease, 232 ± 360 vs 113 ± 425 U/L; P < .001), or week 96 (decrease, 269 ± 368 vs 97 ± 400 U/L; P < .001). There were greater decreases in serum levels of K18 in children with histologic improvements than in those without histologic improvements at week 48 (decrease, 197 ± 467 vs 47 ± 350 U/L; P = .005) and week 96 (decrease, 206 ± 432 vs 2 ± 474 U/L; P < .001). However, reductions in serum levels of K18 were not better than reductions in levels of alanine aminotransferase in identifying adults with histologic improvement (area under the receiver operator characteristic [AUROC], 0.71; 95% confidence interval [CI], 0.63-0.80; vs AUROC, 0.68; 95% CI, 0.61-0.79; P = .34) or children (AUROC, 0.72; 95% CI, 0.63-0.81; vs AUROC, 0.79; 95% CI, 0.70-0.87; P = .42). CONCLUSIONS: Decreases in serum levels of K18 are associated strongly with improved liver histologies in adults or children with NAFLD. However, reductions in K18 do not perform better than those in alanine aminotransferase level in identifying histologic changes in NAFLD.


Assuntos
Queratina-18/sangue , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Adolescente , Adulto , Biópsia , Criança , Histocitoquímica , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Soro/química
14.
Ann N Y Acad Sci ; 1281: 106-22, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23363012

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ~5% is believed to improve steatosis, whereas ~10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Fígado Gorduroso/etiologia , Obesidade/etiologia , Animais , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/patologia , Humanos , Resistência à Insulina/fisiologia , Hepatopatia Gordurosa não Alcoólica , Obesidade/patologia , Obesidade/fisiopatologia , Fatores de Risco
15.
Lab Invest ; 92(12): 1712-25, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23007134

RESUMO

Lumican, an extracellular matrix proteoglycan was previously shown to be upregulated with increasing severity of nonalcoholic steatohepatitis (NASH). Although lumican is involved in collagen fibrillogenesis in extra-hepatic tissues, little is known about the role of lumican in hepatic disease. We therefore determined lumican expression in etiologies other than clinical NASH. Our results indicated that lumican is upregulated in clinical samples of hepatitis C virus infection, in experimental rodent models of chronic and acute liver injury and could additionally be induced in vitro in response to the pro-fibrotic cytokine transforming growth factor ß1 (TGFß1) and to lipotoxic palmitic acid. Together, these results suggested a role for lumican in hepatic fibrosis. To investigate the functional role of lumican in hepatic fibrosis, lumican null (Null) and wild-type (WT) littermates were administered carbon tetrachloride intra-peritoneally. Serum and liver tissue were analyzed for indices of liver injury, fibrosis, matrix turnover, and proliferation. Hepatic fibrosis was greatly reduced in null animals (P<0.05). Paradoxically, gene expression of fibrosis-related genes such as TGFß1 and collagen 1 was numerically higher in null animals though statistically insignificant from WT animals. On the other hand, α smooth muscle actin expression (α-SMA), a marker for activated fibroblasts, the main contributors of collagen production was significantly higher (P<0.05) in null animals as compared with WT littermates. Among the matrix metalloproteases (MMP), MMP13 was significantly increased (P<0.05) in null animals. Ultra-structural imaging indicated differences in the organization and spatial distribution of hepatic collagen fibrils of null and WT mice. Cell proliferation was significantly increased (P<0.05) in null animals. We conclude that lumican is a prerequisite for hepatic fibrosis. The protective effect of lumican deficiency in hepatic fibrosis appears to be downstream of collagen production and mediated through the combined effects of impaired collagen fibrillogenesis, increased matrix turnover, and an enhanced proliferative response.


Assuntos
Proteoglicanas de Sulfatos de Condroitina/metabolismo , Sulfato de Queratano/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/efeitos dos fármacos , Animais , Tetracloreto de Carbono , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/genética , Colágeno/química , Colágeno/metabolismo , Dieta , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histocitoquímica , Humanos , Sulfato de Queratano/genética , Fígado/citologia , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Lumicana , Camundongos , Camundongos Endogâmicos C57BL , Estatísticas não Paramétricas , Fator de Crescimento Transformador beta1/metabolismo
16.
Clin Liver Dis ; 15(4): 699-715, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22032524

RESUMO

Cholangiocarcinoma (CCA) is a primary hepatic neoplasm that arises from malignant transformation of the biliary epithelium. Chronic biliary tree inflammation as occurs in primary sclerosing cholangitis (PSC) is a risk factor for the development of CCA. Surgical resection and liver transplantation following neoadjuvant therapy in patients with early extrahepatic CCA are the only potentially curative modalities. Biliary stenting, chemotherapy, radiation therapy, and photodynamic therapy are palliative treatment options for patients who are not surgical candidates. Liver transplantation following neoadjuvant therapy is an effective therapy for patients with hilar cholangiocarcinoma that is unresectable or arising in the setting of PSC.


Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Colangiocarcinoma/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/patologia , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Estadiamento de Neoplasias , Cuidados Paliativos , Fatores de Risco , Resultado do Tratamento
17.
J Lipid Res ; 52(8): 1517-25, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21633093

RESUMO

Saturated free fatty acids (FFA) induce hepatocyte lipoapoptosis, a key mediator of liver injury in nonalcoholic fatty liver disease (NAFLD). Lipoapoptosis involves the upregulation of the BH3-only protein PUMA, a potent pro-apoptotic protein. Given that dysregulation of hepatic microRNA expression has been observed in NAFLD, we examined the role of miRNA in regulating PUMA expression during lipotoxicity. By in silico analysis, we identified two putative binding sites for miR-296-5p within the 3' untranslated region (UTR) of PUMA mRNA. Enforced miR-296-5p levels efficiently reduced PUMA protein expression in Huh-7 cells, while antagonism of miR-296-5p function increased PUMA cellular levels. Reporter gene assays identified PUMA 3'UTR as a direct target of miR-296-5p. The saturated FFA, palmitate, repressed miR-296-5p expression; and Huh-7 cells were sensitized to palmitate-induced lipotoxicity by antagonism of miR-296-5p function using a targeted locked nucleic acid (LNA). Finally, miR-296-5p was reduced in liver samples from nonalcoholic steatohepatitis (NASH) patients compared with patients with simple steatosis (SS) or controls. Also miR-296-5p levels inversely varied with PUMA mRNA levels in human liver specimens. Our results implicate miR-296-5p in the regulation of PUMA expression during hepatic lipoapoptosis. We speculate that enhancement of miR-296-5p expression may represent a novel approach to minimize apoptotic damage in human fatty liver diseases.


Assuntos
Proteínas Reguladoras de Apoptose , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , MicroRNAs , Palmitatos/farmacologia , Proteínas Proto-Oncogênicas , Regiões 3' não Traduzidas/genética , Idoso , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Sítios de Ligação/genética , Linhagem Celular Tumoral , Fígado Gorduroso/patologia , Fígado Gorduroso/terapia , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Luciferases/análise , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/farmacologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo
18.
Clin Liver Dis ; 15(2): 385-93, vii-x, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21689620

RESUMO

Despite significant advances in nonsurgical treatments of hepatocellular carcinoma, these approaches rarely result in cure. Surgery remains the mainstay of curative therapy for hepatocellular carcinoma. Liver transplantation, in particular, has emerged as one of the most beneficial therapeutic modalities. Questions remain, however, regarding hepatocellular carcinoma surveillance, the choice of surgical resection versus transplantation, the role of chemotherapy, optimal selection criteria for transplantation, and the role of ablative therapies to halt tumor progression and downsize tumors exceeding transplant criteria.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Humanos , Seleção de Pacientes
19.
J Biol Chem ; 284(44): 30039-48, 2009 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-19734538

RESUMO

The mechanisms of free fatty acid-induced lipoapoptosis are incompletely understood. Here we demonstrate that Mcl-1, an anti-apoptotic member of the Bcl-2 family, was rapidly degraded in hepatocytes in response to palmitate and stearate by a proteasome-dependent pathway. Overexpression of a ubiquitin-resistant Mcl-1 mutant in Huh-7 cells attenuated palmitate-mediated Mcl-1 loss and lipoapoptosis; conversely, short hairpin RNA-targeted knockdown of Mcl-1 sensitized these cells to lipoapoptosis. Palmitate-induced Mcl-1 degradation was attenuated by the novel protein kinase C (PKC) inhibitor rottlerin. Of the two human novel PKC isozymes, PKCdelta and PKC, only activation of PKC was observed by phospho-immunoblot analysis. As compared with Jurkat cells, a smaller PKC polypeptide and mRNA were expressed in hepatocytes consistent with an alternative splice variant. Short hairpin RNA-mediated knockdown of PKC reduced Mcl-1 degradation and lipoapoptosis. Likewise, genetic deletion of Pkc also attenuated Mcl-1 degradation and cytotoxicity by palmitate in primary hepatocytes. During treatment with palmitate, rottlerin inhibited phosphorylation of Mcl-1 at Ser(159), a phosphorylation site previously implicated in Mcl-1 turnover. Consistent with these results, an Mcl-1 S159A mutant was resistant to degradation and improved cell survival during palmitate treatment. Collectively, these results implicate PKC-dependent destabilization of Mcl-1 as a mechanism contributing to hepatocyte lipoapoptosis.


Assuntos
Apoptose , Ácidos Graxos/farmacologia , Hepatócitos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Linhagem Celular Tumoral , Hepatócitos/citologia , Humanos , Células Jurkat , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Palmitatos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Desnaturação Proteica , Proteína Quinase C/metabolismo , Estearatos/farmacologia
20.
Arch Surg ; 144(8): 780-2, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19687384

RESUMO

Worldwide, methamphetamine (ie, "crystal meth") abuse is increasing, and is especially prevalent in rural America. However, ischemic colitis secondary to methamphetamine abuse has rarely been reported. We describe the case of a young man who presented with signs and symptoms suggestive of ischemic colitis.


Assuntos
Estimulantes do Sistema Nervoso Central/intoxicação , Colite Isquêmica/induzido quimicamente , Colite Isquêmica/terapia , Metanfetamina/intoxicação , Transtornos Relacionados ao Uso de Substâncias/terapia , Adulto , Colite Isquêmica/diagnóstico por imagem , Colonoscopia , Meios de Contraste , Humanos , Masculino , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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