Diagnostic Performance of Real-Time Elastography in the Assessment of Advanced Fibrosis in Chronic Hepatitis C.

BACKGROUND AND AIMS: Since liver fibrosis index (LFI) was developed by Fujimoto et al., real-time elastography (RTE) has become a promising non-invasive technique to assess fibrosis in chronic hepatitis C (CHC). The aims of this study were to compare the diagnostic performance of RTE versus laboratory tests to predict advanced fibrosis (METAVIR scoring system: F ≥ 3) in patients with CHC, using liver biopsy (LB) as the reference standard; and to evaluated the impact of patient anthropometric features on RTE histogram acquisition. METHODS: This prospective study included 37 patients with CHC scheduled for LB. Aspartate aminotransferase (AST)/alanine aminotransferase (AST) ratio, AST/platelet ratio index (APRI), and Fibrosis-4 index (FIB-4) were calculated from recent (≤6 months) laboratory data. RTE was performed by two independent operators blind to each other' findings and to LB results, using Hitachi HI-VISION Avius ultrasound system. According to Hitachi RTE software, liver elasticity was evaluated through the LFI. Percutaneous ultrasound-assisted LB was performed in the same day of RTE. All LB specimens were analyzed by an expert pathologist blind to RTE results. Hepatic fibrosis was staged according to METAVIR scoring system. The diagnostic performance of the LFI, AST/ALT ratio, APRI and FIB-4 for predicting advanced fibrosis was assessed using area under receiver-operating characteristic curve (AUROC), sensitivity, specificity, positive-predictive and negative-predictive (NPV) values. RESULTS: Thirty-seven LB were performed without complications. The distribution according to METAVIR scoring system was F0-1 in 13 patients (35%), F2 in 13 (35%), F3 in 9 (25%) and F4 in 2 (5%). Thirty-seven RTE procedures were performed. Histogram acquisition was successfully achieved in 32 patients (86%). Abdominal wall thickness ≥23 mm was associated with no histogram acquisition (p = 0.018). Using the optimal cut-off value of 2.38, the AUROC for the LFI was 0.73. The AUROC for the AST/ALT ratio, APRI and FIB-4 were 0.62, 0.79, and 0.82, respectively. CONCLUSIONS: The LFI calculated by RTE showed a very good diagnostic performance to predict advanced fibrosis in CHC, with remarkable sensitivity and NPV (both 100%).

INTRODUÇÃO E OBJETIVOS: Após o desenvolvimento do liver fibrosis index (LFI) por Fujimoto K. et al., a elastografia em tempo real tornou-se uma técnica não invasiva promissora na avaliação do grau de fibrose na hepatite C crónica. Os objetivos deste estudo foram comparar a acuidade diagnóstica da elastografia em tempo real com a de testes laboratoriais para predizer fibrose avançada (sistema de estadiamento METAVIR: F≥3) em doentes com hepatite C crónica, utilizando a biópsia hepática como goldstandard; e avaliar o impacto das características antropométricas do doente na aquisição de histograma. MÉTODOS: Este estudo prospetivo incluiu 37 doentes com hepatite C crónica referenciados para biópsia hepática. A razão aspartato aminotransferase (AST)/alanina aminotransferase (AST) (AST/ALT ratio), o índice da razão AST/plaquetas (APRI) e o índice Fibrosis-4 (FIB-4) foram calculados a partir de dados laboratoriais recentes (≤6 meses). O procedimento de elastografia em tempo real foi realizado por dois operadores independentes, cegos entre si e para o resultado da biópsia hepática, utilizando o ecógrafo Hitachi HI-VISION Avius. De acordo com o software de elastografia em tempo real da Hitachi, a elasticidade hepática foi avaliada através do LFI. No mesmo dia da elastografia em tempo real, realizou-se biópsia hepática percutânea após marcação ecográfica do local de punção. Todas as biópsias hepáticas foram analisadas por um anatomopatologista cego para o resultado da elastografia em tempo real. Para estadiamento da fibrose hepática foi utilizada a classificação METAVIR. A acuidade diagnóstica do LFI, AST/ALT ratio, APRI e FIB-4 para predizer fibrose avançada foi avaliada com base nos valores da área abaixo curva recebedora das características dos operadores (AUROC), sensibilidade, especificidade e valores preditivos positivo e negativo. RESULTADOS: Foram realizadas 37 biópsias hepáticas, sem complicações. A distribuição segundo o sistema de estadiamento METAVIR foi F0-1 em 13 doentes (35%), F2 em 13 (35%), F3 em 9 (25%) e F4 em 2 (5%). Foram realizados 37 procedimentos de elastografia em tempo real. A aquisição de histograma foi conseguida em 32 doentes (86%). A espessura da parede abdominal ≥23 mm foi um factor independente associado a não aquisição de histograma (p = 0,018). Utilizando o cut-off óptimo de 2,38, o valor da AUROC para o LFI foi 0,73. Os valores da AUROC para o AST/ALT ratio, APRI e FIB-4 foram 0,62, 0,79 e 0,82, respectivamente. CONCLUSÕES: O LFI determinado por elastografia em tempo real demonstrou uma performance diagnóstica muito boa para predizer fibrose avançada (F≥3) na hepatite C crónica, com sensibilidade e valor preditivo negativo excepcionais (ambos 100%).

Fanconi syndrome and chronic renal failure in a chronic hepatitis B monoinfected patient treated with tenofovir

Tenofovir disoproxil fumarate (TDF) is one of the first-line treatment options in chronic hepatitis B (CHB). Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients. Here the authors report a case of a 40 year-old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal), proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate (AU)

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Jejunal plasmablastic lymphoma presenting as obscure overt gastrointestinal bleeding: diagnosis by wireless capsule endoscopy

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Fanconi syndrome and chronic renal failure in a chronic hepatitis B monoinfected patient treated with tenofovir.

Tenofovir disoproxil fumarate (TDF) is one of the first-line treatment options in chronic hepatitis B (CHB). Despite its efficacy in suppressing viral load and a high resistance barrier, long life maintenance therapy is required. Registration studies demonstrated TDF to be a safe drug. However, post-marketing experience reported cases of serious nephrotoxicity associated with hypophosphatemia, osteomalacia and, even more recently, Fanconi syndrome associated with TDF therapy in CHB monoinfected patients.Here the authors report a case of a 40 year-old male, with a CHB monoinfection, that, three years after TDF therapy, developed a progressive chronic kidney disease with a serious hypophosphatemia and a secondary osteomalacia that was manifested by bone pain and multiple bone fractures. Further investigational analyses unveiled a proximal renal tubular dysfunction, which fulfilled most of the diagnostic criteria for a Fanconi syndrome. After TDF withdrawal and oral supplementation with phosphate and calcitriol, his renal function stabilized (despite not returning to normal), proximal renal tubular dysfunction abnormalities resolved as well as osteomalacia. In conclusion, physicians should be aware that, in CHB monoinfected patients under TDF therapy, serious renal damage is possible and preventable by timely monitoring serum creatinine and phosphate.

Chronic tubulointerstitial nephritis induced by 5-aminosalicylate in an ulcerative colitis patient: a rare but serious adverse event.

The 5-aminosalicylate is widely prescribed in inflammatory bowel disease patients. Its potential for renal damage has been seldom described. We report a case of a 23-year-old man who started 5-aminosalicylate after being diagnosed with ulcerative colitis. One year after, a significant decline on his creatinine clearance was noted, however, at that time, he was on an acute flare of his bowel disease and the 5-aminosalicylate dose was increased. Six months later, his renal function kept worsening and, on drug-induced toxicity suspicion, 5-aminosalicylate was halted and a kidney biopsy demonstrated a chronic tubulointerstitial nephritis. Steroids and azathioprine were started leading to partial recovery and stabilisation of his renal function. Physicians who prescribe 5-aminosalicylate to patients with inflammatory bowel disease should be aware of this adverse event.

Re-bleeding events in patients with obscure gastrointestinal bleeding after negative capsule endoscopy.

AIM: To investigate long-term re-bleeding events after a negative capsule endoscopy in patients with obscure gastrointestinal bleeding (OGIB) and the risk factors associated with the procedure. METHODS: Patients referred to Hospital Egas Moniz (Lisboa, Portugal) between January 2006 and October 2012 with OGIB and a negative capsule endoscopy were retrospectively analyzed. The following study variables were included: demographic data, comorbidities, bleeding-related drug use, hemoglobin level, indication for capsule endoscopy, post procedure details, work-up and follow-up. Re-bleeding rates and associated factors were assessed using a Cox proportional hazard analysis. The Kaplan-Meier method was used to estimate the cumulative incidence of re-bleeding at 1, 3 and 5 years, and the differences between factors were evaluated. RESULTS: The study population consisted of 640 patients referred for OGIB investigation. Wireless capsule endoscopy was deemed negative in 113 patients (17.7%). A total of 64.6% of the population was female, and the median age was 69 years. The median follow-up was forty-eight months (interquartile range 24-60). Re-bleeding occurred in 27.4% of the cases. The median time to re-bleeding was fifteen months (interquartile range 2-33). In 22.6% (n = 7) of the population, small-bowel angiodysplasia was identified as the culprit lesion. A univariate analysis showed that age > 65 years old, chronic kidney disease, aortic stenosis, anticoagulant use and overt OGIB were risk factors for re-bleeding; however, on a multivariate analysis, there were no risk factors for re-bleeding. The cumulative risk of re-bleeding at 1, 3 and 5 years of follow-up was 12.9%, 25.6% and 31.5%, respectively. Patients who presented with overt OGIB tended to re-bleed sooner (median time for re-bleeding: 8.5 mo vs 22 mo). CONCLUSION: Patients with OGIB despite a negative capsule endoscopy have a significant re-bleeding risk; therefore, these patients require an extended follow-up strategy.

Health-related quality of life and utilities in gastric premalignant conditions and malignant lesions: a multicentre study in a high prevalence country.

BACKGROUND AND AIMS: A recent review of economic studies relating to gastric cancer revealed that authors use different tests to estimate utilities in patients with and without gastric cancer. Our aim was to determine the utilities of gastric premalignant conditions and adenocarcinoma with a single standardized health measure instrument. METHODS: Cross-sectional nationwide study of patients undergoing upper endoscopy (n=1,434) using the EQ-5D-5L quality of life (QoL) questionnaire. RESULTS: According to EQ-5D-5L, utilities in individuals without gastric lesions were 0.78 (95% confidence interval: 0.76-0.80), with gastric premalignant conditions 0.79 (0.77-0.81), previously treated for gastric cancer 0.77 (0.73-0.81) and with present cancer 0.68 (0.55-0.81). Self-reported QoL according to the visual analogue scale (VAS) for the same groups were 0.67 (0.66-0.69), 0.67 (0.66-0.69), 0.62 (0.59-0.65) and 0.62 (0.54-0.70) respectively. Utilities were consistently lower in women versus men (no lesions 0.71 vs. 0.78; premalignant conditions 0.70 vs. 0.82; treated for cancer 0.72 vs. 0.78 and present cancer 0.66 vs. 0.70). CONCLUSION: The health-related QoL utilities of patients with premalignant conditions are similar to those without gastric diseases whereas patients with present cancer show decreased utilities. Moreover, women had consistently lower utilities than men. These results confirm that the use of a single standardized instrument such as the EQ-5D-5L for all stages of the gastric carcinogenesis cascade is feasible and that it captures differences between conditions and gender dissimilarities, being relevant information for authors pretending to conduct further cost-utility analysis.

Phenotype-genotype profiles in Crohn's disease predicted by genetic markers in autophagy-related genes (GOIA study II).

BACKGROUND: About 70 loci are associated with susceptibility to Crohn's disease (CD), particularly in pathways of innate immunity, autophagy, and pathogen recognition. Phenotype-genotype associations are inconsistent. METHODS: CD susceptibility polymorphisms ATG16L1 rs2241880, ICAM1 rs5498, IL4 rs2070874, IL17F rs763780, IRGM rs13361189, ITLN1 rs2274910, LRRK2 rs11175593, and TLR4 rs4986790 were genotyped in a Portuguese population (511 CD patients, 626 controls) and assessed for association with CD clinical characteristics. RESULTS: There is a significant association of CD with the single nucleotide polymorphisms (SNPs) in ATG16L1 (odds ratio [OR] 1.36 [1.15-1.60], P = 2.7 × 10(-6) for allele G), IRGM (OR 1.56 [1.21-1.93], P = 3.9 × 10(-4) for allele C), and ITLN1 (OR 1.55 [1.28-1.88], P = 4.9 × 10(-4) for allele C). These SNPs are associated with ileal location (OR, respectively, 1.49, 1.52, and 1.70), ileocolonic location (OR, respectively, 1.31, 1.57, and 1.68), and involvement of the upper digestive tract (OR, respectively for ATG16L1 and IRGM, 1.96 and 1.95). The risk genotype GG in ATG16L1 is associated with patients who respond to steroids (OR 1.89), respond to immunosuppressants (OR 1.77), and to biologic therapy (OR 1.89). The SNPs in ITLN1 and IRGM are both associated with a positive response to biologic therapy. The risk for ileal, ileocolonic, and upper digestive tract locations increases with the number of risk alleles (OR for three alleles, respectively, 7.10, 3.54, and 12.07); the OR for positive response to biologic therapy is 3.66. CONCLUSIONS: A multilocus approach using autophagy-related genes provides insight into CD phenotype-genotype associations and genetic markers for predicting therapeutic responses.

Chronic hepatitis C treated with peginterferon alfa plus ribavirin in clinical practice.

BACKGROUND/AIMS: The role of genotype and viremia were retrospectively evaluated on sustained virological response (SVR) rates in routine clinical practice. METHODOLOGY: From 1907 patients with chronic hepatitis C proposed for treatment, we analysed 1380 (1124 naive and 256 treatment-experienced) with complete follow-up. Genotype and HCV RNA quantification were assayed by commercial tests. Viremia was considered high if >800,000IU/mL, and low if <400,000IU/mL. Liver fibrosis was staged in 614 patients. RESULTS: Genotype 1 was the most frequent (60%), followed by 3 (25%), 4 (9%) and 2 (2%); 3.2% had other or unclassified genotype. Genotype 1 was more prevalent in central Portugal and genotype 4 in the south. Viremia was =800,000IU/mL in 54.6% and <400,000IU/mL in 34.6% of the patients, particularly in genotype 2 (p<0.03) and 4 (p<0.001). Genotype non-1 had a significantly lower viral load (p=0.004). Mild or moderate fibrosis was present in 71.7% and bridging fibrosis or cirrhosis in 28.3%, with no differences among genotypes. Treatment was discontinued in 19.8%. SVR was achieved in 55.3% of naive and 36.3% of re-treated patients. CONCLUSIONS: Standard treatment of chronic hepatitis C in real-life achieves similar results obtained in clinical trials, despite differences of demographic and viral parameters.