Correlation between neuroimaging, neurological phenotype, and functional outcomes in Wilson's disease.

INTRODUCTION: Wilson's disease (WD) is associated with a variety of movement disorders and progressive neurological dysfunction. The aim of this study was to correlate baseline brain magnetic resonance imaging (MRI) features with clinical phenotype and long-term outcomes in chronically treated WD patients. METHODS: Patients were retrospectively selected from an institutional database. Two experienced neuroradiologists reviewed baseline brain MRI. Functional assessment was performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) scale, and disease severity was classified using the Global Assessment Scale for Wilson's Disease (GASWD). RESULTS: Of 27 patients selected, 14 were female (51.9%), with a mean (standard deviation [SD]) age at onset of 19.5 (7.1) years. Neurological symptoms developed in 22 patients (81.5%), with hyperkinetic symptoms being the most common (70.4%). Baseline brain MRI showed abnormal findings in 18 cases (66.7%), including T2 hyperintensities in 59.3% and atrophy in 29.6%. After a mean (SD) follow-up of 20.9 (11.0) years, WD patients had a mean score of 19.2 (10.2) on WHODAS 2.0 and 6.4 (5.7) on GASWD. The presence of hyperkinetic symptoms correlated with putaminal T2 hyperintensities (p = 0.003), putaminal T2 hypointensities (p = 0.009), and mesencephalic T2 hyperintensities (p = 0.009). Increased functional disability was associated with brain atrophy (p = 0.007), diffusion abnormalities (p = 0.013), and burden of T2 hyperintensities (p = 0.002). A stepwise regression model identified atrophy as a predictor of increased WHODAS 2.0 (p = 0.023) and GASWD (p = 0.007) scores. CONCLUSIONS: Atrophy and, to a lesser extent, deep T2 hyperintensity are associated with functional disability and disease severity in long-term follow-up of WD patients.

Brain MRI in the Decision for Liver Transplantation in Pediatric Neurological Wilson's Disease.

Background: Neurological Wilson's disease (WD) presentation in the pediatric population is rare, and liver transplantation (LT) in these patients remains controversial. The aim of the present study was to assess the role of brain magnetic resonance imaging (MRI) in predicting reversion of brain lesions and neurological outcomes in pediatric WD patients after LT. Methods: Patients with confirmed WD (Leipzig score ≥4), disease onset in pediatric age (<18 years), neurological involvement, and submitted to LT were selected. Clinical records and pre- and post-LT brain MRI were evaluated. Results: Six patients met the pre-defined inclusion criteria, one of whom died shortly after LT and was excluded. The indication for LT was end-stage liver disease in two patients and neurological worsening despite optimized treatment in three patients. After LT, the neurological picture progressively improved in all patients. Pre-LT brain MRI showed T1-weighted hyperintensities in four patients, which quickly resolved afterward. T2-weighted hyperintensities were observed in four patients before LT, completely resolving in one patient, stabilizing in two, and improving in one after LT. A direct correlation could not be found between clinical and neuroradiological improvement. Progressive clinical improvement was observed even in patients with irreversible brain MRI changes. Conversely, some patients with normal MRI had only slight neurological improvement. Conclusions: The pattern of T2-weighted hyperintensities after LT was unpredictable and did not correlate with neurological outcomes, suggesting that these changes may not entail irreversible clinical damage. Therefore, brain MRI does not seem to have prognostic value for assessing clinical response to LT.

Systemic inflammation as a risk factor for portal vein thrombosis in cirrhosis: a prospective longitudinal study.

BACKGROUND AND AIMS: Various risk factors for portal vein thrombosis (PVT) development in patients with cirrhosis have been identified, but the role of systemic inflammatory reaction is unknown. The study aims to assess the association between markers of systemic inflammation and PVT in cirrhosis. METHODS: Between January 2014 and October 2015, 107 outpatients with cirrhosis and no PVT were recruited, and followed till February 2017. White blood cell count, serum concentrations of high-sensitive C-reactive protein, ferritin, tumor necrosis factor-alpha and interleukin-6 (IL-6) were evaluated at baseline and every 3 or 6 months till PVT diagnosis or end of follow-up. RESULTS: Median age, model for end-stage liver disease (MELD) score and follow-up period of the studied population was 55 years (IQR 46-62 years), 9.6 points (IQR 7.5-12 points) and 19 months (12-24 months), respectively. PVT developed in 10.3% of the patients. Lymphocyte count below 1.2 ´ 109/L [hazard ratio, 6.04; 95% confidence interval (CI), 1.29-28.2; P = 0.022], IL-6 above 5.5 pg/mL (hazard ratio, 5.64; 95% CI, 1.21-26.33; P = 0.028) and neutrophil-to-lymphocyte ratio (hazard ratio, 1.46; 95% CI, 1.04-2.04; P = 0.028) were associated with a higher risk of PVT development. IL-6 and lymphopenia remained associated with subsequent PVT development after adjustment for nonselective beta-blockers, spleen size, portosystemic collaterals, oesophageal varices (grade ≥2) and ascites, but also with alcohol as the cause for cirrhosis and MELD ≥13. CONCLUSION: In patients with cirrhosis, markers of systemic inflammation IL-6 and lymphopenia are predictive of PVT independently of markers of portal hypertension. These results draw our attention on a factor so far overlooked in the pathogenesis of PVT.

Nonselective beta-blockers and the risk of portal vein thrombosis in patients with cirrhosis: results of a prospective longitudinal study.

BACKGROUND: Nonmalignant portal vein thrombosis is a significant event in the course of cirrhosis that can contraindicate liver transplantation and even impact survival after the surgical procedure. Risk factors are not completely known or validated and are still debated. AIM: To identify in patients with cirrhosis the risk factors for portal vein thrombosis that are assessable in clinical practice. METHODS: Between January 2014 and February 2017, 108 outpatients with cirrhosis and no portal vein thrombosis (78% Child A) were enrolled. Doppler ultrasound was performed every 3 or 6 months, for a median follow up of 19 months. RESULTS: Portal vein thrombosis developed in 11 patients. Nonselective beta-blockade (hazard ratio [HR] 10.56; 95% confidence interval [CI]: 1.35-82.73; P = 0.025), and medium or large-sized oesophageal varices (HR 5.67; 95% CI: 1.49-21.63; P = 0.011) at baseline were associated with portal vein thrombosis development. Although heart rate (P < 0.001) and portal blood flow velocity at baseline (P = 0.005) were significantly reduced by nonselective beta-blockers, they were not related to portal vein thrombosis development. CONCLUSIONS: Our findings confirm an association between portal vein thrombosis development and oesophageal varices at baseline, but suggest that the association could be explained by exposure to nonselective beta-blockers, independently from effects on heart rate and portal blood flow velocity. The mechanisms that explain portal vein thrombosis development in patients on nonselective beta-blockers require elucidation in order to optimise targeting of nonselective beta-blockade in patients with cirrhosis.

Evaluation of fibrosis and inflammation in diffuse liver diseases using intravoxel incoherent motion diffusion-weighted MR imaging.

PURPOSE: The purpose of the study was to evaluate the role of intravoxel incoherent motion (IVIM) diffusion model for the assessment of liver fibrosis and inflammation in diffuse liver disorders, also considering the presence of liver steatosis and iron deposits. METHODS: Seventy-four patients were included, with liver biopsy and a 3 Tesla abdominal magnetic resonance imaging examination, with an IVIM diffusion-weighted sequence (single-shot spin-echo echo-planar sequence, with gradient reversal fat suppression; 6 b-values: 0, 50, 200, 400, 600, and 800 s/mm2). Histological evaluation comprised the Ishak modified scale, for grading inflammation and fibrosis, plus steatosis and iron loading classification. The liver apparent diffusion coefficient (ADC) and IVIM parameters (D, D*, f) were calculated from the IVIM images. The relationship between IVIM parameters and histopathological scores were evaluated by ANOVA and Spearman correlation tests. A test-retest experiment assessed reproducibility and repeatability in 10 healthy volunteers and 10 randomly selected patient studies. RESULTS: ADC and f values were lower with higher fibrosis stages (p = 0.009, p = 0.006, respectively) and also with higher necro-inflammatory activity grades (p = 0.02, p = 0.017, respectively). Considered together, only fibrosis presented a significant effect on ADC and f measurements (p < 0.05), whereas inflammation had no significant effect (p > 0.05). A mild correlation was found between ADC and f with fibrosis (R S = -0.32 and R S = -0.38; p < 0.05) and inflammation (R S = -0.31 and R S = -0.32, p < 0.05; respectively). The AUROC for ADC and f measurements with the different dichotomizations between fibrosis or inflammation grades were only fair (0.670 to 0.749, p < 0.05). Neither D nor D* values were significantly different between liver fibrosis or inflammation grades. D measurements were significantly different across histologic grades of steatosis (p < 0.001) and iron overload (p < 0.001), whereas f measurements showed significant differences across histologic steatosis grades (p = 0.005). There was an excellent agreement between the different readers for ADC, f, and D. CONCLUSIONS: Although fibrosis presented a significant effect on ADC and f, IVIM measurements are not accurate enough to stage liver fibrosis or necro-inflammatory activity in diffuse liver diseases. D values were influenced by steatosis and iron overload.

Sorafenib Improves Survival in Metastatic Hepatocellular Carcinoma: A Case Report.

Hepatocellular carcinoma (HCC) is a very common cancer. Curative treatments and local ones are well validated. Sorafenib, a multi-kinase receptor inhibitor was introduced in 2007 for advanced HCC in patients with preserved liver function. HCC is known to be resistant to systemic chemotherapy, and there are no validated therapies improving survival for metastatic disease. Herein, we report a case of a 45 years old woman with chronic hepatitis B infection submitted to a right hepatectomy in May 2001 for an hepatic tumor with more than 10 cm wide, confirmed as a HCC moderately differentiated. Three years later, a solitary pulmonary metastasis was documented and a metastectomy was done. In February 2009, the patient started on sorafenib 400 mg twice daily due to an inferior mediastinal metastasis with a vena cava thrombus associated. Computed tomography (CT) scan done 13 months after revealed a consistently mass reduction in more than 50% and a clinically well patient without important collateral effects. HCC is a highly vascularized tumor and sorafenib is known to inhibit both tumor angiogenesis and tumor cell survival. It is already approved for the treatment of advanced and metastatic renal cell cancer. In our case, the combination of two well done surgical procedures and the posterior use of sorafenib when a metastasis was found in an inaccessible surgical place with macroscopic vascular invasion, led to a long survival without important side effects.

Growth hormone (GH)-induced reconstitution of CD8+ CD28+ T lymphocytes in a rare case of severe lymphopenia associated with Juvenile Haemochromatosis and Turner's syndrome.

This paper describes a rare case of Turner's syndrome associated with Juvenile Haemochromatosis and severe lymphopenia, followed-up for a period of 5 years. Because of the indication for treatment with growth hormone (GH), this case was observed as a model to analyse the effects of GH on growth, iron mobilization and lymphocyte reconstitution. For this purpose, a serial study of the T lymphocyte subpopulations CD4+, CD8+, CD8+ CD28+ and CD8+ CD28- was performed by immunophenotyping during the follow-up period. Besides the impact of both phlebotomy treatment and GH on the rapid growth and mobilization of 20.8 g of iron in 136 weeks, the most relevant observation was the finding of a significant expansion of CD8+ T lymphocytes expressing the costimulatory marker CD28 in the setting of the severe lymphopenia. These findings constitute new clinical evidence supporting the notion that the GH/IGF-1 system has an important role on the maintenance of T cell homeostasis in vivo, and that GH may be regarded as a putative therapeutic agent in T lymphocyte reconstitution.