[show abstract][hide abstract] ABSTRACT: IMPORTANCE In recent years, the CD40/CD40L system has been implicated in the pathophysiology of severe chronic inflammatory diseases. Recently, obesity has been described as a low chronic inflammatory disease, so this system could also be involved in the inflammatory process. OBJECTIVE To study soluble CD40 ligand (sCD40L) and other factors implicated in coagulation (plasminogen activator inhibitor 1, antithrombin III, and fibrinogen) and inflammation (C-reactive protein) in patients with morbid obesity and different body mass indexes (BMIs) (calculated as weight in kilograms divided by height in meters squared), before and after weight loss induced by bariatric surgery. DESIGN Plasma samples were obtained before and after a bariatric surgery intervention. Several inflammatory markers were then studied (sCD40L, plasminogen activator inhibitor 1, antithrombin III, and C-reactive protein). The values obtained were compared with a control group of nonobese persons. PARTICIPANTS Thirty-four morbidly obese patients undergoing gastric bypass surgery and 22 normal-weight controls matched for age and sex. INTERVENTIONS A Roux-en-Y gastric bypass was performed in morbidly obese patients. MAIN OUTCOME MEASURES Levels of sCD40L, plasminogen activator inhibitor 1, antithrombin III, fibrinogen, and C-reactive protein 12 months after bariatric surgery. RESULTS Obese men showed a tendency for decreased plasma sCD40L levels 1 year after surgery (mean [SEM], 246.5 [70.4] pg/mL before vs 82.2 [23.2] pg/mL after surgery; P < .05), whereas there were not any significant changes in obese women (285.9 [67.5] pg/mL before vs 287.0 [56.9] pg/mL after surgery). Levels of the other markers studied decreased significantly with weight loss in both sexes. However, all other studied markers tend to have higher concentrations in patients with higher BMIs, except for sCD40L, which tended to have lower concentrations in patients with BMIs higher than 55. The decreases with weight loss were lower with higher BMIs for all measurements, except for antithrombin III. CONCLUSIONS AND RELEVANCE Increased BMI, but not sex, influences recovery to normal levels for the markers studied, possibly indicating a worse prognosis.
[show abstract][hide abstract] ABSTRACT: To evaluate the effects of surgical weight loss (Roux-en-Y gastric bypass with a modified Fobi-Capella technique) on non alcoholic fatty liver disease in obese patients.
A group of 26 morbidly obese patients aged 45 ± 2 years and with a body mass index > 40 kg/m(2) who underwent open surgical weight loss operations had paired liver biopsies, the first at surgery and the second after 16 ± 3 mo of weight loss. Biopsies were evaluated and compared in a blinded fashion. The presence of metabolic syndrome, anthropometric and biochemical variables were also assessed at baseline and at the time of the second biopsy.
Percentage of excess weight loss was 72.1% ± 6.6%. There was a reduction in prevalence of metabolic syndrome from 57.7% (15 patients) to 7.7% (2 patients) (P < 0.001). Any significance difference was observed in aspartate aminotransferase or alanine aminotransferase between pre and postsurgery. There were improvements in steatosis (P < 0.001), lobular (P < 0.001) and portal (P < 0.05) inflammation and fibrosis (P < 0.001) at the second biopsy. There were 25 (96.1%) patients with non alcoholic steatohepatitis (NASH) in their index biopsy and only four (15.3%) of the repeat biopsies fulfilled the criteria for NASH. The persistence of fibrosis (F > 1) was present in five patients at second biopsy. Steatosis and fibrosis at surgery were predictors of significant fibrosis postsurgery.
Restrictive mildly malabsorptive surgery provides significant weight loss, resolution of metabolic syndrome and associated abnormal liver histological features in most obese patients.
World journal of hepatology. 12/2012; 4(12):382-8.
[show abstract][hide abstract] ABSTRACT: Brain magnetic resonance (MR) study has shown metabolic abnormalities and changes in water distribution of the brain tissue that may relate to the pathogenesis of hepatic encephalopathy (HE). We designed a study to investigate the disturbances in brain water and metabolites during episodic HE using a 3-T MR scanner. Cirrhotic patients with different grades of HE underwent MR during hospitalization (n=18). The MR was repeated at 6 weeks' follow-up (n=14). The results were compared with those of a group of healthy volunteers (n=8). During episodic HE, brain diffusion-weighted imaging showed a high apparent diffusion coefficient (ADC) (12% to 14%) that decreased during follow-up (-1% to -4%). These disturbances were accompanied by high glutamine (581%), low choline (-31%), and low myo-inositol (-86%) peaks on MR spectroscopy. In overt HE, patients showed high glutamine that decreased during follow-up (-22%). In addition, these patients exhibited a rise in plasma S100 beta and enlargement of brain white-matter lesions. In conclusion, several disturbances detected by MR support the presence of impaired brain water homeostasis during episodic HE. Although astrocytes have a major role in this condition, brain edema during episodic HE may be extracellular and does not appear to be directly responsible for the development of neurologic manifestations.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 November 2012; doi:10.1038/jcbfm.2012.173.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2012; · 5.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Increased C-reactive protein (CRP) levels strongly predict inflammatory diseases such as obesity and tissue damage. We wanted to study the CRP in plasma and tissue in morbidly obese patients before and after surgery and relate it with the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in tissues.
We analyzed CRP concentration in plasma, adipose and liver, and the expression of IL-6 and TNF-α, in those tissues, in 34 morbidly obese patients before and 1, 6 and 12 months after gastric bypass.
Morbidly obese had a greater amount of CRP in plasma (3 times) and tissues (21, 5 and 7 times more in liver, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), respectively) than control subjects. The expression of IL-6 in SAT showed a similar profile to plasma and SAT CRP in both obese patients and after weight loss, despite no significant correlation was found. We were only able to detect IL-6 in the liver of a subset of patients. The expression of TNF-α after surgery showed a no significant slight tendency to decrease in SAT with weight loss, but in the liver, we did not observe any change.
IL-6 in SAT, but not in liver, seems to be more closely related to plasma and tissue CRP than TNF-α in both obese patients and after weight loss. Plasma CRP protein perfectly reflects the decrease in inflammation and improves with weight loss in the tissues.
Obesity Surgery 01/2012; 22(1):131-9. · 3.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Falls are frequent among patients with debilitating disorders and can have a serious effect on health status. Mild cognitive disturbances associated with cirrhosis may increase the risk for falls. Identifying subjects at risk may allow the implementation of preventive measures. Our aim was to assess the predictive value of the Psychometric Hepatic Encephalopathy Score (PHES) in identifying patients likely to sustain falls. One hundred and twenty-two outpatients with cirrhosis were assessed using the PHES and were followed at specified intervals. One third of them exhibited cognitive dysfunction (CD) according to the PHES (<-4). Seventeen of the forty-two patients (40.4%) with CD had at least one fall during follow-up. In comparison, only 5 of 80 (6.2%) without CD had falls (P < 0.001). Fractures occurred in 4 patients (9.5%) with CD, but in no patients without CD (P = 0.01). Patients with CD needed more healthcare (23.8% versus 2.5%; P < 0.001), more emergency room care (14.2% versus 2.5%; P = 0.02), and more hospitalization (9.5% versus 0%; P = 0.01) as a result of falls than patients without CD. Patients taking psychoactive treatment (n = 21) had a higher frequency of falls, and this was related to an abnormal PHES. In patients without psychoactive treatment (n = 101), the incidence of falls was 32.4% in patients with CD versus 7.5% in those without CD (P = 0.003). In the multivariate analysis, CD was the only independent predictive factor of falls (odds ratio, 10.2; 95% confidence interval, 3.4-30.4; P < 0.001). The 1-year probability of falling was 52.3% in patients with CD and 6.5% in those without (P < 0.001). CONCLUSION: An abnormal PHES identifies patients with cirrhosis who are at risk for falls. This psychometric test may be useful to promote awareness of falls and identify patients who may benefit from preventive strategies.
[show abstract][hide abstract] ABSTRACT: The objective of this study was to establish the relationship between the plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (ATIII), fibrinogen, and white blood cell (WBC) levels in severely obese patients. We analyzed various plasma parameters implicated in the intrinsic and extrinsic coagulation pathway from 34 severely obese patients before and 1, 6, and 12 months after gastric bypass. In obese people, ATIII, fibrinogen, and WBC levels were in the upper limit of the normal range, and all were higher and significantly different from nonobese people. After bariatric surgery, the ATIII level continued to be high during the first month and increased until 12 months, while fibrinogen decreased only at that time. PAI-1 plasma protein and PAI-1 mRNA levels in liver and adipose tissue show similar profiles and had a strong positive correlation (r = 0.576, P = 0.0003 in liver; r = 0.433, P = 0.0004 in adipose tissue). They were higher in obese patients compared with nonobese control, but tended to recover normal values 1 month after surgery. Thus, the liver and adipose tissue could be an important source of PAI-1 protein in plasma. Gastric bypass surgery leads to a normalization of the hematological profile and a decrease in PAI-1 levels, which entails a decrease of risk for thromboembolism in severely obese.
[show abstract][hide abstract] ABSTRACT: Occult HBV infection (OBI) is defined by the presence of HBV DNA in the liver and/or serum and negative HBsAg testing. Since the implementation of highly sensitive HBV DNA screening, OBI is also detected in healthy blood donors. The aims of this study were to investigate HBV-specific immune responses and genetic variability in donors with OBI, established by HBV DNA in serum.
HBV-specific T-cell responses to HBV antigens were tested in 34 OBI donors by IFN-γ ELISpot, cytometric bead array, and intracellular cytokine staining. As comparison populations, 36 inactive HBV carriers, 22 donors with spontaneously resolved HBV infection, 24 vaccinated donors, and 25 seronegative donors were also included. Surface, pre-S, and pre-c/core genes from 44 genotype D isolates (24 OBI and 20 HBsAg-positive) were sequenced.
The immune response of OBI donors to the 3 HBV antigens was 29-41%, similar to the response in subjects with resolved HBV infection and higher than that in HBsAg-positive subjects. On sequence analysis, OBI donors presented a higher HBsAg mutation rate than HBsAg-positive subjects. Mutations were clustered in the major hydrophilic region of HBsAg, and no stop codons or relevant mutations that could affect antigen formation or detection were observed.
Our results suggest that immune response can suppress viral replication to low levels and HBsAg expression to undetectable levels in OBI blood donors. Relevant mutations were not found in the genomic HBsAg coding region. Hence, the fact that HBsAg was not detected in OBI is likely due to low HBsAg production, rather than to a failure of laboratory reagents.
Journal of Hepatology 12/2011; 56(4):765-74. · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.
[show abstract][hide abstract] ABSTRACT: DTI has shown increased MD of water molecules in the brain of patients with cirrhosis, consistent with low-grade edema. This study further characterizes this edema by using biexponential analysis of DTI data, a technique that may differentiate cytotoxic and vasogenic edema.
A total of 41 patients with cirrhosis awaiting liver transplantation and 16 healthy controls were studied by DTI by using a single-shot echo-planar technique with 11 b-values (range, 0-7500 s/mm(2)) and 6 noncollinear directions. Measurements were fitted to biexponential function to determine MD and FA for the fast and slow diffusion components. Regions of interest were selected in the parietal white matter and corticospinal tract. The assessment was repeated 1 year after liver transplantation in 24 of these patients.
In parietal white matter, patients with cirrhosis showed an increase in fast MD and a decrease in fast FA that normalized after liver transplantation. In the corticospinal tract, there was an increase in fast and slow MD that normalized after transplantation, and a decrease in FA that persisted posttransplantation. There was no association of DTI parameters with minimal HE (n =12).
Biexponential analysis of DTI supports the presence of edema in the brain of patients with cirrhosis that reverts after transplantation. In parietal white matter, the increase in brain water was mainly located in the interstitial compartment, while the corticospinal tract showed a mixed pattern (intra- and extracellular). In addition, the findings on posttransplantation were consistent with microstructural damage along the corticospinal tract.
American Journal of Neuroradiology 06/2011; 32(8):1510-7. · 3.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: The risk of recurrent hepatitis B virus (HBV) infection and prognosis of liver transplantation in patients with HBV has dramatically changed with the use of prophylaxis including hepatitis B immune globulin (HBIg) and antiviral agents.
This study analyzes the prognostic value of HBV DNA level before orthotopic liver transplantation (OLT) and the effect of HBV prophylaxis on rates of HBV recurrence and survival. Between 1988 and 2008, 859 patients underwent OLT in our center; 60 patients had HBV-related liver disease and in 49, HBV DNA was determined by real time-PCR before OLT. Survival and HBV recurrence were analyzed according to preoperative viral load (HBV DNA <10(3) IU/mL vs. HBV DNA ≥10(3)) and prophylaxis regimens (HBIg vs HBIg and antivirals).
On multivariate analysis, prophylaxis with HBIg alone, but not HBV-DNA levels was independently associated with poor survival, with a relative risk (RR) of death of 6.5 (95% CI 2.1-19.8, P = 0.001). The risk of HBV recurrence, in this small series, was also associated with monoprophylaxis with HBIg (RR 27, 95% CI 5.2-147.2, P < 0.0001), but not with HBV-DNA levels.
When prophylaxis with HBIg and antiviral agents was administered, survival and HBV recurrence were not influenced by HBV-DNA levels determined by real time-PCR prior to OLT.
Annals of hepatology: official journal of the Mexican Association of Hepatology 01/2011; 10(2):180-7. · 1.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatic encephalopathy (HE) is a common complication of cirrhosis that is associated with brain atrophy and may participate in impaired cognitive function after liver transplantation. This study analyzes the relationship of HE with cognitive function and brain volume after transplantation. A total of 52 consecutive patients with cirrhosis (24 alcohol abuse, 24 prior HE, 14 diabetes mellitus) completed a neuropsychological assessment before liver transplantation and again, 6 to 12 months after transplantation. In 24 patients who underwent the posttransplant assessment, magnetic resonance imaging was performed in addition, with measurement of brain volume and relative concentration of N-acetylaspartate (NAA) and creatine/phosphocreatine (Cr), a neuronal marker, by magnetic resonance spectroscopy. Neuropsychological assessment prior to transplantation identified minimal HE in 28 patients. All cognitive indexes improved after liver transplantation, but 7 patients (13%) showed persistent mild cognitive impairment. Global cognitive function after transplantation was poorer in patients with the following variables before liver transplantation: alcohol etiology, diabetes mellitus, and HE. Brain volume after transplantation was smaller in patients with prior HE. Brain volume correlated to NAA/Cr values (r = 0.498, P = 0.013) and poor motor function (r = 0.41, P = 0.049). In conclusion, the association of HE with cognitive function and brain volume suggests that having experienced HE before liver transplantation impairs the posttransplantation neurological outcome.
[show abstract][hide abstract] ABSTRACT: Minimal hepatic encephalopathy (MHE) reduces quality of life and impacts daily functioning. It is known to impair fitness to drive, but deficits in attention and reaction may also be associated with falls. Falls may have important consequences in patients with cirrhosis due to coagulopathy, osteoporosis, and operative risk. However, the relationship between MHE and falls has not yet been evaluated. The objective of this study is to retrospectively investigate whether MHE is associated with falls in patients with cirrhosis.
We included 130 cirrhotic outpatients and 43 controls. MHE was diagnosed according to the results of the psychometric hepatic encephalopathy score (PHES). We recorded the reported incidence and number of falls in the 12 months before the study, the severity of injuries, and the need for healthcare services.
Forty-five (34.6%) patients with cirrhosis exhibited MHE. The proportion of patients with MHE that reported falls (40%) was higher than those without MHE (12.9%, P<0.001), which was similar to controls (11.6%). In patients with MHE, there was a higher need for primary healthcare services (8.8 vs. 0%, P=0.004) and hospitalization (6.6 vs. 2.3%, P=0.34) due to falls than in patients without MHE. Patients on psychoactive drugs (n=21) showed a stronger association between MHE and falls: 6/8 (75%) patients with MHE presented falls vs. 2/13 (15.3%) patients without MHE (P=0.01). In patients not receiving psychoactive drugs (n=109), the incidence of falls was 12/37 (32.4%) in patients with MHE vs. 9/72 (12.5%) in those without MHE (P=0.01). Multivariate analysis showed that MHE (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.13-7.48, P=0.02), previous encephalopathy (OR: 2.87, 95% CI: 1.10-7.50, P=0.03), and antidepressant therapy (OR: 3.91, 95% CI: 0.96-15.9, P=0.05) were independent factors associated to previous falls.
Falls are more frequent in cirrhotic patients with MHE, particularly in those on treatment with psychoactive drugs, and are a significant cause for healthcare and hospitalization requirements.
The American Journal of Gastroenterology 10/2010; 106(3):476-82. · 7.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: A prolonged survival in liver transplant recipients due to a better management exposes them to multiple factors that can impair neurologic function in the long term.
Twenty-two patients were studied by brain magnetic resonance and completed a neuropsychologic assessment shortly before liver transplant, 6 to 12 months after (short term), and 6 to 9 years (long term) after liver transplant. Thirteen healthy controls matched by age were studied in parallel.
An enlargement in the ventricular size (an indirect measure of brain volume) was observed in the short term (+8%) and in the long term after liver transplant (+22%); the size of ventricles was larger than in healthy controls. In addition, a progression in the volume of focal T2 white matter lesions (an index of small vessel cerebrovascular disease) was detected in the long term (+49%) and was related to vascular risk factors in those with larger increases (>12.5% per year). Neuropsychologic function showed a significant improvement after liver transplant and remained stable in the long term, except for memory loss in those patients with larger increases in white matter lesions.
Improvement in neuropsychologic function after successful liver transplant can be demonstrated up to 9 years. However, these patients experience a progressive accumulation of focal T2 brain lesions and show a smaller brain volume than controls, which can be related to their previous cirrhosis. A good management to minimize brain injury before transplantation and an accurate treatment of vascular risk factors may be important to prevent consequences on cognitive function.
[show abstract][hide abstract] ABSTRACT: The relationship between C-reactive protein (CRP), nitric oxide (NO), leptin, adiponectin, and insulin growth factor 1 (IGF-1) is poorly defined in morbidly obese patients before and after gastric bypass and, in some cases, is controversial.
We examined the plasma of 34 morbidly obese patients before and 1, 6, and 12 months after Roux-en-Y gastric bypass surgery.
Obese people had more CRP (21.3 +/- 1.8 microg/ml) and leptin (36.9 +/- 4.0 ng/ml) than those in the control group (nonobese people: CRP = 6.9 +/- 0.9 microg/ml, p < 0.0001; leptin = 7.5 +/- 0.4 ng/ml, p < 0.0001). However, they had less NO (30.4 +/- 2.7 nmol/ml), IGF-1 (77.5 +/- 6.6 ng/ml), and adiponectin (11.1 +/- 1.0 microg/ml) than those in the control group (NO = 45.8 +/- 3.9 nmol/ml, p = 0.0059; IGF-1 = 202.0 +/- 12.0 ng/ml, p < 0.0001; adiponectin = 18.0 +/- 2.0 microg/ml, p < 0.0001). During weight loss, the amount of CRP and leptin decreased until they reached the nonobese values, but the level of NO remained lower than in nonobese people, even 1 year after surgery. The linear regression slopes were negative and very significant for leptin (p = 0.0005) and CRP (p = 0.0018) but were less significant for NO (p = 0.0221). IGF-1 displayed a very good linear regression (both negative and significant) with some anthropometric parameters, including body mass index (p = 0.0025), total fat (p = 0.0177), and the percentage of fat (p < 0.0001).
For the first time, we report the relationship between IGF-1 and CRP, NO, leptin, and adiponectin. For all these parameters, the best and most widely demonstrated improvements in comorbidities before and during weight loss in morbid obesity were associated with CRP and leptin.
Obesity Surgery 03/2010; 20(5):623-32. · 3.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although bariatric surgery is currently the most common practice for inducing weight loss in morbidly obese patients (BMI>40 kg/m2), its effect on the lipid content of adipose tissue and its lipases (lipoprotein lipase [LPL] and hormone-sensitive lipase [HSL]) are controversial.
We analyzed LPL and HSL activities and lipid content from plasma as well as subcutaneous (SAT) and visceral (VAT) adipose tissue of 34 morbidly obese patients (MO) before and after (6 and 12 months) Roux-en-Y gastric bypass surgery and compare the values with those of normal weight (control) patients.
LPL activity was significantly higher in MO (SAT=32.9+/-1.0 vs VAT=36.4+/-3.3 mU/g tissue; p<0.001) than in control subjects (SAT=8.2+/-1.4 vs VAT=6.8+/-1.0 mU/g tissue) in both adipose depots. HSL activity had similar values in both types of tissue (SAT=32.8+/-1.6 and VAT=32.9+/-1.6 mU/g) of MO. In the control group, we found similar results but with lower values (SAT=11.9+/-1.4 vs VAT=12.1+/-1.4 mU/g tissue). Twelve months after surgery, SAT LPL activity diminished (9.8+/-1.4 mU/g tissue, p<0.001 vs morbidly obese), while HSL (46.6+/-3.7 mU/g tissue) remained high. All lipids in tissue and plasma diminished after bariatric surgery except plasma nonesterified fatty acids, which maintained higher levels than controls (16+/-3 vs 9+/-0 mg/dL; p<0.001, respectively).
When obese patients lose weight, they lose not only part of the lipid content of the cells but also the capacity to store triacylglycerides in SAT depots.
Obesity Surgery 06/2009; 19(8):1150-8. · 3.10 Impact Factor