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Biomedical subjects

Paul Angulo

Publications and source records attributed to Paul Angulo.

At least 37 records · Page 2Linked to original sources
PubMed2005

Hyaluronic acid, an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease.

AIM: To determine whether serum hyaluronic acid reliably predicts the severity of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We studied 79 patients with histologically confirmed NAFLD. Hyaluronic acid was measured in serum obtained at the time of liver biopsy. Severity of fibrosis was staged based on Brunt's classification. The prediction levels for fibrosis were determined by area under the receiver operating characteristic curve (AUC). RESULTS: The logarithm of serum hyaluronic acid was significantly different among the stages of fibrosis (P<0.0001, analysis of variance) and had a significant positive correlation with the degrees of fibrosis after adjusting for age and serum albumin (partial r=0.44, P<0.0001). AUCs were 0.67, 0.87, 0.89, and 0.92 for any levels of fibrosis, > or =moderate fibrosis, > or =severe fibrosis, and cirrhosis, all of which were significantly higher than 0.5 (P<0.05). The cut-off value of serum hyaluronic acid of 46.1 mug/l was associated with the highest AUC for severe fibrosis, yielding a sensitivity of 85% and a specificity of 80%. The corresponding positive and negative predictive values were 51% and 96%, when assuming prevalence of severe fibrosis in NAFLD patients of 20% at referral centers. CONCLUSIONS: Measurement of serum hyaluronic acid is useful to identify NAFLD patients with severe fibrosis.

Adult↗
PubMed2005

Mycophenolate mofetil for the treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Despite advances in understanding the pathophysiology underlying this disorder, no effective medical therapy has been identified for halting disease progression. The aim of this investigation was to determine the safety and estimated efficacy of mycophenolate mofetil (MMF) for the treatment of PSC. Thirty patients with PSC received MMF 1 g daily to a maximum of 3 g daily for 1 yr. Liver tests were determined at 3-month intervals with the Mayo risk score calculated at baseline and at the end of therapy. Twenty-three (77%) patients completed 1 yr of therapy. Significant but clinically marginal improvement in serum alkaline phosphatase level after 1 yr of therapy was observed (1135 +/- 581 U/L vs 912 +/- 463 U/L, p= 0.02). No other significant changes in liver biochemistries or Mayo risk score was observed. Seven patients (23%) discontinued MMF due to adverse events possibly related to therapy. Adverse reactions resolved spontaneously or with dose reduction in 10 (33%) patients. One patient developed pancreatitis, bacterial cholangitis, and sepsis during the eighth month of MMF therapy. No patient developed cytopenia on therapy. In conclusion, MMF does not appear to have clinically important benefits for PSC despite being tolerated by most patients. The results of this pilot study do not support further study of MMF as a single agent in the treatment of PSC.

Adult↗
PubMed2005

Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis.

OBJECTIVES: The natural history of secondary sclerosing cholangitis (SSC) is ill-defined. In order to better determine the natural history of this condition, we retrospectively reviewed data from the Mayo Clinic in Rochester, Minnesota. We also compared the natural history of patients diagnosed with SSC to a cohort with a diagnosis of primary sclerosing cholangitis (PSC). METHODS: We used a computer-assisted search to identify patients with a diagnosis of SSC seen from 1992 to 2002. The diagnosis was confirmed by chart review and information about age, gender, etiology, therapy, and clinical course was sought. We excluded those presumed SSC patients who had a history of inflammatory bowel disease, those with malignancy at the time of diagnosis, and those who had undergone liver transplantation prior to the diagnosis of SSC. Patients with PSC matched for age, gender, and serum bilirubin level served as disease controls. RESULTS: We identified 31 patients, average age 57, (range 28-79). The causes of SSC included surgical trauma from cholecystectomy (13 patients), intraductal stones (12 patients), recurrent pancreatitis (4 patients), and abdominal injury (2 patients). Nine patients with SSC ultimately required liver transplantation and 4 patients have died. When compared to matched patients with PSC, the survival free of transplant was significantly shortened (p<0.03). CONCLUSIONS: When the long-term outcome of SSC patients was compared to matched PSC controls, the SSC patients had a poorer outcome. The natural history of SSC is characterized by a shortened life expectancy.

Abdominal Injuries↗
PubMed2005

Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

BACKGROUND & AIMS: Despite evidence for therapeutic efficacy with ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC), only 30-50% of patients achieve complete biochemical remission within 1 year of therapy. Mycophenolate mofetil (MMF) is an immunosuppressive medication that inhibits T and B lymphocyte proliferation. The aim of this investigation was to determine the safety and estimated efficacy of MMF in patients with PBC. METHODS: Twenty-five patients with incomplete responses to UDCA (defined as persistent elevation of serum alkaline phosphatase > or =2 times the upper limit of normal) received MMF 1 g daily to a maximum of 3 g daily with UDCA (13-15 mg/kg per day) for 1 year. Liver biochemistries were determined at 3-month intervals with Mayo Risk Score calculated at baseline and end of therapy. RESULTS: Nineteen (76%) patients completed 1 year of therapy. Despite improvements in serum alkaline phosphatase (920 +/- 308 vs. 709 +/- 242 IU/L, P = 0.001) and AST (65 +/- 31 vs. 51 +/- 19 IU/L, P = 0.007) levels, these findings were clinically insignificant. Exploratory analysis revealed a strong correlation between advanced PBC defined by higher Mayo Risk Score and reduction in serum alkaline phosphatase levels (r = -0.74, P = 0.006). Six patients (24%) did not complete therapy; adverse drug events were responsible for study withdrawal in 3 individuals. Adverse reactions that resolved spontaneously or by dose reduction occurred in 13 patients. CONCLUSIONS: MMF is not associated with important clinical benefits in PBC based on the results of this pilot investigation.

Administration, Oral↗
PubMed2004

Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis.

Patients with primary sclerosing cholangitis (PSC) may develop and bleed from esophageal varices. However, the exact prevalence of esophageal varices in patients with PSC remains unknown and potential predictors of esophageal varices in this population have not been identified. Our aim was to determine the prevalence of esophageal varices in patients with PSC and the variables that predict their presence. Data were collected on 283 patients with PSC treated for the first time at the Mayo Clinic (Rochester, MN) during 8 consecutive years. Thirty-six percent (102 of 283) of patients had esophageal varices including 56% (57 of 102) with moderate/large varices. After excluding 28 patients with a history of variceal bleeding, data on 183 patients were analyzed to identify independent predictors of esophageal varices and of moderate/large size varices. Platelet count, albumin level, and advanced histologic disease were independent predictors of esophageal varices (area under the receiver operator characteristic [ROC] curve = 0.88). After controlling for the presence of advanced histologic stage and albumin levels, the odds ratios (OR) of platelet count less than 150 x 10(3)/dL for the presence of esophageal varices was 6.3 (95% CI: 2.6-15.8). The diagnostic accuracy of these results was corroborated by cross-validation of the data in an independent set of 72 patients with PSC (area under the ROC = 0.90). In conclusion, in patients with PSC, noninvasive markers of portal hypertension and of advanced liver disease predict the presence of esophageal varices. Our results suggest a clinically applicable and useful approach to identify patients with PSC who are more likely to benefit from endoscopic screening for esophageal varices.

Adult↗
PubMed2004

Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial.

No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical studies. We randomized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre- and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH.

Alanine Transaminase↗
PubMed2004

Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction.

Patients with hypopituitarism develop a phenotype similar to metabolic syndrome with central obesity and diabetes. Similarly, patients with hypothalamic damage may develop central obesity, insulin resistance, and hyperphagia. We sought to examine the clinical associations between hypopituitarism, hypothalamic dysfunction, and nonalcoholic fatty liver disease (NAFLD). A case series of patients seen at our institution with diagnoses of hypopituitarism, hypothalamic obesity, or craniopharyngioma and NAFLD was undertaken. Clinical, laboratory, and liver biopsy features were reviewed. Twenty-one patients were identified. NAFLD was diagnosed 6.4 +/- 7.5 years (median 3 years) after the diagnosis of hypothalamic/pituitary dysfunction. Mean gain in body mass index (BMI) between diagnoses of hypothalamic/pituitary disease and NAFLD was 11.3 +/- 8.9 kg/m(2) at an average yearly rate of 2.2 +/- 2.2 kg/m(2). The majority of patients developed elevated glucose levels and dyslipidemia by time of diagnosis of NAFLD. Of the 10 patients biopsied, six were cirrhotic, two had nonalcoholic steatohepatitis (NASH) with fibrosis, and two had simple steatosis. Long-term follow-up of 66 +/- 33 months (range 12-120) was available for 18 patients. Two required liver transplantation. Six patients died, two from liver related causes. In conclusion, patients with hypothalamic and/or pituitary disease are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of NAFLD. This group has a high prevalence of cirrhosis placing them at risk for liver-related death. The novel evidence that hypothalamic/pituitary dysfunction may be accompanied by progressive NAFLD has important implications for the work-up and management of patients with hypothalamic/pituitary disease.

Acanthosis Nigricans↗
PubMed2004

Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis.

Investigations examining the use of magnetic resonance cholangiography (MRC) for the diagnosis of primary sclerosing cholangitis (PSC) have described comparable accuracy when compared to endoscopic retrograde cholangiopancreatography (ERCP). The effectiveness of MRC based on overall cost, however, remains unknown. Our aim was to determine the average cost per correct diagnosis using MRC or ERCP as the initial testing strategy for the diagnosis of PSC. A decision analysis model was constructed employing diagnostic test parameters prospectively determined among 73 patients with clinically suspected biliary disease. ERCP was performed within 24 hours after MRC. Cost data were derived from average Medicare reimbursement fee schedules. The prevalence of PSC in the study cohort was 32%. The sensitivity and specificity of MRC for the diagnosis of PSC were 82% and 98%, respectively. The average cost per correct diagnosis of PSC was 724.00 US dollars for initial MRC (including the cost of ERCP following a negative MRC examination) versus 793.17 US dollars for initial ERCP. In the absence of biliary obstruction, the average cost per correct diagnosis of PSC was 549.64 US dollars with MRC versus 623.25 US dollars or ERCP. The average cost of managing post-ERCP-related complications among patients with PSC was 2902.20 US dollars (range, 1915.40-5031.54 US dollars). For ERCP to be the optimal initial test strategy, a prevalence rate of PSC greater than 45%, MRC specificity less than 85%, or reduction in the average cost per diagnosis to 538.30 US dollars would be required. In conclusion, MRC has comparable accuracy to ERCP and results in cost savings when used as the initial test strategy for diagnosing PSC.

Adult↗
PubMed2004

Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae?

BACKGROUND/AIMS: The etiology and pathogenesis of primary biliary cirrhosis (PBC) remain elusive. Both an infectious etiology and molecular mimicry have been implicated. The aim is to study the prevalence of Chlamydial antigens and RNA in the liver tissue of patients with PBC. METHODS: We compared the prevalence of Chlamydial antigen and RNA in 25 explants with PBC who underwent orthotopic liver transplantation with 105 explanted livers from other chronic liver disease. We also studied 14 liver biopsies from patients with early stages of PBC. Donor livers were also studied. RESULTS: In all 39 patients with PBC, Chlamydia pneumoniae antigens were present but not Chlamydia trachomatis, and only 9/105 (8.5%) of patients in the other categories were positive (P<0.01) for C. pneumoniae. Eight explanted PBC livers were tested for C. pneumoniae 16S RNA by in situ hybridization and were positive. CONCLUSIONS: The presence of C. pneumoniae antigen and RNA in liver tissue of patients with PBC suggests that C. pneumoniae antigen may trigger an immune response based on molecular mimicry.

Adult↗
PubMed2004

Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD. METHODS: Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls. RESULTS: Leptin levels were significantly greater in patients with more advanced fibrosis (P = 0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted P = 0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted P = 0.006) and insulin sensitivity (adjusted P = 0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9 +/- 16 months. Leptin levels were not significantly different between patients who had fibrosis progression (n = 10) and those who did not (n = 29). CONCLUSIONS: In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.

Adult↗
PubMed2004

Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.

Adolescent↗
PubMed2004

The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease.

OBJECTIVES: Autoantibodies may exist in serum of patients with nonalcoholic fatty liver disease (NAFLD) although their prevalence and clinical significance is uncertain. We aimed at examining the prevalence of autoantibodies and autoimmune hepatitis among patients with NAFLD. METHODS: Prevalence of antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and autoimmune hepatitis (AIH) based on the International AIH Group were determined in 225 patients with liver biopsy-proven NAFLD. RESULTS: Fifty-one patients [23% (95% CI 17.3-28.2%)] had autoantibodies in serum which is significantly higher than the prevalence in the general population. ANA were present in 46 patients (20%), SMA in 6 (3%), and both antibodies in one patient. Positive autoantibodies were associated with higher fibrosis stage (p= 0.03), higher inflammatory grade (p= 0.02), and higher levels of gammaglobulin (p= 0.01). Prior to liver biopsy, 45 of the 51 (88%) patients with positive autoantibodies fulfilled diagnostic criteria for 'probable' or 'definite' AIH. After liver biopsy, however, only four patients fulfilled diagnostic criteria. CONCLUSIONS: Routinely measured autoantibodies are present in one quarter of patients with NAFLD and are associated with more severe histological damage. Liver biopsy is required to rule out AIH in most NAFLD patients with positive autoantibodies.

Adolescent↗
PubMed2004

A pilot trial of pentoxifylline in nonalcoholic steatohepatitis.

OBJECTIVES: Tumor necrosis factor alpha (TNF alpha) contributes to liver damage and insulin resistance among patients with nonalcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF alpha production. We therefore conducted a 12-month pilot trial to assess the efficacy and safety of pentoxifylline (1,600 mg/day) among 20 patients with NASH. METHODS: Patients had biopsy-confirmed NASH with other causes of liver disease and secondary causes of NASH excluded. Patients who drank more than 40 gm of ethanol weekly were also excluded. Pentoxifylline (400 mg q.i.d.) was given for 12 months. Liver enzymes and adverse events were monitored every 3 months until completion. RESULTS: The 20 patients had a mean age of 50 +/- 11 yr. Eleven (55%) were female, 14 were obese (body mass index > or =30 kg/m(2)), and 7 (35%) were diabetic. At baseline, median steatosis grade was 2 (range 1-3), median necroinflammatory grade was 1 (1-2), and median fibrosis stage was 2 (0-4). Nine patients withdrew from the study, primarily because of nausea. No serious adverse events occurred. Alanine and aspartate aminotransferase levels were significantly lower at 12 months compared to baseline (84 +/- 64 vs 138 +/- 76, p= 0.002 and 58 +/- 37 vs 102 +/- 62, p= 0.003, respectively). Bilirubin did not change significantly from baseline (0.8 +/- 0.4 vs 0.8 +/- 0.3, p= 0.95), nor did alkaline phosphatase (193 +/- 68 vs 180 +/- 53, p= 0.62) or albumin (4.0 +/- 0.2 vs 4.2 +/- 0.3, p= 0.41). CONCLUSIONS: Aminotransferase levels among patients with NASH improve with administration of pentoxifylline. Strategies to overcome side effects will be needed for future trials.

Chi-Square Distribution↗
PubMed2003

Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.

BACKGROUND & AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction. METHODS: Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis. RESULTS: TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls. CONCLUSIONS: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.

Adult↗