PubMed Health⌕ Search

Biomedical subjects

Paul J Thuluvath

Publications and source records attributed to Paul J Thuluvath.

At least 19 recordsLinked to original sources

Complementary and alternative medicine in hepatology: review of the evidence of efficacy.

There is an increase in the use of complementary and alternative medicine (CAM), especially herbal therapy, among patients with liver disease. The most commonly used herbal agent is silymarin. In animal models, many of the commonly used agents have shown anti-inflammatory and antifibrotic effects. Although many human studies have shown improvements in subjective symptoms (well being) and liver biochemistry, there are no convincing data to suggest a definite histologic and/or virologic improvement with most of these agents. Poorly designed studies, heterogeneous patient populations, lack of standardized preparations, and poorly defined nonobjective end points may partly explain the conflicting reports in the literature. Hepatotoxicity and drug interactions are common with many herbal medications, and therefore physicians need to be cognizant of known or occult use of CAM by their patients. Only well-designed, randomized, controlled trials will be able to ascertain whether CAM has any role in the management of patients with acute or chronic liver diseases. Until such time, the use of CAM cannot be recommended as a therapy for patients with liver disease.

Acupuncture Therapy↗

Cryptogenic cirrhosis and NAFLD: are they related?

Cryptogenic cirrhosis (CC), literally meaning cirrhosis of obscure or unknown origin, is a diagnosis of exclusion. The circumstantial evidence indicates that nonalcoholic fatty liver disease (NAFLD) is perhaps one of the important causes of CC. There is also evidence, especially from the European literature, that some patients with CC may have undiagnosed or burnt-out autoimmune hepatitis (AIH). Other rare causes may include "unknown" viral (non-A, non-B, non-C) hepatitis, and occult alcoholism. In this review, we examine the role of NAFLD and other causes in the pathogenesis of CC, and the impact of obesity on patients with chronic liver disease.

Adult↗

Sirolimus monotherapy versus sirolimus in combination with steroids and/or MMF for immunosuppression after liver transplantation.

Calcineurin inhibitor (CI)-associated renal dysfunction has emerged as a major cause of morbidity and mortality after liver transplantation. In this retrospective study, we compared the efficacy, safety, and renal protective effect of sirolimus monotherapy (Group A; n = 26) with sirolimus in combination (Group B; n = 34) with steroids and/or mycophenolate mofetil (MMF) in liver transplant recipients who were switched from CI. Patients were switched abruptly or over a period of 2-4 weeks and followed for 17 +/- 10 months. Preconversion renal biopsies in five of six patients showed histological features consistent with CI nephrotoxicity. Serum creatinine increased in the year prior to conversion from 1.7 +/- 0.4 to 2.1 +/- 0.7 mg/dl (P = 0.009) and improved thereafter (1 month, 1.7 +/- 0.6, P < 0.001; 6 months, 1.6 +/- 0.5, P < 0.001; last follow-up, 1.7 +/- 0.9, P = 0.02); only four patients showed a significant decline in renal function after conversion. Seven (11.3%) patients experienced acute rejection (Group A, two; Group B, five; P = NS) and this resulted in the discontinuation of sirolimus in one patient. Fifty-four adverse events occurred in 40 (67%) patients, with similar numbers of adverse events in Group A and Group B. Most episodes of rejection (5/7; 71%), adverse events (45/54; 83%), and discontinuations (5/8; 63%) occurred within 6 months of conversion. We conclude that both sirolimus monotherapy and sirolimus in combination with prednisone and/or MMF are efficacious and safe in liver transplant recipients. Conversion to sirolimus was associated with an immediate improvement in renal function that was sustained during the follow-up.

Aged↗

Diagnosis of primary sclerosing cholangitis: a blinded comparative study using magnetic resonance cholangiography and endoscopic retrograde cholangiography.

BACKGROUND: We hypothesized that magnetic resonance cholangiography (MRC) may have less accuracy for the diagnosis and the assessment of the severity of primary sclerosing cholangitis (PSC) than endoscopic retrograde cholangiography (ERC). OBJECTIVE: The aim of this study was to determine the diagnostic accuracy and interobserver agreement of both ERC and MRC in PSC. DESIGN: A case-control study. SETTING: University Hospital. PATIENTS: ERCs and MRCs of 36 patients with PSC and 51 controls (normal/other biliary tract diseases) were read in an independent, blinded, and random fashion by 2 magnetic resonance radiologists and 2 interventional endoscopists by using a previously validated classification system. Readers had no access to clinical history, laboratory results, or patient mix. RESULTS: Extrahepatic ductal (EHD) and intrahepatic ductal (IHD) visualization was excellent in 64% of 66% of MRCs and 86% of 74% of ERCs. Sensitivity and specificity for diagnosis of PSC for readers 1 to 4 were 91% and 85%, 88% and 90%, 81% and 96%, and 83% and 96%. respectively. Receiver operating curve values were excellent for all readers (all >0.9). Interobserver agreement (kappa statistics) for the diagnosis of PSC (MRC, 0.83; ERC, 0.73) and for identifying the presence of IHD strictures (MRC, 0.64; ERC, 0.86) was good for both modalities, but only ERC (ERC, 0.55; MRC, 0.36) was good for the presence and the severity of EHD strictures. When assessment of disease severity was limited to the 36 patients with PSC, interobserver agreement was very poor for both MRC (0.23 and 0.07 for EHD and IHD, respectively) and ERC (0.24 and 0.34 for EHD and IHD, respectively). LIMITATIONS: The retrospective case-control study made it difficult to assess the impact of the diagnosis on patient management. CONCLUSIONS: ERC and MRC were comparable for diagnosing PSC, with very good interobserver agreement for the diagnosis of PSC and IHD strictures. Only ERC had good agreement for EHD strictures. Interobserver agreement was very poor for both MRC and ERC when disease severity of PSC was assessed.

Bile Ducts, Extrahepatic↗

Utility of bile duct brushings for the early detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.

BACKGROUND: In patients with primary sclerosing cholangitis, there are no reliable markers or imaging modalities to detect malignant changes or early cholangiocarcinoma when curative interventions may still be possible. METHODS: Clinical features and outcomes were evaluated for 47 patients who underwent 101 endoscopic retrograde cholangiopancreatography (ERCP) procedures with bile duct brushings and cytopathologic examination for the detection of malignant changes between January 2001 and 2004. Bile duct cytology was characterized as unsatisfactory, benign, atypical, or malignant. RESULTS: Fifteen patients had at least one sample that was abnormal. Patients with abnormal findings were older (P = 0.03); otherwise the groups were similar. Three of six patients with marked atypia have undergone transplantation for these abnormal findings, and of these, two had cholangiocarcinoma and one had no cancer detected in the explant. Of the nine patients with focal atypia, seven are doing well, one underwent transplantation for marked atypia seen on brushings at another hospital, and the other underwent transplantation for decompensated cirrhosis. Two patients with benign findings developed cholangiocarcinoma, whereas 29 others have not. CONCLUSION: Cytopathologic examination of bile duct brushings taken at ERCP may be useful for the early detection of malignant changes in patients with primary sclerosing cholangitis. However, long-term prospective studies are needed to confirm the utility of surveillance ERCP and brushings.

Adult↗

Noninvasive markers of fibrosis for longitudinal assessment of fibrosis in chronic liver disease: are they ready for prime time?

Over the past decade, there has been a renewed enthusiasm to develop noninvasive serum markers or tests to assess the presence and severity of fibrosis in chronic liver disease. Although a single marker or test has lacked the necessary accuracy to predict fibrosis, different combinations of these markers or tests have shown encouraging results. However, inter-laboratory variability and inconsistent results with liver diseases of varying etiologies have made it difficult to assess the reliability of these markers in clinical practice. In this issue of the journal, Poynard et al. describe the "histological" response to lamivudine in patients with chronic Hepatitis B Virus (HBV) over a 24-month period using surrogate serum biomarkers (Fibrotest-Actitest, FT-AT) without corroborating histological data. Investigators found improvement in fibrosis and inflammation in 85% and 91%, respectively, despite the emergence of YMDD mutation in 41.5% of patients. The higher improvement rates reported in this study should be interpreted with caution for a number of reasons including the absence of data on virological response rates, corroboratory histological data, and data on the validity of FT to evaluate fibrosis in a longitudinal manner. Although FT has been studied extensively by the authors of the current study, to date there are only few independent studies. In addition to significant inter-laboratory variations, these studies have shown that significant fibrosis could be missed, or conversely significant fibrosis diagnosed in the absence of minimal or no fibrosis in about 15% to 20% of patients. We may be approaching a time when serum biomarkers may become an integral part of the assessment of patients with chronic liver disease, but published evidence suggests that these markers are not yet ready for prime time.

Biomarkers↗

Higher prevalence and severity of hepatic encephalopathy in patients with HCV cirrhosis and diabetes mellitus: is presence of autonomic neuropathy the missing part of the puzzle?

Hepatic encephalopathy (HE) is a complex and variable neuropsychiatric syndrome that is seen in patients with acute and chronic liver diseases. The presence or severity of HE does not always show a strong and consistent relationship with the severity of liver disease or portal hypertension suggesting that other predisposing or precipitating factors may be involved. In this issue of the journal, it has been suggested that DM may contribute to the presence and severity of HE independent of the severity of liver disease in patients with HCV cirrhosis. This editorial examines the limitations of the study and potential mechanisms that could explain the relationship between DM with HE including the role of autonomic neuropathy.

Diabetes Complications↗

Autonomic neuropathy may be associated with delayed orocaecal transit time in patients with cirrhosis.

UNLABELLED: Orocaecal transit (OCT) time is delayed in patients with cirrhosis, but the reasons for this remain unclear. We hypothesized that autonomic neuropathy (AN) may explain the delay in OCT. METHODS: We determined OCT and autonomic function tests (AFT) in 48 patients (Child A-15, B-27, C-6) with cirrhosis of various aetiologies. AFT were categorized as normal, borderline, or abnormal. OCT was measured using the lactulose hydrogen (H2) breath test. OCT was defined as the time from baseline when there was a rise in H2 levels of >20 ppm over baseline or >10 ppm over baseline sustained over 2 consecutive time points. RESULTS: Based on OCT, patients were separated into those with delayed OCT (>90 min, group I) and normal OCT (< or = 90 min, group II). Mean OCT time of patients in group I was 169.7+/-49.7 min vs. 84.4+/-12.1 min in group II. Baseline clinical characteristics of patients with and without AN, and those with normal and delayed OCT were similar. Presence of mild encephalopathy did not have an effect on OCT. AN was seen more frequently in group I than group II [16/32 (50%) vs. 3/16 (19%), p=0.03]. Logistic regression analysis showed that the presence of AN was the only independent variable associated with delayed OCT (OR 7.3, CI 1.3-39.4, p=0.02). CONCLUSION: Our study showed that the presence of AN was associated with delayed OCT in patients with cirrhosis.

Adult↗

Diarrhea in liver transplant recipients: etiology and management.

Diarrhea is common after liver transplantation (LT). The true incidence of diarrhea in liver transplant recipients is unknown but possibly ranges from 10% to 43% based on a few published studies in other solid organ and bone marrow transplantation. Infectious etiologies, including cytomegalovirus (CMV), Clostridium difficile, and occasional atypical intestinal infections, are the most common causes. Diarrhea is also a frequent side effect of immunosuppressive medications. To variable extents, mycophenolate mofetil (MMF), cyclosporine A (CSA), tacrolimus, and sirolimus are all known to be associated with diarrhea. Rarely, graft-versus-host disease (GVHD), lymphoproliferative disorder, de novo inflammatory bowel disease (IBD), or colon cancer may present as diarrhea. Flare-up of preexisting IBD is also not uncommon after LT. However, the cause of acute diarrhea remains unidentified in 1 of 3 patients. This review summarizes the literature and provides recommendations on the management of acute diarrhea after LT. Although our focus is on LT, the etiology and management recommendations apply to most transplant recipients.

Colonic Neoplasms↗

When is diabetes mellitus a relative or absolute contraindication to liver transplantation?

1. Diabetes mellitus is common in patients with cirrhosis; patients with DM undergoing liver transplantation often have many other co-morbid illnesses including obesity, coronary artery disease (CAD), autonomic neuropathy, gastroparesis, and nephropathy. 2. Long-term survival of patients with diabetes mellitus (DM) is significantly lower and morbidity higher when compared to non-diabetics mainly because of cardiovascular complications, infections, and renal failure. 3. Obesity, CAD, and renal failure are confounding factors that result in poor patient survival. 4. Patients with DM should undergo careful cardiovascular diagnostic work up, including routine coronary arteriogram, and necessary interventions before liver transplantation. This is especially important in those over 50 years old, and in those with retinopathy, nephropathy, and neuropathy. 5. Patients with coronary artery disease that is not amenable to surgery or stents, and those with impaired left ventricular function, should not be considered for liver transplantation. Other relative or absolute contraindications are those with proteinura and renal failure who are not candidates for combined liver/kidney transplantation, those with severe gastroparesis, especially when it is associated with diabetic autonomic neuropathy, and those with two or more risk factors such as CAD, morbid obesity, and renal failure. 6. Future studies should focus on risk stratification of patients with DM undergoing liver transplantation and better interventions to reduce the risk of diabetic complications before and after liver transplantation.

Cardiovascular Diseases↗

A randomized controlled trial of beta-blockers versus endoscopic band ligation for primary prophylaxis: a large sample size is required to show a difference in bleeding rates.

Primary prophylaxis with nonselective beta-blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective beta-blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, > or = 12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 +/- 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or beta-blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 +/- 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and beta-blocker therapy.

Adrenergic beta-Antagonists↗

The utility of TIPS in the management of Budd-Chiari syndrome.

BACKGROUND AND AIM: Budd-Chiari syndrome (BCS) is a rare condition associated with hepatic venous outflow obstruction classically treated with portosystemic shunts or liver transplantation. Recent reports indicate promising results with the use of transjugular intrahepatic portosystemic shunts (TIPS) in the treatment of these patients. PATIENTS AND METHODS: We reviewed a 10-year single-institution experience with TIPS in patients diagnosed with BCS. RESULTS: Eleven patients with BCS underwent TIPS procedures, 3 of whom carried a diagnosis of paroxysmal nocturnal hemoglobinuria, a relative contraindication for liver transplantation. One TIPS procedure was unsuccessful for technical reasons. No patient suffered mortality or major morbidity related to the TIPS procedure. The mean reduction of portal venous pressures was 43.7%, with a mean decrease of 73% in the pressure gradient. Of the 7 patients where long-term follow-up was available, 57% had shunts which remained patent but required several nonsurgical revisions for occlusion, with an average assisted patency of 37.5 months. CONCLUSIONS: TIPS is an effective modality in the treatment of patients with BCS, especially for those who are not candidates for liver transplantation. TIPS can be successfully used as a bridge to surgical portosystemic shunting, as well as liver transplantation, but may cause technical difficulties when performing transplantation.

Budd-Chiari Syndrome↗

Short-term postliver transplant survival after the introduction of MELD scores for organ allocation in the United States.

BACKGROUND: It has been suggested that the introduction of model for end-stage liver disease (MELD) for organ allocation may reduce overall graft and patient survival since elevated serum creatinine is an important predictor of poor outcome after liver transplantation. OBJECTIVE: In this study, we determined the outcomes of liver transplantation before (PreMELD group, 1998-February, 2002) and after (MELD group, March-December, 2002, n = 4642) the introduction of MELD score, and examined the impact of MELD scores on the outcome in the United States (US). PATIENTS & METHODS: After excluding patients for a variety of reasons (children, live-donor, fulminant liver failure, patients with hepatoma and others who received extra MELD points, multiple organ transplantation, re-transplantation, incomplete data), there were 3227 patients in the MELD group. These patients were compared with 14,593 patients in the preMELD group after applying similar exclusion criteria. The survival was compared using Kaplan-Meier survival analysis and Cox regression survival analysis. RESULTS: There was no difference in short-term (up to 10 months) graft and patient survival between MELD and preMELD groups. However, graft and patient survival was lower in patients with MELD score > or = 30 when compared with those with MELD score <30 after adjusting for the confounding variables. CONCLUSION: Introduction of MELD score for organ prioritization has not reduced the short-term survival of patients, but patients with MELD score of 30 or higher had a relatively poor outcome.

Adult↗

Noninvasive markers of fibrosis for longitudinal assessment of fibrosis in chronic liver disease: are they ready for prime time?

Over the past decade, there has been a renewed enthusiasm to develop noninvasive serum markers or tests to assess the presence and severity of fibrosis in chronic liver disease. Although a single marker or test has lacked the necessary accuracy to predict fibrosis, different combinations of these markers or tests have shown encouraging results. However, interlaboratory variability and inconsistent results with liver diseases of varying etiologies have made it difficult to assess the reliability of these markers in clinical practice. In this issue of the Journal, Poynard and colleagues describe the "histological" response to lamivudine in patients with chronic HBV over a 24-month period using surrogate serum biomarkers (FibroTest-ActiTest) without corroborating histological data. Investigators found improvement in fibrosis and inflammation in 85% and 91%, respectively, despite the emergence of YMDD mutation in 41.5% of patients. The higher improvement rates reported in this study should be interpreted with caution for a number of reasons including the absence of data on virological response rates, corroboratory histological data, and data on the validity of FibroTest to evaluate fibrosis in a longitudinal manner. Although FibroTest has been studied extensively by the authors of the current study, to date there are only few independent studies. In addition to significant interlaboratory variations, these studies have shown that significant fibrosis could be missed, or conversely significant fibrosis diagnosed in the absence of minimal or no fibrosis in about 15-20% of patients. We may be approaching a time when serum biomarkers may become an integral part of the assessment of patients with chronic liver disease, but published evidence suggests that these markers are not yet ready for prime time.

Biomarkers↗

Mac-2-binding protein is a diagnostic marker for biliary tract carcinoma.

BACKGROUND: Biliary tract carcinoma is a deadly disease, accounting for nearly 4500 malignancy-related deaths each year in the United States. Early detection has the potential to improve survival for patients with biliary tract malignancies, enabling curative surgical resection. Early detection approaches would benefit from an accurate, minimally invasive diagnostic test. To identify novel diagnostic markers, the authors recently completed a comprehensive proteomic study of bile samples from patients with biliary carcinoma. One of the proteins identified by tandem mass spectrometry was Mac-2-binding protein (Mac-2BP). The authors evaluated the performance of Mac-2BP and its ligand, galectin-3, as diagnostic markers for patients with biliary carcinoma. METHODS: Levels of Mac-2BP, galectin-3, and CA19-9 were measured using an enzyme-linked immunosorbent assay (ELISA) in bile samples from patients with biliary tract carcinoma (n = 26), benign biliary conditions (n = 32), and primary sclerosing cholangitis (n = 20). Serum levels of Mac-2BP and galectin-3 also were determined using ELISA. Mac-2BP tissue expression was investigated by immunohistochemical methods using a biliary carcinoma tissue microarray. RESULTS: Biliary Mac-2BP levels were elevated by a factor of approximately 3 in the biliary carcinoma group compared with the group of patients who had PSC or another type of nonneoplastic biliary disease. In contrast, Mac-2BP levels were not elevated in serum samples from patients with biliary carcinoma. According to the immunohistochemical analysis, Mac-2BP was expressed in 34 of 36 patients (94.4%) with biliary tract carcinoma. As a diagnostic marker for biliary carcinoma, Mac-2BP levels were as accurate as biliary CA19-9 levels, with an area under the curve (AUC) of 0.70 on receiver operator characteristic analysis. The use of both of these bile markers in combination, however, led to significantly better diagnostic accuracy compared with the accuracy achieved using CA19-9 alone (AUC, 0.75; P < 0.001). Serum and biliary galectin-3 levels did not differ in the biliary carcinoma group relative to the control groups. CONCLUSIONS: Biliary Mac-2BP levels, especially when used in conjunction with biliary CA19-9 levels, showed promise as a novel diagnostic marker for biliary tract carcinoma.

Aged↗

A proteomic analysis of human bile.

We have carried out a comprehensive characterization of human bile to define the bile proteome. Our approach involved fractionation of bile by one-dimensional gel electrophoresis and lectin affinity chromatography followed by liquid chromatography tandem mass spectrometry. Overall, we identified 87 unique proteins, including several novel proteins as well as known proteins whose functions are unknown. A large majority of the identified proteins have not been previously described in bile. Using lectin affinity chromatography and enzymatically labeling of asparagine residues carrying glycan moieties by (18)O, we have identified a total of 33 glycosylation sites. The strategy described in this study should be generally applicable for a detailed proteomic analysis of most body fluids. In combination with "tagging" approaches for differential proteomics, our method could be used for identification of cancer biomarkers from any body fluid.

Amino Acid Sequence↗