Trough Levels of Everolimus Are Associated With Recurrence Rates of Hepatocellular Carcinoma After Liver Transplantation.

PURPOSE: Everolimus, a mammalian target of rapamycin inhibitor, may have a protective role on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but data regarding the impact of its trough serum levels on HCC recurrence are missing. METHODS: Fifty-five patients (43 men, age 55 ± 8 years) who underwent LT for HCC were evaluated. Several demographic and clinical variables were recorded, including radiological and histological characteristics of HCC as well as dosages and trough levels of immunosuppressive regimens. RESULTS: HCC recurrence occurred in 11 (20%) patients: 5 (25%) of 20 patients under calcineurin inhibitors and 6 (17%) of the 35 patients under everolimus (P = .48). The patients with HCC recurrence (n = 11, group 1), compared to those without recurrence (n = 44, group 2), had significantly more frequent HCC in the explant: outside Milan criteria (P = .001), microvascular invasion (P < .001), and higher number of nodules (P = .001). In multivariate analysis, microvascular invasion was the only independent factor significantly associated with HCC recurrence (OR: 2.3, 95% CI: 1.4-10.5, P = .03). Among the patients who received everolimus-based immunosuppression, the recipients with HCC recurrence, compared to those without HCC recurrence, had significantly lower mean trough levels of everolimus at 7-12 months post-LT (3.9 vs 5.9 ng/mL, P = .001), while the patients with mean trough levels of everolimus >6 ng/mL had decreased HCC recurrence rates (log rank: 2.3, P = .007). CONCLUSIONS: We found for the first time mean concentrations of everolimus between 7-12 months post-LT as the only modifiable variable related with HCC recurrence in LT recipients. However, larger studies are needed for final conclusions.

Minimally symptomatic hypocalcaemia unmasking celiac disease.

INTRODUCTION: Celiac disease is an autoimmune disease of the small intestine which occurs in genetically predisposed people of all ages. A large clinical spectrum of manifestations accompanies the onset of the disease with diarrhoea, flatulence and weight loss being the most common. However, findings like osteoporosis, iron deficiency, anaemia and hypocalcaemia could also insinuate the existence of the disease. CASE PRESENTATION: We report the case of a 55-year-old man with numbness and tingling of the upper extremities due to hypocalcaemia that proved to be an uncommon case of celiac disease. CONCLUSION: A non-negligible number of adult patients with celiac disease can present with only minor and subclinical manifestations of the disease. As such, hypocalcaemia may be the sole manifestation of celiac disease. A high index of suspicion is needed for prompt diagnosis.

Nucleos(t)ide analog(s) prophylaxis after hepatitis B immunoglobulin withdrawal against hepatitis B and D recurrence after liver transplantation.

BACKGROUND/AIMS: Nucleos(t)ide analogs (NAs) have made a hepatitis B immunoglobulin (HBIG)-sparing protocol an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, this approach is considered controversial in patients transplanted for HBV and hepatitis D (HDV) co-infection. MATERIAL/METHODS: All patients transplanted for HBV/HDV cirrhosis were evaluated. After LT, each patient received HBIG + NAs and then continued with NAs prophylaxis. All patients were followed up with HBV serum markers and HBV DNA, while anti-HDV/HDV RNA was performed in those with HBV recurrence. RESULTS: A total of 34 recipients were included (22 men, age: 46.7 ± 16 years). After HBIG discontinuation, NAs were received as monoprophylaxis (lamivudine [LAM]: 2, adefovir [AFV]: 1, entecavir: 9, tenofovir [TDF]: 12) or dual prophylaxis (LAM + AFV [or TDF]: 10 patients). Two (5.8%) of the 34 patients had HBV/HDV recurrence after HBIG withdrawal (median follow-up: 28 [range, 12-58] months). These 2 patients had undetectable HBV DNA at LT. Statistical analysis revealed that those with recurrence had received HBIG for shorter period, compared to those without recurrence (median: 9 vs. 28 months, P = 0.008). CONCLUSIONS: We showed for the first time, to our knowledge, that maintenance therapy with NAs prophylaxis after HBIG discontinuation was effective against HBV/HDV recurrence, but it seems that a longer period of HBIG administration might be needed before it is withdrawn after LT.

Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy.

AIM: Eosinophils are potent proinflammatory cells that are involved in the pathogenesis of ulcerative colitis (UC). We evaluated the infiltration of eosinophils into the lamina propria in patients with active and inactive ulcerative colitis (UC) and investigated its clinical significance, among other variables, in predicting the outcome of medical treatment in active disease. METHOD: We studied colorectal biopsy specimens from 18 UC patients with disease in long-standing remission, from 22 patients with active disease who responded to therapy (12 with complete response and 10 with partial response) and from 10 patients who were nonresponders. Demographic information was obtained at baseline, and clinical, endoscopic and laboratory data were obtained at baseline and 12 weeks post-treatment. We evaluated five histological features: mucosal ulceration; mucosal erosions; crypt abscesses; cryptitis; and eosinophilic infiltration of the lamina propria. The severity of these lesions was graded as: none or minimal; mild; moderate; or severe. Statistical analyses were performed between responders and nonresponders for differences in demographic, clinical, laboratory, endoscopic and histological parameters. RESULTS: Laboratory, endoscopic and histological parameters were significantly improved after treatment only in the complete responders group. Analyses of baseline data revealed no significant differences in parameters between complete or partial responders and nonresponders, except for a less severe eosinophilic infiltration of lamina propria in complete responders (P < 0.05). Multiple logistic regression analysis showed that severe eosinophilic infiltration in colonic biopsies was the most significant predictor of poor response to medical therapy. CONCLUSION: Assessing the severity of eosinophilic infiltration in the lamina propria of colonic biopsies in patients with ulcerative colitis could be a valuable predictive tool of response to medical therapy.

Low-molecular-weight heparin (enoxaparin) as adjuvant therapy in the treatment of active ulcerative colitis: a randomized, controlled, comparative study.

BACKGROUND: Heparin could be beneficial to the treatment of active ulcerative colitis because of its anticoagulant, anti-inflammatory and immunomodulatory properties. AIM: To evaluate the tolerability, safety and efficacy of low-molecular-weight heparin as adjuvant therapy in patients with active ulcerative colitis. METHODS: Thirty-four adult patients with active ulcerative colitis were consecutively included in a prospective, randomized, comparative study, and were treated for 12 weeks. Eighteen patients in the 'standard therapy' group were treated with aminosalicylates and weekly tapered corticosteroids. Sixteen patients in the 'heparin therapy' group were treated with standard therapy plus enoxaparin 100 Anti-Xa IU/kg/day subcutaneously. RESULTS: Seventeen patients in the 'standard therapy' group and 15 patients in the 'heparin therapy' group completed the study. Tolerability and compliance to therapy were excellent and no withdrawals were noted because of complications. There was a significant improvement in the disease severity in both groups (P<0.001), without any difference between them (P=not significant). Both treatment groups showed similar proportions of disease improvement (65% and 73%, respectively; P=not significant). There were no significant differences in inflammation (fibrinogen, ESR, CRP) and coagulation (thrombin-antithrombin complex, F1+2, D-dimers) parameters during and at the end of the study between treatment groups. CONCLUSION: Adjuvant administration of low-molecular heparin in patients with active ulcerative colitis is safe and well tolerated, but no additive benefit over standard therapy for ulcerative colitis was noted.

Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Long-term treatment with lamivudine is required to control viral replication in patients with hepatitis B e antigen-negative chronic hepatitis B, but is associated with a high rate of viral resistance. The role of adefovir dipivoxil in these patients has not been definitively evaluated. AIM: To address the role of adefovir in the management of patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. METHODS: Patients were assigned to receive adefovir 10 mg once daily plus ongoing lamivudine 100 mg once daily for 52 weeks. The primary end point was reduction in serum hepatitis B virus DNA level (hepatitis B virus DNA response). Secondary end points included the proportion of patients with undetectable hepatitis B virus DNA at week 52 (complete virological response) and the percentage of patients with normalization of alanine transferase level at week 52 (biochemical response). RESULTS: A total of 49 consecutive patients were enrolled in this study. After 52 weeks of treatment, all patients had an hepatitis B virus DNA response and 57.1% had complete virological response. Biochemical response occurred in 75.6% of patients. CONCLUSIONS: Administration of adefovir in patients with lamivudine-resistant chronic hepatitis B results in significant suppression of viral replication. Nevertheless, continuous therapy will probably be needed in order to maintain remission in these patients.

Serum concentrations of insulin-like growth factor-I (IGF-I) in patients with liver cirrhosis.

BACKGROUND/AIMS: Insulin-like growth factor-I is an important anabolic polypeptide with various effects. The circulating insulin-like growth factor-I is mainly liver derived. The aim of this study was to determine insulin-like growth factor-I serum levels in patients with cirrhosis and to clarify their association with patients' clinical condition and the etiology of cirrhosis. METHODOLOGY: Forty patients with liver cirrhosis were enrolled. Cirrhosis was in 22 cases induced by virus, in 10 due to primary biliary cause and in the rest 8 of alcoholic origin. The Child score index was found as A (n = 26), B (n = 9), C (n = 5). Twenty, age-matched healthy subjects, were used as a control group. Serum insulin-like growth factor-I was measured by an immunoradiometric assay in all subjects. RESULTS: Serum insulin-like growth factor-I levels in liver cirrhosis were found very significantly lower than in healthy individuals (57.4 +/- 7.0 ng/mL vs. 198.8 +/- 16.3 ng/mL, p = 0.0000001). In liver cirrhosis insulin-like growth factor-I was negatively correlated with spleen enlargement (r = -0.46, p = 0.0031). Child B and C patients showed significantly reduced insulin-like growth factor-I levels in comparison to patients staged as Child A (28.9 +/- 3.0 ng/mL vs. 72.8 +/- 9.3 ng/mL, p = 0.0016). The comparison of 12 patients with viral induced cirrhosis (Child A) to 14 patients with non-viral cirrhosis, of the same clinical stage, showed non-significant difference (84.2 +/- 16 ng/mL vs. 63.1 +/- 10.3 ng/mL, p = 0.27). CONCLUSIONS: Insulin-like growth factor-I synthesis is disturbed in liver cirrhosis and reflects the severity of the clinical stage. It represents a good marker of hepatic function. The etiology of cirrhosis does not seem to influence its levels.

Treatment of complications of hepatic hydatid disease by ERCP.

BACKGROUND: The aim of this study was to evaluate the effectiveness of endoscopic sphincterotomy for preoperative and postoperative complications of hepatic hydatid disease. METHODS: Nineteen patients underwent endoscopic treatment for complications of hepatic hydatid disease. Indications for ERCP in 5 patients treated before surgery (Group A) were obstructive jaundice in 1 and acute cholangitis in 4. In 14 patients treated after surgery (Group B), the indication was acute cholangitis in 6, obstructive jaundice 2, and persistent external drainage in 6 patients. OBSERVATIONS: In group A, ERCP detected hydatid vesicles within the bile duct. All patients underwent endoscopic sphincterotomy and clearance of the duct with no complications. The 6 patients in Group B with persistent external drainage had biliary fistulas that resolved after endoscopic treatment within 10 to 20 days. Among the 8 patients with postoperative obstructive jaundice or acute cholangitis, 7 had cyst remnants obstructing the bile duct and 1 had findings of sclerosing cholangitis. All underwent endoscopic sphincterotomy and clearance of the bile duct without complications. After treatment, all patients, with the exception of the one with sclerosing cholangitis, remained asymptomatic. CONCLUSION: Endoscopic sphincterotomy is a safe and effective treatment for biliary complications of hepatic hydatid disease.

Endoscopic band ligation of Dieulafoy-like lesions in the upper gastrointestinal tract.

BACKGROUND AND STUDY AIMS: Endoscopic band ligation (EBL) is currently considered to be the treatment of choice for esophageal variceal bleeding. This study reports on the efficacy and safety of EBL in patients with Dieulafoy-like bleeding lesions in the upper gastrointestinal tract. PATIENTS AND METHODS: Between December 1994 and February 2000, 23 patients with upper gastrointestinal tract hemorrhage (median age 58, range 28-75) were treated using EBL. EBL was used as a rescue therapy in four patients and as the initial treatment in 19 patients. RESULTS: The site of bleeding was the stomach in 10 patients, Billroth II anastomosis in 10, the first part of the duodenum in one, the second part of the duodenum in one, and the jejunum in one patient. Endoscopic band ligation was successful in 22 of the 23 patients. The remaining patient, a young man with a Dieulafoy-like lesion in the jejunum, had recurrent bleeding on day 5 after EBL and underwent elective surgery. CONCLUSIONS: Endoscopic band ligation is an effective and safe endoscopic treatment for Dieulafoy-like lesions. It is easy to use and relatively inexpensive.