Carolina Rumbo

Rapamycin Successfully Treats Post-Transplant Autoimmune Hepatitis

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post‐transplant autoimmune hepatitis (AIH) with Rapa. Post‐transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post‐transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post‐transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non‐responders and one other patient with post‐transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Prospective analysis of nonadherence in autoimmune hepatitis: a common problem.

Objectives: To prospectively assess nonadherence to medications, the relationship between nonadherence and medical outcome and the relationship between a psychiatric risk factor (posttraumatic stress) and nonadherence in patients with a diagnosis of autoimmune hepatitis. Patients and Methods: Data were obtained in children with autoimmune hepatitis, who had consented to prospective monitoring of adherence, during 1 year of follow-up in our pediatric liver program. An electronic monitoring device as well as posttransplant trough blood levels of tacrolimus was used to evaluate adherence. A validated self-report questionnaire was used to assess posttraumatic stress. The medical outcome measure was the maximal alanine transaminase (ALT) for each monitored patient. Results: Of 37 pediatric patients, 34 (15 posttransplant) enrolled. Fourteen (41%) used the monitoring device as directed. Monitor readings ranged between 28% and 94% of optimal adherence (100%). No patient took the medications exactly as prescribed. Electronic monitoring device readings correlated inversely with maximal ALT (P = 0.03, r = −0.59), and were also correlated with the tacrolimus level variability as a measure of adherence (P = 0.04, r = −0.72). Posttraumatic stress disorder questionnaire scores were correlated with both measures of adherence (for electronic monitoring, P = 0.02, r = −0.70, for tacrolimus levels, P = 0.03, r = 0.62). Conclusions: Nonadherence to immunosuppressants was common in this cohort, and it correlated with higher maximal ALT. Nonadherence is therefore an important risk factor for poor outcome in patients with autoimmune hepatitis. Posttraumatic stress symptoms, which were correlated with nonadherence, may serve as a focus for adherence-improving interventions.

Hepatitis C in children : A quaternary referral center perspective

Introduction: Chronic hepatitis C virus (HCV) infection affects 0.3% of children in the United States, and the general impression is that it has a benign course in childhood. We analyzed a pediatric population with chronic HCV in a quaternary referral center. Material and Methods: This is a retrospective clinical review comprising all patients with chronic HCV referred to the Pediatric Liver/Liver Transplant Program between January 1999 and December 2004. Results: Ninety-one patients (52% female; mean age, 9 years) were assessed. Eight-three percent of the patients were genotype 1. Twenty-one patients received/are receiving interferon and ribavirin for chronic HCV (treatment indications-advanced disease, 9; clinical trial, 6; genotype 2, 2; social, 2; prerenal transplant, 1). Eight (53%) of 15 patients, who have completed therapy and follow-up, achieved sustained viral response. Seven of 91 patients had cirrhosis at presentation (mean age, 11.7 years). Four underwent liver transplantation, all experienced HCV recurrence, 2 died, 1 was retransplanted, and 1 has compensated cirrhosis. Conclusion: Although, in general, HCV in children has a slow progression, there are cases with an accelerated course and early development of cirrhosis requiring liver transplant. Hepatitis C virus recurs universally after transplant, and its prognosis is usually poor; therefore, the most promising long-term approach is to clear this infection before transplantation.

First case of toxoplasmosis following small bowel transplantation and systematic review of tissue-invasive toxoplasmosis following noncardiac solid organ transplantation.

Background. Toxoplasmosis prophylaxis is standard following heart and heart lung transplantation, when an increased risk of allograft transmitted Toxoplasma is well-recognized. In contrast, prophylaxis and routine serologic evaluation of donors and recipients for Toxoplasma in noncardiac solid organ transplantation (SOT) is not recommended. We report the first case of disseminated toxoplasmosis following small bowel transplantation, presumably transmitted via the transplanted intestine and systematically review reported cases of toxoplasmosis in noncardiac SOT recipients to determine if current guidelines should be reconsidered. Methods. Systematic MEDLINE review was performed for tissue invasive toxoplasmosis in noncardiac SOT recipients and analysis of clinical features, serologic status, and treatment regimens with respect to mortality. Results. Fifty-two cases of toxoplasmosis in noncardiac SOT recipients were identified. Eighty-six percent developed disease within 90 days of transplantation. Presentation was nonspecific and consisted of fever (77%), respiratory distress (29%), neurologic manifestations (29%), and bone marrow suppression (26%). Multivariate analyses demonstrated that localized disease (odds ratio [OR]=37.36, 95% CI 1.85–754.85), treatment received (OR=1.814, 95% CI 1.193–3.480) and donor and recipient serostatus (OR=1.39, 95% CI 1.068–1.815) were predictors of survival. High-risk recipients (donor seropositive/recipient seronegative) developed disease earlier (16 days vs. 31 days P=0.002) and were less likely to survive (OR=0.14, 95% CI 0.03–0.69) than standard-risk recipients. Conclusions. Toxoplasmosis is recognized following noncardiac SOT. Reduction of morbidity and mortality necessitates knowledge of donor and recipient Toxoplasma serostatus, prophylaxis, early diagnosis, and treatment. The findings support a reconsideration of pretransplantation evaluation and prophylaxis strategies in SOT recipients.

Azathioprine metabolite measurements in the treatment of autoimmune hepatitis in pediatric patients: a preliminary report.

Potential adverse effects of azathioprine (AZA), such as neutropenia and hepatotoxicity, make its use in autoimmune hepatitis (AIH) problematic. Objective To determine longitudinal AZA metabolite levels in a cohort of children with AIH, correlate them with therapeutic effects, medication-induced toxicity and adherence. Methods From January 2000 to January 2002, 122 blood samples from 30 pediatric patients with AIH were prospectively analyzed. Ten patients had previously been treated with AZA (mean dose of 1.3mg/kg/day) for an average of 30 months. At the outset, 24 patients were taking steroids and 10 had cirrhosis/hypersplenism. Routine biochemical studies, 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) levels were assessed every 8 weeks. Red blood cell thiopurine methyltransferase (TPMT) enzyme activity was determined in each patient. AZA dose was adjusted to achieve a target 6-TG level 235-450 pmoles per 8 × 108 RBC. Results 8/10 patients who had previously been treated with standard doses of AZA had 6-TG below target levels. Increasing AZA mean dose by 50% in those patients resulted in 6/10 patients in target range; ALT levels and steroid requirements were reduced. AZA dosing was safely increased in patients with cirrhosis/hypersplenism. In spite of normal TPMT levels, 64% of patients did not make measurable concentrations of 6-MMP. Inappropriately low 6-TG levels revealed non-adherence in 5 patients. Two patients were identified with AZA hepatotoxicity. Conclusion AZA metabolite testing in children with AIH is useful in identifying medication toxicity and non-adherence. AZA dose escalation is safe and may be required in order to achieve 6-TG target levels described for inflammatory bowel disease.

Utility of azathioprine metabolite measurements in post‐transplant recurrent autoimmune and immune‐mediated hepatitis

Abstract:  Patients with post‐transplant immune‐mediated hepatitis (IMH) and recurrent autoimmune hepatitis (RAIH) have a poor outcome and a higher need for retransplantation. Azathioprine (AZA) is used as adjunctive immunosuppression after transplantation; optimizing its dose may be a key point in preserving graft function. Complications of high AZA dosing make dose escalation potentially problematic. Our aim was to correlate AZA metabolite levels with therapeutic effects, toxicity, and adherence to medication in children with IMH and RAIH. Charts of 14 patients were retrospectively reviewed. The post‐transplant diagnosis was based on liver biopsy and autoimmune markers. AZA was prescribed after establishing the post‐transplant diagnosis. AZA was started at 1.1 (1.0–1.8) mg/kg/day. Routine biochemical studies, tacrolimus levels, 6‐thioguanine (6‐TG) and 6‐methylmercaptopurine levels were assessed every 8 wk. AZA dose was routinely adjusted to achieve 6‐TG levels between 235 and 450 pmol per 8 × 108 RBC. A total of 92 samples from 14 patients were reviewed. Four patients were excluded because of non‐adherence. AZA dose was increased by 245% resulting in eight of 10 patients in the target range; no hepatic or bone marrow toxicity was observed. ALT levels and steroid requirements were significantly reduced (p < 0.05). The AZA dose required to achieve target 6‐TG levels was significantly greater in children <10 yr. AZA metabolite testing in children post‐liver transplant is useful in assessing adherence to medication and it is potentially helpful in optimizing medication dosing. In younger children the AZA dose requirements were two to four times higher than previously reported standard doses.

Autoimmune hyperlipidemia in a child with autoimmune hepatitis

The first reported case of a girl with a combination of autoimmune hyperlipidemia and autoimmune hepatitis is described. She presented at the age of 9 years with fever, headaches, and abnormal lipid profile. Months later, she had clinical manifestations, biochemical findings, and the histologic picture of autoimmune hepatitis. Subsequently, she also showed signs and symptoms of systemic lupus erythematosus. All of her clinical manifestations and biochemical abnormalities dramatically improved with immunosuppression. The overlapping syndrome of systemic lupus erythematosus, autoimmune hepatitis, and autoimmune hyperlipidemia is discussed.

Azathioprine metabolite measurements: its use in current clinical practice.

Abstract:  Azathioprine (AZA) is one of the oldest immunosuppressive agents available today. It is used as an immunomodulator in different disciplines such as hematology, dermatology, rheumatology, gastroenterology, and transplant. The present article presents a summary of AZA metabolism and the role of AZA metabolite measurements in the current clinical practice.

Hepatitis C: current approaches in pediatrics.

Abstract:  Chronic hepatitis C virus is one of the leading causes of liver diseases in adults and it is the most common cause of liver transplantation in the USA. Hepatitis C infection in children is less frequent; there is less information about its clinical course. Compared with adults, there are differences in its mode of acquisition, natural history, complications and even available treatments. The aim of this paper is to give an overview of chronic hepatitis C in children.

Successfully in Situ Right-Left Split Liver Transplantation: First Report of in Argentina

Introduction In-situ or ex-vivo left lateral segmentectomy and right trisegmentectomy split-liver transplantation had become and standard practice in Argentina. Over the last 10 years more than 150 split procedures has been performed, but until recently none in-situ right-left split was performed. We aim to report the first case done at a single institution. Material and Method Report of an in-situ right-left split liver procurement performed more than 1 thousand kilometers far from the transplant center. Follow by the engraftment into an adult recipient (54 years) with a non respectable metastatic NET and a pediatric recipient (14 years), with cystic fibrosis and severe portal hypertension (24 mmHg). Results After grafts allocations, our liver procurement team flew to the donor hospital, with the necessary devices to perform the in-situ liver parenchymal transection. Donor was hemodynamically stable without inotropic drugs. After midline incision, hiliar dissection was performed, to identify the right hepatic artery, right portal vein and bile duct; Intraoperative cholangiography showed normal billiary anatomy. A bulldog clamp was placed in the right portal and hepatic artery to delineate the transaction line. The cava and middle hepatic veins were left to left graft (LG). Billiary tree and common hepatic artery were left in the right graft (RG). HTK solution was used for preservation. Operative time for the procurement was 3.5 hours. Right graft weight 980 grs. and left graft 450 grs. The RG was used in an adult recipient and the LG in a pediatric recipient, CIT were: 475 min and 430 min respectevily. GRWR for the RG and LG were 1.53 and 1.67 respectively. The LG required re-exploration for intra-abdominal hemorrhage, and postop. ascitis was present and medically treated; in spite of a reduction in the portal pressure to 17 mmHg). Recipients were discharge on postop. day: 7 and 14 respectively. Conclusions Right and left split-liver transplantation should be considered as a source to expand the cadaveric donor liver pool. A trained committed surgical team is needed to successfully perform these procedures. The adequate donor and recipient selection will increase motivation to routinely use it for adolescents or adult recipients.