Steven J. Lobritto

Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants

CONTEXT Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. OBJECTIVE To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. DESIGN, SETTING, AND PATIENTS Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). MAIN OUTCOME MEASURES The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. RESULTS Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). CONCLUSION In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C

BACKGROUND & AIMS Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C. METHODS HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy). RESULTS SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups. CONCLUSIONS The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.

Significant pulmonary toxicity associated with interferon and ribavirin therapy for hepatitis C

OBJECTIVE:The aim of this study was to analyze the clinical presentation and outcomes of significant pulmonary toxicity associated with interferon and ribavirin.METHODS:We conducted a retrospective review of patients enrolled in four clinical trials at three sites, two academic medical centers and one community practice, and reviewed the literature.RESULTS:Four patients, while on therapy with interferon α and ribavirin for chronic hepatitis C, developed significant pulmonary signs and symptoms. Further workup, which included lung biopsy in three, revealed bronchiolitis obliterans organizing pneumonia in two, and interstitial pneumonitis in two other cases. There were no other predisposing factors for lung disease identified. Resolution of symptoms occurred in all patients upon discontinuation of interferon and ribavirin, with or without corticosteroid therapy. One of the patients developed pulmonary complications while on a clinical trial of pegylated interferon and represents the first reported case associated with the use of long-acting interferon in chronic hepatitis C infection.CONCLUSIONS:A spectrum of significant pulmonary toxicity, including bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis, can occur with interferon or pegylated interferon in combination with ribavirin. Though pulmonary toxicity of interferon is well known, these cases represent the first cases reported in the literature with combination therapy. It is likely that pulmonary toxicity may not be investigated in patients on combination therapy because of the frequent pulmonary symptoms with ribavirin. Though usually reversible, at least one case has required long-term steroids with inadequate resolution. Though pulmonary toxicity is rare, symptoms which are more than mild or progressive in nature should likely be investigated.

Reversal of intestinal failure–associated liver disease in infants and children on parenteral nutrition: experience with 93 patients at a referral center for intestinal rehabilitation

PURPOSE Intestinal failure (IF)-associated liver disease (IFALD) complicates the treatment of children with IF receiving parenteral nutrition (PN). We hypothesized that prevention or resolution of IFALD was possible in most children and that this would result in improved outcomes. METHODS We reviewed prospectively gathered data on all children referred to the intestinal rehabilitation and transplantation center at our institution. Total bilirubin level (TB) was used as the marker for IFALD. Patients were grouped based on TB at referral and at subsequent inpatient stays and outpatient visits. Standard treatment consisted of cycling of PN, limiting lipid infusion, enteral stimulation, use of ursodeoxycholic acid, and surgical intervention when necessary. Outcomes such as mortality, dependence on PN, and need for transplantation were assessed. Statistical analyses were performed using Fishers exact, Mann-Whitney U, and Wilcoxon signed rank tests. RESULTS Ninety-three patients with intestinal failure and on PN were treated at our center from 2003 to 2009. Median age at referral was 5 months (0.5-264 months). Prematurity was a complicating factor in 63 patients and necrotizing enterocolitis was the most common diagnosis. Eighty-two children had short bowel syndrome, whereas the remaining 11 had extensive motility disorders. 97% of children required significant alteration of their PN administration. At referral, 76 of 93 children had TB 2.0 mg/dL or higher, and 17 had TB below 2.0 mg/dL. TB normalized in 57 of 76 children with elevated TB at referral, and TB remained elevated in 19. Normalization of TB was associated with a mortality of 5.2%, and transplantation was needed in 5.2%. Conversely, when TB remained elevated, mortality was 58% (P = .0002 vs TB normalized), and transplantation occurred in 58% owing to failure of surgical and medical rehabilitation. CONCLUSIONS Most children referred for treatment of IF have IFALD. A dedicated IF rehabilitation program can reverse IFALD in many children, and this is associated with improved outcome.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial

N‐acetylcysteine (NAC) was found to improve transplantation‐free survival in only those adults with nonacetaminophen (non‐APAP) acute liver failure (ALF) and grade 1‐2 hepatic encephalopathy (HE). Because non‐APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non‐APAP PALF. Children from birth through age 17 years with non‐APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo‐controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1‐year survival. Secondary outcomes included liver transplantation‐free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1‐year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1‐year LTx‐free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0‐1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion: NAC did not improve 1‐year survival in non‐APAP PALF. One‐year LTx‐free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non‐APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults. (HEPATOLOGY 2013)

Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause

OBJECTIVE. Acetaminophen cysteine protein adducts are a widely recognized correlate of acetaminophen-mediated hepatic injury in laboratory animals. The objective of this study was to use a new assay for the detection of acetaminophen cysteine protein adducts in children with acute liver failure to determine the role of acetaminophen toxicity in acute liver failure of unknown cause. METHODS. Serum samples from children with acute liver failure were measured for acetaminophen cysteine protein adducts using high-performance liquid chromatography with electrochemical detection. For comparison, samples from children with well-characterized acetaminophen toxicity and children with known other causes of acute liver failure also were measured for acetaminophen cysteine protein adducts. The analytical laboratory was blinded to patient diagnoses. RESULTS. Acetaminophen cysteine protein adduct was detected in 90% of samples from children with acute liver failure that was attributed to acetaminophen toxicity, 12.5% of samples from children with acute liver failure of indeterminate cause, and 9.6% of samples from children with acute liver failure that was attributed to other causes. Adduct-positive patients from the indeterminate cause subgroup had higher levels of serum aspartate aminotransferase and alanine aminotransferase and lower levels of bilirubin. Adduct-positive patients also had lower rates of transplantation and higher rates of spontaneous remission. CONCLUSIONS. A small but significant percentage of children with acute liver failure of indeterminate cause tested positive for acetaminophen cysteine protein adducts, strongly suggesting acetaminophen toxicity as the cause of acute liver failure. An assay for the detection of acetaminophen cysteine protein adducts can aid the diagnosis of acetaminophen-related liver injury in children.

Gc-globulin and prognosis in acute liver failure†‡

Serum concentrations of the actin scavenger Gc‐globulin are reduced in acute liver failure (ALF). Prospectively, we tested Gc‐globulins value to predict outcome following ALF using sera from 182 patients with ALF from the U.S. ALF Study Group. Admission serum levels of Gc‐globulin (normal range: 350‐500 mg/L) were studied by an immunonephelometric method. The median (range) serum Gc‐globulin level on admission for the entire group was 91 (5‐307) mg/L. Gc‐globulin levels were significantly higher in spontaneous survivors than in patients who died or underwent transplantation (113 [5‐301] mg/L vs. 73 [5‐307] mg/L, P < 0.001). Those surviving non‐acetaminophen (paracetamol)‐induced ALF without transplantation had higher Gc‐globulin levels than nonsurvivors (102 [5‐301] mg/L vs. 61 [5‐232] mg/L, P = 0.002), whereas there was no significant difference in levels between the groups in patients with acetaminophen‐induced ALF. A cutoff level of 80 mg/L in the non‐acetaminophen group yielded positive and negative predictive values of 85% and 43%, respectively. The corresponding figures for the Kings College criteria were 90% and 49%, respectively. In conclusion, we found that Gc‐globulin levels were markedly decreased in patients with ALF; the lowest levels were observed in patients who died or were transplanted. In contrast to previous studies, this study demonstrated that Gc‐globulin has prognostic value in patients with non‐acetaminophen‐induced ALF, in the same range as the Kings College criteria. Further refinements of the assay would be necessary to make it more accurate and of practical utility. (Liver Transpl 2005;11:1223–1227.)

Multiple Cutaneous Infantile Hemangiomas Associated With Hepatic Angiosarcoma: Case Report and Review of the Literature

Multiple cutaneous hemangiomas can be associated with internal hemangiomas, with the liver being the most common site. Here we report a case of a premature female neonate who presented with cardiac failure at birth and had typical-appearing infantile hemangiomas on the skin in association with vascular lesions in the liver. Her clinical presentation was felt to be consistent with cutaneous and hepatic infantile hemangiomas. After failure to respond to systemic steroids and chemotherapy, she underwent liver transplantation. Histopathologic evaluation of the liver revealed a diagnosis of type 2 infantile hepatic hemangioendothelioma (regarded as synonymous with angiosarcoma) rather than benign infantile hemangioma of the liver. Subsequent skin biopsies confirmed that her multiple cutaneous lesions were infantile hemangiomas and not metastatic angiosarcoma. We report this case and a review of the literature on pediatric angiosarcoma of the liver associated with cutaneous infantile hemangiomas.

Analysis of Donor Risk in Living‐Donor Hepatectomy: The Impact of Resection Type on Clinical Outcome

The progressive shortage of liver donors has mandated investigation of living‐donor transplantation (LDT). Concerns about increasing risk to the donor are evident, but the impact of the degree of parenchymal loss has not been quantified. We analyzed clinical and biological variables in 45 LDT performed by our team over 2years to assess risks faced in adult LDT. All donors are alive and well with complete follow‐up through to February 2001. When the three operations were compared, right hepatectomy (RH) was significantly longer in terms of anesthesia time and blood loss compared with left hepatectomy (LH) and left lobectomy (LL). Donor remnant liver was significantly reduced after RH compared with LH and LL. There were significant functional differences as a consequence of the remnant size, measured by an increase in peak prothrombin time after RH. RH for adults represents a markedly different insult from pediatric donations in terms of parenchymal loss and early functional impairment. Left hepatectomy donation offers modest advantage over right lobes but seems to confer substantial technical risk for a small gain in graft size. Unless novel strategies are developed to enhance liver function of the LH graft in the adult recipient, right lobe donation will be necessary for adult LDT.

Pegylated interferon for chronic hepatitis C in children affects growth and body composition: results from the pediatric study of hepatitis C (PEDS-C) trial

Weight loss and changes in growth are noted in children treated with interferon alpha (IFN‐α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha‐2a (Peg‐IFN‐α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS‐C) trial underwent anthropometric measurements, dual‐energy X‐ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5‐unit decrement in height‐for‐age z (HAZ) score. Though weight‐for‐age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post‐therapy for the long‐treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat‐free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. Conclusions: Peg‐IFN‐α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV. (HEPATOLOGY 2012)