Ruben E. Quiros-Tejeira

Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with Rituximab for post-transplant lymphoproliferative disease

The evaluation of long‐term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti‐CD20 monoclonal antibody (Rituximab) has not yet been explored. At our institution, one child with EBV‐related mononucleosis‐like syndrome and five children with polymorphic‐EBV‐PTLD occurring 6–88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B‐lymphocytes were undetectable in the peripheral blood and EBV‐load, monitored with real‐time PCR, decreased to undetectable levels in all children from >4000 copies/μg DNA at diagnosis. Four to eight months after Rituximab, EBV‐load increased (>4000 copies/μg DNA) in four children, and PTLD recurred in three. Their frequency of EBV‐specific T‐cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV‐specific T‐cell immunocompetence, which may be crucial for the long‐term control of EBV‐mediated proliferation, did not improve.

Increased hepatic stiffness as consequence of high hepatic afterload in the fontan circulation: A vascular doppler and elastography study

Hepatic dysfunction is a recognized complication after Fontan palliation of congenital heart disease. We sought to quantitatively measure hepatic stiffness and vascular Doppler indices using ultrasound (US) and shear wave elastography (SWE) in a Fontan cohort. Subjects were prospectively recruited for echocardiography and real‐time hepatic duplex US with SWE for hepatic stiffness (kPa). Doppler peak velocities, velocity time integral, resistive, pulsatility, acceleration indices (RI, PI, AI), and flow volume were measured in celiac artery, superior mesenteric artery, and main portal vein (MPV). A subset underwent cardiac catheterizations with liver biopsy. Correlations were explored between SWE, duplex, hemodynamic, and histopathologic data. In all, 106 subjects were studied including 41 patients with Fontan physiology (age 13.8u2009±u20096 years, weight 45.4u2009±u200923 kg) and 65 controls (age 15.0u2009±u20098.4 years, weight 47.9u2009±u200922 kg). Patients with Fontan physiology had significantly higher hepatic stiffness (15.6 versus 5.5 kPa, Pu2009<u20090.0001), higher celiac RI (0.78 versus 0.73, Pu2009=u20090.04) superior mesenteric artery RI (0.89 versus 0.84, Pu2009=u20090.005), and celiac PI (1.87 versus 1.6, Pu2009=u20090.034); while MPV flow volume (287 versus 420 mL/min in controls, Pu2009=u20090.007) and SMA AI (829 versus 1100, Pu2009=u20090.002) were lower. Significant correlation was seen for stiffness with ventricular end‐diastolic pressure (Pu2009=u20090.001) and pulmonary artery wedge pressure (Pu2009=u20090.009). Greater stiffness correlated with greater degrees of histopathologic fibrosis. No significant change was seen in stiffness or other duplex indices with age, gender, time since Fontan, or ventricular morphology. Conclusion: Elevated hepatic afterload in Fontan, manifested by high ventricular end‐diastolic pressures and pulmonary arterial wedge pressures, is associated with remarkably increased hepatic stiffness, abnormal vascular flow patterns, and fibrotic histologic changes. The MPV is dilated and carries decreased flow volume, while the celiac and superior mesenteric arterial RI is increased. SWE is feasible in this population and shows promise as a means for predicting disease severity on liver biopsy. (Hepatology 2014;58:251–260)

Induction of remission in a child with autoimmune enteropathy using mycophenolate mofetil

Intractable diarrhea of infancy is a term used to define different disease processes that share similar symptoms and histologic findings of mucosal injury. Autoimmune enteropathy is an extremely rare cause of intractable diarrhea. In most cases, it is associated with high mortality and morbidity (1–7). In this disorder, the inflammatory process usually is severe, involves the small intestinal and colonic mucosa, and is associated with circulating anti-enterocyte antibodies, malabsorption, and diarrhea (1–4,8). Autoimmune enteropathy is usually treated with elemental formula and/or parenteral nutritional support along with immunosuppressive therapy. Its response to immunosuppressive therapy such as steroids, cyclosporine, azathioprine, cyclophosphamide, methotrexate, and tacrolimus has been variable (1–14). We report a case of autoimmune enteropathy diagnosed at 4 months of age in a patient who presented with intractable diarrhea and required parenteral nutritional support. Remission of the autoimmune process was achieved with the addition of Mycophenolate Mofetil (MMF) to her immunosuppressive therapy. This therapy allowed discontinuing parenteral nutrition and tapering of corticosteroid to a low level.

Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient.

Abstract:u2002 The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long‐acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole‐blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole‐blood concentration following liver transplantation. Phenobarbital, through its up‐regulation of hepatic cytochrome p450 system increases the elimination of whole‐blood tacrolimus concentration in acute overdose situations.

Resolution of hypophosphatemia is associated with recovery of hepatic function in children with fulminant hepatic failure.

Fulminant hepatic failure (FHF) is a rare but often fatal disease in children. Clinical and laboratory predictors of liver regeneration and recovery, however, have not been well established. We hypothesized that hypophosphatemia may indicate recovery of liver synthetic function in children with FHF. We retrospectively reviewed the medical records of children with FHF who were admitted to UCLA and recovered hepatic function either spontaneously or by liver transplantation (LTx). Serum phosphate (Ph) and prothrombin time or international normalized ratio (INR) were compared over the patients clinical course. Records of 39 children who spontaneously recovered experienced profound hypophosphatemia that resolved as liver synthetic function improved. Similar patterns were seen in the 84 children who recovered after LTx. We found that hypophosphatemia precedes the recovery of liver synthetic function in children with FHF who recovered with or without transplantation, and that Ph levels return to normal as liver synthetic function improves. These data suggest that hypophosphatemia may be a useful laboratory indicator of recovering liver function in children with FHF.

Late-onset bacteremia in uncomplicated pediatric liver-transplant recipients after a febrile episode

Abstract The aim of this study was to analyze the incidence and risk factors of bacteremia after a febrilc episode in uncomplicated pediatric recipients more than 2 months after liver transplantation, which has not previously been studied. This cross‐sectional study was conducted over a 4‐year period. Patients with known risk factors for sepsis at the time of admission were excluded from the study. Seventy‐one patients were hospitalized on 128 occasions, with bacteremia occurring in the case of 11 admissions (8.6%). No laboratory tests were predictive of bacteremia. The bacteremic group most frequently presented with ill appearance (P<0.001), lethargy (P<0.01), decreased physical activity, and a history of early‐onset bacteremia after transplantation and segmental graft (P<0.05). This study identified a significant incidence of bacteremia in uncomplicated patients many months after liver transplantation.