Nada Yazigi

Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy.

MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction. Conclusion: We therefore propose that mutations in the MPV17 gene be considered in the course of evaluating the molecular etiology for isolated, rapidly progressive infantile hepatic failure. (HEPATOLOGY 2007.)

Pattern of Diagnostic Evaluation for the Causes of Pediatric Acute Liver Failure: An Opportunity for Quality Improvement

OBJECTIVEnTo describe the frequency of diagnostic testing for the 4 most common causes of pediatric acute liver failure (PALF) (drugs, metabolic disease, autoimmune process, and infections) in indeterminate PALF within the PALF Study Group Database.nnnSTUDY DESIGNnPALF was defined by severe hepatic dysfunction within 8 weeks of onset of illness, with no known underlying chronic liver disease in patients from birth through 17 years of age.nnnRESULTSnOf the 703 patients in the database, 329 (47%) had indeterminate PALF. In this group, a drug history was obtained in 325 (99%) urine toxicology screenings performed in 118 (36%) and acetaminophen level measured in 124 (38%) patients. No testing for common metabolic diseases was done in 179 (54%) patients. Anti-nuclear antibody, anti-smooth muscle antibody, and anti-liver kidney microsomal autoantibodies associated with autoimmunity were determined in 239 (73%), 233 (71%), and 208 (63%) patients, and no tests were obtained in 70 (21%). Testing was performed for hepatitis A virus, hepatitis B virus, and Epstein Barr virus in 80%, 86%, and 68%, respectively.nnnCONCLUSIONSnCurrent practice indicates that investigation for metabolic and autoimmune causes of PALF are infrequent in patients ultimately given a diagnosis of indeterminate acute liver failure. This offers an opportunity to improve diagnosis and potential treatment options in children with acute liver failure.

Expansion of transplanted hepatocytes during liver regeneration.

BACKGROUNDnSuccessful clinical application of hepatocyte transplantation has been limited by poor engraftment of the recipient liver by transplanted hepatocytes.nnnMETHODSnTo address the hypothesis that liver regeneration induced by an acute hepatotoxic injury promotes expansion of transplanted hepatocytes, we injected beta-galactosidase-labeled hepatocytes intrasplenically into mice 24 hr after treatment with carbon tetrachloride (CCl4) and into untreated controls.nnnRESULTSnMacroscopic examination of whole liver segments identified clusters of transplanted hepatocytes uniformly spread on the capsular surface of the recipient liver and in the liver core following the distribution pattern of portal vein branches. Frozen sections showed that although the degree of initial engraftment of transplanted hepatocytes was similar in CCl4-treated and control livers, there was a fourfold increase of engrafted hepatocytes in CCl4-treated livers 10 days after transplantation which persisted to 28 days.nnnCONCLUSIONSnWe conclude that the number of transplanted hepatocytes increases in response to regeneration signal triggered by an acute hepatocyte-specific liver injury.

Immunophenotype predicts outcome in pediatric acute liver failure.

Objectives: We sought to determine whether markers of T-cell immune activation, including soluble interleukin 2 receptor alpha (sIL2R&agr;) levels predict outcome in pediatric acute liver failure and may target potential candidates for immunomodulatory therapy. Methods: We analyzed markers of immune activation in 77 patients with pediatric acute liver failure enrolled in a multinational, multicenter study. The outcomes were survival with native liver, liver transplantation (LT), and death without transplantation within 21 days after enrollment. Results: Adjusting for multiple comparisons, only normalized serum sIL2R&agr; level differed significantly among the 3 outcomes, and was significantly higher in patients who died (Pu200a=u200a0.02) or underwent LT (Pu200a=u200a0.01) compared with those who survived with their native liver. The 37 patients with normal sIL2R&agr; levels all lived, 30 with their native liver. Of the 15 subjects with markedly high sIL2R&agr; (≥5000 IU/mL), 5 survived with their native liver, 2 died, and 8 underwent LT. Conclusions: Evidence of immune activation is present in some patients who die or undergo LT. Patients with higher sIL2R&agr; levels were more likely to die or undergo LT within 21 days than those with lower levels. Identifying a subset of patients at risk for poor outcome may form the foundation for targeted clinical trials with immunomodulatory drugs.

Spontaneous perforation of the bile duct in infancy: a rare but important cause of irritability and abdominal distension.

Spontaneous biliary perforation (SBP) is a rare but important cause of jaundice in infancy, requiring prompt diagnosis and surgical intervention. First described in 1932, fewer than 150 cases have been reported to date. The classic presentation is that of a previously healthy infant who develops progressive ascites and abdominal distension, irritability, and fluctuating mild jaundice. The etiology of SBP is unknown. Proposed theories have included congenital mural weakness of the common bile duct, trauma, ischemia, distal biliary obstruction, and pancreatic reflux. We present a case of SBP in a previously healthy 10-week-old infant with ascites and intermittently acholic stools. A hepatobiliary scan suggested rupture of a choledochal cyst, but laparotomy revealed a ruptured common bile duct at the junction of the cystic and common bile duct.

Incidence of acute and chronic graft-versus-host disease and donor T-cell chimerism after small bowel or combined organ transplantation

PURPOSEnGraft-versus-host disease (GVHD) after organ transplantation is a rare but life-threatening complication with very high mortality.nnnMETHODSnA retrospective review was performed of all patients undergoing small bowel or combined organ transplantation at a single institution during 2003 to 2009. Patients with donor T-cell chimerism were analyzed in detail for development of GVHD.nnnRESULTSnThirty-two patients were included in the study. Of 32 patients, 11 (34%) had donor T-cell chimerism (range, 0%-53%) studies performed; 7 (64%) of those 11 patients demonstrated clinical features of GVHD. All patients who demonstrated GVHD had detectable donor T-cell chimerism. All patients with GVHD presented with skin involvement. Graft-versus-host disease responded to increased immune suppression therapy. Mortality was 43% (3/7) among patients with GVHD and was caused by multiorgan failure and sepsis in all cases.nnnCONCLUSIONnAcute and chronic GVHD were observed frequently after combined solid organ transplantation and were associated with significant mortality and morbidity. Alloreactive donor T cells cotransplanted with the organ likely play a role in the pathophysiology because levels of donor-derived T-cell chimerism correlated with the clinical course of GVHD.

Hyponatremia increases mortality in pediatric patients listed for liver transplantation

Carey RG, Bucuvalas JC, Balistreri WF, Nick TG, Ryckman FR, Yazigi N. Hyponatremia increases mortality in pediatric patients listed for liver transplantation.u2028Pediatr Transplantation 2010: 14: 115–120.

Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

Objective: Viral infections are often suspected to cause pediatric acute liver failure (PALF), but large-scale studies have not been performed. We analyzed the results of viral testing among nonacetaminophen PALF study participants. Methods: Participants were enrolled in the PALF registry. Diagnostic evaluation and final diagnosis were determined by the site investigator and methods for viral testing by local standard of care. Viruses were classified as either causative viruses (CVs) or associated viruses (AVs). Supplemental testing for CV was performed if not done clinically and serum was available. Final diagnoses included “viral,” “indeterminate,” and “other.” Results: Of 860 participants, 820 had at least 1 test result for a CV or AV. A positive viral test was found in 166/820 (20.2%) participants and distributed among “viral” (66/80 [82.5%]), “indeterminate” (52/420 [12.4%]), and “other” (48/320 [15.0%]) diagnoses. CVs accounted for 81/166 (48.8%) positive tests. Herpes simplex virus (HSV) was positive in 39/335 (11.6%) who were tested 26/103 (25.2%) and 13/232 (5.6%) among infants 0 to 6 and >6 months, respectively. HSV was not tested in 61.0% and 53% of the overall cohort and those 0 to 6 months, respectively. Supplemental testing yielded 17 positive, including 5 HSV. Conclusions: Viral testing in PALF occurs frequently but is often incomplete. The evidence for acute viral infection was found in 20.2% of those tested for viruses. HSV is an important viral cause for PALF in all age groups. The etiopathogenic role of CV and AV in PALF requires further investigation.

Radiofrequency ablation of a large hepatic adenoma in a child

Hepatic adenomas are rare benign liver tumors seen most commonly in young women on oral contraceptives. Large hepatic adenomas are at risk of malignant transformation and require treatment in select patients, usually by surgical resection. Radiofrequency ablation (RFA) has become a widely used and accepted tool for the curative treatment of small primary hepatocellular carcinomas in adults; however, its use in the treatment of other liver lesions, such as hepatic adenoma, has only recently been described. Use of RFA for liver lesions in pediatric population remains novel. We present a case of large hepatic adenoma successfully treated with RFA in a child with chronic liver disease secondary to alpha-1-antitrypsin deficiency. RFA may be an attractive option in pediatric liver tumor management in selected cases because of its less invasive characteristics.

Sensitization and Preformed Donor Specific Antibody in Intestinal Transplantation: survival and rejection outcomes

Introduction: Sensitization has historically been shown to decrease allograft survival in intestinal transplantation (ITx). Contemporary data increasingly demonstrates that donor specific antibody (DSA) is responsible for increased risk of rejection and graft loss in sensitized ITx recipients. Methods: Beginning in 2008 recipients were screened for preformed DSA prior to transplant at our institution. All ITx performed at our institution from 2008 through 2016 were included in this study and evaluated with the use of a prospectively maintained database. DSA prior to transplant was determinedwith the use of solid phase assays andwas considered positivewith amedian fluorescence intensity (MFI) >1000. Standard immunosuppression (IS) consisted of IL2 blockade induction with maintenance IS of tacrolimus, sirolimus, and prednisone. Sensitized recipients generally received thymoglobulin induction and IVIG followed by standard maintenance IS. Results: 144 ITx transplants were performed during this period (69 pediatric and 75 adult) including 101 isolated intestine, 26 liver/intestine, 13 multivisceral transplants and 4 modified multivisceral transplants. The median follow up was 56.4 months. There were 3 comparison groups: non-sensitized recipients (n=74), sensitized recipients without preformed DSA (n=57) and sensitized recipients with preformed DSA (n=13). The 13 recipients with preformed DSA included 11 isolated intestine transplants, 1 multivisceral transplant and 1 modified multivisceral transplant and 9 were adults. The mean PRA +/− SD in the sensitized group without preformed DSA was 77 +/− 28 and 36 +/− 30 in the sensitized group with preformed DSA (p<0.001). Recipients with a positive T cell and/or B cell flow crossmatch was 7% in the sensitized group without preformed DSA and 54% in the sensitized group with preformed DSA (p=0.007); no patient in the non-sensitized group had a positive flow crossmatch. In the sensitized group without preformed DSA compared to the non-sensitized group, there was no statistical difference in 1-, 3, and 5-year patient survival (72%, 65%, and 65% versus 86%, 79%, and 75% p=0.065), 1-, 3-, and 5-year graft survival (70%, 65%, and 59% versus 84%, 78%, and 69% p=0.163), and 1-, 3-, and 5-year freedom from rejection (66%, 66%, and 51% versus 77%, 77%, and 71% p=0.160). In the sensitized group with preformed DSA compared to the non-sensitized group, there was a statistically lower 1-, 3-, and 5-year patient survival (49%, 49%, and 49% versus 86%, 79%, and 75% p=0.015), 1-, 3-, and 5-year graft survival (49%, 39%, and 39% versus 84%, 78%, and 69% p=0.017), and 1-, 3-, and 5-year freedom from rejection (25%, 25%, and 25%versus 77%, 77%, and 71% p=0.0001). Conclusions: Sensitized intestine recipients with preformed DSA have an increased risk of rejection, graft loss and mortality. Avoidance of preformed DSA in sensitized recipients may improve outcomes following intestine transplant. 205.2