Michael B. Ishitani

Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization

Passive immunization with hepatitis B surface antibody (anti-HBs) is important to prevent hepatitis B virus (HBV) recurrence after orthotopic liver transplantation for chronic HBV cirrhosis. Hepatitis B immune globulin (HBIG) dosing regimens have been poorly defined, utilize numerous routes of administration, and result in a high rate of HBV relapse and mortality. Twenty-five of 27 (93%) patients transplanted (four retransplants) for chronic HBV cirrhosis show no evidence of recurrent HBV (range, 2-55 months). Anti-HBs titers necessary to minimize the risk of hepatitis B surface antigen detectability were >500 IU/L for days 0 to 7, >250 IU/L for days 8 to 90, and >100 IU/L thereafter. Pretransplant HBV E antigen (HBeAG)-positive patients required more HBIG to achieve these goals than HBeAG-negative individuals. The elimination of anti-HBs changed continually for the initial 3 posttransplant months. The anti-HBs half-life increased from 0.7 days to 14.1 days. Anti-HBs elimination was significantly different in HBeAG+ and HBeAG- patients for the first week, but was subsequently indistinguishable after week 1. After 3 months, the half-life was statistically less for HBeAG+ patients, but the difference did not influence the clinical treatment regimens. Quantitative hepatitis B DNA levels did not predict the amount of HBIG required. HBV recurrence after orthotopic liver transplantation can be reduced by aggressive passive immunization. Pharmacokinetic analysis of anti-Hbs elimination can improve immunoglobulin therapy and prevent recurrence of clinical hepatitis.

Clinical and histologic patterns of early graft failure due to recurrent hepatitis C in four patients after liver transplantation

Hepatitis C viral recurrence after orthotopic liver transplantation is almost universal. Hepatitis C-induced graft failure may occur, but the clinical and histologic profiles are not well defined. The aim of this study was to describe the pattern of early graft failure in patients with recurrent hepatitis C after liver transplantation. Thirty patients with hepatitis C underwent liver transplantation from October 1989 through September 1994. Four patients were excluded because of death (2 patients), graft failure unrelated to hepatitis C (1 patient), and lost to follow-up (1 patient). Hepatitis C recurred in 24 of the 26 remaining patients. In 4 patients with hepatitis C virus recurrence and cholestasis, graft failure developed at 5.25, 11.0, 11.0, and 18.5 months. The medical records and liver biopsies were reviewed. In all 4 patients, a histologic pattern characterized by centrilobular ballooning degeneration developed and progressed to involve more than two-thirds of the lobules. Moderate to severe cholestasis and bridging fibrosis were present in all grafts at explant. Two patients had portal inflammation on 3-month biopsies consistent with viral hepatitis. All patients had mild macrovesicular steatosis, but only 1 patient had significant lymphoid aggregates. No patient had evidence of hepatic artery thrombosis. One patient had potential drug-induced cholestasis. One patient had 3 episodes of rejection that were not believed to contribute to graft loss. All 4 patients developed clinical features of hepatic failure and were retransplanted. Two patients had early recurrence of graft failure. We conclude that a pattern of progressive centrilobular ballooning degeneration, bridging fibrosis, and cholestasis occurs in some patients with hepatitis C with early graft failure, similar to fibrosing cholestatic hepatitis seen in some transplant patients with recurrent hepatitis B.

Predictors of graft survival in pediatric living-related kidney transplant recipients.

BACKGROUNDnA successful kidney transplant from a living-related donor (LRD) remains the most effective renal replacement therapy for children with end-stage renal failure. The use of LRD kidneys results in decreased time on dialysis, increased graft survival, and better function compared with kidneys transplanted from cadaver donors. We retrospectively analyzed data from the United Network of Organ Sharing (UNOS) Scientific Renal Transplant Registry to determine risk factors for graft loss in children who received an LRD kidney.nnnMETHODSnData was obtained from the UNOS Scientific Renal Transplant Registry on 2418 children ranging in age from 0 to 18 years who underwent an LRD kidney transplantation between January 1988 and December 1994. Multivariate analysis of graft survival was performed using Kaplan-Meier and Cox regression models.nnnRESULTSnThe effects of age, pretransplantation dialysis, early rejection, and race were found to significantly affect graft survival. Gender, peak panel-reactive antibody, and ABO blood type were not found to be significant risk factors. Infants <2 years of age initially had the worst graft survival; however, over time their results stabilized, and at 7 years estimated graft survival was good (71%). Adolescents ranging in age from 13-18 years had the best initial graft survival, but as time went on graft survival worsened (55%). Patients who underwent pretransplantation dialysis had a relative risk for graft loss of 1.77 (P<0.001), whereas those who had an early rejection had a relative risk for graft loss of 1.41 (P<0.002). African-Americans had a significantly higher relative risk for graft loss than either Caucasians (1.57, P<0.0005) or Hispanics (2.01, P<0.0003).nnnCONCLUSIONSnPredictors of graft survival for children who receive LRD kidney transplants include age at transplantation, pretransplantation dialysis, early rejection, and race. Over time, adolescents and African-Americans seem to have the lowest graft survival.

Reversible posterior leukoencephalopathy following organ transplantation Description of two cases

Although neurologic changes after organ transplantation are often secondary to opportunistic infections or vascular insults, new pathological entities are emerging. We have recently encountered two patients who, a few days after liver and heart transplant, respectively, developed neurological signs and symptoms. Head computerized tomography (CT) scan showed nonenhancing areas of low attenuation, and magnetic resonance imaging (MRI) demonstrated multiple areas of increased signal intensity in the subcortical white matter on T2-weighted images. Stereotactic biopsy of the intracranial lesions was performed in one case. Light microscopic examination demonstrated only mildly edematous white matter. No infectious organisms were observed on light or electron microscopy. In one patient, follow-up MRI 3 months later showed almost complete resolution of the signal abnormalities. Both patients clinical condition progressively improved. The neuroradiological abnormalities described are consistent with the reversible posterior leukoencephalopathy syndrome associated with cyclosporine toxicity. The pathophysiology of these lesions is unclear; however, it has been suggested that cyclosporine causes an acute ischemic insult secondary to vascular spasm with resultant axonal swelling. This hypothesis is supported by the hypoattenuation seen on CT, the prolonged T2 relaxation seen on MRI, and the absence of contrast enhancement. Concomitant factors (such as hypocholesterolemia or associated therapy with high dose steroids) are important in the development of these lesions as in both of our patients cyclosporine levels were in the normal range. Fortunately, these lesions and the associated manifestations are most often reversible and regress with adjustments of cyclosporine dosage and/or correction of concomitant facilitating factors.

Early subclinical coronary artery calcification in young adults who were pediatric kidney transplant recipients

Coronary artery disease (CAD) is the leading cause of death in adults after successful kidney transplantation. Children who have undergone successful kidney transplantation are entering young adulthood; however, the prevalence and extent of CAD in this population is unknown. We conducted a pilot study in young adults with stable allograft function, who received kidney transplants as children to measure coronary artery calcification (CAC), a marker of coronary artery atherosclerosis and CAD. We evaluated 19 young adults after successful pediatric kidney transplantation for known CAD risk factors; these patients underwent noninvasive imaging with electron‐beam computed tomography (EBCT) for measurement of CAC. Prevalence and quantity of CAC were then compared to asymptomatic individuals from the community. All patients had multiple risk factors for CAD. Mean age at evaluation was 32 years (range: 21–48 years). CAC is uncommon in individuals in the community in this age range; however, nearly half of our patients had CAC detected with the quantity of CAC comparable to asymptomatic individuals from the community 10–40 years older. These data suggest young adults who received pediatric kidney transplants are at increased risk for developing early CAC and need close monitoring to detect early CAD so as to prevent premature cardiac morbidity and mortality.

Retransplantation of patients with severe posttransplant hepatitis B in the first allograft

BACKGROUNDnThe outcome of orthotopic liver transplantation (OLTX) in patients retransplanted for severe hepatitis B virus (HBV) in the first allograft has been poor due to high rates of HBV reinfection and even more aggressive disease in the second graft. Recent data suggest that hepatitis B immunoglobulin (HBIg) given after transplantation can be successful in delaying or preventing HBV reinfection in patients transplanted for chronic hepatitis B cirrhosis. We report the successful retransplantation of patients who developed recurrent or de novo hepatitis B after OLTXY.nnnMETHODSnUsing similar HBIg regimens, two centers retransplanted seven patients after they developed recurrent or de novo hepatitis B in the first allograft. At retransplantation all seven patients were HBs antigen (Ag) positive; four patients were positive for HBeAg and HBV DNA by immunoblot assay, two patients were negative for HBeAg and HBV DNA, and one patient was positive for HBV DNA and negative for HBeAg. All patients were either HDV Ag or anti-HDV negative. One patient was anti-HCV positive. All patients received HBIg infusions after retransplantation to maintain serum anti-HBs levels >500 IU/L indefinitely.nnnRESULTSnAfter retransplantation, six of seven patients are alive (86%): all are without evidence of HBV recurrence with serum negative for HBsAg, HBeAg, and HBV DNA by immunoblot assay. Liver biopsies are normal on routine studies with immunohistochemical stains for HBcAg and HBsAg also being negative. Mean follow-up of these six patients is 40.1 months (range 21-63 months). One patient (14%) developed HBV reinfection 7 months after his second transplant, in spite of maintaining target anti-HBs levels. He maintained stable liver function with minimal evidence of clinical hepatitis B, but died 8 months later from an unrelated stroke.nnnCONCLUSIONSnWe conclude that patients with recurrent or de novo hepatitis B after OLTX can be successfully retransplanted using aggressive immunoprophylaxis to prevent HBV reinfection. The failure of HBIg therapy in one patient underscores the need for other effective adjunctive anti-HBV modalities.

The international autoimmune hepatitis score in chronic hepatitis C

SUMMARY. Clinical and laboratory findings of autoimmunity are common in chronic hepatitis C. Autoimmune hepatitis (AIH), a disease of unknown cause, has been defined by use of the International Autoimmune Hepatitis Group Score (AIH score), which quantifies clinical and laboratory parameters. To further validate the specificity of the International AIH score and investigate the similarities between hepatitis C and AIH, we measured the International Autoimmune Hepatitis Group Score in patients with well‐defined chronic hepatitis C. Thirty consecutive non‐cirrhotic patients with chronic hepatitis C were evaluated. Scoring was performed using both components of the AIH score: a set of minimum required parameters including laboratory and historical data and a second set of additional parameters dominated by histological criteria. Autoantibodies were positive in 21 of 30 hepatitis C patients and associated (patient or first‐degree relative) autoimmune diseases were present in eight of 30 patients. Histologically, chronic active hepatitis with periportal piecemeal necrosis was seen in 24 of 30 patients and lymphoid follicles in 16 of 30 patients. No patient scored as probable or definite AIH using the minimum required parameters of the AIH score. When histological parameters were included, four of 30 patients scored as probable AIH but none as definite AIH. Therefore, AIH was excluded by the minimal and additional criteria of the AIH score in 86% of patients with hepatitis C despite a high prevalence of autoantibodies in these patients. We conclude that the criteria set forth by the International AIH scoring system defines a distinct disease although it shares some features with chronic hepatitis C. Modification of the AIH scoring system to include other commonly accepted risk factors for hepatitis C and additional histological parameters would further improve its specificity.

Anteriorly displaced anus : an under-recognized cause of chronic constipation

Anterior displacement of a normal anus is recognized as a cause of severe constipation in some children. We have reviewed our experience with 13 children treated for this disorder over the past 8 years at the University of Virginia Health Sciences Center. Twelve of the patients were female and the age at the time of operation ranged between 12 months and 9 years. In all patients constipation began in the first 3 to 6 months of life. Symptoms were characterized by marked straining upon passage of stool, often accompanied by perineal pain. All patients had been unsuccessfully treated with agressive use of stool softeners and cathartics. The anus had a normal appearance, although it was located anterior to its normal position in every case. There was no evidence of anal stenosis on digital examination; in each case a large posterior rectal cul-de-sac could be palpated. A barium enema examination disclosed a prominent posterior shelf of the rectum, often with enormous dilation of the colon posteriorly. All patients underwent surgical treatment using a posterior anoplasty with advancement of the posterior rectal wall. In 10 patients a posterior rectal myomectomy was added to the procedure. Pathologic evaluation of the rectal muscle was normal in each instance. Complete relief of constipation was achieved in all patients, with follow-up extending for as long as 6 years. One patient continues to require occasional use of stool softeners. Anterior displacement of the anus is a frequently overlooked, although easily corrected, cause of severe constipation in childhood.

Primary hyperoxaluria: new directions for diagnosis and treatment

Abstract Primary hyperoxaluria type 1 (PH1) is a rare genetic autosomal recessive disorder caused by deficient function of the liver-specific metabolic enzyme alanine:glyoxalate aminotransferase (AGT). AGT normally catalyzes the breakdown of glyoxalate to glycine; in PH 1 , AGT function is abnormal and oxalate accumulates within the body. Oxalate can only be removed from the body by renal excretion, leading to hyperoxaluria with deposition of oxalate in the kidneys and progressive nephrocalcinosis, urolithiasis and renal failure. As renal function declines, oxalate deposition rapidly occurs in tissues throughout the body and results in systemic multiorgan dysfunction and early mortality. Diagnosis of PH1Sn the past was based on clinical presentation in conjunction with high plasma and urinary oxalate measurements. Confirmation of the diagnosis was made by examining liver biopsies for AGT activity. Treatment was primarily based on measures to increase urine flow and decrease oxalate crystallization within the kidney tubules. Pyridoxine therapy was empirically found to be helpful in a number of cases. Renal replacement therapy (dialysis and renal transplantation) met with limited success due to the low rate of oxalate clearance with both haemo- and peritoneal dialysis and the rapid deposition of oxalate within the transplanted kidney. Over the last 5 years, new understanding of the structure and function of AGT and the molecular basis of AGT dysfunction has resulted in the development of new diagnostic techniques which can in some cases eliminate the need for invasive liver biopsies. In addition, characterization of a known genetic polymorphism in combination with a specific amino acid mutation has been found to correlate with response to pyridoxine therapy in a third of patients. Improved long term results in patients who have progressed to renal failure have been reported with combined liver–kidney transplantation in conjunction with aggressive perioperative measures to reduce serum oxalate levels and systemic oxalate stores. Some experience with preemptive liver transplant prior to the development of renal failure has been reported. The role of pre-emptive liver transplantation remains uncertain given the unpredictability of the timing of renal failure and risks of liver transplantation and life-long immune suppression. Continuing efforts at developing specific gene therapy are ongoing.

Liver Transplantation WorldwideThe decreasing incidence of diaphragmatic dysfunction in liver transplantation: A probable advantage of the piggy-back liver transplant technique

BACKGROUNDnPediatric orthotopic liver transplantation (OLT) has a low mortality. Some children, however, have an adverse outcome defined as a prolonged ventilatory support requirement and protracted pediatric intensive care unit (PICU) stay. The aim of this study was to determine if that adverse outcome related to the childs condition pre-OLT and/or the development of a pleural effusion or diaphragmatic dysfunction.nnnMETHODSnThe study included 210 children with a median age at transplantation of 45.5 months (range 0.2-252 months). Fourteen had undergone retransplantation. The duration of ventilatory support (intermittent positive pressure ventilation [IPPV]) and PICU admission and development of a pleural effusion and/or diaphragmatic dysfunction were documented for each child. The patients were divided into three groups according to whether they had acute liver failure (ALF), chronic liver disease at home (CHOM), or chronic liver failure sufficiently ill to be in the hospital awaiting transplantation (CHOSP).nnnRESULTSnThe 36 children with ALF were of similar age to the 138 CHOM and 36 CHOSP children but required longer IPPV (P < 0.0001) and PICU stay (P < 0.0001). Overall, 17 children developed diaphragmatic dysfunction and 138 pleural effusions; affected children required longer IPPV and PICU stay (P <0.01). Regression analysis demonstrated that diaphragmatic dysfunction, but not pleural effusion development, was associated with prolonged ventilation (P <0.01) and protracted PICU stay (P <0.05). Other risk factors were ALF (P <0.01), retransplantation (P <0.01), and young age (P <0.05).nnnCONCLUSIONnDiaphragmatic dysfunction adversely influences PICU morbidity after OLT. Early assessment of diaphragmatic function, and if necessary aggressive management, might improve outcome.