Search

Symptoms and complications associated with severe SARS-CoV-2 infection such as acute respiratory distress syndrome (ARDS) and organ damage have been linked to SARS-CoV-2 spike protein S1-induced increased production of pro-inflammatory cytokines by immune cells. In this study, the effects of an extract of Garcinia kola seeds and garcinoic acid were investigated in SARS-CoV-2 spike protein S1-stimulated human PBMCs. Results of ELISA experiments revealed that Garcinia kola extract (6.25, 12.5, and 25 μg/ml) and garcinoic acid (1.25, 2.5, and 5 μM) significantly reduced SARS-CoV-2 spike protein S1-induced secretion of TNFα, IL-6, IL-1β, and IL-8 in PBMCs. In-cell western assays showed that pre-treatment with Garcinia kola extract and garcinoic acid reduced expressions of both phospho-p65 and phospho-IκBα proteins, as well as NF-κB DNA binding capacity and NF-κB-driven luciferase expression following stimulation of PBMCs with spike protein S1. Furthermore, pre-treatment of PBMCs with Garcinia kola extract prior to stimulation with SARS-CoV-2 spike protein S1 resulted in reduced damage to adjacent A549 lung epithelial cells. These results suggest that the seed of Garcinia kola and garcinoic acid are natural products which may possess pharmacological/therapeutic benefits in reducing cytokine storm in severe SARS-CoV-2 and other coronavirus infections., (© 2021 John Wiley & Sons Ltd.)

This supplement celebrates the 50th anniversary of Alpha-1 antitrypsin deficiency (AATD). Initially AATD was associated with an inherited form of emphysema. This historical article describes the predisposition of AATD to liver disease. The morphologic findings contributed to a better understanding of low serum levels of A1 AT by the finding of AAT accumulating and stuck in the lumen of the rough endoplasmic reticulum of the hepatocyte. Thus, only low levels of PiZ were secreted for the rest of the human body and the only clinical correction was by liver transplantation.

Epidemiological data on bacterial translocation (BT), colonization and inflammation in normal human livers is lacking. In this study we investigated the status of bacterial colonization and inflammation in the normal, cirrhotic primary biliary cirrhosis (PBC), and nonalcoholic steatohepatitis (NASH) human liver tissues. Comparatively normal livers showed increased bacterial colonization than PBC and NASH. We analyzed mRNA levels of Toll-like receptors (TLR) 2 and TLR4, and protein levels of TLR4. Phosphorylated IKKα (pIKKα) protein estimation served as a marker for nuclear factor-kappa B (NF-κB) activation. In spite of the increased bacterial colonization in normal liver tissues, lower levels of TLR2/4 mRNA and TLR4 and pIKKα proteins were found compared to PBC and NASH indicating the maintenance of suppressed inflammation and immune tolerance in normal livers. To our knowledge, this is the first clinical evidence showing suppressed inflammation despite bacterial colonization in normal human livers thus maintaining liver immune homeostasis., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients., Methods: The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database., Results: Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH., Conclusions: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.

Aims: We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man., Methods: Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue (AI). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII)., Results: The AI-TT and AI-KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI-KLH conjugate vaccine resulted in a significant immune response to AI. A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction., Conclusion: KLH was shown to be a suitable alternative to TT as a carrier protein for AI, thus supporting continued evaluation of our AI-KLH conjugate vaccine for treatment of hypertension in man.

Presentation of autosomal recessive polycystic kidney disease (ARPKD) ranges from severe renal impairment and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis (CHF), cholangitis and portal hypertension. Renal transplantation improves prognosis but it is unclear whether CHF in transplanted children follows the same clinical course as in older children with less severe renal disease. The aim of this study was to evaluate morbidity from CHF in ARPKD post renal transplantation. Data were analyzed for six males and eight females, transplanted for ARPKD (mean age 8.3 years, range 1-22.3 years) at the University of Minnesota between 1972 and 1998. Follow-up was for a mean of 14.5 years (range 3.1-33.6 years). One and 5 years patient survival rates were 93% and 86%, respectively. Overall five patients (36%) died; 4/5 deaths were related to CHF. Causes of death were hepatic failure immediately post transplant (n = 1), septicemia related to bile duct dilatation (n = 3) and multiorgan failure (n = 1). One and 5years graft survival rates were 87% and 70%, respectively. One patient had a combined liver-kidney transplant and two were re-transplanted. Initial signs of CHF were splenomegaly (n = 5), hepatosplenomegaly (n = 4) and gastrointestinal bleed (n = 2). Progression of CHF through childhood included hypersplenism (n = 7), esophageal varices with gastrointestinal bleeding (n = 5) and bile duct dilatation (n = 5). Portal hypertension was treated with portosystemic shunt (n = 3), sclerotherapy (n = 2), banding of varices (n = 1) and transjugular intrahepatic portosystemic shunt (n = 1). Of the nine survivors (mean age 12.8 years) 78% have functioning grafts (one liver-kidney transplant), 63% have portal hypertension and 22% have asymptomatic biliary dilatation. Complications of CHF developed in 79% of children who received a renal transplant for ARPKD. Mortality related to CHF occurred in 29% and accounted for 80% (4/5) of the deaths.

Biliary stricture is a recipient graft complication, occurring late in the post-operative period, which appears to occur with increased frequency in living-related donor liver transplantation (LRD LTx). We reviewed the experience at the University of Minnesota in managing a biliary complication of LRD LTx. Since January 1997, 13 LRD transplants have been performed using the technique of transplantation of the left lateral segments with a small portion of segment IV. All patients had hepaticojejunostomies using a Roux-en-Y loop. Of the 11 surviving patients, eight had evidence of cholangitis (Gram-negative sepsis, two patients; ascending cholangitis, three patients; or unexplained fever with elevated liver enzymes, three patients) 4-8 months after otherwise successful transplantation. Six of the patients underwent percutaneous transhepatic cholangiography (PTC) with demonstration of a stenosis at the site of the biliary anastomosis. Repeated dilation of the anastomosis led to resolution of the stenoses, normalization of liver enzymes, and prevention of further episodes of infection. No patient required revision of the hepaticojejunostomy. Computed axial tomography evidence of ductal stenosis may be subtle in this group of patients, but PTC is diagnostic. We suggest a high index of suspicion of biliary stricture in the LRD LTx population. Biliary dilation reduces the risk of life-threatening sepsis.

1. Male, Sprague-Dawley rats were actively immunized with novel angiotensin vaccines, and their pressor responses to exogenous angiotensin I (AI) and angiotensin II (AII) were assessed in vivo. Serum antibody titres were also measured. 2. The most effective vaccine consisted of an AI analogue conjugated with a tetanus toxoid carrier protein and adjuvanted with aluminium hydroxide. When this vaccine was injected on days 0, 21 and 42, pressor responses to AI on day 63 were significantly inhibited (maximum, 8.9 fold shift), but responses to AII were unaffected. The anti-angiotensin antibody titre was increased 32,100 fold, and, uniquely, these antibodies also cross-reacted with angiotensinogen. 3. These findings indicate that active immunization against AI may be a useful approach for treating cardiovascular disorders involving the renin-angiotensin system.

Background: The cause of fulminant hepatic failure in children remains unknown, but a viral origin has been suspected in most cases. The recently discovered blood-borne virus, hepatitis G, has been suggested as a possible causative agent., Method: Six consecutive children who underwent liver transplantation for fulminant hepatic failure were studied. The children were tested for hepatitis G virus antibodies and hepatitis G virus RNA by polymerase chain reaction after excluding other causes of fulminant hepatic failure., Results: No evidence of hepatitis G virus infection was found in these patients., Conclusion: Hepatitis G virus is unlikely to be a common cause of fulminant hepatic failure in pediatric patients from the upper midwestern United States.

Post-transplant hemolytic uremic syndrome (HUS) is an uncommon but well-described complication in solid organ transplant recipients. Believed to be secondary to immunosuppressive therapy, it has been reported after kidney, liver, pancreas, heart, and lung transplants. In all reported cases, the primary organ affected was the kidney (transplant or native). But until now, no cases after small-bowel transplants and no cases in which the kidney was not the primary organ affected have been reported. We report two cases of HUS in small-bowel transplant recipients. In our first case, clinical presentation was with renal failure; biopsy of the native kidney demonstrated the typical histological changes seen with HUS, namely occlusion of the microcirculation by thrombi and platelet aggregation. Immunosuppression was changed from tacrolimus to cyclosporin, but with no improvement in renal function. In our second case, the transplanted bowel was the primary organ affected. This recipient presented with ulcers in the bowel mucosa, which were believed to be ischemic in origin, secondary to occlusive vascular lesions affecting the small vessels in the transplanted bowel. Her tacrolimus dose was decreased with resolution of ulcers and no evidence of rejection. These two cases represent the first reports of HUS after small-bowel transplants; in addition, our second case represents the first report of an extrarenal graft as the primary organ affected. When caring for small-bowel transplant recipients, physicians must be alert to the possibility of HUS and its various presentations.

We herein report the first case of immunosuppression-associated thrombotic microangiopathy (TMA) in which an extrarenal graft was primarily affected by the characteristic microvascular lesions. Although TMA is a well-known complication of cyclosporine (CSA) or tacrolimus therapy in renal and extrarenal (liver, heart, lung) transplant recipients, the kidney (transplanted or native) is typically the site primarily affected. We describe a combined liver-small bowel transplant recipient who developed tacrolimus-associated TMA that affected both her transplanted small bowel and her native kidneys. Involvement of the bowel, with evidence of microvascular occlusion on biopsy, led to the development of ischemic mucosal ulcers and eventual bowel perforation. Involvement of the kidney manifested with a doubling of the recipient's baseline serum creatinine level. Significant lowering of the tacrolimus dose resulted in healing of the small bowel ulcers and return to her baseline level of renal function. Therefore, it is important to note that, in transplant recipients, TMA with microvascular occlusion may affect extrarenal sites. In small bowel transplant recipients, the result might be ischemic ulcers in the graft and eventual bowel perforation.

Background: Intestinal transplants using cadaver donors have become an alternative to total parenteral nutrition (TPN) for the treatment of irreversible intestinal failure. Intestinal transplants using living-related donors have rarely been attempted, and the surgical technique has not been standardized., Methods: We performed a living-related intestinal transplant for a paraplegic, 16-year-old boy with life-threatening TPN complications, including lack of vascular access, recurrent line infections, and intermittent liver dysfunction., Results: A four antigen-matched donor (father) underwent resection of 200 cm of the ileum on a vascular pedicle comprising the ileocolic artery and vein. This resection left the donor with 300 cm of proximal small bowel, 20 cm of the most distal terminal ileum, the ileocecal valve, and all of the large intestine. The donor's ileocolic artery and vein were anastomosed to the recipient's infrarenal aorta and cava; bowel continuity was restored with an end-to-end anastomosis between the recipient's jejunum and the donor's ileum. Both donor and recipient had uneventful postoperative courses. Recipient maintenance immunosuppression has been with tacrolimus, mycophenolate mofetil, and prednisone. One year after transplant, urine methylmalonic acid indicates good vitamin B12 absorption in both the donor and recipient. The recipient has been completely off TPN since discharge (posttransplant day 21), has gained 20 kg, and has had no evidence of rejection, infection, or graft-versus-host disease., Conclusions: Intestinal transplants from living-related donors can be lifesaving for selected patients with chronic intestinal failure and can be done with minimal risk to the donor.

Background: Endoscopic variceal ligation is the initial treatment of choice in the management of esophageal varices. Few reports include its use in the pediatric population. We review our experience with this therapeutic modality in pediatric patients with end stage liver disease and esophageal varices., Methods: We reviewed the medical records of pediatric patients with end stage liver disease who underwent endoscopic variceal ligation from January 1994 until December 1996., Results: Thirty-two endoscopic variceal ligation procedures were performed in six pediatric patients during the period of study. In all patients, the esophageal varices classification was improved at the end of treatment. Only one patient had an episode of bleeding from esophageal varices during the period of study; only one patients had a complication associated with endoscopic variceal ligation., Conclusions: Endoscopic variceal ligation is feasible, safe, and effective for the management of esophageal varices in pediatric patients with end stage liver disease.

Bile duct cells (BDCs), especially intrahepatic cholangiocytes, are primary targets of immune-related injury in such pathologic processes as liver graft rejection, liver graft-versus-host disease, and primary sclerosing cholangitis. Cholestasis and progressive loss of intrahepatic BDCs indicate chronicity in these diseases. The present investigation characterizes the acquisition of immune markers of intrahepatic BDCs isolated from mice after bile duct ligation. Purified BDCs from cholestatic C57BL/6 (H-2b) mice express not only the major histocompatibility complex (MHC) class I and class II antigens but also the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The expression of the MHC class II molecules on BDCs before and after interferon (IFN)-gamma exposure is also demonstrated by immunohistochemistry on the cultured cells. Cytotoxicity assays indicate the vulnerability of these cells as targets for immunologic injuries. Effector cells generated from B10.BR splenocytes (H-2k) against C57BL/6 splenocytes (H-2b) show comparable killing of BDCs and EL4 cells, the latter being a lymphoma line that was established from the C57BL/6N (H-2b) mouse. An immortalized mouse BDC line (IBDC) is included in this study to validate some of the findings from BDCs isolated from bile duct-ligated mice. We suggest that cholestatic BDCs express surface antigens different from those of normal epithelial cells that result in increased susceptibility to damage by immune mechanisms.

Protoporphyria is a genetic disorder in which patients may develop severe protoporphyrin-induced liver damage and require transplantation. Because unique problems occur in the perioperative period and because excess production of protoporphyrin by the bone marrow continues after liver transplantation, the efficacy of this procedure for protoporphyric liver disease is uncertain. We present follow-up of nine patients who underwent liver transplantation. Two patients died within 2 months of transplantation, one from complications of abdominal bleeding and the other from sepsis after bowel perforations. The remaining seven patients had follow-up at 14 months to 8 years after transplantation (mean, 3.8 years). Two of the seven had suffered skin burns from exposure to operating room lights, which healed without scarring. Three had axonal neuropathies in the postoperative period requiring prolonged mechanical ventilation, and motor defects persisted in two. Five patients had normal liver chemistries at follow-up (mean, 3.5 years), with liver biopsy results normal or showing mild portal triad abnormalities, but erythrocyte protoporphyrin levels remained significantly elevated (1,765 +/- 365 mcg/dL; normal, < 65). The other two patients, both of whom had rejection, cytomegalovirus infection, and biliary tract obstruction requiring endoscopic therapy, had a recurrence of protoporphyric liver disease as indicated by liver biopsy features. One died 5 years after transplantation from complications of the liver disease. The other was stable 3.3 years after transplantation and was being monitored for possible retransplantation. Thus, liver transplantation can be performed successfully in patients with protoporphyric liver disease, with intermediate survival rates comparable to the general transplant population. However, disease may recur in the graft, particularly if there are complications that cause cholestasis.

Freshly harvested rat hepatocytes form spheroids on uncoated positively charged polystyrene surfaces. Time lapse microscopy revealed that cell movement and reorganization were involved in spheroid formation. Ultrastructural evaluation using scanning and transmission electron microscopy indicated polarized cellular morphology and extensive cell-cell communication within spheroids. Bile canalicular structures were observed to surround each individual hepatocyte, forming an intricate three-dimensional continuous network of channels that appeared to end as pores/holes on the surface of the spheroid. The maintenance of differentiated cellular morphology coincided with preservation of hepatocyte viability and enhanced levels of tissue specific functions in spheroids.

Wilson's disease, genetic and neonatal hemochromatosis, protoporphyria, tyrosinemia, and alpha1-antitrypsin deficiency are updated. Cost effectiveness of screening is discussed. Current therapies are evaluated, including the role of transplantation. The molecular biologic technique PCR is covered. Gene therapy is introduced.

Objective: To describe our experience with cystic fibrosis (CF)-associated colitis and fibrosing colonopathy, and to assess treatment strategies., Study Design: We reviewed hospital charts and autopsy reports of all University of Minnesota patients with CF between 1975 and August 1994. We identified six patients with colonopathy and compared them with a cohort of 79 patients with CF in the same age range and seen during the same period., Results: All patients with colonopathy had bloody diarrhea; five of the six had abdominal pain. Stool frequency and related symptoms distinguished the patients with colonopathy from the cohort population. All took a higher median dose of pancreatic enzymes than the cohort population during the 3 months preceding the onset of symptoms (p < 0.002). For all six patients, barium studies revealed loss of haustration, and shortening and diffuse narrowing of the colonic lumen with relative rectal sparing. The distal ileal mucosa was irregular in four patients. A histopathologic study reveal fibrosis of the submucosa or lamina propria, and focal acute cryptitis in all six patients. Other features included ascites (2/6) and nodular regenerative hyperplasia of the liver (1/6). One patient continues to have symptoms, three had subtotal colectomy, and the condition of two improved after a regimen including a low-fat diet, withholding of pancreatic enzymes, and supplemental parenteral nutrition was initiated., Conclusions: Fibrosing colonopathy represents a newly recognized gastrointestinal complication of cystic fibrosis. Affected persons have taken larger doses of pancreatic enzymes than similar patients with cystic fibrosis, and have bloody diarrhea. We developed a medical protocol that may avoid surgical resection of the colon in some of these patients.

The clinical findings in 33 patients with progressive familial intrahepatic cholestasis (PFIC) are presented. Symptoms developed almost invariably before 6 months of age with severe pruritus and moderate jaundice. Other clinical findings included wheezing and nosebleeds, fat-soluble vitamin deficiency states, and cholelithiasis. Lower values for gamma-glutamyl transpeptidase, averaging 15 IU/L before the administration of phenobarbital, and cholesterol, which averaged 156 mg/dl, are helpful in distinguishing PFIC from other pediatric cholestatic liver diseases. Autosomal recessive inheritance is probable. Twenty-six patients are alive at 12.9 +/- 6.7 years of age, all having had successful surgical treatment, either partial biliary diversion (n = 17) or orthotopic liver transplantation (n = 10). Seven patients died at a mean age of 3.9 +/- 2.4 years, as a result of liver failure in two, hepatocellular carcinoma in two, and complications of liver transplantation in three.

Purpose: It has been stated that arteriohepatic dysplasia is a form of biliary paucity with a good prognosis. We wished to determine the long-term morbidity and mortality associated with arteriohepatic dysplasia., Patients and Methods: The charts of all patients with arteriohepatic dysplasia followed by the pediatric gastroenterologists of the University of Minnesota into adulthood were reviewed., Results: Over the last 33 years, the pediatric gastroenterologists have followed 16 children with syndromic paucity, six of whom are now beyond age 18 years. Although five of six patients responded to medical therapy with improvement in their cholestasis and appeared stable clinically through childhood, five of six patients had complications of arteriohepatic dysplasia after age 16 years that resulted in severe morbidity (three) or death (two). These complications included hepatic failure (two), renal failure (one), cerebellar herniation (one), and hepatocellular carcinoma (one). In only one patient were symptoms of the complications present prior to the age of 18 years., Conclusion: As more patients with arteriohepatic dysplasia reach adulthood, it appears that this syndrome may be accompanied by long-term manifestations extending beyond childhood. It is important that physicians assuming management of these patients from pediatricians be aware that new abnormalities may appear without warning and that the hepatic disease may deteriorate despite apparent stability through childhood.

Women with severe liver disease often have amenorrhea that resolves as liver disease abates. We describe three patients with mild to moderate chronic liver disease and amenorrhea. In each case amenorrhea resolved when spironolactone therapy was discontinued. We suggest that spironolactone, an androgen inhibitor, may also cause reversible amenorrhea.

To further define the clinicopathologic spectrum and pathogenetic mechanism of the nephropathy associated with alpha 1-antitrypsin (A1AT) deficiency, we evaluated renal specimens from 34 patients with chronic hepatic disease, including 20 with A1AT deficiency (study patients), and correlated these findings with urinalysis evaluation. Glomerular lesions were noted in 79% (15 of 19) of A1AT patients with the PiZZ phenotype, including seven with mesangio-capillary glomerulonephritis (MPGN and focal segmental MPGN), six with mesangial proliferative glomerulonephritis (Mes GN), one with diffuse endocapillary proliferative glomerulonephritis (DPGN), and one with focal segmental mesangial proliferative glomerulonephritis with segmental necrosis (FS Nec GN). One A1AT patient with the PiMZ phenotype did not demonstrate glomerular abnormalities. Focal segmental Mes GN was found in 43% (six of 14) of patients in an age-matched group with chronic hepatic failure unrelated to A1AT deficiency. In nine study patients, glomerular pathology was noted in the presence of a normal urinalysis. Immunofluorescence studies revealed the presence of immunoproteins and the A1AT protein isoelectric forms, PiM and PiZ, in the subendothelial region of glomerular basement membranes in A1AT patients with MPGN, Mes GN, and DPGN. Our results emphasize the heterogeneity of glomerular lesions associated with A1AT deficiency and hepatic disease and the relatively high incidence of MPGN in these children. The presence of abnormal PiZ protein in the subendothelial region of the glomerular basement membrane in A1AT patients with glomerulonephritis suggests a possible role for this protein in the pathogenesis of this lesion.

Liver transplantation is now accepted as the treatment of choice for tyrosinemia type I (hereditary tyrosinemia). In an effort to determine whether any factors in these patients would aid in predicting optimal timing of the transplant procedure, we evaluated several clinical, biochemical, and radiographic parameters in five successive patients undergoing liver transplant for tyrosinemia type I at the University of Minnesota. All five patients evidenced prolonged periods of clinical and metabolic stability with dietary therapy and four of five remained stable at the time of evaluation for transplantation. Nevertheless, all five suffered significant and unexpected complications of tyrosinemia prior to the time of liver transplant. Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant. We could identify no clinical, biochemical, or radiographic study that was predictive of the likelihood of significant complications of the disorder. Survival from the transplant procedure itself was 100%. The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.

In an effort to better understand chronic liver transplant rejection, we studied 110 children and adults who survived for at least 2 mo after the transplant procedure. Chronic rejection was defined using a combination of clinical and histopathological criteria and was diagnosed in 10 of the 110 patients for an incidence of 9.1%. All 10 patients were children with the mean age 3.4 yr vs. 21.7 yr for patients without chronic rejection (p less than .001). Males and females were equally represented, and nine received a liver from a gender-matched donor. Four patients were non-Caucasian, resulting in an incidence of 21.7% in non-Caucasian recipients vs. 6.6% in Caucasian recipients (p less than .05). All chronic rejection patients received a liver from an ABO-compatible donor. T-cell crossmatch was negative in all patients in whom it was assessed, and no significant disparity in either the class I or class II human leukocyte antigen loci was noted. Patients who had chronic rejection experienced acute rejection earlier, 11 days vs. 16 days (p less than .05), than patients who did not. In 8 of 10 patients, chronic rejection appeared to evolve directly from early episodes of acute rejection that were unresponsive to immunosuppressive therapy. Two distinct histological presentations were noted. One was progressive loss of bile ducts without hepatocellular injury (four patients), and the other was characterized by worsening ischemic hepatocellular damage and fibrosis (six patients) in addition to severe ductular injury. The first was associated with a more benign clinical course, the second with rapidly deteriorating hepatic function. Three patients recovered spontaneously 9 to 14 mo after transplant, one died awaiting a donor for retransplant, and five had retransplants. We conclude that chronic rejection after the operation is a relatively uncommon complication of liver transplantation with a variable clinical course and unpredictable outcome.

We reviewed the clinical presentation, subsequent course, and outcome of 98 patients with alpha 1-antitrypsin deficiency seen at our institution during the past 20 years to obtain answers to the following questions: (1) What prognostic factors aid in determining the course of liver disease in affected patients? (2) When is the appropriate time for referral to a liver transplant center? (3) Does breast-feeding prevent chronic liver disease? (4) What is the incidence of severe liver disease in family members? Our analysis revealed that the initial values of alanine aminotransferase, prothrombin time, and trypsin inhibitory capacity may have prognostic value. During clinical follow-up the recurrence or persistence of hyperbilirubinemia along with deteriorating results of coagulation studies indicated the need for liver transplantation because of imminent poor outcome. Girls had a worse prognosis than boys. Initial breast-feeding versus feeding of commercial formulas did not influence overall overcome. The incidence of significant liver disease among "at risk" siblings was 21% (3/14); if one assumes mendelian inheritance from heterozygous parents, the overall risk for siblings in our families was 5%.

The source of population renewal for Kupffer cells (KC), the major antigen-presenting cells of the liver, remains controversial. Using a well-described murine bone marrow transplantation (BMT) model in which the donor and recipient are disparate at the major histocompatibility complex (MHC), we have studied (a) the source of KC renewal by genotypic analysis, cell surface (class II or Ia) antigens, and immune function assays; (b) the level of KC Ia expression post-BMT in transplant recipients; and (c) the capacity of newly repopulating KC to present antigen to an Ia-restricted T cell clone of donor Ia type. Kupffer cell engraftment, as assessed by each of these three methods, was noted to be predominantly of donor marrow origin by day 21 post-BMT. Cell surface Ia expression was comparable to that of nontransplanted controls of the same strain as donor mice. Within 7 days post-BMT, KC were mature antigen-presenting cells. We conclude that KC rapidly repopulate the liver from donor bone marrow post-BMT, and these macrophages are able to interact with T lymphocytes in an immunocompetent manner.

The asymptomatic course of two adolescents with hepatobiliary complications of inflammatory bowel disease are reported. As has previously been documented in adult patients, liver biopsy and cholangiography of the biliary tree are indicated procedures when the cholestatic enzymes are elevated in children with colonic involvement.

alpha 1AT deficiency predisposes children to liver injury and adults to emphysema. Pi typing has clarified that the inherited deficiency is codominant. Amniocentesis is unproved as a reliable technique in detecting the homozygous deficient patient (another controversial issue). Even if this procedure were to become diagnostic, present knowledge cannot predict the clinical course of each individual born with homozygous alpha 1AT deficiency, therefore confronting the physician and parents with a moral dilemma that neither of us feels comfortable with in regard to family counseling. Presently, we can only educate the family with the current state of the art summarized in this review. The fundamental steps in evaluating a child and the involved family are outlined in Table 2. Steps 1, 2 and 5 should be readily available. Pi typing can specifically identify susceptible individuals who can be counseled concerning work habits and known toxins such as smoking and alcohol. Liver biopsy is not essential for diagnostic purposes but may prove to be prognostic concerning the child's ultimate outcome. More certain is the evidence that no infant should be explored for a bile duct lesion during the early cholestatic period because no surgical lesion will be found. Therefore, all children with infantile cholestasis should be evaluated for alpha 1AT deficiency prior to a laparotomy. Although medical therapy is only supportive at the present time, further research should eventually provide therapeutic approaches to the basic defect.

An enzyme assay was developed to measure the conversion of the bile acid precursor, 3alpha, 7alpha, 12alpha-trihydroxy-5beta-cholestan-26-oic acid (THCA), into cholic acid using homogenates of human liver biopsies. The average rate of metabolism of THCA into cholic acid was found to be 3.9 +/- 0.5 (+/- 1 SD) pmoles of cholic acid formed/mg liver/minute in twelve normal liver biopsies. This assay system can be used to determine if the syndrome of neonatal cholestasis associated with a metabolic block in the conversion of THCA into cholic acid is transmitted as a genetic trait.

The observation of vacuolated lymphocytes in a coarsely featured two year old female with hepatosplenomegaly, mitral insufficiency, and mild psychomotor retardation led to the first diagnosed case of aspartylglucosaminuria in the United States. Although physical characteristics and bone roentgenograms were consistent with a mucopolysaccharide disorder, analysis of the urine showed no mucopolysaccharide elevation. The chromatographic, enzymatic, and ultrastructural studies confirming the diagnosis are presented.

In a randomized trial we studied the impact of providing total parenteral nutrition (TPN) to bone marrow transplant (BMT) patients during their cytoreductive therapy, and for 4 weeks following BMT, on 8 parameters of outcome. A total of 137 patients over 1 year of age and with normal nutritional status were randomized either to receive TPN starting one week prior to transplant or to receive hydration with a 5% dextrose solution containing electrolytes, minerals, trace elements, and vitamins. TPN was ultimately required by 40 of the 66 control patients when nutritional depletion was documented. Average total calorie and protein intake was significantly higher for the TPN group than for the control group. Minimum follow-up was 1 year and median was 2 years. Overall survival, time to relapse, and disease-free survival were significantly improved in the TPN group. Engraftment, duration of hospitalization, and incidences of acute and chronic graft-vs.-host disease and bacteremia were not different. Thus TPN during BMT had a positive effect on long-term outcome. Prophylactic nutritional therapy appears to be indicated even for well-nourished individuals during cytoreduction and BMT.

In 84 consecutive patients with cystic fibrosis, oral cholecystography was abnormal in 39 (46.4%). The incidence of abnormal cholecystograms increased with patient age. The 26 patients with a nonvisualized gallbladder following double-dosage oral cholecystography were evaluated with intravenous cholangiography; 19 (70.3%) of these were abnormal. Ten patients were found to have calculi, an incidence of 11.9%. Awareness of the high incidence of cholecystographic abnormalities and calculi should be helpful in the evaluation of patients with cystic fibrosis, particularly since symptoms of abdominal pain are frequent in such patients and may lead to radiographic investigations.

Severe hypoproteinemia often accompanies the development of graft-versus-host disease of the intestine in allogeneic bone marrow transplant patients. To determine whether or not protein loss occurs across the intestinal mucosa in this severe diarrheal illness, we measured fecal alpha 1-antitrypsin once per week in 24-h stool specimens from 25 consecutive patients during hospitalization for bone marrow transplantation. The mean alpha 1-antitrypsin concentration and serum clearance for these patients before transplantation were below 2.6 mg/g stool and 13.0 ml/day (upper limits for normals). Values for all patients increased moderately after pretransplant conditioning. Values for patients who did not develop graft-versus-host disease of the intestine returned to baseline levels; however, those for patients with graft-versus-host disease of the intestine became markedly and persistently elevated (concentration ranged from 16.6 to 51.1 mg/g, clearance from 66.6 to 384.5 ml/day). We conclude that mucosal protein exudation contributes to the hypoproteinemia of graft-versus-host disease of the intestine and that measurement of fecal alpha 1-antitrypsin can be used as a marker for this disease.

The histopathological features of orthotopic liver transplants were evaluated in 63 serial biopsy specimens from 17 patients. Biopsies were taken at the time of insertion of the liver (six biopsies), at the time of development of liver function abnormalities (11 biopsies) and as follow-up to previously abnormal biopsies (46 biopsies). The biopsies taken at the time of insertion all showed diffuse hepatocellular ballooning with confluent areas of necrosis in one case. Biopsies taken at the time of onset of rejection (nine cases) all showed a mixed portal inflammatory infiltrate, bile duct damage and central or portal vein endothelialitis (i.e., attachment of lymphocytes to the vein endothelium). Follow-up biopsies showed several patterns including: (i) resolution of changes of acute rejection with subsequent development of recurrent acute or chronic rejection (four cases); (ii) prolonged acute rejection simulating extrahepatic biliary obstruction (four cases); (iii) prolonged acute rejection with predominance of eosinophils simulating a drug reaction (one case); and (iv) rapidly progressive acute rejection leading to death (one case). Biopsy of the transplanted liver at the time of transplantation is useful to provide a baseline for comparison with later biopsies. Biopsy at the time of onset of changes in liver function is essential to confirm the presence of rejection prior to alteration of immunosuppression.

The cellular changes that take place as the intestinal cell migrates from crypt to villus are morphologically and biochemically remarkable. It is fortunate that many of these phenomena can be delineated by following enzymic activities. Sucrase-isomaltase is a particularly fascinating enzyme complex because it is a marker of the differentiated cell. Sucrase is inducible with steroids and protected by the substrate sucrose. Purified enzyme can be used to stimulate production of specific antibodies in goats; these antibodies have been used as probes to locate enzymically active and inactive antigen in the cells of the crypt and villus respectively. Further examination of the enzyme has indicated a molecular weight of 200 000--350 000. These higher molecular weight components are located in the brush border of the enterocytes. Lower molecular weight subunits are antigenically active and are in the cytosol. It is assumed that these smaller components are enzymically inactive pre-combination subunits of the sucrase-isomaltase complex and that the sucrase-isomaltase of the brush border is an aggregate of these subunits. The California sea lion, which is deficient in intestinal sucrase activity, does have isomaltase activity. This finding supports the concept that there are different gene complexes for sucrase and for isomaltase.