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J C Iezzoni

Publications and source records attributed to J C Iezzoni.

At least 19 recordsLinked to original sources
PubMed2001

A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.

OBJECTIVES: Troglitazone is a thiazolidinedione and peroxisome proliferator-activated receptor gamma (PPARgamma) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market. METHODS: We studied 10 female patients (age 44 +/- 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 +/- 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for < or = 6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy. RESULTS: Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 +/- 38 before to 39 +/- 9 at the end of treatment (p = 0.01), and AST decreased from 77 +/- 23 to 30 +/- 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy. CONCLUSIONS: Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.

Adult↗
PubMed2001

Nonneoplastic endometrial signet-ring cells. Vacuolated decidual cells and stromal histiocytes mimicking adenocarcinoma.

We describe 5 patients (mean age, 50 years; all had uterine bleeding) whose routine endometrial biopsy and curettage specimens contained prominent signet-ring cells. Each specimen contained loose aggregates of signet-ring cells scattered within the endometrial stroma that were characterized by peripherally displaced, small, uniform nuclei with indistinct nucleoli and showed no mitotic activity. The central portion of the cytoplasm was occupied by single or multiple cytoplasmic vacuoles. In all cases, the signet-ring cells were reactive for vimentin and negative for epithelial membrane antigen and cytokeratin. Four cases were focally positive for muscle-specific actin or smooth muscle actin and negative for CD68, Mac387, periodic acid-Schiff, mucicarmine, and alcian blue. In these 4 cases, the surrounding endometrial stroma showed decidual changes, and the signet-ring cells demonstrated a morphologic continuum with more typical decidualized stroma. As such, the signet-ring cells in these cases were vacuolated, decidualized endometrial stromal cells. In the remaining case, the vacuolar contents of the signet-ring cells were periodic acid-Schiff-positive and resistant to diastase predigestion, and the cells reacted with Mac387 and CD68. The surrounding stroma showed no decidual reaction. Thus, the signet-ring cells in this case were of histiocytic differentiation. Endometrial stroma occasionally may contain nonneoplastic signet-ring cells that closely mimic adenocarcinoma. At least 2 directions of differentiation, decidual and histiocytic, are possible.

Adenocarcinoma↗
PubMed2000

Prediction of liver allograft fibrosis after transplantation for hepatitis C virus: persistent elevation of serum transaminase levels versus necroinflammatory activity.

Recurrence of hepatitis C virus (HCV) after orthotopic liver transplantation (OLT) remains a significant source of morbidity and mortality. Factors that reliably predict allograft injury from HCV have not been identified. Demographics, clinical data, and histopathological characteristics of recipients with and without persistently elevated serum transaminase levels (PEST) were compared. Twenty-four patients with HCV-induced end-stage liver disease who underwent OLT between October 1995 and December 1998 were entered into a longitudinal, prospective evaluation for identification of parameters associated with graft injury. Liver biopsies were performed preoperatively and between posttransplantation days 1 to 28, 29 to 60, 61 to 180, 181 to 360, and then every 6 to 12 months thereafter. Biopsy specimens were reviewed in a blinded fashion and scored for rejection, necroinflammatory activity, extent of fibrosis, and infiltrating cell type, location, and magnitude. Transplant recipients with PEST (alanine transaminase level >1.5 times normal for 3 consecutive months) and cholestatic hepatitis showed an increased viral load compared with their own preoperative values (16-fold and 256-fold, respectively). Compared with control transplant recipients, PEST was associated with macrovesicular steatosis within 28 days after OLT (P <.05) and showed an increased rate of fibrosis (P <.003) despite similar degrees of rejection and necroinflammatory activity. There was no difference in demographics or immunosuppression. Macrovesicular steatosis may be the earliest predictor of graft fibrosis. Despite similar degrees of necroinflammatory activity, transplant recipients with PEST had an increased rate of fibrosis that could be predicted on average within 6 months posttransplantation.

Alanine Transaminase↗
PubMed2000

Pretransplantation hepatitis C virus quasispecies may be predictive of outcome after liver transplantation.

The evolution of hepatitis C virus (HCV) envelope variation was studied using a liver-transplant model to evaluate the role of HCV quasispecies for hepatocyte infection. Twelve HCV polymerase chain reaction (PCR)-positive liver-transplant recipients (6 with posttransplantation biochemical hepatitis and 6 without hepatitis [controls]) were prospectively evaluated and underwent detailed quasispecies analysis of pre- and postoperative serum samples. HCV amino acid sequence diversity and complexity at the first hypervariable region (HVR1) of the second envelope protein (E2) was correlated with outcome. Recurrence of HCV-induced allograft injury was defined by persistently elevated serum alanine transaminase (ALT) levels. The major variant (sequences >10% of all clones) of recipients with hepatitis accounted for a significantly smaller percent of all preoperative clones compared with controls (41% +/- 6% vs. 69% +/- 8%; P <.015). Recipients with hepatitis had an increased number of pretransplantation major variants (2.5 +/- 0.3 vs. 1.1 +/- 0.2; P <.006). Eighty-three percent of controls had a predominant variant (accounting for >50% of clones) compared with 17% of those with recurrence (P <.05). These differences did not persist postoperatively. In addition, recipients without a pretransplantation predominant variant demonstrated an increased allograft fibrosis score (2.3 +/- 0.3 vs. 0.5 +/- 0.3; P <.015) at 181 to 360 days posttransplantation compared with those in whom a predominant variant was present. Increased HCV envelope complexity may act as a stronger antigenic stimulus or improve hepatocyte receptor binding and lead to allograft hepatitis and fibrosis. Although pretransplantation differences in HCV quasispecies did not persist postoperatively, pretransplantation quasispecies may be a predictor of HCV-induced hepatitis and graft fibrosis after liver transplantation.

Adult↗
PubMed2000

Hepatitis C-induced hepatic allograft injury is associated with a pretransplantation elevated viral replication rate.

Hepatitis C virus (HCV) allograft infection after liver transplantation follows a variable but accelerated course compared with the nontransplantation population. Predictors of outcome and mechanisms of reinfection remain elusive. The accelerated HCV-induced allograft injury associated with a 10- to 20-fold increase in serum viral quantity posttransplantation was hypothesized to be the result of elevated intrahepatic viral replication rates. Patients (N = 23) with HCV-induced end-stage liver disease who underwent liver transplantation between October 1995 and December 1998 were prospectively studied. HCV-induced allograft injury was defined by posttransplantation persistent biochemical hepatitis or allograft fibrosis not explained by other diagnoses. Liver biopsies (N = 92) were obtained by protocol and when clinically indicated. Negative-strand HCV RNA (putative intermediate for replication) was detected by a strand-specific reverse-transcription polymerase chain reaction (RT-PCR) assay and semiquantatively compared with constitutively expressed 18S rRNA. Recipients with increased pretransplantation replication were at increased risk for the development of posttransplantation biochemical hepatitis (P =.03), an increased rate of allograft fibrosis (P =.006), and increased mortality rate (40.0% vs. 0.0%; P =.02). There was no correlation with quantities of genomic HCV RNA in the serum with relative intrahepatic viral replication either before or after liver transplantation. The relative rate of HCV replication within the allograft was not elevated in the posttransplantation period compared with that seen within the explanted liver. Accelerated allograft injury caused by HCV may be predicted by viral replication rates within the explanted liver. The stable intrahepatic replication rate after transplantation suggests that elevated serum viral loads are the result of decreased viral clearance, possibly secondary to immunosuppressive therapy.

Adolescent↗
PubMed1999

Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.

We characterized 70 consecutive patients with cryptogenic cirrhosis to assess major risks for liver disease. Each patient was reevaluated for past alcohol exposure, scored by the International Autoimmune Hepatitis (IAH) score and assessed for viral hepatitis risks and risks for nonalcoholic steatohepatitis (NASH). The results were compared with 50 consecutive NASH patients, 39 nonalcoholic patients age 50 and over with cirrhosis from hepatitis C, and 33 consecutive patients with cirrhosis caused by primary biliary cirrhosis (PBC). Among the cryptogenic group, 49 (70%) were female, and the mean age was 63 +/- 11 years. Although ascites and variceal bleeding were common, almost one half lacked major signs of complicated portal hypertension. A history of Type 2 diabetes mellitus and/or obesity was present in 51 (73%). Nineteen (27%) patients had a history of blood transfusions antedating the diagnosis of cirrhosis. No clinical or histological features distinguished this group from the other patients, and 14 (74%) of these had a history of obesity and/or diabetes. Nineteen of the remaining nontransfused patients had indeterminant IAH scores but were histologically and biochemically indistinguishable from the others. Twelve of these (63%) also had a history of obesity and/or diabetes. Both diabetes and obesity were significantly more common in the cryptogenic cirrhotic patients compared with the cirrhotic patients with PBC or hepatitis C. In contrast, the prevalence of obesity and diabetes was similar to the NASH patients who were, on average, a decade younger. Although there is some diversity that indicates more than one cause, our findings suggest that NASH plays an under-recognized role in many patients with cryptogenic cirrhosis, most of whom are older, type 2 diabetic and obese females.

Adult↗
PubMed1999

Mitochondrial abnormalities in non-alcoholic steatohepatitis.

BACKGROUND/AIMS: We assessed mitochondrial morphology by electron microscopy and the prevalence of a mitochondrial gene deletion in patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease and non-fatty liver diseases. Respiratory chain function using a cytoplasmic hybrid (cybrid) assay was further studied in NASH patients and healthy controls. METHODS: Electron microscopy was performed in 26 specimens. Fifteen patients were studied by polymerase chain reaction to detect a 520-bp deletion product of the mitochondrial genome (dmtDNA). Cybrids were created by fusion of platelets with anaerobic neuroblastoma cells in six NASH patients and 12 controls. RESULTS: Eight of ten NASH, one of seven alcoholics and two of nine other patients had linear crystalline inclusions in megamitochondria (p<0.05). Three of five patients with alcohol-related liver disease had dmtDNA compared to one of five NASH patients and one of five non-steatohepatitis controls. Cybrid respiratory chain function in platelets was not different from that of controls. CONCLUSIONS: Respiratory chain dysfunction, if present in NASH, is not expressed in platelet-derived mitochondria. In contrast to alcohol-related liver disease with active drinking, NASH patients do not commonly express the 5-kb mitochondrial DNA gene deletion in liver tissue. As previously described in early alcohol-related liver disease, crystalline inclusions of unknown composition are seen in hepatic mitochondria in NASH. Their presence suggests either an adaptive process or mitochondrial injury.

Adult↗
PubMed1999

Inhibin is not an immunohistochemical marker for hepatocellular carcinoma. An example of the potential pitfall in diagnostic immunohistochemistry caused by endogenous biotin.

Inhibin is a heterodimeric glycoprotein originally detected in gonadal tissues. One report described inhibin immunopositivity in 17 of 19 hepatocellular carcinomas (HCCs) and the hepatocytes of the surrounding nonneoplastic parenchyma. The reported immunohistochemical method, which used avidin-biotin complex, did not describe blocking endogenous biotin. Since liver tissue may contain high levels of biotin, endogenous biotin may result in false-positive immunostaining. We wondered whether this reported immunopositivity represented a false-positive result due to unblocked endogenous biotin. By using a similar antigen retrieval technique and the same specificity, titer, and clonal source of primary antibody as the aforementioned study, we performed immunostaining for inhibin with and without an endogenous biotin blocking step on 23 cases of HCC and the surrounding cirrhotic liver. In all cases, the HCC and the hepatocytes in the cirrhotic nodules were negative for inhibin when the endogenous biotin blocking step was used. When the blocking step was omitted, apparent immunostaining was noted in 20 of 23 HCCs and in the hepatocytes in all cases. Accordingly, HCC and the hepatocytes of the surrounding cirrhotic liver are immunohistochemically negative for inhibin. The previously reported immunopositivity of HCC and nontumoral hepatocytes for inhibin represents a false-positive result due to endogenous biotin.

Biomarkers↗
PubMed1998

Expression and specific immunolocalization of the human parathyroid hormone/parathyroid hormone-related protein receptor in the uteroplacental unit.

OBJECTIVE: Our purpose in these studies was to determine the expression and cellular localization of the parathyroid hormone/parathyroid hormone-related protein receptor in the human uteroplacental unit. STUDY DESIGN: Human uteroplacental tissues were obtained and ribonucleic acid was extracted. Reverse transcriptase-polymerase chain reaction was performed with use of primers for both the parathyroid hormone/parathyroid hormone-related protein receptor and human phosphoglyceraldehyde dehydrogenase. Ethidium bromide-stained gels and Southern blots were evaluated, and polymerase chain reaction fragments were sequenced. For immunohistochemistry, slides were incubated with a newly developed antibody (3D1.1) specific for the parathyroid hormone/parathyroid hormone-related protein receptor, and bound monoclonal antibody was detected by use of the avidin-biotin technique. RESULTS: Reverse transcriptase polymerase chain reaction gels and blots showed that receptor messenger ribonucleic acid was present in choriodecidua, placenta, and myometrium. Sequence analysis revealed complete identity of the receptor product and the known nucleotide sequence in the receptor. There was intense receptor staining of the myometrial smooth muscle as well as staining of the endothelium and smooth muscle of the associated vasculature. In umbilical cord immunoreactive receptor was found in the vascular endothelium and vascular smooth muscle cells and in stromal cells. In choriodecidua receptor was found in chorionic trophoblasts and decidualized endometrial stromal cells. In all tissues immunostaining was specific, as evidenced by the blocking of staining after addition of receptor peptide to the antibody (absorbed controls). CONCLUSION: The parathyroid hormone/parathyroid hormone-related protein receptor is widely expressed in the human uteroplacental unit. The cellular localizations of the receptor in smooth muscle reflect the ability of parathyroid hormone-related protein to relax both uterine and vascular smooth muscle. The presence of novel autocrine and paracrine systems in the human uteroplacental unit is suggested by the finding that the same cells or adjacent cells produce both parathyroid hormone-related protein and its receptor.

Cells, Cultured↗
PubMed1998

Coexpression of parathyroid hormone-related protein and its receptor in breast carcinoma: a potential autocrine effector system.

Parathyroid hormone-related protein (PTHrP), the pathogenic factor in most cases of humoral hypercalcemia of malignancy, is also expressed by many normal tissues. Its diverse biologic activities in these tissues are mediated by the PTH/PTHrP receptor through autocrine and paracrine mechanisms. Recent data suggest that PTHrP and its receptor might also influence the growth and metastatic spread of some cancers through similar local actions. Accordingly, immunohistochemical studies using murine monoclonal antibodies to detect coexpression of PTHrP and the PTH/PTHrP receptor were performed on 52 invasive breast carcinomas to assess the existence of this potential autocrine effector system. All of the 52 invasive breast carcinomas expressed reactivity for PTHrP, and 50 (96%) of these tumors also expressed reactivity for the receptor. Although additional investigations are necessary for evaluation of the role of PTHrP and PTH/PTHrP receptor in tumor pathogenesis, our current study demonstrates the presence of this potential autocrine effector system in the great majority of invasive breast carcinomas.

Adult↗
PubMed1997

Pancreatic adenocarcinoma in the pregnant patient: case report and review of the literature.

BACKGROUND: In this case report, the authors discuss the presentation and treatment of pancreatic adenocarcinoma in a pregnant woman. Pancreatic adenocarcinoma is extremely rare in the pregnant patient. Only three cases of pancreatic adenocarcinoma diagnosed antepartum have been reported. METHODS: A case report and a review of the literature are reported. RESULTS: The authors report a case of pancreatic adenocarcinoma in a pregnant woman at 17 weeks' gestation. Endoscopic retrograde cholangiopancreatography with stent placement and a pancreaticoduodenectomy were performed successfully. CONCLUSIONS: Pancreatic adenocarcinoma is very rare in the pregnant patient. However, pancreaticoduodenectomy can be performed successfully. To the authors' knowledge, this is the first report of a pregnant woman treated with pancreaticoduodenectomy for pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Predictive value of intraoperative biopsies and liver function tests for preservation injury in orthotopic liver transplantation.

Eighty liver allografts were studied to determine the predictive value of intraoperative biopsies and postoperative liver function tests for the development of preservation injury (PI). Peak transaminase (aspartate transaminase [AST] and alanine transaminase [ALT]) and prothrombin time (PT) values achieved by each patient during postoperative days (POD) 1 through 7 were determined. PI in day 0 preperfusion biopsies (0Pre) (obtained immediately before implantation) and postperfusion biopsies (0Post) (obtained immediately after revascularization) was categorized by histological criteria as present or absent. PI in biopsies taken during POD 2 through 14 was histologically graded as either moderate-to-severe, mild, or absent. Of the 80 allografts, 8 were omitted because of primary nonfunction or postoperative complications. 0Pre and 0Post biopsies were available on 25 of 72 (35%) and 69 of 72 (96%) allografts, respectively. Only 2 (8%) of the 0Pre biopsies showed histological PI compared with 48 (70%) of the 0Post biopsies. Fifty-nine patients were biopsied between POD 2 through 14. Of these, 15, 28, and 16 patients developed moderate-to-severe, mild, or no evidence of PI, respectively. The presence of PI in the 0Post biopsy strongly correlated with the development of PI during POD 2 through 14 (P < .0005). Peak AST and ALT values in patients with moderate-to-severe PI on POD 2 through 14 were significantly elevated compared with those patients with either mild (P = .01 and .03) or no PI (P = .02 and .006). Because of extensive overlap in AST and ALT values between the three groups, however, transaminase values were not useful in predicting the presence or absence of PI in the individual case. The development of PI during POD 2 through 14 correlated with advanced donor age (P = .06) but was unassociated with 0Pre biopsy findings, cold ischemia time, or peak PT values. We conclude that the 0Post biopsy is a valuable tool for the prediction of subsequent PI in the early postoperative period. In contrast, 0Pre biopsy findings and peak AST and ALT values are not useful in the assessment of PI.

Adolescent↗
PubMed1997

Hepatocytic globules in end-stage hepatic disease: relationship to alpha1-antitrypsin phenotype.

Hepatic explant specimens from 171 patients with cirrhosis were examined to determine the incidence of periodic acid-Schiff (PAS)-positive diastase-resistant globules (PDRGs) in end-stage hepatic disease and whether the globules bear a specific relationship to the alpha1-antitrypsin (A1AT) phenotype or to causes of hepatic disease other than A1AT deficiency. PAS-positive diastase-resistant globules were detected in 17 (10%) of the hepatic explant specimens, and the globules in all of these cases were strongly immunoreactive for A1AT. In the 17 patients with PDRGs, the cirrhosis was attributed preoperatively to A1AT deficiency (3 patients), ethanol abuse, viral hepatitis, or both (10 patients), cryptogenic cirrhosis (3 patients), and autoimmune hepatitis (1 patient). The A1AT isoelectric phenotypes classified according to the protease inhibitor (Pi) nomenclature for 16 of these patients were as follows: Pi ZZ (3 patients), Pi SS (1 patient), Pi MZ (8 patients), and Pi MM (4 patients). Because PDRGs were seen in a variety of A1AT phenotypes, serum electrophoretic analysis, not histologic examination, is required for the correct diagnosis of an A1AT abnormality. Furthermore, although PDRGs were seen in a variety of hepatic diseases, the majority of patients with globules had an undetected A1AT abnormality. Accordingly, on identification of hepatocytic PDRGs, the clinician should be alerted to the possibility of an unsuspected A1AT abnormality even in the presence of other causes of hepatic disease.

Adult↗
PubMed1997

Gonadoblastomas in 45,X/46,XY mosaicism: analysis of Y chromosome distribution by fluorescence in situ hybridization.

Gonadoblastomas are composed of nests of neoplastic germ cells and sex cord derivatives surrounded by ovarian-type stroma. These tumors are found almost exclusively in persons with gonadal dysgenesis associated with a Y chromosome or Y chromosome fragment, and accordingly, the Y chromosome has been implicated in gonadoblastoma oncogenesis. To evaluate this association, we used two-color fluorescence in situ hybridization with chromosome-specific probes to determine the distribution of the X and Y chromosomes in the tumor nests and surrounding stromal cells in paraffin tissue sections of three gonadoblastomas in two patients with gonadal dysgenesis and 45,X/46,XY mosaicism. Statistical analysis of the data from the fluorescence in situ hybridization demonstrated that in all three gonadoblastomas, the proportion of nuclei with a Y chromosome signal was significantly higher in the tumor cells than in the nontumoral cells of the surrounding stroma (P<.001). These results suggest that Y chromosome material participates in gonadoblastoma tumorigenesis.

Adolescent↗
PubMed1996

Clonal analysis of focal nodular hyperplasia of the liver.

Recent evidence suggests that focal nodular hyperplasia of the liver (FNH) may represent a hyperplastic response to a vascular malformation, but the precise etiology remains unclear. We performed a clonal analysis of ten FNHs from nine patients by patterns of X chromosome inactivation. DNA isolated from paraffin-embedded specimens was subjected to polymerase chain reaction amplification for a highly polymorphic region of the human androgen receptor gene (HUMARA). Predigestion of tumor DNA with the methylation-sensitive, restriction enzyme HpaII allowed for selective amplification of the methylated (inactivated) allele. Of the nine patients analyzed, seven were heterozygous for the HUMARA polymorphism and informative for analysis. One informative patient had two lesions, for a total of eight FNHS. Amplification of lesional DNA after HpaII digestion demonstrated clonality in six of the eight informative cases. Paired tissue samples from different lesional areas were available in four of the six FNHs with evidence of clonality. In three of the four cases, DNA extracted from the two tissue samples showed both evidence of clonality and an identical pattern of X chromosome inactivation. In the remaining case, one sample showed evidence of clonality whereas the other was nonclonal. Three hepatic adenomas from two informative patients were also analyzed for comparative purposes, all of which showed evidence of clonality after HpaII digestion. The current study illustrates that most cases of FNH show a uniform pattern of X chromosome inactivation consistent with clonality.

Adenoma↗