Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.

BACKGROUND: The incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood. AIMS: To examine the expression of the proinflammatory cytokines IL-8 and IL-1beta along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-kappaB. PATIENTS AND METHODS: Fresh biopsy specimens were collected from patients with reflux esophagitis (n=15), Barrett's esophagus (n=35), Barrett's adjacent to adenocarcinoma (n=8), and esophageal adenocarcinoma (n=35). IL-8 and IL-1beta expression were measured using enzyme-linked immunosorbent assay. NF-kappaB expression was measured by electrophoretic mobility shift assay. RESULTS: Elevated expression of NF-kappaB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-kappaB. IL-8 and IL-1beta were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1beta, and NF-kappaB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1beta in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-kappaB positive had significantly higher levels of both IL-8 (p=0.04) and IL-1beta (p=0.03) compared to adenocarcinoma patients who were NF-kappaB negative. CONCLUSIONS: The proinflammatory cytokines IL-8 and IL-1beta are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-kappaB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-kappaB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-kappaB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.

Factors influencing the development of Barrett's epithelium in the esophageal remnant postesophagectomy.

BACKGROUND: Barrett's esophagus results from chronic reflux of both acid and bile. Reflux of gastric and duodenal contents is facilitated through the denervated stomach following esophagectomy, but the development of Barrett's changes in this model and the relationship to gastric and esophageal physiology is poorly understood. AIMS: To document the development of new Barrett's changes, i.e., columnar metaplasia or specialized intestinal metaplasia (SIM) above the anastomosis, and relate this to the recovery of gastric acid production, acid and bile reflux, manometry, and symptoms. PATIENTS AND METHODS: Forty-eight patients at a median follow-up of 26 months (range = 12-67) postesophagectomy underwent endoscopy with biopsies taken 1-2 cm above the anastomosis. The indication for esophagectomy had been adenocarcinoma (n = 27), high-grade dysplasia (n = 2), and squamous cell cancer (n = 19). Physiology studies were performed in 27 patients and included manometry (n = 25), intraluminal gastric pH (n = 24), as well as simultaneous 24-hour esophageal pH (n = 27) and bile monitoring (n = 20). RESULTS: Duodenogastric reflux increased over time, with differences between patients greater than and less than 3 years postesophagectomy for acid (p = 0.04) and bile (p = 0.02). Twenty-four patients (50%) developed columnar metaplasia and of these 13 had SIM. The prevalence of columnar metaplasia did not relate to the magnitude of acid or bile reflux, to preoperative neoadjuvant therapies, or to the original tumor histology. The duration of reflux was most significant, with increasing prevalence over time, with SIM in 13 patients at a median of 61 months postesophagectomy compared with 20 months in the 35 patients who were SIM-negative (p < 0.006). Supine reflux correlated with symptoms. CONCLUSIONS: The development of Barrett's epithelium is frequent after esophagectomy, is time-related, reflecting chronic acid and bile exposure, and is not specific for adenocarcinoma or the presence of previous Barrett's epithelium. This model may represent a useful in vivo model of the pathogenesis of Barrett's metaplasia and tumorigenesis.

Transvenous liver biopsy via the femoral vein.

AIM: To study the safety, effectiveness and diagnostic value of transvenous forceps biopsy of the liver in 54 patients with coagulopathy, gross ascites or morbid obesity and suspected liver disease in whom percutaneous liver biopsy was contraindicated. MATERIAL AND METHODS: Forceps biopsy of the liver via the femoral vein was attempted in 54 adult patients with advanced liver disease of unknown aetiology who had coagulation disorders (41 cases), gross ascites (11 cases) or morbid obesity (two cases). In each patient two to six biopsies (average four) were taken using a radial jaw forceps inserted via the right or left femoral vein. RESULTS: The procedure was successful in 53 cases. Hepatic vein catheterization failed in one patient. Adequate liver tissue for diagnosis was obtained in 84% of cases. One patient developed delayed haemorrhage at 12 h from a capsular leak that was undetected during the biopsy procedure. This patient required blood transfusions and laparotomy to control bleeding. There were no deaths in the 53 patients studied. Transient minor chest and shoulder pain was encountered during sheath insertion into a hepatic vein in 23 patients. Three patients developed a femoral vein haematoma, which resolved with conservative treatment. CONCLUSION: Transvenous liver biopsy via the femoral vein is another safe, effective, simple alternative technique of biopsy when the percutaneous route is contraindicated.

The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C.

BACKGROUND & AIMS: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype 1b from a single inoculum. METHODS: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects. RESULTS: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs. 8.8% and 14.2%, respectively; P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively; P = 0.001). Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy. CONCLUSIONS: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection.

Guided versus blind liver biopsy for chronic hepatitis C: clinical benefits and costs.

BACKGROUND/AIMS: Our objectives were: (1) to assess the clinical benefits and costs of performing ultrasound-guided liver biopsy with an automated needle compared to blind biopsy with a conventional Trucut needle in patients with chronic hepatitis C; (2) to compare the histological yield of automated needles with Trucut needles. METHODS: We prospectively studied 166 patients with hepatitis C virus who underwent either ultrasound-guided biopsy using automated ASAP needles or blind biopsy using conventional Trucut needles. Both groups were matched for age, sex, cirrhosis, needle gauge and operator experience. Patient tolerance, complications and histological adequacy were assessed. In a separate in vitro study, we assessed the histological adequacy of liver biopsy specimens obtained using automated and Trucut needles from 10 fresh autopsy cases. RESULTS: Ultrasound-guided biopsy caused significantly less biopsy pain (36.4% vs. 47.3%; p < 0.0001) and significantly less pain-related morbidity (1.8% vs. 7.7%, p < 0.05). Although, there was no significant difference in diagnostic yield between guided and blind biopsy (98% vs. 94%, p = 0.15), 3 blind biopsies (3.3%), including 2 which yielded extra-hepatic tissue, had to be repeated. The additional expense of performing guided liver biopsy with automated needles was 42 Irish Pounds per patient. In vitro, automated ASAP 15G needles provided liver specimens comparable to Trucut 15G needles and had the highest histopathologic score among the automated needles assessed. CONCLUSIONS: Even in the absence of major complications, ultrasound-guided liver biopsy with an automated needle in HCV patients is safer, more comfortable and only marginally more expensive than blind Trucut biopsy.

The development of hepatic granulomas following interferon-alpha2b therapy for chronic hepatitis C infection.

Hepatic granulomas have been detected in cases of chronic hepatitis C virus (CHCV) infection. Here we report upon three selected cases of CHCV infection who were treated with IFN alpha, in whom hepatic granulomas were absent on initial liver biopsies, but in whom granulomas developed following IFN alpha therapy. In one case, complete regression of these granulomas was noted 17 months following discontinuation of treatment, more strongly implicating IFN alpha in the aetiopathogenesis of such granulomas in this case. These findings suggest that IFN alpha may have a biological role in the pathogenesis of granulomatous liver disease in these patients. All three cases were poor/non-responders to IFN alpha, suggesting that the development of hepatic granulomas during IFN alpha therapy may be associated with a poor response to treatment.

Liver biopsy pathology in human immunodeficiency virus infection.

OBJECTIVES: To determine the hepatic changes in patients with human immunodeficiency virus (HIV) infection in Dublin and to assess the usefulness of liver biopsy in this condition. DESIGN: A consecutive series of liver biopsies was examined retrospectively and correlated with clinical findings. METHODS: A histological review was conducted of specimens from all patients who had undergone liver biopsy in a tertiary referral centre for HIV-infected patients in Dublin. RESULTS: Thirty-nine liver biopsies were studied from 36 patients. Thirty-one (86%) showed pathological changes. Non-specific changes were most frequent, followed by viral-induced chronic hepatitis (15 cases). Acute hepatitis was documented in five and cirrhosis in four cases. Five biopsies performed for pyrexia of unknown origin (PUO) or suspected tuberculosis showed granulomas. Organisms were rarely identified (2) and bile duct changes were uncommon. CONCLUSIONS: Liver biopsy was useful in detecting primary hepatic pathology and, in some cases, the cause of PUO, but not useful in detecting opportunistic infections despite their known presence in other organs.

Risk of hepatitis C infection in neonates transfused with blood from donors infected with hepatitis C.

This look-back study was undertaken to identify newborn infants who had been infected with the hepatitis C virus (HCV) as a result of transfusions received before the introduction of routine screening in 1991 and to determine the transmission rates and persistence of transfusion-transmitted HCV infection acquired in the neonatal period. A total of 24 infants, transfused between 1980 and 1991, were identified as having received potentially infected blood from 11 blood donors. Ten of the donors had been administered batches of anti-D in 1977 known to have transmitted HCV genotype 1b infection. HCV RNA was detected in five of these donors when tested in 1994-95; the past donations of five of the donors, who had received anti-D immunoglobulin and had serological evidence of previous HCV infection but who were PCR negative when tested in 1994-95, were considered of lower risk. The source and time of acquisition of HCV infection for the one remaining donor in the study was not determined. Twenty-one (88%) of the 24 children were living at time of lookback. The median age at transfusion was 12 days. The median age at time of testing was 6.3 years. One child, who tested negative, was excluded from further analysis of HCV transmission, due to incomplete transfusion records. Overall, 12 of 20 (60%) children tested were positive for anti-HCV and seven (35%) were HCV RNA positive. Twelve (71%) of the 17 recipients of viraemic blood were ELISA positive and seven (41%) were PCR positive. Resolved HCV infection, as determined by ELISA pos, RIBA pos or indeterminate and PCR negativity, occurred in five of 12 (42%). In many instances there was more than one recipient per HCV infected donation. All of the reported children are clinically asymptomatic. However, the duration of HCV infection is relatively short and there is evidence of a degree of hepatitis in five of the seven children who are HCV RNA positive as judged by mildly elevated transaminase levels. The three who have undergone liver biopsy show mild hepatitis. The lower rates of persistence of HCV infection in this study may be due to the young age at exposure or to the source of infection which for all but one of the children was linked to one HCV genotype from female donors. Sharing of units of blood among multiple infants should be discouraged.

Microalbuminuria correlates with intestinal histopathological grading in patients with inflammatory bowel disease.

It has previously been shown that microalbuminuria is a useful disease activity marker for inflammatory bowel disease (IBD). Microalbuminuria correlates strongly with the markers of clinical and laboratory disease activity such as erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). The aim of this study was to discover if microalbuminuria accurately reflects the intestinal inflammation by correlating it with intestinal inflammation using a standard histopathological grading system in patients with ulcerative colitis and Crohn's colitis. Forty two patients with IBD who had undergone endoscopic examination of the entire colon for the assessment of severity and extent of the disease (Crohn's colitis (n = 21), ulcerative colitis (n = 21)) were recruited to the study. Patients with small bowel Crohn's disease were not studied. Twenty four patients had left sided colonic disease and 18 patients had extensive colonic disease. Each patient's colonic biopsy specimens were scored blindly by a histopathologist and a composite score was compiled on the basis of the severity of changes in the enterocytes and crypts and the cellularity of the lamina propria. A clinical disease activity was obtained using the simple index of Harvey and Bradshaw. Microalbuminuria was measured in all patients by an immunoturbiditimetric method. ESR and CRP were also measured, as indicators of acute phase response in the same patients. It was found that patients with active IBD had higher concentrations of microalbuminuria compared with those patients in remission (median 222 micrograms/min (range 40-686 micrograms/min) v median 96 micrograms/min (range 30-376 micrograms/min); p < 0.001)). Significantly higher concentrations of microalbuminuria were also detected in patients with extensive colonic IBD compared with those patients with left sided disease (median 297 micrograms/min (range 132-686 micrograms/min) v median 101 micrograms/min (range 30-433 micrograms/min); p < 0.001)). A strong positive correlation was seen between microalbuminuria and intestinal histopathological score in IBD patient groups with left sided colitis (r = 0.77; p < 0.001) and extensive disease (r = 0.71; p < 0.01). The standard histopathological grading system correlated with the clinical disease activity (r = 0.64; p < 0.005) and CRP (r = 0.62; p < 0.02), however, it did not correlate with ESR. In conclusion, the strong correlation of microalbuminuria with a standard intestinal histopathological grading system suggests that microalbuminuria accurately reflects the severity of colonic inflammation in patients with Crohn's colitis and ulcerative colitis.

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome. Assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide.

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In-pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

The emerging AIDS epidemic in Ireland--clinicopathological findings in 23 early cases.

A longitudinal study with follow up to the end of 1989 was carried out on 23 patients with AIDS who had attended St. James's Hospital, Dublin, by the end of 1987. Until then only 33 cases of AIDS had been reported in Ireland. The patients, all of whom had antibodies to human immunodeficiency virus (HIV), were predominantly male, young (mean age 31.3 years) and belonged about equally to three major risk groups: homosexuals, intravenous drug abusers (IVDA) and haemophiliacs. AIDS was diagnosed because of oesophageal candidiasis (8 cases), Kaposi's sarcoma (4), mycobacterial infection (4), pneumocystis carinii pneumonia (3), toxoplasmosis (2) or encephalopathy (2). Malignant lymphoma and a variety of infections occurred in the course of illness, and neurological involvement developed in 11 patients (48%). Mortality following diagnosis of AIDS was 39% at one year and 64% after two years. Autopsy in 10 of the 16 deaths contributed much to defining the extent and nature of the disease. The demographic pattern, risk group status, survival and range of complications were broadly similar to the pattern of AIDS as seen elsewhere in developed countries. However, compared to the profile of disease reported from the United States, oesophageal candidiasis (52%) and Mycobacterium tuberculosis (22%) were more prominent, pneumocystis carinii pneumonia (39%), Kaposi's sarcoma (22%) and Mycobacterium avium intracellulare (13%) were less frequent and cryptococcal infection was not identified. These regional variations in the frequency of the various complications and particularly the prominence of tuberculosis, probably reflect the interaction of the immunocompromised patient with the local environment and may have important diagnostic and therapeutic implications.

Spontaneous primary dissection of the coronary artery.

A 41 year old woman died suddenly and unexpectedly as a result of a spontaneous primary dissection of a coronary artery. This rare condition occurs typically in pre-menopausal women often in the peripartum period and hormonal changes have been among several suggested aetiological factors. In this case an association with auto-immune thyroiditis is described for the first time and the importance of extensive examination of the coronary arteries at autopsy is emphasised as the lesion was confined to a small focus near the apex of the heart.

Heterozygous FZ alpha 1 antitrypsin deficiency associated with severe emphysema and hepatic disease: case report and family study.

A patient with advanced emphysema and cor pulmonale had the changes of alpha 1 antitrypsin deficiency in a liver biopsy specimen and was shown to have the phenotype PiFZ. This case supports the contention that the F allele of alpha 1 antitrypsin predisposes to the development of emphysema, particularly when it occurs in conjunction with the Z allele.

Prolonged IgM antibodies and histopathological evidence of chronicity in hepatitis A.

The case of a young man with hepatitis A and a chronic course is presented. The patient received a short course of steroid therapy for recurrence of symptoms following acute hepatitis A. Thereafter, liver enzymes have remained marginally elevated for 4 years and annual liver biopsies have shown evidence of chronicity. HAV IgM Ab persisted for 1034 days with subsequent development of HAV IgG Ab. The possibility of other viruses in the aetiology and the role of steroids in the development of chronicity are discussed.

Modification of caecal lymphoid tissue and relationship to granuloma formation in sporadic ileocaecal tuberculosis.

The histopathology of eight cases of sporadic ileocaecal tuberculosis is described with particular reference to caecal lymphoid tissue. Adjacent to areas of ulceration in all cases there was an increase in lymphoglandular complexes (LGC) and proliferation of paravascular lymphoid aggregates deeper in the gut wall. Early and fully-developed granulomas were present in locations comparable to LGC and lymphoid aggregates. Immunocytochemical staining of paraffin sections with monoclonal antibodies UCHL1 (T-lymphocyte membrane antigen) and LN-1, LN-2 and LN-3 (B-lymphocyte and Ia antigens) showed that central cells in LGC and lymphoid aggregates stained like follicular centre B-lymphocytes. Both LGC and lymphoid aggregates had a distinct peripheral rim of cells staining as T-lymphocytes, but LN-2 and LN-3 also stained scattered peripheral cells, some of which were recognizable as interdigitating reticulum cells. Most lymphocytes within and around granulomas stained as T-lymphocytes. In lymph nodes, granulomas appeared to occur first at the periphery of, and later to efface, cortical follicles. Lymph node compartments showed the expected T- and B-zonation, and lymphocytes associated with granulomas stained as in caecal granulomas. Our observations suggest that LGC are sites of mycobacterial antigen sampling, of T-lymphocyte and macrophage activation, and of (potential) granuloma formation in ileocaecal tuberculosis. Lymphoid aggregates deeper in the gut wall probably subserve a similar function during extension of the lesion. The location of both LGC and lymphoid aggregates beside lymphatics is suited to the transfer of their cellular constituents throughout the gut and to regional lymph nodes.

Operation-associated neutrophils in a percutaneous liver biopsy: effect of prior transjugular procedure.

A young man with chronic active hepatitis was heavily sedated during an attempted transjugular liver biopsy. The procedure was abandoned after 3 h and an immediate percutaneous liver biopsy was performed. This showed features of chronic active hepatitis but, in addition, groups of polymorphonuclear leukocytes in the parenchyma. These were similar to the operation associated neutrophils encountered in liver biopsies taken during the course of abdominal surgery. In a review of 78 liver biopsies from patients with chronic active hepatitis, this type of infiltrate was seen in four of eight surgically resected specimens but not in 70 percutaneous biopsies. The neutrophilic infiltrate in the present case appears to be an unique occurrence in a percutaneous liver biopsy. It was probably related to hypoperfusion during the preceding prolonged sedation and illustrates the ease with which an already diseased liver can be further damaged.