James K. Kelly

Polypoid Prolapsing Mucosal Folds in Diverticular Disease

Redundant or polypoid mucosal folds were found in eight surgically resected sigmoid colons with diverticular disease. Grossly, they were either swellings of mucosal folds or larger, leaflike, smooth-surfaced polyps with broad bases arising from mucosal folds. The number of lesions ranged from one to 11, and when multiple they formed two rows between diverticula. Swollen mucosal folds showed submucosal and mucosal vascular congestion, scanty thrombi, edema, hemorrhage, and hemosiderin deposition. Some were markedly inflamed, Polypoid lesions also showed crypt elongation and fission, upgrowth of muscle from the muscularis mucosae, and hyperplastic-metaplastic change typical of mucosal prolapse. One polyp showed evidence of an inverted diverticulum. Two cases displayed diffuse mucosal inflammation resembling inflammatory bowel disease in the region of the polyps. We speculate that these lesions result from a combination of venous congestion and mucosal redundancy secondary to spastic contraction of the muscle coat.

The histogenesis of adenocarcinoma of the gallbladder

A prospective study of 277 cholecystectomy specimens for evidence of isolated epithelial dysplasia of gallbladder mucosa is presented. In addition, 15 cases of primary adenocarcinoma of the gallbladder are retrospectively reviewed with particular reference to the presence of metaplasia and dysplasia adjacent to the infiltrating tumor, in order to establish the relationship between metaplasia, isolated epithelial dysplasia, and adenocarcinoma of the gallbladder. Only one case of isolated epithelial dysplasia was found in the 277 cholecystectomy specimens, and this arose within focal incomplete intestinal metaplasia. In the 15 cases of adenocarcinoma of the gallbladder, benign antral and/or incomplete intestinal metaplasia was found adjacent to the tumor in 11 cases. In 10 cases, dysplasia of this metaplastic epithelium was found in continuity with the tumor. The authors conclude that the most common pathway to adenocarcinoma is via dysplasia of metaplastic gallbladder epithelium.

Idiopathic retractile (sclerosing) mesenteritis and its differential diagnosis

We report a case of retractile mesenteritis presenting as an abdominal mass with incomplete small-bowel obstruction. Histological features included fat necrosis, fibrosis, elastosis, dystrophic calcification, and chronic inflammation. Lymphatic obstruction resulted in the accumulation of lipid-laden macrophages in the ileal mucosa. Ultrastructurally, myofibroblasts were the principal cells present. The differential diagnosis of retractile mesenteritis is discussed with particular attention to myofibroblastic disorders such as inflammatory pseudotumors, desmoids, retroperitoneal fibrosis, and other uncommon conditions that appear to be morphologically or clinically distinguishable although the etiology and pathogenesis are obscure.

Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis.

The purpose of this pilot study was to determine whether daily administration of cyclosporin A to symptomatic patients with primary biliary cirrhosis for 1 yr would lead to a significant and sustained improvement in liver enzyme abnormalities. Twelve adult patients (11 female, 1 male; aged 52.6 +/- 8.9 yr, mean +/- SD) with serologic and histologically defined primary biliary cirrhosis were randomized to receive either oral cyclosporin A or vehicle placebo. Cyclosporin A was administered at sufficient dosages to maintain serum radioimmunoassay trough levels between 100 and 200 ng/ml (starting dosage, 2.5 mg/kg.day). After 1 yr of therapy, significant changes from pretreatment values were seen only in recipients of cyclosporin A. These included a 37% decrease in mean serum alkaline phosphatase and a 43% decrease in gamma-glutamyltransferase (controls +3% and -14%, respectively). Mean serum bilirubin and albumin levels and prothrombin times remained unaltered in the two groups, as did the extent of inflammation and fibrosis and the histologic staging of liver biopsy specimens. Although mean serum creatinine levels increased by 51% in recipients of cyclosporin A (+2% in controls), there were no associated changes in diastolic blood pressure or creatinine clearance values. Other side effects including thrombocytopenia, hirsutism, headaches, tremor, and parasthesiae were common in the treated group but not of sufficient severity to warrant adjustment in the dosage or discontinuation of therapy. The observed changes in hepatic, renal, and hematologic tests tended to return to baseline after discontinuation of therapy. Two patients, both placebo recipients, died of liver failure during the study period. The results of this study indicate that in symptomatic primary biliary cirrhosis, cyclosporin A administration is associated with a significant improvement in cholestatic liver enzyme abnormalities that persists for the duration of therapy. A progressive rise in serum creatinine levels and a high incidence of side effects raise concerns regarding the long-term safety of this agent in primary biliary cirrhosis.

Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis

Reovirus type 3 (Reo-3) infection has recently been implicated in the pathogenesis of certain idiopathic, cholestatic liver diseases of newborns. In the present study, antibody titres to Reo-3 virus (anti-Reo-3) were determined in sera from 43 adults with idiopathic cholestatic liver disease, including 34 patients with primary biliary cirrhosis (PBC) and 9 patients with primary sclerosing cholangitis (PSC). Seventy-four adults with various other causes of chronic liver disease and 16 healthy volunteers served as controls. Geometric mean titres of anti-Reo-3 were significantly higher in PBC and PSC sera than chronic liver disease and healthy controls (P less than 0.005). Mean antibody titres for all patient groups, however, were within the 95% confidence limits for normals. Seven of 34 (21%) PBC patients and 3/9 (33%) PSC patients had elevated titres of anti-Reo-3, as compared to only 4/74 (5%) chronic liver disease (P less than 0.05) and 0/16 (0%) healthy control subjects (P less than 0.05) (Fishers Exact Test). Antibody titres to five other common viruses were normal in patients with high anti-Reo-3 titres when compared to age- and sex-matched controls with liver disease. Immunoperoxidase staining for Reo-3 viral markers and cultures of liver biopsy material for Reo-3 virus were negative in both patients and controls. The results of this study indicate that, although patients with PBC and PSC have higher anti-Reo-3 antibody titres than patients with other forms of chronic liver disease or healthy volunteers, only a minority of these patients have titres that exceed the 95% confidence limits for normals.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic and gastric cytoprotective effects of long-term prostaglandin E1 administration in cirrhotic rats

BACKGROUND Acute administration of prostaglandin E (PGE) may be cytoprotective for hepatocytes in acute hepatitis and for gastric mucosa in cirrhotic rats. We examined the effects of long-term PGE treatment on liver and stomach in cirrhotic rats. METHODS Cirrhosis was induced by bile duct ligation. Controls had a sham operation. Half the rats received a PGE1 analogue, misoprostol (PGE1) (10 micrograms orally, daily) on days 1-29 postsurgery, and the others received vehicle only. On day 31, all rats underwent ex vivo gastric chamber procedures. Liver chemistry, portal pressures, and hepatic and gastric tissue levels of prostaglandin E2, leukotriene B4, myeloperoxidase, and collagen were determined. RESULTS PGE1-treated cirrhotic rats had less hepatosplenomegaly, lower serum alanine aminotransferase levels, and portal pressures and higher arterial pressure than vehicle-treated cirrhotic rats. Hepatic and gastric leukotriene B4, myeloperoxidase and collagen levels were significantly lower in the PGE1-treated compared with vehicle-treated cirrhotic rats. Vehicle-treated cirrhotic rats had greater spontaneous and ethanol-induced gastric damage and failed to show a gastric hyperemic response to ethanol, whereas PGE1-pretreated rats did. PGE1 did not significantly affect sham-operated rats. CONCLUSIONS Long-term PGE1 administration was cytoprotective for both the liver and gastric mucosa in cirrhotic rats. Clinical trials of PGE in human cirrhosis or portal hypertensive gastropathy may be warranted.

Familial idiopathic adulthood ductopenia: a report of five cases in three generations

BACKGROUND/AIMS Idiopathic adulthood ductopenia is a cholestatic liver disease of unknown etiology. Although most cases are sporadic, familial cases do occur. METHODS We describe a series of adult-onset bile duct depletion involving five members of an extended family spanning three generations. The proband, a 49-year-old man, presented in 1989 with asymptomatic elevation of liver enzyme tests. Investigations for chronic liver disease, including endoscopic retrograde cholangiopancreatography, were negative. Findings on liver biopsy progressed from normal in 1989 to striking loss of interlobular bile ducts in 1992. Ursodeoxycholic acid has resulted in improvement of liver enzyme tests. The probands brother required a liver transplant at age 35 for cryptogenic cirrhosis. The probands sister, age 42, has had intermittent jaundice and elevation of liver enzyme tests since 1971. Her liver biopsy findings progressed from normal in 1975, to striking bile duct damage by 1997. The probands 21-year-old son has elevated liver enzyme tests and a liver biopsy consistent with idiopathic adulthood ductopenia. The probands father had a liver biopsy at age 70 for investigation of a liver mass. It revealed extensive fibrosis and striking bile duct destruction. RESULTS/CONCLUSIONS This is the largest series of familial idiopathic adulthood ductopenia reported, and the first with multiple generations described. Genetics appears to play a role in some cases of adulthood ductopenia. Ursodeoxycholic acid may be beneficial in the treatment of this condition.

Chronic Active Hepatitis Associated with Trazodone Therapy

Trazodone (Desyrel, Bristol-Myers Squibb Canada, Montreal, Quebec) is a nontricyclic antidepressant that has been available in North America since the early 1980s. Three previous cases of hepatic injury associated with this drug have been reported [1-3]. In two cases, the patients had been taking trazodone only briefly, and the biopsy specimens confirmed acute injury. In the third case, a patient had taken trazodone for 7 months and showed liver chemistry abnormalities for 6 months after drug cessation. However, no liver biopsy was done in that case. We describe a patient who developed chronic active hepatitis in association with trazodone therapy. Case Report A 75-year-old Asian woman came to the emergency department with jaundice. She had noted the onset of dark urine and pale stools 3 weeks previously, and her family noticed that she was jaundiced 1 week before. She reported nausea and anorexia that had started approximately 8 months before the onset of jaundice, concomitant with the initiation of a course of trazodone therapy, 150 mg daily, prescribed for depression. She had no previous history of jaundice, blood transfusion, intravenous drug abuse, parenteral drug therapy, acupuncture treatment, or alcohol use. She had no significant past medical problem other than a cholecystectomy 15 years previously. The only medication she was taking was trazodone. She reported no history of herbal medicine ingestion. The physical examination at admission was unremarkable except for jaundice. No hepatosplenomegaly, abdominal tenderness, or ascites were present. Stigmata of chronic liver disease were absent. A rectal examination showed guaiac-negative pale stool. The hemoglobin concentration was 136 g/L. The prothrombin time and partial thromboplastin times were elevated at 13.9 s and 40.8 s, respectively (normal, < 11.7 s and < 36 s, respectively). The bilirubin level was 306 mol/L (normal, < 20 mol/L), with a conjugated bilirubin level of 175 mol/L (normal, < 5 mol/L). Initial liver enzyme levels were as follows: alanine aminotransferase, 15.55 kat/L (normal, < 0.58 kat/L); aspartate aminotransferase, 14.05 kat/L (normal, < 0.53 kat/L); -glutamyltransferase, 6.33 kat/L (normal, < 0.58 kat/L); and alkaline phosphatase, 2.4 kat/L (normal, < 2.4 kat/L). Results of chest and abdominal radiographs and an abdominal ultrasound scan were normal. Serologic tests for hepatitis A virus (IgM anti-HAV) and hepatitis B surface and e antigens were negative. An assay for IgM antibody against hepatitis B core antigen was also negative, but IgG antibodies against hepatitis B surface and core antigens were detected. Serologic test results for hepatitis C virus were negative using a first-generation enzyme-linked immunosorbent assay (Ortho Diagnostics, Raritan, New Jersey) and, subsequently, a second-generation recombinant immunoblot assay (Ortho). Serologic tests for Q fever, cytomegalovirus, and herpes simplex, Epstein-Barr, and varicella zoster viruses were all negative. Serologic tests for antimitochondrial, antismooth muscle, and antinuclear antibodies were also negative. The prothrombin time and partial thromboplastin times remained elevated despite a 3-day course of therapy with subcutaneous vitamin K. Because of the abnormal coagulation factors, a transjugular approach was used for liver biopsy. Measurements of hepatic venous pressures done in conjunction with biopsy showed a modestly elevated hepatic venous pressure gradient (corresponding to portal pressure) of 9 mm Hg (normal, 1 to 4 mm Hg). The liver tissue was fragmented and nodular and showed a pattern consistent with chronic active hepatitis (Figure 1). Between the nodules there was reticulin condensation but no deposition of elastica, indicating that the lesion was relatively recent. The portal tracts were expanded by an infiltrate of lymphocytes and plasma cells, with erosion of limiting plates and portoportal and portocentral bridging necrosis. Eosinophils were rare. The parenchyma showed thickening of liver cell plates, occasional acidophil bodies, mild focal inflammation, low-grade parenchymal and reticuloendothelial hemosiderosis, and no -1-antitrypsin bodies or metallothionein. Centrilobular areas showed liver cell dropout and lipofuscin-laden macrophages that stained strongly positive with diastase-periodic acid-Schiff. Immunostains for hepatitis B surface and core antigens were negative. Figure 1. Liver specimen showing the pattern of chronic active hepatitis. Trazodone therapy was discontinued and within 1 week the patients nausea and anorexia had resolved. Ten days after stopping the drug, the aminotransferase enzyme levels had markedly decreased and by 4 weeks had returned to normal. The prothrombin and partial thromboplastin times returned to normal within 2 weeks. The bilirubin and -glutamyltransferase levels were slow to decrease but gradually declined, returning to normal approximately 6 months after the last dose of trazodone. The patient has been followed for 2 years since resolution and has showed no further clinical or laboratory evidence of hepatic dysfunction. Discussion To our knowledge, this is the first reported case of trazodone-induced chronic active hepatitis. Chu and colleagues [1] described a case of acute trazodone-induced hepatotoxicity. Their patient developed an exfoliative, macular, pruritic rash and elevated liver enzyme levels 3 weeks after starting a course of trazodone therapy (500 mg daily). The liver biopsy specimen showed a mixed hepatocellular-cholestatic pattern [1]. Sheikh and Nies [2] described a patient who developed intrahepatic cholestasis 2 weeks after starting trazodone therapy (50 mg daily). In these two patients, symptoms resolved rapidly after discontinuation of therapy, and liver enzyme levels returned to normal within 8 weeks of stopping trazodone. Longstreth and Hershman [3] described a patient who developed jaundice, pruritus, nausea, leukonychia, and elevated liver enzyme levels after a 7-month course of trazodone therapy (200 mg daily). The patients symptoms and jaundice rapidly resolved after cessation of trazodone. The liver enzyme levels were nearly normal 5 weeks after stopping the drug, but there were an intermittent slight elevations of the aspartate aminotransferase and alkaline phosphatase levels for as long as 6 months after the discontinuation of trazodone therapy [3]. It is possible that the patient had drug-induced chronic hepatitis, especially given the prolonged abnormalities in liver enzyme levels; however, because a liver biopsy was not done, this remains speculative. In our case, both bilirubin and -glutamyltransferase levels remained elevated until 6 months after cessation of the drug, probably reflecting the chronicity of the hepatotoxic process. Given the extensive damage that the biopsy specimen showed, this slow resolution of all liver chemistry abnormalities was not surprising. Chronic active hepatitis has many causes. However, we are confident that the chronic hepatitis in our patient was caused by trazodone. Hepatitis B serologic test results were consistent with remote past exposure to hepatitis B but not with ongoing viral infection, which was confirmed by the negative immunostains on the biopsy specimen. The serologic and biopsy findings effectively ruled out other causes of chronic hepatitis. Finally, the temporal relation of the symptoms and liver enzyme abnormalities to the starting and stopping of the drug strongly implicates trazodone as the cause of the chronic hepatitis. We suggest that clinicians be alert to the possibility of hepatic injury in patients taking this medication.

Absence of an Association Between Enteric Parasites in the Manifestations and Pathogenesis of HIV Enteropathy in Gay Men

49 gay men confirmed to be infected with the human immunodeficiency virus (HIV) and 9 HIV seronegative gay men participated in a pilot study comparing clinical status and enteric parasite load with gastrointestinal structure, function and symptomatology. Cases included 16/49 (33%) men who were CDC stage II, 7/49 (14%) who were CDC stage III, and 26/49 (53%) who were CDC stage IV. The mean CD4-lymphocyte count was 476 ± 199 (SD)/μl. The prevalence of enteric parasitic flora was similar in HIV seropositive patients and controls. Seven cases had enteric infection with pathogenic agents including 3 patients with Entamoeba histolytica, and 4 patients with Giardia lamblia, one of whom also had cryptosporidiosis. Other cases were most frequently colonized with Blastocystis hominis (44%) and Endolimax nana (41%) regardless of the HIV clinical status. HIV seropositive patients with enteric parasitic colonization tended to have lower mean levels of serum IgA than cases without parasites. Duodenal morphometric mucos...

Effects of Yersinia enterocolitica infection on rabbit intestinal and colonic goblet cells and mucin: morphometrics, histochemistry, and biochemistry.

The effects of Yersinia enterocolitica on intestinal goblet cells were investigated in New Zealand white rabbits. Animals infected with Y enterocolitica were compared with weight matched and pair fed controls. Goblet cell hyperplasia developed in the distal small intestine of infected rabbits on day 1, in the mid small intestine on day 3, and in the upper small intestine on day 6. In all regions hyperplasia persisted throughout the 14 day study. The degree of hyperplasia was greater in the distal small intestine than the upper and mid regions. Goblet cells in the proximal colon of infected animals seemed to respond as those in the distal small intestine. Thus goblet cell hyperplasia developed more rapidly and to a greater extent in the ileocaecal region where mucosal injury was most severe. These changes resulted directly from Y enterocolitica infection since goblet cell numbers did not increase in pair fed controls. Histochemically, goblet cell mucins from infected rabbits were unchanged at either six or 14 days. Biochemical analysis, however, established that purified mucins from animals on day 6 after infection were less sialylated (in the small intestine) and more sulphated (in the small intestine and proximal colon). In addition, mucins from the distal small intestine and the proximal colon seemed to contain fewer but longer oligosaccharide chains.