James A. Barrowman

Intestinal absorption and lymphatic transport of fish oil (MaxEPA) in the rat

Adult male, chow-fed Sprague-Dawley rats were given intraduodenally a bolus of emulsion of 0.5 ml of fish oil (MaxEPA) or olive oil plus 0.5 ml of 20 mM sodium taurocholate. Intestinal lymph was collected from a cannula in the main intestinal lymph trunk for various times after oil administration. There was no difference in the absorption of either type of oil over 6 and 24 h, over which times about 40 and 70% of the administered dose was taken up. For MaxEPA, the flux of triacylglycerols remained at a basal level of 0.07 mumol/min for 30 min, after which it rose rapidly to a maximum of 0.87 mumol/min between 90 and 120 min. The flux was 0.4 mumol/min for the subsequent 4 h. After 30 min, the composition of the lymph triacylglycerols began to change to show the presence of large proportions of fatty acyl chains that were characteristic of fish oil, especially eicosapentaenoate (20:5(n-3] and docosahexaenoate (22:6(n-3]. The composition of the lymph remained fairly similar to that of the fish oil for up to 6 h, the last time point at which detailed analysis was done. The docosahexaenoate in the triacylglycerols of the fish oil was primarily in the sn-2 position of glycerol, whereas a more random distribution of eicosapentaenoate over all glycerol positions was found. The positional distribution of the acids in the lymph triacylglycerols was similar to that in the fish oil. There was no evidence of substantial chain elongation or shortening during absorption. The results indicate that fish oil is effectively absorbed from the rat intestine without substantial alteration in the acyl chains of the triacylglycerols.

Further studies on the mechanism of inhibition of intestinal chylomicron transport by Pluronic L-81

This study explored further the hypothesis that intestinal cells have two pathways for producing large triacylglycerol-rich lipoprotein particles. The hydrophobic surfactant Pluronic L-81 (L-81) inhibits formation of chylomicrons (containing triacylglycerol synthesized from dietary fatty acids and monoacylglycerol, through the monoacylglycerol pathway), but not formation of very-low-density lipoproteins. L-81 does not inhibit lymphatic lipid transport during infusion of egg phosphatidylcholine, whose fatty acid is processed through the alpha-glycerol phosphate pathway and is transported in lymph in very-low-density lipoproteins. Thus, the first part of this study tested whether L-81 cannot inhibit the alpha-glycerol phosphate pathway, and thus L-81 can only affect chylomicron lipid secretion. Intestinal lymph fistula rats were infused with a lipid emulsion containing [1-14C]oleic acid, but no monoacylglycerol, to ensure that the oleic acid will be channeled to the alpha-glycerol phosphate pathway. Experimental rats received 1 mg/h of L-81 in their emulsion whereas control rats lacked L-81. Lymphatic triacylglycerol output, measured both chemically and radioactively, was markedly suppressed in the experimental rats as compared to the controls. Thus, these data indicate that the reason why lipid transport was unaffected by L-81 when egg phosphatidylcholine was infused was not because of the pathway used for the resynthesis of triacylglycerol from phosphatidylcholine. In the second part of this study, we measured the appearance time for chylomicron (in control rats) and for very-low-density lipoprotein (in L-81-treated rats). The appearance time is defined as the time between placement of radioactive fatty acid into the intestinal lumen and the appearance of radioactive lipid in the central lacteal. The average appearance time for the control rats was 10.8 min, which was significantly shorter than the 16.2 min in the L-81-treated experimental rats. This difference in appearance time further supports the hypothesis that chylomicron and very-low-density lipoprotein are packaged separately in the enterocytes and only the formation of chylomicron is inhibited by L-81.

Endoscopic Diagnosis of Intestinal Metaplasia in Canada and Japan

We carried out comparative studies on chronic atrophic gastritis with accompanying intestinal metaplasia using the methylene blue dye spraying, endoscopic technique on 167 Japanese and 77 Canadian outpatients free of gross stomach disease. In both population samples (Kyoto, Japan and St. Johns, Newfoundland) with increasing subject age, the fundic-pyloric (F-P) border shifted cephalad indicating atrophy of the fundic mucosal glands. Japanese subjects, however, showed greater variation in location of the F-P border. The reduction in fundic gland area with aging was followed by intestinal metaplasia, the incidence and severity of which was greater in Japanese than in Canadian outpatients. From these data we conclude that a difference in the gastric mucosa in these two countries may be related to the pathogenesis of gastric cancer.

Double pylorus--in evolution.

Double pylorus is a rare abnormality. Over a 4-year period, we have found two cases of double pylorus in 2,500 endoscopic examinations, an incidence of 0.08%. In one patient, the development of double pylorus from a prepyloric ulcer was followed by serial endoscopies. Most cases of double pylorus are acquired from peptic ulcer disease.

Influence of gastric pH on digoxin biotransformation

High‐performance liquid chromatography (HPLC) analysis was performed on methylene chloride extracts of urine from six subjects after administration of 3H‐digoxin‐12α and unlabeled digoxin by nasogastric tube under four conditions: pentagastrin and control saline infusions, each in the supine and ambulatory states. There were no differences with change in position. With pentagastrin stimulation of acid secretion, there was extensive intragastric hydrolysis, mainly to digoxigenin; there was further extensive biotransformation leading to an increase in both extractable and unextractable metabolites in urine, particularly the latter. In the first 5 hr mean digoxin was only 17% and unextractable metabolites were 54% of total urine radioactivity. Extractable radioactivity was found under HPLC peaks with retention times of digoxin, digoxigenin, and its mono‐ and bis‐digitoxosides. There were also three other peaks that were not identified; two correlated with gastric H+ activity and with the peak for digoxigenin, which is probably their precursor since similar peaks were found after ingestion of digoxigenin. The third unidentified peak eluted immediately after the digoxin, with which it correlated: it may have a close structural relationship to digoxin. Gastric acid stimulation induced a major increase in the production of urinary metabolites and may prove a useful model for the study of digoxin biotransformation, which is not yet well defined.

Periosteal new bone formation and disseminated granulomatosis in a patient with Crohn's disease

In a 20-year-old man, a proliferative periosteal new bone growth developed over the left forearm. Crohns disease had been diagnosed the year before. Bone biopsy demonstrated granuloma formation. Biopsy specimens of skin lesions demonstrated granulomas as well. Bowel studies indicated active small intestinal inflammation with fistula formation. Despite the superficial resemblance to hypertrophic osteoarthropathy, it is believed that this case represents Crohns disease with disseminated granulomatosis involving skin and periosteum.

Fusidic acid-induced hyperbilirubinemia

SummaryA 72-year old man developed jaundice while on fusidic acid therapy for suspected osteomyelitis. Hyperbilirubinemia was predominantly of the conjugated variety and elevation in liver enzymes was mild and transient. Although serum bilirubin fell rapidly after fusidic acid was stopped, complete resolution of the hyperbilirubinemia took nearly a month. Other possible causes of jaundice were excluded. Light microscopy of a needle liver biopsy showed focal hepatocyte feathery degeneration, intracellular bile retention, and canalicular bile plugging, most prominent in perivenous regions. Electron microscopy revealed varying degrees of canalicular dilatation, loss of microvilli, and disruption of the canalicular membrane with vesicular bleb formation as well as canalicular bile plugs. Widening of the pericanalicular ectoplasmic zone with accumulation of cytoskeletal filaments was also noted. These findings are similar to those reported in experimental cholestasis induced by bile acids. Possible mechanisms of jaundice caused by fusidic acid are discussed.

A chylous mesenteric cyst and a study of its contents.

SummaryA case of a patient with a large chylous cyst in the mesentery of the small intestine is presented. After excision of the cyst, the chyle was analyzed with special reference to its protein and lipid content. The composition of the chyle compared with that of intestinal lymph of experimental animals suggests that the fluid in the cyst has undergone concentration in terms of protein.

Sclerosing hepatitis and azathioprine.

To The Editor: Reports of direct hepatotoxic effects of azathioprine are uncommon, although cholestasis has been recorded (1, 2) and its metabolite, 6-mercaptopufine, in high doses can cause hepatitis (3). We wish to repo~I a case of rapidly progressive sclerosing hepatitis in a patient receiving high doses of azathioplfine for a neurological disease. A 35-year-old white male developed a demyelinating motor and sensory neuropathy diagnosed as dysimmune polyneuropathy treated initially with prednisone and subsequently with azathioprine (3-3.5 mg/kg/day) over eight years. For four years he also had a course of 35 plasmaphereses with plasma replacement. Twelve years after the start of the neurological di,;ease, he developed fatigue, fever, and jaundice with cholestatic features. There was no history of excessive alcohol ingestion or of drug abuse. A liver biopsy showed a moderate lymphocytic infiltration of the ported tracts with intact marginal plates and changes of cholestasis. The jaundice persisted; the main biochemical changes were hypoalbuminemia (2.7 g/dl), SGOT 350 units/liter (normal < 40 units/ liter), sermn alkaline phosphatase 287 units~ter (normal < 110 units/liter), and serum bilirubin 10 mg/dl. The serum ferritin was 3550 ng/ml (normal < 320 ng/ml). ERCP showed a normal biliary tree. An autoantibody screen was negative, and viral studies, CM and EB virus, were negative; hepatitis B surface antigen was negative. The azathioprine was stopped. Four months later, with continuing evidence of ongoing liver disease, liver biopsy was repeated showing moderate centrilobular cholestasis and an increase in portal and periportal fibrosis with infiltration of acute and chronic inflammatory cells and erosion of the marginal plates. He subsequently developed ascites, peripheral edema, and renal failure with steady deterioration in liver function, and he died in hepatic encephalopathy five months after the onset of clinical liver disease. Autopsy showed an extensive fibroinflarnmatory process of zones I and II involving more than 50% of the liver, with atrophy and disruption of liver cell cords. There was phlebitis and sclerosis of the terminal hepatic veins. Electron microscopic studies showed no evidence of a viral agent in the hepatocytes or bile ductular cells. The cause of this rapidly progressive liver disease in a patient irnmunosuppressed with azathioprine is unclear. There is some similarity to a case of a renal transplant patient who received azathioprine (3 mg/kg/day) and developed a fatal fibrosing liver disease which began 16 months after transplantation (4). Nevertheless, reports of liver injury with azathioprine are very uncommon and, since its use is generally in patients with complex medical problems, it is probable that multiple factors contribute to liver damage in these rare cases. Possibilities include a reaction to viral infection in an immunosuppressed host, although in our patient no cytopathic changes were observed in hepatobiliary cells suggestive of a viral infection and the rapid progression of a sclerosing process is unusual for most known viral liver diseases. In general it appears that where azathioprine dosage is kept below 2 mg/kg/day there is no substantial incidence of clinical liver disease (5). Recently, De Pinho et al (6) have described a possible idiosyncratic effect of azathioprine in a patient with systemic lupus erythematosus. The hepatic changes, centrilobular cholestasis and edema, regressed in two weeks fop lowing discontinuation of the drug: Thus, there is evidence that cholestasis and hepatocellular injury, which are usually reversible, are associated with azathioprine treatment, but it is possible that a fibroinflammatory process may be initiated, which on rare occasions rapidly progresses, leading to hepatic failure. J.A. BARROWMAN, FRCP P.K. KuyrY, FRCP(C) M.U. RA, FRCP(C) S.-N. HUANG, FRCP(C) Departments of Medicine and Pathology Faculty of Medicine Memorial University of Newfoundland Health Sciences Centre St. Johns, Newfoundland, A1B 3V6

Proteins of ascitic fluid in constrictive pericarditis

A patient with chronic calcific pericarditis, hepatic congestion, and fibrosis had massive ascites with a protein concentration of 5.1 g/100 ml. This fluid was in all likelihood largely derived from hepatic interstitial fluid. The ascites-serum concentration ratio for several protein species and molecular exclusion chromatography of these fluids suggested two processes may be involved in the transfer of protein from serum to ascites, namely bulk transfer of all species and molecular sieving.SummaryA patient with chronic calcific pericarditis, hepatic congestion, and fibrosis had massive ascites with a protein concentration of 5.1 g/100 ml. This fluid was in all likelihood largely derived from hepatic interstitial fluid. The ascites-serum concentration ratio for several protein species and molecular exclusion chromatography of these fluids suggested two processes may be involved in the transfer of protein from serum to ascites, namely bulk transfer of all species and molecular sieving.