Iron-rich foci in chronic viral hepatitis.

Stainable iron in the liver (hemosiderosis) is most commonly seen in individuals with homozygous genetic hemochromatosis, prior transfusion, hemolysis, porphyria cutanea tarda, and chronic alcohol-induced liver disease. In chronic viral hepatitis, however, significant hepatocellular hemosiderosis is uncommon. This report describes unusual foci of hepatocellular hemosiderosis ("iron-rich foci" or IRF) in liver biopsy specimens from three patients with chronic hepatitis with or without cirrhosis (two hepatitis C-related, one hepatitis B-related). IRF present within the lobular parenchyma or cirrhotic nodules contrasted sharply with the immediately adjacent hemosiderin-negative liver tissue. Serum iron indices were abnormal in all three patients, but homozygous hemochromatosis was ruled out based on the hepatic iron concentration and hepatic iron index for each case. These cases highlight the potential for irregular iron storage in chronic viral liver disease and possible confusion with genetic hemochromatosis. The possible pathogenesis of IRF and the relationship of iron storage to the outcome of interferon therapy in chronic viral hepatitis are discussed.

Escalating interferon-alpha-2b dose for patients with chronic hepatitis C.

BACKGROUND/AIMS: We examined the effectiveness of escalating the dose of interferon-alpha-2b in subjects with chronic hepatitis C who did not respond to usual treatment with 3,000,000 units 3 times a week. METHODOLOGY: Treatment was started with 3,000,000 units of interferon-alpha-2b 3 times a week. If serum alanine aminotransferase activity was not normal at 12 weeks, the dose was increased to 3,000,000 units daily. If serum alanine aminotransferase activity was not normal after 12 weeks, the dose was increased to 5,000,000 units daily. RESULTS: Fifty-one subjects started treatment. Twenty-nine subjects had their dose increased to 3,000,000 units daily and only 1 responded (3%, 95% confidence interval 0-10.9%) while 41% (95% confidence interval 21.4-60.6%) had to discontinue treatment at this dose because of adverse events or intolerance. Of 14 subjects who had their dose increased to 5,000,000 units daily, none (95% confidence interval 0-3.6%) responded, while 43% (95% confidence interval 13.5-72.5%) had to discontinue treatment. CONCLUSIONS: Escalating doses of interferon-alpha-2b are not effective and are associated with increased toxicity and intolerance in patients with chronic hepatitis who do not respond to initial treatment with 3,000,000 units 2 times a week.

Apolipoprotein synthesis in normal and abetalipoproteinemic intestinal mucosa.

The genetic disease abetalipoproteinemia is characterized by a total absence of apolipoprotein B-containing lipoproteins from plasma. A presumed synthetic defect in apolipoprotein B synthesis was thought to be responsible for this disorder. The present study quantitates apoprotein B synthesis and apolipoprotein B messenger RNA levels in duodenal mucosa from normal patients and four patients with abetalipoproteinemia. After in vitro [3H]leucine incorporation, small intestinal biopsy specimens from three of four patients with abetalipoproteinemia synthesized immunoprecipitable apolipoprotein B of identical mobility (on sodium dodecyl sulfate gel electrophoresis) to normal apolipoprotein B. In abetalipoproteinemia, the apolipoprotein B content of intestinal mucosa by radioimmunoassay was 15% of normal mucosal values, whereas apolipoprotein B messenger RNA quantitation showed 3-20-fold increased levels compared with normal mucosa. In one patient, smaller-molecular-weight fragments of apolipoprotein B were immunoprecipitated from duodenal biopsy specimens. The synthesis rates and messenger RNA levels of two other chylomicron apoproteins (apolipoprotein A-I and apolipoprotein A-IV) were found to be reduced by 50%. These results show the synthesis of immunologically recognizable apolipoprotein B48 in abetalipoproteinemia. The significance of mucosal apolipoprotein B content in abetalipoproteinemia is discussed in terms of factors controlling apolipoprotein B synthesis in normal mucosa and in abetalipoproteinemia.

Acute deterioration of renal function associated with enteric hyperoxaluria.

Enteric hyperoxaluria due to malabsorption syndromes has been well documented to cause renal calculi and chronic tubulointerstitial renal damage. Rarely, in the setting of intestinal bypass operations for morbid obesity, enteric hyperoxaluria has produced acute renal failure. We report two patients who suffered acute deterioration of renal function associated with increased intestinal absorption and renal excretion of oxalate associated with steatorrhea. One patient had a large portion of his small bowel resected many years prior to the onset of the renal failure and the second patient had chronic pancreatitis causing steatorrhea. Both patients had renal biopsy documentation of the acute nature of the tubular damage produced by oxalate deposition. The mechanisms of their deterioration of renal function may relate to sudden increases in steatorrhea in association with episodes of volume depletion. Enteric hyperoxaluria may be an easily overlooked and potentially preventable etiology of acute renal dysfunction.

Intracellular apoA-I and apoB distribution in rat intestine is altered by lipid feeding.

Intracellular forms of chylomicrons, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) have previously been isolated from the rat intestine. These intracellular particles are likely to be nascent precursors of secreted lipoproteins. To study the distribution of intracellular apolipoprotein among nascent lipoproteins, a method to isolate intracellular lipoproteins was developed and validated. The method consists of suspending isolated enterocytes in hypotonic buffer containing a lipase inhibitor, rupturing cell membranes by nitrogen cavitation, and isolating lipoproteins by sequential ultracentrifugation. ApoB and apoA-I mass are determined by radioimmunoassay and newly synthesized apolipoprotein characterized following [3H]leucine intraduodenal infusion. Intracellular chylomicron, VLDL, low density lipoprotein (LDL), and HDL fractions were isolated and found to contain apoB, and apoA-IV, and apoA-I. In the fasted animal, less than 10% of total intracellular apoB and apoA-I was bound to lipoproteins and 7% of apoB and 35% of apoA-I was contained in the d 1.21 g/ml infranatant. The remainder of intracellular apolipoprotein was in the pellets of centrifugation. Lipid feeding doubled the percentage of intracellular apoA-I bound to lipoproteins and increased the percentage of intracellular apoB bound to lipoproteins by 65%. Following lipid feeding, the most significant increase was in the chylomicron apoB and HDL apoA-I fractions. These data suggest that in the fasting state, 90% of intracellular apoB and apoA-I is not bound to lipoproteins. Lipid feeding shifts intracellular apolipoprotein onto lipoproteins, but most intracellular apolipoprotein remains non-lipoprotein bound. The constant presence of a large non-lipoprotein-bound pool suggests that apolipoprotein synthesis is not the rate limiting step in lipoprotein assembly or secretion.

Intestinal apolipoprotein A-I and B-48 metabolism: effects of sustained alterations in dietary triglyceride and mucosal cholesterol flux.

In recent studies (1985. J. Lipid Res. 26:368-379 and 1986. J. Lipid Res. 27:30-39) we characterized aspects of synthesis of rat intestinal apolipoproteins (apo) A-I and B-48 in vivo, and their short term regulation by dietary and biliary lipid flux. We now report studies extending these observations to the effects on intestinal apoA-I and apoB-48 metabolism of sustained (3 or 6 weeks) isocaloric intake of diets containing 0-30% (by weight) triglyceride, the latter as either butter fat (saturated) or corn oil (polyunsaturated). Additional studies were conducted to determine, separately, the effects of perturbations of intestinal mucosal cholesterol flux and hypothyroidism on intestinal apoA-I and apoB-48 metabolism. Intestinal synthesis (% total protein) of apoA-I and apoB-48 was not influenced by either dietary triglyceride quantity or quality (saturated vs. polyunsaturated fat); the values that were obtained were strictly comparable to those of both chow-fed animals and animals maintained for 3 weeks on fat-free chow. Intestinal apoA-I synthesis was not influenced by either acute or chronic perturbations of mucosal cholesterol flux. Hypothyroid rats demonstrated a 50% suppression of jejunal apoA-I synthesis. Intestinal synthesis of apoB-48, by contrast, appeared to undergo regulation by chronic (but not acute) perturbations of mucosal cholesterol flux. Maneuvers that augmented intestinal cholesterol uptake (particularly hypothyroidism) appeared to suppress intestinal apoB-48 synthesis by over 40%, while Surfomer (AOMA) administration reduced cholesterol absorption (control, 54 +/- 7%; AOMA, 26 +/- 8%; P less than 0.0005) and resulted in a 24% increase in apoB-48 synthesis by jejunal enterocytes. Intracellular intestinal lipoproteins demonstrated marked cholesteryl ester enrichment of the triglyceriderich lipoprotein fractions in hypercholesterolemic, hypothyroid rats. When all the groups were compared, cholesterol absorption (used as an index of mucosal cholesterol uptake) was negatively correlated with jejunal apoB-48 synthesis (r = -0.92, P less than 0.05). The data suggest that regulation of rat intestinal apoA-I and apoB-48 metabolism is independent of triglyceride flux. It is further concluded that an important regulatory effect of mucosal cholesterol flux can be demonstrated on enterocyte apoB-48 synthesis. Finally, the data suggest the additional possibility that circulating levels of thyroid hormone may exert an independent effect on the expression of rat intestinal apolipoproteins A-I and B-48.

Isolation of high density lipoproteins from rat intestinal epithelial cells.

Previous studies have defined forms of high density lipoproteins (HDL) in rat mesenteric lymph, suggesting that they have a secretory origin. This study describes the isolation and characterization of intestinal intracellular HDL. Two preparations were made as follows: (a) Rat enterocytes were isolated and a Golgi organelle fraction was prepared. (b) Cell homogenates were subjected to nitrogen cavitation and a cytoplasmic fraction was prepared. Lipoproteins were isolated from both preparations by sequential ultracentrifugation. When the HDL fraction (1.07-1.21 g/ml) was subjected to isopyknic density gradient ultracentrifugation, a peak of apoproteins A-I and B (apoA-I and apoB, respectively) was found at a density of 1.11-1.14 g/ml. Electron microscopy of the fraction showed spherical particles ranging in size from 6 to 13 nm. Immunoelectrophoresis revealed a precipitin arc in the alpha region against apoA-I which extended into the pre-beta region where a precipitin arc against apoB was also seen. ApoB antisera depleted the pre-beta particles whereas the alpha migrating particles remained. Lipid analysis of the whole HDL fraction revealed phospholipid, cholesteryl ester, and triglyceride as the major lipids. [3H]leucine was then administered into the duodenum and a radiolabeled intracellular HDL fraction was isolated. The newly synthesized apoproteins of the HDL fraction, as determined by gel electrophoresis, were apoB, apoA-I, and apolipoprotein A-IV (ApoA-IV). Immunoprecipitation of the apoB particles revealed apoA-I and apoA-IV in the supernatant. These data demonstrate that there are at least two intracellular intestinal forms of HDL particles, one of which contains apoB. The other particle contains apoA-I and apoA-IV, has alpha mobility, is spherical, and resembles a particle found in the lymph.

Intestinal strongyloidiasis. A case report and review of the literature.

A patient infected with Strongyloides stercoralis presented with hematemesis and abdominal pain mimicking peptic ulcer disease. Radiologic evaluation, however, suggested Crohn's disease of the proximal small intestine. Aspiration of intestinal fluid and a small bowel biopsy lead to a diagnosis of invasive strongyloidiasis. This case is presented and the literature reviewed to demonstrate the protean manifestation of this parasite which commonly involves the gastrointestinal tract.

Colorectal carcinoma 15 years after the diagnosis of perianal Paget disease.

We report a patient with perianal Paget disease who developed a colorectal carcinoma fifteen years later, complicated by pseudomyxoma peritoneal. While perianal Paget disease is often associated with underlying carcinomas noted at the time of the diagnosis, we suggest that perianal Paget disease may also predispose to the future development of colorectal cancer.