Mammalian liver is a sex steroid-responsive tissue. The effects of these hormones presumably are mediated by hepatic estrogen receptors (ER) and androgen receptors (AR). Serum levels of sex hormones display circadian rhythms. Further, estrogens and androgens are commonly administered; administration of these agents is associated frequently with liver disease. Therefore, we investigated whether the cytosolic and nuclear sex steroid receptors also display a similar circadian rhythm, and whether variations occurred in the distribution of receptors between cytosolic and nuclear compartments. Animals were killed every 4 h from midnight till the following midnight; cytosolic and nuclear levels of both ER and AR were measured. Cytosolic ER reached a maximum level at 4 AM, and a minimum at 8 PM and midnight of both days. Nuclear ER was highest at 8 AM and lowest at 4 PM and 8 PM, a pattern which parallels variations in serum estradiol levels. Cytosolic AR was highest at 8 PM and lowest at midnight and 4 AM. Nuclear AR was highest at 4 AM and lowest at 4 PM and 8 PM. The highest level of nuclear AR does not correspond to the maximum serum testosterone level, which occurred at 4 PM. The total hepatic content of both ER and AR was not constant over the 24-h period, but varied considerably with time of day. These studies suggest that both ER and AR show a distinct circadian rhythm in subcellular compartmentalization, and that total hepatic content of ER and AR varies significantly during a 24-h period.

Proximal and distal rat small intestine from control, diabetic, and insulin-treated diabetic rats was cut into strips measuring 6.0 X 10.0 mm. Strips cut along the oral-caudal axis were called longitudinal strips, while those cut 90 degrees to that axis were called circular strips. The strips were stretched to their optimum lengths and subjected to electrical field stimulation (0.1-1.0-ms pulse duration, 30-270 mA, 1-26 Hz) in the presence of Krebs' solution and Krebs' solution plus 10(-6) M atropine. Field stimulation produced atropine-sensitive and atropine-resistant contractions in all strips. Significant differences among the three groups were found in the amplitudes of atropine-sensitive contractions in strips from distal longitudinal muscle. Controls showed the highest amplitude contractions and diabetics the lowest, whereas the insulin-treated diabetics showed contractions intermediate in amplitude. No significant differences were noted among the atropine-resistant contractions. Field stimulation delivered at pulse durations of 5.0 and 50.0 ms in the presence of neural blockade with tetrodotoxin (5 X 10(-6) M) produced similar contraction amplitudes among the three groups. These results suggest that streptozotocin-induced diabetes mellitus is associated with defective cholinergic neuromuscular transmission in the myenteric plexus of the distal small intestine. Insulin therapy seems to improve the abnormality.

Phytohemagglutinin (PHA), derived from red kidney bean (Phaseolus vulgaris), can induce malabsorption and diarrhea when fed to rats. In this study, we determined the effect of PHA on ion transport in the rabbit ileum in vitro. Compared with control tissues, PHA (1 mg/ml) added to the mucosal solution increased short-circuit current (1.1 +/- 0.2 microEq/cm2 X h, p less than 0.001), decreased net Na (-1.0 +/- 0.5 microEq/cm2 X h, p less than 0.02) and Cl (-1.2 +/- 0.6 microEq/cm2 X h, p less than 0.025) absorption, and decreased tissue conductance (-1.8 +/- 0.5 mS/cm2, p less than 0.001). Serosal addition of PHA had no effect on the short-circuit current or tissue conductance. Mucosal PHA did not increase mucosal levels of cyclic adenosine monophosphate or cyclic guanosine monophosphate. Removal of serosal calcium did not affect the increase in short-circuit current induced by mucosal PHA. Utilizing fluorescent microscopy, rhodamine-labeled PHA was found to bind to the luminal border of villus cells, but not to crypt cells, in the ileum. In the descending rabbit colon, PHA did not affect either the short-circuit current or conductance, and rhodaminated PHA did not bind to the epithelial surface. Using the increase in short-circuit current as an indicator of absorption, PHA did not affect Na-coupled glucose or amino acid absorption in the ileum. This study suggests that dietary lectins may play a role in regulating intestinal fluid and electrolyte transport.

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.

The surface epithelial cells of Barrett's esophagus were characterized using quantitative scanning electron microscopy and light microscopy with mucin histochemical stains. Fifty-one biopsy specimens of Barrett's esophagus from 15 patients and 31 control specimens of the stomach and intestines from 9 patients were examined. Three distinct surface cell types, in addition to the goblet cell, were recognized in Barrett's epithelium: the gastric-like cell in 31% of specimens, which was similar to the normal gastric surface cell by quantitative scanning electron microscopy; the intestinal-like cell in 41%, which was most similar to the normal small intestinal surface cell; and the variant cell in 80%, which had a range of surface features. By light microscopy, all specimens with variant and intestinal-like cells were classified as specialized columnar epithelium. The surface mucous cells in Barrett's epithelium displayed a variety of mucin staining patterns with acid nonsulfated (small intestinal-like) mucin present in 90% of specimens and acid sulfated (colonic-like) mucin in 43% of specimens. Quantitative scanning electron microscopy and mucin histochemical stains reveal a striking cellular heterogeneity not apparent by routine light microscopy.

In portal hypertension the hemodynamic events after episodes of bleeding and blood transfusions may have important pathophysiological and therapeutic implications. The present study was designed to evaluate the effect of hemorrhage and blood restitution on splanchnic and systemic hemodynamics in a rat model of portal hypertension induced by portal vein constriction. In 16 portal hypertensive rats, sequential measurements of arterial and portal pressure were obtained during withdrawal and reinfusion of 15 ml X kg-1 body wt of blood. At the completion of the hemorrhage, a decrease of 16.9% +/- 2.6% in arterial pressure and 27.3% +/- 2.2% in portal pressure was observed. After blood reinfusion, arterial pressure returned to baseline values while portal pressure increased by 20.4% +/- 3.2% (p less than 0.01). This increase in portal pressure was not observed in 5 normal rats that were subjected to the same blood volume changes. Hemodynamic studies using a radioactive microsphere technique revealed that the withdrawal of 15 ml X kg-1 body wt of blood is followed by a decrease in portal venous inflow (6.4 +/- 0.4 vs. 10.4 +/- 0.6 ml X min-1 X 100 g-1 body wt in the control group, p less than 0.01). After blood volume restitution, the portal venous inflow returned to control values while the portal-collateral resistance increased significantly (2.06 +/- 0.13 vs. 1.67 +/- 0.07 mmHg X min X ml-1. 100 g, p less than 0.05). These results indicate that during hypovolemia there is a marked reduction in portal pressure because of a reduction in portal venous inflow. Blood volume restitution returns the portal venous inflow to control values. However, the portal pressure increases beyond control values because of an increase in portal-collateral resistance.

We studied liver regeneration after partial hepatectomy and the effects of inhibition of ornithine decarboxylase (ODC) and putrescine administration. The specific ODC inhibitor, alpha-difluoromethylornithine was given as a 3% oral solution (5.4 g/kg X day intake) to hepatectomized rats as well as sham-operated controls. alpha-Difluoromethylornithine had no effect other than inhibition of the low basal levels of ODC in sham-operated rats, but it markedly inhibited increases in ODC by 85% in hepatectomized rats. alpha-Difluoromethylornithine reduced hepatic deoxyribonucleic acid synthesis by 61%, protein synthesis by 46%, and liver weight increased by 83%, showing that alpha-difluoromethylornithine inhibition of ODC inhibits liver regeneration. Putrescine (2 mmol/kg X day) was then given intraperitoneally to hepatectomized rats and controls. Putrescine had no effect in rats not given alpha-difluoromethylornithine. In rats given alpha-difluoromethylornithine, putrescine markedly reversed the inhibitory effect of alpha-difluoromethylornithine on ODC (83%), deoxyribonucleic acid synthesis (94%), protein synthesis (95%), and liver regeneration (85%). These results document that the increases in ODC are important in hepatic regeneration and that polyamine metabolism plays an important role in the increased deoxyribonucleic acid and protein synthesis in this hepatic proliferative response.

The medical, anesthesia, and surgical records of 89 consecutive pediatric patients who underwent an orthotopic hepatic transplantation procedure at the University of Pittsburgh from February 1981 to May 1984 were reviewed to evaluate the effect of prior abdominal surgery upon the morbidity and mortality of orthotopic liver transplantation in children. Fifty-seven children (group 1) had had prior abdominal surgery, whereas 32 (group 2) had not. The group 1 subjects were younger (p less than 0.001), had better prothrombin times (p less than 0.01), and better platelet counts (p less than 0.02) than did those in group 2. No difference in the duration of anesthesia or intraoperative use of fresh frozen plasma or platelets was evident between the two groups. However, group 1 patients were given more red blood cells intraoperatively than were the group 2 patients (p less than 0.01). The group 1 patients had more total postoperative infections (p less than 0.05), which was due solely to a greater number of abdominal infections (p less than 0.05), but similar total hospital and intensive care unit stays as did the group 2 patients. When those in group 1 were divided into those having a previous Kasai procedure versus those who did not, no differences between the two groups were apparent except for age. Based upon these data, we conclude that prior abdominal surgery does not affect mortality, the duration of hospital or intensive care unit stay, plasma or platelet requirements, and total anesthesia time required for orthotopic liver transplantation, but does enhance the number of red blood cell transfusions and infections, particularly abdominal infections, in children undergoing this procedure.

Morphologic and enzymic differentiation occurs in rat small intestinal epithelium during 16-20 days of postnatal life. This change is considered to be initiated by an ontogenic timing mechanism and is modulated by extrinsic systemic and luminal factors. The importance of the ontogenic timing was tested directly using a transplantation technique in which jejunal isografts from newborn (day 0) and 5-day-old (day 5) rats were implanted under the skin of newborn (day 0) hosts. Isografts showing cryptvillus architecture were obtained in 44% and 21% of transplants, respectively. Day 0 isografts and host intestine expressed sucrase activity at about 16-18 days of age and showed similar crypt cell labeling and epithelial migration after [3H]thymidine injection. Day 5 isografts expressed sucrase activity when the hosts were 13 days of age, whereas host intestine showed no detectable sucrase activity. Isograft lactase activities in both experimental transplant models were significantly higher than host intestinal lactase up to 28 days of age, suggesting that luminal factors are important in modulating lactase activity during the first 4 wk of postnatal life. It is concluded that (a) no systemic factors at day 13 inhibit the expression of sucrase activity and (b) an ontogenic timing mechanism in the jejunum initiates the expression of sucrase activity.

Identifying the source of lower gastrointestinal hemorrhage in patients with chronic liver disease and portal hypertension can be challenging. We present 2 cases of hemorrhage from rectal varices and a discussion on the differences between simple hemorrhoids and rectal varices. Evaluation of rectal bleeding in patients with portal hypertension is discussed and possible therapeutic options are described.

We report 3 cases of hepatic venocclusive disease occurring in renal transplant patients receiving azathioprine and combine our experience with 4 other previously reported cases. The data suggest a clinical syndrome characterized by (a) delayed clinical onset, (b) striking male predominance, (c) presentation with jaundice followed by evidence of portal hypertension, and (d) poor prognosis. One of our patients, who is still alive 40 mo after the first onset of symptoms of liver disease, showed striking clinical improvement with discontinuation of azathioprine and subsequent deterioration on reinstitution. We suggest that azathioprine may be closely linked with the development of venocclusive disease in renal transplant patients and that the frequency of this disorder may be more common than previously reported. To attempt to prevent a fatal outcome, this group of patients should be closely monitored for the earliest signs of hepatic venocclusive disease through periodic serum bilirubin and alkaline phosphatase determinations. Patients with abnormal tests should undergo liver biopsy. If hepatic venocclusive disease is found, prompt withdrawal of azathioprine is indicated.

Protoporphyria was diagnosed in a 56-yr-old man based upon a typical clinical and family history, marked increases in erythrocyte and fecal protoporphyrin concentrations, and a marked decrease (21% of normal) in activity of hepatic heme synthase. Routine tests of liver function and histology were normal, except for a slight increase in bromsulphalein retention (9% at 45 min). Liver chemistries remained normal for 8 more years, but deteriorated rapidly when the patient was 63 yr old, with cholestasis precipitated by injury due to excess intake of ethanol. This, in turn, led to a defect in hepatic protoporphyrin excretion and to further worsening of liver injury due to porphyrin deposition. Our patient represents the 21st and oldest patient thus far reported to have died of liver failure complicating protoporphyria.

Hepatic morphology and immunocytology were evaluated in 4 children with clinical and immunologic characteristics of the acquired immune deficiency syndrome or acquired immune deficiency syndrome related complex. All 4 children had hepatomegaly and increased serum alanine and aspartate aminotransferase activity. Both lobular and portal changes were noted. Lymphocytic infiltration, piecemeal necrosis, hepatocellular and bile duct damage, sinusoidal cell hyperplasia, and endothelialitis were prominent. Vesicular rosettes in sinusoidal lymphocytes and tubuloreticular structures in sinusoidal endothelial cells were demonstrated by electron microscopy. The lymphocytic infiltrate in both the lobular and portal spaces was characterized by a relative increase of cytotoxic/suppressor (T8) cells. Hepatitis may be a common feature of pediatric acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. Although the histopathologic changes are consistent with chronic active hepatitis, the specific pathogenesis remains to be determined.