Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high-risk patients - a POCER study analysis.

BACKGROUND: Crohn's disease recurs in the majority of patients after intestinal resection. AIM: To compare the relative efficacy of thiopurines and anti-TNF therapy in patients at high risk of disease recurrence. METHODS: As part of a larger study comparing post-operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine-intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment. RESULTS: A total of 101 patients [50% male; median (IQR) age 36 (25-46) years] were included. There were no differences in disease history between thiopurine- and adalimumab-treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2-i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab-treated patients [intention-to-treat (ITT); P = 0.028] or 24 of 62 (39%) vs. 3 of 24 (13%) respectively [per-protocol analysis (PPA); P = 0.020]. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab). CONCLUSIONS: In Crohn's disease patients at high risk of post-operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.

Epidemiology of hepatitis B-associated hepatocellular carcinoma in Victoria.

BACKGROUND: Chronic hepatitis B (HBV) and cirrhosis are major risk factors for hepatocellular carcinoma (HCC). The proportion and characteristics of cases with cirrhosis are not well documented. AIM: Our aim was to compare demographic, viral and tumour characteristics of HBV-associated HCC in an Australian cohort, in patients with and without cirrhosis. METHODS: Existing HCC databases at six Melbourne teaching hospitals were reviewed for cases associated with HBV. Patient demographics, HBV viral characteristics, presence of cirrhosis, serum alpha-fetoprotein and tumour size were assessed. Mode of diagnosis was recorded through surveillance or symptoms, and treatment was either palliative, percutaneous or surgical. RESULTS: We identified 197 cases of HBV-related HCC. The mean age was 57.9 ± 12.9 years; 83% were male, and 55.3% and 35.3% were of Asian and European descent respectively. Of 168 patient with available data, 146 (87%) had cirrhosis versus 22 (13%) without. Patients with cirrhosis tended to be older (median 60 vs 52 years, P = 0.078). Asian patients were more likely to have HCC without cirrhosis than Europeans (17% vs 6%, P = 0.04). There were no other differences identified between cirrhotic and non-cirrhotic patients. Thirty-four per cent of patients had tumours greater than 5 cm at diagnosis, and 47% were diagnosed after presenting with symptoms. Twelve patients with HBV-HCC were outside current screening guidelines. CONCLUSION: Most patients in Melbourne with HBV-associated HCC have cirrhosis. HCC characteristics in non-cirrhotic and cirrhotic patients were similar. The large number of patients detected through symptoms and with large tumours reinforces the need for vigilance in screening.

Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression.

H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130(757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting.

Sleep-disordered breathing in stable methadone programme patients: a pilot study.

AIMS: To explore the possibility that stable MMP patients have sleep-disordered breathing (SDB) and abnormal sleep architecture defined by nocturnal sleep stages and sleep efficiency. DESIGN: Observational. SETTING: Regional Methadone Service and sleep disorders laboratory in a university affiliated hospital. Participants and measurements. Ten stable MMP patients and nine normal subjects were assessed clinically and with overnight polysomnography. FINDINGS: There were no differences in age, sex and body mass index between the groups. The methadone dose ranged between 50 and 120 mg/day. Six patients had central apnoea index (CAI) greater than 5, four had a CAI greater than 10 and three of these exhibited periodic breathing. No normal subject had central sleep apnoea. The patients had lower sleep efficiency (p < 0.05), less slow wave sleep (p < 0.01), less rapid eye movement sleep (p < 0.05) and more Stage 2 sleep (p < 0.05) than controls. CONCLUSIONS: Stable MMP patients have more sleep architecture abnormalities than controls and a higher prevalence of central sleep apnoea. Further studies are needed to confirm these findings, to delineate the mechanisms for the abnormalities and to assess whether the SDB is related to sudden death in stable MMP patients. We recommend that MMP patients have awake and sleep respiration assessed to identify those potentially at risk.

Adult asthma and gastro-oesophageal reflux: the effects of omeprazole therapy on asthma.

BACKGROUND: Approximately 40-60% of patients with asthma have gastro-oesophageal reflux (GOR) and it has been postulated that this may worsen asthma severity. AIMS: To investigate the effect of the potent gastric acid inhibitor omeprazole 40 mg orally daily on peak expiratory flow rate (PEFR), asthma symptoms and histamine bronchial responsiveness in adult patients with both asthma and GOR. METHODS: This was a double blind, randomised, placebo controlled, crossover study. Upper gastrointestinal endoscopy, 24 hour oesophageal pH measurements, spirometry and histamine bronchoprovocation test (HIT) were performed prior to entry. Phase 1:2 week placebo run-in period, with baseline recording of PEFR, asthma and GOR symptoms, and use of inhaled beta 2-agonist. Phase 2: patients randomised to receive either placebo or omeprazole 40 mg/d for four weeks. Phase 3: placebo for two weeks. Phase 4: patients crossed over to opposite treatment from that of phase 2. Spirometry, and diary cards were assessed at beginning and end of phases 2 and 4. HIT was performed at the end of phase 2 and at the beginning and end of phase 4. RESULTS: Twenty patients (eight female and 12 male) completed the study. The evening but not morning PEFR (% predicted) were significantly higher on omeprazole vs placebo (82 +/- 4% SEM vs 79 +/- 4% SEM; p < 0.05). No significant differences were found in FEV1, FVC, histamine bronchial responsiveness and diurnal variation of PEFR between placebo and omeprazole treatments. Similarly, there were no significant differences during placebo and omeprazole periods in day time wheeze, cough, breathlessness, beta 2-agonist use or night time wheeze and breathlessness. Day and night heartburn symptoms were significantly better on omeprazole vs placebo (p < 0.05). CONCLUSIONS: Omeprazole 40 mg daily improved evening PEFR in asthma patients with GOR. However, asthma symptoms, inhaled beta 2-agonist use and histamine bronchial responsiveness did not change.

High prevalence of duodenal ulcer in Indochinese immigrants attending an Australian university hospital.

Indochinese migrants to Australia appear to have a high prevalence of duodenal ulcer (DU). To examine this hypothesis a 2 year audit of the prevalence of symptomatic DU among patients attending a general hospital was conducted. The last 6 months of this period included a prospective assessment of ulcer risk factors. In Australian-born patients DU prevalence was 8.4 per 1000 admissions. By comparison, prevalence in Indochinese was 24.6 per 1000 admissions (P < 0.001) with an age standardized prevalence of 30.3 per 1000 (P < 0.001). This represented a relative risk in Indochinese of 2.9 using crude data and 3.6 after age standardization. The increased risk was demonstrated only in males: very few DU were diagnosed in female Indochinese. Ulcer prevalence increased in Indochinese for each age decile between 10 and 80 years, with statistical significance (P < 0.01) reached in the age brackets 0-19, 20-39 and 60-79 years. Ulcer prevalence was also increased in some other ethnic groups. However, when referral bias was taken into account (by calculating the ratio of endoscopies to total admissions for each group), a significant increase in DU prevalence could only be confidently demonstrated in Indochinese. Analysis of risk factors showed that among DU patients, Indochinese were significantly less likely to smoke (P < 0.05) and also had a tendency to ingest less non-steroidal anti-inflammatory drugs (NSAID) and to consume less alcohol.

The characteristics of alcoholic liver disease in Japan. Clinicopathologic comparison with alcoholic liver disease in the United States.

Alcoholic liver disease (ALD) in Japan was compared clinicopathologically with the occurrence in the U.S.A. ALD found in Japan was more frequently complicated by other hepatic diseases including non-A, non-B chronic hepatitis than ALD found in the U.S.A. (9.9% versus 21.9%). Patients with such complications were excluded from this study. The chief complaints of the total of 51 alcoholics studied in the U.S.A. were abdominal distension or jaundice and those of 98 alcoholics studied in Japan were non-specific: general fatigue, weakness or appetite loss. The U.S. patients exhibited more elevated levels of serum bilirubin (8.1 +/- 7.5 versus 1.9 +/- 2.4 mg/dl, mean +/- SD) and a higher incidence of leukocytosis (49.0% versus 5.1%). While the serum glutamic-oxalacetic transaminase (GOT) levels were not significantly different between the two groups (146.5 +/- 116.8 versus 140.8 +/- 147.7 IU/L), the serum glutamic-pyruvic transaminase (GPT) levels among Japanese alcoholics were higher (38.6 +/- 31.4 versus 87.4 +/- 99.1 IU/L) and in about one quarter of these patients, serum GPT was higher than serum GOT, a feature not seen in the patients in the U.S.A. Comparative histopathologic study of 337 U.S. patients and 210 Japanese patients disclosed a higher frequency of cirrhosis (46.9% versus 33.8%), the presence of Mallory bodies (58.5% versus 13.8%) and marked neutrophilic exudation (45.1% versus 6.2%). Thus, the majority of Japanese alcoholics exhibited progression of liver disease, eventually leading to cirrhosis, due to hepatocellular drop-out and fibrosis caused by a mechanism different from alcoholic hepatitis. In addition, ALD in the U.S.A. revealed more striking extension of fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of reflux oesophagitis with a carbenoxolone/antacid/alginate preparation. A double-blind controlled trial.

Twenty-nine patients were treated with a carbenoxolone/antacid/alginate preparation (Pyrogastrone) and 30 with antacid/alginate alone four times each day for 8 weeks, in a double-blind study, to ascertain the value of carbenoxolone in the treatment of patients with endoscopically confirmed reflux oesophagitis. Symptom review every 2 weeks and endoscopic findings every 4 weeks were converted to a 6-point grading system to facilitate statistical comparison, using a stochastic model for predicting the rate of change in grades during treatment. Carbenoxolone-treated patients showed an 82% improvement in symptom grades over 8 weeks and improved 50% faster (P less than 0.01) than did control patients, who showed a 63% improvement. Endoscopic improvement was not significantly different in the first 4 weeks, although healing was better maintained in carbenoxolone-treated patients during the second 4 weeks (P less than 0.05). At the low doses used (5 X 20 mg daily) no significant side effects of carbenoxolone were encountered. Pyrogastrone should be considered as a therapeutic alternative in patients who fail to respond to routine management with antacids.

Factors that determine refractoriness of ascites to conventional therapy.

We compared the charts of 33 patients who had refractory ascites with those of 33 patients who had responsive ascites to identify factors responsible for resistance to conventional therapy. The results of biochemical tests of liver function were more abnormal in the responsive group than in the refractory group on admission to hospital, whereas the results of kidney function tests were worse in the refractory group. The transhepatic portal pressure was similar in the 7 patients with refractory ascites and the 11 patients with responsive ascites in whom it was measured. The portal vein pressure as calculated from the difference in albumin content between the serum and the ascitic fluid was similar in the two groups, as were the findings at histologic examination of the liver. We conclude that neither the severity of the liver disease nor the portal pressure is a critical factor in the development of refractory ascites. Kidney dysfunction, however, is important, but its mechanism remains unclear.

Effects of sulindac and ibuprofen in patients with cirrhosis and ascites. An explanation for the renal-sparing effect of sulindac.

Nonsteroidal antiinflammatory drugs impair renal function in susceptible patients with cirrhosis and ascites. A new antiinflammatory drug, sulindac, is reported not to affect renal function. To evaluate its renal-sparing mechanism, sulindac was administered for 5 days and ibuprofen for 1 day to 10 patients and paraaminohippurate and inulin clearances, serum and urine eicosanoids, and serum and urine sulindac metabolites were monitored. Ibuprofen reduced renal clearances in the 5 subjects with greatest sodium retention, whereas sulindac had no effect. Plasma concentration of the active sulfide metabolite was markedly increased in liver patients, and this concentration correlated with the inhibition of serum thromboxane (r = 0.75, p = 0.01). The percent inhibition of serum thromboxane with sulindac administration correlated with the inhibition of urinary eicosanoids (r = 0.68-0.81, all p less than 0.02). Ibuprofen was generally a more potent inhibitor of serum and urine eicosanoids. Thus, a major factor in the renal-sparing effect of sulindac appears to be its less potent inhibition of renal and extrarenal cyclooxygenase systems.

Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites: evidence that sulindac affects renal prostaglandins.

Nonsteroidal anti-inflammatory drugs (NSAID) suppress prostaglandin-dependent renal blood flow and furosemide-induced diuresis in patients with cirrhosis and ascites. Since sulindac may selectively spare inhibition of renal prostaglandins, we evaluated the interactions of acute administration of sulindac or indomethacin with furosemide in 15 patients with cirrhosis and ascites. Prior to furosemide, indomethacin reduced creatinine clearance (by 55%), urinary volume (by 82%), sodium (by 93%), and prostaglandin E2 (by 87%) (all P less than 0.05), whereas sulindac had no effect. However, both drugs reduced furosemide-induced diuresis. Indomethacin appeared slightly more potent in reducing the diuresis (55% v 38%), natriuresis (67% v 52%), and prostaglandin E2 (PGE2) release (81% v 74%). In a similar protocol in healthy subjects, furosemide-induced diuresis and natriuresis were also blunted by both drugs. Thus, under conditions of enhanced prostaglandin activity from furosemide, sulindac does affect renal function. These data suggest that renal function should be monitored in patients with cirrhosis and ascites who receive sulindac as well as other NSAID.

High serum levels of alkaline phosphatase are associated with cancer in cholestatic jaundice.

In a prospective study of liver function tests in cholestatic jaundice, the median serum level of alkaline phosphatase (ALP) in 129 patients with cancer involving extrahepatic ducts and liver (556 IU/1) was significantly higher (P less than 0.001) than that in 121 patients without cancer (264 IU/1). Of patients with an ALP level of greater than 10 X N, 88% had cancer whereas serum levels of ALP of less than 3 X N were observed in only 9% of patients with cancer but in 45% of those without cancer, most of whom had bile duct stones. A high serum level of ALP is associated with cancer involving extrahepatic ducts and liver.

Therapeutic trial of thromboxane synthesis inhibition in the hepatorenal syndrome.

Urinary excretion of the vasoconstrictor metabolite thromboxane B2 is increased in some patients with the hepatorenal syndrome. To define the role of thromboxanes in this syndrome and to evaluate a potential treatment for the renal impairment, we administered the thromboxane synthetase inhibitor dazoxiben to 5 patients with alcoholic hepatitis and rapidly progressive renal failure. Dazoxiben 200 mg/day followed by 400 mg/day reduced urinary thromboxane B2 by approximately 50% without altering prostaglandin E2 or 6-keto prostaglandin F1 alpha and without improving creatinine clearance (6 +/- 2 to 6 +/- 3 ml/min). In 3 additional patients, a higher dose of dazoxiben of 600 mg/day reduced thromboxane B2 by approximately 75% without consistent improvement in renal function. Thus, as judged by selective thromboxane inhibition with dazoxiben, thromboxanes are unlikely to be the key renal vasoconstrictor factor in the hepatorenal syndrome.

Alcoholic hyalin-containing hepatocytes--a characteristic morphologic appearance.

We studied the morphologic appearance of alcoholic hyalin (AH)-containing hepatocytes in liver biopsies from 14 patients with alcoholic liver disease. Most hepatocytes had a characteristic appearance. The cells were swollen and hydropic with an intact cell membrane. The mitochondria had variable-sized cristae which were both shortened and elongated. The smooth endoplasmic reticulum was markedly decreased. The rough endoplasmic reticulum was bizarre, with detachment of the ribosomes that surrounded the AH. The hepatocytes that contained AH bodies had lost almost all the glucose-6-phosphate activity but had variable amounts of succinic dehydrogenase and diphosphopyridine nucleotide diaphorase activities. The neutrophils admixed with mononuclear cells attached themselves to the hepatocytes and then invaginated into the hepatocytic cytoplasm with focal lysis of the cell membrane mediated via the release of neutrophilic lysosomes. The distortion of protein-synthesizing organelles and decrease in glucose-6-phosphatase activity suggest that the AH-containing hepatocyte is metabolically decompensated. The final cell death may be related to the neutrophilic attack, rather than the metabolic derangement.

Acute viral hepatitis: morphologic and functional correlations in human livers.

The usual histologic pattern in acute viral hepatitis (AVH) includes cellular abnormalities predominantly in the perivenular (zone 3) hepatocytes and changes interpreted as representing regenerative activity in the periportal (zone 1) hepatocytes. Enzyme histochemical and ultrastructural studies of livers of 12 patients with AVH were undertaken to see whether these features support the concept of regeneration of hepatocytes in zone 1. The swollen hepatocytes in the perivenular areas were hydropic, with dilated or eccentric rough endoplasmic reticulum and decreased or vesicular smooth endoplasmic reticulum; correspondingly, the glucose-6-phosphatase activity (reflecting, when present, intact and functional endoplasmic reticulum) was markedly decreased. Succinic dehydrogenase and diphosphopyridine nucleotide diaphorase activities, representing mitochondrial enzymes, were limited to the perinuclear or pericanalicular cytoplasm of swollen hepatocytes. gamma-Glutamyl transpeptidase activity was increased. The periportal hydropic hepatocytes were small and arranged in clusters displacing sinusoids. Ultrastructurally, these hepatocytes had nearly normal organelles but scanty smooth endoplasmic reticulum. Activities of the enzymes glucose-6-phosphatase, succinic dehydrogenase, and diphosphopyridine nucleotide diaphorase were weak, although glycogen was abundant. gamma-Glutamyl transpeptidase activity was scanty in these hepatocytes. These findings from enzyme histochemical and electron microscopic studies could be interpreted as evidence of functional deterioration of perivenular swollen hepatocytes and relative functional immaturity of periportal hydropic clustered hepatocytes, suggesting regeneration of zone 1 hepatocytes.

Giant mitochondria in the alcoholic liver diseases--their identification, frequency and pathologic significance.

Three types of giant mitochondria have been described in hepatocytes, and we have investigated their ultrastructural features and occurrence in alcoholic liver disease. Type I mitochondria are spherical, with a paucity of cristae. Type II are elongated and have long crystalline insertions. Type III are relatively smaller and often bizarre in shape, containing multiple crystalline insertions. We defined megamitochondria as spheroidal giant mitochondria with a diameter roughly more than one third of the hepatocyte nucleus and visible under light microscopy. Type I was the most common form of megamitochondria in livers with ALD. Megamitochondria were present in livers of 58 (27.8%) of 209 consecutive patients with alcoholic liver disease, compared with 1 (0.7%) of a series of 145 patients with non-alcoholic liver disease. The frequency and occurrence of megamitochondria varied in different types and/or stages of alcoholic liver disease. In particular, livers with alcoholic foamy degeneration had significantly increased frequency and numbers of megamitochondria compared to other patterns of alcoholic liver disease. The ultrastructural studies showed that hepatocytes containing Type I mitochondria frequently had other damaged organelles and extensive focal cytoplasmic degradation. Enzyme histochemistry showed the foamy hepatocytes containing Type I had markedly decreased staining for glucose-6-phosphatase and slightly decreased staining for succinic dehydrogenase activities, while the hepatocytes with Type II or III had normal staining. In general, Type I giant mitochondria seem more characteristic to alcoholic liver disease, or conditions that produce similar hepatic morphology. It is particularly seen in alcoholic foamy degeneration and may be part of decompensation of the hepatocytes, while Types II and III occurred in hepatocytes of both alcoholic and non-alcoholic patients and had preserved function.

Antibodies to liver membrane antigens in chronic active hepatitis (CAH). II. Specificity for autoimmune CAH.

An immunoradiometric assay for IgG class autoantibody to liver membrane antigens, based on serum binding to glutaraldehyde treated monkey hepatocytes, was used to examine sera from patients with chronic active hepatitis (CAH) and other acute and chronic liver diseases. All sera from normals and patients showed binding, up to a titre of 1/2,048. For comparison of assays, results were normalized by selecting two reference sera, one with a high degree of binding, and one from a healthy subject with a low degree of binding: at a dilution of 1/2,048, these sera were given binding values of 100% and 0%. The values for the binding of unknown sera at the same dilution were calculated from these two reference values. For 26 patients with autoimmune CAH, the mean (+/- s.d.) percentage binding value (70 +/- 33%) was significantly higher than the mean value for 26 healthy subjects (10 +/- 15%), and high binding values were significantly associated with biochemically active hepatitis. The mean percentage binding value was moderately increased for eight patients with HBsAg associated CAH (42 +/- 12%), 13 patients with alcoholic hepatitis with cirrhosis (37 +/- 25%) and 45 patients with acute viral hepatitis A (40 +/- 27%) or B (52 +/- 37%). At a cut-off binding value of 65%, the assay as a single diagnostic procedure was shown to have a 70% sensitivity and a 95% specificity for the diagnosis of autoimmune CAH. Better understanding of the pathogenetic significance of antibodies to liver membrane antigens in CAH and other liver diseases will depend upon biochemical analysis of the presumably multiple antigenic determinants on the hepatocyte membrane.

Hepatocellular carcinoma in a patient with sarcoidosis-associated chronic active hepatitis and the MZ alpha-1-antitrypsin phenotype.

A case of primary hepatocellular carcinoma is described in a patient with long-standing sarcoidosis of the liver associated with chronic active hepatitis, and the MZ alpha-1-antitrypsin phenotype. This association appears to be unique. The respective roles of alpha-1-antitrypsin deficiency, sarcoidosis and chronic active hepatitis in the development of hepatocellular carcinoma in this case are uncertain.

Urinary thromboxane B2 and prostaglandin E2 in the hepatorenal syndrome: evidence for increased vasoconstrictor and decreased vasodilator factors.

Vasodilatory prostaglandins function to maintain renal perfusion in patients with cirrhosis and ascites. To evaluate the potential contribution of the vasodilator prostaglandin E2 and the vasoconstrictor metabolite thromboxane B2 to the development of the hepatorenal syndrome, we measured urinary excretion of these products in 14 patients with hepatorenal syndrome and in control populations with acute or chronic liver or kidney failure. Radioimmunoassay measurements were confirmed by bioassay and by mass spectrometry. Prostaglandin E2 was decreased compared with healthy controls (2.2 +/- 0.3 vs. 6.3 +/- 0.8 ng/h, p less than 0.01) and compared with acute renal failure (9.6 +/- 2.1 ng/h) and with alcoholic hepatitis (9.2 +/- 3.3 ng/h). Thromboxane B2 concentration was normal in patients with alcoholic hepatitis (0.12 +/- 0.02 vs. 0.15 +/- 0.03 ng/ml) and minimally increased in acute renal failure (0.18 +/- 0.15 ng/ml), but markedly elevated in hepatorenal syndrome (0.69 +/- 0.15 ng/ml, p less than 0.001). Urinary thromboxane B2 concentration fell with improved renal function in 3 patients who survived. These data suggest an imbalance of vasodilator and vasoconstrictor metabolites of arachidonic acid in patients with the hepatorenal syndrome.