Does long-term profound inhibition of gastric acid secretion increase the risk of ECL cell-derived tumors in man?

OBJECTIVE: Since the description of ECL cell-derived tumors in rodents after long-term profound acid inhibition inducing hypergastrinemia, there has been concern that proton pump inhibitors (PPIs) could also do that in man. The recent description of a Spanish family with gastric ECL cell tumors at the age of about 30 years secondary to a defect in the proton pump due to mutation in the ATP4A gene clearly shows that hypergastrinemia alone also is sufficient to induce ECL cell neoplasia in man. The present review aims to evaluate the risk of gastric neoplasia secondary to gastric acid inhibition. METHODS: Literature (MEDLINE) was searched for the role of the ECL cell in gastric carcinogenesis in animals and man in general and particularly secondary to long-term inhibition of acid secretion. RESULTS: An important proportion of patients treated with PPI develops hypergastrinemia causing ECL cell hyperplasia and the first descriptions of ECL cell carcinoids secondary to PPI have been reported. The role of the ECL cell has hitherto been under estimated in gastric carcinogenesis in man where for instance the signet ring cell type of gastric carcinoma seems to originate from the ECL cell. CONCLUSIONS: The first two of three steps in rodent ECL cell carcinogenesis (hyperplasia, carcinoid, and carcinoma) secondary to PPI dosing, have been described for man. It is every reason to believe that the final step, gastric carcinoma, will develop also in man. Clinical decisions should be based not only on so-called evidence based medicine, but also on physiological knowledge and animal studies.

5-Aminosalicylic acid, a specific drug for ulcerative colitis.

OBJECTIVE: The etiology of the inflammatory bowel diseases is unknown, although genetic factors play a role, and tobacco smoking has opposite effect on the two entities. Inflammation is central in the pathogenesis, and treatment is aiming to suppress it. The active part of salazopyrin, the oldest drug in use in the treatment of ulcerative colitis, is 5-aminosalicylic acid (5-ASA). In the present paper, we wanted to discuss the etiology and pathogenesis of ulcerative colitis in relation to the beneficial effects of 5-ASA and particularly whether this compound has a specific effect on ulcerative colitis. METHODS/RESULTS: 5-ASA seems to have a selective positive effect on ulcerative colitis in inducing remission, preventing relapse and possibly reducing the risk of cancer. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA does not have any known anti-inflammatory effect on other organs or other colonic inflammatory diseases like diverticulitis. Moreover, the effect on experimental colitis in rodents is not convincing. CONCLUSION: 5-ASA seems to have a specific effect on the inflammation in ulcerative colitis. Research on the mechanism of its action may give information on the etiology of ulcerative colitis. 5-ASA is a first-line treatment that should be given once daily in high doses and for long term to reduce the possibility of recurrence and risk of colonic cancer. Side effects with 5-ASA are rare, and every patient with ulcerative colitis who tolerate this drug, should be treated with 5-ASA.

Gastrin May Mediate the Carcinogenic Effect of Helicobacter pylori Infection of the Stomach.

Gastric cancer occurs almost exclusively in patients with gastritis. Since Helicobacter pylori (Hp) was proved to cause gastritis, Hp was also expected to play a role in gastric carcinogenesis. Despite extensive studies, the mechanisms by which Hp cause gastric cancer are still poorly understood. However, there is evidence that the anatomical site of Hp infection is of major importance. Infection confined to the antral mucosa protects against gastric cancer but predisposes to duodenal ulcer, whereas Hp infection of the oxyntic mucosa increases the risk of gastric cancer. Hp infection does not predispose to cancers in the gastric cardia. In patients with atrophic gastritis of the oxyntic mucosa, the intragastric pH is elevated and the concentration of microorganisms in the stomach is increased. This does not lead to increased risk of gastric cancer at all anatomical sites. The site specificity of Hp infection in relation to cancer risk indicates that neither Hp nor the changes in gastric microflora due to gastric hypoacidity are carcinogenic per se. However, reduced gastric acidity also leads to hypergastrinemia, which stimulates the function and proliferation of enterochromaffin-like (ECL) cells located in the oxyntic mucosa. The ECL cell may be more important in human gastric carcinogenesis than previously realized, as every condition causing long-term hypergastrinemia in animals results in the development of neoplasia in the oxyntic mucosa. Patients with hypergastrinemia will far more often develop carcinomas in the gastric corpus. In conclusion, hypergastrinemia may explain the carcinogenic effect of Hp.

The normal neuroendocrine cells of the upper gastrointestinal tract lack E-cadherin.

OBJECTIVE: E-cadherin plays a crucial role in the adhesion between epithelial cells and thus epithelial integrity. Moreover, germline mutations in the E-cadherin gene (CDH1) causing loss of E-cadherin function (adhesion) leads to hereditary gastric cancer of the diffuse type, according to Laurén. Even sporadic gastric carcinomas of the diffuse type often lose E-cadherin expression due to mutations. Lack of E-cadherin has been recorded at an early phase in such carcinomas. For 25 years, we have provided evidence for neuroendocrine (NE) cell origin of gastric carcinomas of diffuse type. The present study was, therefore, done to examine whether normal NE cells in the gastrointestinal tract express E-cadherin or not. METHODS: During upper gastrointestinal endoscopy, biopsies were taken from normal oxyntic mucosa, gastric carcinoids, gastric carcinomas, and from normal duodenal mucosa. Tissues were examined by immunohistochemistry (IHC) using antibodies toward chromogranin A, synaptophysin, and E-cadherin. Isolated mucosal cells were prepared from biopsies of normal mucosa and examined by antibodies against the same markers by immunofluorescence. RESULTS: Normal gastrointestinal NE cells did not express E-cadherin as assessed by IHC or immunocytochemistry. No expression of E-cadherin was found on tumor cells from gastric carcinoids or cancer of diffuse type examined by IHC. CONCLUSION: Our findings, which are in contrast to some previous studies, may explain why there is a discrepancy between lack of atypia and malignant biological behavior of such tumors. Since they normally lack the adhesion molecule E-cadherin, reflected in their spread occurrence, only minor changes may result in malignant behavior.

Venous plasma serotonin is not a proper biomarker for pulmonary arterial hypertension.

OBJECTIVES: Serotonin (5-HT) most likely plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to test if venous plasma 5-HT is a potential biomarker of PAH. We also measured venous blood ß-thromboglobulin (ß-TG) in all participants to ensure that any increase in serotonin levels measured is due to platelet release. DESIGN: Blood samples from patients (n = 9) with pulmonary arterial hypertension (Group 1 of the World Health Organization classification of pulmonary hypertension) as well as healthy volunteers (n = 9) were analyzed. We used enzyme-linked immunosorbent assay (ELISA) to measure venous platelet-poor plasma 5-HT and ß-TG in patients with pulmonary arterial hypertension (PAH) and in age-matched normal controls. RESULTS: Venous platelet-free plasma 5-HT and ß-TG were almost similar in patients with PAH and healthy controls with only a slight trend toward increased 5-HT levels in patients with PAH. No correlation was found between venous platelet-poor plasma 5-HT and disease severity. There was no association between venous plasma 5-HT and the mean pulmonary artery pressure. CONCLUSIONS: Our data suggest that 5-HT is not significantly elevated in venous platelet-free plasma in patients with PAH and may accordingly not be a useful biomarker in this condition.

Serotonin in blood: assessment of its origin by concomitant determination of ß-thromboglobulin (platelets) and chromogranin A (enterochromaffin cells).

BACKGROUND: Serotonin is produced in enterochromaffin (EC) cells, taken up and stored in platelets and released during platelet activation. Measurement of platelet-poor plasma serotonin is difficult, mainly due to platelet activation during blood sampling. We aimed to establish a method to assess the influence of platelet release upon platelet-poor plasma serotonin measurement by concomitant determination of serotonin, ß-thromboglobulin (ß-TG) and chromogranin A (CgA). METHODS: Blood samples from patients with thrombocytosis, thrombocytopenia and small intestinal neuroendocrine (EC-cell) tumors (SI-NETs) as well as healthy volunteers were analyzed. We also measured serotonin in venous and arterial samples from patients undergoing coronary angiography to evaluate peripheral serotonin metabolism. RESULTS: Serotonin and CgA were significantly higher in patients with SI-NETs compared to all other groups implying EC cell origin of serotonin in patients with SI-NETs. We found that the serotonin concentration was similar in patients with thrombocytosis and thrombocytopenia, whereas plasma ß-TG was higher and lower respectively. A high EDTA concentration in the sampling tubes gave significantly lower serotonin concentrations. Serotonin concentrations did not differ between arterial and venous blood. CONCLUSIONS: Our methodology to measure platelet-poor plasma serotonin was appropriate. Blood platelet numbers did not affect the level of serotonin in contrast to ß-TG.

Survival Trends in Patients with Small Intestinal Neuroendocrine Tumours-A Cohort Study in Central Norway.

Improved surgical resection and oncological treatment, or an earlier diagnosis may increase survival in small intestinal neuroendocrine tumours (SI-NETs), but only few studies have examined survival trends. We aimed to examine the trend in overall survival and associated factors in SI-NET patients. All patients with SI-NETs at a regional hospital from June 2005 to December 2021 (n = 242) were identified, and the cohort was divided in half, constituting a first period (until November 2012) and a second period (from November 2012). Disease and treatment characteristics, including European Neuroendocrine Tumour Society (ENETS) stage, surgery, oncological treatment and survival, were recorded. The majority (n = 205 (84.7%)) were treated surgically and surgery was considered curative in 137 (66.8%) patients. Median survival was longer in the second period (9.0 years 95% CI 6.4-11.7 in the first period vs. median not reached in the second period, p = 0.014), with 5-year survival rates of 63.5% and 83.5%, respectively. ENETS stage and oncological treatment did not differ between the periods, but factors associated with surgical quality, such as lymph node harvest and resection of multiple SI-NETs, were significantly higher in the second period. Age, ENETS stage, time period and tumour resection were independently associated with survival in a multivariate analysis.

Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor.

We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

Animal models to study the role of long-term hypergastrinemia in gastric carcinogenesis.

Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models.

Five-year follow-up of patients treated for 1 year with octreotide long-acting release for enterochromaffin-like cell carcinoids.

BACKGROUND: Gastric carcinoids type 1 (GC1) are neuroendocrine tumors (NETs) arising from the enterochromaffin-like (ECL) cells in patients with chronic atrophic gastritis (CAG). The treatment of GC1 has been endoscopic polypectomy or surgical tumor excision and antrectomy. One year treatment with somatostatin analogs (SSAs) diminished tumor load and ECL cell density. The effect persisted 1 year after treatment was discontinued. However, the optimal SSA dose and treatment duration are unknown. OBJECTIVES: The aim of the present work was to study macroscopic and histopathological changes in the stomach and serum markers gastrin and chromogranin A (CgA) in GC1 patients 5 years after 1 year of octreotide long-acting release (LAR) treatment. MATERIAL AND METHODS: Five patients with GC1 were included 5 years after the initial year of octreotide LAR treatment. All patients underwent upper gastrointestinal endoscopy including tumor and mucosal biopsies from oxyntic mucosa, chest and abdominal computer tomography and octreotide scintigraphy. Fasting serum gastrin and CgA were also measured. RESULTS: At 5 years, one patient had a highly malignant gastric tumor, one patient had an increased number of GCs, regional and distant metastases and three patients had an increased number of GCs. Serum gastrin and CgA increased to pre-treatment levels after 1 year of follow-up and were unchanged at the 5-year follow-up. CONCLUSIONS: The disease had progressed in all five GCs patients treated with octreotide for 12 months at 5 years of follow-up. This suggests that, if started, octreotide treatment should not be discontinued in these patients.

Parietal cell activation by arborization of ECL cell cytoplasmic projections is likely the mechanism for histamine induced secretion of hydrochloric acid.

BACKGROUND AND AIMS: Enterochromaffin-like (ECL) cells are central in the regulation of acid secretion. G cells release gastrin and activate ECL cell histamine secretion which stimulates parietal cell H(2) receptors initiating acid secretion. It is unclear whether histamine-mediated parietal cell activation is via a vascular or paracrine pathway. To assess this, we utilized immunohistochemistry (IHC) and electron microscopy to examine gastric tissue and used visualization of formalin fixed dispersed gastric cells and glands to investigate and define the anatomical relationship between ECL and parietal cells. MATERIAL AND METHODS: Sprague-Dawley rat stomachs were instilled with formalin. Thereafter fixed mucosal cells and whole gastric glands were dispersed by mechanical and chemical dissolution and enzymatic digestion. Smears with fixed isolated cells and whole glands were stained by IHC with histidine decarboxylase (HDC) and H+/K+-ATPase antibodies. Whole tissue samples of Sprague-Dawley and cotton rat oxyntic mucosa were investigated with IHC using HDC, VMAT2 and H+/K+-ATPase antibodies, and electron microscopy was performed to further delineate the precise anatomic relationship between ECL cells and parietal cells. RESULTS: Each ECL cell generated a network of HDC- and VMAT2-positive dendritic-like elongations that were in direct contact with several parietal cells. Thus, ECL cells at the base of the gland were in communication with parietal cells in the middle of the gland. Electron microscopy confirmed that the cytoplasmic ECL cell elongations containing secretory vesicles were in direct juxtaposition to parietal cells. CONCLUSIONS: These findings indicate that ECL cells directly regulate parietal cell function in a neurocrine manner via slender neuron-like elongations.

Survival and Disease Recurrence in Patients with Duodenal Neuroendocrine Tumours-A Single Centre Cohort.

BACKGROUND: Duodenal neuroendocrine tumours (D-NETs) are rare but increasingly diagnosed. This study aimed to assess the overall survival and recurrence rate among patients treated for D-NETs. METHODS: Patients with D-NETs were retrospectively reviewed with a median follow-up time of 4.8 years (range 0.0-17.2 years). RESULTS: A total of 32 patients with median age 68.0 years were identified. Fifteen patients underwent surgery while ten patients underwent endoscopic treatment. Mean estimated overall survival for the entire population was 12.1 years (95% CI 9.5-14.7 years), while 5-year overall survival was 81.3%. Tumour grade G1 was associated with longer mean estimated survival compared to G2 tumours (13.2 years versus 4.4 years, p = 0.010). None of the 23 patients who underwent presumed radical endoscopic or surgical resection had disease recurrence during follow-up. Tumours <10 mm could be treated endoscopically whereas a high proportion of patients with tumours 10-20 mm should be considered for surgery. CONCLUSION: Patients with D-NETs had long overall survival, and mortality was more influenced by other diseases. Both endoscopic and surgical resections were effective as no recurrences were diagnosed during follow-up.

Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells.

BACKGROUND & AIMS: Gastrin is a key regulator of gastric acid secretion. We aimed to isolate pure G cells to identify the mechanistic basis of luminal- and strain-mediated regulation. METHODS: Using gradient centrifugation and fluorescence-activated cell sorting, rat G cells were prepared and luminal, neural, hormonal, and mechanical activation of secretion and signaling pathways studied. RESULTS: Pure G-cell preparations (>97%) were isolated. Reverse-transcription polymerase chain reaction identified neural, hormonal, bacterial, and luminal G protein-coupled receptors, and immunostaining visualized specific sweet/bitter receptors and the tastant-associated G protein alpha-gustducin. Gastrin release was stimulated by forskolin (adenosine 3',5'-cyclic monophosphate [cAMP] inducer, 10 micromol/L; >3-fold), potentiated by 3-isobutyl-1-methylxanthine (IBMX; phosphodiesterase type 5 inhibitor and adenosine antagonist, 10 micromol/L) and phorbol myristate acetate (phorbol ester, 10 micromol/L), and inhibited by H-89 (protein kinase A inhibitor, 10 micromol/L), PD98059 (MEK1 inhibitor, 0.1 micromol/L), and wortmannin (phosphatidylinositol 3-kinase inhibitor, 1 nmol/L). Gastrin release was stimulated by neuronal G protein-coupled receptor ligands, pituitary adenylate cyclase-activating protein (20 pmol/L, >8-fold) and bombesin (0.1 micromol/L, 8-fold) through cAMP signaling. The tastants sucralose, glucose, caffeine, denatonium, and the vanilloid receptor activator capsaicin all stimulated secretion (>3-fold), as did bacterial lipopolysaccharides Salmonella enteritidis (0.24 nmol/L, 5-fold) greater than Helicobacter pylori (0.57 micromol/L, 3-fold). Secretion was associated with elevated cAMP levels (approximately 2-fold) and could be inhibited by H-89 and PD98059 and potentiated by IBMX and cholera toxin (250 microg/mL). Bacterially mediated secretion also involved activation of nuclear factor kappaB and the c-Jun-N-terminal kinase pathway. Mechanical strain stimulated (2-fold to 8-fold) gastrin release, and decreasing pH from 7.4 to 5.5 inhibited release. The adenosine receptor 2B antagonist MRS1754 inhibited mechanically induced gastrin release. CONCLUSIONS: G cells are luminal sampling chemomechanosensory cells whose secretion is regulated by neural, hormonal, luminal, and mechanical factors through protein kinase A activation, cAMP signaling, and mitogen-activated protein kinase phosphorylation.

A meal test improves the specificity of chromogranin A as a marker of neuroendocrine neoplasia.

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Long-term gastric changes in achlorhydric H(+)/K(+)-ATPase beta subunit deficient mice.

OBJECTIVE: Hypergastrinemia is known to induce enterochromaffin-like (ECL) cell derived tumors in rodents and man. In this study, we have examined the effect of life-long gastric anacidity and secondary hypergastrinemia in H(+)/K(+)-ATPase beta subunit knockout (KO) mice. MATERIAL AND METHODS: Female H(+)/K(+)-ATPase beta subunit KO mice and controls were followed up to 20 months before being sacrificed. At termination, intragastric acidity was measured and internal organs were examined for macroscopic and histological changes. Plasma gastrin and serum albumin were measured. RESULTS: KO mice were anacidic and hypergastrinemic. The oxyntic mucosa was markedly, and with increase in age, hyperplastic with cystic dilatations resembling the changes seen in patients with Menetrier's disease. Serum albumin in KO mice did not differ from controls. KO mice had a marked ECL cell hyperplasia, but only one gastric carcinoma was found. CONCLUSION: H(+)/K(+)-ATPase beta subunit KO mice develop Menetrier-like changes in the stomach, and may be useful in studying the pathogenesis and treatment of Menetrier's disease. The reason why only one KO mice developed gastric neoplasia whereas the histamine-2 blocker loxtidine has previously been found to regularly induce ECL cell carcinoids in mice is not known.

Survival and disease recurrence in patients operated for small intestinal neuroendocrine tumors at a referral hospital.

BACKGROUND AND OBJECTIVES: Small intestinal neuroendocrine tumors (SI-NETs) are slow growing but have frequently metastasized at the time of diagnosis. Most patients are operated with either curative intent or with intent to prolong overall survival. In the current study we have examined overall and disease-free survival in patients operated for SI-NETs. METHODS: All patients with a histological diagnosis of SI-NET at St Olav's hospital in the period 1998-2018 were reviewed retrospectively. Patient, disease and treatment characteristics including European Neuroendocrine Tumor Society (ENETS) TNM staging classification, surgery type, time to recurrence and survival were recorded. RESULTS: A total of 186 patients were identified, whereof 54.3% male, median age at operation 68 years. The majority (n = 141 (75.8%)) underwent elective surgery and surgery was considered curative (radical) in 120 (64.5%) patients. Median estimated overall survival was 9.7 years (95% CI 7.6-11.8) for the entire population. Stage of disease, carcinoid heart disease, age, elective surgery, preoperatively known SI-NET, curative surgery and synchronous cancer were associated with survival in a multivariate analysis. Thirty-six of 120 (30%) patients had disease recurrence after a median follow-up time of 5.5 years, with a median estimated recurrence-free survival of 9.1 (5.4-12.9) years. Recurrence free survival was associated with age and synchronous cancer. CONCLUSIONS: Patients with SI-NETs had long overall survival which seemed influenced by stage of disease, presence of carcinoid heart disease, an elective surgery, preoperatively known SI-NET, age and synchronous cancer. Appropriate preoperative diagnostic procedures and elective surgeries seem beneficial and should be aimed for.

The effect of terguride in carbon tetrachloride-induced liver fibrosis in rat.

BACKGROUND: Hepatic stellate cells (HSCs) are considered to be of vital importance in the pathogenesis of liver fibrosis. In vitro studies have demonstrated antiproliferative effects of 5-hydroxytryptamine(2) (5-HT(2), serotonin) receptor antagonists upon HSCs. Terguride, recognized as a partial dopamine agonist, also has potent 5-HT(2) receptor antagonist qualities and has been shown to prevent serotonin-induced organ changes and fibrosis in rats. AIM: In the current study, the carbon tetrachloride (CCL(4)) hepatic fibrosis rat model was used in combination with daily administration of terguride to evaluate potential preventive effects of a 5-HT(2) receptor antagonist upon liver fibrosis. MATERIALS AND METHODS: Forty rats (Sprague-Dawley) were included in the study. Twelve animals received terguride in combination with CCL(4) and 12 animals were given only CCL(4). The remaining 16 animals served as model controls. The extent of fibrosis was evaluated by liver weight, histologic analysis, biochemical analysis, and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry. RESULTS: There were no significant differences in liver weight, hydroxyproline content, serum alanine and aspartate transaminases, serum hyaluronic acid, or alpha-SMA immunostaining between rats treated with terguride in combination with CCL(4) and rats given only CCL(4). All parameters, however, were significantly lower (P < 0.01) in the model controls. CONCLUSION: Terguride, a potent 5-HT(2) antagonist, did not prevent the development of liver fibrosis in rats given CCL(4).