Immunohistochemical localization of somatostatin and pancreatic polypeptide in smokers with chronic pancreatitis

Recent studies have demonstrated a significant role of tobacco smoking in the development of chronic pancreatitis. Although there are published papers on the effects of cigarette smoking on insulin secretion in patients, no data are available on the effects of smoking on pancreatic endocrine cells secreting somatostatin and pancreatic polypeptide. The aim of the study was to evaluate the effects of cigarette smoking on endocrine pancreatic function by immunolocalization of somatostatin and pancreatic polypeptide in the pancreas from smokers and non-smoking patients with chronic pancreatitis in comparison with healthy controls. The LSAB2-HRP technique with polyclonal antibodies was used for the immunolocalization of somatostatin and pancreatic polypeptide in histological preparations of the pancreas. The intensity of immunohistochemical reaction was calculated with digital image analysis. The study demonstrated increased numbers of somatostatin (D) secreting cells and pancreatic polypeptide (PP) cells and their altered location in pancreatic islets and parenchyma of smoking patients with chronic pancreatitis, as compared to non-smoking patients and healthy controls. Smoking patients showed significantly higher immunostaining of the hormones in the pancreas compared to non-smoking patients and healthy persons. This study indicates that smoking may play a significant role in the development of endocrine disturbances in the development of chronic pancreatitis.     

Premalignant conditions of the pancreas

Premalignant conditions of the pancreas include benign tumours of the pancreas, intraepithelial neoplasia arising within pancreatic ducts, and tumours of the neuroendocrine cells of the pancreas. In addition, there is a variety of rare genetic conditions that predispose to pancreatic exocrine malignancies such as Peutz-Jeghers syndrome, hereditary non-polyposis colorectal cancer syndrome, familial pancreatitis, germline BRCA2 mutations, and pancreatic endocrine malignancies such as type 1 neurofibromatosis (von Recklinghausen's disease) and multiple endocrine neoplasia type 1. More controversial is the concept of chronic pancreatitis and diabetes mellitus as conditions that increase the risk of pancreatic cancer. However, there is no doubt that smoking is a potentiating factor for pancreatic cancer, especially in people who have familial/genetic risk factors. This review will include the recently proposed new nomenclature and classification system for intraepithelial neoplasia in the pancreatic ducts, an overview of the various familial syndromes that are associated with an increased risk of pancreatic tumours, the surveillance programmes that have been introduced to monitor such families, and methods for early diagnosis.     

Differences in immunohistochemical expression of xenobiotic-metabolizing enzymes between normal pancreas, chronic pancreatitis and pancreatic cancer

Metabolic activation of many toxins, carcinogens, drugs, and anti-cancer agents is governed by the cytochrome P450 (CYP) drug-metabolizing enzyme system. To help elucidate the role of this enzyme system in the pathogenesis of chronic inflammatory and malignant pancreatic diseases, we compared the immunohistochemical expression pattern of 8 CYP-enzymes in 24 normal, 20 chronic pancreatitis, and 21 pancreatic cancer specimens using antibodies to CYP 1A1, 1A2, 2B6, 2C8/9/19, 2D6, 2E1, and 3A4, and the NADPH cytochrome P450 oxido-reductase (NA-OR). Compared to the normal pancreas, a higher frequency of immunopositivity for CYP 1A2, 2B6, 2C8/9/19, 2D6, and NA-OR was found in chronic pancreatitis, and of all CYPs but 1A2 in pancreatic cancer. On the other hand, CYP 1A1 and 2E1 antibody staining was less frequently observed in chronic pancreatitis. In all specimens with pancreatic polypeptide (PP)-rich regions (pancreas head), more islet cells than ductal and acinar cells were immunopositive. Moreover, the immunoreactivity of islet cells from PP-rich specimens with anti-CYP antibodies was consistently more frequent and intense than in islet cells from PP-poor areas (body and tail). Immunoreactivity for xenobiotic-metabolizing enzymes was frequently observed in the normal pancreas, chronic pancreatitis, and pancreatic cancer, and displayed differences of its frequency and intensity between the 3 groups. Considering immunohistochemical evidence of enzyme expression and pancreatic blood supply together, islet cells appear to be an important and possible early site of CYP-enzyme induction in pancreatic diseases.     

Evidence for platelet-activating factor as a late-phase mediator of chronic pancreatitis in the rat.

The role of platelet-activating factor (PAF) as a mediator of pancreatic inflammation was examined in the rat pancreatic duct ligation model of obstructive pancreatitis. Pancreatic generation of PAF, as measured by bioassay (ie, platelet [3H]serotonin secretion), was determined at various times after induction of inflammation. Tissue levels of PAF in the normal pancreas averaged 600 +/- 49 pg/g, but PAF was not detectable during the initial 24 hours of pancreatitis, a time when the inflammatory reaction would be considered acute, that is, during the period of maximal serum amylase release and the development of interstitial edema. However a substantial increase in pancreatic PAF levels (12 times control levels) was observed 7 to 14 days after duct ligation during the late-phase response interval similar to the situation characteristic of chronic pancreatitis in which parenchymal atrophy, fibrosis, and pancreatic insufficiency evolve. One week after duct ligation when PAF levels peaked, an evaluation was made of the effects of PAF antagonists (BN52021 and WEB2170) on pancreatic lesions using Evan's blue extravasation, pancreatic myeloperoxidase (MPO) activity, and acid phosphatase activity in peritoneal lavage fluid. BN52021 or WEB2170 treatment was shown to reduce pancreatic damage and inflammation significantly. Long-term in vivo administration of exogenous PAF (20 micrograms/kg/hr for 7 days) exhibited a reduction of [3H]thymidine uptake into and amylase release from pancreatic acini in vitro. Our observations 1) that pancreatic PAF levels increased significantly during the chronic phase of obstructive pancreatitis induced by duct ligation; 2) that inhibition of the action of PAF, through specific receptor antagonism, caused an attenuation of pancreatic lesions; and 3) that chronic administration of PAF resulted in decreased pancreatic regeneration and exocrine function are consistent with a pivotal role for PAF as a late-phase inflammatory mediator in chronic pancreatitis in rats.     

Coxsackievirus-induced pancreatitis

In humans, infections with the group B coxsackieviruses (CVBs) range from asymptomatic infections to chronic, debilitating diseases. The CVBs are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. A major focus in CVB pathogenesis is to understand the mechanisms by which these viruses cause acute diseases that resolve or acute diseases that progress to chronic diseases. The present review explores CVB infections in the development of acute and chronic pancreatitis. Mouse models of CVB-induced pancreatitis share many features with the human diseases and are providing insight into the multi-faceted processes of pancreatic tissue repair and irreversible tissue destruction. The development and progression of CVB-induced pancreatic inflammatory disease is an extremely complex process, involving both viral and host factors. The review examines the roles of the virus and host in contributing to the disease process. Recent studies of global gene expression during CVB-induced pancreatitis have increased our understanding of host factors that influence the outcome of infection and have highlighted interrelationships among complex biological programs. As we unravel the complexity of the disease process, the information gained will lead to the design of therapeutics that not only prevent the progression of chronic inflammatory disease, but that also restore functionality of affected tissues and organs.     

Paraduodenal pancreatitis: a new unifying term and its morphological characteristics

Two inflammatory lesions represent the major differential diagnosis of pancreatic cancer clinically and on imaging: autoimmune (IgG4) pancreatitis and paraduodenal pancreatitis. This latter lesion has been described under various denominations, especially in most early reports by using the term “cystic dystrophy developed in heterotopic pancreas”. Most cases present in young alcoholic males as cystic and inflammatory mass forming lesions centred in the duodenum and the juxtaduodenal pancreatic tissue, predominating in the region of the minor papilla. They may be associated with chronic calcifying pancreatitis. Pathogenetically, key factors are alcohol and anatomical or functional obstruction of the papilla minor.     

Mitochondrial function and malfunction in the pathophysiology of pancreatitis

As a primary energy producer, mitochondria play a fundamental role in pancreatic exocrine physiology and pathology. The most frequent aetiology of acute pancreatitis is either gallstones or heavy alcohol consumption. Repeated episodes of acute pancreatitis can result in the development of chronic pancreatitis and increase the lifetime risk of pancreatic cancer 100-fold. Pancreatic cancer is one of the most common causes of cancer mortality with only about 3?C4?% of patients surviving beyond 5?years. It has been shown that acute pancreatitis involves Ca²⁺ overload and overproduction of reactive oxygen species in pancreatic acinar cells. Both factors significantly affect mitochondria and lead to cell death. The pathogenesis of inflammation in acute and chronic pancreatitis is tightly linked to the induction of necrosis and apoptosis. There is currently no specific therapy for pancreatitis, but recent findings of an endogenous protective mechanism against Ca²⁺ overload??and particularly the potential to boost this protection??bring hope of new therapeutic approaches.     

Treatment with pravastatin attenuates progression of chronic pancreatitis in rat

As appropriate therapies for pancreatic fibrosis and inflammation are limited, prognosis of chronic pancreatitis has not improved to date. Recent studies have shown that statins improve inflammation and fibrosis in several organs. We therefore examined the therapeutic effect of pravastatin on progression of chronic pancreatitis by starting this treatment after induction of pancreatic fibrosis in rats. Chronic pancreatitis was induced by continuous pancreatic ductal hypertension (PDH) for 14 days according to our previous study. Pravastatin at a dose of 10 mg/kg/day was administrated directly into the duodenum via cannula from 2 days after induction of PDH. Progression of pancreatic fibrosis and expression levels of transforming growth factor-β1 and tumor necrosis factor-α mRNA were markedly attenuated after commencement of pravastatin compared with untreated group with PDH. In addition, pravastatin treatment markedly improved pancreatic exocrine function and significantly elevated expression level of interleukin (IL)-10 and superoxide dismutase activity in the pancreas compared with the untreated group with PDH. These results revealed that pravastatin substantially attenuates the progression of pancreatic inflammation, fibrosis and exocrine dysfunction probably by its anti-oxidative property and overproduction of IL-10 in animal model of chronic pancreatitis. These results provide an experimental evidence that pravastatin exerts beneficial effect for progression of chronic pancreatitis.     

ErbB2 oncogene expression supports the acute pancreatitis-chronic pancreatitis sequence

The pathogenesis of chronic pancreatitis remains controversial. According to the general opinion, chronic pancreatitis is a de novo disease with a silent but progressive restructure of the pancreas in response to environmental, nutritional or genetic factors. The necrosis-fibrosis sequence hypothesis, on the other hand, postulates that relapsing attacks of acute pancreatitis with subsequent development of fibrosis leads to chronic pancreatitis. Since in our previous studies the expression of two anti-ErbB2 growth factor receptor (ErbB2) antibodies was shown to discriminate between primary chronic pancreatitis, normal tissue, and secondary chronic pancreatitis caused by pancreatic cancer, we studied the ErbB2 expression in tissues obtained from acute, recurrent acute, and chronic pancreatitis to investigate a possible evolution of the ErbB2 expression pattern during the course of the disease. We subjected 14 normal pancreas, 15 chronic pancreatitis, and 12 acute pancreatitis (three with recurrent acute pancreatitis) specimens to immunohistochemical studies using polyclonal anti-ErbB2 antibodies from Santa Cruz and Dako. The immunoreactivity of islet cells in acute pancreatitis cases with the Santa Cruz antibody was less than that in normal pancreas in relation to the degree of tissue damage and fibrosis, and was negative in recurrent acute and chronic pancreatitis tissues. The Dako antibody, on the other hand, revealed a membrane staining of ductal and ductular cells only in chronic pancreatitis specimens and in some areas of recurrent acute pancreatitis. In conclusion, the similarities in the immunoreactivity of anti-ErbB2 antibodies in recurrent acute pancreatitis and chronic pancreatitis support the hypothesis that acute pancreatitis can be a forerunner of chronic pancreatitis.     

Uncommon types of chronic pancreatitis

Alcoholic chronic pancreatitis and obstructive chronic pancreatitis are the most frequent and the better characterized types of pancreatitis. Recent advances in biology and genetics have brought new insights into the understanding of rare forms of chronic pancreatitis such as tropical chronic pancreatitis, hereditary chronic pancreatitis and chronic pancreatitis in cystic fibrosis. Some other rare forms of chronic pancreatitis have been identified: eosinophilic chronic pancreatitis, chronic pancreatitis after radiotherapy or during hypercalcemia, minimal change chronic pancreatitis and chronic pancreatitis associated with gut diseases or connectivitis. Recently, a particular form of non alcoholic chronic pancreatitis with duct destruction has been described often presenting as a pancreatic mass, leading in some cases to surgical resection of the pancreas. New insights into the understanding of chronic pancreatitis lead to new physiopathological concepts, and many arguments suggest that combined factors may lead to chronic inflammatory lesions of the pancreas.     

The role of nitric oxide in experimental cerulein induced pancreatitis

An enhanced formation of nitric oxide (NO), due to the induction of inducible nitric oxide synthase (iNOS), has been implicated in the pathogenesis of shock and inflammation, but its role in acute pancreatitis still remains controversial. To clarify the role of NO in acute pancreatitis, the present experiment investigated the expression of iNOS and the effect of NOS inhibition on cerulein-induced pancreatitis in rats. Group I received intraperitoneal (ip) injection of normal saline. Group II received two ip injections of cerulein (20 microgram/kg). Group III received injections of N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg) with cerulein. Group IV received L-arginine (250 mg/kg) with cerulein and L-NAME. The expression of iNOS in the pancreas was examined by western blot analysis. The plasma concentration of NO metabolites was measured. The severity of pancreatitis was assessed by measuring serum amylase, pancreas water content and histopathological examination. Compared with controls, the cerulein group displayed significantly increased expression of iNOS and raised plasma NO metabolites. Treatment with L-NAME significantly decreased hyperamylasemia, plasma NO level, and the extent of pancreatic injury. Treatment with L-arginine reversed the effects of L-NAME. These findings suggest that an enhanced formation of NO by iNOS plays an important role in the development of acute pancreatitis, and inhibition of NO production has the beneficial effects in reducing pancreas injury.     

Expression of apoptosis related proteins during malignant progression in chronic ulcerative colitis

BACKGROUND: Chronic ulcerative colitis (CUC) is associated with increased risk of developing colon cancer through a dysplasia (intraepithelial neoplasia)-carcinoma sequence. AIMS: To investigate the expression of apoptosis and inflammatory related proteins in CUC. METHODS: The expression of proteins involved in apoptosis and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Bcl-xl, Fas, and active caspase 3) was investigated and compared with that seen in sporadic colon carcinoma. RESULTS: COX-2 was negative in the epithelium of all samples. iNOS was clearly present in inflammatory areas in CUC epithelium, weakly expressed in dysplasia, and absent or weakly expressed in tumour cells. Bcl-xl was absent in CUC, increased in dysplasia, and highly expressed in most carcinomas. Fas expression was positive in the surface epithelium of CUC, dysplasia, and most tumour cells. Activated caspase 3 was weakly positive in all samples, indicating limited apoptosis. Compared with CUC associated carcinoma, iNOS was consistently expressed in sporadic colon carcinoma cells, whereas Bcl-xl was almost absent in these tumour cells and Fas was only weakly expressed. Activated caspase 3 was present in normal mucosal samples and some tumour cells. CONCLUSION: Apoptosis related proteins--particularly iNOS, Bcl-xl, and Fas-show a distinct pattern of expression in the CUC to carcinoma sequence, which differs from that seen in sporadic carcinoma, but bears a striking resemblance to that seen during neoplastic progression in Barrett's oesophagus. These results support a causal role for chronic inflammation in cancer development in CUC, and treatment of ulcerative colitis should aim to minimise inflammation.     

Immunohistochemical staining of pancreatic cancer with CA19-9, KM01, unabsorbed CEA, and absorbed CEA. A comparison with normal pancreas and chronic pancreatitis.

In order to test the effectiveness of CA19-9, KM01, unabsorbed CEA (carcinoembryonic antigen) and absorbed CEA by immunoperoxidase staining, we evaluated the staining distribution, intensity, and cellular localization in pancreatic cancer. The results were then compared with those of normal pancreas and chronic pancreatitis. The positive staining rate of the pancreatic cancer with any of the four tumor markers was higher than that of the normal pancreas. However, all markers except absorbed CEA showed a higher positive staining rate for chronic pancreatitis than for pancreatic cancer. There was no stromal type in normal pancreatic or chronic pancreatitis tissues with any of the four tumor markers. Our findings, therefore, indicate that absorbed CEA is useful in differentiating pancreatic cancer from normal pancreatic tissues. It is not useful in distinguishing chronic pancreatitis, however, unless a specific staining pattern is observed.     

Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens

Background and Aims Autoimmune pancreatitis seems to be a disease with a heterogeneous appearance. Our intention was to establish key diagnostic criteria, define grades of severity and activity, identify features of potential subtypes and evaluate the diagnostic relevance of biopsy specimens.Methods Histopathological criteria and clinical features were recorded in pancreatic resection specimens from 53 patients who were found to have chronic pancreatitis lacking pseudocysts, calculi, irregular duct dilatations, pancreas divisum and/or duodenal wall inflammation. The severity of the chronic inflammation was graded, and the activity of the acute inflammatory component and the granulocytic epithelial lesion (GEL) were determined. Additionally, pancreatic biopsy specimens from 9 patients with suspected AIP were assessed.Results Periductal lymphoplasmacytic infiltration was identified in all cases, followed in order of frequency by periductal fibrosis and venulitis. These changes were absent in 147 pancreatic specimens that showed chronic pancreatitis associated with pseudocysts, calculi, pancreas divisum and/or duodenal wall inflammation. In 90% of the cases, these chronic changes were graded as 3 or 4. In 81%, the inflammatory process resided in the head of the pancreas and involved the common bile duct. GELs were present in 42% of the patients, who had a mean age of 40.5 years, an almost equal male–female ratio and a high coincidence of ulcerative colitis or Crohns disease. Patients without GELs were older (mean age 64 years), showed a male preponderance, commonly had Sjögrens syndrome and often developed recurrent bile-duct stenosis. Diagnostically relevant lesions were present in two of five wedge biopsy specimens and three of four fine-needle specimens.Conclusions Periductal lymphoplasmacytic infiltration and fibrosis, preferential occurrence in the pancreatic head and venulitis characterize autoimmune pancreatitis. GELs predominantly occur in a subset of patients who are younger, more commonly have ulcerative colitis and Crohns disease and seem to have fewer recurrences than patients without GELs. Pancreatic biopsy material proved to be a very helpful adjunct for establishing the diagnosis.     

Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma

Pancreatic adenocarcinoma is a disease with high mortality for which chronic pancreatitis confers a markedly increased risk. We hypothesize that chromosome instability and genomic damage occur in pre-neoplastic pancreatic ductal epithelium, and that this damage may be related to oxidative stress. We used dual-color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosome arms 11q, 17p, and 18q to identify genomic instability in cultures of normal-appearing human pancreatic ductal epithelium from normal organ donor controls compared to patients with chronic pancreatitis or pancreatic adenocarcinoma. To examine early pancreatic tumorigenesis, we studied only normal-appearing pancreatic ductal cells adjacent to pancreatitis or carcinoma. We found that, compared to the finding in normal controls, chromosomal abnormalities are present in normal-appearing human pancreatic ductal epithelia obtained from patients with chronic pancreatitis or pancreatic adenocarcinoma. Furthermore, these chromosomal abnormalities could be induced in cultured pancreatic ductal epithelium from normal organ donors by chronic exposure to dilute hydrogen peroxide, suggesting that oxidative stress may contribute to the development of chromosomal instability in the pancreas. These results elucidate a potential mechanism linking chronic pancreatitis to pancreatic cancer and suggest that chromosomal instability may be an early event in the pathogenesis of pancreatic cancer.     

F-18 FDG hypermetabolism in mass-forming focal pancreatitis and old hepatic schistosomiasis with granulomatous inflammation misdiagnosed by PET/CT imaging

Purpose: We report the case of a 59-year-old male patient who presented with space-occupying lesions in the pancreas and liver suggestive of metastatic pancreatic cancer. Materials and methods: Whole-body F-18 fluorodeoxyglucose (FDG) PET/CT imaging and enhanced CT imaging of the lesions were performed in addition to abdominal ultrasound, ERCP, and MRCP. Tumor markers, including CA199 and AFP, were also evaluated. Results: PET/CT imaging showed a soft tissue mass with indistinct boundaries in the head of the pancreas with a maximum SUV of 4.39. A less dense shadow was also found in the left lobe of the liver with an indistinct boundary and a maximum SUV of 4.13. Enhanced CT revealed an enhancing mass in the head of the pancreas on arterial phase imaging as well as a mildly enhancing focus in the left lobe of the liver. The patient was diagnosed with a space-occupying lesion of the uncinate process of the pancreas suggestive of pancreatic cancer with metastasis to the liver. However, serum tumor markers were normal. Postoperative pathology was consistent with chronic pancreatitis and old hepatic schistosomiasis associated with granulomatous inflammation of the liver. Conclusion: This case of mass-forming pancreatitis and granulomatous inflammation in old hepatic schistosomiasis mimicked metastatic pancreatic cancer on PET/CT. Such false positive lesions have not been reported before, and further exploration and investigation are needed.     

Platelet-activating factor: a mediator of pancreatic inflammation during cerulein hyperstimulation.

Hyperstimulation of the exocrine pancreas with cerulein causes acute pancreatitis, characterized by intensive interstitial edema, acinar vacuolization, leukocytic infiltration, and hyperamylasemia. Whereas the pathogenesis of cerulein-induced pancreatitis is not well-defined, a local inflammatory response may contribute to the full expression of acute pancreatitis. Platelet-activating factor (PAF) seems to be an important mediator of the inflammatory response. The present evidence includes: 1) pancreatic PAF levels increased in rats in which cerulein-induced pancreatitis was initiated, concomitant with an increase in calcium concentrations in the pancreatic tissue; 2) treatment of rats exposed to cerulein with WEB2170, a PAF receptor antagonist, was shown to reduce inflammatory injury, as demonstrated by decreases in pancreatic weight, Evan's blue extravasation, and myeloperoxidase activity and an improvement in pancreatic histology. In an idealized in vitro experiment mimicking cerulein-induced acute pancreatitis, in which pancreatic acini were employed, cerulein induced amylase release, an increase in [Ca2+]i, and an increase in PAF synthesis. Whereas amylase release was induced by low concentrations of cerulein (10(-11) mol/L), relatively high concentrations of cerulein (10(-9) mol/L) were required for the observed increases in PAF synthesis and the [Ca2+]i, indicating that these two responses may not occur under physiological conditions. The present study suggests that the pancreatic accumulation of PAF coupled with Ca2+ overload are important biochemical components of the pathophysiology of cerulein-induced acute pancreatitis. In fact, PAF production may serve as a primary mediator of inflammation observed during pancreatic hyperstimulation. This is an important observation that will allow a more detailed characterization of the molecular basis of cerulein-induced acute pancreatitis.     

Significance of urinary 11-dehydro-thromboxane B2 in age-related diseases: Focus on atherothrombosis

Platelet activation plays a key role in atherogenesis and atherothrombosis. Biochemical evidence of increased platelet activation in vivo can be reliably obtained through non-invasive measurement of thromboxane metabolite (TXM) excretion.Persistent biosynthesis of TXA₂ has been associated with several ageing-related diseases, including acute and chronic cardio-cerebrovascular diseases and cardiovascular risk factors, such as cigarette smoking, type 1 and type 2 diabetes mellitus, obesity, hypercholesterolemia, hyperhomocysteinemia, hypertension, chronic kidney disease, chronic inflammatory diseases.Given the systemic nature of TX excretion, involving predominantly platelet but also extraplatelet sources, urinary TXM may reflect either platelet cyclooxygenase-1 (COX-1)–dependent TX generation or COX-2–dependent biosynthesis by inflammatory cells and/or platelets, or a combination of the two, especially in clinical settings characterized by low-grade inflammation or enhanced platelet turnover.Although urinary 11-dehydro-TXB₂ levels are largely suppressed with low-dose aspirin, incomplete TXM suppression by aspirin predicts the future risk of vascular events and death in high-risk patients and may identify individuals who might benefit from treatments that more effectively block in vivo TX production or activity. Several disease-modifying agents, including lifestyle intervention, antidiabetic drugs and antiplatelet agents besides aspirin have been shown to reduce TX biosynthesis. Taken together, these aspects may contribute to the development of promising mechanism-based therapeutic strategies to reduce the progression of atherothrombosis.We intended to critically review current knowledge on both the pathophysiological significance of urinary TXM excretion in clinical settings related to ageing and atherothrombosis, as well as its prognostic value as a biomarker of vascular events.