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David C Whitcomb

Publications and source records attributed to David C Whitcomb.

At least 55 records · Page 3Linked to original sources
PubMed2004

Analysis of tumor necrosis factor-alpha, transforming growth factor-beta 1, interleukin-10, and interferon-gamma polymorphisms in patients with alcoholic chronic pancreatitis.

The pathophysiologic mechanisms underlying alcoholic chronic pancreatitis are poorly understood. Cytokines participate in the immunologic progression of acute and chronic pancreatitis and may play an important role in the development of pancreatic fibrosis. Functional polymorphisms in cytokine genes have been identified that alter cytokine production. The aims of the current investigation were to determine whether functional polymorphisms in the tumor necrosis factor-alpha (TNF-alpha) gene at positions -308 and -238; in the transforming growth factor-beta 1 (TGF-beta(1)) gene at positions -509, +869 (codon 10), and +915 (codon 25); in the interleukin-10 (IL-10) gene at position -1082; and in the intron 1 of the interferon-gamma (IFN-gamma) gene at position +874 are associated with alcoholic chronic pancreatitis. We investigated 42 patients with alcoholic chronic pancreatitis. We studied 94 control subjects for the TNF-alpha polymorphisms and 73 control subjects for the remaining polymorphisms. Mutation analysis was performed by direct DNA sequencing or by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). The genotype frequencies were similar between patients and control subjects for all investigated cytokine polymorphisms (P>.05). We did not find an association between the different genotypes and the clinical course of the disease. Therefore, we assume that these genetic variants do not play a dominant role in alcoholic chronic pancreatitis.

Alcoholism↗
PubMed2004

Alcoholic pancreatitis.

Without doubt, alcohol consumption is one of the most important considerations in adults with acute or chronic pancreatitis. Understanding chronic pancreatitis as a complex disorder in which complimentary factors are required for recurrent acute and late chronic pancreatitis to develop in subsets of patients is critical for the early diagnosis and management of these individuals. Recent pathophysiological and genetic findings represent the beginning of major diagnostic and treatment breakthroughs that are likely to continue for the foreseeable future. The information provided in this article should provide the physician with a fresh perspective and remind the clinician of the importance of an accurate and complete history, and the need to document the actual alcohol consumption, pattern of drinking, and raise appropriate concerns if signs of alcoholism are detected. If alcohol-associated pancreatitis is detected, then limitation of pancreatic damage, limitation of progression, or preventative intervention should become the major concern.

Alcohol Drinking↗
PubMed2004

Predictors of severity and necrosis in acute pancreatitis.

C-reactive protein remains the single standard biochemical marker for predicting the severity of AP. Because the combination of clinical-physiological scores and CRP provide good information at 48 hours, research has focused on the predictive ability of various markers when applied in the initial 24 hours after admission to the hospital. After detailed review of the literature, the authors conclude that there is no single tool that serves as the optimal predictor of severity. There are, however, data that support the use of certain tests to improve upon the clinician's early predictive ability on the subsequent course of AP. These include an APACHE II score greater than 7 and IL-6 at the time of admission, and urine TAP, urine trypsinogen-2, and serum PMN elastase at 24 hours (Table 4). These markers only will be able to help the clinician's predictive ability if they can be performed locally and if the results can be available ina timely manner. Future research should focus on promising markers such as procalcitonin, IL-8, IL-I ra, sTNFR, CAPAP, PLA-2, novel markers, and the combined use of more than one marker. The conventional research approach in predicting severity used in the last 15 years has limitations and appears to have reached its maximal potential. Novel conceptions and approaches, such as identification of genetic polymorphisms that predispose to severe course and complications of AP or other approaches are needed for a quantum step forward.

Acute Disease↗
PubMed2004

Theories, mechanisms, and models of alcoholic chronic pancreatitis.

Alcoholic chronic pancreatitis is a severe, disabling, chronic inflammatory condition of the pancreas that is seen in fewer than 5% of alcoholics. The severity and unpredictability of this condition has lead to several theories on the mechanism causing chronic pancreatitis based on careful clinical observation. Hypothetical mechanisms were applied to various animal models. Finally, following multiple lines of evidence, there is a convergence of thought and development of some new models that are quite instructive. Taken together, chronic alcohol consumption by rats results in multiple effects on the pancreas that increase the risk of acute pancreatitis, including ongoing acinar cell injury that lowers the threshold for hyperstimulation-induced acute pancreatitis, neurohormonal injury, and adaptation that results in acinar cell hyperstimulation, increased susceptibility to viral mediated acute pancreatitis, and possibly other factors. After acute pancreatitis initiates the inflammatory process, the chronic inflammation and fibrosis of alcoholic chronic pancreatitis are driven by diet, the acinar cell stress response to continued alcohol that may be potentiated by toxic alcohol metabolites, hypoxia, hyperstimulation, and partial duct obstruction; plus the effects of proinflammatory immunocytes and cytokines; and by stellate cell-mediated fibrosis driven by anti-inflammatory cytokines, alcohol, and alcohol metabolites. The factors determining which alcoholic will develop alcoholic chronic pancreatitis likely involve genetic factors, dietary factors, and susceptibility to pancreatic injury through several mechanisms ranging from trauma to gallstones to viruses.

Animals↗
PubMed2004

Clinical and genetic characteristics of hereditary pancreatitis in Europe.

BACKGROUND & AIMS: Hereditary pancreatitis is an autosomal dominant disease that is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to determine phenotype-genotype correlations of families in Europe. METHODS: Analysis of data obtained by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer was undertaken using multilevel proportional hazards modelling. RESULTS: There were 112 families in 14 countries (418 affected individuals): 58 (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12) years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to resection was significantly reduced for females (P < 0.001) and those with the N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was 44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence ratio of 67% (50%, 82%). CONCLUSIONS: Symptoms in hereditary pancreatitis start in younger patients and endpoints take longer to be reached compared with other forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine failure are much higher. There is an increasingly high risk of pancreatic cancer after the age of 50 years unrelated to the genotype.

Adult↗
PubMed2004

Chronic alcohol-induced alterations in the pancreatic secretory control mechanisms.

Chronic alcohol ingestion appears to increase susceptibility of the pancreas to pancreatitis through multiple mechanisms. The aim of the current study was to determine the effect of chronic low- and high-dose alcohol consumption on the neurohormonal control of the exocrine pancreas in rats. Male Wistar rats were fed Lieber DeCarli liquid control-, low-, and high-dose alcohol diets for 3 months. Pancreatic exocrine secretion was measured under basal and 2-deoxy-D-glucose (2-DG)-, CCK-, bethanechol-, or meal-stimulated conditions while on chronic alcohol diets and after 2-DG or CCK stimulation during alcohol withdrawal in awake rats. Chronic alcohol ingestion was associated with a dose-related inhibition of basal pancreatic protein secretion, which was reversed upon alcohol withdrawal. Low-dose alcohol feeding had no effect on bethanechol-stimulated pancreatic secretion but altered 2-DG-stimulated pancreatic secretion. In chronic high-dose alcohol rats, meal- and bethanechol-stimulated protein secretion was significantly potentiated during early and late phases. The response to CCK appeared to be disinhibited, whereas the response to 2-DG was uniformly blunted. Upon withdrawal of low-dose alcohol, the response to 2-DG was potentiated, whereas with the withdrawal of high-dose alcohol, the response to CCK was potentiated. Adaptation to chronic alcohol consumption differs depending on the alcohol dose. The most significant effects were seen after high-dose alcohol withdrawal, with apparent loss of central inhibitory regulation combined with exaggerated response at the acinar cell level. This combination of factors could increase susceptibility to acute alcoholic pancreatitis through a hyperstimulation mechanism.

Alcohols↗
PubMed2004

Mechanisms of disease: Advances in understanding the mechanisms leading to chronic pancreatitis.

Chronic pancreatitis remains a challenging and frustrating clinical problem. In the past few years, however, advances in genetic and immunologic research have spawned new insights and approaches to chronic pancreatitis. Genetic and environmental risk assessment may help identify individuals who are likely to develop severe chronic pancreatitis early in the disease course, and allow targeted attention to reduce confounding risks and slow or prevent this problem in the future.

Chronic Disease↗
PubMed2004

A mathematical model of the pancreatic duct cell generating high bicarbonate concentrations in pancreatic juice.

OBJECTIVE: To develop a simple, physiologically based mathematical model of pancreatic duct cell secretion using experimentally derived parameters that generates pancreatic fluid bicarbonate concentrations of >140 mM after CFTR activation. METHODS: A new mathematical model was developed simulating a duct cell within a proximal pancreatic duct and included a sodium-2-bicarbonate cotransporter (NBC) and sodium-potassium pump (NaK pump) on a chloride-impermeable basolateral membrane, CFTR on the luminal membrane with 0.2 to 1 bicarbonate to chloride permeability ratio. Chloride-bicarbonate antiporters (Cl/HCO3 AP) were added or subtracted from the basolateral (APb) and luminal (APl) membranes. The model was integrated over time using XPPAUT. RESULTS: This model predicts robust, NaK pump-dependent bicarbonate secretion with opening of the CFTR, generates and maintains pancreatic fluid secretion with bicarbonate concentrations >140 mM, and returns to basal levels with CFTR closure. Limiting CFTR permeability to bicarbonate, as seen in some CFTR mutations, markedly inhibited pancreatic bicarbonate and fluid secretion. CONCLUSIONS: A simple CFTR-dependent duct cell model can explain active, high-volume, high-concentration bicarbonate secretion in pancreatic juice that reproduces the experimental findings. This model may also provide insight into why CFTR mutations that predominantly affect bicarbonate permeability predispose to pancreatic dysfunction in humans.

Animals↗
PubMed2004

Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer.

Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.

Adenocarcinoma↗
PubMed2003

Mucins in gastrointestinal cancers.

The mucin family has been under study by molecular biologists, biochemists, pathologists and immunologists interested in cancer because of the role these molecules can play in the diagnosis and treatment of cancer. Immense knowledge has been accumulated, but the high speed of progress in the laboratory has not been matched by the progress towards applying this knowledge in the clinic. For example, specific knowledge of cancer-associated changes in the expression and glycosylation of various mucins, which can aid in the diagnosis as well as prognosis of GI cancers, has not yet led to the use of a panel of anti-mucin antibodies as a standard diagnostic tool. Similarly, many more opportunities exist for using mucin-based therapies than are currently being considered in the clinic. This chapter aimed to highlight some of these opportunities and to interest clinician scientists in exploring them in the near future.

Cancer Vaccines↗
PubMed2003

Genetic polymorphisms in alcoholic pancreatitis.

Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies have demonstrated that alcohol consumption alone does not directly cause pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present before the mechanisms protecting the pancreas from pancreatitis are circumvented and pancreatitis develops. The discovery that mutations in the cationic trypsinogen gene (R122H, N29I) predisposed to acute and chronic pancreatitis focused attention on possible genetic predispositions. Mutations in the cationic trypsinogen gene, however, are rarely associated with alcoholic chronic pancreatitis. Mutations in the SPINK1 gene (e.g. N34S) provide a threefold increased risk, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations continue to be investigated. However, the major cofactor associated with alcoholic chronic pancreatitis is yet to be identified.

Acute Disease↗
PubMed2003

Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States.

Mutations in the SPINK1 gene (e.g. N34S) have been reported in patients with idiopathic, familial, tropical, and alcoholic pancreatitis. The prevalence of SPINK1 N34S differs between different patient populations, and its contribution to the risk and the severity of alcoholic chronic pancreatitis has not been defined in the United States. Mutational analysis of the exon 3 was performed in 32 patients with alcoholic chronic pancreatitis, 39 patients with nonalcoholic chronic pancreatitis or recurrent acute pancreatitis, and 190 previously studied healthy controls. The course of alcoholic chronic pancreatitis with and without N34S was compared in age of onset- and sex-matched patients. All SPINK1 gene sequence variations were heterozygous. SPINK1 N34S was present in 3/190 (1.6%) and P55S was found in 2/190 (1.1%) of controls. In alcoholics, the N34S mutation was identified in 2/32 patients (6.3%, P > 0.05). In nonalcoholics, N34S and P55S were identified in 6/39 patients (15.4%, P < 0.005, N34S N = 4, P55S N = 1, N34S/P55S N = 1). The clinical course of alcoholic chronic pancreatitis was similar between patients with and without the N34S mutation. The N34S mutation is uncommon in patients with alcoholic chronic pancreatitis in the United States; its prevalence is similar to other countries and appears not to alter the onset or the severity of alcoholic chronic pancreatitis.

Adult↗
PubMed2003

Genetic predisposition to alcoholic chronic pancreatitis.

The mechanisms leading to alcoholic chronic pancreatitis in humans have remained elusive. Numerous questions surround the apparent random nature of the disease in which 1 person is hit with alcoholic chronic pancreatitis while the next is spared. Why do fewer than 10% of chronic, heavy alcohol users ever develop pancreatitis, while others develop alcoholic liver disease, neuropathy, or other alcohol-associated problems? Why do laboratory animals, fed large amounts of alcohol for prolonged periods of time, fail to develop typical chronic pancreatitis? Why are heavy alcohol users from a black African background more likely to develop pancreatic diseases than Caucasians, whereas the opposite is true for the development of liver disease? The answers underlying these questions appear to reflect the differences in underlying genetic susceptibility, environmental exposure, and the interaction between these factors. Thus, even cases of "typical" alcoholic chronic pancreatitis or other forms of pancreatitis appear to be complex diseases. Recently, several genetic mutations have been identified that increase the susceptibility to pancreatitis. However, the major common gene mutations in CFTR, PRSS1, and SPINK1 only slightly increase the risk of alcoholic chronic pancreatitis. New genetic, environmental, and triggering factors must be considered to gain further insight into the mechanisms leading to alcoholic chronic pancreatitis so that strategies for treatment and prevention can be developed.

Alcohol Drinking↗
PubMed2003

Motion--genetic testing is useful in the diagnosis of nonhereditary pancreatic conditions: arguments for the motion.

Mutations of three major genes are associated with an increased risk of acute and chronic pancreatitis: the cationic trypsinogen (PRSS1) gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the pancreatic secretory trypsin inhibitor (PSTI) or serine protease inhibitor, Kazal type 1 (SPINK1) gene. Some autosomal dominant forms of hereditary pancreatitis are associated with mutations of the PRSS1 gene, which can be readily identified by genetic testing. Mutations of the CFTR gene can lead either to cystic fibrosis or to idiopathic chronic pancreatitis, and to a variety of cystic fibrosis-associated disorders, including congenital bilateral absence of the vas deferens and sinusitis. These mutations, as with those of the SPINK1 (or PSTI) gene, are prevalent in North America; thus, the presence of such a mutation in an asymptomatic person does not confer a high risk of developing pancreatitis. Combinations of mutations of the PRSS1 and SPINK1 genes lead to more severe disease, as indicated by an earlier onset of symptoms, which suggests that SPINK1 is a disease modifier. The major fear expressed by potential candidates for genetic testing is that the results could lead to insurance discrimination. Studies of the positive predictive value of genetic tests are hampered by recruitment bias and lack of knowledge of family history of pancreatitis. Genetic testing is most useful for persons for whom family members have already been found to exhibit a particular pancreatitis-associated mutation. In the future, increased knowledge of the myriad genetic causes of pancreatitis, as well as advances in the diagnosis and treatment of early chronic pancreatitis, should enhance the utility of genetic testing.

Codon↗
PubMed2002

SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent.

Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease.

Chronic Disease↗
PubMed2002

A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34.

Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in approximately 10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer.

Adult↗