Kishore Vipperla

Fat, fibre and cancer risk in African Americans and rural Africans

Rates of colon cancer are much higher in African Americans (65:100,000) than in rural South Africans (<5:100,000). The higher rates are associated with higher animal protein and fat and lower fiber consumption, higher colonic secondary bile acids, lower colonic short chain fatty acid quantities and higher mucosal proliferative biomarkers of cancer risk in otherwise healthy middle aged volunteers. Here we investigate further the role of fat and fiber in this association. We performed two-week food exchanges in subjects from the same populations, where African Americans were fed a high-fiber, lowfat African-style diet, and rural Africans a high-fat low-fiber western-style diet under close supervision. In comparison to their usual diets, the food changes resulted in remarkable reciprocal changes in mucosal biomarkers of cancer risk and in aspects of the microbiota and metabolome known to affect cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis and suppressed secondary bile acid synthesis in the African Americans.

The Microbiota and Its Metabolites in Colonic Mucosal Health and Cancer Risk

Recent advances in our ability to identify and characterize the human microbiota have transformed our appreciation of the function of the colon from an organ principally involved in the reabsorption of secretory fluids to a metabolic organ on a par with the liver. High-throughput technology has been applied to the identification of specific differences in microbial DNA, allowing the identification of trillions of microbes belonging to more than 1000 different species, with a metabolic mass of approximately 1.5 kg. The close proximity of these microbes with the mucosa and gut lymphoid tissue helps explain why a balanced microbiota is likely to preserve mucosal health, whereas an unbalanced composition, as seen in dysbiosis, may increase the prevalence of diseases not only of the mucosa but also within the body due to the strong interactions with the gut immune system, the largest immune organ of the body. Such abnormalities have been pinpointed as etiological factors in a wide range of diseases, including autoimmune disorders, allergy, irritable bowel syndrome, inflammatory bowel disease, obesity, and colon cancer. Recognition of the strong potential for food to manipulate microbiota composition has opened up new therapeutic strategies against these diseases based on dietary intervention.

Portosplenomesenteric Venous Thrombosis in Patients With Acute Pancreatitis Is Associated With Pancreatic Necrosis and Usually Has a Benign Course

BACKGROUND & AIMS Although there are some data on prevalence of portosplenomesenteric venous thrombosis (PSMVT) in patients with acute pancreatitis (AP), the progression of PSMVT in patients who have and have not received anticoagulants has not been studied systematically. We evaluated the prevalence and natural history of PSMVT in a well-defined cohort of individuals with AP. METHODS In a retrospective study, we analyzed data from the University of Pittsburgh Medical Center on 162 patients with a sentinel attack of AP from 2003-2010. Data were collected on patient demographics, clinical presentation, etiology, clinical course, and outcomes. One hundred twenty-two patients underwent contrast-enhanced computed tomography; the scans were reviewed to identify thromboses and/or narrowing of splanchnic veins (splenic, superior mesenteric, and portal). RESULTS PSMVT was detected in 22 patients overall (14%; 18% among patients who underwent contrast-enhanced computed tomography). Median time to detection of PSMVT was 17 days (interquartile range, 11-40 days). PSMVT formed most frequently in the splenic vein (19 of 22, 86%), followed by portal (8 of 22, 36%) and superior mesenteric (6/22, 27%) veins. Development of PSMVT was associated with presence (21 of 22, 95%), location, and extent of pancreatic necrosis. Fifty-three percent of patients (21 of 40) with necrosis developed PSMVT. Anticoagulants were administered infrequently (6 of 22, 27%) and always for indications unrelated to PSMVT. Most patients with PSMVT developed collateral veins (19 of 22, 86%), and 27% (6 of 22) were found to have varices during endoscopic evaluation, but clot resolution was infrequent (2 of 22, 9%). No patient developed complications directly related to PSMVT. CONCLUSIONS PSMVT develops in about half of patients with necrotizing AP and is rare in the absence of necrosis. Despite infrequent administration of anticoagulants, complications directly related to PSMVT are rare.

Targeted therapy of short-bowel syndrome with teduglutide: the new kid on the block.

Extensive intestinal resection impairs the absorptive capacity and results in short-bowel syndrome-associated intestinal failure (SBS-IF), when fluid, electrolyte, acid-base, micro-, and macronutrient homeostasis cannot be maintained on a conventional oral diet. Several factors, including the length and site of the resected intestine, anatomical conformation of the remnant bowel, and the degree of postresection intestinal adaptation determine the disease severity. While mild SBS patients achieve nutritional autonomy with dietary modification (eg, hyperphagia, small frequent meals, and oral rehydration fluids), those with moderate-to-severe disease may develop SBS-IF and become dependent on parenteral support (PS) in the form of intravenous fluids and/or nutrition for sustenance of life. SBS-IF is a chronic debilitating disease associated with a poor quality of life, and carries significant morbidity and health care costs. Medical management of SBS-IF is primarily focused on individually tailored symptomatic treatment strategies, such as antisecretory and antidiarrheal agents to mitigate fluid losses, and PS. However, PS administration is associated with potentially life-threatening complications, such as central venous thromboses, bloodstream infections, and liver disease. In pursuit of a targeted therapy to augment intestinal adaptation, research over the past 2 decades has identified glucagon-like peptide, an intestinotrophic gut peptide that has been shown to enhance intestinal absorptive capacity by causing an increase in the villus length, crypt depth, and mesenteric blood flow and by decreasing gastrointestinal motility and secretions. Teduglutide, a recombinant analog of glucagon-like peptide-2, is the first targeted therapeutic agent to gain approval for use in adult SBS-IF. Teduglutide was shown to result in significant (20%–100%) reduction in PS-volume requirement and have a satisfactory safety profile in three randomized control trials. Further research is warranted to see if reduction in PS dependency translates to improved quality of life and reduced PS-associated complications.

Study of teduglutide effectiveness in parenteral nutrition-dependent short-bowel syndrome subjects

Loss of intestinal absorptive capacity from congenital defect, surgical resection or mucosal disease results in short bowel syndrome (SBS)-associated intestinal failure. In the past, few medical management options were available besides dietary modification, controlling diarrhea or high stomal output, and providing parenteral fluid, electrolyte and nutrient support (parenteral support). Recent research on strategies to enhance the intestinal absorptive capacity focused on glucagon-like peptide-2, an intestinotrophic hormone that has been shown to increase the villus height and crypt depth, and decrease gastric motility and intestinal secretory losses. STEPS is a Phase III randomized double-blinded controlled trial in which teduglutide, a recombinant analog of glucagon-like peptide-2, or placebo was given subcutaneously to SBS patients for 24 weeks. A clinically meaningful response, defined as a 20–100% reduction in parenteral support volume, was achieved in 63% of the treatment group compared with 30% in the placebo group (p = 0.002) without an increase in serious side effects. Teduglutide offers a new targeted approach to SBS-associated intestinal failure management. Its specific role in clinical practice remains to be evaluated.

Clinical Profile and Natural Course in a Large Cohort of Patients With Hypertriglyceridemia and Pancreatitis.

Goals: To report the clinical profile and natural course in a large series of patients with hypertriglyceridemia (HTG) and acute pancreatitis (AP). Background: The natural history of HTG-related pancreatitis is poorly defined. Study: Medical records of 121 patients with serum triglycerides (TG) levels of ≥500 mg/dL suffering 225 attacks of AP between January 2001 to August 2013 treated at the University of Pittsburgh Medical Center were retrospectively studied. Structured data were collected on initial presentation and long-term outcomes (mean follow-up 64.7±42.8 mo). AP severity was classified using Revised Atlanta Classification. Results: Most patients were young-middle aged (mean 44±12.7 y), male (70%), white (78%), and had sentinel AP (63%). Peak serum TG recorded was ≥1000 mg/dL in 48%. At least 1 secondary risk factor (diabetes, high-risk drinking, obesity, offending medications) was present in the majority (78%). Sentinel AP attack varied in severity between mild (41%), moderate (26%), and severe (33%). Recurrent AP attacks occurred in 32%, often in patients with poorly controlled diabetes, alcoholism, and TG levels. A cumulative increase in prevalence of pancreatic and/or peripancreatic necrosis was observed, with 45% patients having it at some time during observation. Local complications were higher in patients with serum TG ≥1000 mg/dL. Chronic pancreatitis was noted in 16.5% patients (new-onset in 9%). Conclusions: Patients with HTG-related pancreatitis have a high prevalence of secondary risk factors. Frequent recurrences in them are usually due to poor control of secondary factors or TG. Serum TG ≥1000 mg/dL increases the risk of local complications. A subset can have or develop chronic pancreatitis.

Teduglutide for the treatment of short bowel syndrome

Extensive resection of the intestine impairs its absorptive capacity and results in short bowel syndrome when the nutritional equilibrium is compromised. The remnant intestine adapts structurally to compensate, but nutritional autonomy cannot be achieved in patients with intestinal failure, requiring intravenous fluids and parenteral nutrition (PN) for sustenance of life. PN is expensive and associated with serious complications. Efforts to minimize or eliminate the need for PN heralded research focusing on the therapeutic utility of intrinsic gut factors involved in the postresection adaptation process. With the breakthrough recognition of the intestinotrophic properties of glucagon-like peptide-2, teduglutide, a recombinant analogue of glucagon-like peptide-2, is being investigated as a promising hope to mitigate the requirement of PN. Clinical studies to date have demonstrated a desirable benefit-to-risk profile in regards to its safety and efficacy. If approved for marketing, it will be the first of its class in short bowel syndrome management, offering an innovative therapeutic modality for this debilitating condition.

Intestinal Microbes, Diet, and Colorectal Cancer

Colorectal cancer (CRC) is the most common gastrointestinal cancer, and a significant health care problem globally. Dietary factors, for example high meat consumption and deficiency of fiber, calcium, vitamin D, and folate, are well-recognized to be associated with a risk of developing CRC. Colonic microbiota, by living in a mutual relationship and participating in key metabolic functions that compliment host physiology, is crucially important in the maintenance of our health. A state of imbalance in host–microbe homeostasis, termed dysbiosis, is associated with several diseases, including CRC. Epidemiological studies have revealed strong associations between diet, microbiota, and CRC. Substantial in-vitro and in-vivo evidence suggests that the dynamic composition and diversity of colonic microbiota are affected by alteration of the diet, and that the balance between the beneficial and detrimental microbial metabolites is of crucial importance in mediation of the dietary risk factors of colonic carcinogenesis. A better understanding of complex diet–microbiota–CRC relationships can help us understand how diet affects the risk of CRC and will provide a more scientific approach to the development of novel strategies to prevent CRC.

Metronidazole Induced Liver Injury: A Rare Immune Mediated Drug Reaction

Drug induced liver injury (DILI) can result either from dose-dependent direct hepatotoxicity or from an unpredictable dose-independent idiosyncratic reaction. Incidence of idiosyncratic DILI is estimated to be approximately 10–15 per 100,000 patient years. Here we report an extremely rare case of metronidazole induced delayed immune-allergic hepatocellular liver injury masquerading as autoimmune hepatitis. A previously healthy 54-year-old Caucasian male, who was treated with metronidazole for Clostridium difficile associated diarrhea, presented 3 months later with right upper quadrant abdominal pain. Laboratory tests revealed total bilirubin level of 12.7 mg/dL, direct bilirubin of 7.2 mg/dL, alanine aminotransferase (ALT) of 973 IU/L, aspartate transaminase (AST) of 867 IU/L, alkaline phosphatase (AP) of 96 IU/L, and an INR of 1.9, suggestive of hepatocellular pattern of injury. A detailed workup for hepatitis revealed no other etiology. A clinical diagnosis of metronidazole induced liver injury was made. With a persistent rise in his bilirubin and transaminase levels, the patient was started on oral prednisone. At the 2-week posthospitalization follow-up visit, the patient reported a significant improvement in his overall sense of being well and liver functions tests trended down substantially (total bilirubin 7.2 mg/dL, ALT 420 IU/L, AST 276 IU/L, AP 183 IU/L, and INR 1.5).

Risk of New-Onset Diabetes Is Determined by Severity of Acute Pancreatitis.

FIGURE 1. Risk of new-onset diabetes based on persistent OF and pancreatic necrosis (PN). A cute pancreatitis (AP) and diabetes have a bidirectional relationship. In a recent systematic review, the pooled prevalence of prediabetes and diabetes after the first attack of AP was 16% (95% confidence interval, 9–24) and 23% (95% confidence interval, 16–31), respectively. The risk of new-onset diabetes at the end of 1 year was 15%, which increased by 2.7-fold at 5 years. Interestingly, age, sex, etiology, or the severity of AP had little or no effect on subsequent development of diabetes. We hypothesized that the risk of diabetes is dependent on the severity of AP. Among patients enrolled in the Severe Acute Pancreatitis Study, a well-characterized cohort at the University of Pittsburgh Medical Center, we evaluated the probability of and factors influencing the development of diabetes after AP.