Although a characteristic clinical history and biochemical pattern of liver injury can strongly suggest the diagnosis of alcoholic hepatitis (AH), a definitive diagnosis is confirmed with liver biopsy only. In fact, in 30% of patients clinically diagnosed as having AH, a liver biopsy may lead to an alternative diagnosis.1Understandably, many physicians are reluctant to proceed with biopsy in this fragile patient population given the associated risks, notably bleeding. For this reason, most patients with AH are clinically diagnosed without a liver biopsy. However, there are certain instances in which a biopsy can be helpful, including when:2
- Diagnosis of AH is in doubt
- Suspicion for another disease process that may be contributing in parallel to AH is high
- Obtaining prognostic data or identification of advanced hepatic fibrosis or cirrhosis in AH is desired
Thus, liver biopsy findings may influence short- and long-term management in AH. For these reasons, the European Association for the Study of the Liver recommends consideration of a liver biopsy in patients with AH.3 To minimize the bleeding risk, the transjugular approach is preferred.
- Mookerjee RP, Lackner C, Stauber R, et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011; 55:1103-1111 Link
- Altamirano J, Miquel R, Katoonizadeh A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology 2014;146: 1231-1239. PDF
- European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57:399-420. PDF
Contributed by Jay Luther, MD, Gastrointestinal Unit, Mass General Hospital, Boston, MA.
Yes! Although an elevated serum lipase has a negative predictive value of 94%-100% for acute pancreatitis (1), there are ample reports in the literature of patients with CT findings of pancreatitis in the presence of abdominal symptoms but with normal serum lipase and/or amylase (2,3).
A case series and review of literature of acute pancreatitis with normal lipase and amylase failed to reveal any specific risk factors for such observation (2). More specifically, the etiologies of acute pancreatitis in the reported cases have varied, including drug-induced, cholelithiasis, alcohol, hypertriglyceridemia, and postoperative causes.
But what accounts for this phenomenon? Many cases have been associated with the first bout of pancreatitis without evidence of pancreatic calcifications which makes the possibility of a “burned-out” pancreas without sufficient acinar cells to release lipase as a frequent cause unlikely. Other potential explanations for normal lipase in acute pancreatitis have included measurement of serum lipase at a very early phase of the disease before significant destruction of acinar cells has occurred (increases in 3-6 h, peaks at 24 h ) and more rapid renal clearance of serum lipase due to tubular dysfunction (2).
Of note, unlike amylase, lipase is totally reabsorbed by renal tubules under normal conditions (5). Thus, it’s conceivable that even a reversible tubular dysfunction may lead to increased clearance of serum lipase and potentially lower its levels.
1. Ko K, Tello LC, Salt J. Acute pancreatitis with normal amylase and lipase. The Medicine Forum. 2011;11 Article 4. https://jdc.jefferson.edu/tmf/vol11/iss1/4/
2. Singh A, Shrestha M. Acute pancreatitis with normal amylase and lipase-an ED dilemma. Am J Emerg Med 2016;940.e5-940.e7. https://www.ncbi.nlm.nih.gov/pubmed/26521195
3. Limon O, Sahin E, Kantar FU, et al. A rare entity in ED: normal lipase level in acute pancreatitis. Turk J Emerg Med 2016;16:32-34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882216/
4. Shah AM, Eddi R, Kothari ST, et al. Acute pancreatitis with normal serum lipase: a case series. J Pancreas (Online) 2010 July 5;11:369-72. PDF
5. Lott JA, Lu CJ. Lipase isoforms and amylase isoenzymes: assays and application in the diagnosis of acute pancreatitis. Clin Chem 1991;37:361-68. https://www.ncbi.nlm.nih.gov/pubmed/1706232
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Although there are many potential sources for Klebsiella sp. bacteremia, C. difficile infection (CDI) itself may be associated with GI translocation of enteric organisms.
A retrospective study of over 1300 patients found an incidence of 1.8% for CDI-associated bacteremia. E. coli, Klebsiella sp. , or Enterococcus sp. accounted for 72% of cases. History of malignancy, neutropenia (at the time of CDAD), and younger age (mean 59 y) were among the risk factors.1 Another study reported over 20 cases of bacteremia caused by C. difficile plus other bacteria often of enteric origin such the aforementioned organisms, Bacteroides sp, Candida sp, and Enterobacter sp.2
CDI is thought to predispose to bacterial translocation through the GI tract by alteration of mucosal indigenous microflora, overgrowth of certain pathogens, and presence of inflammation in the mucosa.3 Interestingly, C. difficile toxin A or B may play an active role in the bacterial adherence and penetration of the intestinal epithelial barrier.4
Bonus pearl: Did you know that C. difficile may be found in the normal intestinal flora of 3% of healthy adults, 15-30% of hospitalized patients, and up to 50% of neonates? Why neonates seem immune to CDI is another fascinating story!
- Censullo A, Grein J, Madhusudhan M, et al. Bacteremia associated with Clostridium difficile colitis: incidence, risk factors, and outcomes. Open Forum Infectious Diseases, Volume 2, Issue suppl_1, 1 December 2015, 943, https://doi.org/10.1093/ofid/ofv133.659 https://academic.oup.com/ofid/article/2/suppl_1/943/2635179
- Kazanji N, Gjeorgjievski M, Yadav S, et al. Monomicrobial vs polymicrobial Clostridum difficile bacteremia: A case report and review of the literature. Am J Med 2015;128:e19-e26. https://www.amjmed.com/article/S0002-9343(15)00458-1/abstract
- Naaber P, Mikelsaar RH, Salminen S, et al. Bacterial translocation, intestinal microflora and morphological changes of intestinal mucosa in experimental models of Clostridium difficile infection. J Med Microbiol 1998; 47: 591-8. https://www.ncbi.nlm.nih.gov/pubmed/9839563
- Clostridium difficile toxins may augment bacterial penetration of intestinal epithelium. Arch Surg 1999;134: 1235-1242. https://jamanetwork.com/journals/jamasurgery/fullarticle/390434
Melena, characterized by black tarry stools, can occur with as little as 50 cc of blood in the stomach. How do we know this? We need to go back to clinical experiments involving oral administration of citrated blood in human subjects back in 1930’s and 40’s. 1-3 One study was performed on a group of “healthy medical students” who drank their own blood!3
Melena suggests an upper GI bleeding source where there is more time for enzymatic breakdown to transform blood to melena. Although gastric acid may also contribute to its formation, it does not appear to be a pre-requisite to melena as blood inserted into the small bowel or cecum can also produce melenic stools if it stays there long enough. Melena is dependent primarily on the length of transit time of blood in the GI tract, such that very rapid movement of 1 liter of blood from upper GI tract may lead to bright red blood per rectum, not melena, within 4 hours.2,4
Don’t get melena confused with other causes of dark stools such as oral iron supplementation and bismuth-containing medications (eg, Peptobismol®). In addition to its tarry texture, melena also has a characteristic pungent odor.
- Schiff L, Stevens R, Shaprio N, et al. Observations on the oral administration of citrated blood in man. Am J Med Sci 1942;203:409-12.
- Srygley FD, Gerardo CJ, Tran T, et al. Does this patient have a severe upper gastrointestinal bleed. JAMA 2012;307:1072-79. https://jamanetwork.com/journals/jama/article-abstract/1105075?redirect=true
- Daniel WA, Egan S. The quantity of blood required to produce a tarry stool. JAMA 1939;113:2232.
- Wilson ID. Hematemesis, melena, and hematochezia. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The history, physical, and laboratory examinations. 3rd edition. Boston: Butterworths:1990. Chapter 85. Available from: https://www.ncbi.nlm.nih.gov/books/NBK411/
Contributed in part by Brad Lander, MD, Mass General Hospital, Boston, MA.
Yes, enteric pathogens such as Salmonella can predispose patients to inflammatory bowel disease (IBD) through several potential mechanisms: 1
- Causing permanent changes in the intestinal microbiota
- Altering the epithelial barrier in the gut
- Altering the interaction between the body’s immune system and the intestines
More specifically, Salmonella utilizes oxidized endogenous sulfur compounds released during acute intestinal inflammation to outgrow the fermentative microbiota of the colon.2 In addition, the neutrophil response to Salmonella infection can alter the constituent microbiome.3 Salmonella also modifies the tight junctions in the intestinal epithelium as it invades, thus activating the immune system (particularly toll-like-receptors), and creating a pro-inflammatory state with structural loss of the intestinal mucosa. 4 Lastly, Salmonella promotes cytokine release and neutrophil migration through pathogen recognition receptors, leaving the intestine in a pro-inflammatory state even following resolution of the infection. 1
Keep in mind that initial Salmonella infection may also mimic IBD, as it causes diffuse lesions in the colon similar to ulcerative colitis, and may cause ileitis in some patients. Stool cultures and biopsies of the colonic mucosa should help differentiate IBD from Salmonella infection. 5
- Schultz BM, Paduro CA, Salazar GA, et al. A potential role of Salmonella infection in the onset of inflammatory bowel diseases. Front Immunol 2017;8:191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329042/pdf/fimmu-08-00191.pdf
- Winter SE, Baumler AJ. A breathtaking feat: to compete with the gut microbiota, Salmonella drives its host to provide a respiratory electron acceptor. Gut Microbes 2011;2:58-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225798/pdf/gmic0201_0058.pdf
- Gill N, Ferreira RB, Antunes LC, et al. Neutrophil elastase alters the murine gut microbiota resulting in enhanced Salmonella colonization. PLoS ONE 2012;7:e49646. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049646
- Bueno SM, Riquelme S, Riedel CA, et al. Mechanisms used by virulent Salmonella to impair dendritic cell function and evade adaptive immunity. Immunology 2012;137:28-36. https://www.ncbi.nlm.nih.gov/pubmed/22703384
- De Hertogh G, Geboes K. Crohn’s disease and infections: a complex relationship. MedGenMed 2004;6:14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435589
Contributed by Yasmin Islam MD, Mass General Hospital, Boston, MA.
Yes! Although a common cause of colitis, an increasing number of reports in the literature suggest C. difficile can cause enteritis as well.1 Antibiotic use is a major risk factor in most reports, with nearly one-half of the cases reported in patients with inflammatory bowel disease, many post-colectomy. 1-3
Mortality of C. difficile enteritis based on the first 83 cases in the literature appears to be 23%,1 but as high as 60%-83% depending on the report!2 Its diagnosis post-colectomy requires a high index of suspicion, as patients may not complain of “diarrhea” with chronically loose stools in the ileostomy bag. Be particularly on the lookout for C. difficile enteritis in these patients when there is increased stool output, fever, hypotension, and/or leukocytosis2, and when in doubt, send a stool specimen from the ileostomy bag for C. difficile testing.
Although the pathophysiology of C. difficile enteritis is not fully understood, few observations are particularly intriguing:
- Small bowel mucosa may be colonized by C. difficile in about 3% of the population, potentially serving as a reservoir.2
- Patients with ileostomy may develop a metaplasia of the terminal end mimicking colonic environment.4
- Exposure of rabbit ileum to C. difficile toxin A also causes significant epithelial necrosis with destruction of villi and neutrophil infiltration.5
- Dineen SP, Bailey SH, Pham TH, et al. Clostridium difficile enteritis: a report of two cases and systematic literature review. World J Gastrointest Surg 2013;5:37-42. https://www.wjgnet.com/1948-9366/full/v5/i3/37.htm
- Boland E, Thompson JS. Fulminant Clostridium difficile enteritis after proctocolectomy and ileal pouch-anal anastomosis. Gastroenterology Research and Practice 2008; 2008: Article ID 985658. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633454/pdf/GRP2008-985658.pdf
- Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clin Infect Dis 2001;33:1429-31. https://pdfs.semanticscholar.org/333b/d84978cfc4ac8fd21a15bc8fd26ff3160387.pdf
- Apel R, Cohen Z, Andrews CW, et al. Prospective evaluation of early morphological changes in pelvic ileal pouches. Gastroenterology 1994;107:435-43. http://www.gastrojournal.org/article/0016-5085(94)90169-4/pdf
- Triadafilopoulos G, Pothoulakis C, Obrien MJ, et al. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 1987;93:273-279. https://www.ncbi.nlm.nih.gov/pubmed/3596162
Proton pump inhibitors (PPIs) have been associated with increased risk of Clostridium difficile infection, as well as acute gastroenteritis (AG) caused by Salmonella, Campylobacter, and most recently, norovirus. 1,2
A recent prospective study1 of over 38,000 patients (mean age ~ 70 y) found a significant association between PPI use and AG leading to hospitalization with a dose-response relationship. PPI use increased the risk of Salmonella, Campylobacter, and C. difficile infections. Of note, H2 receptor antagonists were not associated with AG-related hospitalization in this study.
A 2017 retrospective case-control study also showed an association between PPI use and norovirus infection in hospitalized patients (mean age ~80 y in both groups). Most cases occurred during epidemic years with a median hospital stay of 5 days before onset of symptoms. Given the usually short incubation period of norovirus AG (typically 12-48 h), many of these cases likely acquired the infection during their hospital stay.
Besides reducing the acidity of gastric juice, PPIs may increase the risk of AG by causing an overgrowth of bacteria in the GI tract, reduce its motility and adversely affect the immune response, including neutrophil chemotaxis. 3
Does your patient really need a PPI?
- Chen Y, Liu B, Glass K, et al. Use of proton pump inhibitor and the risk of hospitalization for infectious gastroenteritis. PLoS One 2016;11:e0168618. Doi:10.1371/journal.pone. 0168618. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168618
- Prag C, Prag M, Fredlund H. Proton pump inhibitors as a risk factor for norovirus infection. Epidemiol Infect 2017;145:1617-23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426289/pdf/S0950268817000528a.pdf
- Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut 1992;33:617-21. https://www.ncbi.nlm.nih.gov/pubmed/1319381