Page 69 – Practical Gastro

Juan Castro-Combs,

Evelyn Eichler,

Richard W. McCallum

Unexplained bloating is one of the most common and bothersome gastroenterology complaints in gastrointestinal (GI) specialty and primary care clinics. This article attempts to provide physicians with a simple and rational approach to unexplained abdominal bloating and to identify underdiagnosed entities that could be responsible for this symptom.

Unexplained bloating is one of the most common and bothersome gastroenterology complaints in gastrointestinal (GI) specialty and primary care clinics. Abdominal bloating is likely to present in association with other complaints including belching, flatulence, post-prandial distension, borborygmi, abdominal pain and diarrhea. Given the lack of a systematic approach to these complaints, symptomatic patients are often asked to keep a food diary and dietary modifications are suggested. If symptom resolution does not occur, further testing (blood and stool tests, imaging studies, endoscopic procedures) to rule out organic disorders is initiated. A “negative” or unremarkable work up often places patients into the “functional” GI disorder compartment. This article attempts to provide physicians with a simple and rational approach to unexplained abdominal bloating and to identify underdiagnosed entities that could be responsible for this symptom.

Juan Castro-Combs, MD¹ Evelyn Eichler MS, RD, LD² Richard W. McCallum, MD, FACP, FRACP (Aust), FACG³ ¹Texas Tech University Health and Sciences, Internal Medicine Department, Gastroenterology ²University Medical Center, Food and Nutrition Care Services ³Texas Tech University Health and Sciences, Department of Internal Medicine, Gastroenterology, Center for Neurogastroenterology and GI Motility, El Paso, TX

INTRODUCTION

Abdominal bloating is a nonspecific term whose definition varies among gastroenterologists with an even broader meaning for patients in general. Bloating can be defined as the objective abdominal distention originating from gas or as a subjective feeling of abdominal distention or abdominal wall tension without objective distension. These symptoms have been linked with different pathophysiologic mechanisms that are not fully understood. Several functional gastrointestinal disorders (functional dyspepsia,^1,2 irritable bowel syndrome (IBS),^1,2,3 functional constipation^1,2,4,5 and functional bloating⁶) have bloating as a manifestation despite the absence of a somatic abnormality.

Bloating is likely to present in association with other nonspecific GI complains including belching, flatulence, borborygmi, abdominal pain, nausea and diarrhea. Patients with such gastrointestinal (GI) symptoms, especially those with alarm symptoms, usually undergo multiple studies to rule out organic disorders. Testing includes but is not limited to blood work, stool tests, imaging studies and endoscopic procedures. When these tests fail to expose any abnormality, patients are diagnosed with functional GI disorders.

Carbohydrate intolerance or malabsorption and small bowel bacterial overgrowth (SIBO) are common problems frequently encountered in the GI and primary care clinics. These disorders are responsible for bloating as well as other unspecific symptoms. Their exact prevalence is unknown because they are poorly recognized and, as a consequence, are poorly managed. The current report attempts to provide physicians with a rational approach to address these GI symptoms and to identify underdiagnosed or underappreciated entities before patients are placed into the GI functional disorders compartment where further investigations may be limited.

Small Intestinal Bacterial Overgrowth

SIBO is the presence of excessive bacteria in the small intestine, defined as a bacterial population, possibly colonic-type species, exceeding 10⁵-10⁶ organisms/ml in jejunal fluid.^7,8 Symptoms of SIBO are nonspecific and include bloating, abdominal distension, abdominal pain or discomfort, diarrhea, constipation, fatigue and weakness. The severity of symptoms likely reflects the degree of bacterial overgrowth and the extent of mucosal inflammation.

Risk factors for SIBO include GI tract structural or anatomic abnormalities (e.g. small bowel diverticulosis, strictures), post-surgical changes (e.g. vagotomy, Bilroth I and II anastomoses, bariatric surgery, gastro- jejunostomy, colectomy with ileocecal valve resection), radiation damage to the small bowel, motility disorders (e.g. gastroparesis, small bowel dysmoltility), systemic diseases that affect bowel motility (e.g. diabetes, scleroderma, amyloidosis), IBS, cirrhosis, pancreatitis, immunodeficient states, hypochlorhydria (e.g. atrophic gastritis, proton pump inhibitor (PPI) use), advanced age which may overlap with hypochlorhydria, recurrent antibiotic use and medications that decrease motility (e.g. narcotics, anticholinergics) (Table 1).

The presenting symptoms of SIBO can sometimes also reflect the underlying cause (e.g. abdominal pain, early satiety and vomiting may point towards gastroparesis or small bowel dysmotility). Other symptoms can reflect complications of SIBO, including malabsorption, nutritional deficiencies (e.g. B12 related anemia) and metabolic bone disorders.⁹ The nonspecific nature of these complaints makes SIBO difficult to distinguish clinically from other disease entities, such as IBS, lactose intolerance and fructose intolerance.

Fructose Malabsorption

Dietary fructose intolerance (DFI), although its role is somewhat controversial, is often implicated in the causation of GI symptoms. Several studies reported a prevalence of fructose malabsorption in patients with the diagnosis of functional dyspepsia or unexplained GI symptoms between 40 and 73%.^10,11 Another study has estimated that up to one third of patients with suspected IBS had DFI.¹²

Undigested or poorly digested fructose generates an osmotic force driving water into the lumen of the small bowel and leading to decrease transit times of bowel contents which then reach the colonic flora producing fermentation of this carbohydrate.¹³ This may result in symptoms including abdominal pain, excessive gas, bloating and variable diarrhea, especially in patients with visceral hypersensitivity.¹⁴

Symptoms, and self-rated health, improve if patients are willing to adhere to a low fructose diet.¹⁵ Fructose is present in a variety of fruits, vegetables and honey but it is also produced from the digestion of high fructose corn syrup, commonly found in processed food. The amount of fructose in the diet of the average American has definitely increased during the last 50 years when high fructose corn syrup was introduced to the food industry in the late 1960s. GI symptoms might develop after the consumption of 37.5 gm of fructose per day¹⁶ (for reference, an 8 ounce can of Coca-Cola contains 25 gm of fructose). It is possible that a rise in fructose consumption in the United States (US) population has resulted in a rise in fructose malabsorption and intolerance.¹⁰

Breath Testing

Hydrogen breath tests are currently utilized as diagnostic tests to confirm or eliminate the possibility of carbohydrate malabsorption or SIBO in such patients. Currently available breath tests include: lactose, fructose (FBT), lactulose and glucose.

Lack of standardization has led to subjectivity of these tests and institutional comparisons are difficult given the variability of parameters such as the dose of substrate administered, duration of the test, the interval of breath testing and cut-off values.¹⁷

The breath tests measure hydrogen (H₂), methane (CH₄) and CO₂ present in the exhaled air. H₂ is a common gas produced by bacteria during the metabolism of these carbohydrates; conversely, methanogenic flora is far less common and has been described to be present in up to 30% of patients with Scandinavian descent and in less than 10% of US population. By adding methane measurements the sensitivity of the tests is increased. CO₂ level is determined to ensure that the sample measures actual alveolar air to assure accuracy of breath samples.

The glucose hydrogen breath test (GBT) is more acceptable for diagnosis of SIBO whereas lactose and fructose hydrogen breath tests are used for detection of lactose and fructose maldigestion respectively. Lactulose hydrogen breath test has been used for SIBO as well but glucose breath test has greater advantages over lactulose because of its higher specificity. Lactulose breath test is also used in GI motility to measure the orocecal transit time. These methods are noninvasive and inexpensive. Breath tests, though valuable tools, are underutilized in evaluating dyspepsia, functional bloating and diarrhea as well as suspected malabsorption.

Our extensive experience with glucose breath testing to rule out SIBO has indicated us that the optimal protocol should include the administration of a 100 gm oral glucose challenge with collection of breath samples every 20 minutes for 3 hours to measure hydrogen and methane concentrations. Over the last 2 two years we have performed this study in 188 patients presenting with unexplained abdominal bloating to our motility Center at University Medical Center at Texas Tech Health and Sciences, El Paso. We found that 85 of these patients were positive for SIBO representing 45% of the total of patients tested. A glucose breath test was considered to be positive if there was an increase in hydrogen concentration exceeding 20 parts per million (ppm), an increase over 10 ppm for methane or when the baseline values are >20 ppm. 38 of these patients with negative glucose breath tests and unexplained bloating underwent further testing using fructose breath tests (FBT) performed after 25 gm fructose oral administration with collection of breath samples in the same fashion. 18 out of the total 38 patients were found to be FBT positive. This represents 47% of the FBTs evaluated. The parameters utilized for a positive fructose test include H₂ or CH₄ peaks of more than 20 ppm and 10 ppm respectively. Usually these peaks occur in the range of 90 min to 3 hours after fructose intake when unabsorbed fructose is metabolized by colonic flora.18

Approach to Abdominal Bloating, Gas and Distension

Patients with abdominal distension, bloating and excess gas, with or without additional GI symptoms, often have a negative GI work up. Evaluation may include laboratory tests for hypothyroidism, stool tests for bacterial, helminthic and protozoa infections, imaging for bowel obstruction or ascites, endoscopy for common disorder such as celiac disease, H. pylori infection and lactose intolerance exclusion through a dairy free diet.

As a next step in evaluating bloating without a determined etiology, a GBT to assess for SIBO could be performed. A positive GBT may indicate the presence of excess bacteria in the small bowel requiring appropriate antibiotic treatment. Acceptable antibiotic regimes include metronidazole 500 mg PO BID, neomycin 500 mg PO BID, amoxicillin/clavulanic acid 500 mg PO BID, doxycycline 100 mg PO BID or rifaximin 400 mg PO TID (non-standard dosing)^19,20,21 for 2 to 3 weeks. (Table 2) Refractory symptoms in the setting of a repeat positive GBT may require an alternative antibiotic or combination therapy. Patients with continued symptomatic or recurrence may benefit from 1) gastric and small bowel prokinetics (eg. low dose erythromycin, metoclopramide or pyridostigmine) in settings of gastric or small bowel motility disorders, 2) treating constipation with linaclotide or lubiprostone, 3) probiotics, specifically containing bifidobacterium infantus, 4) discontinuing PPI to reduce hypochlorhydria which promotes the possibility of bacterial colonization of the small bowel and 5) stopping or decreasing doses of anticholinergic drugs and/or narcotics which reduce gut motility and enhance bacterial colonization. A negative GBT may prompt a FBT. A positive fructose test would indicate the presence of fructose intolerance and should trigger the treatment with a low fructose diet. A patient with a negative FBT on the other hand may be empirically treated with a low FODMAP diet to assess if there is any improvement of symptoms. Hence the algorithm we illustrate can unmask the presence of DFI and see if a less restrictive diet would help before recommending a more demanding low FODMAP diet (Figure 1).

Dietary Management

A low fructose diet is a less restrictive alternative than the low FODMAP diet since it only limits the consumption of fructose from some fruits (e.g. prunes, pears, cherries, peaches, apples, plums, dates, mango, watermelon) vegetables (e.g. sugar snap peas, tomatoes, corn, carrot, sweet potatoes) honey and other processed foods with fructose on the label.

FODMAPs (fermentable oligosaccharides, disaccharides, monosacharides and polyols) are osmoticaly active carbohydrates that are high in fructose (e.g. honey, peaches, dried fruits), fructans (e.g. wheat, rye, onions), sorbitol (e.g. dried fruits, sugar alcohols and sweeteners), and rafinose (e.g. lentils, cabbage, legumens). The high osmolality of FODMAPs leads to increased water in the small bowel, decreasing transit time resulting in increasing gas and colonic distention from bacterial fermentation of poorly absorbed carbohydrates.¹³ This diet limits the consumption of high fiber foods such as beans, fruits, vegetables and grains. The low FODMAP diet implementation is flexible and can be tailored to meet individual’s lifestyle and preferences.

The low FODMAP diet was developed by a research group in Australia as a new dietary management of IBS and other functional gastrointestinal disorders with bloating and abdominal pain.²² A pilot study showed that a low FODMAP diet led to sustained improvement in all gut symptoms in 86% of the patients diagnosed with IBS compared to the standard diet group of 49%.¹⁹

Subsequently several high-quality clinical studies have further confirmed that FODMAP diet allows drug-free symptom relief in many patients with IBS.^23,24,25

A typical approach in the implementation of the low FODMAP diet would involve restricting problematic (elimination diet) FODMAPs for 6 to 8 weeks, or until symptomatic control is achieved. This is performed by substituting high FODMAP foods with lower options or by reducing the total FODMAP load consumed in each meal or across the day. After this, small amounts of FODMAP-containing foods are reintroduced through challenges. The aim of challenging is to gradually increase to levels well-tolerated by the individual, while widening the diet as much as possible.

Food Sensitivity

Food sensitivity is an evolving science in nutrition, and it is different than food allergy or food intolerance. Food allergy is an IgE mediated immune response that occurs reproducibly on exposure to a given food, with a physiological response usually within 2 hours of exposure. Food intolerance can be due to lack of enzymes or bacterial changes. Food sensitivity is a reaction from an assault to the gut from food irritants, toxins (mold, pesticides), infections (SIBO), pharmacological decreases and increases in gut permeability, malabsorptions and psychological stress. True food sensitivity is a non-IgE adverse food reaction, where the individual may or may not have an initial reaction because it is usually delayed and dose dependent. Symptoms of food sensitivity can be similar to a food allergy resulting in skin changes, but it may also be systemic causing fatigue, asthma, migraines and body aches.

Serum testing for IgG and IgE antibodies to specific food antigens has been performed in the past with some degree of success. In a study in which 20 IBS patients unresponsive to standard therapy where enrolled, IgG and IgE levels to different food and mold panels were obtained. The most frequent positive serologic IgG antigen-antibody complexes in the study were: 4 or more molds, baker’s yeast, onion mix, pork and peanut. These patients underwent targeted elimination diet followed by controlled food challenges and were followed at 1 year after trial completion with a questionnaire. This approach resulted in a sustained clinical response and improvement in overall well-being and quality of life.²⁶ These specific testing and treatment for food sensitivities really comes into play where breath testing has not been fruitful and other GI medical diagnoses are excluded. Determination of IgG serum antibodies to food constituents, elimination diets and re-challenge play a role in food sensitivity approaches.

Take Home Pearls

When the standard gastrointestinal work up for bloating of undetermined origin fails to expose any abnormality, providers should consider SIBO and DFI before patients are placed into the functional GI disorder compartment. Glucose and fructose breath tests are specific and sensitive diagnostic tests that can be used to either confirm or eliminate the possibility of SIBO or fructose intolerance in such patients.

For refractory cases of SIBO, the authors recommend to improve GI motility with low dose prokinetics when gastroparesis and/or small bowel dysmotility are present; chronic constipation should be aggressively treated if present; bifidobacterium infantus containing probiotics should be started to augment host defense; PPI should be tapered or stopped when possible to improve hypochlorhydria. Additionally, stop or attempt to decrease dose of anticholinergic drugs and/or narcotics when possible.

A positive fructose test would indicate the presence of fructose intolerance and should result in treatment with a low fructose diet. A negative FBT on the other hand should lead to a trial with the low FODMAP diet to assess if there is any improvement of symptoms. Finally food sensitivity and “food allergy” are a consideration to provide a rational approach for the practitioner.

We hope this article enlightens our readers and most of all we hope it improves the caring treatment and quality of life of your patients with abdominal bloating.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #96

Inflammatory Bowel Disease in the Elderly: Hazards of Generalizing the Evidence

Vineet S. Gudsoorkar,

Bincy P. Abraham

Several challenges exist in managing the geriatric population with inflammatory bowel disease (IBD). The physiology of aging affects not only disease expression, but also the treatment and surveillance strategies. The existing evidence for their treatment is extrapolated from studies that often suffer from a suboptimal representation of this patient subgroup. In this review, we discuss the existing evidence for IBD in the elderly and the potential hazards of its unchecked extrapolation to, arguably, a more fragile and susceptible population.

Vineet S. Gudsoorkar, MD, Gastroenterology Fellow, Houston Methodist Hospital. Bincy P. Abraham, MD, MS, FACG, Director, Gastroenterology Fellowship Program Director, Underwood Center – Fondren Inflammatory Bowel Disease Program, Houston Methodist Academic Gastroenterology Office, Houston, TX

The prevalence of inflammatory bowel disease (IBD) in the elderly population is on the rise. Several challenges exist in managing the geriatric population with these chronic disorders. The physiology of aging affects not only disease expression, but also the treatment and surveillance strategies. Despite such considerations, which are unique to elderly IBD patients, the existing evidence for their treatment is extrapolated from studies that often suffer from a suboptimal representation of this patient subgroup. In this review, we discuss the existing evidence for IBD in the elderly and the potential hazards of its unchecked extrapolation to, arguably, a more fragile and susceptible population.

INTRODUCTION

Ulcerative colitis (UC) and Crohn’s disease (CD) collectively referred to as inflammatory bowel disease (IBD), continue to pose significant challenges to the healthcare system. The latest estimates show that IBD affects approximately 1.2 million Americans.¹ Despite such extensive burden, our understanding of the pathogenesis of IBD remains incomplete; and although significant strides have been made in the field of therapies aimed at keeping the disease under control, no definite cure has yet been identified. With the advent of new therapies, the epidemiology of IBD appears to be changing; and with improved patient longevity, gastroenterologists are expected to encounter more and more elderly patients with IBD in their clinical practice. Yet, there remains a remarkable paucity of literature focusing primarily on the geriatric IBD patient population.

Changing Epidemiology: A Function of Overall Survival, or Missing Links in Pathogenesis?

Classically, IBD has been thought to carry a bimodal distribution of incidence with a peak in the 2nd- 4th decade of life, followed by a smaller second peak in the 6th- 7th decade. As the etiology of IBD is considered multifactorial involving interactions between environmental influences, adaptive and innate immunity, and genetics; the exact reason of such bimodal distribution is unclear.² Current epidemiologic studies demonstrate that approximately 10-15% of the newly diagnosed IBD patients are above 60 years of age.³

One such study analyzing over a decade of data in the Department of Veterans Affairs suggested that the incidence of IBD has stabilized in the USA, but there appears to be an increase in the prevalence.⁴ Considering IBD is a chronic disease without a significant direct mortality risk, this can be thought of a direct result of increased survival.

Such change in epidemiology of IBD has several direct and important implications that affect short and long-term management of the disease. In the age of evidence-based medicine, the older, and arguably more fragile patient population has the least amount of evidence on management of IBD.

IBD in the Elderly: Hazards of Generalizing the Evidence

Despite the rising prevalence of IBD in the geriatric population, evidence- based data specifically addressing the management of older IBD patients is scarce. The reasons for such scarcity are manifold, starting with the definition of the term “elderly”. In the literature, the age cut-off for defining the elderly population has been variable, ranging most commonly from 50 to 65 years of age. Without a standardized cut-off, the generalizability of evidence remains limited.

Similarly, the current opinions on the management of such patients are derived from subgroup analyses of clinical trials involving the general population. Geriatric patients are often excluded or poorly represented in such trials. A valid statistical analysis cannot be performed of the outcomes in non-predefined subgroups. Additionally, at extremes of the age distribution curve the statistical power is expected to be quite low given the low number of the patients analyzed.

Apart from statistical considerations, applying the results of clinical trials to the geriatric population would fail to take into consideration age-related physiologic changes such as alterations in pharmacokinetics of the medications, physiology of aging, presence of comorbidities and importantly, quality of life. This article aims at exploring practical considerations and caveats in application of current management principles of IBD to the geriatric population.

IBD in the Elderly:Review of Evidence and Caveats

Despite the limitations outlined above, given the lack of data addressing exclusively the geriatric population clinical decisions are often made extrapolating the current available evidence to the elderly population. The following section reviews the available evidence and problems unique to the elderly.

a) Disease Characteristics

The disease phenotype of IBD in elderly is distinct from that in the young. Several factors may account for such difference: immune senescence, less contribution of genetic influences and possibly, altered environmental factors such as the gut microbiota. Compared to the younger patients (17-59 years old), the elderly-onset patients with CD tend to have ileocolonic or colorectal involvement, less frequent involvement of the upper gastrointestinal tract, and a less aggressive disease course with relatively lower rate of progression to stricturing or penetrating disease.^5,6 Similarly, compared to the younger patients the elderly onset UC patients tend to have more limited (proctitis or left sided) colonic disease and also seem to have a less aggressive disease course.^5,6 Such key differences in epidemiology, disease phenotype and disease progression highlight the heterogeneity of the disease among the different age groups.

b) Medical Therapy: Drug Metabolism, Eficacy and Safety Considerations

Important pharmacokinetic changes in the elderly population result from the physiology of aging. These physiologic alterations include changes in body composition such as reduced lean body mass and subsequent reduction in total body water, reduced first-pass metabolism and a reduction in renal mass and glomerular filtration rate (GFR).⁶ Also, the elderly patients are frequently on a variety of other medications increasing the risk of drug-drug interactions in the setting of altered pharmacodynamics.

5-Aminosalicylic acids

Oral 5- aminosalicylic acid (5-ASA) derivatives are used in the treatment of active disease as well as for maintaining remission in CD and UC, although their therapeutic utility appears to be more evident in UC.^7,8 The safety and efficacy of the various 5-ASA formulations appear to be uniform across all patient populations without any significant age-related variations.⁹ Older data from rheumatoid arthritis patients treated with sulfasalazine suggest that the elderly patients have higher steady-state concentration of its metabolites;¹⁰ however has not been observed with the newer 5-ASA (mesalamine) formulations. Pharmacokinetics of 5-ASA may not be very relevant from an efficacy standpoint as most of its therapeutic effect is topical in nature and pharmacokinetic variations may be driven more by genetic influences (such as enzymatic polymorphism) rather than age.¹¹ Nephrotoxicity, which is perhaps the most concerning adverse effect of these compounds, occurs at an incidence of less than 1 in 500.¹¹ A recent retrospective study showed that there was a significant dose- and treatment duration- dependent decline in creatinine clearance (CrCl) in IBD patients treated with 5-ASA. Although the patient age at treatment onset did not significantly affect the CrCl, a pre-treatment renal dysfunction correlated with a greater decline in CrCl.¹² To conclude, ASA drugs remain a reasonable option in the armamentarium of clinicians treating geriatric IBD patients but close monitoring of renal function, particularly during the initiation of therapy and yearly thereafter is warranted considering the physiological decline in renal function in this age group.

Antibiotics

Antibiotics are frequently used to treat infectious complications of IBD such as abscesses, fistulizing CD, and pouchitis in UC. Metronidazole and ciprofloxacin have been the most studied in IBD. Their role in modifying the primary disease process is controversial although alteration of gut microbiota has been recently suggested as a putative mechanism for their actions. Metronidazole is eliminated mainly via hepatic metabolism. Data regarding the influence of age on its pharmacokinetics, derived mainly from non-IBD patient population, suggest a decreased renal excretion of metronidazole and its metabolites in the elderly,¹³ although age-dependent dose adjustment is not common.

Ciprofloxacin, on the other hand, is eliminated renally. While some studies have shown an increased serum concentration, slower renal clearance, and prolonged half-life of ciprofloxacin in the elderly, recommending a dose frequency of not less than every 12 hours;¹⁴ whereas others did not find such difference its elimination half-life, and attributed the higher serum concentration to a lower volume of distribution.¹⁵ Considering the physiologic decline in GFR, attention should be paid to the dosage even in the absence of overt renal insufficiency given that adverse effects of quinolones such as diarrhea can often be mistaken for a flare of the underlying IBD. Additionally, older age (>60 years) and concurrent steroid use are known risk factors for tendonopathy associated with quinolones.¹⁶

Clostridium difficile infection remains an important risk associated with antibiotic use. Other important risk factors include older age, fluoroquinolone exposure, and immunosuppression. These place the geriatric IBD patients at a significantly higher risk of acquiring C. difficile infection which, in addition to confounding the underlying disease activity assessment, is associated with a greater morbidity, mortality, healthcare costs as well as need for colectomy.¹⁷

Corticosteroids

Corticosteroids have long been used to induce remission in the treatment of IBD, which is either severe or unresponsive to 5-ASA therapy. The risks associated with prolonged steroid use in general population are well known. In the geriatric population steroids have been associated with increased relative risk for developing adverse effects such as hypertension, diabetes, altered mental status as compared to younger (< 50 years old) patients.¹⁸ Additionally the age-specific incidence rate ratio (IRR) of osteoporotic fractures is 40% higher in all IBD patients as well as the elderly subgroup (>60 years of age) compared to the age- and sex- matched general population. The incidence of fractures in IBD patients increases with age.¹⁹ Chronic use of steroids, combined with vitamin D deficiency, which is often coexistent in IBD,²⁰ further increases this risk. Age related loss of muscle mass and nutritional deficiencies may also exacerbate steroid-induced myopathy in the elderly. It has been suggested that persons above the age of 65 may have increased unbound (free) fraction of prednisolone;²¹ although it is not clear whether a dose reduction is necessary in the elderly patients.

Budesonide and budesonide MMX, synthetic corticosteroids that have linear pharmacokinetics, differential absorption when administered orally versus rectally, and fewer acute adverse effects;²² is an alternative to prednisone for elderly patients. However, it should be noted that most patients included in major trials evaluating the conventional corticosteroids as well as the formulations of budesonide were in the 3rd to 4th decade of life.^23-26 Older age and chronic steroid use have been associated as the two key risk factors for potential drug interaction.²⁷ As noted by Parian and Ha, a majority of late-onset IBD patients- including those in remission or those with mild disease activity- often receive chronic maintenance therapy with steroids and steroid-sparing therapies remain underused in these patients. Therefore, caution should be exercised in older patients on long-term steroids (typically, >7.5 mg per day of prednisone for > 1 month).

Appropriate screening including bone mineral density, vitamin D levels, electrolytes and blood glucose must be periodically performed; feasibility of a steroid-sparing regimen should be considered early; medications should be reviewed for potential drug-drug interactions and clinical predisposition for infections should be assessed frequently in older patients on steroid therapy.

Immunomodulators

Immunomodulators such as methotrexate (MTX), azathioprine (AZA), and 6-mercaptopurine (6-MP) are most commonly used as steroid-sparing agents or in combination therapy with biologic agents. AZA and 6-MP, the thiopurine compounds are catabolized by the enzyme thiopurine S-methyltransferase (TPMT). Patients with TPMT gene mutations and enzyme deficiency are at higher risk for developing severe hematological toxicity such as bone marrow suppression. While screening patients for TPMT deficiency prior to starting thiopurine therapy is standard of care, age-related variations in TPMT activity have been documented.^28,29 Although these findings suggest a multifactorial regulation and not necessarily only age related linear association of TPMT activity, clinicians should be aware of a potentially exaggerated myelosuppression in the elderly patients, particularly considering the physiological changes in the bone marrow activity with aging.³⁰

Concern exists regarding the risk of malignancy- particularly lymphomas, melanoma and non-melanoma skin cancers in association with immunomodulator therapy. Studies have shown an increased risk of lymphoma as high as fourfold with thiopurines.³¹ Of note, a German study demonstrated 18% incidence of lymphoma in IBD patients over 50 years of age, as compared to 4% incidence in those less than 50 years old, when treated with thiopurines.³² A meta-analysis of immunomodulator use with AZA/6MP/ MTX showed a bimodal risk distribution with relative risk of lymphoma being higher in patients below 35 years of age but the highest absolute lymphoma risk with a standardized incidence ratio of 4.78 (1:354 cases per patient-year) was seen in IBD patients older than 50 compared to the younger IBD population. However these observations were not reproduced when data from a previously excluded “outlier” study were included in the analysis.³³

With regards to skin cancer, a large population- based study showed an association between immunomodulatory use for more than 5 years and non- melanoma skin cancer [Odds ratio (OR) 1.78],³⁴ whereas a similar study from Olmstead County, Minnesota reported an increased risk of melanoma in patients treated with immunomodulators.³⁵ A meta-analysis addressing the association between non-melanoma skin cancers and thiopurine use demonstrated a modest risk (pooled adjusted hazard ratio 2.28), but this association lost statistical significance after excluding studies with a relatively short-term (< 3 years) follow-up. The authors concluded that there is not enough evidence to suggest that the cancer risk outweighs the treatment benefit with thiopurines.³⁶ None of these studies identified age as an independent risk modifier.

Periodic monitoring of complete blood count, liver and kidney function and skin examinations should be a part of routine surveillance of all IBD patients on immunomodulator therapy but special precautions should be taken in the elderly as they are at higher risk of the drugs adverse effects than their younger counterparts.

Biologics

The fourth major class of drugs used to treat moderate to severe IBD is biologics, either antibodies against tumor necrosis factor (TNF)-a (infliximab, adalimumab, certolizumab, golimumab), or anti-integrins (natalizumab and vedolizumab). These agents have been shown to induce and maintain remission, improve quality of life, and reduce hospitalizations for IBD patients.^37,38

An analysis of IBD patients >65 years of age treated with TNF-a inhibitors demonstrated an 11% incidence of severe infections and 10% total mortality in the elderly group- as compared to 2.6% and 1% incidence of severe infections and mortality, respectively, in the younger patients.³⁹ Another study confirmed these results with a 3 times high risk of severe adverse events in the >65 year old IBD patients compared to those <65 on anti-TNF therapy.⁴⁰ These findings further prompt concerns about the applicability of results of clinical trials to the geriatric population.

Older age has been shown to be a statistically significant predictor of suboptimal early response to anti-TNF therapy.^40,41 Additionally, Desai et al. noted a 70% discontinuation rate at the end of 2 years of anti-TNF therapy in patients > 60 years of age, and concluded that older age was a significant risk factor for discontinuation of this treatment.⁴²

Of the two anti-integrin molecules, vedolizumab was recently approved for the treatment of moderate to severe IBD. The mean age of patients in the two phase 3 randomized trials comparing vedolizumab to placebo for CD and UC was 35-40 years.^43,44 Similarly, randomized clinical trials involving natalizumab for the treatment of CD had the mean patient age of approximately 35- 40 years.^45,46 Although no age-specific differences were seen in efficacy or safety analyses in these clinical trials, surveillance strategies in patients above the age of 65 on anti-integrin therapy remain undefined as the clinical data of anti-integrin therapy in the elderly population is quite sparse.

c) Surgical Therapy: Restorative Surgery versus Permanent Ileostomy

Advanced age is a significant risk factor and predictor of outcomes for patients undergoing surgery for IBD. Advanced patient age is associated with a longer operating room time, longer length of hospitalization and higher odds for postoperative complications.⁴⁷ Ileo- pouch anal anastomosis (IPAA), being a more complex procedure was traditionally reserved for “younger” patients with IBD. In a population-based study of veterans above 50 years of age with UC, Longo et al. noted that 64% of the patients underwent proctocolectomy and permanent ileostomy.⁴⁸ However, a recent systematic review evaluating medical and surgical complications in IBD patients observed encouraging outcomes after IPAA in the elderly population. Neither was there an increase in mortality in the IPAA group compared to total proctocolectomy group regardless of age, nor an association between age and IPAA failure rates seen. The functional outcomes were also comparable between the older and younger patients with no difference in daytime functional impairment. However, an increased incidence of post-IPAA nocturnal bowel incontinence was noted in the elderly group, as well as an association between age and nocturnal bowel movements.⁴⁹ From the patient perspective, however, 89-100% reported that they would undergo their surgery again, and 93-100% reported that they would recommend it to others.⁵⁰

d) Colorectal Cancer Screening/Surveillance

While the IBD population is at a higher risk for developing colorectal cancer (CRC), the exact magnitude of this relationship is not clear. A meta- analysis from 2001 showed an increased risk for developing CRC in UC patients- 2% by 10 years, 8% by 20 and 18% by 30 years.⁵¹ In contrast, more recent data have suggested a progressive reduction in the excess CRC risk in IBD patients and that the disease extent and duration are important risk factors for developing CRC.⁵² In a case-control study, the histological inflammation score was the only significant determinant of CRC risk.⁵³ Taken together, the risk of CRC in IBD patients has reduced in magnitude but remains present as long as the patients are not in histological remission. Therefore, elderly patients- particularly the early-onset subgroup- will still carry a higher risk of progression to CRC, unless complete histological remission is achieved. This brings forward the issue of screening and surveillance strategies in the elderly subgroup. The current guidelines do not specify an upper age cutoff for endoscopic screening and surveillance in the IBD population. In general population, colonoscopy in the elderly has been shown to be associated with a lower rate of procedure completion,⁵⁴ a higher likelihood of suboptimal bowel preparation,⁵⁵ and an incremental risk of perforation with increasing age and comorbidities.⁵⁶

Although the risk of neoplasia increases with age,
overall life expectancy decreases. A study showed that
the mean extension of life expectancy in the patients
undergoing routine screening colonoscopy was 0.17
years in the healthy population between the age 75-79,
and 0.13 years in those older than 80 years of age; as
compared to 0.85 years in those between 50-54 years
of age, respectively.⁵⁷ However, data addressing this
issue specifically in the IBD are lacking, and decisions
regarding surveillance need to be individualized.

CONCLUSION

The growth of the elderly IBD population in the
upcoming decades will bring on a unique set of
management challenges. Studies evaluating this
population are disproportionally low as clinical trials
often exclude this population. Thus, extrapolating the
efficacy and risk data from the younger population
may not always accurately describe the effects that we
need to take into account for the geriatric population.
Specifically, changes in metabolism and potentially
poorer response to medications, increased risk of
infections, and lack of specific guidelines such as
colorectal cancer surveillance for this population
contributes to this challenge. At this time providers
should take into account not just physiologic age but
also comorbidities to individualize potential risks and
create a treatment plan that provides optimal benefit
for the elderly IBD population.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #144

Getting Critical About Constipation

Jean-Louis Vincent,

Jean-Charles Preiser

Gastrointestinal motility is a complex process, which is often altered during critical illness, an effect that can lead to constipation. There is no consensus definition for constipation and it is therefore difficult to accurately assess incidence across studies. More recently, the term “paralysis of the lower gastrointestinal tract” has been suggested. Constipation can cause abdominal distension and discomfort, and reduce tolerance to enteral feeding. It can impair respiratory function and has been associated with worse patient outcomes including prolonged ICU length of stay and prolonged mechanical ventilation. The etiology of constipation in ICU patients is multifactorial and includes immobility, fluid and electrolyte disturbances, adverse effects of medication, and sepsis. Management must focus on treating the underlying cause and re-establishing regular bowel movements.

Jean-Louis Vincent MD PhD, Jean-Charles Preiser MD PhD, Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium

INTRODUCTION

Gastrointestinal motility is a complex process regulated by a number of hormones and peptides. Constipation is a frequent problem in intensive care unit (ICU) patients,^1,2 but is often overlooked. Staff often react more quickly to diarrhea, which is usually obvious, than to constipation, which is often less apparent. The definition of constipation is not as simple as it may seem. In the general population, the Rome criteria are frequently used, assessing objective (stool frequency [<3 stool movements per week], need for manual maneuvers to defecate) and subjective (straining, hard stool, sensation of incomplete bowel movement or anorectal blockage) factors.³ However, in critically ill patients, subjective symptoms are often difficult to assess and a diagnosis of constipation essentially relies on absence of defecation, although the chosen time period varies among studies. Because of the subjective nature of constipation, some debate the use of the term “constipation” in critically ill patients and a recent Working Group on Abdominal Problems from the European Society of Intensive Care Medicine recommended that the term “paralysis of the lower gastrointestinal (GI) tract” be preferred.⁴ They defined this as “the inability of the bowel to pass stool due to impaired peristalsis” and suggested that clinical signs would include absence of stool for three or more consecutive days without mechanical obstruction regardless of bowel sounds.⁴ Indeed, whatever term is employed, bowel sounds, which have been widely used as an indicator of bowel activity, are unreliable and should not form part of the diagnostic criteria.⁵

Epidemiology

There are few published epidemiological data specifically related to constipation in critically ill patients. Constipation has been reported to occur in 5 – 90.5% of patients depending on the specific population studied and the definition used (Table 1).

Clinical Impact

Constipation can cause abdominal distension and discomfort, poor tolerance of enteral feeding, confusion, and intestinal obstruction with vomiting and risk of pulmonary aspiration (Table 2).^2,9,10,12 It may also be associated with raised intra-abdominal pressure, which can impact on respiratory function. Abdominal distension associated with constipation may be associated with bacterial overgrowth^12,13 and increased bacterial translocation. Gacouin et al. reported reduced bacterial ICU-acquired infections in patients who passed stools early (< 6 days) rather than late (> 6 days).⁹ Constipation in critically ill patients has been associated with worse outcomes including prolonged ICU length of stay and prolonged mechanical ventilation.^2,8,9,14 Patanwala et al.¹⁵ noted that patients with constipation had more severe illness, as indicated by higher APACHE II scores. Montejo et al. reported that patients with GI complications, including constipation, had longer ICU stays and higher mortality than those without GI complications.⁶

Contributing Factors

A number of factors can contribute to constipation in critically ill patients, some of which are more obvious than others, for example spinal cord injury. Recent abdominal surgery is a common cause, although the delay before first defecation in these patients can vary considerably and may be related to the effects of the anesthesia and analgesia and not just to the surgery per se. Immobility, common in ICU patients, is also an important factor in reduced gut motility and patients who are unconscious or sedated may not feel the need to defecate.

The effects of morphine and other opioids on gut motility are well known,^16,17 but opioids have other effects that also increase the risk of constipation, including reducing intestinal secretions.^16,17 Other medications that may be used in the ICU can also cause gut hypomotility, including dopamine,^18,19 phenothiazines, diltiazem, verapamil, and anticholinergic drugs.¹

Sepsis may also increase the likelihood of constipation in critically ill patients. Indeed, recent data suggest that sepsis may enhance the inhibitory effects of opioids on colonic motility via Toll-like receptor 4,²⁰ a key signaling molecule in sepsis pathogenesis.²¹

Electrolyte disturbances, including hypokalemia, hypercalcemia, and hypomagnesemia, can also reduce gut motility and increase the risk of constipation, in part via impaired smooth muscle contraction.²² Inadequate fluid administration or inappropriate use of diuretics leading to dehydration also promotes constipation, but, conversely, too much fluid can lead to splanchnic edema, impairing gut motility.

Gacouin et al.⁹ reported that hypotension, defined as a systolic blood pressure < 90 mmHg, was independently associated with late (> 6 days) passage of first stools, as was a PaO₂/FiO₂ ratio of <150 mmHg (hazard ratio 1.40 [95% confidence interval 1.06-1.60], p=0.003).

In most critically ill patients with constipation, the etiology will be the result of a combination of several of the above factors (Table 3).

Interaction with enteral feeding

The relationship between the type and delivery of enteral nutrition (EN) and constipation is interesting. On the one hand, delayed administration of EN may contribute to constipation,¹ while, on the other hand, constipation in the critically ill can be associated with an intolerance to EN.¹⁰ Early EN is recommended in critically ill patients.²³ Boelens et al.²⁴ reported that early EN was associated with a significantly shorter time to first defecation compared to early parenteral nutrition (PN) in patients undergoing major rectal surgery. Continuous EN is usually recommended to improve the delivery of nutrients. However, meals and bolus delivery of nutrients cause gastric and colonic distention, leading to increased antro-pyloric pressure waves and motility.²⁵ In a pseudo-randomized controlled trial in 30 critically ill mechanically ventilated patients receiving EN for more than 72 hr, Kadamani et al. reported that continuous EN was associated with more constipation, defined as absent bowel movements for at least three consecutive days, than bolus EN.²⁵

Management

Because of the potential complications associated with constipation listed above, appropriate treatment of constipation is important. The most important factor in treating these patients is to make it a priority to re- establish, and then maintain, regular bowel movements. In a recent prospective randomized controlled trial, de Azevedo et al. (personal communication) reported that maintenance of daily defecation resulted in an improvement in organ function, as reflected by a faster decline in sequential organ failure assessment (SOFA) scores.

Treating the Underlying Cause

Full physical examination must include rectal examination and imaging when necessary to exclude the presence of any mechanical obstruction that requires surgical management. In acute colonic pseudo-obstruction (Ogilvie’s syndrome), a therapeutic colonoscopic examination may be required to decompress the pseudo-obstruction.^26,27 Electrolyte imbalances should be corrected and fluid administration optimized. As part of routine patient management, the need for analgesic agents should be regularly reviewed.28 Fentanyl may be associated with less constipation than morphine,^29,30 but these differences may not be large, especially with short-term use. If continued opioid use is necessary, administration of opioid antagonists, such as methylnaltrexone, should be considered as this can be useful to counteract the effects of opioids on gut motility.^31,32 Methylnaltrexone is a selective opioid µ-receptor antagonist that poorly crosses the blood- brain barrier, and hence interferes with GI effects, but not the central pain-relieving actions of opioids.³³ Lubiprostone, a selective chloride channel-2 activator that acts locally in the small intestine to increase fluid secretion and improve gut motility,³³ has been recently proposed as an alternative.³⁴ The enteral administration of naloxone, which has low bioavailability when given orally, may represent a cheaper option.³⁵

Treating the Constipation
Laxatives and Enemas

There are essentially two types of treatment for constipation after efforts have been made to remove the underlying cause: oral laxatives and suppositories or enemas. Oral laxatives can be broadly divided into bulking agents, osmotic laxatives, stimulant laxatives, and stool softeners (Table 4).^12,36 The choice of laxative is largely a matter of personal preference and availability with few published recommendations, especially in the critically ill population. Lactulose is perhaps the most widely used,¹⁴ with a recommended starting dose of 10 ml twice a day increasing to a maximum of 20 ml three times daily. Lactulose use can result in production of intestinal gases with uncomfortable bloating in some patients.¹⁴ Senna (10 ml/day) is a commonly used alternative.^2,15,37 Polyethylene glycol (PEG) is also widely used and can be administered intermittently or continuously. Van der Spoel et al.¹⁴ compared administration of lactulose (13 g three times daily), PEG or placebo in patients with multiple organ failure who were receiving mechanical ventilation and intravenous circulatory support and who had had no defecation by day 3 after admission. The authors reported that lactulose and PEG were both more effective in promoting defecation than placebo. There was an increased occurrence of acute intestinal pseudoobstruction in patients receiving lactulose, possibly related to increased intestinal gas production, and PEG seemed to be more effective than lactulose in patients receiving opioids.¹⁴ Enemas are generally reserved for patients in whom orally administered laxatives do not have an effect.³⁷

Neostigmine

In severe cases of functional colonic pseudo-obstruction, after exclusion of treatable causes, administration of neostigmine, an acetylcholinesterase inhibitor, may be considered to increase peristalsis and promote gut motility. Many studies have shown the efficacy of neostigmine in this situation, including the classical study by Ponec et al.³⁸ in which 21 patients with acute colonic pseudo-obstruction with no response to > 24 hours of conservative treatment, were randomized to receive a single dose of 2 mg of intravenous neostigmine or intravenous saline. Ten of the 11 patients who received neostigmine had rapid evacuation of flatus or stool, with a median time to response of just 4 minutes, as compared with none of the 10 patients who received placebo (p<0.001). Van der Spoel et al.³⁹ randomized 24 mechanically ventilated patients with multiple organ failure and critical illness-related colonic ileus to a continuous infusion of intravenous neostigmine (0.4-0.8 mg/h over 24 h) or placebo, and again reported good efficacy with 11 of the 13 patients receiving neostigmine passing stools, compared to none of the placebo-treated patients (p < 0.001). Neostigmine can cause bradycardia and cardiac arrest has even been reported,⁴⁰ so care should be taken, especially in patients with severe cardiocirculatory problems. Neostigmine use has also been associated rarely with colonic perforation.⁴¹

Prophylaxis of Constipation

A couple of studies have suggested beneficial effects of prophylactic laxative administration in critically ill patients.^11,42 Masri et al.⁴² reported that prophylactic use of lactulose 20 ml twice daily for 3 days in critically ill ventilated patients was associated with increased incidence of bowel movement in the first 72 hours compared to no intervention (18% vs 4%, p<0.05). More recently, in a sequential phase trial, Guardiola et al. compared treatment of lower GI tract “paralysis” with prophylaxis. Patients who received PEG as prophylaxis on the first day of mechanical ventilation had more rapid resolution of the paralysis than those who received PEG as treatment on day 4.11

It is important to remember that early sitting and mobilization of patients is a cheap and effective way to stimulate gut function. See Table 5 for a summary of suggestions to prevent and treat constipation in the ICU.

CONCLUSION

Constipation is common in ICU patients. Attempts should be made to prevent and treat it when necessary to avoid complications. There are few published data to guide treatment choices in this population. When considering constipation in these patients, one can identify two vicious cycles that need to be avoided. The first is the problem of abdominal distension that can induce discomfort, which results in increased opioids for pain relief, causing more constipation, and so the cycle starts again. The second potential cycle is the development of abdominal bloating, leading to withholding of EN, which in fact can worsen constipation as EN can promote peristalsis. Indeed, although not often considered as such, EN can be considered as, perhaps the optimal form of prophylaxis against constipation! Other general patient management strategies, including ensuring adequate hydration and encouraging mobilization when possible, must not be forgotten.

A CASE REPORT

Malignant Extrarenal Rhabdoid Tumor (MERT) of the Colon

Deepti Dhavaleshwar,Kofi Clarke

Ten cases of primary colonic malignant extrarenal rhabdoid tumors (MERT) have been reported. We report a case in a 31-year-old female who presented with abdominal pain, nausea and vomiting. Her initial evaluation was significant for leukocytosis and an elevated erythrocyte sedimentation rate. On colonoscopy, a 4-cm localized inflammatory-appearing lesion at the ileocecal valve was noted. Biopsies showed poorly differentiated adenocarcinoma. Surgical pathology after right hemi-colectomy revealed a malignant neoplasm with rhabdoid features. Despite aggressive chemotherapy, the patient died four months after diagnosis. MERT cases are rare and have poor prognosis. A better understanding of these tumors may help to improve outcomes.

Deepti Dhavaleshwar, MD; Kofi Clarke, MD, FRCP, Allegheny Health Network, Allegheny General Hospital, Division of Gastroenterology, Pittsburgh, PA

BACKGROUND

Malignant extrarenal rhabdoid tumors (MERT) of the gastrointestinal tract are extremely rare. To our knowledge, only 10 cases of primary colonic MERT have been reported.^1-9 We report a case of MERT involving the colon in a 31 year-old female patient.

CLINICAL CASE

A 31-year-old Caucasian female with no significant past medical or surgical history presented with right lower quadrant abdominal pain, nausea and vomiting. The pain was non-radiating, rated 10/10 in intensity and had no aggravating or relieving factors. She denied diarrhea, constipation, loss of appetite or weight changes. Her family history was significant for Crohn’s disease in a maternal aunt.

Initial work up was significant for leukocytosis of 14,000 cells/mL (normal range: 4,000-10,000 cells/ mL) and an elevated erythrocyte sedimentation rate of 44 mm/hr (normal range: 0-20 mm/hr). Computed tomography (CT) scan of the abdomen and pelvis with contrast showed small bowel obstruction (SBO), focal thickening of the terminal ileum, mesenteric engorgement and upstream inflammation with skip lesions in the distal ileum (Figure 1). Colonoscopy performed after resolution of the SBO showed a 4-cm localized inflammatory-appearing lesion at the ileocecal valve. The terminal ileum could not be intubated because of partial obstruction (Figure 2). Biopsies showed poorly differentiated adenocarcinoma (Figure 3), and the patient underwent a right hemi-colectomy. Surgical pathology revealed a poorly differentiated malignant neoplasm with rhabdoid features, and 9 out of 15 pericolonic lymph nodes were positive for metastatic malignancy. Immunostains showed the tumor cells were positive for cytoketain AE1/AE3, negative for CK7, CK20 and CDX-2. Post-operative workup including positron emission tomography (PET) CT revealed multiple fluorodeoxyglucose (FDG) avid hepatic lesions, consistent with metastatic disease. The patient underwent chemotherapy with FOLFOX (a combination of leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin), but despite the aggressive therapy, the patient succumbed to the disease four months after diagnosis.

DISCUSSION

The term malignant rhabdoid tumor (MRT) was originally used to describe a variant of pediatric renal tumor, which was clinicopathologically distinct from Wilms tumors. MRT of the kidney demonstrates a particularly aggressive growth and poor prognosis.¹⁰ Malignant tumors with similarly appearing rhabdoid cells were subsequently described at extrarenal sites, and these have been described as MERT.

There appears to be no sex predilection and overall survival is less than 12 months. MERT is derived from primitive pluripotential cells, which have the potential for a wide range of differentiation.¹¹ As such, phenotypic heterogeneity is observed in different tumors as well as in the same tumor.

Approximately 100 cases of extra renal MERT have been reported, which demonstrated partial and global rhabdoid features on conventional microscopic examinations. Colonic MERT is an extremely rare tumor that has been described in elderly individuals. It is typically located proximal to the transverse colon. To our knowledge, only 10 cases of primary rhabdoid colonic tumors (RCT) have been reported, and our patient, at 31 years of age, is the youngest (Table 1).

The two described histologic types of RCT are pure and composite. Composite refers to adenocarcinoma with rhabdoid features and has been associated with polyposis syndromes. Three RCT out of the 10 previously reported tumors were composite and associated with multiple polyposis.

Treatment of colonic MRTs is typically surgical resection without chemotherapy or radiotherapy. Prognosis is very poor in cases with metastases. Given that the tumors are so rare, no clear consensus exists about the choice of chemotherapeutic agents. Single agent chemotherapy with bevacizumab, cetuximab⁷ and multi-agent chemotherapy with capecitabin and oxaliplatin has been described.² Recent studies have suggested considering monoclonal antibodies against the epidermal growth factor receptor for RCTs that exhibit “wild type” KRAS gene,^2,4,7 however no case reports were found where this was used.

In summary, rhabdoid tumors of the gastrointestinal tract are rare and associated with a poor prognosis. They do not respond to conventional therapeutic regimens. A better understanding of the genetic and molecular basis of these tumors may help guide management to improve prognosis.

FELLOWS' CORNER

Fellows’ Corner

Justin Chen,

Kheng-Jim Lim,

Arkady Broder

Justin Chen, Medical Student, Drexel University College of Medicine. Kheng-Jim Lim MD, Gastroenterology Fellow, Robert Wood Johnson Medical School, Rutgers University. Arkady Broder MD, Gastroenterology Saint, Peter’s University Hospital

CASE PRESENTATION

A 53-year-old Asian male with a history of chronic hepatitis B presents to a university hospital with jaundice for seven days. Prior to admission, he had intermittent post-prandial right upper quadrant discomfort, nausea, vomiting and jaundice and was evaluated by his primary care physician. An outpatient abdominal ultrasound found a 2 cm common bile duct (CBD) stone and a dilated CBD up to 13 mm. He did not have any fevers or abdominal pain. His only medication was entecavir for chronic hepatitis B. His vital signs were within normal limits, physical exam was notable for jaundice, a benign abdomen and Murphy’s and Courvoisier’s sign were not present. Laboratory studies were significant for alkaline phosphate (ALP) 138 U/L, aspartate and alanine aminotransferase (AST, ALT) 34, 79 IU/L, respectively, total bilirubin 14.6 mg/dL, lipase 24 U/L, CA 19-9 of 2910 U/mL, and white blood cell count (WBC) 5,500 cell/µl. Endoscopic ultrasound found choledocholithiasis and CBD dilation. Endoscopic retrograde cholangiopanctreatography (ERCP) with sphincterotomy was performed and an exudate was seen in Figure 1. Subsequently, cannulation of the ampulla demonstrated the findings in Figure 2.

1. What is the diagnosis?
2. What is the substance exuding from ampulla?
3. What are the therapeutic options?
4. What other associated illnesses need to be investigated and how?

This is a 53-year-old male with a clinical presentation, laboratory values, and imaging suggesting choledocholithiasis but on ERCP had a diagnosis of Mirizzi syndrome (MS). Upon contrast injection, ERCP revealed contrast dye only filling the cystic duct and the guide wire in the CBD (Figure 2). Further manipulation confirmed a gallstone within the cystic duct compressing the CBD (Figure 3).

Mirizzi syndrome is a complication of gallstone disease that involves obstruction of the CBD by a stone in the cystic duct. It is more predominant in women, ages 53-70 years old, with a 0.2-1.5% prevalence in individuals with gall bladder disease. There is an increased prevalence in individuals with anatomical abnormalities of the biliary tree, like the long cystic duct with low insertion of cystic duct seen in this patient.¹ The most popular classification for MS involves four types described by Csendes in 1989.² Type I: external compression of CBD due to a stone impacted at the neck of the gallbladder or at the cystic duct. Type II: presence of a cholecystobiliary fistula that affects less than 1/3 of the circumference of the CBD. Type III: presence of a cholecystobiliary fistula with erosion of the CBD that involves up to 2/3 of its circumference. Type IV: presence of a cholecystobiliary fistula with complete destruction of the entire wall of the CBD.³

MS is often misread on transabdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) as choledocholithiasis and is ultimately diagnosed with ERCP. Transabdominal ultrasound is found to be diagnostically accurate in 29% of cases with a sensitivity of 8.3-27%. Transabdominal ultrasound classically shows dilatation of biliary system proximal to the stone and normal width of the CBD distal to the stone. MRCP has a diagnostic accuracy of 50% and can show external compression of the CBD and visualize a fistula if present for staging. ERCP can confirm or diagnose MS with a diagnostic accuracy of 55-90%. ERCP with stent placement and sphincterotomy is often performed as therapy for symptoms of jaundice and ascending cholangitis.¹

Prolonged cholestasis in this patient led to the development of “milk of calcium” or “limy bile” exuding from the ampulla after sphincterotomy. Although the pathophysiology of “milk of calcium” is not completely understood, it is believed that obstruction of the gall bladder neck, cystic duct or CBD with subsequent biliary stasis leads to precipitation of calcium carbonate crystals in the bile. The exudate manifests as a thick, radiopaque paste in the gallbladder or common bile duct.⁴ MS is typically diagnosed on imaging, including abdominal X-rays and CT scan, which shows filling of the gallbladder or CBD as if contrast was administered. Prevalence of limy bile syndrome ranges between 0.1- 1.7% of all surgeries for cholelithiasis with a male to female ratio of 1:3.⁵

The treatment for MS is typically surgical and the pre-operative diagnosis may not always be known prior to surgery. Surgical treatment options are determined by the classification of MS. Open cholecystectomy is usually performed due to inflammation that cause adhesions and distorts the anatomy increasing risk of biliary tree injury.¹ Laparoscopic surgery is controversial and reserved for Type I MS because of a high laparoscopic to open conversion and complication rate. Type I MS can be treated with total or subtotal cholecystectomy with stone extraction. Treatment for Type II MS is dependent on fistula size and can involve partial cholecystectomy, suture repair or T tube placement to repair the fistula. Type III can be treated with choledochoplasty or enterobiliary anastomosis with cholecystectomy and Type IV MS requires cholecystectomy and enterobiliary anastomosis, most commonly Roux-en Y hepaticojejunostomy.² Stone removal can be attempted with ERCP using stone removal techniques (e. g. balloon, basket, lithotripsy), but it is reserved for patients who are poor surgical candidates due to increased risk of bleeding and perforation.¹

In patients with MS, it is necessary to evaluate for gallbladder cancer preoperatively with imaging or a CA19-9 level, intraoperatively, or post operatively with pathology. Gallbladder cancer is present in 5.3%- 27.8% of patients with MS compared to 1-2% in patients with benign biliary disease.⁶ The underlying chronic cholestasis found in MS is proposed to be the risk factor for gallbladder cancer.⁷ Although the average CA19-9 is 987 units/ml in patients who had both MS and gallbladder cancer, 4.7% of patients who had cholangitis or cholestasis with no gallbladder cancer had CA19-9 levels >1000 units/ml.^7,8

As in many patients with MS, this patient was misdiagnosed initially with transabdominal ultrasound and EUS as choledocholithaisis, but later found to have MS on ERCP. An MRCP later showed no fistula and confirmed Type I MS and an open partial cholecystectomy was then performed. Post operatively, a partial gallbladder pathology showed no malignancy with evidence of chronic cholecystitis and his CA19-9 decreased from 2910 U/mL to 19 U/mL. The patient was subsequently discharged from the hospital in good health.

A CASE REPORT

A Rare Presentation of a Common Condition: A Squamous Cell Papilloma Causing Dysphagia and Hematemesis

Carla Duffoo,Ghassan Tranesh,Mohammed Barawi

Carla Duffoo DO,¹ Ghassan Tranesh MD,¹ Mohammed Barawi MD¹ ¹Department of Gastroenterology, ²Department of Pathology, St. John Medical Center, Detroit, MI

INTRODUCTION

Squamous papillomas of the oral cavity are common, benign, painless lesions that arise from the squamous epithelium of the lips, tongue, pharynx, esophagus and others. They are most often found in the mucosa of the hard and soft palate, but they can also be found in the uvula. Although there is an association with the human papilloma virus (HPV), they are neither transmissible nor threatening.1 These lesions, although benign, are thought to be pre-malignant.2 They are also generally asymptomatic; only two cases of symptomatic squamous papillomas arising from the uvula have been reported in the literature.^3,4 Here we present a case of a symptomatic squamous papilloma of the oral cavity.

CASE REPORT

A 41-year-old African American woman presented to our institution with nausea, vomiting and several episodes of hematemesis. She also described a feeling that “something was stuck in the back of her throat,” and she had been able to manipulate an ‘object’ and push it to the side of her inner cheek, but on occasion this ‘object’ would protrude out of her mouth when she coughed. She reported having a choking sensation and difficulty swallowing solids but not liquids. She did not report any weight loss, odynophagia, abdominal pain, hematochezia or melena. She also denied having any previous episodes of similar symptoms and had no history of gastrointestinal bleeding. She denied any oral intake over the previous 24 hours and had no history of food impaction. The patient underwent an esophagogastroduodenoscopy (EGD) two years prior to this presentation, which only revealed the presence of gastritis. Upon presentation to the hospital, her vital signs were stable, except for mild tachycardia. Her hemoglobin was 13.2 g/dL. A computerized tomography (CT) of the neck was unremarkable except for a possible right parotid gland lymph node versus nodule. Due to her complaints of acute dysphagia and hematemesis, the patient underwent an urgent EGD. On endoscopy, a long, finger-like polypoid lesion was seen projecting from the soft palate; this lesion measured approximately 2 cm in length. The lesion had a cauliflower like tip with areas of superficial ulceration (Figures 1 (a) and (b)). The remainder of the exam was normal. It was difficult to clearly visualize the exact origin of this lesion; therefore, an otorhinolaryngology (ENT) consult was requested. The patient underwent a flexible fiberoptic evaluation, which revealed an elongated polypoid lesion arising from the uvula. She was taken to the operating room for surgical excision of the lesion. Pathology revealed a 2 cm long polypoid, pedunculated, papillary tissue that was pink-tan in color, containing a fibrovascular core consistent with a squamous papilloma with acute and chronic inflammation that was not associated with HPV (Figures 2 (a) and (b)). The patient’s postoperative course was uneventful and she reported complete resolution of her symptoms.

DISCUSSION

Squamous cell papillomas are small exophytic growths composed mostly of parakeratinized, stratified, squamous epithelium that are arranged in papillary projections, giving them a cauliflower-like appearance.⁵ They are common benign neoplasms of the oral mucosa that typically present as a single pedunculated mass and are often found on the hard and soft palate. The tongue was described as the most common site of growth in one series,⁶ while others report that the soft palate-uvula complex was the most common site.^7,5 In our patient, the lesion was seen as a long, polypoid elongation of the uvula with a cauliflower-like appearance at the tip (Figures 1 (a) and (b)). These lesions are not considered contagious or transmissible, however the literature suggests an association with HPV-6 and HPV-11.³ Squamous papillomas of the oral cavity are generally diagnosed in people ages 30 to 50 years; however, in one series, the age range was 2 to 91 years.⁵ There is conflicting information regarding the impact of gender on the predisposition for this condition, but it seems that these lesions may be more common in men. One study revealed a greater percentage of white patients, while other series did not make a reference to racial distribution.⁵ These lesions tend to be asymptomatic and are often found incidentally. There have been two case reports of symptomatic squamous papillomas, with dysphagia as the presenting symptom.^3,4 None of the cases reported hematemesis as a complaint. The cases in which the papilloma caused symptoms reported that the lesion was greater than 1 cm in length; this was the case in our patient who presented with complaints of dysphagia and hematemesis. We believe the hematemesis was due to vomiting of ingested blood as a result of mechanical trauma to the papilloma as it protruded out from the patient’s mouth when she coughed. In one series, 24% of cases (34/141) had lesions that were greater than 1 cm in length, and of those, 7.8% (11/141) were between 2 cm and 3 cm long.⁵ It is postulated that the greater the length of the papilloma, the more likely it is to cause symptoms. Squamous papillomas of the oral cavity are not typically associated with malignancy, unlike those found in the larynx,³ but surgical removal is the treatment of choice. Recurrence after excision is uncommon.

A SPECIAL ARTICLE

The Complications of Diabetes in the Gastrointestinal Tract

Priya Simoes,

Lisa Ganjhu

Diabetes and hyperglycemia have immediate and long term effects in the gastrointestinal (GI) tract. In this article, we comprehensively review the complications of diabetes in the gastrointestinal tract including oral and esophageal candidiasis, gastroesophageal reflux disease (GERD), esophageal dysmotility, gastroparesis, small intestinal bacterial overgrowth, diarrhea and nonalcoholic fatty liver disease (NAFLD). We also describe the increased risk of GI malignancies in these patients.

Diabetes mellitus affects millions of people worldwide. With improved therapy, many patients are living longer, albeit with complications of the disease. Diabetes and hyperglycemia have immediate and long term effects in the gastrointestinal (GI) tract. We comprehensively review the complications of diabetes in the gastrointestinal tract including oral and esophageal candidiasis, gastroesophageal reflux disease (GERD), esophageal dysmotility, gastroparesis, small intestinal bacterial overgrowth, diarrhea and nonalcoholic fatty liver disease (NAFLD). We also describe the increased risk of GI malignancies in these patients.

Priya Simoes, MD¹ Lisa Ganjhu, DO, AGAF2 ¹Department of Medicine, St Luke’s Roosevelt Health Center, Mount Sinai Health System, New York, NY 2Division of Gastroenterology, NYU Langone Medical Center, New York, NY

Diabetes mellitus (DM) affects 9.3 % of the population of the United States (U.S.) and roughly 1.7 million new cases are diagnosed each year. Four percent of those diagnosed are type 1 diabetics.¹ Diabetes currently affects 382 million people worldwide, and this is expected to increase to 592 million by 2035.² With improved therapies, survival has increased and many patients live with long-term complications of the disease. Diabetes affects nearly every organ system including the gastrointestinal (GI) tract. The major gastrointestinal complications of diabetes are oral and periodontal infection, esophageal candidiasis, esophageal dysmotility, gastroesophageal reflux disease (GERD), gastroparesis, small intestinal bacterial overgrowth (SIBO), diabetic diarrhea, nonalcoholic fatty liver disease (NAFLD) and increased risk of GI malignancies.³⁴ Here we comprehensively review the effects of diabetes on the gastrointestinal tract.

Oral Cavity

Candidiasis And Periodontal Disease

Epidemiology

Diabetes has several oral manifestations including fungal
infections, periodontal disease, mucosal ulcerations,
xerostomia and aguesia. The reported incidence of oral
candidiasis is 11 to 30% and periodontal disease is 30 to 60% among poorly controlled diabetic patients.⁵⁶

Pathophysiology

Candida species normally colonize the oral cavity of healthy individuals, without causing infection. Hyperglycemia causes an increase in buccal mucin and glucose and decreased activity of salivary antimicrobial factors like lysozymes.⁷ This increases proliferation of buccal candida, the most common species being Candida albicans.⁸ Compromised neutrophil function from decreased adherence, chemotaxis and phagocytic function in the presence of uncontrolled hyperglycemia predispose to periodontal destruction and infection.⁶

Diagnosis and Treatment

Symptoms usually include loss of taste and cotton-like sensation in the mouth. Oral candidiasis is diagnosed on inspection of the oral cavity; exam often reveals whitish, adherent plaques with erythematous and friable underlying mucosa.

Oropharyngeal candidiasis can initally be treated with topical antifungal agents such as nystatin 400,000 to 600,000 units daily in a swish and swallow manner.

If topical agents are ineffective, oral “azoles”, such as fluconazole or itraconazole are the mainstay of therapy. A loading dose of 200 mg followed by 100 to 200 mg daily for 7 – 10 days is recommended.⁹ Resistant cases may be treated with an oral suspension of amphotericin B.¹⁰

Esophagus

Candidiasis

Epidemiology and Pathophysiology

Diabetes mellitus is associated with higher incidence of esophageal candidiasis, especially among elderly patients.

Diagnosis and Treatment

The typical presenting symptoms are odynophagia, dysphagia, heartburn and reflux in a patient with oral candidiasis. Rarely, it may present with gastrointestinal bleeding.

Upper endoscopy, often revealing whitish adherent plaques, ulcerations or stricturing of the mucosa, may be performed to confirm the diagnosis. Biopsy or brushings yield yeast and pseudo hyphae invading the mucosa and positive fungal cultures. Empiric treatment with oral azoles may be started in an uncontrolled diabetic with odynophagia and dysphagia. If the candida infection is resistant to fluconazole, alternate azoles such as itraconazole, voriconazole or posaconazole can be used. Intravenous caspofungin is preferred to amphotericin B for treatment failures.¹¹

Esophageal Dysmotility and Gastro Esophageal Reflux Dsease (GERD)
Epidemiology

The prevalence of GERD is estimated at 10-20 % in the Western world.¹² Diabetes is associated with a prolonged esophageal transit time and a 1.6 times higher risk of developing GERD than the general population, particularly among women and young patients.^13,14,15

Pathophysiology

Esophageal dysmotility in diabetes is multifactorial with damage to interstitial cells of Cajal and vagal/autonomic neuropathy. This is characterized by smaller amplitude and velocity of lower esophageal contractions.^16,17 As a result, there is impaired esophageal peristalsis with frequent retrograde waves, decreased lower esophageal sphincter (LES) tone and frequent transient LES relaxation causing heartburn, regurgitation and dysphagia.^18,19

Diagnosis

GERD is diagnosed clinically from typical symptoms of regurgitation and heartburn. Endoscopy may be performed for atypical, unresponsive or alarm symptoms. Ambulatory pH monitoring and esophageal manometry are recommended prior to surgical treatment.²⁰

Treatment

Lifestyle modifications such as weight loss, avoidance of meals two to three hours before bed time, elimination of foods triggering symptoms and elevation of the head of the bed are recommended. GERD is treated symptomatically with proton pump inhibitors (PPIs). If symptoms are unresponsive to PPIs, endoscopic or laparoscopic fundoplication surgery may be considered.²⁰

Stomach

Gastroparesis

Gastroparesis is a motility disorder characterized by delayed gastric emptying in the absence of mechanical obstruction.

Epidemiology

Gastroparesis generally develops in long standing diabetes of more than 10 years duration with autonomic dysfunction. One third of gastroparesis is attributable to diabetes.^21,22 The disorder is female predominant (4:1 compared to males), and a higher prevalence has been described in type 1 diabetes.23 Gastroparesis is characterized by nausea, vomiting, bloating, epigastric pain and early satiety.

Delayed gastric emptying was associated with other comorbid conditions such as hypertension, cardiovascular disease and retinopathy and may lead to more frequent hospitalizations among patients with diabetes.²⁴

Pathophysiology

Autonomic neuropathy, damage to the interstitial cells of Cajal by hyperglycemia and oxidative stress result in decreased gastric motility, impaired pyloric relaxation and increased post prandial resistance subsequently leading to delayed gastric emptying.²⁵ Acute hyperglycemia (> 288 mg/dl) can be associated with increased gastric emptying time and worsening symptoms.²⁶

Diagnosis

The diagnosis is made by nuclear tests measuring the gastric emptying of solid phase meals. Evaluation is prompted by symptoms, poor glycemic control or in patients in whom oral hypoglycemic medications known to slow down gastric emptying time are being considered.²⁷ The gold standard is gastric emptying scintigraphy or scinti scanning. A radionuclide labeled low fat, solid meal is ingested and the gastric emptying time is calculated by observing the fraction of the meal remaining in the stomach at baseline, 1, 2 and 4 hours after ingestion. Having patients observe an overnight fast and well controlled blood sugars (< 275 mg/dl fasting) ensure accuracy of the test.²⁸ Modified scinti scanning, which measures the gastric emptying over a shorter time period, has lower sensitivity and specificity.

Gastric emptying breath test (GEBT), which measures gastric emptying by measuring the breath excretion of CO₂ labeled with C¹³ radioisotope incorporated into a meal, has shown comparable sensitivity and specificity to scinti scanning in studies, but requires further validation.^27,29 Upper endoscopy, performed after an overnight fast, that shows evidence of food retention in the stomach may also assist in making the diagnosis of gastroparesis.

Wireless capsules (“Smart Pill”) are used to measure the pH, temperature and pressure in the GI tract. A small capsule, with the ability to transmit data to a receiver worn around the patient’s neck, is ingested. It measures gastric emptying time by sensing the abrupt change in pH as the capsule passes from the stomach into the duodenum and thus is used to diagnose gastroparesis.^30,31 Wireless capsule studies have a sensitivity and specificity of 83 % compared with gastric scintigraphy.²⁹

Treatment

Management strategies generally consist of optimizing glycemic control, improving hydration and nutritional status, controlling symptoms and managing complications.

Dietary factors play an important role in gastroparesis. Small, frequent low fat, low fiber meals are recommended with 55% to 60% of dietary calories from carbohydrates, 15% from protein and 25% to 30% from fat. Vitamins and minerals should be replaced through oral supplementation. If patients are unable to tolerate solid meals, more liquid calories are recommended since they empty more easily by gravity ³²

The mainstays of pharmacologic therapy are prokinetics such as metoclopramide, erythromycin and domperidone, which hasten gastric emptying. Erythromycin has the maximum effect on gastric emptying and is generally used for acute symptom management.³² Newer drugs such as 5HT4 receptor agonists (prucaloprid/velusetora)³³ and muscarinic antagonists (acotiamide) are being studied for their efficacy in gastroparesis.³⁴ Non pharmacologic methods such as intrapyloric botulinum toxin injection and gastric electrical stimulation are used to treat medically refractory gastroparesis.³⁵ Anti-diabetic drugs, such as GLP1 analogs, that slow gastric emptying should be discontinued. Repeated hospitalizations in gastroparesis are usually for nausea, vomiting and pain management. Additional diagnostic testing rarely changes management and should be avoided to decrease prolonged hospitalizations and increased healthcare costs.³⁶ Refractory nausea may be treated with tricyclic antidepressants (TCA), phenothiazines and antihistamines such as meclizine. Selective serotonin reuptake inhibitors and low dose TCAs may also help improve abdominal pain.²⁹

Small Intestine and Colon

Small Intestinal Bacterial Overgrowth

Definition and Epidemiology

Small Intestinal bacterial overgrowth (SIBO) refers to an increase in the number of bacteria or a change in the composition of the small bowel microbiome.

The incidence of SIBO in diabetic patients with autonomic neuropathy varies between 30 and 60%.^37,38

Pathophysiology

Decreased intestinal motility, malabsorption and increased intestinal secretion cause SIBO in patients with diabetes. The disorder may present with abdominal pain, bloating, distention, flatulence and diarrhea and may result in nutritional deficiencies, chronic anemia, steatorrhea, and malnutrition.

Diagnosis

The gold standard for making the diagnosis of SIBO is a culture of jejunal aspirates. Noninvasive testing methods include hydrogen and methane breath testing after an oral glucose or lactulose load. An early peak in breath hydrogen or methane production is due to bacterial fermentation of glucose in the small bowel, indicating SIBO.³⁹ However, as a false positive early peak in the production of hydrogen and methane can occur with bacterial fermentation of glucose or lactulose in the cecum, this test has limited sensitivity, though good specificity.⁴⁰

Treatment

Glycemic control and cyclical antibiotics are the treatments of SIBO in patients with diabetes. Metronidazole (750 mg/day) or rifaximin (1200 mg/ day) are the antibiotics of choice for SIBO.^41,42 Prebiotics and probiotics may be used to modify the inflammatory response, however, they are contraindicated in patients who have lactobacilli overgrowth. Since SIBO is thought to be secondary to motility disorders, pro- kinetics such as metoclopramide or cyclic gut lavage with polyethylene glycol may be of benefit.

Diabetic Diarrhea
Definition and Epidemiology

Diarrhea in patients with diabetes may be caused by diabetes itself, coexisting conditions or by medications. It is often described as episodic, explosive diarrhea in the absence of an infectious or non-infectious cause.⁴³ The prevalence of diarrhea among diabetic patients is estimated at 15%.⁴⁴

Pathophysiology

Several mechanisms as to the etiology of diarrhea in diabetic patients have been postulated; these include autonomic dysfunction of the enteric neurons from autoantibodies as well as enteric inflammation with increased IL6 levels causing alteration of intestinal motility.⁴⁵ Exocrine pancreatic insufficiency, celiac disease, small intestinal bacterial overgrowth and microscopic colitis have an increased prevalence in patients with diabetes and may cause diarrhea.⁴⁶ Medications such as biguanides and acarbose inhibitors and dietary products like sorbitol based sweeteners may also contribute.⁴⁵ Poor glycemic control may also worsen the diarrhea.⁴⁶

Treatment

Strict glycemic control, eliminating possible food triggers and treatment of underlying causes form the basis of treatment. Pharmacotherapy is with anti- motility agents such as loperamide or tincture of opium. Topical or oral clonidine and somatostatin analogs may be used for severe symptoms.^47,48

Liver

Non Alcoholic Fatty Liver Disease
and Non Alcoholic Steato Hepatitis

Definition and Epidemiology

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of secondary causes. In the United States, NAFLD is the most common chronic liver disease. NAFLD is commonly associated with diabetes as part of the metabolic syndrome, which also includes central obesity, low levels of high density lipoprotein (HDL), hypertriglyceridemia and hyperglycemia.⁴⁹ Non- alcoholic steatohepatitis (NASH) is characterized by hepatocyte fat accumulation with concomitant hepatocyte injury and fibrosis. Studies have reported a 69 to 87% prevalence of NAFLD and 60% prevalence of NASH in patients with diabetes, compared with a roughly 20% prevalence of NAFLD and 3-5 % prevalence of NASH in the general population.^{49, 50}

Pathophysiology

Development of NAFLD and NASH in DM is explained by a “two-hit” hypothesis. Accumulation of triglycerides in hepatocytes is considered to be the first step. The second hit is linked to the formation of advanced glycation end products that produce oxidative stress on hepatocytes and increase the fibrogenic potential of the stellate cells.^51,52 Hyperinsulinemia and increased insulin resistance are associated with greater hepatic inflammation and fibrosis and patients with diabetes and NAFLD have a higher risk of progression to NASH.⁵³

Diagnosis

Liver biopsy remains the gold standard for diagnosing NAFLD/NASH and should be performed in patients at high risk and in whom a competing etiology cannot be excluded. Imaging by ultrasound, computed tomography (CT) or magnetic resonance (MRI) may not accurately assess the degree of fibrosis and steatohepatitis. However, when coupled with non-invasive fibrosis markers like ultrasonic fibro-elastography and fibrosis prediction scores, they have excellent specificity and sensitivity and are gradually replacing liver biopsy for diagnosis of NASH. ^{53, 54}

Treatment

Weight loss of 3 to 5% of total body weight will improve steatosis and greater than 10% weight loss improves steatohepatitis. Other lifestyle modifications reducing alcohol consumption and increasing exercise are also recommended. Over the years, several clinical trials, involving many medications and supplements have been undertaken in an effort to improve NASH and NAFLD. While some have shown promise, there is insufficient evidence to support the use of any drug as the sole treatment for NASH in diabetics.⁵⁵

Gastrointestinal Malignancies

Diabetes mellitus is associated with an increased risk of various GI malignancies. Two mechanisms have been hypothesized.

Insulin receptor (IR) and insulin-like growth
factor-1 receptor – (IGF-1R) pathway:

Chronic hyperinsulinemia leads to up regulation
of IGF-1R, epidermal growth factor (EGF)
and its downstream pathways. This results
in cellular proliferation, angiogenesis and
inhibition of apoptosis, which promote tumor
development in the pancreas and pre-malignant
advanced adenomatous polyp formation in the
colon. ^56,57,58,59

Hyperinsulinemia also leads to increased
pro-inflammatory cytokines like interleukin
6 (IL- 6) and decreased anti-inflammatory
compounds such as adiponectin subsequently
causing hepatic inflammation and fibrosis,
which are precursors to HCC.⁶⁰
Receptor for advanced glycation end products
(RAGE):

Advanced glycation end products accumulate at
an accelerated rate in diabetes. In vitro studies
show that up regulation of RAGE is associated
with inflammation and tumorigenesis in colon
and pancreatic cancer.^61,62

Pancreatic Adenocarcinoma
Epidemiology

Several studies have shown an increased risk of pancreatic adenocarcinoma in diabetes and there is roughly around 70% prevalence of diabetes or impaired glucose tolerance in patients with pancreatic cancer.64,65 It is unclear whether diabetes is causal in the pathogenesis of pancreatic cancer or whether it is an effect of it.

New onset diabetes is peculiar to pancreatic cancer with a recent diagnosis of diabetes conferring a 50% greater risk of malignancy than long-standing (> 5years) diabetes^65,66 Pannala et al. demonstrated that new onset diabetes associated with pancreatic cancer resolved after a curative resection.⁶⁷

Diagnosis

Presenting symptoms are weight loss, epigastric pain, anorexia, painless jaundice and nausea. Several imaging modalities may be used to diagnose suspected pancreatic cancer. Diagnostic accuracy of CT varies between 73%-87 % depending on the size of the mass.⁶⁸ MRI is superior to CT with 90% sensitivity; this increases to 97% when combined with magnetic resonance cholangiopancreatography (MRCP).⁶⁹

Endoscopic ultrasound (EUS) provides clear resolution images and allows for needle sampling of pancreatic cells. It has 98% sensitivity and is becoming the diagnostic modality of choice for pancreatic cancer.⁷⁰ Tumor markers such as carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) are used more commonly as prognostic indicators and for assessing response to treatment.

Colorectal Cancer (CRC)
Epidemiology

Diabetes is associated with an increased risk for colon cancer in both men and women and increased risk of rectal cancer in men.⁷¹ Diabetic patients with colon cancer have increased perioperative mortality, disease recurrence, worse response to chemotherapy, more treatment complications and increased risk of hepatic decompensation.^72,73,74

Diagnosis

Presenting symptoms are usually hematochezia or melena, change in bowel habits, abdominal pain, unexplained iron deficiency anemia or weight loss. Rectal cancer may cause tenesmus and rectal pain.⁷⁵

Screening for colon cancer focuses on detecting pre malignant polyps to prevent them developing into advanced disease. Colonoscopy is considered the test of choice as polyps can be removed and suspicious lesions can be biopsied. Other noninvasive screening methods include CT colonography and stool DNA testing. Assays to detect blood in stool such as fecal immunochemical testing (FIT) and guaiac occult blood testing (gOBT) have roughly 65%-80% sensitivity and 85%-95% specificity for CRC detection. However, sensitivity is lower for detecting advanced adenomas.⁷⁶

Hepatocellular Carcinoma
Epidemiology

Long standing NAFLD and NASH can lead to cirrhosis and the development of cirrhosis is the greatest risk factor for developing hepatocellular carcinoma (HCC). Diabetes confers a two to three times increased risk of HCC, especially in older, Caucasian patients.⁶⁴ Prevalence of diabetes may be double among HCC patients compared with controls, which remained significant even after adjusting for confounding factors like alcohol use, hepatitis B or C infection, obesity and hemochromatosis.⁷⁷ A longer duration of diabetes may increase the risk of developing HCC.⁷⁸

Diagnosis

Cirrhosis is the most important risk factor with 1 % to 6 % of cirrhotics developing HCC annually.⁷⁹

Surveillance with ultrasound (US) at 6 months intervals has been associated with a reduction in mortality in these patients.⁸⁰ Alfa fetoprotein (AFP) levels have historically been used for surveillance, but is no longer recommended.⁸¹

Typical appearance on four phase (unenhanced, arterial, venous and delayed) CT scan and on MRI both have excellent sensitivity and specificity (> 90%) for lesions >2cm. Dual imaging with MRI and ultrasound has excellent positive predictive value for smaller lesions.⁸²

Management

While no specific recommendations exist for early screening of patients with diabetes for GI malignancies, knowledge of the increased risk warrants further investigation of gastrointestinal symptoms in these patients.

Metformin has been associated with decreased risk of pancreatic and hepatocellular carcinoma and is protective against colorectal cancer among patients with diabetes. Conversely, insulin and sulfonylureas have been associated with an increased risk of malignancy, supporting the hypothesis that hyperinsulinemia has tumorigenic effects.^83,84,85

CONCLUSION

Knowledge of the gastrointestinal complications of diabetes is important for physicians to make an appropriate diagnosis, manage symptoms and improve the quality of life of patients living with long- standing diabetes. Awareness of the increased risk of malignancies in this population may help in early referral and diagnosis.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #143

Low Residue vs. Low Fiber Diets in Inflammatory Bowel Disease: Evidence to Support vs. Habit?

Neha D. Shah,

Berkeley N. Limketkai

Inflammatory bowel disease (IBD) involves chronic inflammation of the gastrointestinal tract. Patients with IBD may experience gastrointestinal distress through abdominal pain, cramping, diarrhea, and hematochezia. Despite lack of evidence to support the practice, IBD patients are often instructed to limit fiber or residue during active flares to reduce gastrointestinal distress. The same advice is common when intestinal strictures are identified or suspected, to reduce the risk of obstruction. Low residue and low fiber diets are often recommended interchangeably, although they comprise two distinct diets. This review discusses the similarities and differences between “residue” and “fiber” and presents the studies that have evaluated the use of low residue and low fiber diets in IBD.

Neha D. Shah, MPH, RD, CNSC Berkeley N. Limketkai, MD Digestive Health Center, Stanford Health Care Division of Gastroenterology & Hepatology Stanford University School of Medicine, Palo Alto, CA

INTRODUCTION

Inflammatory bowel disease (IBD) encompasses two primary disorders: Crohn’s disease (CD) and ulcerative colitis (UC). It is characterized by chronic inflammation of the gastrointestinal tract.¹ Common clinical manifestations of IBD include abdominal pain, cramping, diarrhea and hematochezia. CD patients, in particular, may also experience intestinal strictures with obstructive symptoms, abscesses, and fistulizing disease.

Dietary recommendations for IBD patients have been highly variable, largely due to the dearth of research data available to guide clinical practice. Nonetheless, IBD patients are often instructed to limit their consumption of fiber or residue during an active flare in order to help minimize gastrointestinal distress, particularly when intestinal strictures are suspected. Recommendations for a “low residue” or “low fiber” diet are often used interchangeably and incorrectly as synonymous terms; although there are similarities between the low residue and low fiber diets, they are indeed distinct diets with different theoretical effects on digestion.

The purpose of this review is to clarify what constitutes “residue” and “fiber”, discuss their physiologic effects on digestion and present the studies that have investigated the use of low residue and low fiber diets in IBD.

RESIDUE vs. FIBER What is Residue?

Historically, the term “residue” has denoted the by-products of the digestive process that were eventually defecated in stool. This definition covers the gamut of partially or completely undigested food particles, ash, gastrointestinal secretions, intestinal epithelial sloughing, and bacterial waste. In early canine studies, the appearance of stools after food consumption was generically called “residue”.² In other discussions, residue was described as “crude fiber”: a component of foods not digestible by pancreatic and intestinal enzymes in humans and therefore not available for intestinal absorption.³ Crude fiber, also called “roughage” or “bulk”, is primarily comprised of cellulose, hemicellulose and lignin. Finally, residue has also been designated as any food that increased stool output, including meats, fats and dairy products, even if the foods underwent enzymatic digestion or had low amounts of crude fiber.

The actual composition of a high or low “residue” diet has been a topic of investigation for over a century, yet it continues to have no clear definition. In early canine studies, the rate of passage of foods was thought to correlate with digestion of foods and appearance of residue. In an early study from 1884, Müller found that meat fed to dogs produced stool similar to that defecated during fasting.⁴ Later in 1905, Heile published that up to 98% of lean meat and 100% of rice were absorbed.⁵ By contrast, milk increased bulk and accelerated the passage of stool. In 1928, Hosoi et al. systematically evaluated intake of various foods and then measured stool output in dogs with ileal fistulas.² Proteins (e.g., lean meats, hardboiled egg) and some carbohydrates (e.g., rice, bread) were found to have a slow rate of passage through the intestines. Foods with little or no cellulose did not produce residue even 8 hours after consumption. On the other hand, fruits (e.g., canned pineapple, skinless apple, banana and prunes) had an increased rate of passage, with residues appearing within an hour of consumption. Whole milk and Swiss cheese significantly increased residue within 15-30 minutes after consumption, an effect assumed to stem from lactose malabsorption. Gelatin, broth, hardboiled eggs, lean meat, liver, rice, farina and cottage cheese produced the least amount of residue, whereas fruits, baked potatoes, bread, lard, butter and whole milk produced the largest residue. The authors concluded that “the best basis for a low residue diet is lean meat… rice, hard boiled eggs, sugars (except lactose), and probably small amounts of fruit juices, tea and coffee” and that “less material will be carried into the colon if the diet is kept fairly dry.”

What is Fiber?

In an early definition, fiber was considered to be the non-digestible plant-based components of cell walls that are not found in foods of animal origin.⁶ Subsequent definitions were broadened to include associated plant- based substances, such as gums, mucilages, pectin and phytates. Other definitions specified methods of extraction of fiber from foods. In 2001, the Institute of Medicine (IOM) proposed new definitions for “dietary fiber” and “added fiber” to standardize the definition. Similar to an earlier description of crude fiber, “dietary fiber” is defined as “non-digestible carbohydrates and lignin that are intrinsic and intact in plants” and “added fiber” is defined as the “isolated, non-digestible carbohydrates that have beneficial physiological effects in humans.” Thus, the “total fiber” is then considered the sum of both dietary and added fiber (http://www.nal. usda.gov/fnic/DRI/DRI_Proposed_Definition_Fiber/ proposed_definition_fiber_full_report.pdf). See Table 1 for the definitions of what constitutes residue and fiber.

The physiologic effects of fiber vary based on its
chemical composition and properties, with solubility,
or the ability to dissolve in water, being the most salient
property. As such, fiber has often been classified as
“soluble fiber” or “insoluble fiber” with respect to
its role in health, particularly in the management of
gastrointestinal disorders, cardiovascular disease,
diabetes, and obesity. The IOM recommends phasing
out these terms and instead favors classifying fiber by
its fermentability and viscosity, since these properties
better outline the physiological benefits of fiber on
gastric and small bowel function. Fermentability refers
to the ability of colonic bacteria to digest the fiber,
while viscosity concerns the ability of the fiber to hold
water, thicken stool, and resist flow.⁶ See Table 2 for
definitions of the physiochemical properties of fiber.

The fibers traditionally considered to be soluble
are generally fermentable and viscous; they include
guar gum, pectin, some hemicelluloses, fructo-
oligosaccharides and inulin. Once fermented by colonic
bacteria, they contribute to the production of short chain
fatty acids (SCFAs) – such as acetate, butyrate, and
propionate – that are used as fuel by colonocytes.⁷
The SCFAs, especially butyrate, stimulate growth of
beneficial nonpathogenic intestinal bacteria, which are
thought to play an anti-inflammatory role, enhance
immune function, and optimize intestinal barriers
to pathogenic bacteria. Additionally, the increase in
intestinal bacteria through fermentation contributes
to bulk in stools. The insoluble fibers, including
cellulose and lignin, provide “roughage” and are
generally considered to be non-fermentable and non-
viscous. By increasing bulk and frequency of stool, they
promote passage of stool through the intestinal tract
and ease defecation.⁸ The food sources of fermentable
fibers include bananas, potato, brown rice, and oats,
whereas good sources of non-fermentable fibers include
bran, nuts, seeds, whole wheat and skins of fruits and
vegetables.⁹ See Table 3 for a review of fiber types and
food sources of each.

To complicate matters, most foods have a mix of various fibers. Although the fiber content of foods is easily found on food labels listed as “dietary fiber,” unfortunately, there is no requirement that manufacturers classify the fiber further.

RESIDUE AND FIBER DIET STUDIES IN IBD
The Low Residue Diet

The low residue diet has traditionally been used to reduce fecal volume in a number of situations: to treat diarrhea, keep wounds free from stool, promote wound healing in patients with decubitus ulcers or those who have undergone rectal surgeries. As there is no consensus on the composition of residue, studies that evaluated the low residue diet have used various definitions of residue and degree of food restrictions. We speculate that the low residue diets in these studies would limit intake of crude fiber, meats and dairy.

There are limited studies on the use of the low residue diet in IBD. A two-year prospective Italian trial compared long-term effects of a low residue diet, which the authors defined as the elimination of whole grains, legumes and all fruits and vegetables (except for bananas and skinless potatoes). Many clinicians would call this a “low fiber” diet and a regular diet in 71 adult patients with active CD.¹⁰ Eighty-five patients were identified for possible participation and all patients, except for five recently diagnosed patients, had already been prescribed a low residue diet. After eliminating 4 patients due to radiologic strictures and another 10 patients due to lack of willingness to adhere to the low residue diet, the remaining 71 patients were randomized to either continue following the low residue diet or transition to an unrestricted Italian diet. The consumption of dairy was allowed as tolerated in both groups. There were no differences in outcomes between the two groups when evaluating rates of flares, intestinal obstructions, need for a hospital admission and/or need for surgery. The addition of fiber into the “regular” Italian diet was tolerated well overall. The study authors concluded that patients should be encouraged to eat an unrestricted diet as tolerated.

The Low Fiber Diet

In contrast to the low residue diet, the low fiber diet only restricts fiber; however, to our knowledge there appears to be no consensus of what defines a low fiber diet. Review of various patient education handouts on the low fiber diet, reveals a trend to limit the type of fiber that is traditionally viewed as insoluble. Although there are limited studies to support this practice, the low fiber diet is often recommended to those who have, or who are suspected to have, intestinal strictures to reduce risk of obstruction. Some clinicians may favor and instruct patients to follow the diet if small bowel bacterial overgrowth has arisen from the intestinal strictures. There are very limited studies to support the restriction of fiber during an IBD flare. Quite the contrary; the inclusion of fiber has generally been of greater interest to researchers and has been suggested to play a role in treatment as well as maintenance of remission-in both CD and UC, mainly via the anti- inflammatory properties of SCFAs. Nonetheless, the bulk of evidence remains inconclusive in supporting fiber as a treatment or as maintenance therapy in IBD. See Table 4 for a comparison of the restrictions between the two diets

Crohn’s Disease

The use of fiber in CD has produced inconsistent outcomes. In an early four-year prospective study, 32 adult patients with active CD, including those with intestinal strictures, were treated with a fiber rich diet in addition to corticosteroids, azathioprine and sulfasalazine, as appropriate.¹¹ The participants were compared with historical controls who were matched by age, site of disease at diagnosis, previous resections and disease duration. The fiber rich treatment group was found to have fewer and shorter stays in the hospital. Only one patient in each group underwent bowel surgery for stricturing disease. The average intake of fiber was 33 g per day by the patients on the fiber rich diet, much more than the national average intake of 20 g per day. The study suggests that fiber restriction may not be necessary and that fiber may instead have a favorable impact on the prognosis of CD patients. In another two- year single blinded study, 352 adult patients with mildly active or inactive CD on sulfasalazine were randomized to either receive a low or a high fiber diet.¹² The weekly average for fiber consumption was 110 g (16 g/day) for the low fiber group and 195 g (28 g/day) for the high fiber group. There were no significant differences in intestinal surgeries, hospital admissions, or outpatient treatments between the two groups.

Ulcerative Colitis

Evidence for the use of fiber in UC also remains inconclusive. In an open label, multicenter randomized trial, 102 adult patients in UC remission were divided into three groups to receive 20 grams of Plantago ovata seeds (fermentable fiber), daily mesalamine or a combination of the seeds with the mesalamine.¹³ Treatment failure was seen in 14 of 35 (40%) patients in the seeds group, 13 out of 37 (35%) in the mesalamine group and 9 out of 30 (30%) in the seeds and mesalamine group. An increase in fecal butyrate levels was found in the groups that were given the seeds. While the authors suggested that fiber may have comparable effectiveness as mesalamine, the sample size is too small to assert this conclusion.

CONCLUSION

There is no consensus of what constitutes residue; in contrast, clear definitions of fiber exist, as does a wealth of data on various types of fiber and the fiber content of foods. However, the low residue and low fiber diets are not synonymous, and due to lack of a clear definition of the former, these diets may impose different limitations on dietary choices. The low residue diet is more restrictive as in addition to restricting some fiber; it also limits meats and dairy. Low residue or low fiber diet prescriptions are common in clinical practice for symptomatic IBD patients, despite a lack of research on their efficacy. If these diets are utilized there should be careful follow up, and if symptomatic relief does not occur, then restrictions should be lifted. Regarding intestinal strictures, there is insufficient evidence to encourage or discourage the use of a low fiber diet in this patient population. However, some clinicians may argue a low fiber diet would be worth trying in patients who have developed small bowel bacterial overgrowth as a consequence from the intestinal strictures. See Table 5 for a summary of findings.

FRONTIERS IN ENDOSCOPY, SERIES #20

Diagnosis and Management of Barrett’s Esophagus

Marisa Belaidi,

Virendra Joshi

Marisa Belaidi, Virendra Joshi MD, AGAF Louisiana State University School of Medicine, Ochsner Clinic Foundation, New Orleans, LA

INTRODUCTION

First described by surgeon Norman Barrett in the mid-twentieth century, Barrett’s Esophagus (BE) refers to the transformation of normal stratified squamous epithelium to simple columnar epithelium in the distal esophagus, secondary to chronic injury and inflammation. Because intestinal metaplasia is a major risk factor for esophageal adenocarcinoma, the incidence of which has been steadily increasing in recent years, early detection and treatment have become a major priority in the gastrointestinal community. Historically, surveillance practice standards for patients with a history of BE followed the Seattle Protocol, a system that required physicians to obtain several random, 4-quadrant biopsies for every 1-2cm of involved esophageal mucosa under the visualization of white-light endoscopy (WLE).¹ However, a growing body of evidence suggests that, in addition to being both time-consuming and inconsistent in detecting dysplasia, this method does not more reliably predict the detection of cancer.² This revelation, coupled with increased understanding of the underlying histology and pathogenesis of Barrett’s Esophagus, has led to the creation of several new tools aimed at improving detection rates and yielding better patient prognoses. This review will describe the most current diagnostic techniques and treatment options of Barrett’s Esophagus and early esophageal cancer, their basic risks and benefits, and their clinical applicability.

DETECTION Chromoendoscopy

In the setting of BE, chromoendoscopy refers to the topical application of dye to esophageal mucosa in order to improve tissue visualization on endoscopy (Figure 1). Based on their staining properties, dyes are divided into one of three categories: contrast, absorptive (vital) or reactive. Methylene Blue (0.5%-1.0%), a vital dye taken up by actively absorbing epithelial cells, is by far the most frequently studied stain in the assessment of BE.^3-6 Though initial reports by Canto et al. yielded promising results regarding the diagnostic capabilities of MB for dysplastic tissue, subsequent studies have yielded discordant conclusions regarding its efficacy.³ Additionally, skeptics have cited a lack of technique standardization, variability in operator skill, and inconsistency of staining and interpretation as major deterrents to this diagnostic test.

In 2013, Qumseya et al.¹conducted a meta-analysis and systemic review of several “advanced imaging technologies” including chromoendoscopy and virtual chromoendosopy, to determine the diagnostic yield of these techniques in comparison to traditional random biopsy sampling. Based on their observations, they concluded that the newer imaging modalities improved detection of dysplasia/cancer by 34% (95% CI, 20%- 56%; P <.0001), which may lend some credibility to the controversial staining technique.

VIRTUAL (ELECTRONIC) CHROMOENDOSCOPY
Narrow Band Imaging (NBI)

First described by Gono et al. in 2004,⁶ Narrow Band Imaging (NBI) has been touted as a more practical, cost-effective and user-friendly alternative to chromoendoscopy (Figure 2). In NBI, short wavelengths of blue (440-460 nm) and green (540- 560 nm) light pass through an electronic endoscopic filter to penetrate the superficial esophageal mucosa.^6-9 The shallow penetration of blue and green light allows for enhanced visualization of surface pit pattern morphology. Additionally, the peak absorption spectrum of hemoglobin lies within this narrow band spectrum, thus clarity of specific superficial vascular patterns is markedly improved.^3,6

Initial studies have yielded promising outcomes in the detection of high-grade dysplasia (Sensitivity 96%, specificity 94%),³ lending credibility to the observation that pathologic tissue in BE exhibits abnormal mucosal and/or vascular patterns. However, the procedure is not yet standardized and requires further study to determine efficacy in detecting low-grade metaplasia.

Autofluorescence Imaging (AFI)

AFI is a relatively new endoscopic procedure that utilizes autofluorescence, a technique that exposes esophageal tissue to short wave light (usually UV or Blue light), causing intracellular substances called fluorophores to emit longer wavelength fluorescent light.^3,19-22 Normal, metaplastic and dysplastic tissue types each exhibit unique autofluorescence spectra due to differing tissue architecture, chromophore content (especially hemoglobin) and fluorophore composition.¹⁹ These discrepancies may help distinguish tissue types and aid in the detection of high grade dysplasia and/ or early esophageal cancer in the setting of BE. However, data is currently limited and this procedure has repeatedly been associated with a very high false positive rate (as high as 50%).³

HIGH-MAGNIFICATION ENDOSCOPY
Confocal Laser Endomicroscopy (CLE)

Confocal laser endomicroscopy (CLE) is a novel endoscopic technique that can be used to identify early neoplastic changes in BE. Based on the concept of confocal microscopy, CLE employs an endoscopic or probe-based laser (Argon Blue, 488 nm) which focuses light on the tissue of interest. Fluorescent light from the tissue then reflects back through a pinhole aperture and is recorded by a photodetector, which relays a high- resolution image to an attached monitor for immediate observation and future retrieval.^1,10-14 Available in either an endoscope-based (eCLE) or probe-based (pCLE) system, CLE provides real-time in vivo histologic imaging of esophageal mucosa at up to 1000-fold increased magnification. Intravenous contrast (typically 2.5-5 mL of 10% flourescin sodium)¹¹ is administered concurrently to improve visualization of tissue and cell structures. To ensure the highest image quality, the endoscopist must achieve adequate contact between the endoscope/probe and mucosal surface, which can be aided via gentle suction to stabilize the connection.¹⁰

In order to classify BE, eCLE utilizes the Mainz Confocal Barrett’s Classification System. Established by Keisslich et al, the Mainz Criteria relies on cell and vessel architecture to distinguish nondysplastic BE (columnar mucosa with goblet cells in a villiform pattern, normal capillaries) from neoplastic BE (irregularly shaped black cells, leaky capillaries),^10-111 pCLE relies on the Miami criteria for dysplastic BE, which includes irregular vessels, fusion of villi and crypts and epithelial irregularities (thickness, inhomogeneity, dark border).

Additionally, recent studies indicate that combining eCLE with high-definition white light endoscopy may increase diagnostic yield of neoplasia versus traditional random biopsy sampling, without requiring as many unnecessary biopsies.

Optical Coherence Tomography (OCT)

Optical coherence tomography (OCT) is a well- established imaging modality that utilizes low- coherence interferometry (near-infrared light) to generate high-resolution (10 – 15-µm), three dimensional cross-sectional imaging of in vivo tissue pathology.^15-17 Initially utilized in ophthalmology, OCT has proved helpful in the diagnosis of various medical conditions, including specialized intestinal metaplasia in BE (sensitivity 81%). It has also been used in the detection of buried Barrett’s epithelium following radiofrequency ablation.¹⁸ However, the scan does not allow simultaneous biopsy of tissue, cannot clearly distinguish low-grade vs. high-grade dysplasia in the context of BE, and would be a tedious and impractical method to survey the full length of the esophagus.16

Volumetric Laser Endomicroscopy (VLE) is a
next-generation technology, based upon OCT. While
traditional OCT relies on Time Domain Interferometry
to measure depth intensity, VLE utilizes Fourier
Domain Interferometry (optical frequency domain
imaging). This proprietary swept-source laser enables
dramatically greater resolution (~7 microns) and faster
acquisition times (100x faster) than conventional OCT.
Its optical probe enables volumetric (circumferential

longitudinal) measurement of the entire distal
esophagus.¹⁶
Suter et al.¹⁷ recently conducted a small, single- center feasibility study to assess the safety and practicality of VLE-guided biopsy in vivo, from which they determined that VLE-guided esophageal biopsy is a well-tolerated procedure that may have utility as a “first-look” procedure to mark tissue regions of interest for subsequent biopsy and therapeutic guidance. TREATMENT In addition to new detection methods, treatment options for Barrett’s Esophagus with high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) are constantly evolving. Once regarded as the gold standard of treatment, esophagectomy has been largely replaced with endoscopic, organ-sparing therapies that are equally as efficacious and incur significantly lower morbidity and mortality rates than traditional surgery. RESECTION
Endoscopic Mucosal Resection (EMR) and Endoscopic Submucosal Dissection (ESD) EMR and ESD are two types of endoscopic treatment aimed at eradicating both HGD and intramucosal EAC in the setting of Barrett’s Esophagus. Due to their relative non-invasiveness, high post-procedure remission rates (up to 97%) and ability to provide a definitive histologic diagnosis, resection techniques are becoming increasingly popular therapeutic modalities.^22,23 While EMR is primarily utilized in the treatment of small (<2cm) superficial tumors, ESD is preferred for larger (>2cm), more extensive lesions whose histologic accuracy and clinical outcome may be jeopardized by piece-meal resection. Both procedures require a high operator skill level and can be associated with adverse events such as bleeding, stricture formation (more common in ESD) and esophageal stenosis. Resection techniques may also be combined with ablative therapies for a potentially superior response rate with less post-procedure complications. TISSUE ABLATION
Radiofrequency Ablation (RFA) Over the past 5 years RFA has become a primary therapy for high-grade dysplasia in Barrett’s epithelium. RFA replaced other previously used ablative therapies including Argon Plasma and Nd:YAG laser. RFA refers to a process of controlled thermal injury (damage is limited to mucosa and lamina propria) that occurs secondary to the induction of an electromagnetic field via an alternating electrical current. The exothermic reaction necessary for RFA can be generated by one of two specific devices: the HALO360 and the HALO90 (BARRX Medical, Inc, Sunnyvale, CA, USA). Shaheen et al. conducted a multicenter, sham- controlled trial in which they assessed the efficacy of radiofrequency ablation versus a sham procedure in 127 patients with dysplastic BE. The authors concluded that RFA was associated with a significantly higher rate of complete eradication of both dysplasia (81.0%-90.5% vs. 19.0-22.7%, P<0.001) and intestinal metaplasia (77.4% vs. 2.3%, P<0.001) compared to the control25. Overall, RFA is generally a safe, well-tolerated procedure. Side effects may include mild non-cardiac chest pain, nausea, and bleeding.²² Cryotherapy Cryotherapy is an ablative noncontact ablative method that delivers a cryogen (most commonly liquid nitrogen, LN2) under low-pressure spray with a decompressive gastric tube to the BE esophageal mucosa. The cryogen is administered in several cycles of rapid freezing (-196?C) and slow thawing. The extreme flash freezes tissue, selectively kills cells while preserving collagen matrix, creates vascular stasis and induces an analgesic effect.^26-28 In contrast to burning techniques, spray cryotherapy promotes less fibrosis and preserves underlying tissue architecture. It is a safe, well-tolerated, non-toxic therapy that literature indicates may serve as a compliment to other established technologies for BE, including EMR, or may be of use when all other treatments are ill advised.^{27 28} Notably, cryotherapy should be avoided during pregnancy, in the setting of compromised or damaged tissue and in the event of increased anatomical flow resistance (gas evacuation). Cryoablation can successfully eradicate residual Barrett’s in patients with esophageal cancer post chemo- radiation.²⁸. In a retrospective review of 32 patients Greenwald et al. found CE-HGD was 100% (32/32), and CE-IM was 84% (27/32) at 2-year follow-up. At last follow-up (range 24-57 months), CE-HGD was 31/32 (97%), and CE-IM was 26/32 (81%). Recurrent HGD was found in 6 (18%), with CE-HGD in 5 after repeat treatment. One patient progressed to adenocarcinoma, downgraded to HGD after repeat cryotherapy. BE segment length =3 cm was associated with a higher recurrence of IM (P = .004; odds ratio 22.6) but not HGD. No serious adverse events occurred. Stricture was seen in 3 patients (9%), all successfully dilated.³⁴ A prospective study of patients undergoing cryoablation suggested recurrent disease commonly involves the area just below the NSCJ ( neosquamocolumnar junction). Surveillance endoscopies should include this area to accurately identify patients with disease recurrence.³³ In addition, cryotherapy appears to be a promising new strategy for salvage therapy of patients who “fail” thermal therapy with RFA. Photodynamic Therapy (PDT) PDT is characterized by the activation of a chemical photosensitizer present in neoplastic tissue (most commonly porphimer sodium) by an endoscopic laser. The activated photosensitizer then reacts with oxygen, producing free radicals that induce cell damage and eventual apoptosis.²² PDT has often been used as an adjunct therapy to proton pump inhibitors (PPI) because the combination has shown superior eradication of BE with HGD and prevention of disease progression than either treatment alone. However, remission rates are significantly lower than esophageal resection techniques and side effects may include photosensitivity, fever, dysphagia, recurrence and progression of disease.³⁰ One of the major side effects seen in a multicenter study by Overholt et al.³⁰ was incidence of strictures, which correlated with number of applications and overlap of treatment. Overall, 36% of patients developed strictures, which were managed successfully with dilations. 12% of patients developed strictures after one PDT as opposed to 32% from two treatments and 9% after a third treatment. Additionally, they reported no improvement in the rate of stricture formation when oral steroids were administered after PDT.³² Careful patient education is critical for the management of side effects and to reduce the risk of photosensitivity reactions.³¹ CONCLUSION
There has been a paradigm shift in the detection and
management of Barrett’s esophagus over the past
decade with use of advanced imaging for detection and
management dysplastic Barrett’s and early esophageal
cancer. Novel advanced imaging modalities as Narrow
Band Imaging (NBI), Confocal Laser Endomicroscopy
(CLE ) and more recently developed volumetric
endomicroscopy (VLE) will continue to impact
early detection by serving as “red flag technologies”
helping to target biopsies and decrease sampling
errors. Dysplastic Barrett’s and early cancer can now
be treated by ablative therapies (thermal, non-thermal)
and endoscopic mucosal resection (EMR, ESD) with
minimal morbidity. These minimally invasive diagnostic
and therapeutic strategies should be individualized and
tailored to individual patient needs.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #95

The Gut Microbiome – Clinical Implications for the Practicing Gastroenterologist

Sara Iqbal,

Eamonn M.M. Quigley

These are exciting times in microbiome research. In this article, we discuss a field that simply did not exist a few years ago and has exponentially expanded to become one of the hottest in all of biomedicine. As techniques develop, become more rapid and less costly, the delineation of the true extent of the role of our bacterial fellow travelers in health will soon be realized.

Sara Iqbal MD,¹ Eamonn M.M. Quigley MD FRCP FACP FACG FRCPI² ¹Department of Medicine ²Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX

The Human Gut Microbiome: The Basics

In recent years biomedical research has witnessed a paradigm shift away from an exclusive focus on the human genome and its functions and towards a greater understanding of our fellow travelers: the microorganisms that live within and on our bodies. Formerly studied exclusively in terms of their pathogenic and disease-promoting potential, bacteria, viruses, archaea, fungi and other microorganisms are now being examined in a completely different light – as commensals critical for the homeostasis of the host. Such studies have not only opened a new platform for research into disease pathophysiology, but also revealed the potential for developing new management strategies for several disease states and syndromes. Much of the progress in this field can be attributed to major and ever evolving developments in technology, which now permit the rapid and complete identification of all of the bacterial inhabitants of a given locus.¹ With these technologies comes new terminology, a terminology that will be new to many and confusing to some. To facilitate the reader’s access to the literature on this field a list of the more commonly used terms and their definition is provided in Table 1. You will notice one striking omission from this list: “flora”. This term, which dates from the time when bacteria were included in the plant kingdom, has now been largely abandoned and replaced by “microbiota”.

The results of the human genome project were a surprise to researchers with the discovery of only 20- 25000 genes, about one fifth of what was expected.² So, to look for the missing pieces in the puzzle, other sources of genetic information were explored; giving birth to the concept of the microbiome and ultimately to the human microbiome project.³ It turns out that microbes are not “mere bugs in our system” but in fact are playing a very important symbiotic role. Insights into the function of these organisms have been provided, in the first instance, by an interrogation of their genome, through metagenomics and thereby, to the identification of genes linked to certain biological functions. Correlations with function have been taken a step further through the application of metabolomics and other techniques that identify the products of bacterial synthetic and metabolic processes.^4,5

While the microbiome of each individual is quite distinct at the level of individual bacterial strains, data from a European consortium indicated that at a higher level of organization, some general patterns can be identified across populations.⁶ They identified three broad groupings driven by the predominance of certain species: Prevotella, Bacteroides and Ruminococcus. Enterotype prevalence seemed independent of age, body mass index or geographic location but may be driven by differing dietary habits. Indeed, the importance of diet in shaping, both in the short- and in the long-term, the composition of the microbiome is now a subject of active study and the impact of dietary changes on the microbiome may well have been underappreciated in former studies.⁷

The Microbiome in Health

At birth the intestinal tract is sterile. The infant’s gut is first colonized by maternal and environmental bacteria during birth and continues to be populated through feeding and other contacts.^1,8 The mode of delivery (vaginal birth vs. caesarean section), diet (breast milk vs. formula), level of sanitation and exposure to antibiotics all influence the development of the infant’s microbiome.^8-11 By 2 to 3 years of age, the child’s microbiota fully resembles that of an adult in terms of composition.^1,12,13

Thereafter the microbiota is thought to remain relatively stable until old age when changes are seen possibly related to alterations in digestive physiology and diet.^13-15 It needs to be emphasized that there are relatively few longitudinal studies.

What Regulates the Microbiota?

Because of the normal motility of the intestine (peristalsis and the migrating motor complex) and the antimicrobial effects of gastric acid, bile and pancreatic and intestinal secretions, the stomach and proximal small intestine, though certainly not sterile, contain relatively small numbers of bacteria in healthy subjects.^1,16 The microbiology of the terminal ileum represents a transition zone between the jejunum containing predominantly aerobic species and the dense population of anaerobes found in the colon. Bacterial colony counts may be as high as 10 ⁹ colony forming units (CFU)/ mL in the terminal ileum immediately proximal to the ileocecal valve, with a predominance of gram-negative organisms and anaerobes. On crossing into the colon, the bacterial concentration and variety of the enteric microbiota changes dramatically. Concentrations of 10¹² CFU/mL, or higher, may be found; comprised mainly of anaerobes such as Bacteroides, Porphyromonas, Bifidobacterium, Lactobacillus and Clostridium, with anaerobic bacteria outnumbering aerobic bacteria by a factor of 100-1000:1. The predominance of anaerobes in the colon reflects the fact that oxygen concentrations in the colon are very low; the microbiota has simply adapted to survive in this hostile environment.

Though most studies of the human gut microbiota have been based on analyses of fecal samples it must be pointed out that at any point along the gut differences are also evident between bacterial populations resident in the lumen and those adherent to the mucosal surface. These mucosa-associated bacterial species and strains will not be accurately represented in fecal samples, a major limitation of this approach. It stands to reason that bacterial species resident at the mucosal surface, or within the mucus layer, are those most likely to participate in interactions with the host immune system whereas those that populate the lumen may be more relevant to metabolic interactions with food or the products of digestion.

Antibiotics, whether prescribed or in the food chain, have the potential to profoundly impact the microbiota.¹⁶ In the past, it was believed that these effects were relatively transient with complete recovery of the microbiota occurring very soon after the course of antibiotic therapy was complete. However, while recent studies have confirmed that recovery is pretty rapid for many species, some species and strains show more sustained effects.¹⁷ Furthermore, antibiotic exposure and related disruptions of the microbiome may be especially critical in infancy as the microbiome develops.

The Functions of the Microbiome

It is now abundantly evident that an intact microbiome is essential for many aspects of the development of the gastrointestinal tract including such vital components as the mucosa-associated immune system, immunological tolerance, epithelial and barrier function, motility and vascularity. The resident commensal microbiota continues to contribute to such homeostatic functions during life as pathogen exclusion, immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function.¹⁸

The sophistication of the relationship between the microbiota and its host is elegantly illustrated by the manner in which the immune system of the gut differentiates between friend and foe when it encounters bacteria.¹⁹ At the epithelial level, for example, a number of factors may allow the epithelium to “tolerate” commensal (and thus probiotic) organisms. These include the masking or modification of microbial associated molecular patterns that are usually recognized by pattern recognition receptors (PPR’s), such as Toll-like receptors (TLR’s)²⁰ and the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-.B) inflammatory pathway.²¹ Responses to commensals and pathogens may also be distinctly different within the mucosal and systemic immune systems. For example, commensals such as Bifidobacterium infantis and Faecalobacterium prasunitzii, have been shown to differentially induce regulatory T cells (Tregs) and result in the production of the anti-inflammatory cytokine, IL-10.²² Other commensals may promote the development of T helper cells, including T_H17 cells and result in a controlled inflammatory response which is protective against pathogens in part, at least, through the production of IL- 17.²³ The induction of a low-grade inflammatory response (“physiological” inflammation) by commensals could be seen to “prime” the host’s immune system to deal more aggressively with the arrival of a pathogen.²⁴ It is also now evident that host-microbe immune interactions are bidirectional; innate immune responses can shape the microbial ecology of the gut and this, in turn, can influence the development of disease susceptibility in the host.

Some of the metabolic functions of the microbiome have been known for years: the ability of bacterial disaccharidases to salvage unabsorbed dietary sugars, such as lactose, and alcohols and convert them into short-chain fatty acids (SCFAs), the synthesis of nutrients and vitamins, such as folate and vitamin K, the deconjugation of bile salts²⁵ and metabolism of certain drugs (e.g. sulfasalazine). Now a fuller picture of the metabolic potential of the microbiome is being revealed and includes the production of other chemicals, including neurotransmitters and neuromodulators, which can modify other gut functions, such as motility or sensation, or even influence the development²⁶ and function²⁷ of the central nervous system, thereby leading to the concept of the microbiota-gut-brain axis.^28-30

The Gut Microbiota and Disease

The idea that the bacterial contents of the gastrointestinal tract could contribute to symptoms and disease is not a new one; the role of enteric bacteria in hepatic encephalopathy was described over 50 years ago and several other human ailments have been clearly defined as originating from a disturbed microbiome and/or how it interacts with the host. Well accepted examples are listed on Table 2. The availability of high-throughput sequencing techniques, as well as exciting data from animal experiments, has spurred a host of studies of the microbiome in almost every known gastrointestinal, liver and pancreaticobiliary disease. Based on such studies, a role for the microbiome and/or host-microbiome interactions has been proposed for a long list of diseases and syndromes, some of which are listed on Table 3. While, in some instances, such as inflammatory bowel disease (IBD), there is compelling evidence for a role for microbe-host interactions in disease pathogenesis, in others, this remains more speculative. It must be emphasized that, for most of these disorders, available data describe a mere association and no conclusions can be drawn with respect to causation.

With respect to disease causation, the period of maturation of the microbiota may be critical; there is accumulating evidence from a number of sources that disruption of the microbiota in early infancy may be a critical determinant of disease expression in later life. It follows that interventions directed at the microbiota later in life may, quite literally, be too late and are, potentially, doomed to failure.

Helicobacter Pylori

Helicobacter Pylori, one of the most studied of all bacteria, provides a beautiful illustration of host-microbe interactions with the disease phenotype resulting from infection with this fascinating organism reflecting complex interactions between bacterial properties, host factors and other environmental influences, including the resident gastric microbiome. For example, certain Bifidobacterium strains display anti-Helicobacter effects through the production of antimicrobial peptides.³¹

Diarrheal Illness

Infectious diarrheas, still a major cause of morbidity and
mortality worldwide, represent an overwhelming assault
on the commensal microbiome and the host. Pathogens
have evolved a number of strategies to survive in the gut
and evade immunological and physiological responses
by the host. Here again, microbe-host responses play
a critical role; some bacteria take advantage of the
host’s inflammatory response to its presence to create
a favorable environment that allows them to outgrow
resident microbes. For example, gastroenteritis due to
Salmonella typhi has been well studied in terms of the
genetic adaptations of the pathogen and the role of the
host immune system in determining disease outcome.

Antibiotic-associated diarrhea and its most
concerning manifestation, Clostridium difficile-
associated disease (CDAD), is a potent reminder of what
can happen when we disrupt the normal microbiome,
albeit with good intentions. Some individuals seem
especially susceptible to the development of CDAD
when administered broad-spectrum antibiotics and it has
been shown that some of this susceptibility may reside
in the composition of the pre-exposure microbiota.³²
Evidence suggests that the predilection to C. difficile
illness is largely a function of how resilient the indigenous
microbiota is following an antibiotic assault, with some
bacterial communities being better able to recover than
others. The management of CDAD is now complicated
by the emergence of hypervirulent strains and an ever-
increasing rate of recurrence following initial treatment
with metronidazole or vancomycin. Recurrence rates of
25 percent or more are now commonly reported. The
role of an indigenous healthy microbiome is perhaps
most dramatically illustrated by the overwhelming
success of fecal microbiota transplantation (FMT) in
the management of recurrent CDAD.

Irritable Bowel Syndrome (IBS)

Several strands of evidence suggest a role for the gut microbiota in IBS.³³ First and foremost among these is the clinical observation that individuals can develop IBS de novo following exposure to enteric infections and infestations, post-infectious IBS (PI-IBS).³⁴ More contentious has been the suggestion that IBS subjects may harbor small intestinal bacterial overgrowth (SIBO).³⁵ More indirect evidence for a role for the microbiota can be gleaned from some of the metabolic functions of components of the microbiota. Thus, changes in bile salt deconjugation could, given the effects of bile salts on colonic secretion, lead to changes in stool volume and consistency. Similarly, changes in bacterial fermentation could result in alterations in gas volume and/or composition. Further evidence comes from the clinical impact of therapeutic interventions, such as antibiotics, prebiotics or probiotics, which can alter or modify the microbiota. Sequencing studies have shown that IBS patients, regardless of subtype, do exhibit a fecal microbiota that is clearly different from control subjects.³⁶ Such studies have demonstrated reduced microbial diversity in IBS³⁷ and the existence of different IBS subgroups³⁸ defined by the relative proportion of the two major phyla, Firmicutes and Bacteroidetes, as well as significant changes at species and strain level.^38,39 The primacy of these microbial shifts and their potential to disturb mucosal or myoneural function in the gut wall, impact on the brain-gut axis, or induce local or systemic immune responses remains to be defined.

Obesity, the Metabolic Syndrome and Related Disorders

A considerable body of basic research suggests an important role for the microbiota in the development of obesity and related disorders, such as the metabolic syndrome.^40,41 Qualitative changes in the gut microbiota have also been identified in man but findings have been less clear-cut. Nevertheless, a microbial signature predictive of the development of type II diabetes has also been identified and FMT was shown to restore insulin sensitivity in a small study among individuals with the metabolic syndrome.⁴² Fundamental to all theories of the role of the microbiota in these disorders is the concept that a shift in the composition of the microbiota towards a population where bacteria that are more avid extractors of absorbable nutrients, results in the availability of these nutrients for assimilation by the host; thereby, contributing to obesity.⁴⁰

Colorectal Cancer

Recent studies have identified specific signatures in the gut microbiome associated with colorectal cancer (CRC) and suggested that the microbiome may serve as a valuable screening tool; the efficacy of this approach in clinical practice has yet to be demonstrated. While microbiome-based analyses, on their own, can detect precancerous and cancerous lesions, combining such data with body mass index, a known clinical risk factor of CRC, and occult blood testing, provided an excellent discrimination between healthy individuals to those with malignant and premalignant lesions.⁴⁰

While a disturbed microbiota has been linked with CRC, defining a causal link has proven more problematic. In recent years, research has focused on identifying bacterial species or strains that are particularly linked with CRC.⁴⁴ Two bacteria in particular, Fusobacterium nucleatum and Escherichia coli, have been consistently associated with CRC. Proposed pathways to cancer formation related to bacteria have included bacteria- induced chronic inflammation leading to cell proliferation or the direct effects of bacterial virulence factors inducing tumor formation.⁴⁵

Inflammatory Bowel Disease (IBD)

A considerable body of experimental and clinical evidence indicates that the microbiota and microbiota- host interactions are critical to the pathogenesis of IBD.⁴⁵ Defining the precise nature of the fundamental pathophysiology has proven more challenging; is it an abnormal microbiota, an abnormal host immune response to a normal microbiota or some combination of these factors? There is some evidence for the presence of a disturbed microbiota in IBD but results are not consistent. For example some studies demonstrated that patients with Crohn’s disease (CD; either colonic or ileal) exhibited microbiota profiles distinctly different from those of healthy controls or patients with ulcerative colitis (UC). Furthermore, the fecal microbiota in patients with ileal CD differed from that in patients with predominantly colonic disease.⁴⁷ In contrast, data from a twin study suggested that the microbiome was abnormal in UC also.⁴⁸ Several factors contribute to sorting out the role of the microbiome in IBD: the heterogeneity of the disease population, diet, medications and disease activity. For example, it is distinctly plausible that changes in the microbiome seen in IBD could reflect the consequences of inflammation and have nothing to do with causation. Longitudinal studies of the gut microbiota throughout the course of the disease are needed.

Liver Disease and its Complications

That the microbiota-gut-liver axis plays an important role in the occurrence of infectious and noninfectious complications of liver disease is well established. More recent is the proposal that the microbiota could be involved in the pathogenesis of liver diseases, such as non-alcoholic liver disease (NAFLD).⁴⁹ From a considerable body of experimental and some clinical data some common themes have emerged. Thus, a disturbed microbiota (small intestinal overgrowth and/ or qualitative changes in the microbiota), impaired gut barrier function and the host immune response have been shown to conspire to impact on liver metabolism (contributing to lipogenesis, for example), promote inflammation and even contribute to the progression to fibrosis, cirrhosis and hepatocellular carcinoma. The microbiota has also been implicated in alcoholic liver disease. Alcohol impairs the host immune response.⁵⁰ and its metabolites can conspire with lipopolysaccharide (LPS) produced by Gram-negative bacteria to induce liver injury.⁵¹ The microbiota also contributes to alcohol-related liver injury by promoting the growth of endotoxin-producing gram-negative bacteria in the gut and increasing intestinal permeability.

The role of antibiotic therapy is well established in the prevention and management of hepatic encephalopathy and infectious complications of liver disease.⁵² Now microbiota-modulating strategies are being explored in the management of liver disease per se. For example, the probiotic organism Lactobacillus rhamnosus, has been shown to promote gut homeostasis by modulating the growth of Gram- negative bacteria⁵³ and restoring intestinal barrier integrity; as a consequence liver fat content and circulating levels of pro-inflammatory cytokines are reduced.^54,55

Therapeutic Modulation of the Microbiome

While it is undoubted that food is the primary modulator of the microbiome, it is not the only one. Specifically, extensive antibiotic use in modern animal husbandry exerts a selective pressure for antibiotic resistance that eventually spreads to the human microbiome. Because of the rapid and efficient transfer of resistance genes from one bacterium to another, even nonpathogenic (so-called commensal) bacteria can carry and express resistance genes.

Probiotics and prebiotics aim to confer a health benefit by modulating the microbiome. Prebiotics selectively stimulate the growth and/or activity of bacteria that contribute to colonic and host health.⁵⁶ Probiotics may provide benefits through the multiple aforementioned mechanisms whereby the normal commensal microbiota interacts with the host. While the traditional concept of probiotics is based on the functions of live organisms, it is evident that dead bacteria, bacterial components or bacterial metabolites are biologically active. For example, probiotics have the potential to either stimulate or suppress host immunity via microbe-derived immunomodulatory molecules.⁵⁷ A complete discussion of the use of probiotics in man is beyond the scope of this review. Suffice it to say that, given the current regulatory climate, major quality control issues surround the probiotic market. At the very least a probiotic should be characterized at genome level and should have been demonstrated to survive passage through the digestive tract to its desired site of action. Furthermore, clinical claims should be supported by high quality clinical trial data. Although there is no such thing as zero risk, probiotics are generally regarded as safe and truly probiotic-related adverse events in healthy individuals and those seen in an ambulatory care setting have been vanishingly rare.⁵⁸

CONCLUSION

These are exciting times in microbiome research. A
field that simply did not exist a few years ago has
exponentially expanded to become one of the hottest in
all of biomedicine. As techniques develop, become more
rapid and less costly, the delineation of the true extent of
the role of our bacterial fellow travelers in health will
soon be realized. In terms of disease states, while many
tantalizing associations have been described, defining
causation will take some time given the heterogeneity
of many disease populations, the dynamics of the
microbiota over time, the bidirectional nature of
interactions between the host and the microbiome and
the impact of so many confounding factors. There is
much to be done.