Page 54 – Practical Gastro

David Valadez,

Mazyar Malakouti,

Tisha Lunsford

David Valadez MD, Resident, Department of Medicine, UT Health San Antonio Mazyar Malakouti, MD, Fellow, Division of Gastroenterology, Department of Medicine, UT Health San Antonio Tisha Lunsford, MD Associate Professor, Division of Gastroenterology, Department of Medicine, UT Health San Antonio, Long School of Medicine San Antonio, TX

The interaction between diet, gut microbiota, and inflammatory bowel disease is an immense process with many complex mechanisms. Food additives are one component of the human diet that face intense scrutiny by society, governing bodies, and science. Simply defined, food additives are compounds added to food. This definition has changed throughout history, which provides context for how additives are regulated. Food additives can include, but are not limited to, taste enhancers, emulsifiers, microparticles, preservatives, antioxidants, and polyphenols. Research has shown that food additives modulate the activity of inflammatory bowel disease, particularly through microbial mechanisms, as food additives impact bacterial dysbiosis, colonization, and metabolism. While the available literature is rich with useful information for the primary care physician and gastroenterologist, it highlights the need for continued research on long-term and clinical outcomes.

BACKGROUND HISTORY

The human diet and its impact on inflammatory bowel disease (IBD) have been extensively studied, and we know that both food itself and its relationship with the gut microbiota modulate the natural course of IBD.^1-3 Given society’s boosted attention to health and nutrition, the content of what we eat is facing increasing scrutiny. Food additives are of particular interest because their presence in one’s food is frequently unknown to the consumer. Scientific literature generally defines a food additive as a compound added to foods during any part of their production, processing, treatment, packing, or storage.⁴ The regulation of food additives is a comprehensive process to ensure the safety of such substances for widespread consumption.⁵ However, there are regulatory differences based on definitions and legal stratifications.

The Food and Drug Administration (FDA) is the federal agency that oversees food safety for the United States. In 1958, the Food Additives Amendment to the Federal Food, Drug, And Cosmetic Act defined a food additive as “any substance intentionally added to food,” unless that substance is designated as Generally Recognized as Safe (GRAS). Substances with GRAS exemption have the general consensus, but not necessarily unanimity, of “qualified experts” that their intended uses in food are safe.⁶ These substances are not subject to specific food additive regulations or premarket approval by the FDA. There are over 1,000 substances currently with GRAS exemption.⁷ Since 1997, the FDA no longer affirms GRAS exemption status for substances when petitioned, but instead permits individuals to notify the FDA that they believe a substance meets GRAS exemption. The FDA will review this notification within 30 days, but does not provide affirmation of the individual’s claim.⁸ The FDA can report the notification did not provide a “basis for a GRAS determination,” which has occurred in only 17 out of the 780 GRAS exemption notifications since 1998.⁹

While food additives represent technologic advancements in how we process and consume food, there are still concerns regarding their safety, especially with the possibility of conflicts of interest in regulatory oversight. Common food additives have previously been shown to induce metabolic disease through interactions with the gut microbiota.¹⁰ Table 1 includes examples of food additives within categories by function. Here, we review how certain food additives may influence the pathogenesis of IBD, with an emphasis on how food additives affect mechanisms of the gut microbiota. We begin with a brief review of the relationship between IBD and the microbiota itself.

MICROBIOTA AND IBD

The gut microbiota is the community of micro-organisms, predominately bacteria, which influences gut health through metabolic functions and host responses.¹¹ The core microbiota represents the majority of bacterial species shared among most individuals, and commonly includes Bacteroides, Firmicutes, Fusobacterium.¹² Dysbiosis, an imbalance to the microbiota and a lack of bacterial diversity, has been associated with both Crohn’s disease (CD) and ulcerative colitis (UC).^13-15

Dysbiosis is supported by increased colonization and adherence of bacteria, generally more associated with IBD: Bacteroides, enterobacteria, E. coli (particularly pathogenic AIEC strains), and sulfite-reducing bacteria such as Fusobacterium and B. wadsworthia.^16-22 In particular, increased transportation of E. coli species across the follicular associated epithelium and biofilms of gram-negative species, including Bacteroides fragilis, have been found in microscopic samples in IBD patients.^23-25 Once bacteria have permeated the gut, they can exert direct and indirect influence on the degree of inflammation. Lipopolysaccharide (LPS), bacterial toxins, and hydrogen sulfide, a byproduct of sulfite-reducing bacteria, have been associated with increased inflammation and IBD.^26-29 Short-chain fatty acids (SCFA) are other bacterial byproducts. Butyrate, in particular, is commonly generated by Firmicutes and Faecalibacterium, and may protect against inflammation by enhancing the integrity of the gut barrier, altering gene expression, and promoting Treg cell differentiation.^14,29-35

REVIEW OF FOOD ADDITIVES

Food additives can be natural or synthetic and serve a variety of purposes in food preparation, including, but not limited to, flavoring, preservation, coloring, or stabilizing.^4,36 For our review, we have focused on food additives that have been shown to influence the microbiota and IBD, and stratified them into categories based on their similar characteristics: taste enhancers, emulsifiers, microparticles, preservatives, antioxidants, and polyphenols.

Taste Enhancers

Taste is a sensation with multiple aspects (sweet, salty, bitter, etc.) and taste enhancers serve to augment these various components. Taste enhancers can include sweeteners (natural or artificial) and monosodium glutamate (MSG)^4,36 Sweeteners have been frequently studied given their impact on metabolism and obesity, and it is suggested that alterations in gut microbiota may play a role.³⁷³⁹ Non-caloric artificial sweeteners have been associated with significant dysbiosis and modification of over 40 microbial operational taxonomic units, primarily with an increase in the Bacteroides genus.³⁷ Increased Bacteroides content was also seen in rat models that consumed sugar monosaccharides.⁴⁰ A direct link between sweetener-induced microbiota changes and IBD has not been closely studied. However, a broad review of dietary risk factors did find that increased consumption of sucrose or refined carbohydrates was more common in CD patients.⁴¹ The polysaccharide maltodextrin was also shown to promote E. coli biofilm growth, which may improve colonization of invasive E. coli species.⁴² Gut microbiota in CD has also been found to have an increased amount of maltodextrin-related byproducts.

Contrarily, two artificial sweeteners have been associated with gut environments less favorable for IBD development. Aspartame and xylitol, two ubiquitous dietary sweeteners, have been shown to increase the Firmicutes:Bacteroides ratio and promote increased levels of SCFA, including propionate and butyrate.^27,43 MSG was also seen to promote F. prausnitzii colonization, with this microbe previously shown to have anti-inflammatory effects.⁴⁴

Emulsifiers

Emulsifiers, or food stabilizers, are substances that help avoid the breakdown of food items, specifically by preventing separation, melting, or precipitation.³⁶ Emulsifiers can include polysorbates, gums, lecithin, or gelatins.^4,36 Emulsifiers have been linked to IBD, with studies noting an increase in CD incidence and the development of gut inflammation in animal models when exposed to emuslifiers.^45-47 Bacterial colonization is thought to be aided by the presence of these compounds, with polysorbate 80 and carboxymethylcellulose (cellulose gum) cited as two particular substances.^48,49 Consumption of emulsifiers promote a breakdown of the protective gut mucus layer, which increases the gut permeability and improves the ability of bacteria to both adhere and migrate along the GI tract.^47,50 In particular, increased translocation of E. coli across M cells and human Peyer’s patches is associated with polysorbate 80.⁵¹ Studies have also noted an increase in bacteria-associated pro-inflammatory molecules, such as LPS and flagellin.^47,49 On a larger scale, emulsifiers have also been associated with a decrease in microbial diversity, in particular increasing levels of Bacteroides or decreasing levels of Firmicutes and clostridales.⁴⁹ As previously discussed, these compositional changes have been linked with IBD.

Not all emulsifying food additives have been positively correlated with inflammatory changes, however. Chronic consumption of guar gum was linked to the prevention of colitis in mice. Specifically, guar gum was associated with an anti-inflammatory environment with increased growth of clostridial species and higher levels of fecal SCFA.⁵² Guar gum has been also been shown to downregulate the level of lipopolysaccharide-binding protein in rat models.⁵³

Microparticles

Microparticle is a general term describing non-biologic particles, with sizes in the micron to submicron range, which are similar to bacterial sizes. The two most common dietary microparticles are titanium dioxide and aluminum-based silicates.⁵⁴ Titanium dioxide is a commonly used food additive that can increase whiteness or brighten foods.⁵⁴ Its consumption alone has not been shown to significantly alter the existing microbiota composition.⁵⁵ However, bacterial LPS has been shown to conjugate with titanium dioxide, and this combination can potentiate downstream inflammatory effects in IBD patients.^56,57 Specifically, this molecular conjugate promotes the assembly of the intestinal inflammasome and increases the secretion of IL-1.^58,59 Aluminosilicates help to prevent caking of powder-based foods in association with pressure, moisture, or temperature.⁵⁴ Aluminum-based microparticles have also been shown to bind with LPS to produce pro-inflammatory effects similar to titanium dioxide.^54,56 Aluminum itself was also shown to worsen the intensity and duration of colitis in mice models, with possible mechanisms including damaging the gut barrier and inducing granuloma formation (with in vitro studies).⁶⁰

Preservatives

Preservatives promote food safety and maintain reasonable shelf lives by preventing microorganism growth. Common preservatives include benzoates and sulfites.4,36 Benzoate, or benzoic acid, was found to increase the proportion of lactic acid producing bacteria, including Lactobacillus.⁶¹ Lactobacilli have been postulated to compete for colonization against more pathogenic species. However, catechols (such as 1,2-dihydroxybenzene), which are intermediates in the metabolism of benzoates, have been associated with increased growth and virulence of Enterobacteriaceae species.⁶² Sulfites have been shown to decrease four species of beneficial bacteria, including Lactobacilli.⁶³ This study was notable for using sulfite dilutions at “safe for food” levels.

Antioxidants

Antioxidants are compounds that slow food spoilage and prevent oxidation of food’s fatty content. Common antioxidants include vitamin C and vitamin E.4,36 Oxidative stress or an inadequate antioxidant response has previously been associated with IBD.^64,65 In vivo, LPS has been shown to inhibit the intestinal absorption of ascorbic acid (vitamin C), which underscores importance of adequate dietary intake in individuals with gut inflammation.⁶⁶ Antioxidants can also impact microbial compositions, as administering an antioxidant blend to piglets was shown to increase counts of Lactobacillus and decrease counts of E. coli.⁶⁷

Polyphenols

Polyphenols, or phenolic compounds, are naturally occurring compounds found in fruits, vegetables, and grains.⁶⁸ Their role in nutrition has been expanded to utilize them as food additives in a multipurpose fashion as antioxidants, antimicrobials, texture modifiers, and preservatives.^69,70 In general, polyphenols are considered to be anti-inflammatory and promote growth of “good” microbiota. Studies have associated polyphenols with increases in Lactobacilli and bifidobacterium species.⁷¹ Other studies have noted an ability of polyphenols to reduce luminal pH and potentially inhibit proteolytic bacteria often found in IBD.⁶⁸ More pathogenic gut bacteria, such as Enterobacteriaceae, certain clostridiales (C. perfringens and C. histolyticum), and gram-negative Bacteroides have decreased in number when exposed to polyphenols.^68,71-73 Polyphenols have also been seen to inhibit certain pro-inflammatory markers, such as TNF and IL-6, and reduce oxidative stress.^68,74 These properties may help explain how polyphenol extract was associated with prevention of colitis development in rat models.⁷⁵ Curcumin is a particular polyphenol trending as a therapeutic option in IBD. It has been shown to increase the amounts of Lactobacillus species, butyrate-producing bacteria and promote Treg cell expression in the gut mucosa.^76,77 Still, polyphenols have also been associated with a decreased Firmicutes:Bacteroides ratio and can decrease circulating SCFA, two characteristics found in IBD patients.^68,74

CONCLUSION

This review, while not comprehensive, summarizes the effects of food additives on the gut microbiota and IBD, and highlights the potentially clinical relevant substances. While many food additives are generally thought of as safe for consumption, further research is needed to better assess if chronic exposure to these substances is associated with IBD and how the long-term clinical course of patients is impacted.

Combining Women’s Cancer Screening Examinations Shows A Positive Impact On Colorectal Cancer Screening Rates

Marianne T. Ritchie,

Apeksha Shah,

Bilal A. Asif

Colorectal cancer (CRC) is the 3rd most common cancer among women. In the article we present PINK PLUSTM, an innovative program combining three women’s screenings in one visit; mammogram, gynecology exam (GYN) and pre-colonoscopy visit (GI). PINK PLUSTM is a flexible and convenient program demonstrating a high rate of compliance with colonoscopy, which could serve as a national template aimed at increasing adherence to all women’s cancer screenings, especially in underserved communities, by combining these life-saving screenings into one visit.

Marianne T. Ritchie, MD, Clinical Associate Professor, Jefferson Gastroenterology and Hepatology Director, Sidney Kimmel Cancer Center Colon Cancer Screening/Outreach Apeksha Shah, MD, Fellow, Gastroenterology and Hepatology Bilal A. Asif, MD, Resident, Internal Medicine Thomas Jefferson University Hospital

INTRODUCTION

Timely colorectal cancer (CRC) screening can detect and remove precancerous polyps before they become cancer1,2 and find CRC at an early stage, when a cure is more likely.3 Yet according to the American Cancer Society,³ only 60% of women over age 50, the recommended age to begin CRC screening, undergo screening with endoscopy (colonoscopy or sigmoidoscopy). Lower still is the adherence rate among women ages 50 to 64 (55%). As a result, CRC is the third leading cause of cancer death in US women and a major public health risk.

Women are less likely to undergo CRC screening than men even though CRC mortality rates are similar (4.6% for men vs. 4.2% for women).³ Barriers to screening in women differ from those in men but are not clearly understood.^4,5 Lack of physician recommendation has been cited as a barrier to CRC screening,^6,7 along with embarrassment, expense, discomfort, fear of results, and inconvenience.⁸ Past sexual abuse may also deter women from colonoscopy, as it may stir unwanted memories.⁹

Patient education appears to play an important role. In one study, women were invited to have a conversation about CRC screening while visiting a health care center for a mammogram. Capturing the attention of patients during the visit for mammography led to increasing their CRC screening rates, especially when the program included navigation.¹⁰

Previous studies have also shown that women who engage in other cancer prevention behaviors are more likely to undergo CRC screening.^8,11 For women who had a mammogram within 2 years or Papanicolau smear within 3 years, the likelihood of CRC screening increased from 24% to 60.6% and from 33.3% to 56%, respectively.¹¹

Yet women who practice other forms of preventive care may still avoid CRC screening. CRC screening rates for women lag behind screening rates for breast cancer by about 10% and cervical cancer by about 20%.¹² This lag may result from a lack of public awareness that CRC is both common and preventable,¹¹ and that CRC occurs about equally in men and women. It may also reflect increased general awareness of the benefits of breast cancer screening and cervical cancer screening compared to CRC. Finally, the higher rates of screening for breast and cervical cancer may simply reflect differences in the ease of completing these tests compared to CRC screening.

Gender-related distinctions also exist in location of colonic neoplasia. Women are more likely to have purely right-sided polyps and tumors.¹³ Surveillance, Epidemiology, and End Results Program (SEER) data show CRC in the right colon more often in women (45%) than in men (36%).¹⁴ Another factor that increases the risk for proximal cancers is cholecystectomy, which is more commonly performed in women than in men.¹¹ These data should be considered when making screening recommendations.

Another consideration is ethnicity. Hispanic women have the lowest risk while black women manifest the highest rates of CRC, similar to the white male population.³ There also appears to be a more proximal distribution of CRC and adenomas in African Americans (AA).¹³

Based on what is known about CRC screening barriers and behaviors among women, we created PINK PLUS™, a program that aims to enhance screening rates and compliance by combining screening for breast, cervical, and CRC in one setting. The objective of this report is to describe the implementation of PINK PLUS™ and to detail its impact on screening rates among patients who enrolled in the program.

METHODS

PINK PLUS™ is a program that offers women bundled cancer screenings in one visit at one location by all women health care providers. A pilot at the Thomas Jefferson University Breast Imaging Center was promoted with campus flyers and university intranet announcements. Twelve women participated, each undergoing a mammogram, gynecology examination (GYN) and pre-colonoscopy visit (GI), all within 2.5 hours. A gastroenterologist conducted the GI visit; a history and physical followed by an explanation of the preparation and risks of colonoscopy. Based on positive feedback from the initial cohort, the program was expanded to include several screening combination options during evening hours (mammogram-GI, mammogram-GYN-GI) and daytime hours (mammogram-GI, GYN-GI). At the end of each brief GI visit, patients were scheduled for colonoscopy. Patients were considered ineligible because they were not due for screening, not medically stable, or had insurance issues. A retrospective chart review of all PINK PLUS™ participants collected data including patient age, family and personal history of CRC/polyps, date of subsequent colonoscopy, and any findings of advanced lesions.

RESULTS

In all, 118 women (average age 57.1 years) participated in the program. Eighteen were excluded because they were ineligible for CRC screening (Table 1). Of the 100 remaining women, 77 returned for colonoscopy screening (77%) (Figure 1). Of those individuals who returned for colonoscopy screening, 28 (36.4%) had undergone a prior colonoscopy. Of these patients, 15 (19%) had a personal history of colon polyps (Table 2). A majority of patients had no family history of CRC or polyps; 16 (21%) had a family history of only CRC and an additional 5 (6%) had a family history of both CRC and polyps (Figure 2). On colonoscopy, 35 patients (45%) had a normal examination, 26 patients (34%) had adenomatous polyps, and 15 patients (19%) had hyperplastic polyps. Of those who underwent mammography, 10% had abnormal findings, defined as new mass or lesion detected on mammogram. Of these 77 patients who underwent colonoscopy, most (61%) had the colonoscopy within 3 months, and an additional 14% had colonoscopy within 3 to 6 months (Table 3). DISCUSSION Past attempts to enhance screening rates by media campaigns, fecal occult-blood tests, and other methods have met with limited success, especially in medically underserved communities.¹⁰ By bundling women’s cancer screenings, PINK PLUS™ provides an innovative approach to improving women’s health.

A major strength of the program is convenience. With one phone call, a patient can have up to three cancer screenings in one place on one day, during daytime or evening hours. We showed that the practice of combining two or three cancer screening examinations in one visit improved CRC screening rates in the women who participated in PINK PLUS™. CRC screening was included in each of the three PINK PLUS™ options offered because of the three screenings, CRC has the lowest adherence rates. To our knowledge, no other program adds CRC screening with other women’s cancer screenings in one clinical setting.

Our program’s bundled approach to women’s cancer screenings was built on findings that women who adhere to screening for breast and/or cervical cancer are more likely to undergo CRC screening.^8,11 In particular, one study found that women who had breast and cervical cancer screenings were four times more likely to undergo endoscopic CRC screening.⁶

Several studies have identified a primary care physician (PCP) recommendation as a strong predictor for cancer screening adherence.8 Studies also show that some women consider their Obstetrician-Gynecologist (OB-GYN) doctor as their PCP.¹⁵ PINK PLUS™ enables OB-GYN doctors to refer patients for double or triple screenings, which will help boost CRC screening rates. In addition, there is an association between the risks for CRC and gynecologic cancers. Approximately 10% of patients with both endometrial cancer and CRC are due to the Lynch Syndrome (inherited CRC syndrome) but in the majority of cases, no genetic disorder is found.¹⁶ If endometrial cancer is diagnosed before age 50 or ovarian cancer before age 65 (especially before age 50) there is a marked increase in CRC risk.⁹ PINK PLUS™ considers these related risks by combining these screening options in one visit. Screening recommendations should also reflect these effects on CRC risk.

PINK PLUS™ was also based on capturing opportunities for physicians to provide patients with education about preventive cancer screening. One program that bundled education about breast, cervical and CRC led to positive changes in knowledge and attitude about screenings.¹⁷ Another study added CRC screening education at the time of a mammogram and resulted in improved CRC screening rates.10 The PINK PLUS™ education advantage also includes a full explanation of risks and benefits of various screening tools, and particularly, of colonoscopy over fecal immunochemical testing (FIT) screening¹⁸ or flexible sigmoidoscopy. Colonoscopy enables visualization of the entire colon, and unlike screening tests for other women’s cancers (breast, cervical), is both diagnostic and therapeutic. Precancerous polyps can be removed and prevent the progression to malignancy.¹

PINK PLUS™ enables physicians to focus on the specific needs of women that relate to CRC screening, addressing the potential for different risk factors and presentations in women than in men. Adenomas and CRC in the proximal colon are more common in women, especially African American women under age 40,¹⁹ or those who are post-cholecystectomy.¹¹ Women are also more likely to have flat (sessile serrated) polyps with advanced pathology and cancer,¹³ which also have a predilection for the proximal colon. Smoking is a significant risk for colorectal adenomas and CRC for both men and women, but recent studies show that female smokers are more susceptible than male smokers in developing sessile serrated polyps and proximal CRC, as well as an earlier age of onset and death from CRC.¹³ Upon learning about the several factors that increase the likelihood of proximal colon neoplasia, women understand why colonoscopy is the most optimal screening tool because it enables visualization of the entire colon.

PINK PLUS™ can also eliminate obstacles that may reduce screening rates for some patients. A recent decline in incidence and mortality from CRC that has been noted in white patients has not been paralleled in minority communities. CRC incidence rates are about 20% higher in blacks than in non-Hispanic whites and death rates are 40% higher, according to data from 2009-2013.³Age appropriate Hispanics are less likely to undergo CRC screening (45%) than non-Hispanic whites (61%), as reported in a study from 2013.²⁰ Racial and ethnic disparities in CRC result from several factors including differences in socioeconomic status and levels of education, differences in behavior that increase risk (smoking, obesity) and underuse of screening.^7,19,21 Obstacles to screening include lack of health insurance and health care, language barriers and lack of physician recommendation.^6,7,21

Since the ACS recommends mammography at age 45 with the option to begin at age 40, PINK PLUS™ is an ideal program to identify at-risk patients and facilitate earlier CRC screening when needed. This would include patients with a family history of CRC or colon polyps, inherited CRC syndromes, or those with a personal history of inflammatory bowel disease. In addition, CRC incidence has increased steadily in patients under age 50, from 6% in 1990 to 11% in 2013.³ Most of these cases (72%) are found in patients in their 40s. The risk for developing CRC at a younger age is particularly high for African Americans.¹⁹ In 2017, the Multi-Society Task Force of Colorectal Cancer recommended initiating CRC screening for African American patients at age 45.²² More recently, the American Cancer Society updated their guidelines by adding a qualified recommendation that all average-risk patients should begin CRC screening at age 45.²³ Should the United States Preventive Services Task Force²⁴ also change their national guidelines to begin CRC screening at age 45, PINK PLUS™ will facilitate the screening of these younger patients who are also undergoing mammography.

PINK PLUS™ offers several other advantages aimed at improving cancer screening rates. The convenience of “one-stop shopping” with daytime and evening hours appeals to women of all socioeconomic strata and education levels. One visit with multiple screenings saves costs for transportation and childcare. A face-to-face visit with the gastroenterologist and a navigator is more likely to win the trust of a patient whose cultural fears or a language barrier might otherwise obviate access to screening.

Direct-access-colonoscopy is a growing trend which eliminates an office visit prior to the procedure. With PINK PLUS™, a brief GI visit may also increase the appeal of CRC screening for those patients who are more comfortable meeting the endoscopist before examination day. PINK PLUS™ is staffed by all women health care providers which may eliminate embarrassment as a barrier. In general, data show that women are more compliant than men in utilizing health care services.²⁵ If PINK PLUS™ draws women for screenings, perhaps it will bring additional family members for preventive health services.

Our report on PINK PLUS™ has some limitations. This summary does not describe a formalized study and the cohort includes a small number of patients. Also, patients were not surveyed to learn whether the convenience of PINK PLUS™ enhanced their adherence to screenings. In addition, for those with a personal history of colon polyps, their procedures were considered surveillance and not screening examinations; however the program still facilitated a convenient follow-up plan. Lastly, for patients who did not return for colonoscopy, it would have been helpful to give each one a FIT kit so some form of screening could have been documented.

Looking to the future, we see PINK PLUS™ playing an important role in addressing shifting U.S. demographics. By the year 2050, more women will be heads of households, living under the poverty level, and facing food insecurity and lack of adequate health care.¹³ Rates of CRC are predicted to increase among women, and CRC screening efforts should reflect and address their specific needs. Gender differences in location of CRC in women, along with racial and socioeconomic disparities, should be considered in future strategies for screening, prevention and treatment protocols.

To learn more about the effectiveness of PINK PLUS™ for improving screening rates for women’s cancers, particularly CRC, we plan to conduct a prospective, randomized study with a large primary care group with a diverse population. Based on our findings to date, we believe that the program can have a positive impact on screening rates by increasing convenience, accessibility and education. With the success at our institution, PINK PLUS™ could serve as a national template for other health care institutions with the same goals.

Dispatches From The Guild Conference, Series #16

Advances in Barrett’s Esophagus

Alina Wong,

Seth A. Gross

Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma making evaluation for Barrett’s esophagus of utmost importance. Currently screening and surveillance are accomplished with regular white light endoscopy; however, new advances in both population screening and surveillance are being developed. This review will cover selecting the appropriate patient population for Barrett’s esophagus screening, available and upcoming technologies for screening and surveillance, and lastly treatment of Barrett’s esophagus.

Esophageal adenocarcinoma is increasing in frequency in the United States. Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma making evaluation for Barrett’s esophagus of utmost importance. Currently screening and surveillance are accomplished with regular white light endoscopy; however, new advances in both population screening and surveillance are being developed. This review will cover selecting the appropriate patient population for Barrett’s esophagus screening, available and upcoming technologies for screening and surveillance, and lastly treatment of Barrett’s esophagus.

Alina Wong, MD¹ Seth A. Gross, MD² ¹Division of Gastroenterology, University of Washington, Seattle, WA ²Department of Gastroenterology, New York University Langone Medical Center, New York, NY

BACKGROUND

Esophageal cancer is increasing in frequency and is the sixth leading cause of cancer death in the world.^1,2 While squamous cell carcinoma is more common in the developing world, adenocarcinoma is more common in the United States. Esophageal adenocarcinoma carries a poor prognosis, making it imperative to diagnose it early. The strongest risk factor for esophageal adenocarcinoma is Barrett’s esophagus, which increases the risk of esophageal adenocarcinoma 30-50 fold.^3,4

Barrett’s esophagus is defined as the replacement of squamous epithelium by intestinal epithelium. Diagnosis requires endoscopic evidence of columnar mucosa in the esophagus with histologic confirmation of intestinal metaplasia with goblet cells. The Prague classification system is used to systematically describe a segment of Barrett’s esophagus. The classification system assesses the circumferential and maximal extent of an endoscopically visualized Barrett’s esophagus segment to help facilitate diagnosis and treatment.⁵ Barrett’s esophagus has been divided into long segment (≥3 cm in length), short segment (< 3 cm in length), and very short segment (< 1 cm in length).^5,6 Increasing length of Barrett’s segment is associated with increased risk of dysplasia.⁷

Very short segment Barrett’s esophagus remains controversial as the most recent guidelines from the American College of Gastroenterology (ACG) and British Society of Gastroenterology require at least 1 cm of columnar mucosa for the diagnosis of Barrett’s esophagus, while the American Gastroenterological Association does not have a similar restriction.^6,8 This controversy stems from previous studies showing that very short segment Barrett’s esophagus, otherwise known as an irregular Z line, does not have the same association with high-grade dysplasia or adenocarcinoma.⁹ A recently published paper performed a prospective, multicenter cohort study of patients who underwent endoscopic examination for Barrett’s esophagus in the United States and Europe and found that none of the patients with irregular Z line developed high-grade dysplasia or esophageal adenocarcinoma within a median follow-up period of 4.8 years.¹⁰

Risk factors for Barrett’s esophagus include age over 50, male sex, chronic reflux disease, white ethnicity, smoking, and obesity.^11,12 Roughly 5-15% of patient with chronic gastroesophageal reflux disease have Barrett’s esophagus.¹³

Screening

Despite retrospective studies showing that adenocarcinomas diagnosed in screening programs tend to be earlier stage, screening for Barrett’s esophagus remains controversial. The main questions revolve around whom to screen, as symptomatic gastroesophageal reflux disease remains a poor predictor of Barrett’s esophagus on endoscopy. The most recent guidelines by the ACG published in 2016 recommend screening for Barrett’s esophagus be considered in men with chronic (>5 years) and/or frequent (weekly or more) symptoms of gastroesophageal reflux and two or more risk factors for Barrett’s esophagus including age >50, Caucasian race, presence of central obesity, history of smoking, or a family history of Barrett’s or esophageal adenocarcinoma.⁶

Conventional endoscopy remains the gold standard for screening for Barrett’s esophagus. This involves using standard white light endoscopy with collection of biopsy specimens from any suspicious lesions as well as random four quadrant biopsies of endoscopically visible columnar tissue. The examination should be conducted carefully with a high-definition endoscope. Longer Barrett’s inspection time significantly increases high-grade dysplasia and adenocarcinoma detection rates.¹⁴ Special attention needs to be paid to the right hemisphere of the Barrett’s segment as early adenocarcinomas have a predilection to develop in this area.¹⁵ If initial endoscopy does not show Barrett’s esophagus, society guidelines do not recommend repeating future endoscopies.⁶

Given the costs and specialist expertise associated with upper endoscopy, investigators have studied other techniques for Barrett’s detection. Transnasal endoscopy involves using a smaller caliber endoscope that is inserted nasally without the need for sedation. It has been shown to have similar efficacy compared to standard endoscopy.16 Non-endoscopic techniques have also been developed. The cytosponge is a gelatin-coated sponge attached to a string that is swallowed and collects cytology specimens when withdrawn. Cells are retrieved from the cytosponge and analyzed for expression of markers specific to Barrett’s esophagus. Trefoil factor 3 is a marker that distinguishes the columnar cells in Barrett’s esophagus cells from columnar cells in the rest of the gastrointestinal and upper airway tracts. Studies with cytosponge have shown 73% to 90% sensitivity for detecting Barrett’s esophagus, however, the diagnostic accuracy is still being determined.^17,18

Biomarkers have been investigated extensively and the most promising of these include P53, copy number alterations and methylation panels. However, as of now no single biomarker is adequate for risk stratification. Though, when coupled with the cytosponge, biomarkers could potentially provide a cost-effective method for community based screening for Barrett’s esophagus by risk stratifying patient’s risk of progression to dysplasia and adenocarcinoma. The recently done BEST2 multicenter cohort study showed that the Cytosponge could be coupled with biomarkers (P53, c-Myc, Aurora kinase A, and methylation markers) to identify a cohort of patients at low risk of progression of Barrett’s esophagus who may be suitable for non-endoscopic follow-up.¹⁹ However, more studies are needed, especially randomized control trials to address accuracy and long-term follow-up. A new screening technique under development for the identification of Barrett’s esophagus is breath testing. Breath testing uses an electronic nose device to measure subtle volatile organic compounds (VOC). A group from Mayo Clinic performed a cross-sectional study and evaluated the breath VOCs of a cohort of patients with a history of dysplastic

Barrett’s esophagus for the presence or absence of Barrett’s esophagus.²⁰ They were able to detect Barrett’s esophagus with 82% sensitivity and 80% sensitivity. More data will be needed on testing healthy subjects, but if successful may potentially become an important non-invasive community screening technique for Barrett’s esophagus.

Surveillance

Early detection of esophageal adenocarcinoma improves survival. Several studies have demonstrated that adenocarcinomas detected in surveillance programs are detected in earlier stages thus suggesting a potential improvement in survival.^21,22 While there is no prospective data proving this concept, a large population based cohort study found that patients with adenocarcinoma who had undergone endoscopic surveillance had increased survival compared to patients who had not undergone surveillance.²³

Surveillance is aimed at detecting dysplasia, which can be categorized as indeterminate, low-grade, high-grade, or adenocarcinoma. The degree of dysplasia dictates recommended surveillance intervals. Similar to screening, surveillance endoscopy is accomplished with high definition white light endoscopy. According to the Seattle protocol, random four quadrant biopsies are taken every 2 cm.²⁴ However, adherence to the Seattle protocol in the community is low and non-adherence is associated with decreased dysplasia detection.²⁵ The Seattle protocol is also time-intensive, labor-intensive, expensive and fraught with sampling error. Subsequently, new imaging techniques for Barrett’s surveillance have been developed.

Advanced imaging modalities include narrow band imaging (NBI), chromoendoscopy with acetic acid, and confocal laser endoscopy (CLE). NBI allows for enhanced visualization of subtle mucosal and vascular changes thus allowing for targeted biopsies. Using the Barrett’s international NBI group (BING) criteria, a newly validated NBI classification system, NBI can identify dysplasia in patients with Barrett’s esophagus with 80% sensitivity and 88% specificity.²⁶ Chromoendoscopy uses dye to highlight irregular areas for biopsy. CLE provides up to 1000-fold magnification of the esophageal mucosa as well as real-time histologic evaluation of esophageal mucosa.

The American Society of Gastroenterology (ASGE) created the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) initiative to establish diagnostic and therapeutic thresholds for endoscopic technologies. The committee established that imaging technology for targeted biopsy should have a per-patient sensitivity of ≥90%, a negative predictive value of ≥98% for the detection of high-grade dysplasia and/or esophageal adenocarcinoma, and a specificity of 80% compared to the gold standard. Only NBI, acetic acid chromoendoscopy and CLE currently meet these criteria.²⁷ However, most of the studies examined in the meta-analysis were performed by experts at referral centers. Since community centers have not been adequately studied, the PIVI guidelines only recommend the use of advanced imaging techniques by endoscopists proficient in these modalities.

Wide-area transepithelial sampling (WATS) is a new brush sampling technique that can provide extensive as well as full thickness sampling results. Analysis is complemented by a computer scan that identifies potentially abnormal cells. A recent multicenter, prospective randomized trial showed that the use of WATS in addition to standard four quadrant biopsies increased the detection of high-grade dysplasia and esophageal adenocarcinoma compared to biopsy sampling alone.²⁸ However, this modality adds extra time to an already time intensive procedure. It has also not been studied with other advanced imaging techniques or in the community setting.

Treatment

Proton pump inhibitors (PPI) remain the mainstay of medical treatment even in patients without reflux symptoms. A meta-analysis in patients with Barrett’s esophagus showed a 71% decrease in the risk of progression to esophageal adenocarcinoma and/or high-grade dysplasia. This effect was seen independent of the presence of erosive esophagitis.²⁹

Endoscopic treatment for Barrett’s esophagus depends on confirmation of dysplasia on biopsy samples. This is in itself controversial as there is significant inter-observer variability between pathologists in the interpretation of dysplasia. Current guidelines subsequently recommend the confirmation of dysplasia by a second experienced pathologist.⁶

Per recent society guidelines, flat mucosal non-dysplastic Barrett’s lesions should have repeat endoscopic surveillance in 3-5 years. Indefinite lesions should be optimized with PPI therapy and have repeat endoscopy in one year. Low-grade or high-grade dysplasia in both flat and nodular lesions merits endoscopic ablative therapy.⁶ Treatment of low-grade dysplasia with ablative endoscopic therapy was once disputed. However, recent data shows that presence of low-grade dysplasia along with Barrett segment length, and nodularity were independent predictors for progression to high-grade dysplasia and adenocarcinoma.⁷ Furthermore, other studies demonstrate that ablative therapy for low-grade dysplasia significantly reduces progression to high-grade dysplasia and adenocarcinoma.³⁰ Endoscopic treatment for low-grade dysplasia has now become commonplace.

CONCLUSION

Barrett’s esophagus is highly prevalent among the United States population. It is an established risk factor for esophageal adenocarcinoma and follows a direct sequence from metaplasia, to low-grade dysplasia, to high grade-dysplasia, and eventually adenocarcinoma. Given esophageal cancer’s poor survival rate and association with Barrett’s esophagus, screening and surveillance are important. This is currently an exciting field with advances in population screening and surveillance technology. However, risk of progression to adenocarcinoma will have to be balanced with cost-effectiveness and patient tolerability as we continue to explore new technology.

Frontiers In Endoscopy, Series #45

Endoscopic Management of Zenker’s Diverticulum

Bilal Aslam,

Moamen Gabr

Zenker’s diverticulum (ZD) is a pharyngeoesophageal pulsion diverticulum which presents in the elderly and contributes to morbidity due to dysphagia and pulmonary aspiration. Open surgery and rigid endoscopy have previously been the primary modalities for therapy, however with a favorable safety profile and similar success rates, flexible endoscopy has become an emerging therapeutic modality in the treatment of ZD. This review seeks to highlight endoscopic techniques and tools in the management of ZD.

INTRODUCTION

Zenker’s diverticulum (ZD), first reported by Ludlow in 1769,¹ is a pharyngeoesophageal pouch characterized by posterior herniation through Killian’s triangle or Killian dehiscence, anatomically located superior to the cricopharyngeus muscle and inferior to the inferior pharyngeal constrictor muscle (Figure 1). After a detailed case series of pulsion diverticula was published in 1867 by Friedrich Zenker, the entity was eponymized.² An uncommon entity with a reported prevalence of 0.01%-0.11%,³ ZD often presents in the seventh to eighth decade, with a male predominance.⁴

Although the mechanism of development is not entirely clear, diminished upper esophageal sphincter (UES) opening leading to increased intraluminal pressures and subsequent tissue migration through an anatomic defect has been suggested;⁵ structural abnormalities of the cricopharyngeus muscle have been implicated as an explanation for the diminished UES relaxation and increased bolus flow pressure.⁶ Reported to have an association with GERD,⁷ also of unclear mechanism, acid-induced muscle shortening has been proposed as a unifying hypothesis linking the two conditions.⁸

Presentation includes, but is not limited to, dysphagia, post-prandial emesis, regurgitation of food, retention of food and other contents within diverticular space, halitosis, cough, weight loss, malnutrition and pulmonary aspiration. Dysphagia in patients suffering from ZD can manifest as malnutrition⁹ reported in 54% of patients in one series. ZD has been associated with the retention of video capsule and subsequent endoscopic retrieval.^10-12 There are also case reports of ZD complicated by the presence of carcinoma within the diverticulum,^13-17 however this is exceedingly rare.

The most common modality for diagnosis is a barium-contrasted study (i.e. barium esophagram/barium swallow, videoflouroscopy/modified barium swallow) (Figure 2), with outpouching most prominently characterized on lateral projections;18 there is also a role for cross-sectional imaging and endoscopy. There are limited reports of characterizing ZD on ultrasound,^19-22 however this has no role in initial diagnostic workup. Validated scoring tools for the assessment of dysphagia (SWAL-QOL, Dakkak-Bennet) have been reported and used for evaluating pre and post intervention status.^23,24

The mainstay of treatment was previously open surgical correction and endoscopic management with rigid endoscope, but advances in flexible endoscopic tools and techniques have brought flexible endoscopic management to the forefront over the past two decades. This review seeks to highlight endoscopic techniques and tools in the management of ZD.

Management

Although there are no specific guidelines for treatment, intervention should be reserved for symptomatic patients only. The current treatment modalities are open surgery (including diverticulectomy, diverticulopexy, diverticular inversion, myotomy), rigid endoscopy (electrocautery, CO2 laser, stapler, Harmonic scalpel) and flexible endoscopy. As previously reported, the rate of successful management of ZD is comparable between the three established modalities, however adverse effects including mortality are significantly lower in the flexible endoscopic approach.²⁵ Rigid endoscopy and flexible endoscopy share similar outcome profiles, but flexible endoscopy does not require general anesthesia or neck hyperextension.

The first flexible endoscopic therapy for ZD was reported in 1995.²⁶ The mainstay of therapy has focused on the division of the cricopharyngeal muscle through an endoscopic myotomy resulting in obliteration of the diverticular cavity and improvement of dysphagia; with many accessories (APC, bipolar forceps, clutch cutter, hood, hook knife, needle knife, stag beetle knife, transparent cap) and new techniques (Z-POEM) at endoscopists’ disposal, flexible endoscopic approaches are numerous and effective for treatment of ZD.

Flexible Endoscopic Septum Division:

Flexible endoscopic septum division (FESD) (Figure 3) is the incision of the mucosal layer and myotomy, partial or complete, of the cricopharyngeal muscle resulting in septum division. In a recent meta-analysis²⁷ FESD reported overall good outcomes with pooled success of 91%, pooled adverse event (AE) rate of 11.3% and pooled recurrence rate of 11%. As there is no standardization to FESD, there is wide heterogeneity among studies and numerous approaches to septum division. Most endoscopic approaches to FESD are multi-modal with combination of accessories or techniques employed. The blind pouch of the diverticulum increases perforation risk, as it can be confused for the esophageal lumen, most often highlighted during endoscopic retrograde cholangiopancreatography (ERCP).²⁸

The introduction of transparent caps or soft rubber duck-billed diverticuloscope (Cook Medical, Winston-Salem, NC) has improved visualization and endoscopic outcomes.²⁹ The diverticuloscope and cap devices allow for improved visualization, through exposure and fixation of the septum, and aiding in the separation of fibers with gentle spreading pressure. When compared to caps, diverticuloscope use is associated with fewer AE, decreased procedure time, and superior symptom remission,²⁹ however the overtube system unfortunately is not currently approved by the United States Food and Drug Administration, and its use is reported only in case series from Canada and Europe.

Widely reported,30-34 the use of a Savary guide wire with nasogastric (NG) tube placement delineates the esophagus from ZD orifice and protects the anterior wall of the septum during myotomy. There is also reported variation across the literature regarding the use of closure clips at the end of the procedure and antibiotics given prior to and after endoscopic treatment.

Post-intervention care lacks a standardized approach but primarily consists of hospital observation, soft diet, and barium contrasted studies to evaluate for perforation.30,32,34,35 Rates of AE (perforation/cervical emphysema, hemorrhage) vary with FESD, however overall remain relatively low,27 and are predominantly managed with a conservative approach. There are varying rates of symptom recurrence, with most being amenable to repeat FESD having reasonable outcomes.

Septum Division Techniques
Needle Knife

Ishioka et al. reported the first FESD in 1995; intervention was carried out with Needle-Knife (NK) and noted improvement in all patients within the series (N=23).³⁰ Subsequent studies^{29,31,32,34-37} detailed effectiveness of NK in the endoscopic management of ZD. Costamagna et al. evaluated prognostic variables for FESD success and reported on short and long-term success (6 and 48 months respectively) having a correlation with septotomy length and size of ZD.³⁸ The criticism of NK approach is the concern for perforation risk. Hesitancy to extend septotomy length due to lack of direct visualization may contribute to recurrence rates.

Hook Knife

The Hook Knife (Olympus Corporation, Center Valley, PA,USA) first reported by Recipe at al.,³⁹ showed clinical efficacy in septal myotomy; this finding has been reproduced in subsequent studies33,34,40-43 and clinical trends appear to favor Hook Knife as the preferred endoscopic tool for FESD. The inherent advantage of the Hook Knife is that the upward pulling of muscle fibers prior to obliteration minimizes perforation risk at time of intervention.

Thermal Therapy

Mulder et al. first reported on a pilot study in which Argon Plasma Coagulation (APC) was used to perform FESD with symptom improvement and no AE;26 similar results are reported with varying reports of perforation which is the concern with the modality.^{26, 44-46}

Submucosal Tunneling
Endoscopic Septum Division

Submucosal tunneling endoscopic septic division (STESD/Z-POEM) (Figure 4) is a novel endoscopic technique in the management of ZD first reported by Li et al.47 Z-POEM was created utilizing techniques from peroral endoscopic myotomy (POEM) to decrease the risk of perforation encountered during FESD, which is reported in as high as 6.5% of patients.²⁷ The approach to Z-POEM consists of the following four steps: mucosal incision (consisting of submucosal injection 3cm proximal to diverticular septum and 1-2cm longitudinal mucosal incision to create tunnel entry), submucosal tunneling (either to the end of the diverticulum or 1-2cm distal), septum division (septal myotomy) and mucosal closure (through the scope clips). Reports from small case series reveal that Z-POEM shows good success with return to normal anatomy, lack of perforation and symptom resolution on follow-up.^47-49 The limited data and the expertise required to perform POEM limit Z-POEM as a widespread therapeutic modality.

Novel Modalities

FESD with the Clutch Cutter (Fujifilm, Tokyo, Japan) has shown promise when used with or without a clear cap; to our knowledge there are only two case reports,^50,51 both reporting success. The device, originally intended for endoscopic submucosal dissection (ESD), and is not approved by the FDA.

The Stag beetle knife (SB-knife; Sumitomo Bakelite, Tokyo, Japan) was first reported in the use of diverticuloplasty in 2013.52 Initially intended for ESD, SB-knife has shown good outcomes in a small series and case reports.53-56 with the concomitant use of an overtube. Myotomy was performed in midline fashion except for Battaglia and Golder who provided a novel approach by creating two lateral dissections and using a monopolar snare to complete myotomy. Despite current reported success, further prospective trials are needed to determine long-term efficacy and recurrence rates.

DISCUSSION

The advancement of endoscopic tools, with similar efficacy and decreased risk of AE as compared to prior accepted modalities of surgery and rigid endoscopy, are increasingly making endoscopic therapy the “first line” approach to ZD management. The introduction of the diverticuloscope has allowed for better outcomes in European case series,38 owing to greater stabilization of the endoscopic field and improved visualization during septum division. In the United States, a transparent cap serves a similar purpose. Emerging tools such as the SB-knife and Clutch Cutter are likely to yield improved outcomes as they allow for grasping and thermal therapy, limiting perforation risk. New endoscopic approaches such Z-POEM appear promising but are limited by endoscopic skill required and lack of data. It is clear that there needs to be highly scrutinized prospective data comparing flexible endoscopy and its wide armament of tools against rigid endoscopic approaches.

Nutrition Issues In Gastroenterology, Series #179

Pragmatic Management of Nutrition in Severe Acute Pancreatitis

Dushant Uppal

Severe acute pancreatitis (SAP) is a clinically debilitating condition with significant morbidity and mortality that requires attention to optimal supportive management. In this article we discuss nutrition management options, which are critical to supportive management, with appropriate route and timing of nutritional support paramount to optimal outcomes.

Severe acute pancreatitis (SAP) is a form of acute pancreatitis (AP) with significant morbidity and mortality. Nutrition is critical to supportive management, with appropriate route and timing of nutritional support paramount to optimal outcomes. Previous paradigms of maintaining patients (NPO) while utilizing parenteral nutrition (PN) have evolved. Enteral nutrition (EN) is now gener?ally preferred, with PN being utilized only in select situations. Additionally, data support the use of early initiation of EN, within 48 hours of admission, to reduce gut barrier dysfunction and infectious complications. While limited data suggest that gastric EN may be pragmatic and non-inferior to jejunal EN, caution is recommended if using gastric EN. Finally, while it is reasonable to trial oral nutrition in patients experiencing a less protracted course with improved pain and hunger, long term EN is recommended in those patients expected to have a prolonged need for nutrition support.

Dushant Uppal, MD, MSc, Assistant Professor of Medicine, Division of Gastroenterology & Hepatology, University of Virginia, Charlottesville, VA

INTRODUCTION

Acute pancreatitis (AP) is an inflammatory condition of the pancreas ranging in severity from mild to severe and contributing to significant burden/cost to the healthcare system. In 2012, AP accounted for approximately 280,000 hospital admissions in the USA, with a median length of stay (LOS) of 4 days and a total cost to the healthcare system of $2.6 billion.¹ Management predominantly involves supportive care with IV fluids and pain control in the acute setting. The severity of AP, as defined by the revised Atlanta criteria, may be classified as mild, moderate, and severe. Severe acute pancreatitis (SAP) occurs in approximately 15-20% of patients with AP and is defined by the presence of persistent organ failure (>48 hours).² A further 20% of patients with SAP may have necrotizing pancreatitis, defined as focal areas of non-viable pancreatic parenchyma >3cm in size or >30% of the pancreas.² Predicting the severity of AP is critical to optimizing management strategies including timing and type of nutrition. While scoring systems may be cumbersome, simple clinical and lab parameters may provide ample distinction between predicted mild AP and SAP at the time of presentation. In particular, persistent (>48 hours) systemic inflammatory response syndrome (SIRS), defined by two or more of the following four criteria: (1) temperature < 36°C (96.8 °F) or >38°C (100.4 °F), (2) heart rate >90/min, (3) respiratory rate >20/min, and (4) white blood cells (<4 x 109/L (<4 K/mm3), >12 x 109(>12 K/mm3) or 10% bands, is predictive of SAP.3 This distinction permits optimization of management and support in SAP including the delivery of nutrition support. Nutrition is a critical element of supportive care as it is thought to diminish:

1. damage to gut barrier with resultant increasing intestinal permeability and initiation of SIRS, sepsis and associated infected necrosis
2. translocation of bacteria/toxins which is considered the main cause for superinfection/SIRS
3. pancreatic inflammation predisposing to gastric stasis/abdominal distension²

Certainly, keeping a patient with SAP ‘nil per os’ (NPO) may be appropriate at presentation if they are intolerant or incapable of eating. However, fear of worsening inflammation and/or infection in SAP with eating based on the physiologic understanding that gastric accommodation and delivery of partially digested proteins and fats lead to pancreatic stimulation, has pervaded nutrition management in AP. This led to the long-held belief that keeping patients NPO for prolonged periods, while providing parenteral nutrition (PN), was optimal. The paradigm has evolved with literature now demonstrating improved outcomes in patients with SAP being trialed on oral nutrition or receiving enteral nutrition (EN) compared with PN. Furthermore, recent data and critical assessments of the literature have shed more light on the optimal route and timing of EN in patients with SAP. Certainly, the merits of each nutrition modality should be considered in specific clinical scenarios to optimize patient outcomes (Table 1).

Parenteral Nutrition (PN) vs Enteral Nutrition (EN)

The belief that keeping a patient NPO and utilizing PN would lead to optimal outcomes was germane to management of AP for years. However, data from a number of studies have refuted this notion, demonstrating that outcomes with PN tend to be worse.4-9 In particular, patients with AP who are placed on PN may experience more hyperglycemia and suffer increased line related infections or other infectious complications.²

Additionally, it has been demonstrated that gut mass and barrier function may be improved in patients with SAP who are enterally fed compared with those patients kept NPO and/or placed on PN.2,10 This altered physiology has been postulated to be responsible for increased systemic infections, organ dysfunction, increased need for surgical intervention, hospital LOS and mortality.^4-9

A Cochrane review of 8 trials with a total of 348 patients with AP demonstrated a reduction in death, MOF, systemic infection, need for operative intervention and hospital LOS for patients receiving EN compared to those receiving PN.⁹ Furthermore, a subgroup analysis of patients with SAP receiving EN had a lower risk of death and MOF compared with those patients on PN. This improvement in major complications and death was corroborated in a subsequent meta-analysis of 8 RCTs including 381 patients comparing PN to EN in patients with SAP.⁸ Thus the data to date support the notion that EN should be favored over PN as it leads to improved outcomes in patients with SAP.

Although PN use in patients with AP, including SAP, is not advised as the initial form of nutrition support, there are certain conditions where it may be indicated. For instance, in the rare instances of mechanical bowel obstruction or bowel perforation, EN would be ill advised and PN preferred, or when adequate nutrition intake cannot be met by EN and/or po intake. Additionally, in patients with lymphatic disruption and chylous ascites not responding to a fat free or fat restricted diet or elemental EN, transient PN may be indicated.^11,12

EN vs Oral Nutrition

While the data demonstrating the benefit of EN over PN is robust, data regarding EN vs oral nutrition in SAP is somewhat limited and incongruent. Although some studies have demonstrated improved gut mass and barrier function in patients receiving EN over PN, another study by Powell et al.,¹³ demonstrated no difference in inflammatory markers, interleukin 6, soluble tumor necrosis factor receptor1 and C-reactive protein between patients with SAP who were fed by mouth and those receiving EN. Several additional studies comparing oral nutrition vs EN in patients with AP found no statistical significance in complications between the two groups.^14,15 The study by Stimac et al.,¹⁵ demonstrated a RR reduction in death and MOF in pts on EN vs ‘nil by mouth’ (NBM), but these did not meet statistical significance. However, the NBM group received more IVF early and during the remaining hospital course and oral nutrition was introduced to both groups variably, but as early as 3 days. It is thus unclear if longer duration of EN could have resulted in statistically significant reductions in risk of mortality, MOF, and infectious complications. Furthermore, all patients received prophylactic antibiotics for 10 days, a practice that is no longer recommended and could have contributed to similar outcomes between both groups.

The Python trial,¹⁴ compared early EN within 24 hours of admission with oral diet after 72 hours in patients with AP at high risk for complications. Two hundred eight patients at 19 centers were randomized with a primary composite end point of major infection or death. The primary end-point occurred in 30% of the early EN group vs 27% of the on demand group leading the authors to conclude that there was no superiority of early nasoenteric feeding compared with oral feeding after 72 hours. However, caution is advised in extrapolating the results of this study to clinical practice for those patients with proven SAP due to several limitations. A substantial proportion (one third) of patients did not meet initial criteria for SAP at the time of enrollment into the trial, nor did the study identify differences in outcomes among those patients with true SAP following initial resuscitation. Additionally, the transition to oral nutrition occurred for both groups during their hospital course (full oral tolerance at 9 days for EN group vs 6 days for on demand group), yet the primary outcome compared 6-month mortality and major infections without additional assessment of symptoms and oral feeding tolerance in the interim. Further, the results from the intention to treat (ITT) analysis, as it pertains to those patients with true SAP, may be misleading as a large proportion of the on-demand group received EN (31%), yet were included in the analysis as patients in the on-demand arm instead of the early EN arm. Thus, it remains possible that longer duration EN, through and beyond the primary hospitalization, may result in improved morbidity and mortality in patients with SAP.

The paucity of data and these disparate data should lead practitioners to act cautiously when introducing oral diet for patients with SAP. Nevertheless, in those patients with a more benign clinical course who improve rapidly, a trial of po intake is appropriate. At our institution, EN is often used preferentially in those patients with severe necrotizing pancreatitis and infection, or at the first signs of intolerance in those patients with SAP cautiously initiated on oral nutrition.

Type of EN

With respect to types of enteral formulations, elemental or polymeric products may be used as there are no data to support the superiority of one over the other.^16,17 Alhough some studies have demonstrated pancreatic exocrine insufficiency, based on fecal elastase and quantitative fecal fat testing, to be a variably common occurrence (13%-87%) following SAP, paricularly alcohol related and/or necrotizing pancreatitis,^18-21 other studies have demonstrated likely recovery of exocrine function, particularly in those patients not requiring pancreatic debridement or drainage.^22-24 Our institutional practice is to first employ polymeric EN as it has been well tolerated and less costly. If steatorrhea develops or persists, and there does not appear to be sufficient pancreatic damage suspected, we then undertake an evaluation for clostridium difficile infection. In our experience, if infective colitis is ruled out, patients generally will accommodate well to polymeric feeds as the acute decrement in exocrine function experienced with SAP resolves. However, should steatorrhea or weight loss persist to suggest more semi-acute or chronic exocrine insufficiency, or there is significant pancreatic necrosis on imaging, then transition to semi-elemental or full elemental EN, or the addition of pancreatic enzymes, may be considered. In these scenarios, fecal elastase may help to guide changes in EN formulation in those patients suspected as having pancreatic insufficiency, so long as the patient is not experiencing diarrheal stools, which could dilute fecal elastase, leading to a false positive result.

Timing of EN

The benefit of EN on morbidity and mortality in SAP is supported by the literature with additional data demonstrating improved outcomes with early initiation of EN.

A retrospective review of 197 patients with predicted SAP compared patients receiving early EN, within 48 hours of admission to those receiving delayed EN, after 48 hours and demonstrated reduced mortality, development of infected necrosis, respiratory failure, and need for ICU admission in the early EN group.²⁵ However, the study results must be considered carefully, given the study’s retrospective nature, as bias may have existed with respect to the allotment of each type of therapy for the included patients. For instance, the delayed group had a trend towards greater use of PN. Taken together, the increased need for ICU admission and PN use in the delayed group may be reflective of a more critical course that resulted in delayed initiation of EN and resultant increased morbidity/mortality.

Nevertheless, subsequent studies have demonstrated improved outcomes with early initiation of EN.^7,13,25-31 A Cochrane review of 11 RCTs by Petrov et al.,³² demonstrated improved outcomes with respect to MOF, pancreatic infectious complications, and mortality in those patients with AP receiving EN within 48 hours of admission compared with those receiving PN. The improved outcomes are postulated to be due to improved immune function with early initiation of nutrition support. This improvement in immune function was evidenced by Sun et al.,²⁹ who showed that compared with delayed EN, those patients receiving early EN experienced lower levels of cytotoxic CD4+ T lymphocytes and CRP in addition to reduced MOF, SIRS, pancreatic infection, and ICU LOS. Thus, the available data support the initiation of EN in patients with SAP within 48 hours, if clinically feasible.

Gastric Nutrition vs Jejunal Nutrition

While EN in SAP is clearly of benefit, literature regarding route of enteral support is somewhat disparate. As discussed earlier, studies comparing PN with EN demonstrate reduced mortality and morbidity in patients with SAP receiving EN. Most of these early studies utilized jejunal feeding. However, given the sometimes cumbersome nature of jejunal feeding tube placement, more recent studies have attempted to elucidate the difference in outcomes between patients with SAP receiving nasogastric tube (NGT) vs nasojejunal tube (NJT) feedings. In a clinical feasibility study conducted by Eatock et al.,³³ 22 out of 26 patients with SAP receiving NGT feeds within 48 hours of admission tolerated the feedings well without evidence of clinical or biochemical deterioration. A subsequent RCT of early NGT vs NJT feeding in SAP, conducted by the same group, found no statistically significant difference in inflammatory markers or pain scores between the groups.³⁴ However, they did not objectively evaluate long-term outcomes or differences among patients with necrosis. Subsequently, a RCT by Kumar et al.,³⁵ comparing NJT to NGT feedings in patients with SAP found no difference in LOS, need for surgical intervention, or death. However, time to initiate EN was up to one month after presentation with SAP, and both groups only received low EN infusion rates. Furthermore, long-term outcomes were not compared. Additionally, the authors concluded that EN was tolerated in both groups. However, if the EN rate had been optimized to meet true nutritional requirements and volumes, a difference in tolerance may have been appreciated. These two studies and a third RCT, comprising a total of 157 patients, comparing NGT vs NJT feeding in SAP were used to conduct a meta-analysis.³⁶ The authors of the study reported no significant differences between groups receiving NGT feeds vs NJT feeds in their RR of mortality, diarrhea, exacerbation of pain, and meeting energy balance, leading them to conclude that NGT feeding was not inferior to NJT feeding in patients with predicted SAP. However, the authors also cautioned that the results of the study would require larger RCTs as their evaluation was not adequately powered. Moreover, the meta-analysis was limited by the small and heterogeneous trials included, non-blinding, delay in patients being initiated on EN in the two studies from India, and the lack of confirmation of NJT positioning. Although the available data suggest that NGT feeding may be non-inferior and that NGT placement may be more pragmatic given the potential difficulties in NJT placement, the data are not robust. Furthermore, jejunal feeding in SAP may be physiologically sensible.

Data demonstrate higher secretions of trypsin and lipase in subjects who have formula delivered to the duodenum compared with those receiving jejunal feedings at least 40cm beyond the ligament of Treitz and this may potentiate further pancreatitis.³⁷ Nevertheless, if NGT feedings are pursued in SAP caution is advised and reassessment of the patient’s clinical condition and tolerance of feeding is recommended.

NJT or Percutaneous Endoscopic Gastrostomy Tube with Jejunal Extension (PEG-J)

When the decision is made to utilize EN, an empiric decision to place a NJT or transition to PEG-J must be made. In rare circumstances NJT placement may not be possible due to altered nasopharyngeal anatomy or issues with nasopharyngeal bleeding or infection. If the tube can be placed easily, NJT is generally appropriate for patients initially if transition to oral diet during the hospitalization is likely. Additionally, NJT placement may be appropriate in the setting of necrotizing pancreatitis without gastric outlet obstruction or in patients with significant malnutrition where it remains unclear if they will be able to meet oral caloric targets early, but are likely to transition to full oral diet shortly following hospitalization. However, in the setting of necrotizing pancreatitis with outlet obstruction, which may necessitate gastric venting, PEG-J placement may be more ideal. Long term NJT use out of the hospital may also not be palatable due to cosmetic concerns if the patient is planning on returning to work and cannot otherwise advance to oral diet. Finally, PEG-J may be of benefit in the setting of SAP with significant necrotizing pancreatitis necessitating repeat debridement, as the need for enteral support may be greater than 6 weeks in these circumstances. Relative contraindications to PEG-J placement may include poor window for endoscopic or radiographic placement, ascites, or bleeding diatheses (Table 2).

When to Transition to Oral Nutrition

As mentioned previously, the data regarding oral vs early EN in patients with SAP is limited and caution is advised in early re-introduction of oral diet in these patients. However, in a large majority of patients with SAP, a trial of oral nutrition tolerance prior to discharge may be reasonable, particularly as hunger returns. In a study by Zhao et al.,³⁸ no difference in adverse events or complications were identified in patients with moderate or SAP who received early oral re-feeding based on return of hunger vs those patients who received conventional oral refeeding when clinical symptoms and laboratory parameters had resolved. Of course, if oral tolerance fails due to worsening pain, infection, or inability to meet caloric needs, then EN should be introduced/resumed until clinical re-assessment with or without interval imaging can be undertaken. If the patient is well at that point, re-introduction of oral diet is reasonable. Additionally, though empiric, our institutional practice tends to favor continued EN at the time of discharge in the subgroup of SAP patients with necrotizing pancreatitis with infection or gastric outlet obstruction. In these patients, our pragmatic approach is to maintain EN until clinical reassessment is completed following hospital discharge or debridement/drainage if necessary (Figure 1). If the patient is clinically better and necrosis, if present, is stable/improved and no further intervention is anticipated, oral diet is resumed. Of course, if signs of intolerance occur earlier, interval imaging is obtained more urgently and oral diet is either transitioned back to EN or maintained based on imaging and patient parameters. When the durable tolerance of oral nutrition is demonstrated and imaging, if obtained, is encouraging, feeding tube removal is undertaken. Although this approach may be difficult, owing to the need for close patient follow up and interval imaging, it is undertaken in an effort to limit worsening clinical status of the patient and prevent premature removal of enteral access.

CONCLUSION

SAP is a clinically debilitating condition with significant morbidity and mortality that requires attention to optimal supportive management, including nutrition, for improved outcomes. The classic paradigm of maintaining a patient NPO while providing parenteral support has evolved, with PN now being recommended only in very select situations. Literature supports the early introduction of EN in SAP within 48 hours, if po challenge fails, and while the literature appears to demonstrate clinical equipoise with respect to gastric vs jejunal feeding, it is not robust and clinical management must be approached cautiously. As with other interventions, close reassessment of clinical, laboratory, and radiographic parameters once any nutritional support is initiated is paramount to improved patient outcomes. In an effort to limit cost and simplify management, ongoing assessment of oral diet tolerance is reasonable in those patients with hunger and improved pain prior to discharge. However, pragmatically, the use of long term EN in SAP patients is recommended in those with demonstrated intolerance of oral diet either due to pain, early satiety, or inability to meet caloric requirements. This may be via NJT in those patients expected to transition to oral diet within 4-6 weeks. Alternatively, patients with gastric outlet obstruction, severe necrotizing pancreatitis necessitating debridement, and those patients requiring enteral access, but unable to tolerate NJT placement, a PEG-J may be more appropriate. Ultimately, optimal patient outcomes with respect to nutrition in SAP are realized when attention to literature is married to diligent observation of the individual patient and reorienting therapy based on clinical, biochemical, and radiographic response to implemented strategies.

A Special Article

Hepatocellular Carcinoma Secondary to Chronic Hepatitis C Virus Infection in Veterans at the VA Caribbean Healthcare System – Have Surveillance Measures Been Effective?

August 2018 • Volume XLII, Issue 8

Doris H. Toro

The incidence of hepatocellular carcinoma (HCC) due to hepatitis C virus (HCV) infection has been rising worldwide as well as in the United States. Current American Association for the Study of Liver Disease (AASLD) guidelines recommend performing an abdominal ultrasound in cirrhotic patients every six months for early detection of HCC. The main objective of this study was to retrospectively evaluate a population diagnosed with HCC secondary to HCV in the Veterans Administration (VA) Caribbean Healthcare system and to determine if screening strategies were applied appropriately. Secondary aims were to describe certain patient characteristics upon diagnosis of HCC and determine the median survival time of this population. It was found that in 95.4% of the cases, the diagnosis of HCC was incidental, and not part of a surveillance strategy. More so, the median survival after diagnosis was only 10 months. These findings should help raise awareness of the importance of HCC surveillance in cirrhotic patients with or without HCV.

Sheryl Rosa, Walisbeth Class, Henry DeJesus, Doris H. Toro, VA Caribbean Healthcare System, San Juan, PR

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most feared outcomes of chronic hepatitis C virus (HCV) infection.¹ The incidence of HCC varies widely within different regions of the world and concordantly differs among different racial and ethnic groups within the same country.² This phenomenon is attributed to regional variations in exposure to the different hepatitis viruses, environmental pathogens and inheritance patterns of genetically linked liver diseases.² Although the mechanism of carcinogenesis of the Hepatitis C virus has not been elucidated, studies which have used mouse models suggest that the development of HCC in HCV arises from a rapid cellular turnover and chronic inflammation and not from oncogene activation as is seen in hepatitis B related HCC.³

Epidemiology

There is an estimated global distribution of 185 million people who currently live with chronic HCV infection.⁴ Even more so, approximately 399,000 people die each year because of HCV complications, among them being HCC.^5,6 Liver cancer is the fifth most frequently diagnosed cancer in men, while in women it is the ninth most frequently diagnosed cancer worldwide, and it is the fourth leading cause of cancer-related death in the world.^2,7 In North America, the incidence rates in 2008 for males and females were 6.8 and 2.2 per 100,000 persons, respectively. The differences in gender expression are not clearly understood, but are suspected to be secondary to hepatitis carrier states, exposure to environmental toxins, and the effects of androgens.⁸

Although North and South America are considered low incidence areas for cases of HCC, the incidence in the United States has increased during the past two decades, possibly due to a large pool of people with longstanding chronic hepatitis C.⁹ The rate began to accelerate in the mid-1980s, most likely because of the increased incidence of cirrhosis due to chronic HCV infection and nonalcoholic fatty liver disease, combined with a large influx of immigrants from East Asia and other geographic areas with high endemic rates of hepatitis B viral infection.⁹ The annual incidence of HCC in the US was at least 6 per 100,000 in 2010. Recently, the incidence of HCC among the United States veteran population had been notably rising as well, likely secondary to an increase of HCV infection among this specific population.¹⁰

Risk Factors

In addition to chronic HCV there have been many risk factors associated to developing HCC which include Hepatitis B carrier state, hereditary hemochromatosis, comorbid hepatic disease, environmental toxins and cirrhosis of any cause. The most commonly seen risk factors in the United States are HCV infection, alcohol use and nonalcoholic fatty liver disease; risk factors commonly identified in the veteran population. Risks factors for HCC development among patients with HCV-related cirrhosis can be considered as host related, virus related and of external origin.⁹ Independent risk factors associated with progression to HCC are older age (>55 years: 2- to 4-fold increased risk) and male sex (2-to 3- fold increased risk). Several comorbid conditions are thought to increase the risk of HCC among patients with HCV-related cirrhosis, including porphyria cutanea tarda (PCT), hepatic iron overload, liver steatosis and diabetes mellitus.⁹

Upon review of the 2010 HCV Veterans registry in the region of Veterans Integrated Service Network (VISN 8), to which Puerto Rico belongs, based on serologic evidence of HCV infection status (HCV positive) as well as the subset of those with VA laboratory evidence of HCV viremia, there were 21,997 patients registered with HCV from which 19,649 were HCV positive and 15,587 had HCV viremia.¹¹ Per the report from 2011, a total of 16,026 HCV viremic Veterans were registered with VHA care in VISN ⁸. During the same year in San Juan VA, a total of 1,567 patients were registered as being in care for HCV and 25 of them were first diagnosed with HCC during that year. The prevalence of HCV in veterans is about 3.7 times higher than in the general population, which could explain the many new cases of HCC arising in this population.

As a deadly entity, it is of benefit that HCC is detected early in its course, for management or even if possible, curative treatment. HCC, if untreated, has a mean survival of 1 to 3 months and a 5-year survival rate as low as 3%. For this important reason, surveillance measures guidelines for high-risk populations have been published by the American Association for the Study of Liver Disease (AASLD).¹ Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with cirrhosis. Current AASLD guidelines recommend physicians to perform an abdominal ultrasound in a screening interval of 6 months in patients with confirmed cirrhosis. It is expected that by following this strict routine sonographic surveillance of cirrhotic patients it would be possible to identify any liver lesion with malignant potential in a timely manner, and therefore treat patients at an earlier stage of disease and possibly extend these patient’s survival expectancy and improve their quality of life.¹ It is imperative for primary care physicians and for gastroenterologists to keep this recommendation in mind as part of routine screening in patients with cirrhosis secondary to HCV or any other etiology. However, it is suspected that in real life practice, these recommendations are not being followed as rigorously as expected, and in turn hepatic lesions are either found at a later stage of disease or incidentally when investigating a different disease ailment.

Objective

This study consisted of a retrospective analysis using data gathered from the medical records of Latino veterans from the VA Caribbean Healthcare System who had documented diagnoses of HCV and also HCC. The principal objective of this study was to evaluate if adequate surveillance of hepatoma by imaging was performed in these patients as recommended by AASLD guidelines. The secondary objective was to identify and describe the pertinent sociodemographic and clinical characteristics of these patients. Variables accounted for were gender, comorbid diabetes mellitus, platelet count, body mass index (BMI), coexisting risk factors for HCC development, if surveillance was done appropriately, Child Pugh score upon HCC diagnosis, model for end stage liver disease (MELD) score upon HCC diagnosis, diagnostic study used, stage of diagnosis using the BCLC staging system, treatment modalities applied, and median survival time.

Materials and Methods

This study was conducted by performing a detailed review of the electronic medical charts (CPRS system) of Latino veterans from the VA Caribbean Healthcare System with confirmed chronic HCV infection and HCC diagnosed between January 1, 2001 and May 21, 2013. These cases were identified by patient encounters coded as per ICD-9 diagnosis codes 155.0, 155.2, 230.8, V10.07, 070.44, and 070.54. Inclusion criteria were ages between 22-88, confirmed HCV with HCC, and Latino origin. Exclusion criteria were absence of HCV, ages less than 22 or over 88, and any other ethnic origin which is not Latino. Statistical analysis was performed with the Statistical Package for Social Science, IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.

Results

After a systematic review of all the medical records of patients with HCV and concomitant HCC, we identified a cohort of 131 patients who met the inclusion criteria. Details are in Table 1.

All the patients within our cohort were of male gender. The mean age at diagnosis was 62.2 years. The majority of the patients were of normal body mass index (BMI) (43.5%), but followed closely by patients with BMI compatible with pre-obesity (33.6%). When taking into account diabetes mellitus as a comorbid condition, there was not a substantial difference among those who were diabetic and the non-diabetics which were 45% and 55% respectively. In addition, a significant difference was neither found when considering platelet count with 56.5% of patients with platelet count 100,000 µL or above whereas 43.5% of patients were found with less than 100,000 µL upon diagnosis.

Liver biopsy was performed in 42% of our cohort and within that percentage, 22.9% were patients with histopathology findings reporting cirrhosis which is consistent with a Metavir score of F4. However, in 19.1% of the cases where biopsy was performed, the Metavir score was not described in the pathology report and the grade of fibrosis of the tissue was not specified. Since studies published in 2001, liver biopsy is not required for diagnosis of HCC after the establishment of specific diagnostic criteria by imaging studies which in turn avoids the risks associated to percutaneous biopsies which include bleeding and tumor spread along the needle track.¹² Of the total cohort, 39.7% had a diagnostic imaging study (either quadruple phase computed tomography (CT) or magnetic resonance imaging (MRI)) followed by a confirmatory biopsy whereas 3.2% had a biopsy performed as the sole diagnostic study. Of those diagnosed by imaging studies, 37.4% was by quadruple phase CT and 24.4% was by dynamic MRI, however some patients had both studies done upon diagnosis and therefore are accounted for in each category.

Alfa fetoprotein (AFP) is a glycoprotein considered to be the most commonly associated serum marker with the presence of HCC. Most studies agree that levels above 500 mcg/L are highly suspicious for the presence of HCC although it has also been established that not all tumors secrete AFP and up to 40% of patients with HCC may have normal AFP levels.¹³ This previously described data is validated in our study where only 13.7% of the cohort was found with AFP levels above 500 mcg/L upon diagnosis but most of the cohort (77.8%) had AFP levels less than 250 mcg/L when diagnosed with HCC.

Two predictive models of the prognosis of patients with cirrhosis are the Child Pugh classification and the Model for End Stage Liver Disease (MELD) score.¹⁴ In general terms, A Child Pugh score of A means that a patient has compensated cirrhosis, a score of B is compatible with significant functional compromise, and C signifies decompensated cirrhosis. The MELD score is used to calculate an estimated 90-day mortality in patients with cirrhosis and is a crucial factor in prioritizing patients for liver transplantation. Due to the latter, a MELD exception is given to patients with HCC who are candidates for liver transplant to prioritize those patients due to the high mortality risk of HCC.¹⁵ The MELD score accounted for in this study was without the inflation of the MELD exception points to better characterize these patients upon diagnosis. The data obtained revealed that in terms of both Child Pugh score and MELD score, the majority of that patients were diagnosed within an early stage with 59.5% of patients diagnosed while still being classified within Child Pugh A and notably as well 59.5% of patients with a MELD score less than ¹⁰.

The Barcelona-Clinic Liver Cancer (BCLC) staging system is an HCC treatment algorithm which consists of multiple variables related to HCC that include tumor stage, physical status, liver functional status, and cancer-related symptoms.¹⁶ Essentially, patients at stage 0 are candidates for resection, stage A are candidates for curative therapies, stage B patients should be referred for chemoembolization, stage C can be considered for experimental therapies, and patients with stage D should undergo palliative treatment. Within our cohort, six cases (4.6%) were diagnosed at BCLC stage 0, 59 cases (45%) at BCLC stage A, 40 cases (30.5%) at BCLC stage B, 15 cases (11.5%) at BCLC stage C, and 11 cases (8.4%) at BCLC stage D. Correspondingly, the therapeutic modalities used in these patients were: surgery in three (2.3%), TACE in 72 (55%), RFA in three (2.3%), TACE + RFA in 10 (7.6%), liver transplant in two (1.5%), Sorafenib in 49 (37.4%), palliative care in 53 (40.5%), and experimental or no treatment in 12 (9.2%). It is important to point out that 52 patients received two or more treatment modalities.

Overall, the median survival was 10 months after diagnosis. Of the 131 patients diagnosed with HCC, only six (4.6%) were identified within a routine surveillance program whereas 125 (95.4%) of the cases were diagnosed incidentally. AASLD guidelines recommended screening of cirrhotic patients every 6 to 12 months until 2010 and afterwards guidelines were revised and recommended screening for HCC every 6 months. These changes were considered upon data collection.

Discussion

The data obtained from this retrospective analysis of the medical records of Latino veterans who had HCC within a background of HCV suggests that are no clear predictors indicative of which patients will develop this disease with such a low 5-year survival rate. In contrast to other studies, it was seen that in our population there was not a strong association with risk factors such as diabetes mellitus, elevated BMI, or low platelet count. The majority of patients who were diagnosed with HCC were classified within early stages of the most common prognostic models which are the Child Pugh score and MELD score. Also, this study validates previously described data noting that AFP is not a universal marker for the diagnosis of HCC with only 13.7% of our cohort with levels above 500 mcg/L upon diagnosis. More importantly, although 80.1% of the cohort was diagnosed within BCLC stages B or better, the median survival was only 10 months after diagnosis. However, the most striking point of all the data is that only 4.6% of the patients with HCC were diagnosed within a routine surveillance program.

The main limiting factors in our study were that all patients were male veterans; therefore, these results may not represent the general population of non-veteran men and any women. Another limiting factor was that RFA was not available in our institution until 2007 and therefore unknown if the lack of this treatment modality within this time period would have had an effect in the median survival time after diagnosis if patients would have had that option. It is also fair to mention that when this study was conducted, the new direct acting antiviral treatments for HCV were not available and therefore new studies will need to be performed on that specific population of patients that are treated for HCV.

In conclusion, surveillance was not conducted effectively in our study population. Patients diagnosed with cirrhosis need to be entered in a strict surveillance program due to the lack of clinical or laboratory indicators of HCC development and the poor prognosis once diagnosed. Within our study, 95.4% of the HCC cases were diagnosed incidentally and therefore it is unknown if an earlier diagnosis would have led to a better survival rate for which new studies are recommended within a cohort that has been surveilled as recommended by guidelines.These findings should help raise awareness among all physicians of the importance of HCC surveillance in all cirrhotic patients to grant patients an early diagnosis and hopefully improve their chance of survival and quality of life. With the mandatory widespread use of electronical medical records and the aid of modern technology, it may be of great help to use regulatory medical reminders in the institution of imaging surveillance in cirrhotic patients within all the healthcare facilities in our nation.

The contents of this publication do not represent the views of the VA Caribbean Healthcare System, the Department of Veterans Affairs or the United States Government.

Dispatches From The Guild Conference, Series #15

Management of the Complications of Cirrhosis

August 2018 • Volume XLII, Issue 8

Guadalupe Garcia-Tsao

Cirrhosis is the end result of any chronic liver disease and is an entity that progresses across different prognostic stages, the most important being the compensated (asymptomatic) and the decompensated (symptomatic) stages. Here, we discuss these stages, defined by the absence or presence of overt complications of cirrhosis, specifically variceal hemorrhage, ascites and encephalopathy.1 Each stage has entirely different prognosis, predictors of death and predominant pathogenic mechanisms and therefore should be managed separately both in research and in practice.

Guadalupe Garcia-Tsao, M.D. Professor of Medicine/Digestive Diseases, Yale University School of Medicine, Chief, Digestive Diseases Section, VA-CT Healthcare System

Cirrhosis is the end result of any chronic liver disease and is an entity that progresses across different prognostic stages, the most important being the compensated (asymptomatic) and the decompensated (symptomatic) stages. These stages are defined by the absence or presence of overt complications of cirrhosis, specifically variceal hemorrhage, ascites and encephalopathy.¹ Each stage has entirely different prognosis, predictors of death and predominant pathogenic mechanisms and therefore should be managed separately both in research and in practice.

Portal hypertension (PH) is the initial and main consequence of cirrhosis and is responsible for most of its complications. Portal pressure increases initially as consequence of increased intrahepatic resistance to portal flow due to a) structural vascular distortion (e.g. fibrous tissue, regenerative nodules, microthrombi) which account for about 70% of the increased intrahepatic resistance and b) increased intrahepatic vascular tone which is consequence of endothelial dysfunction resulting mostly from reduced nitric oxide bioavailability.² As portal pressure increases, there is splanchnic vasodilatation, which leads to increased portal venous inflow that further increases portal pressure. Vasodilatation is due to angiogenic factors and increase in nitric oxide and leads to activation of neuro-humoral systems, sodium and fluid retention, resulting in increased cardiac output, and a hyperdynamic circulatory state.³

Stages of Cirrhosis

Complications of cirrhosis do not occur until there is both increase in resistance and flow. When increased resistance is the sole pathogenic factor, portal hypertension is mild (<10 mmHg as determined by the hepatic venous pressure gradient or HVPG) but when there is both increased resistance and flow and the HVPG rises to levels ≥10 mmHg, the patient is at a higher risk (4x) of developing decompensating events.⁴ Therefore, patients with compensated cirrhosis are currently sub-staged into those with mild PH (HVPG >5 but <10 mmHg) and those with clinically significant portal hypertension (CSPH) (HVPG ≥10 mmHg).⁵ Among the latter, roughly half the patients have gastroesophageal varices. Because the HVPG of patients with gastroesophageal varices is of at least 11-12 mmHg, patients with varices have, by definition, CSPH.⁶

Of the decompensating events, ascites is the most common (20-year first event rate of 33%), followed by variceal hemorrhage (15%) and encephalopathy (7%). Jaundice is quite rare as the first decompensating event (3%) because its presence indicates a more advanced disease (further decompensation) or acute-on-chronic liver failure.⁷ Prognosis is different depending on the type and number of decompensating events. Patients with gastrointestinal bleeding as the sole decompensating event; those presenting with a non-bleeding complication (mainly ascites) as sole decompensating event and those with two or more concomitant complications have a progressively worse prognosis (20%, 30% and 88%, respectively).7 Therefore, the prognosis and management of variceal hemorrhage should always be considered in the context of the presence or absence of other decompensating events.

In patients with decompensated cirrhosis, vasodilatation is the main pathogenic mechanisms and is secondary to bacterial translocation (covert infection) or overt bacterial infections, with a main mediator being systemic inflammation.⁸

Reducing Portal Pressure

While HVPG measurements are useful in patient stratification in compensated cirrhosis, it is not as important in the decompensated stage, where markers of liver and kidney dysfunction (model for end-stage liver disease or MELD score) are of greater prognostic significance.⁹ However, both in compensated and decompensated cirrhosis, decreases in portal pressure (induced by non -selective beta-blockers) are associated with improvement in outcomes. Hemodynamic responders are traditionally defined as those in whom HVPG decreases below 12 mmHg or > 20% from baseline. In patients with compensated cirrhosis, a decrease of >10% from baseline has been shown to be predictive of a more favorable outcome.¹⁰

Portal pressure can be decreased by decreasing intrahepatic resistance and/or by decreasing portal vein blood inflow. For over 30 years, treatment of portal hypertension has been based on non-selective beta-blockers (NSBB), drugs that decrease portal pressure by a reduction in splanchnic blood flow. NSBB have been shown to be effective in reducing first and recurrent variceal hemorrhage both in patients with compensated and decompensated cirrhosis.

More recently, attention has been placed on drugs that act by decreasing intrahepatic resistance. Carvedilol, is a unique type of NSBB with additional alpha-adrenergic blocking activity and may therefore also act by vasodilating the intrahepatic circulation. Carvedilol has a larger effect in reducing portal pressure compared to traditional NSBB (nadolol, propranolol) but its vasodilating properties, especially in the decompensated patients, may lead to further vasodilatation and worsening of the already unstable hemodynamic status of the decompensated patient. Statins act by ameliorating endothelial dysfunction and have shown to decrease the HVPG.¹¹ In retrospective studies, statins have been shown to decrease decompensation and in one prospective study simvastatin improved survival in the setting of secondary prophylaxis of variceal hemorrhage¹² (see below).

Variceal Hemorrhage

Acute variceal hemorrhage is the cause of approximately 70% of the episodes of upper gastrointestinal bleeding in patients with cirrhosis. The current standard of care has resulted in a major decrease in mortality. However, even in the last published series, it remains above 15%, which places acute variceal hemorrhage (AVH) as one of the most serious medical emergencies. The immediate goal of therapy in these patients is to control bleeding, to prevent early recurrence (within five days) and to prevent six-week mortality (main treatment outcome).

After initial volume replacement, blood transfusion strategy should be conservative, initiating packed red blood cell (PRBC) transfusion when hemoglobin is < 7 g/dL with a goal of maintaining hemoglobin between 7 and 9 g/dL), prophylactic antibiotic (ceftriaxone 1 g/day) and infusion of a safe vasoactive drug (e.g. octreotide). If the patient was on NSBB these should be discontinued, as they will blunt the cardiovascular response to bleeding.

Endoscopy should be ideally performed within 12 hours of admission, following hemodynamic resuscitation. Current evidence supports endoscopic variceal ligation (EVL) as the endoscopic therapy of choice for the initial control of bleeding, as it is associated with less adverse events and less mortality than sclerotherapy.

Once endoscopy and EVL have been performed, high-risk patients (defined in that study as Child C cirrhosis with a score of 10-13 or Child B with active bleeding on endoscopy) who have a transjugular intrahepatic portosystemic shunt (TIPS) placed within 72 hours (“early” or preemptive TIPS) have been shown to have lower failure and mortality rates both at 6 weeks and at 1 year compared to patients that continue on standard therapy.¹³ Because Child B patients with active hemorrhage were subsequently shown to be at an intermediate risk of mortality,¹⁴ the recommendation of considering a pre-emptive TIPS in patients with variceal hemorrhage applies mostly to Child C patients (score 10-13).¹⁵

Patients not receiving TIPS should continue with vasoactive drugs for at least two days and up to five days. Patients without evidence of rebleeding should be then tapered off octreotide, taken off antibiotics and started on NSBB for secondary prophylaxis (see below). Patients with persistent bleeding or severe rebleeding should receive a “rescue” TIPS.

Patients who recover from the first episode of variceal hemorrhage have a high re-bleeding risk (60% in the first year), with a mortality of up to 33 %. Therapy to prevent re-bleeding is therefore mandatory in these patients and should be instituted prior to hospital discharge. Patients who presented with variceal hemorrhage and other complications (ascites, encephalopathy, spontaneous bacterial peritonitis) with indications for liver transplant should be referred for evaluation. Patients in whom TIPS was placed during the acute episode require no further specific therapy for portal hypertension or varices is required. Surveillance for TIPS patency should be instituted (Doppler ultrasound every six months). For all other patients, the first-line therapy for the prevention of re-bleeding is the combination of NSBB (propranolol or nadolol) and EVL, with NSBB being the key component of combination therapy as shown in a recent individual meta-analysis.¹⁶

NSBB in Patients with Ascites

NSBB have been shown to prevent first and recurrent variceal hemorrhage in patients with cirrhosis and, in hemodynamic responders, NSBB have also been shown to prevent decompensation and death.¹⁷ The effect appears to be independent of the presence or absence of ascites.¹⁸

The main pathophysiologic mechanism in patients with cirrhosis and ascites is splanchnic and systemic vasodilatation that leads to activation of neuro-humoral systems, sodium and fluid retention, resulting in increased cardiac output, and a hyperdynamic circulatory state.³ In patients with refractory ascites, these abnormalities are maximal and a relative decrease in cardiac output can lead to a decrease in renal perfusion and to hepatorenal syndrome.¹⁹ NSBB could precipitate this decrease in cardiac output and lead to renal dysfunction and death. This would be particularly so for carvedilol which, in addition to decreasing cardiac output, can worsen vasodilation. In fact, retrospective studies have shown that NSBB can lead to renal dysfunction in decompensated patients²⁰ and to a higher mortality in patients with refractory ascites.²¹ Subsequent retrospective studies including larger number of patients with ascites and/or refractory ascites (a collective of over 2,000 patients) have shown that beta-blocker (BB) use is either unrelated to an increased mortality. In fact, a recent meta-analysis including these observational studies and randomized studies of BB in the prevention of AVH, shows that BB use was not associated with increased all-cause mortality in patients with ascites, non-refractory ascites alone or refractory ascites alone.²²

In studies showing a deleterious effect of NSBB, the mean arterial pressure is significantly lower in patients in the NSBB group, indicating that this may be the clinical indicator that would lead to NSBB dose reduction or discontinuation.²³ Given the benefit of NSBB, particularly in the prevention of recurrent variceal hemorrhage, the Baveno VI consensus conference recommended that, until further evidence is available, NSBB should be used cautiously in patients with refractory ascites and dose reduced/discontinued in the presence of a systolic blood pressure <90 mmHg, serum sodium <130 mEq/L or development of acute kidney injury.⁶ Further, recent guidance have suggested that NSBB in patients with ascites require adjustment to a maximal daily dose of 160 mg of propranolol or 80 mg/day of nadolol.⁵

Ascites and Complications

The two main mechanisms of ascites formation in cirrhosis are universal: portal (sinusoidal) hypertension and renal retention of sodium. In cirrhosis, fluid extravasates from the hepatic sinusoids rather than from the splanchnic capillaries. Therefore, leakage of fluid into the peritoneal space occurs as a result of sinusoidal hypertension that in turn results from hepatic venous outflow block secondary to regenerative nodules and fibrosis. However, sinusoidal hypertension alone is not sufficient for the continuous formation of ascites. Plasma volume expansion, through sodium and water retention, allows for the replenishment of the intravascular volume and is the other essential factor in the pathogenesis of cirrhotic ascites.

As mentioned above, as portal pressure increases (and collaterals form), there is concomitant arterial splanchnic and systemic vasodilatation that results in a reduction in the effective arterial blood volume.¹⁹ This “underfilling” leads to baroreceptor stimulation and consequent activation of various vasoconstrictor and anti-natriuretic neurohumoral systems (the renin-angiotensin-aldosterone system and sympathetic nervous system) that lead to renal sodium and water retention and to an increase in intravascular volume that maintains ascites formation.³

The natural history of cirrhotic ascites progresses from diuretic-responsive (uncomplicated) ascites to the development of dilutioal hyponatremia, refractory ascites, and finally, hepatorenal syndrome (HRS).

First line therapies for new onset ascites (diuretics) and refractory ascites (therapeutic paracenteses) act downstream of the pathogenic cascade and are mainly symptomatic and therefore have not resulted in a significant improvement in survival. However, treating ascites is important, not only because it improves quality of life but also because spontaneous bacterial peritonitis (SBP), a lethal complication of cirrhosis, does not occur in the absence of ascites.

Most patients with cirrhosis who first develop ascites will respond to treatment with salt restriction and diuretics. Later on, as the pathophysiological mechanisms leading to ascites formation worsen, ascites no longer responds to diuretics and the patient is then said to have developed refractory ascites. First line therapy for these patients is serial large volume paracenteses, the frequency of which is determined by patient discomfort. TIPS acts on the pathophysiological mechanisms and its earlier placement in patients with refractory ascites should be considered. A recent multicenter trial In a recent randomized study of 62 patients with cirrhosis and at least two large volume paracentesis in the previous three weeks, those randomized to covered TIPS stents (average MELD 12, CTP score 9) had a significantly better one-year survival without transplant than those randomized to LVP (93% vs. 52%, respectively) with no differences in encephalopathy, suggesting that TIPS could be first-line therapy for patients with hard to treat ascites and relatively preserved liver function.²⁴

Periodic albumin infusions, by increasing intravascular volume (and perhaps by additional functions that including binding of vasodilators and an anti-inflammatory activity) may play a role in the treatment of ascites. In an open RCT, chronic (weekly or biweekly) albumin infusions were associated with an improved survival in patients with non-refractory ascites.²⁵ This was a small proof-of-concept study and therefore no firm recommendations can be made regarding this approach.

Management of hyponatremia has also been directed downstream of the pathophysiological cascade by the use of “vaptans” that block renal tubular reabsorption of water. However, as expected, the effect is only transient. In a large multicenter randomized trial, tolvaptan used for 30 days in patients with dilutional hyponatraemia (of whom 63 had cirrhosis), was associated with a rapid improvement in serum sodium and significant weight loss compared to placebo, without significant side effects.²⁶ However, a sub-analysis of patients with cirrhosis and hyponatraemia showed that the effect on serum sodium was not only transient but, in those with severe hyponatremia, the effect was not sustained.²⁷

Regarding HRS, vasoconstrictors constitute the current mainstay pharmacological therapy in the treatment of HRS. The rationale for use of these agents is to reverse the intense splanchnic and systemic vasodilatation, the main hemodynamic alteration in HRS. Administration of vasoconstrictors (ornipressin, terlipressin, octreotide with midodrine, noradrenaline) for periods greater than 3 days is associated with significant increas1s in mean arterial pressure, decreased serum creatinine and plasma renin activity as well as an increase in serum sodium .²⁸ Additional evidence is the significant correlation between increases in mean arterial pressure and decreases in serum creatinine induced by vasoconstrictors in HRS.²⁹

In meta-analyses of randomized controlled trials, vasoconstrictor therapy (most studies used terlipressin) was associated with a significantly greater rate of HRS reversal (46-51% vs. 11-22% in control group) and a lower mortality compared to control therapy.^30,31 Studies included in these meta-analyses all defined HRS with a creatinine >2.5 mg/dL. With changes in the definition of acute kidney injury,³² a diagnosis of HRS would be reached with lower creatinine levels and thereby a greater rate of response would be expected.³³ This is important because in all studies survival is significantly better in terlipressin ‘responders’.

Alternative vasoconstrictive therapy has included the use of intravenous noradrenaline infusion which has been shown to be as effective as terlipressin,³¹ and the use of the combination octreotide/midodrine which, despite having shown efficacy in uncontrolled trials, was recently shown to be significantly inferior to terlipressin in a randomized controlled trial³⁴ and inferior to norepinephrine.³¹ Therefore, the vasoconstrictor of choice in HRS is terlipressin, but in countries like the United States, where terlipressin is not available, the combination of octreotide/midodrine can be initiated, and if there is no decline in serum creatinine within a maximum of 3 days, the patient should be transferred to the ICU intensive care unit for a trial of norepinephrine.³⁵

Because patients with refractory ascites and HRS have a higher mortality than those with diuretic-responsive ascites, efforts to avoid drugs/procedures that will lead to worsening vasodilatation and/or to kidney injury in patients with cirrhosis and ascites are essential.

Nutrition Issues In Gastroenterology, Series #178

Full Force Enteral Nutrition – A New Hope, or the Dark Side? A Critical Look at Enhanced Enteral Feeding Protocols

August 2018 • Volume XLII, Issue 8

Joe Krenitsky

In this article, we take a close look at enhanced enteral nutrition (EN) protocols, including volumebased feeding (VBF), which have been highly promoted. Evidence suggests that some enhanced EN protocols may be harmful to some critically ill adult patients and should be avoided. Although observational studies have reported an association between delayed provision of goal nutrition and compromised patient outcomes, interventional studies have reported more compromised outcomes than benefits from early goal nutrition and VBF in critically ill adult patients.

Enteral nutrition (EN) is the preferred method of providing nutrition support to critically ill patients, but EN is often interrupted and, as a result, many patients receive less than full nutrition. Multifaceted strategies for increasing the delivery of EN have been developed, including compensatory increased feeding rates after interruptions (volume-based feeding). Enhanced EN protocols, including volume-based feeding (VBF), have been highly promoted, but evidence suggests that some “enhanced” EN protocols may be harmful to some critically ill adult patients and should be avoided. Although observational studies have reported an association between delayed provision of goal nutrition and compromised patient outcomes, interventional studies have reported more compromised outcomes than benefits from early goal nutrition and VBF in critically ill adult patients. There is a need for additional research before enhanced enteral feeding protocols and VBF are routinely adopted in clinical practice.

Joe Krenitsky, MS, RD Nutrition Support Specialist, University of Virginia Health System, Digestive Health Center, Charlottesville, VA

Background

Anumber of observational studies of adult critically ill patients have reported an association between decreased EN provision and compromised patient outcomes.^1-3 The association between decreased EN provision and compromised ICU outcomes is not a recent finding, since this relationship has been described since the early 1980’s.⁴ Furthermore, observational studies have suggested that the initial days of critical illness are particularly important for providing adequate nutrition. A failure to provide a threshold level of nutrition within the early portion of an adult ICU stay was reported to be associated with increased infectious complications.¹

Clinical nutrition and other medical professionals are trained that associations noted in observational studies should never be used to infer causality, nor should the results of observational studies alone be used to suggest practice changes.^5,6 However, nutrition support professionals also have an intimate understanding regarding the hypermetabolism and accelerated catabolism that occurs during critical illness or injury, as well as the negative consequences of malnutrition. Witnessing the negative clinical sequela caused by severe malnutrition in hospitalized patients often leaves an indelible impression on clinicians. Undoubtedly, for many clinicians, the observational studies documenting associations between nutrition provision and patient outcomes appeared to confirm what their training and experience had suggested about nutritional adequacy in the ICU.

Enteral Nutrition Comes of Age

Studies have consistently documented that many critically ill patients receive only a portion of the amount of EN that is ordered.7-9 EN is frequently and often repeatedly interrupted for essential diagnostic and therapeutic interventions, real and perceived feeding intolerance, routine bedside care, enteral access device occlusion or displacement, and a myriad of other feeding disruptions in the ICU.^7-9 Over the past three decades, increased experience and research with EN has gradually contributed to more effective nutrition provision at many facilities. We have learned that initial feedings do not need to be diluted or initiated at low rates, then gradually advanced over several days, and that physiologic volumes of feeding and secretions in the stomach (gastric residuals) may not be a reason to stop EN.¹⁰ However, studies continue to document that EN is often incompletely delivered.^9,11

Although some professionals have recommended early supplemental parenteral nutrition (PN) to avoid nutrition deficits, concerns regarding the increased cost and infectious complications related to PN have spurred the development of methods to improve EN delivery.^12-14

Full Force Enteral Nutrition

In order to avoid delayed delivery of full nutrition goals, a number of enhanced EN protocols have been developed to permit more timely and complete nutrition. ^11,15-24 One strategy that has been proposed to allow increased EN delivery is volume based feeding (VBF). The strategy of VBF is centered on using a compensatory increase in feeding rate upon restarting a feeding after any EN interruption, so that the daily goal volume is more consistently delivered. VBF has often been studied as part of a multi-faceted enhanced EN protocol and each study has included some, but not all of the following components: education programs for physicians and/or nursing, daily monitoring of amounts of nutrition delivery, early initiation of EN, starting EN at goal flow rate, reducing time without nutrition prior to operative procedures, starting EN with an increased calorie goal, routine use of prokinetics, supplemental protein, use of calorie-dense formulas and/or the use of a semi-elemental feeding formula (See Table 1).^11,15-24 Different studies have utilized various components of these enhanced feeding protocols in addition to different VBF procedures and maximum allowed feeding rates.^11,15-24 The 2016 ASPEN/SCCM guidelines for adult critically ill patients endorses the use of volume-based, multi-strategy enhanced enteral feeding protocols.²⁵

It’s a Trap

Research has documented that enhanced EN protocols can often increase nutrition delivery and reduce the delay for reaching nutrition goals in the ICU. ^11,15-24 However, the real concern is whether increasing the delivery of EN in the ICU actually confers beneficial effects on patient outcomes. In contrast to the associations identified in observation studies, the weight of evidence from randomized studies in the past 8 years is that modest calorie deficits within the first week of critical illness have no negative effects on clinical outcomes.^26-29 It is perhaps not surprising then, to find out that most studies of enhanced feeding protocols reported no improvement in patient outcome, despite significantly improving the timeliness and completeness of EN delivery.^11,15-22 Even more concerning is that several investigations of “enhanced” enteral feeding protocols have reported a dark side, in the form of negative outcomes, including increased mortality in some studies in the group receiving increased EN delivery.^15-18 A closer look at the methods and limitations of the key studies should be helpful for clinicians deciding on EN feeding protocols for their facility.

Intensive EN and Patient Harm?

One study that has increased attention to the potential harm from enhanced EN protocols was a single-center, randomized study of 78 patients from medical or surgical ICUs with acute lung injury.¹⁵ The intensive nutrition group received feeding tubes and started EN sooner, used continuous feeding (no bolus or cyclic feeds), EN infusions were monitored daily, rates were increased after feeding interruptions occurred (VBF), and the amount of nutrition received was recorded. Following extubation, the intensive nutrition group had oral intake initiated as soon as safe swallowing function returned.¹⁵

The intensive EN group received significantly greater kcal/kg/d compared to the standard EN group (mean 25.4 kcal/kg vs. 16.6 kcal/kg, respectively).¹⁵ However, the data safety monitoring board stopped the study early when it was revealed that significantly more deaths occurred in the intensive EN group compared with the standard group (40% intensive EN vs. 16% standard EN).¹³ There were no significant differences between the groups in other outcomes (hospital or ICU stay, duration of mechanical ventilation, number of infections).¹⁵

Due to the fact that this study was terminated early (with less than the full number of participants enrolled), it is possible that this statistically significant difference in mortality occurred from chance alone.¹⁵ However, several other studies of enhanced EN have reported negative outcomes, most without any significant improvement in patient outcomes.^16-24

Another study that has reported only a negative outcome with enhanced EN was a before-after cohort study of 49 medical ICU patients.¹⁶ The intensive EN group received a calorie-dense feeding, and feeding rates were increased to 150% of goal to compensate for EN interruptions.16 The intensive EN group received significantly increased mean calorie provision compared to the standard group (1198 vs. 474 kcals, respectively). Although baseline characteristics were similar (including APACHE II score) between the 2 groups, the intensive EN group had a significantly increased ICU length of stay, compared to the standard group (13.5 vs. 8.0 days).¹⁶

One before-after cohort study in 110 surgical-trauma ICU patients reported a trend towards negative outcomes, without improvement in outcomes.¹⁷ The intensive EN protocol utilized VBF, a 350mL threshold for gastric residuals, plus an educational program for ICU caregivers.¹⁷ This study was notable for delaying the start of the VBF portion of the protocol until patients had established tolerance to the initial goal rate of EN. The intensive EN group received a significantly increased percentage of goal calories, compared to the standard group (89% vs. 63%, respectively). Not only was no outcome improved from the increased calories, there was actually a trend towards a longer ICU length of stay compared to the standard group (15.0 days vs. 12.2 days, respectively).¹⁷ When the patients who died were excluded, the strength of this trend was decreased, but still persisted (P = 0.09). The incidence of diarrhea was significantly increased in the intensive EN group, compared to the standard group.¹⁷

Intensive EN: No Benefit, No Harm

Two studies have reported neither harm, nor outcome benefits from an intensive EN protocol.^19-20 One was a before-after cohort study of 77 mixed ICU patients.¹⁹ Patients in the intensive EN group received a significantly greater percentage of prescribed calories than those in the standard group (74% vs. 57%, respectively). On the initial analysis, patients in the intensive EN group had a significantly longer length of ICU stay (14 vs. 9 days), as well as days on the ventilator (9 vs. 7). However, patients in the intensive EN group had a greater APACHE II score, and after controlling for the admission APACHE II score, the differences in clinical outcomes were not statistically significant.¹⁹

The second study with neither harm nor benefits was a larger multi-center cohort study where the different facilities were randomized to implement either the intensive EN protocol, or continue with standard care (“cluster randomized”).²⁰ This study was one of the larger studies to date with over 1059 patients initially enrolled, but only 252 received the enhanced EN protocol.²⁰ This larger study utilized VBF (PEP uP protocol), initiated EN at goal flow rate, used a peptide-based EN formula for initial feedings, used a prokinetic agent, increased the gastric residual threshold (300mL) and encouraged trophic feeding for patients initially deemed unsuitable for full feeding. Perhaps reflecting the difficulties in implementing a new protocol in diverse hospitals, compliance was not 100%, and as a result only 1/3 of the intervention group had EN started at goal rate, with ultimately only a 12% increase in calorie delivery in the PEP uP protocol group (from 32% of goal at baseline to 44% of goal on the PEP uP protocol).²⁰

Two additional studies of VBF did not report any patient outcomes, only that more EN was received.^21-22 One cohort study of the PEP uP protocol in 57 surgical patients demonstrated no increase in nutrition delivery when compared to surgical patients at sites that did not implement the PEP uP protocol.²¹

A second study of VBF randomized patients to either VBF or standard protocol after they had reached goal EN rate following a slow feeding rate progression over 24 hours.²² In the 57 patients who completed the study, VBF received 92.9% of calorie goals, while the standard group received 80.9% of calorie goals. Although the authors suggest this study provides evidence that VBF is “safe”, no information regarding patient outcomes were reported, and far too few patients were enrolled to provide reliable safety data. ²²

Intensive EN: Reported Benefits (but with fine print)

One study that reported potential benefits of an intensive EN protocol was a before-after cohort study of 239 adult trauma ICU patients.18 Data was collected only for those patients who required ≥ 7 days of mechanical ventilation and who did not receive parenteral nutrition. The enhanced EN protocol consisted of early start of EN, a physician education program, intraoperative small bowel tube placement, EN ordering “bundle”, continued EN prior to procedures until patients were called to the OR and a VBF protocol with “catch-up” feeding rate if feedings were held.¹⁸

The intervention group received significantly increased calories during the first 3 days compared to baseline and received 100% of calorie goals after day 3.¹⁸ The cumulative calorie deficit was -1907 kcals in the intervention group and -7240 kcals in the baseline group. The intervention group had significantly decreased incidence of pneumonia (42%) compared to the baseline group (56%). Although pneumonia incidence was decreased, the intervention group had a greater requirement for mechanical ventilation, with significantly more days on the ventilator at day 28 compared to the baseline group.¹⁸ Although reading the abstract of this study may make it seem in favor of the intensive EN protocol, the exclusion of any data from patients who died before day 7, the high (56%) incidence of baseline pneumonia in the standard group, and the increased need for mechanical ventilation (in the setting of decreased pneumonia) raise concerns that this is not necessarily data in favor of the intensive EN protocol.¹⁸

Another study reporting positive outcomes was a before-after cohort study of 213 adult surgical ICU patients.²³ The intensive EN group focused primarily on increasing protein delivery by increasing the standard initial protein goal from a baseline of 1.5 gm/kg to 2 gm/kg to be achieved with protein supplements. Calorie goals were unchanged from baseline, and although VBF was encouraged, it was not strictly implemented in the intervention group.

The intervention group received significantly more calories/kg (18.6 kcal/kg/d vs. 16.5 kcal/kg/d) and protein/kg (1.2 g/kg/d vs. 0.8 g/kg/d) compared to the standard group.23 The ICU length of stay (LOS) and hospital LOS were both significantly shorter in the intervention group (10 vs. 15 days, and 20 vs. 29 days, respectively). In the intervention group, there was a trend toward fewer late infections (mean 0.7 vs. 0.9, respectively).²¹ A regression analysis that adjusted for age, sex, BMI, APACHE II score, and GI surgery demonstrated that the aggressive EN protocol was associated with a significantly lower risk of late infection.23 Of note, thirty-day mortality was significantly increased in the intervention group compared to the control group (13.6% intervention vs. 7.4% control, respectively), but hospital mortality was not significantly different between the groups.²³ This was primarily a study of increased protein delivery, with a clinically trivial difference in calorie provision between groups, and even the intensive EN group received hypocaloric feeding due to incomplete compliance with the VBF protocol.²³

One of the studies used as evidence for positive outcomes from enhanced enteral feeding protocols was an unblinded, randomized investigation of 82 patients with severe head injury who required mechanical ventilation.²⁴ This study was one of the 2 studies cited in the ASPEN/SCCM guideline endorsing volume-based, multi-strategy enhanced enteral feeding protocols.²⁴ The control patients’ EN was started at a very slow rate of 15mL/hr, with a very conservative feeding advancement schedule.24 The rate of control feedings could be doubled every 8 hours, but the rate was only increased if gastric residual measurement was < 50mL X 2 consecutive measurements, and the feeding rate was reduced by 50% if a single gastric residual volume was ≥ 150mL. The intervention group received nasointestinal feeding when the tube could be successfully advanced (34% of group), or an NG tube when it could not.²⁴ The intervention group had EN started at the goal flow rate; the feeding rate for the NG-fed portion of the intervention group was not decreased unless gastric residuals exceeded 200mL. Considering the very conservative feeding regimen used in the control group, it is not surprising that median calorie and protein delivery were less than 50% of goal even by day 7 of the study.²⁴ The intervention group received significantly greater calories and protein throughout the first week of the study, compared to the control group. Mean energy delivery in the control group was 36.8% of goal, compared to 59.2% of goal in the intervention group.²⁴ The intervention group had significantly less infections compared to the standard group (61% vs. 85%, respectively) and significantly less total other complications (37% vs. 61%, respectively).²⁴ There was also a trend for improved neurologic complications at 3 months in the intervention group, but no difference at 6 months. However, when the results were analyzed by disease severity, there were no statistically significant improvements in patient outcome, but there was still a trend towards improved neurologic outcome at 3 months. When the methods of this study are compared to other enhanced enteral protocols it is important to note that the intervention group did not actually receive VBF, but rather hypocaloric nutrition that was gradually increased over several days to a maximum of just over 70% of goal calories by day 5-6.²⁴

Discussion and Clinical Implications

There are inadequate randomized data to provide strong evidence for how much nutrition should be provided in the early stage of critical illness for optimized patient outcome. The randomized studies that are available suggest that the data from observational studies is misleading.^26-29 The topic of early nutrition adequacy in the medical ICU has been highlighted as one of the notable occasions where data from observational data has led to clinical recommendations demonstrated to be incorrect by randomized data.30 It would seem reasonable that we should first know the proper timing and amount of nutrition to provide to critically ill patients for best outcome, before expending time and energy implementing protocols aimed at maximizing early nutrition delivery.

One of the problems faced when attempting to evaluate the studies of enhanced enteral feeding in critically ill patients is that all of the investigations enrolled a relatively small number of patients.^11,15-24 These studies all lack statistical power to have confidence that any significant outcome difference between groups did not occur by chance alone.^11,15-24 The varied populations as well as different methods used to enhance enteral delivery in the various studies do not lend this data to allow a scientifically valid meta-analysis; even if all of the studies were combined, it is likely that there are too few patients studied to allow adequate analysis of outcomes such as mortality in a mixed medical, surgical, and trauma ICU population.

However, what is striking is that those studies that were successful in increasing early calorie delivery, not only reported no improvement in patient outcome, but some may have actually caused net harm.^15,16 Considering that the intensive EN groups also had other interventions such as nurse or MD education programs and daily monitoring of nutrition delivery, it would be reasonable to expect improved outcomes from staff education and close monitoring alone. The single study that actually provided full calories (Intensive EN group received 25.4 kcals/kg) had to be stopped for patient safety due to increased mortality.¹⁵ The studies that reported no harm, or some improved outcomes, generally were slower to meet calorie goals, had less compliance with VBF (or no VBF), and generally provided hypocaloric feeding to most patients, even in the “intensive EN” group.^23,24 While it is quite possible that meeting full calorie expenditure in the earliest stages of critical illness itself may have detrimental effects, it is also possible that the negative effects reported in VBF studies are related to the method for increasing calorie delivery.

One topic that has not received adequate attention is the potential effect of VBF on glucose variability. Increased variability of serum glucose is associated with compromised outcomes in the ICU, and has been reported to potentially be more important to good ICU outcomes than the absolute glucose values.³¹ We know that providing full calories increases insulin requirements in critically ill patients, compared to hypocaloric feeding.²⁷ No study has provided data about glucose variability during VBF, but accelerating feeding rates immediately after feeding is held, especially while providing full calories may be a risk for increased glucose variability.³² Glucose variability with VBF is potentially more likely, now that many facilities have abandoned insulin infusion protocols with hourly serum glucose checks in favor of basal-bolus protocols with less frequent glucose monitoring.

It is possible that full calories, or even VBF, may be helpful for some patients, but detrimental to others. The average BMI for the studies of intensive EN (see Table 2) demonstrates that, on average, the patients in these studies were overweight, and a number were likely obese. Obese patients appear to benefit from hypocaloric, full protein feedings, even while critically ill.³³ Obese patients in the intensive EN groups of some studies would have exceeded the recommended calorie goals for obese critically ill patients.²⁵

It is also possible that very malnourished patients who receive early full calories may experience detrimental effects. One study has demonstrated that failure to decrease calorie provision in patients who are experiencing refeeding hypophosphatemia may increase mortality.³⁴ However, after refeeding syndrome has resolved, it is possible that patients with more severe malnutrition may benefit from efforts to improve nutrition delivery. Those patients with decreased BMI and minimal fat stores, patients who require extended ICU stays, or those who require repeated surgical interventions may benefit from efforts to minimize accumulated nutritional deficits. The initial days of critical illness, with unavoidable catabolism and increased insulin resistance may also be the wrong time to enforce full calorie provision. It is possible that enhanced EN protocols may have benefits once the initial phase of critical illness has subsided, and patients are capable of recovering from catabolism and regaining lean muscle mass.

More recently, additional associations from observational studies have been used to suggest that nutritional adequacy is critical only for those more severely ill patients (increased NUTRIC score).³⁵ It is important to remember that the NUTRIC score is based on data only from observational studies. Analysis of data from patients randomized to receive reduced-calorie feeding has demonstrated that the NUTRIC score is not a valid indicator of patients who benefit from full calorie nutrition support.³⁶

CONCLUSIONS

There is insufficient evidence to support intensive EN protocols in the early portion of critical illness in adult patients. Furthermore, VBF that meets full calorie expenditure within the first several days of critical illness may have negative effects and may even increase mortality in some populations. The best available data from randomized studies of hypocaloric feeding have demonstrated that the associations described from observational studies are not cause and effect: a modest calorie deficit in the early portion of critical illness does not compromise patient outcome, even in those patients with an increased NUTRIC score. Early VBF that meets calorie goals may be detrimental for some critically ill adult patients, and in the absence of data showing clear benefit, intensive, early VBF EN protocols should be avoided in routine use, especially in patients above their ideal weight. Additional research is required to see if a more gradual increase in calories with a focus on nutrition adequacy after the most critical stress has passed, or a focus on protein adequacy may have outcome benefits. There is a need for studies that focus efforts to increase nutrition provision in patients that are underweight, malnourished and have extended ICU admissions.

Nutrition Issues In Gastroenterology, Series #177

Got Lactase? A Clinician’s Guide to Lactose Intolerance

July 2018 • Volume XLII, Issue 7

Meagan Bridges

Intolerance of lactose-containing foods is a very common condition that usually arises as a result of a genetically programmed decline in the enzyme lactase. Here we discuss the management of lactose intolerance and the challenge of maintaining proper nutrition status – particularly as it pertains to calcium and vitamin D. We provide a variety of additional tools available to help address symptoms. Further work is needed to evaluate the role of lactose and dairy foods in other GI conditions, as well as on methods to avoid unnecessary dietary restriction.

Meagan Bridges, RD, Nutrition Support Specialist, University of Virginia Health System Charlottesville, VA

INTRODUCTION: WHAT IS LACTOSE INTOLERANCE?

Lactose intolerance is a clinical syndrome in which lactose ingestion causes symptoms such as abdominal pain, bloating, flatulence, and diarrhea due to lactose malabsorption. Lactose (milk sugar) is a disaccharide found in milk and milk products. Digestion and absorption require the enzyme lactase, which is found in the brush border of the small intestine. Lactase hydrolyzes lactose into the monosaccharides glucose and galactose, which can then be absorbed and used for energy.

Lactose malabsorption is most commonly caused by reduced lactase levels. Primary lactase deficiency is a genetically modified condition resulting from the physiological decline of lactase activity after infancy. Other terms used to describe this condition include lactase nonpersistence, lactase insufficiency, and adult type hypolactasia. It is estimated that about 68% of the world’s population is lactase nonpersistent, with wide variance levels according to region and ethnicity.¹ In the U.S., 36% of the population is lactase deficient, with highest prevalence levels found in individuals of African, Asian, Latin American, Native American, and South American descent.1

Not everyone with lactose malabsorption is lactose intolerant. In lactose intolerant individuals, unabsorbed lactose transits to the colon, carrying with it an increased osmotic load and serving as a ready substrate for the microbiome to ferment and produce short chain fatty acids and gas. This is what results in the classic symptoms of bloating, flatulence, borborygmi, abdominal pain, and diarrhea. Less often, it can present with nausea or constipation. Symptoms of lactose intolerance can range from mild to severe but generally do not occur until there is at least a 50% reduction in the lactase enzyme.²

There is also secondary hypolactasia, or secondary lactase deficiency, which can occur as a consequence of any condition that damages the brush border of the small intestine. Mucosal damage due to celiac disease, Crohn’s disease, or ulcerative colitis may result in a transient lactase deficiency. Small intestinal bacterial overgrowth, certain medications, infectious enteritis (e.g. giardiasis), radiation enteritis, gastrointestinal surgery, and short bowel syndrome may also result in either a reduction in absorptive capacity or a downregulation of lactase expression in the small intestine. Whereas primary hypolactasia is irreversible, secondary hypolactasia can often be reversed once normal intestinal mucosa is restored.

DIAGNOSIS

Lactose malabsorption can be diagnosed using various methods (Table 1). The hydrogen breath test involves ingestion of a standard dose of lactose, usually 20-50g (roughly 400-1,000 mL cow’s milk), and measuring breath hydrogen at 30-minute intervals. A diagnosis of lactose malabsorption can be made with a hydrogen level > 20 ppm within 3 hours of ingestion. This test is 78% sensitive and 98% specific for lactose malabsorption, but it is susceptible to both false positives (e.g., in the presence of small intestinal bacterial overgrowth) and false negatives (e.g. in the presence of non-hydrogen producing bacteria).

Other tests aimed at detecting lactase deficiency are available, but they are rarely performed. Biopsies of the jejunum are often regarded as the gold standard for determining lactase activity and have the advantage of determining whether a patient may have secondary lactose malabsorption. This procedure, however, is highly invasive and not particularly reflective of intestinal lactase activity as a whole. Lactase deficiency may also be assessed by way of genotyping, but the available genetic tests do not account for all the possible polymorphisms resulting in lactase nonpersistence, nor are they useful for patients with secondary lactase deficiency.

As opposed to lactose malabsorption, lactose intolerance is much more difficult to ascertain. A presumptive diagnosis can be made in patients with symptoms that occur within a few hours after significant lactose ingestion (>2 servings of dairy/day or >1 serving in a single dose that is not associated with a meal), which resolve after 5-7 days of lactose avoidance.³

It is important to note that whereas lactase deficiency and malabsorption can be objectively measured, demonstration of lactose intolerance relies on subjective self-reporting of symptoms, which are very common even in the absence of lactose ingestion and are also highly susceptible to the placebo effect. Indeed, the few double-blind trials that have been conducted reveal a poor association between self-reported lactose intolerance and the occurrence of symptoms after lactose ingestion, even in patients with known lactase deficiency.⁴

SOURCES OF LACTOSE

Lactose is in virtually all milk and milk products (Table 2). By far, the highest concentration of lactose per serving is present in milk, ice cream and some yogurts, while cheeses generally contain much lower quantities of lactose. Lactose may also be found in other foods and beverages containing milk or milk products, including boxed, canned, frozen, packaged, and prepared items. Table 3 lists common types of these foods, as well as terms on the ingredient list that indicate whether a product contains lactose.

There are also certain medications that contain lactose, including over-the-counter pain relievers, multivitamins, and anti-diarrheal agents. Usually, the amount is so small (less than 0.5g) that it will not raise hydrogen levels, much less cause GI symptoms.

MANAGEMENT: LACTOSE RESTRICTION

The most common therapeutic approach to lactose intolerance involves limiting milk and milk products in the diet. Complete lactose avoidance is rarely indicated. Most blinded studies suggest that people with lactose intolerance can consume around 12g of lactose – roughly the same amount in one cup of milk – in a single dose with no or mild symptoms. When consumed with other foods and/or spread out in small amounts over the course of the day, up to 18g of lactose can generally be tolerated.⁵

It may be beneficial for some patients to completely exclude milk and milk products for 2-4 weeks (or long enough for the remission of symptoms), and then gradually reintroduce dairy products up to a threshold of individual tolerance.⁶ An individual’s tolerable level depends on several factors, including the amount of lactose consumed at one time, residual lactase activity, ingestion with other foods and beverages, gut transit time, and the gut microbiome.

Nutrition Considerations

While limiting dairy may reduce lactose intolerance symptoms, it comes with certain risks, particularly as it pertains to osteoporosis and bone fractures secondary to inadequate calcium and vitamin D intake. As dairy remains the primary dietary source of calcium and vitamin D for the general population, several studies have pointed to a relationship between lactose malabsorption, low intake of dairy products, and reduced bone mass.^7,8

The recommended daily intake for calcium is based on age and sex (Table 4). Patients with lactose intolerance should be assessed for dietary calcium adequacy and instructed to increase calcium intake from other foods if necessary (Table 5). They may also need to take calcium supplements, which come in a wide range of preparations and doses (Table 6). Calcium carbonate is the most common and least expensive form of calcium supplementation. It is best absorbed with a low-iron meal, but it may not be as effective in people who take proton pump inhibitors or H2 blockers. Calcium citrate can be taken with or without a meal and may be better suited for people with achlorhydria, inflammatory bowel disease, or absorption disorders. Calcium absorption is highest in doses ≤ 500 mg; amounts greater than this should be taken in divided doses.

Through fortification, milk is also a major source of vitamin D, which is needed for calcium absorption. Few other foods naturally contain significant amounts of vitamin D, with the exception of fatty fish, liver, cheese, and egg yolks. Monitoring of vitamin D status and supplementation may be necessary, especially in patients with Crohn’s or celiac disease, or in other patients at additional risk for deficiency.

There is a growing array of plant-based (non-dairy) alternatives to cow’s milk, most of which are fortified to offer nutrients in amounts comparable to those found in cow’s milk, including calcium (300 mg per cup) and vitamin D (120 international units per cup). These beverages can be a viable alternative for those with lactose intolerance.⁹

OTHER MANAGEMENT OPTIONS
Exogenous Enzyme Supplementation

Exogenous lactase (obtained from yeasts or fungi) can be taken before or during dairy consumption to help hydrolyze lactose. These supplements commonly come in tablet form, and a dose of 6000-9000 units/meal is typically taken (Table 7). Liquid drops, which are not widely available in the U.S. but can be ordered online, may also be added directly to milk. Results of these products vary, and research thus far has been inconclusive regarding the efficacy of supplementation, which may depend on enzyme origin, residual endogenous lactase activity, dosage, the amount of lactose consumed, stomach pH, and bile salt concentration.¹⁰

Low-lactose or lactose-free milk, such as Lactaid®, is milk with added lactase enzymes that have pre-hydrolyzed the lactose. In recent years, there has been an increase in reduced-lactose or lactose-free dairy foods, to include not only milk, but also yogurt and ice cream (see Table 8). These products are readily available in most large grocery stores, but they are typically more expensive than their lactose-containing counterparts. Some store brands are beginning to carry their own products at a lower price.

Yogurt and Probiotics

Plain yogurt has been shown to be as effective as pre-hydrolyzed milk in reducing hydrogen production and intolerance via lactase-containing microorganisms.¹¹ Sweet acidophilus milk contains the same bacteria added to cold milk but is not as effective.¹² Likewise, yogurts that contain milk or milk products added back after fermentation may still produce symptoms.

A related strategy involves probiotic supplementation with the goal of altering intestinal flora so that more lactic acid bacteria may salvage malabsorbed lactose and ferment it without excessive gas production. Some studies have shown that probiotic supplementation can lead to decreased hydrogen production and improved symptoms in lactose intolerant individuals.^13,14 The full body of evidence, however, is insufficient to recommend this approach.

Colonic Adaptation

Although lactase expression cannot be up-regulated by the presence of lactose, it is thought that “tolerance” may be induced despite malabsorption by way of adaptive processes involving the gut microbiota and some colonic functions and features. Consecutive incremental doses of lactose compared to dextrose have been shown to reduce flatulence, but not abdominal pain or diarrhea.¹⁶ Current research, however, is not convincing enough to support incremental increases of lactose ingestion to treat symptoms of intolerance, as results have been variable and often conflated with the placebo effect.¹⁷

Slowing Gastrointestinal Transit

Co-ingestion of other foods has been demonstrated to improve lactose tolerance, possibly by way of delaying gastric emptying, slowing down intestinal transit time, and prolonging contact time with available lactase.¹⁵ It is thought that consuming full-fat milk versus low-fat or skim may have the same effect, but current research is inconclusive. Pharmacological agents such as loperamide can also slow GI transit, but they often come with significant side effects and/or high cost.

CONSIDERATIONS FOR PATIENTS
WITH OTHER GI CONDITIONS

Observational studies point to an overlap between lactose intolerance and irritable bowel syndrome (IBS), as well as other gastrointestinal conditions that may result in secondary lactase deficiency, such as inflammatory bowel diseases, celiac disease, and small intestinal bacterial overgrowth (SIBO).6 Relationships, however, are confounded by several factors, including:

the transient nature of secondary hypolactasia
the preponderance of individuals with a genetic predisposition for primary hypolactasia
the symptom profiles of these GI conditions, which share many of the same attributes as lactose intolerance
the overlap with fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs);
the subjectivity of self-reporting symptoms

Patients with a concomitant GI condition, whose diets may already be limited to some degree, should have suspected lactase deficiency confirmed before starting a low-lactose or lactose-free diet so as to avoid unnecessary restrictions. In patients with secondary lactose malabsorption, successful treatment of the primary disorder can lead to restoration of lactase activity. However, lactose intolerance may persist for months after healing starts.

Irritable Bowel Syndrome

Retrospective studies have shown that up to 85% of IBS patients with lactose malabsorption have improved symptoms when they restrict lactose in their diet.¹⁸ At the same time, prospective studies show that symptom improvement is highly susceptible to the placebo effect, and that lactose restriction alone is not sufficient for effective symptom relief in functional GI diseases.¹⁹ In IBS, lactose intolerance tends to be subsumed under a wider intolerance of FODMAPs and may not be directly related to lactase deficiency. Several randomized controlled trials indicate that IBS patients can benefit from a low-FODMAP diet that includes lactose restriction.²⁰ However, the specific impact of lactose and lactose restriction on symptoms is difficult to assess.

Crohn’s Disease and Ulcerative Colitis

There are no viable studies to date that specifically examine lactose as a symptom mediator in inflammatory bowel diseases (IBD) such as Crohn’s and ulcerative colitis. Patients are often instructed to restrict lactose and dairy intake, but the prevalence of true lactose malabsorption is unclear, as GI manifestations of these diseases are often similar to those of lactose intolerance. Studies indicate that 40-70% of patients with Crohn’s self-report that they are lactose intolerant, but in most cases, lactose malabsorption appears to be driven more by ethnicity and genetic makeup, rather than by a direct association with the disease itself.^21,22 The exceptions to this are Crohn’s patients with small bowel involvement, who do appear to be at higher risk for lactose malabsorption but not necessarily lactose intolerance.²¹

Celiac Disease

If the progression of celiac disease (CD) results in damage to the intestinal brush border, patients are likely to experience secondary lactase deficiency. Most people with CD can eventually rehabilitate their brush border and regain lactase activity within 6-12 months after following a gluten-free diet, assuming they do not also have primary lactase deficiency with lactose intolerance. In some cases, the villi and microvilli damage can take up to 2 years to heal completely.²⁴

Small Intestinal Bacterial Overgrowth

IBS patients with lactose intolerance are more likely to also have small intestinal bacterial overgrowth (SIBO).²⁵ Excessive bacterial fermentation of lactose with production of short-chain fatty acids and gas in the small bowel may particularly trigger abdominal symptoms. If during a hydrogen breath test, a patient complains of abdominal pain and has an early hydrogen peak (within 15-30 minutes of ingesting lactose), SIBO should be ruled out before attributing these symptoms to lactose intolerance.

CONCLUSION

With such a high prevalence of lactase deficiency worldwide and in the U.S., clinicians are more than likely to encounter lactose intolerance in clinical practice. There are many strategies to help patients manage their symptoms (Table 9). Complete elimination of dairy is likely not required; at least 12 mg of lactose (about 1 cup of milk) is often well-tolerated and will not induce GI symptoms. Patients with lactose intolerance may need to be monitored for adequate calcium and vitamin D status and counseled on non-dairy sources and/or supplementation of these nutrients.

Gastrointestinal Motility And Functional Bowel Disorders, Series #25

Revisiting Achalasia and Esophageal Squamous Cell Carcinoma

July 2018 • Volume XLII, Issue 7

Fernando Moran,

Cong Phan,

Richard W. McCallum

After immediate endoscopic or surgical management of achalasia, many patients may not follow through with long-term care. Though less common than adenocarcinoma, squamous cell carcinoma of the esophagus can be associated with achalasia. This article highlights current care in diagnosis, treatment and possible long-term esophageal surveillance strategies.

Fernando Moran, MD, Cong Phan, Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Achalasia is a rare, chronic esophageal motility disorder with an estimated annual prevalence of 1 per 100,000 subjects in the western populations. The disease can occur at all ages but the incidence increases with age.¹ Achalasia results from progressive degeneration of ganglion cells in the myenteric plexus of the smooth muscle of the lower esophageal sphincter and the lower two-thirds of the esophagus, resulting in failure of relaxation of the lower esophageal sphincter, accompanied by a loss of peristalsis in the distal esophagus.² Predominant symptoms are dysphagia and regurgitation. Treatment is purely symptomatic as the etiology of achalasia is still unclear. Treatment aims at lowering the lower esophageal sphincter (LES) pressure to improve the passage of food. Even after treatment there is continued aperistalsis and delayed transit, so sufficient symptom control does not prevent patients from having persistent retention of foods and fluids in the esophagus. This is associated with degrees of bacterial degradation of the retained contents and impaired clearance of regurgitated acid gastric contents. These factors can result in chronic inflammation of the esophageal mucosa, which potentially increases the risk of development of hyperplasia, dysplasia, and esophageal cancer. In addition, lowering of LES pressure does facilitate chronic acid gastroesophageal reflux which in a small percentage of patients leads to Barrett’s metaplasia and adenocarcinoma.1 Currently there are no specific guidelines for cancer surveillance in long term follow up of patients with achalasia.

Case Report

A 58 year-old Caucasian male presented with dysphagia. He had the history of heavy alcohol use (four drinks daily for 35 years). Previously diagnosed with achalasia, he underwent pneumatic balloon dilation in 2012. He experienced an esophageal perforation requiring an open repair and myotomy without any accompanying fundoplication. After surgery, he experienced constant reflux but no achalasia symptoms. He was started on a proton pump therapy immediately after surgery. He noticed weight loss and difficulty swallowing in July 2017, with a 20-pound weight loss and progressive dysphagia to solid food, unable to tolerate anything but a pureed diet.

On physical examination the patient had facial thinning, firm hepatomegaly and scoliosis. There were no Virchow lymph nodes palpable in the neck. His laboratory evaluation was unremarkable, including albumin and hemoglobin. Liver enzymes were also within normal limits.

Barium swallow with a 13 mm barium tablet revealed a tight stricture with a suggestion of “shouldering” in the proximal esophagus, 15 cm proximal to the gastroesophageal (GE) junction, and delay of the barium tablet at the stricture (Figure 1). Distal to the stricture there were no radiographic findings of achalasia. Upper endoscopy revealed that the upper third of the esophagus was normal. A stricture was found 25 cm from the incisors and the endoscope would not pass (Figure 2). Savary dilation was performed at 7 mm, 9 mm, 11 mm and 14 mm. The endoscope could then traverse the stricture after dilation. The stricture extended from 25 to 35 cm from the incisors. Its mucosa was nodular, friable, irregular and polypoid, suspicious for esophageal cancer (Figure 3). Biopsies of stricture showed moderately differentiated squamous cell carcinoma. The biopsies of the esophagus distal to the stricture showed changes of reflux esophagitis but no Barrett’s esophagus.

Subsequent computed tomography (CT) imaging of the chest revealed a circumferential, mass-like thickening of the proximal esophagus, approximately 7.5 cm in length. There was a loss of the fat plane with the aortic arch, proximal ascending aorta, lower trachea and left mainstem bronchus, concerning for tumor infiltration. There were no pulmonary nodules but a couple of small mediastinal lymph nodes were noted (Figure 4).

The patient was referred for chemotherapy and radiation. The esophageal stricture was re-dilated to a 17mm diameter size in preparation for the initiation of the radiation treatment. In addition, a percutaneous gastrostomy tube was placed to ensure adequate nutrition maintained through the treatment course/

Discussion

Esophageal cancer has been a very infrequent complication in the long term follow up of achalasia. Among a large case series, it ranges from 0.4% to 9.2%.³ One review found that the prevalence of esophageal cancer in achalasia was 3% in the long term follow up (five to 20 years), corresponding to a 50-fold increased risk.⁴ Most cases of esophageal cancer in patients with achalasia are squamous cell carcinoma located in the middle third of the esophagus. It is proposed that, although improved symptomatically by medical or surgical therapies, there is continuing stasis of food in the esophagus promoting lactic acid production and fermentation, inducing slow and continuous damage to the esophageal mucosa.^5,7 Conversely, adenocarcinoma may occur after treatment for achalasia, almost invariably arising from Barrett’s esophagus due to longstanding gastroesophageal reflux.⁷ Alcohol use also places patients at higher risk for squamous cell cancer. A combination of the factors described above along with the long history of alcohol abuse may have been the main triggers for squamous cell carcinoma.

Currently there are no guidelines for monitoring squamous cell carcinoma or other late complications such as esophageal and peptic stenosis or megaesophagus.⁶ Whether surveillance endoscopy should be generally recommended for all patients with esophageal achalasia is still controversial due to the long interval between the initial symptoms and diagnosis of achalasia and the development of carcinoma.⁸ Studies have indicated an interval between the diagnosis and treatment of achalasia and the diagnosis of esophageal cancer of at least 15 years.^9,10 Its opponents contend that, even under surveillance, mortality from esophageal cancer in achalasia patients resembles the general population with a survival rate of 40% after year two of diagnosis1 while similar surveillance programs for Barrett’s esophagus improve survival to 73-85% within two years of diagnosis.¹¹ One other consideration is the large cost of such surveillance programs. One study in 1995 has estimated that about 732 endoscopic procedures were needed to detect three cancers over a 15-year study period costing $585,000 thus averaging $195,000 per cancer detected.12 This is contrasted to $31,000 in similar adenocarcinoma surveillance program for patients with Barrett’s esophagus.¹² On the other hand, its proponents for surveillance argue that without strict endoscopy surveillance, esophageal malignancies will be detected very late and in an advanced stage. This is thought to be due to residual dysphagia which can mimic esophageal cancer and recurrent achalasia.¹³ In a recent study in 2016, Ota et al. performed annual endoscopies follow-up in 32 patients over a mean period of 14 years (range 5-40 years) after successful achalasia surgery treatment. They were able diagnose 6 of 32 patients with esophageal cancer at early stage. All six patients were alcoholic drinkers and three had smoking habit.¹⁴ This suggests follow-up endoscopy with biopsy is important in early cancer diagnosis as the risk for malignant transformation still persist even after successful achalasia treatment.

Overall, we suggest to identify a risk assessment profile score in individual achalasia patients based on the type of treatment they initially underwent, esophageal pH data, previous endoscopy biopsy results, barium swallow and other known independent risk factors for squamous cells carcinoma such as age, alcohol, tobacco use and male gender. In high risk patients, we should consider endoscopy with biopsy beginning within five years after diagnosis and possibly every three to five years thereafter.

Take Home Messages

When following patients who have been treated for achalasia, the initial treatment is key. It is expected that after pneumatic dilation there may be recurrence of dysphagia and repeated pneumatics over the next five to 20 years. With a successful myotomy and partial fundoplication there should be minimal or no recurrence of the achalasia.

However, when the myotomy surgery is incomplete, typically because the myotomy is not extended at least 2cm into the stomach, recurrence of “achalasia” dysphagia will occur within the first one to two years. When there is no fundoplication accompanying the Heller myotomy then the scenario for complications of long term reflux are also in the equation, specifically a peptic stricture as witnessed in our case. Finally, there remains a background incidence for squamous cell esophageal cancer in all patients, particularly with age, heavy alcohol intake and or cigarette smoking. The bottom line is to be aware of the different possibilities in the long-term follow-up of achalasia patients.