INTRODUCTION

Murali Dharan,Bhavtosh Dedania,Nayla Ahmed

Leiomyosarcomas (LMS) of the inferior vena cava (IVC) are rare and comprise less than 1% of all soft tissue sarcomas. Patients usually present in the fifth or sixth decade of life with back pain and/or increased abdominal girth. The diagnosis is usually made with noninvasive imaging [computed tomography (CT) or magnetic resonance (MRI)] or by invasive methods such as endoscopic ultrasound (EUS) with biopsy. We report the case of a 76 year-old female with a chief complaint of vague intermittent abdominal pain. CT scan revealed a mass possibly arising from the pancreas. She underwent a diagnostic EUS which confirmed that the mass was retroperitoneal in origin compressing the IVC; fine needle aspiration (FNA) showed spindle cells. The patient underwent laparotomy and pathology revealed a leiomyosarcoma of the IVC.

Nayla Ahmed, Academic Hospitalist, Dartmouth Hitchcock Hospital, Lebanon, NH Bhavtosh Dedania, GI Fellow, UT Health Sciences Center, Houston, TX Murali Dharan, St. Francis Hospital, Hartford & University of Connecticut, Hartford, CT

CASE PRESENTATION

A76-year-old Caucasian woman with a past medical history of coronary artery disease, diabetes mellitus, gastroesophageal reflux disease and anxiety presented with a two month history of progressively worsening sharp lower quadrant abdominal pain radiating to her right upper quadrant. She denied associated fever, chills, weight loss, night sweats, nausea, vomiting, constipation, diarrhea, melena or hematochezia. Initial laboratory evaluation showed mild kidney injury and normal CEA (1.3 ng/ml) and CA 19-9 (30 U/ml). Computed tomography (CT) scan of her abdomen and pelvis showed a 2.3 cm x 2.4 cm hypoechoic, retro-peritoneal mass between the pancreas and inferior vena cava (IVC). Magnetic resonance imaging (MRI) confirmed a solid mass along the posterior head of the pancreas and anterior to the IVC at the origin of renal veins. There was compression of the IVC however there was no thrombus or invasion.

Endoscopic ultrasound (EUS) confirmed a peri-duodenal, peri-pancreatic diffusely hypoechoic, heterogeneous retroperitoneal mass, measuring 3 cm x 2.8 cm x 2.4 cm. Fine needle aspiration (FNA) revealed spindle cells. The positron emission tomography (PET) scan showed increased metabolic activity in the proximal duodenum or pancreatic head, without loco-regional or distant spread. At laparotomy, a 5.0 cm x 4.0 cm x 3.0 cm mass extending from anterior aspect of the IVC was noted, and en- bloc resection performed. Pathology revealed spindle cell proliferation with atypical features without necrosis or increased mitotic activity. Immunohistochemistry was positive for vimentin, desmin, actin, myosin and negative for CD117 (ckit) and S-100 with a Ki67 proliferative index of 40 to 60%. Findings were consistent with high grade, poorly differentiated leiomyosarcoma [Stage 2a (T1bN0M0), Grade 3].

Adjuvant radiotherapy was administered, and outpatient follow up revealed recurrence-free survival at 36 months.

Discussion

Vascular leiomyosarcomas (LMS) are rare soft tissue sarcomas and account for 2% of all leiomyosarcomas¹ and 0.7% of all soft tissue sarcomas in adults.² Over half of these vascular LMS arise from the IVC. Patients usually present in the fifth or sixth decade of their lives with a male to female ratio of 1:4.³ Clinical symptoms are vague and include back pain, increasing abdominal girth, weight loss and abdominal pain.⁴ The tumor commonly grows extra-luminally (in more than 60%)⁵ and hence pedal edema is not a common presentation. Clinical presentation depends on location and luminal versus extraluminal growth. Segment I (infra-renal involvement) occurs in 36% and can present as lower extremity edema, deep vein thrombosis (DVT) and abdominal mass. Segment II involvement (hepatic to renal veins) is the most common (up to 44%) and can present as abdominal pain, nephrotic syndrome and hypertension. Segment III involvement (right atrium to hepatic veins) is least common and can cause cardiac arrhythmias and Budd-Chiari syndrome. Liver involvement by direct contiguity or metastases is less common but has been noted (up to 20%).⁶ These tumors tend to metastasize primarily to lung and liver and occasionally to bone and brain.^7,8

Tumors originating from segment II respond better to therapy.^3,4 Other prognostic factors include tumors arising from tunica media and absence of palpable abdominal mass. Presence of abdominal pain (which occurs earlier in segment II involvement due to rich innervation) portends better prognosis. Improved survival rates are noted with early detection, surgery and neoadjuvant therapy.

Surgical resection is the treatment of choice. The most important predictor of 5-year survival is complete resection of the lesion.^3,9 Other important prognostic factors include the histopathological grade ¹⁰ and location of the tumor.¹⁰ Data regarding prognostic value of tumor size are conflicting.^10,12 Median time to recurrence is 8 to 27 months.¹³ Adjuvant radiotherapy is indicated for high grade tumors and margin-positive resections.⁹

Very little literature is available on the role of EUS in the diagnostic work up of this tumor. To the best of our knowledge, there is one case report of EUS-FNA diagnosis of IVC LMS during evaluation of a large right retro-peritoneal tumor.¹⁴ EUS can be very useful in confirming relation of tumor to IVC and providing tissue diagnosis – as was the case in this patient. It?s role in diagnosis of incidental finding of IVC LMS during EUS for other indications needs to be ascertained. It is likely that EUS is perhaps most helpful in segment II lesions.

CONCLUSION

LMS of the IVC is a rare tumor that presents a diagnostic challenge. It should be considered in the differential of retro-peritoneal tumors, as survival improves with early detection and resection. EUS can be helpful in the diagnostic evaluation.

The Microbiome And Disease, Series #3

The Microbiome and Obesity

Sabine Hazan,

Daniel Frochtzwajg,

Skylar Steinberg

There is a growing body of research suggesting that obesity, metabolic syndrome, and insulin resistance are associated with predictable phyla and gene level compositional changes in the intestinal microbiome of humans and mice. With a better understanding of these changes, we can develop new, robust therapeutic strategies. In this article, we will briefly discuss some of the definitive research related to the microbiome and its impact on obesity and other metabolic derangements.

Sabine Hazan, MD, Gastroenterology/Hepatology/ Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center Daniel Frochtzwajg, DO, Research Assistant, Ventura Clinical Trials Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials, Ventura, CA

In 2016, the World Health Organization (WHO) estimated that, globally, over 1.9 billion adults and 340 million children and adolescents (between the ages of 5 and 19 years), were overweight or obese. Since 1975, the worldwide prevalence of obesity has tripled, and, currently, the majority of the world?s population lives in countries where being overweight or obese kills more than being underweight.²¹ An increased body mass index (BMI) is a risk factor for cardiovascular disease, musculoskeletal disorders, diabetes, and a number of malignancies, including endometrial, breast, ovarian, prostate, liver, gallbladder, kidney, and colon cancers.²¹ Traditional weight loss therapies have proven largely ineffective, and given the dire consequences of obesity on general health, the development of better treatment modalities has become a scientific imperative. There is a growing body of research suggesting that obesity, metabolic syndrome, and insulin resistance are associated with predictable phyla and gene level compositional changes in the intestinal microbiome of humans and mice; ^8,9 with a better understanding of these changes, we can develop new, robust therapeutic strategies. In this article, we will briefly discuss some of the definitive research related to the microbiome and its impact on obesity and other metabolic derangements.

Contemporary, culture-independent techniques for microbial DNA sequencing have identified four dominant bacterial phyla which reside in the mammalian gut.¹⁷ They are the Gram-negative Bacteroidetes and Proteobacteria and the Gram- positive Actinobacteria and Firmicutes.¹⁷ In two foundational studies, one by Ley et al. and another by Turnbaugh et al., researchers used 16S rRNA gene sequencing to demonstrate that the microbial composition of the distal gut of leptin-deficient ob/ob mice was reduced in Bacteroidetes and enriched in Firmicutes when compared to their lean ob/+ and wild-type siblings, despite being fed the same diet.1^5,17,19 In subsequent research, Ley et al. corroborated the findings in the murine studies, observing a similar increase in the Firmicute/Bacteroidetes ratio in obese humans.^13,14,18 However, other researchers have not noted the same pattern of colonization and more recent literature stresses biomarker composition and host-microbe genetics over phyla level profiles.^10,16

One way by which the microbiome affects body weight is through its link to fat storage and energy extraction. For example, Flint et al. showed that the gut microbiota enables energy extraction from otherwise indigestible polysaccharides.¹² Backhed et al. demonstrated that germ-free mice, once conventionalized, exhibited increased triglyceride content in their livers and adipose tissue, as well as increased luminal monosaccharide uptake.⁴ They hypothesized that this change was due to the microbial modulation of Fiaf, also known as angiopoietin-like protein 4, and its inhibitory effect on lipoprotein lipase (LPL). LPL is an enzyme that increases cellular uptake of fatty acids. During feeding, Fiaf is induced in germ- free mice; however, in conventionalized mice, it is functionally suppressed.^1,4 Years later, Backhed et al. shed light on another possible mechanism of microbe-mediated energy capture. They identified Ampk as a “fuel gauge” enzyme and found that the phosphorylated form was increased in the skeletal muscle of lean, germ-free mice.^3,17 Yet another pathway of the microbiome’s influence on host metabolism is through its production of hydrolases, which digest carbohydrates to short-chain fatty acids (SCFA). SCFAs like acetate and propionate are not only energy sources, but also interact with G protein-coupled receptors in the gut, altering motility and affecting inflammatory pathways.^15,17

In addition to the direct effects on host metabolism, it has been proposed that the microbiota composition may cause low-grade, systemic inflammation and play a role in the development of insulin resistance.1,7 Researchers have determined that lipopolysaccharide (LPS), a proinflammatory molecule, derived from Gram-negative bacteria in the mammalian microbiome is increased in the plasma of mice on a high-fat diet; this has also been observed in human studies.^1,7 Furthermore, it has been noted that the gut permeability of obese mice is increased secondary to expressional changes in tight-junction proteins. This, coupled with increased LPS production, elucidates a possible pathway to the generalized inflammation associated with metabolic diseases.^1,5,6,7 From a microbial ecology perspective, there has been an association of diabetic patients with a core microbiota rich in Proteobacteria.¹ Vrieze et al. found that the introduction of intestinal microbes from lean donors resulted in temporary improvements in insulin sensitivity in patients with metabolic syndrome.^1,20 This would lead one to think that fecal microbiota transplantation (FMT) is not a modality restricted to the treatment of C. difficile infection, but could possibly be used to treat obese and/or diabetic patients as well. As we discuss various biomarker-disease associations, it is appropriate to point to a microbiome classification paradigm associated with microbiota composition and biomarker levels. Arumugam et al. found that three energy-modulating molecules correlate with a host’?s BMI, which may mean that there are common microbiome compositions associated with various disease states; this would potentially enable intervention through diet, pre- and probiotics, and medication.^1,2 Lastly, more recent literature has highlighted the interaction between host genes and the microbiome, noting the relationship between leptin (“the satiety hormone”) and commensal bacterial populations, the declines and rises in various bacteria associated with the apolipoprotein A1 gene, and the phospholipase D1 gene, which may offer insight into host genotypic effects on microbiome.¹¹

Obviously, there is a strong body of science linking obesity and other metabolic disease states to changes in the gut microbiome; however, our understanding of the relationship between microbe and host must continue to be refined. Expanding research and interest in the human microbiome could lead to improved treatment strategies for obesity and its long list of comorbidities. With the increasing complexity of the microbe-host relationship, new ground must be broken with new ideas.

Food For Thought - Importance Of Nutrition In Alcoholic Hepatitis

Food For Thought – Importance Of Nutrition In Alcoholic Hepatitis

Ariel W. Aday,

Mack C. Mitchell

Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease, yet many patients suffering from this syndrome are not diagnosed or are inadequately treated. Nutritional support is an essential component of treatment as malnutrition has been associated with poorer outcomes. The role of adjunctive nutritional support, including enteral feeding and specific supplemental micronutrients, needs to be better delineated as it relates to altering clinical outcomes. Here, we review the nutritional aspects of patients with AAH and the effect implementation of various dietary interventions have on clinical outcomes of this frequently deadly condition.

As alcohol consumption increases worldwide, so does the prevalence of various clinical manifestations of alcohol-related liver disease. Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease, yet many patients suffering from this syndrome are not diagnosed or are inadequately treated. Morbidity and mortality are high in patients with severe AAH. Unfortunately, available therapeutic regimens remain few and far between. Nutritional support is an essential component of treatment for AAH as malnutrition has been associated with poorer outcomes. The role of adjunctive nutritional support, including enteral feeding and specific supplemental micronutrients, needs to be better delineated as it relates to altering clinical outcomes. We review the nutritional aspects of patients with AAH and the effect implementation of various dietary interventions have on clinical outcomes of this frequently deadly condition.

Ariel W. Aday, MD Department of Internal Medicine, Division of Digestive & Liver Diseases. Mack C. Mitchell, MD, Nancy S. and Jeremy L. Halbreich Professor, Executive Vice Chairman, Interim Executive Vice President for Health System Affairs, Department of Internal Medicine, Division of Digestive & Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX

INTRODUCTION

Alcoholic liver disease (ALD) refers to a spectrum of diseases including asymptomatic steatosis, alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis, and hepatocellular carcinoma. In its most severe form, AAH refers to decompensation of liver function on a background of heavy alcohol use and chronic ALD. This syndrome is characterized by several clinical features including malaise, anorexia, jaundice, tender hepatomegaly, and features of the systemic inflammatory response syndrome (SIRS) such as fever, tachycardia, and leukocytosis. This syndrome increases catabolism by up to 60% energy expenditure with increasing nutritional requirements necessary to support this state.^1,2 Patients with ALD are prone to a wide range of nutritional issues including direct consequences such as protein/calorie malnutrition and deficiencies in many micronutrients; indirect consequences are often due to other environmental factors largely associated with lifestyle changes.

Therapeutic Approach

Goals of treatment are to reduce short- term morbidity and mortality by utilizing a combination of intensive supportive care and adjuvant pharmacological therapies. Abstinence from alcohol is the cornerstone of therapy that is integral to long-term survival. The currently accepted pharmacological standard of care in treatment of severe AH is glucocorticoid therapy, although the optimal duration of therapy remains unclear.³ Several randomized control trials (RCTs) have demonstrated conflicting results regarding survival benefit. Glucocorticoids have been shown to improve short term mortality at 28 days, but long-term mortality benefits are unproven.^4,5 The efficacy of pentoxifylline for improving mortality is not supported.⁴ Adequate intake of both calories and nutrients is an essential component of intensive supportive care⁶ and has become an area of focus given the lack of other effective treatment modalities.

Nutrition Support

Numerous factors contribute to poor overall nutritional status that is commonly observed in patients with AAH (Table 1). These long- standing observations are a major reason that nutrition support is viewed as an essential part of the standard care for AH. Not surprisingly, patients with malnutrition are at increased risk for impaired recovery from AAH.⁶ Several studies have documented an association between protein- calorie malnutrition and higher short and long-term mortality rates in patients with severe AH.^7,8

Oral Nutrition

Multiple studies have shown that low daily caloric intake is associated with increased mortality in severe AH.9-12 The degree of protein-calorie malnutrition is directly related to mortality with a rate that approaches 80% in those patients who are characterized as severely malnourished.⁹ Patients with severe ALD often have reduced hepatic glycogen stores that result in hypoglycemia and accelerated catabolic breakdown of muscle to support gluconeogenesis.¹⁰ Reducing the length of time without oral calories with an emphasis on eating breakfast and a bedtime snack, as well as avoiding prolonged fasting during hospitalization or for diagnostic testing (i.e., add D5 to IV fluids where possible), may reduce the adverse impact of reduced hepatic glycogen stores.^11,12

Standard per oral dietary intake is often impaired in these patients for a multitude of reasons,¹³ including delayed gastric emptying and prolonged small bowel transit times resulting in early satiety.¹⁴ Furthermore, ascites can result in impaired gastric accommodation leading to postprandial discomfort.¹⁵ In addition to the mental status changes that can be seen in hepatic encephalopathy (HE) limiting ability to eat, HE also contributes to impaired appetite, and in some more covert forms, leading to an overall malnourished state. Finally, the use of lactulose (a non absorbable, but highly fermentable synthetic sugar) in treatment of encephalopathy can contribute to symptoms of bloating and discomfort, thus exacerbating impaired per oral intake.¹⁶ Patients who develop HE are at risk of undernutrition and enteral access may be indicated.^26,27 Normal- to high-protein diets are safe and do not increase the risk of encephalopathy in alcoholic hepatitis.⁶

Enteral Nutrition Support

In the most severe forms of AAH, patients may be intubated or obtunded to the point where conventional nutrition is not an option and enteral nutrition (EN) must be considered. Whether or not NG tubes should be recommended to provide EN remains controversial given potential feeding tube complications seen in some trials,^17,21 although the risk/benefit seems to weigh in favor of providing nutrition in these individuals.

Data suggest that the optimal nutrition goals for recovery are 1.5 g of protein/kg body weight and 30 ? 40 kcal/kg of body weight per day and should be initiated as soon as impaired per oral intake is noted.¹⁸ The American Society for Parenteral and Enteral Nutrition (ASPEN) suggest using an estimated euvolemic weight or usual weight for these calculations rather than actual weight in patients with cirrhosis and hepatic failure given complications of hypoalbuminemia, edema, intravascular depletion, and ascites that are often present in this patient population masking the patient?s true weight.¹⁹ EN is the preferred modality for providing nutrition in these patients unable to tolerate per oral intake based on expert consensus from ASPEN, and the American Gastroenterological Association.^18,19

In a systematic review assessing effects of nutritional intervention for patients with AH or cirrhosis, analysis of 13 randomized controlled trials suggested that nutritional therapy may have beneficial effects on clinical outcomes and mortality yet, given the high risk of bias in all the studies included, the need for higher quality trials was again underscored.²⁰ Several RCTs have shown that EN was comparable with glucocorticoids in reducing 28-day mortality and more effective in reducing long-term mortality. Another study suggested that combining intensive EN via nasogastric (NG) tube with glucocorticoids was not more effective than glucocorticoids alone, but the study was limited by lack of power and a higher than expected rate of NG tube complications in 7.4% of patients including aspiration pneumonia, poorly controlled hyperglycemia, and worsening HE. Premature feeding tube withdrawal was noted in 48.5% of patients predominantly due to intolerance and noncompliance.²¹ Importantly, regardless of the study arm, nutritional intake was found to be an important determinant of mortality, with those patients consuming < 21.5 kcal/kg/day having lower survival. Another study investigated combining EN with corticosteroids revealed improved survival, suggesting a complementary mechanism with these two therapies. Of note, corticosteroids were tapered when serum bilirubin and prothrombin time decreased by 50%, suggesting that a more individualized approach to duration of steroid therapy is key.²² The Lille model is useful to predict mortality rates in patients with severe alcoholic hepatitis treated with steroids and should be utilized to avoid extending therapy in those who are unlikely to respond, thereby reducing the risk of complications of glucocorticoid therapy.²³

In general, EN is preferable to parenteral nutrition support because delivery of nutrition to the gut strengthens gut mucosal immunity and subsequently decreases endotoxemia that may play a role in the pathogenesis of alcoholic hepatitis; it is also a less expensive option with far fewer complications.²⁴ Those patients with hepatic encephalopathy should be treated with nonabsorbable disaccharides, such as lactulose; rifaximin can be added if this treatment is not effective after 24-48 hours.²⁵

Parenteral Nutrition Support

Many randomized control trials have been performed comparing parenteral nutrition (PN) to enteral feeding in hospitalized patients with AAH and ALD. PN was shown in one of these studies to decrease serum bilirubin more rapidly and improve nitrogen balance, one measure of improved nutritional status.²⁸ However, PN did not significantly improve mortality or hepatic encephalopathy and was associated with increased risk of line infections and other complications such as thrombophlebitis. Furthermore, a Cochrane review of 37 RCTs studying therapeutic effects of PN, EN, and nutritional supplements, found no significant difference in mortality. However, all but one of the included trials had a high risk of systematic error highlighting the need for better designed and higher powered randomized trials to prove efficacy of various nutritional therapies.²⁹ Given the known hepatic complications associated with PN including sepsis, coagulopathy, and death in addition to worsening of existing liver disease and steatohepatitis, this modality is not recommended as preferential therapy.³⁰

Supplements

In addition to a high prevalence of severe protein- calorie malnutrition in heavy alcohol users, numerous micronutrient deficiencies including zinc, folate, thiamine, pyridoxine, vitamins A, B12, D, and E, have been reported in patients with heavy alcohol use and ALD.^31-33 These nutritional deficiencies are not solely related to poor intake, but also to impaired absorption placing these patients at risk of osteoporosis, myopathy, insulin resistance, and dyslipidemia, as well as increase the risk of developing alcohol-induced liver injury. Factors contributing to these deficiencies include:

impaired hepatic production of carrier proteins;
decreased bile acid synthesis and their small bowel delivery as a result of cholestasis leading to fat malabsorption.³⁴

Zinc supplementation may attenuate alcohol-induced liver injury and prevent hepatic encephalopathy through several mechanisms including the improvement of intestinal barrier function, decreasing proinflammatory cytokines, oxidative stress, and endotoxinemia, as well as offsetting hepatocyte apoptosis.^35,36 The recommended dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc (220 mg of zinc sulfate) taken once daily with a meal to decrease possible nausea. Of note, long term zinc supplementation can be associated with copper deficiency due to competition at the brush border for absorption. The duration of supplementation requires further investigation.

Obesity

Obesity and excess body weight have been associated with increased risk of development of ALD.^37,38 It is proposed by some experts that preexisting fatty liver due to obesity provides the necessary milieu to potentiate additional injury from alcohol,18 thus explaining the increased risk of AH in these patients. Recent data has also shown that there is increased gut permeability in patients with obesity and hepatic steatosis, which likely plays a role in the development of alcoholic liver disease.³⁹

Microbiome

Newer research suggests that the intestinal dysbiosis induced by alcohol ingestion is integral to the development of alcoholic-induced liver injury, further emphasizing the role of the gut- liver axis in disease development. The ?leaky gut? phenomenon is supported by numerous human and animal studies, which suggest alcohol intake causes impaired intestinal barrier function allowing for bacterial transport across the intestinal basement membrane into systemic circulation.^40-42 One study using a murine model showed that acute on chronic alcohol ingestion led to alterations in gut microbiota.⁴³ Treatment with antibiotics prevented neutrophilic infiltration mimicking acute steatohepatitis in human patients, as well as reduced the expression of several proinflammatory markers and reduced steatosis.⁴³ Other human studies have shown a high level of endotoxinemia associated with chronic alcohol use.⁴⁴ These observed changes in the gut microbiome have spurred investigations into possible interventions, which may normalize alcohol-induced intestinal dysbiosis. One study showed that rats consuming alcohol who were later fed with Lactobacillus- containing probiotics or prebiotic oats achieved similar microbiota compositions to the control mice.⁴⁵ Similar results have been seen in human studies,^46,47 suggesting that probiotics may improve clinical outcomes in patients with AH by reversing dysbiosis. Evidence also suggests that probiotics may prevent or decrease intestinal hyperpermeability thus decreasing intestinal oxidative stress and proinflammatory cascade^48-50 which could potentially ameliorate development of alcoholic liver disease. Although probiotics are not considered a standard of care in the treatment of AAH, several RCTs are underway to study potential benefits of probiotic therapy in patients with moderate AAH (clinicaltrials.gov).

CONCLUSION

Nutritional intake is an essential component in recovery from AAH. Protein-calorie malnutrition is associated with significantly higher short and long- term mortality. Existing data favor early initiation of EN during this critical illness, however, more robust data supporting provision of EN when per oral intake is inadequate is needed. The role of specific therapies, particularly zinc and probiotics, in addition to clear recommendations on optimizing nutritional supplementation in this patient population also needs further study. Table 2 provides suggested nutrition interventions for clinicians in patients with AAH based on available evidence.

Dispatches From The Guild Conference, Series #10

A New Model of Specialty Care -The Inflammatory Bowel Disease Medical Home

Benjamin Click,

Miguel Regueiro

In this manuscript, we review the concept of patient-centered specialty medical homes, potential reimbursement methods, implementation requirements and potential challenges. We also present the process and considerations of developing a specialty medical home, and review our experience with an IBD specialty medical home. We further discuss other alternative value-based IBD models being studied across the country.

Benjamin Click MD, Fellow in Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA Miguel Regueiro MD, Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh School of Medicine, Professor of Medicine, University of Pittsburgh School of Medicine Medical Director, Inflammatory Bowel Disease Center Co-Director, Total Care-IBD Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Senior Medical Lead of Specialty Medical Homes, UPMC Health Plan.Conflict of Interest: Miguel Regueiro serves as a consultant and advisory boards for Abbvie, Janssen, UCB, Takeda, Miraca, Pfizer, Celgene, and Amgen. He also receives research support from Abbvie, Janssen, and Takeda. Benjamin Click serves as consultant for Janssen.

Healthcare costs in the United States are escalating at a staggering rate. New models of healthcare delivery have emerged, including patient-centered medical homes, to improve the patient experience, enhance healthcare quality and decrease costs. Previously employed in primary care, such models have not been tested in specialty patient populations. In collaboration with a large integrated healthcare system, we established a specialty medical home for inflammatory bowel disease (IBD). In this manuscript, we review the concept of patient-centered specialty medical homes, potential reimbursement methods, implementation requirements and potential challenges. We also present the process and considerations of developing a specialty medical home, and review our experience with an IBD specialty medical home. We further discuss other alternative value-based IBD models being studied across the country.

HEALTHCARE IN THE UNITED STATES

The United States spends more than any other country on healthcare, estimated at $3.3 trillion in 2016, accounting for 17.9% of the gross domestic product according to the Centers for Medicare and Medicaid Services. Healthcare spending is expected to continue rising by 5.6% per year through 2025. Chronic disease management accounts for the majority of healthcare expenditures. Despite this spending, the U.S. often fails to provide high-quality and efficient care. With an aging population, we can only expect this economic burden to swell.

New Models of Care

Over the past decade, new models of healthcare delivery have emerged that seek to address the growing healthcare economic burden by transitioning away from traditional fee-for-service, volume-incentivized reimbursement towards value-based care. Including accountable care organizations and patient-centered medical homes, these models seek to improve patient experience, enhance healthcare delivery and outcomes, and reduce costs by emphasizing care quality. Placing the patient at the center of the healthcare universe, a patient-centered medical home seeks to provide whole-person care to individuals by utilizing a small team of providers to coordinate all of the patient?s healthcare needs. Initially trialed in the primary care setting, patient-centered medical home results are mixed. A systematic review of 19 comparative studies demonstrated that patient-centered medical home interventions had a small positive effect on patient experiences and small-to-moderate positive effects on the delivery of preventive care services with modestly improved staff experiences.¹ Among older adults, there was a reduction in emergency department visits (risk ratio, 0.81 [95% confidence interval, 0.67-0.98]) but not in hospital admissions (risk ratio, 0.96 [95% confidence interval, 0.84-1.10]) in this patient population. Overall, however, there was no evidence for cost savings. The lack of clear success and cost savings with primary care-based patient centered medical home models has been attributed to multiple factors including caring for an older patient population with multiple chronic diseases, variability in patient-centered medical home design and structure, minimal reporting of financial plans utilized, and potential evaluation by entities that do not routinely publish in peer-reviewed journals (e.g., consulting firms).

Specialty Medical Homes – An Ideal Target Disease

Inflammatory bowel diseases (IBD) are life- long, chronic inflammatory conditions affecting the gastrointestinal tracts of approximately 1.6 million Americans, with a rising incidence rate, and are generally diagnosed in young adulthood. IBD is estimated to account for between $14- 31 billion in both direct and indirect costs from complex care needs and associated morbidity. IBD patients require integrated medical and surgical management with often costly pharmaceutical and procedural requirements. Additionally, IBD patients have higher rates of behavior comorbidities, which can impact healthcare adherence, medical response, unplanned healthcare utilization, and quality of life. These complex factors can result in fragmented care between multiple providers sometimes in different healthcare systems. Such segmented and fractionated healthcare falls short of seamless integrated care. Due to typical younger age and lack of other medical comorbidities, IBD patients often rely on a gastroenterologist as their primary healthcare coordinator. Thus, IBD may be uniquely situated as a chronic disease with a high economic burden and more focused medical needs to potentially benefit from a patient-centered medical home model.

A Break from Tradition

Patient-centered medical care is unique, especially when considering a specialty population with specialty providers. In traditional specialty care, a provider collaborates with a hospital or medical center, is referred patients by other providers and serves as a consultant, focuses mostly on the specific disease, is reimbursed through a relative value unit (RVU)-, volume-based payment structure, and receives institutional support from downstream revenue such as surgery, pathology, radiology, or infusions. In comparison, in a patient-centered specialty care model, the provider collaborates with a payer(s) and is referred patients by the payer to provide care for all patients with a certain disease in a population. The provider works with an interdisciplinary team to address all healthcare needs of each patient and is reimbursed through a value- based approach, focusing on implementing quality care, preventative medicine, and incorporating tele- or other tech-oriented medicine. The payer partner provides up-front support to develop this multidisciplinary team and resources in hopes of improved value and reduced costs.

SMH Requirements and Challenges

Instituting a SMH requires a significant change and deviation from traditional specialty healthcare. We acknowledge that resources for developing such alternative systems varies from region to region. We previously detailed the necessary factors to implement a specialty medical home.^2,3 These include a willing payer(s), a large enough IBD patient population, a physician champion, and goals with metrics of success. It is likely best if there is one or a few larger payers in the region to approach for potential collaboration. This will maximize the potential benefits and buy-in from the payer(s). As for patient population, we estimate that the smallest necessary IBD population for such an approach to be successful is approximately 500 active patients. The SMH system can be scaled to larger populations. Transitioning to patient-centered medical care is a departure from traditional specialty practice. In addition to addressing the biologic disease, the emphasis is on whole-patient care ? preventive care, behavioral medicine, socioeconomic factors, and provision or coordination of care for non-gastrointestinal symptoms and diseases. In a SMH, the specialist must be willing to incorporate and address all facets of healthcare, addressing unmet needs to improve patient outcomes.

Reimbursement Model

Due to the novelty of SMH, the ideal reimbursement model has yet to be defined. Considerations include a shared-savings or global cap approach with emphasis on total cost of care reduction. This will require particular attention to accrued costs, not only by care for the IBD itself, but also for the total care. While biologic medications incur a significant expense, and will likely continue to increase, this should not deter appropriate utilization in patients that may experience improved IBD outcomes, decreased healthcare use, and optimized work and life productivity from these medications. Leveraging the pharmaceutical negotiating power of payer partners may be able to reduce some of the cost impact. Ultimately, the SMH must work together with its partners to achieve high quality care at a lower cost.

UPMC-Total Care IBD as a New Model of Specialty Care

The University of Pittsburgh Medical Center (UPMC) is a large integrated healthcare delivery and finance system that operates both a large academic health system as well as a health insurance plan and currently covers over 3 million individuals, predominantly in Western Pennsylvania. In collaboration with an integrated healthcare delivery network, we formed an IBD specialty medical home (SMH), termed UPMC- Total Care IBD. Incorporating multidisciplinary care, open-access scheduling, and telemedicine, we have enrolled over 650 IBD patients to the SMH to date. Recognizing the complex medical, behavioral, surgical, and socioeconomic factors that influence IBD patients’? healthcare requirements, we implemented a multidisciplinary team including gastroenterologists, a psychiatrist, a social worker, a nutritionist, schedulers, nurse coordinators, and advanced practice providers. The gastroenterologist becomes the principal care provider for this patient cohort and coordinates the total care of each patient. UPMC-Total Care IBD also coordinates with colorectal surgeons and chronic pain specialists for direct care collaboration. Additional support is provided by the UPMC Health Plan (HP). Health coaches work directly with patients on lifestyle modifications including smoking cessation. UPMC HP also provides operational support in the form of data analytics, collaborative interpretation of data, program publicity, and IBD medication approval facilitation through their pharmacy department.

Patient Enrollment

UPMC-Total Care IBD initiated patient enrollment and care delivery in July 2015. Patients are eligible for enrollment in UPMC-Total Care IBD if they were between 18 and 50 years old and carry a clinical diagnosis of IBD. Initially after launch, the target patient population for UPMC-Total Care IBD were the highest healthcare utilizer patients. Thus, an initial criterion of greater than 25% of medical expenditures in the prior year were related to IBD. After several months of enrollment, to expand the patient population, this requirement was dropped and we now enroll any patient with UPMC HP insurance who has IBD.

Data Collection

At the initial visit, patient demographics and disease characteristics are collected. Prior IBD medications are also reviewed and recorded. At each visit, patient-reported interim healthcare utilization including emergency department visits, hospitalizations, radiographic studies, and endoscopies are documented. IBD medications as well as opiate and antidepressant use are reviewed and updated. Additionally, patient-reported disease activity indices (Harvey-Bradshaw Index [HBI] for CD and ulcerative colitis activity index [UCAI] for UC), disease-related quality of life (QoL) metric (short inflammatory bowel disease questionnaire [SIBDQ]), depression and anxiety screening metrics (patient health questionnaire [PHQ]-9 and generalized anxiety disorder [GAD]-7 respectively) are prospectively collected.

Individualized Treatment Plan

All patients are initially evaluated by the gastroenterologist, dietician, social worker, advanced practice provider, and registered nurse. If scores on mental health metrics indicate a potential mental health issue, the social worker or psychiatrist perform a full evaluation for comorbid behavioral health disorders. Patients requiring further individual psychiatric treatment are scheduled for additional clinical sessions and telemedicine as indicated. Prior to each clinic session, the UPMC-Total Care IBD team meets to discuss individual patients and determine active factors or issues requiring attention. Based on these discussions, the team allots differential amounts of time for the team member(s) addressing those issues. Figure 1. depicts key personnel, patient flow, data collection, and collaboration in UPMC-Total Care IBD.

One Year Outcomes

In the first year, UPMC-Total Care IBD enrolled nearly 350 patients. Enrolled patients experienced significant reduction in both emergency room visits by nearly one-half and hospitalizations by approximately one-third. This was accompanied by significant improvement in disease activity scores, quality of life, and mental health metrics. Patients in the most extreme quartiles of these metrics demonstrated the most improvement. Retention in UPMC-Total Care IBD was high, with over 90% patients staying actively engaged at the end of one year. To date, over 650 patients are now actively participating in UPMC-Total Care IBD with ongoing enrollment. Limitations of this initial evaluation include the lack of a standardized control cohort and relatively short-term follow-up. Creation of a comparable control population and longer-term follow-up are underway.

Other Experimental Models

Other centers are also experimenting was variations of value-based care and patient-centered approaches in IBD. The Division of Digestive Disease at UCLA has introduced a comprehensive, integrated, and holistic approach to the management of IBD, incorporating value-based care (the “value quotient”) and cost-effective IBD management.4-7 The Illinois Gastroenterology Group developed a care management system for patients with IBD utilizing nurse care managers and physician medical directors in a team approach, along with clinical decision support and patient engagement, and has recently partnered with a national payer to create a specialist intensive medical home.^8-10

CONCLUSION

Healthcare spending in the United States is growing exorbitantly and cannot be sustained. Alternative healthcare delivery models are being explored in an attempt to reduce costs of care while improving outcomes, quality of life, and patient experience. IBD is uniquely situated to benefit from a value- based coordinated care model due to the younger patient population affected by a chronic illness requiring multidisciplinary care with a high economic impact. In collaboration with a large integrated healthcare delivery and finance system, we formed a patient-centered specialty medical home for inflammatory bowel disease patients. After one year of enrollment, treatment, and follow- up, we observed a significant reduction in emergent and inpatient healthcare utilization with concordant improvement in disease activity, quality of life, and mental health metrics. This model of caring for IBD patients shows promise in improving outcomes while reducing spending. Extension to other chronic disease models is underway and further evaluation of these alternative models of care will be critical to addressing the future of healthcare in the U.S.

Introduction: Dispatches From The Guild Conference 2018

Dispatches from the GUILD Conference 2018

Uma Mahadevan

Uma Mahadevan MD, Professor of Medicine, Medical Director, UCSF Center for Colitis and Crohn’s Disease

Dear Reader: As Chairman of the GUILD (Gastroenterology Updates, IBD, Liver Disease) Conference (guildconference.com), I would like to welcome you to the second annual series “Dispatches from the GUILD Conference.” The GUILD conference is a 4 day, high impact course held in Maui, HI, focusing on inflammatory bowel disease (2 days), liver disease (1 day) and a fourth day of rotating hot topics in gastroenterology. Continuing medical education (CME) and maintenance of certification (MOC) points are offered. The course features the nation’s top faculty and innovative presentation formats in a relaxed setting conducive to interactive learning, networking and camaraderie. GUILD and Practical Gastroenterology have teamed up to bring you the highlights from GUILD. Mahalo and enjoy!

Sincerely,
Uma Mahadevan, MD

Nutrition Issues In Gastroenterology, Series #172

Amyloid – A Wolf in Sheep’s Clothing

February 2018 • Volume XLII, Issue 2

Hassan Tariq,

Muhammad Umar Kamal,

Ariyo Ihimoyan

Amyloidosis is a complex group of diseases associated with variable presentations characterized by excessive deposition of the misfolded, abnormal, and insoluble proteins in different organs of the body. The goal of management in amyloidosis is to inhibit the excessive production of amyloid fibrils and control symptoms. This article highlights classification, etiologies, diagnosis, and management of amyloidosis, in particular, the management of GI symptoms and malnutrition.

Hassan Tariq, MD, Muhammad Umar Kamal, MD, Ariyo Ihimoyan, MD, Bronx Lebanon Hospital Center, Department of Medicine, Bronx, NY

INTRODUCTION

Amyloidosis is a complex and rare group of diseases associated with diverse etiologies and variable presentations. It is neither a malignancy nor an autoimmune disorder, but it can occur in response to, and along with, chronic infectious and inflammatory diseases. It is characterized by excessive deposition of misfolded, abnormal, and insoluble proteins in different organs of the body resulting in structural change and altered function.¹ The incidence or prevalence is not well known due to the wide spectrum of presentations increasing the chance of under-diagnosis or even missing the diagnosis, resulting in confounding statistics of occurrence. In 1992, Kyle and colleagues reviewed a 40-year data set of primary amyloidosis in Minnesota and reported the overall prevalence of Amyloid light chain (AL) amyloidosis of about 6-10 cases per million person-years (MPY).² This corresponds to disease burden of approximately 2200 cases in the U.S. annually. The prevalence may have increased over the years due to newer diagnostic and therapeutic interventions for chronic infectious and inflammatory diseases contributing to increased morbidity. A recent cohort study of Latin America has reported incidence by describing the disease burden of 6.13 cases per MPY for AL and 1.21 cases per MPY for amyloid A (AA) amyloidosis.³ Given its complicated clinical course, amyloidosis poses diagnostic and therapeutic challenges for the clinicians. In this article, we aim to review the basic pathophysiology, clinical presentations, diagnostic dilemma and treatment hurdles, especially focusing on the management of gastrointestinal (GI) amyloidosis and nutritional implications.

Types of Amyloidosis

The group of diseases that fall under “amyloidosis” can be either genetic or acquired. Genetic/hereditary manifestations are due to mutations in specific genes. Acquired occurs in response to malignancies or chronic inflammatory and infectious states. Amyloid protein production starts in response to these conditions and has the propensity to deposit in certain organs or spread systemically and manifest with localized or systemic disease. The most common type of systemic amyloidosis is primary amyloidosis or, Amyloid light chain (AL).⁴ Other types include secondary amyloidosis (serum amyloid AA),^2,5 dialysis-related (b-2 microglobulin),⁶ senile (Alzheimer?s related apolipoprotein E), and familial amyloidotic polyneuropathy (transthyretin, apolipoprotein AL). Different types are described in Table 1. Primary amyloidosis AL has been described in association with plasma cell disorders like multiple myeloma.4 Secondary AA development occurs in the setting of chronic inflammatory/infectious disorders such as autoimmune diseases, persistent or longstanding microbial infections (leprosy, tuberculosis, bronchiectasis), and various cancers (carcinoma of the GI tract, kidneys, pulmonary, genitourinary system, or skin), etc. The proteolysis of serum amyloid A (acute phase reactant) results in the deposition of AA protein in various organs.^6-8 In familial amyloid polyneuropathy, the mutated transthyretin and apolipoprotein can deposit in any tissue resulting in malfunction, but has a high predisposition towards the liver.^4,9 Senile amyloidosis, commonly seen in the elderly, affects the heart, pancreas, prostate, and brain. Disease is confirmed with congo-red staining of biopsied specimens of above-mentioned organs. The involvement of the brain is considered as one of the etiologies of Alzheimer?s disease in the elderly.⁹ Familial amyloidosis is an autosomal dominant disease caused by abnormal deposition of serum amyloid P in mucosal or neuromuscular regions and results in disruption of tissue structure and function.^6,10

Pathophysiology

The amyloid protein develops in response to chronic inflammatory/infectious disorders including cancers and is deposited in various organs of the body most specifically, heart, kidneys, liver, bowel, skin, etc. depending on the type of amyloidosis. Tissue specimen can be obtained from any organ suspected/confirmed to have amyloidosis. In patients suspected of amyloidosis, subcutaneous (SC) fatty tissue biopsies (usually from the abdomen) are taken and can be stained with different stains like Congo red (appears green under polarizer), hematoxylin eosin (appears red) or thioflavin T (appears yellow green), but the Congo red staining is the most specific for diagnosis.^4,11

Clinical Presentation

The clinical findings of amyloidosis depend on the areas of involvement of the amyloid deposition. General symptoms include weight loss, fatigue, dizziness, and generalized or pedal edema.^4,12

Each type of amyloid has a predisposition to deposit in different organs and infiltration of the amyloid fibrils, commonly seen in kidney, heart, peripheral nerves, and GI tract, lead to the symptoms observed.¹³ Table 2 shows the percentage of organ involvement depending on the type of amyloidosis.

Initial findings of kidney involvement include proteinuria, followed by azotemia and renal failure depending on the underlying cause and severity of disease. Infiltration of the heart can manifest with symptomatology of restrictive cardiomyopathy, which can progress to heart failure or fatal cardiac arrhythmias.4⁴

The amyloid deposition in the GI tract effect the myopathic and neuromuscular function by involving the muscularis mucosae, and gradually damaging blood vessels, nerves and nearby structures.¹⁴ The consequence of which is impaired GI motility leading to gastroparesis with nausea and heartburn, anorexia, and constipation; severe disease might lead to pseudo-intestinal paralysis. Diarrhea occurring in GI amyloidosis can be due to autonomic dysfunction, enteritis, or excessive bacterial overgrowth in the small bowel.^15-17 GI bleeding is a fearsome presentation of systemic amyloidosis seen in 57% patients and can occur anywhere in the GI tract; the cause of which can be ulceration or erosion.¹⁸

Interestingly, AA amyloidosis exhibited the highest percentage of GI findings in the range of 10%-70%; AL amyloidosis is associated with fewer extrahepatic GI symptoms.⁴ The amyloid deposition in the liver occurs in stellate cells resulting in fibrogenesis¹⁹ and subsequently mechanical and functional tissue disruptions. It does not suddenly derange liver function, but initially causes symptoms like weight loss, abdominal pain, decreased appetite and fatigue. Jaundice is rare in amyloidosis, but if present, is associated with an increased mortality rate.^20,21 Macroglossia and clinical splenomegaly have also been described in patients with systemic amyloidosis.²²

DIAGNOSIS

Patients with amyloidosis might undergo a battery of tests due to complex clinical presentations before the final diagnosis is made. Therefore, when suspected, relevant imaging and laboratory testing and appropriate tissue collection is necessary for the definitive diagnosis. It is ideal to biopsy the organ affected as it increases the diagnostic yield, but commonly SC fat tissue is biopsied usually from the abdominal wall, due to less risk of complications; however, any other site of adipose tissue can be biopsied depending on the availability of subcutaneous fatty tissue. Tissue biopsy is under local anesthesia with 2% solution of lidocaine subcutaneously; then using a scalpel, a cutaneous resection of 3-4mm length of skin is done; followed by clipping of subcutaneous fatty tissue with a Kocher and the material is separated with a scalpel. Biopsy site is wrapped with clean dressing for a couple of days. Some recent studies have reported a wide range (13-73%) of sensitivity of SC tissue biopsy, but specificity was 100%.^23-24 The variable sensitivity is due to different types of amyloidosis. Rectum is the next common site of biopsy with sensitivity of 75-85%.²⁵ Other organs may be biopsied when involved, but hepatic biopsy is usually not recommended given high risk of bleeding.^4,26 In patients with systemic AA or AL amyloidosis, the diagnostic sensitivity of whole-body 123I-labeled serum amyloid P (SAP) scintigraphy was 90%. It showed the amount of amyloid infiltrated in the all the affected organs except the heart.²⁷ It is very important to screen other organs such as heart, kidney, bone marrow, GI etc. for amyloidosis if the disease is suspected or confirmed anywhere in the body.^11,12,28

The radiological imaging is usually nonspecific, but can be helpful in leading towards diagnosis. Radiographs, barium studies, CT, and MRI are utilized to evaluate the abnormalities. The findings on imaging of the GI tract include mucosal irregularities, thickened mucosal folds, rough mucosal surface with multiple nodular densities, polyps, narrowed lumen, thickened intestinal wall, etc. They are most prevalent in the small intestine (SI).^29-32 Sometimes thickened and dilated SI can be visualized on the CT.³¹ Laboratory results revealing proteinuria, and abnormal serum protein electrophoresis may suggest the existence of amyloidosis in the patient.¹² These tests provide a clue for further assessment of a patient having an obscure diagnosis.

Alarming GI symptoms warrants endoscopy, which helps in revealing the site of involvement. In the GI tract, the small intestine is mostly affected.^13,33 Studies have reported polypoid appearance and thickened intestinal folds in AL seen during endoscopy that can lead to intestinal obstruction and constipation. A diffuse granular appearance is seen endoscopically in AA and clinically manifests as bleeding, diarrhea, and malabsorption.^12,30,34,35 Gastric findings include submucosal masses, erosions, ulcers, thickened rugae and hemorrhages.³⁶

Management

The goal of management in amyloidosis is to inhibit the excessive production of amyloid fibrils. It includes treating the underlying etiologies of acquired amyloidosis like cancers, chronic infections and auto-immune diseases.³⁷

Plasma cell proliferative disorders causing AL amyloidosis and affecting organ system warrant further investigation. This includes further evaluation by an oncologist for possible chemotherapy or stem cell transplantation (SCT).^37,38 Similarly, patients suspected of having AA amyloidosis are managed by addressing the underlying etiology like chronic infectious or inflammatory disorders and/or malignancies. This is because targeting the underlying cause for AA amyloidosis will halt and prevent the progression of disease. Sometimes it can be difficult to elicit the cause of AA amyloidosis requiring frequent physician visits and extensive diagnostic work up. Studies have reported efficacy with the use of biologics³⁹ i.e., interleukin-6 inhibitors/anti-tumor necrosis factor agents (TNF) for the treatment of rheumatic diseases,⁴⁰ and anti-tumor necrosis factor agents (TNF) for management of inflammatory bowel disease.41⁴¹

Symptoms

The GI symptoms can result in poor intake, nutritional deficiencies, and malabsorption. Initial management of patient requires control of symptoms such as persistent nausea and vomiting with anti-emetics. This includes treating symptomatic diarrhea with antidiarrheal or antisecretory agents, and diarrhea due to small bowel bacterial overgrowth with antibiotics.⁴² Prokinetics like metoclopramide or erythromycin may be tried for gastroparesis or dysmotility.^13,43

Nutritional Considerations

Malnourishment in amyloidosis is multifactorial and requires regular nutrition assessment. Malnutrition should be corrected by managing symptoms and providing nutritional support, as well as vitamin and mineral supplementation when needed. Early nutritional referral and consultation is recommended.^4,44 Patients with mild to moderate involvement of the bowel will benefit from enteral feeding if oral intake is inadequate. In patients with severe malnutrition, severe GI involvement with worsening GI symptoms or pseudo- obstruction, total parenteral nutrition (TPN) may be considered.44 However, TPN is associated with increased risk of infections and edema in these patients, so caution is necessary.⁴⁴ These patients need to be closely monitored to decide if and when to start more aggressive management like TPN, but only after enteral feeding has failed. Intake of various supplements has shown to influence the disease activity in animals, but studies in humans are lacking.^45-47

The response to treatments in AL amyloidosis can be assessed by monitoring the amount of amyloid deposits via serum amyloid P scintigraphy and functional status of organs via laboratory tests and imaging as required.⁴⁸

Prognosis

The survival in these patients depends on the type of amyloidosis and the severity of organ damage. AL amyloidosis has a poor prognosis due to its association with malignancy, even if the patient is undergoing chemotherapy alone. In patients undergoing chemotherapy and stem cell transplantation (SCT), the calculated 5 year survival is approximately 60%.³⁷ Treatment of underlying disorders in AA amyloidosis is associated with regression of amyloid deposits and improvement in mortality.⁴⁹ In addition, the survival of patients also coordinates serum amyloid P concentrations that can be monitored with SAP scintigraphy. This is of utmost importance in targeted management of serum amyloid P for the treatment of amyloidosis by monitoring SAP levels during therapy.⁵⁰ A recent study by Lim et al reported median overall survival of 15.84 months in AL amyloidosis patients without GI involvement and 7.95 months in patients with GI involvement. GI involvement is associated with poor prognosis.51⁵¹

SUMMARY

Amyloidosis usually manifests in a discreet sequela, which include non-specific symptoms such as weight loss, autonomic dysfunction, fatigue, and GI symptoms. Patient with chronic diseases and cancers should be suspected to have amyloidosis if presenting with nonspecific symptoms. The evaluation includes laboratory testing and imaging, and if necessary, biopsy of the organ involved which is the gold standard for diagnosis.

Frontiers In Endoscopy, Series #41

Use of Volumetric Laser Endomicroscopy in the Esophagus

February 2018 • Volume XLII, Issue 2

Arvind J. Trindade

Advanced or optical imaging in the esophagus allows for a detailed view of the esophagus at a level beyond white light endoscopy. The newest commercially available endoscopic advanced imaging tool is volumetric laser endomicroscopy (VLE) or second-generation optical coherence tomography. VLE is currently being used in management of Barrett’s esophagus, squamous cell dysplasia and cancer of the esophagus, and during peroral endoscopic myotomy. This review describes VLE and its current clinical applications to the esophagus.

INTRODUCTION

The principle behind optical coherence tomography (OCT) is to measure the signal intensity of reflected light from a tissue sample. It is similar to endoscopic ultrasound but uses infrared light instead of an acoustic signal. OCT can produce high-resolution cross sectional imaging of the esophagus. The axial resolution is superior to high-resolution endoscopic ultrasound but at the expense of reduced depth of penetration compared to endoscopic ultrasound. The OCT probe is passed through a channel of an endoscope and once activated emits infared light. As light reflectivity from the esophageal tissue is measured, real time images of microscopic mucosal and submucosal changes are measured.

The mainstay of early OCT use in the esophagus was for Barrett’s esophagus. The older generation system consisted of a probe that was in gentle contact with the mucosa. A landmark study in 2001 showed that OCT could reliably distinguish between normal esophagus and intestinal metaplasia (IM).¹ The study showed that normal squamous esophagus contained layered strictures while IM had loss of this layering or effacement. In 2006, OCT criteria were introduced to distinguish neoplastic IM of the esophagus (high- grade dysplasia and intramucosal cancer) from non- neoplastic IM.² These criteria were derived from an in-vivo based study in which imaged areas with an OCT probe were then biopsied with a jumbo biopsy forceps. Histology was then compared to OCT images. Features indicative of neoplasia were 1) a high surface OCT signal to subsurface signal known as incomplete surface maturation and 2) glandular atypia. A scoring system, known as the OCT dysplasia scoring index (OCT-SI) or Evans criteria, was derived that indicated the likelihood of neoplasia in a Barrett’s segment imaged by OCT. When the dysplasia index is greater than or equal to two, a sensitivity and specificity of 83% and 75% was achieved, for diagnosing intramucosal cancer.

Second generation OCT, known as volumetric laser endomicroscopy (VLE), is somewhat different in that it is a balloon based system that contains the imaging probe. The probe is passed through the channel of the endoscope and the balloon is inflated to center the probe (Figure 1). The probe can then spin 360 degrees , emitting infrared light, and real time 360 degree cross sectional images of the esophagus are obtained. This technology is different from the probe-based system in that a whole 6 cm segment of the esophagus can be imaged in 90 seconds; a major improvement to the efficiency of this technology. In addition, the wide field imaging is a feature that other optical imaging platforms lack. This system is commercially available in the United States (Ninepoint Medical, Bedford, MA). The balloons currently come in 14 mm, 17 mm, and 20 mm. Specific details on the performing this procedure can be found in recent reviews of this topic but are beyond this review.^3,4

Normal VLE Images

Normal squamous esophageal mucosa can be seen in Figure 2. It consists of layered architecture without glands in the epithelium. Pits and crypts, a hyperreflective or dark surface, and lack of layered architecture can be seen on VLE in normal gastric cardia (Figure 2).^3-5?

VLE in Barrett’s Esophagus

In Barrett’s esophagus there is loss of layered architecture without any pits and crypts (to distinguish it from gastric mucosa). The features of neoplasia in VLE are generally the same features as first described in the probe based system.² Recently two studies have further characterized neoplasia criteria for VLE using endoscopic mucosal resection specimen that were scanned using VLE ex-vivo.^6,7 Leggett et al. devised a new scoring algorithm for neoplasia detection termed the VLE- DA.⁷ In this algorithm, the degree of effacement (loss of layering) is determined. If complete loss of layering is observed, then one observes the degree of surface to subsurface intensity. If the surface intensity is greater than the subsurface then dysplasia should be suspected. If partial effacement is observed then one determines the degree of atypical glands, if present. If greater than 5 atypical glands is present than one should suspect dysplasia. Based on this algorithm, the sensitivity and specificity for dysplasia detection was 86 and 88% respectively. Figure 3 shows examples of nondyspalstic and dysplastic Barrett’s esophagus. Swager et al. also looked at EMR specimens that underwent VLE scanning and determined three independent VLE features that predict dysplasia: effacement, higher surface to subsurface signal, and the presence of atypical dilated ducts/glands.⁶ They developed a VLE prediction score assigning certain points for each feature. Both criteria are similar, but in clinical practice the VLE-DA is somewhat more practical to use. In addition, effacement is commonly seen, and in our clinical experience not associated with dysplasia. Currently, physicians in practice use these criteria to help guide them when looking for images that possible contain dysplasia. The interobserver variability for VLE image interpretation is favorable.⁸ Given both the Leggett and Swager criteria are based on ex-vivo EMR specimens, in-vivo research is needed to validate these criteria.

In mid 2016, laser marking became commercially available, allowing physicians to mark abnormalities seen on VLE on the esophageal mucosa. The commercially available model was an upgrade from that used in human pilots.⁹ The physician has the option of placing one or two superficial laser marks at sites of VLE abnormalities. This allowed the ability to target lesions specifically rather than estimating where the abnormality was based on the registration line on the balloon and the VLE scan and relation to the abnormality from the GE junction. To date there are case reports and series showing the benefit of VLE in clinical practice.^5,10?-14 Figure 4 shows an example of a case where VLE with laser marking helped diagnose Barrett’s with high- grade dysplasia. Our group presented findings at the American College of Gastroenterology 2017 meeting showing an incremental yield of dysplasia detection in patients with Barrett’s esophagus who underwent surveillance endoscopy with VLE with laser marking compared to patients that underwent VLE without laser marking or patients that had traditional Seattle protocol surveillance biopsies.¹⁵ Currently there is an ongoing multi- center prospective dysplasia detection pilot to confirm in-vivo criteria of dysplasia.

An anticipated upgrade to the VLE system in the near future will be computer automated detection of VLE abnormalities. Although the learning curve for VLE image interpretation seems favorable,¹⁶ many VLE image frames are presented to the user at one time and thus it is possible to miss a suspicious area. A recent computer algorithm pilot based on VLE EMR specimens showed good performance to detect Barrett’s associated neoplasia.¹⁷ Addition of this feature will make VLE more user friendly to endoscopists.

VLE in Squamous Cell Dysplasia and Cancer

The vast majority of esophageal cancers occur in the non-western world with ninety percent of these being esophageal squamous cell carcinoma (ESCC).¹⁸ The precursor to ESCC is squamous intraepithelial neoplasia (SIN).19 Endoscopic therapy is accepted for ESCC and SIN if the lesions are limited to the epithelium or lamina propria.^19,20 Lesions limited to the mucscularis mucosa or superficial submucosa are considered a gray zone for endoscopic treatment19,20 These standards of therapy are based on the risk of lymph node metastasis (LNM).^21,22

Determining which patients have ESCC limited to the lamina propria can be challenging. In a recent retrospective study, specimens from patients that underwent ESD for flat ESCC, were examined.²⁰ The study showed that one third of patients that met clinical and endoscopic criteria for RFA had histologic criteria that were considered contraindications for RFA. The study concluded that determining which patients should receive RFA therapy is challenging. The challenge stems from inaccurate pre-therapy staging of ESCC.²³ High-frequency endoscopic ultrasound (HF- EUS) and EUS are limited in imaging superficial ESCC.²³ However, studies have shown that optical coherence tomography (OCT) can produce high- resolution images of staging ESCC. A prospective study compared OCT to HF-EUS in 123 patients with superficial ESCC and found that OCT had a higher accuracy (95% vs 81%; p<0.05).²³ The probe based first generation OCT, used in that study, is not commercially available.

There is limited experience on the use of VLE for staging superficial squamous cell cancer of the esophagus. In our experience we have found that VLE can be helpful for squamous dysplasia/SIN or superficial cancers involving up to the lamina propria. This staging is based on OCT signal penetration into a layer with preservation of the layers below it. In VLE staging of SIN, a surface hyperreflective (darker) signal from the neoplasm is visualized only involving the epithelium with preservation of the layers below it (Figure 5).²⁴ However with disease involving deeper layers, a surface hyperreflectivity is seen with effacement (loss of the traditional layering) below the darkened surface. The extent or depth of disease involvement is determined by which layers are preserved below it. If there is involvement of the muscularis mucosa or deeper, a surface hyperreflectivity is seen, with complete effacement of all layers below it. An example of a SIN lesion is seen in Figure 5. Studies are needed to confirm our findings. If studies confirm our findings, than it is conceivable that VLE can guide appropriate endoscopic therapy for SIN (RFA or resection) and superficial squamous cell esophageal cancer limited to the lamina propria (RFA or endoscopic resection). Disease determined to involve the muscularis mucosa based on EUS/ VLE could be candidates for endoscopic resection by endoscopic mucosal resection or endoscopic submucosal resection technique.

VLE Use in Peroral Endoscopic Myotomy

Peroral endoscopic myotomy (POEM) has emerged as a first line treatment for achalasia.²⁵ A POEM consists of creation of an esophageal submucosal tunnel, and subsequent myotomy of the distal esophageal circular and lower esophageal sphincter muscles. It is unclear if the tunnel and subsequent myotomy should be in the anterior versus posterior approach.²⁶ Desai and colleagues examined if pre-procedure VLE imaging could determine the optimal approach.²⁶ In this multi- center international registry, they compared outcomes of patients that underwent a VLE tailored POEM versus a traditional POEM. In a VLE tailored exam, if the pre-procedure VLE scan showed a thickened anterior muscle, then the patient underwent an anterior approach. On the other hand if the patient had a thickened posterior muscle (Figure 6) then they underwent a posterior approach. If they had a thickened circumferential muscle, then the approach was dictated by the presence of vasculature. If anterior vessels were noted, then a posterior approach was used. If posterior vessels were noted, then an anterior approach was used.

A total of 84 patients were included in the study by Desai et al. Fifty-one patients underwent pre-POEM VLE. Twenty-four and twenty-seven patients underwent an anterior and posterior approach respectively. Technical success was achieved in 96% of patients. Statistically significant less bleeding was observed in the VLE group versus the traditional group (8% vs 43%, p<0.0001). As a result procedural times was less in the VLE group compared to the traditional group, despite the time taken to perform the VLE (86 min vs 122 min, p=0.0001). This study is limited in that there are no validated scaled scoring systems in place to measure the muscle thickness, however the concept is promising. Further research is needed to show if VLE pre-POEM can indeed reduce peri-procedural bleeding and reduce procedure time.

CONCLUSION

VLE is a tool that can be used in the esophagus to help guide diagnosis of neoplasia and aid or guide the correct endoscopic therapy. The majority of procedures to date have been in Barrett’s esophagus. Not surprising, most of the literature supporting its use is in Barrett’s as well. Although further studies are needed showing the incremental yield of VLE in diagnosing dysplasia, the preliminary data being presented is encouraging. VLE?s potential for guiding staging and therapy in squamous cell esophageal cancer is also promising and may guide which therapy to perform. Finally, the use of pre- procedural POEM may improve outcomes during the procedure. Further studies using computerized measurements of muscle thickness of the VLE scans are needed to validate this approach.

A Case Report

Acute Esophageal Necrosis Caused by Gallstone Pancreatitis

January 2018 • Volume XLII, Issue 1

Bradley M. Yamanaka,Brian J. Hanson

INTRODUCTION

Acute esophageal necrosis is a serious, yet relatively rare clinical condition afflicting hospitalized patients. It is most often observed in medically ill elderly males and nearly always presents with upper gastrointestinal hemorrhage.^1,2,3,4 Endoscopy typically finds black, necrotic mucosa in the distal esophagus with abrupt termination at the gastroesophageal junction.¹ The pathogenesis is unknown, although tissue hypoperfusion and gastric reflux are commonly cited contributing factors.¹ It has been associated with hyperglycemia, hypoproteinemia, hypoxemia, underlying malignancies, dehydration, various infections and antibiotic use.^2,3,5 Treatment remains primarily supportive and overall mortality is heavily dependent on the underlying comorbid conditions.^1,4 While this condition remains uncommon, there are growing numbers of case reports and case series noting its presence. Here we discuss a case of acute esophageal necrosis following gallstone pancreatitis.

Case

A 50 year old man presented in the emergency department following the acute onset of severe, sharp epigastric pain radiating to his back. His symptoms were associated with nausea and non-bloody vomiting. Physical examination was notable for diffuse abdominal tenderness to palpation, worst in the epigastrium. Laboratory results revealed an elevated white blood cell count (25,000/cmm (Normal 4,000-11,000)), elevated lipase 8307 U/L (Nl 73-393), a slightly elevated total bilirubin (1.2 mg/dL (Nl 0.2-1)), and a normal triglyceride level. A computed tomography (CT) scan of his abdomen and pelvis with oral and intravenous contrast demonstrated diffuse enlargement of the pancreatic head and body with extensive peripancreatic fluid consistent with acute pancreatitis. Multiple hyperdense foci were noted within the gallbladder, suggestive of gallstones. No biliary dilation was noted.

The patient was admitted with the diagnosis of acute pancreatitis, thought to be secondary to gallstones, aggressively resuscitated and his pain was managed with hydromorphone.

Over the next two days, his bilirubin rose to 2.5 mg/dL, and an endoscopic retrograde cholangiopancreatography (ERCP) was performed. On examination, a short segment of the proximal esophagus was normal (Figure A), however the mucosa in the remainder of the esophagus was black and necrotic (Figure B). The gastric mucosa was uninvolved with a clear demarcation at the gastroesophageal junction (Figure C). The major papilla could not be located due to duodenal edema.

Repeat endoscopies over the following months demonstrated complete mucosal healing, though he did require an esophageal dilatation to treat a stricture. His course was complicated by the development of pancreatic necrosis initially managed with an endoscopic ultrasound (EUS) guided cystgastrostomy. Due to chronic abdominal pain and complete obstruction of the distal pancreatic duct, he later underwent a pancreaticojejunostomy to relieve the obstruction. His clinical condition improved significantly following this surgical procedure.

Discussion

Acute esophageal necrosis, also known as black esophagus or necrotizing esophagitis, is a relatively rare and often incidentally noted clinical entity. It is characterized by diffuse circumferential black esophageal mucosa that generally involves at least the distal esophagus with abrupt termination at the gastroesophageal junction.^1,4 It is rarely seen in clinical practice; Augusto et al. reported the condition in 29 of 10,295 patients who underwent an upper gastrointestinal endoscopy over a 5 year period (0.28%).³

Most commonly described in elderly hospitalized men, acute esophageal necrosis often presents with symptoms of upper gastrointestinal hemorrhage, though dysphagia and epigastric pain have been observed. It has been associated with diabetes mellitus, malignancy, and vascular diseases, as well as hypoalbuminemia, hypoxemia, and dehydration.^1,4 The pathogenesis has yet to be fully elucidated; the most commonly advanced explanation is transient tissue hypoperfusion leading to diminished esophageal mucosal defense, followed by severe gastric reflux and subsequent tissue injury.⁴

Endoscopy typically discovers diffuse, black, and necrotic mucosa in a circumferential pattern involving varying lengths of the esophagus with stark and abrupt termination at the gastroesophageal junction.^1,2,4,5 While it most often affects the distal third of the esophagus, the condition has been noted in the mid and upper esophagus as well.⁴ Histology usually demonstrates severe mucosal and submucosal necrosis along with muscle fiber inflammation and/or destruction.²

Management is primarily supportive and typically involves oral nutritional rest, intravenous proton pump inhibitor use, short term total parental nutrition, and treatment of the underlying disorders.^2,4 If co-morbid conditions show adequate improvement, case studies suggest that spontaneous mucosal healing can be expected.^1,3 Mortality may be as high as 32.5% due to severe underlying medical conditions.⁵ Esophageal rupture is the most severe immediate complication, occurring in approximately 6% of cases and is typically accompanied by mediastinitis, abscess formation, and an extremely high mortality rate.⁴ Esophageal strictures are commonly encountered during the recovery period and are seen in 10-25% of cases.¹

SUMMARY

Acute esophageal necrosis is a rare but serious medical condition that often presents in medically ill older men with symptoms consistent with upper gastrointestinal bleeding. Endoscopy typically discovers black and necrotic mucosa in the distal esophagus with abrupt termination at the gastroesophageal junction. Management is generally limited to supportive esophageal care and aggressive treatment of the underlying medical issues. While immediate and devastating acute complications can occur, the high mortality associated with this condition is attributed to the severity of the underlying medical issues. Should the medical issues improve, spontaneous esophageal healing can be reasonably expected

References

1. Gurvits G, Cherian K, Shami M, et al. Black esoph- agus: New Insights and Multicenter International Experience in 2014. Dig Dis Sci. 2015; 60: 444-453.

2. Day A, Sayegh M. Acute oesophageal necrosis: A case report and review of the literature. Int’l Journal of Surgery. 2010; 8: 6-14.

3. Moreto M, Ojembarrena M, Zaballa J, et al. Idiopathic Acute Esophageal Necrosis: Not Necessarily a Terminal Event. Endoscopy. 1993; 25: 534-538.

4. Gurvits G, Shapsis, A, Lau N, et al. Acute esophageal Necrosis: a rare syndrome. J Gastroenterology. 2007; 42: 29-38.

5. Augusto F, Fernandes V, Cremers M I, et al. Acute Necrotizing Esophagitis: a Large Retrospective Case Series. Endoscopy. 2004; 36: 411-415.

The Microbiome And Disease, Series #2

The Microbiome and Inflammatory Bowel Disease

January 2018 • Volume XLII, Issue 1

Jessica Murray,

Daniel Frochtzwajg,

Sabine Hazan

An IBD patient’s quality of life can be significantly diminished when treated with conventional therapies. However, like the trend of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection, there is promising evidence that a similar approach will prove efficacious in treating UC and Crohn’s, especially given the increasingly predictable intestinal microbiome perturbation.

Sabine Hazan Steinberg MD, Gastroenterology/ Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center Dr. Daniel Frochtzwajg DO, Research Assistant, Ventura Clinical Trials Jessica Murray BS, Research Assistant, Ventura Clinical Trials, Ventura, CA

Ulcerative colitis (UC) and Crohn’s disease are the two chronic and progressive inflammatory states that commonly define inflammatory bowel disease (IBD). UC is typically characterized by continuous mucosal inflammation that involves that rectum and colon and often presents as bloody diarrhea. In Crohn’s disease, inflammation is spotty, transmural and can be observed in any portion of the gastrointestinal tract. IBD affects roughly 1.4 million people in the United States and some 2.2 million in Europe.^5,6 The steadily increasing incidence and prevalence of IBD, as well as the association of IBD and urban living, suggests that environment plays a critical role in the development of these diseases.^8,13 This hypothesis, in conjunction with the documented variations in gut microbiome associated with industrialization and geography,3 has led researchers to pursue the intestinal microbiota as an avenue for diagnostic and therapeutic intervention.

It is thought that a shift in composition of the intestinal microbiome may contribute to the development of IBD in genetically susceptible individuals. Initially hinted at by studies demonstrating such things as a reduced risk of IBD in breastfed infants or increased risk in those with low vitamin D levels,^1,2,10 the new age of bioinformatics has enabled corroboration of this theory. One example of the complex genetic-microbe interplay is a study by Ijaz et al.. demonstrating that adult relatives of patients with Crohn’s disease had less diverse intestinal microbiota than healthy adults unrelated to IBD patients.4

While there is no singular microbe responsible for IBD, gut dysbiosis is clearly implicated.⁵ An overall reduction in microbial diversity has been observed as well as specific, relative increases and decreases in “good” and “bad” microbes.^5,9,12 In Sartor and Wu’s extensive 2017 review, Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Disease and Therapeutic Approaches, the authors distill the latest documented genetic compositional changes in the intestinal microbiome of IBD patients.¹² They identify the overarching theme of the associated dysbiosis as a decrease in known “protective”” bacteria such as Bifidobacterium species and an expansion of potentially inflammatory microbes like Proteobacteria, Fusobacterium species, and invasive E. coli.¹²

The common treatments for UC and Crohn’s, including immunosuppressive therapies, mesalamine, glucocorticoids, and tumor necrosis factor antagonists, rarely induce remission and colectomy is too often an undesirable endpoint. Furthermore, an IBD patient’s quality of life can be significantly diminished when treated with conventional therapies.¹⁷ However, like the trend of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection, there is promising evidence that a similar approach will prove efficacious in treating UC and Crohn’s, especially given the increasingly predictable intestinal microbiome perturbation. In one of the premier studies of alternative treatments for IBD, Moayyedi et al. demonstrate, in a randomized controlled trial, that FMT can induce remission in UC patients.⁷ Researchers used the Mayo score for UC, which includes scores for stool pattern, rectal bleeding, endoscopic findings, and physician assessment (scores ranges from 0-12, with higher scores correlating with increased disease severity) to assess patients. Eligible enrollees were adults 18 years or older with active UC determined by a Mayo score ≥4 (with an endoscopic score =1); remission was defined as a Mayo score <3 at seven weeks. FMT from healthy donors was completed via retention enemas administered once weekly for six weeks. Overall, 9 of the 38 patients in the FMT treatment arm achieved remission, compared to 2 of the 37 patients in the placebo arm. Moreover, there was no difference in serious adverse events between the two groups. In another promising prospective, uncontrolled study, by Uygun et al. response of UC patients to FMT was examined.¹⁴ Responders were defined as a decrease in Mayo score ≥30%. 21 patients in the study, 70% of the subjects, were ultimately classified as responders. While 9 patients were categorized as non-responders, there was still improvement in CRP and hemoglobin levels after FMT.

Despite the positive findings mentioned above, there is conflicting data, and in another RCT, Rossen et al.¹¹ did not demonstrate a difference in the remission rate of FMT vs. placebo. However, increased intestinal microbiome richness following FMT has been shown in patients with Crohn’s, and there is evidence to suggest that FMT donor species richness determines efficacy of FMT treatment for IBD.^15,16

Ultimately, while current data is cause for optimism, more foundational research is necessary to characterize the microbe-gene interaction and define a treatment paradigm.

Gastrointestinal Motility And Functional Bowel Disorders, Series #23

Gastroesophageal Reflux can be an Explanation for Dysphagia of Otherwise Unknown Etiology

December 2017 • Volume XLI, Issue 12

Pratik Naik,

Yi Jia,

Richard W. McCallum

Dysphagia and gastroesophageal reflux disease (GERD) are common entities in clinical practice. High- resolution manometry (HRM) of the esophagus is a diagnostic test to investigate dysphagia where other esophageal tests and evaluations had not disclosed an etiology. The goals of our study were to investigate the frequency of GERD in patients whose dysphagia cannot be explained by all prior studies, including HRM, and propose that GERD, by inducing esophageal hypersensitivity, could explain this sensation of dysphagia. A retrospective chart review of HRM studies that were performed from 2012-2016 in 167 patients with dysphagia was conducted. Results were categorized based on the Chicago Classifications as follows: achalasia 11%; nutcracker 7%; Jackhammer 2%; scleroderma 4%; diffuse esophageal spasm 1%; elevated integrated relaxation pressure 7%; presbyesophagus 4%; hypertensive LES pressure 3%. In addition, 80 (48 %) had normal and 24 (14%) had minor non-specific HRM findings. Medical records where available for review in 78 of those 104 patients with dysphagia who had normal or minor non-specific HRM findings. We identified Schatzki ring in two and eosinophilic esophagitis in three patients. 73% of the remaining 73 patients had evidence of GERD based on one or more of the following test results: EGD, esophageal biopsy, pH impedance, BRAVO test and barium swallow; while in the other 20 (27%) there was no objective evidence of GERD. 95% were receiving ongoing PPI therapy for symptoms consistent with GERD. In conclusion, when HRM findings are normal or minor non-specific in patients with unexplained dysphagia then evidence for concomitant GERD should be sought since the esophageal hypersensitivity induced by GERD can be one explanation for this dysphagia and can lead to further treatment approaches.

Pratik Naik, MD, GI Motility Fellow, TTUHSC Yi Jia, MD, GI Fellow, PGY-6, TTUHSC 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

Patients with gastroesophageal reflux disease (GERD) may present with various symptoms including heartburn, regurgitation, dysphagia, chronic cough, laryngitis, aspiration and even asthma.¹ An etiology of dysphagia in patients with GERD is sometimes unknown and can be further investigated with High-resolution manometry (HRM) of the esophagus.

Prior to referral for HRM, patients often undergo evaluation including esophagogastroduodenoscopy (EGD) and/or barium swallow study to rule out mechanical causes of dysphagia and to exclude eosinophilic esophagitis (with esophageal biopsies). After undergoing HRM, the diagnosis of a motility disorder is made based on the Chicago Classifications; however, many patients who undergo this evaluation for dysphagia with HRM studies have no recognized abnormalities, being regarded as either normal or minor nonspecific findings. At our center, we have observed concomitant GERD in many patients who were referred for HRM to elucidate a suspected esophageal cause of dysphagia but in whom either normal or minor nonspecific abnormalities are found. Patients with GERD may continue to report dysphagia despite being treated with standard anti reflux medications. This sensation of dysphagia in patients with GERD could be secondary to visceral hypersensitivity of the esophagus. Among practicing clinicians there is limited acceptance and appreciation for the term “visceral hypersensitivity” as far as understanding its role in a patient’s symptoms. The concept of visceral hypersensitivity has been described in the literature in functional bowel disorders such as non-cardiac chest pain, non-ulcer dyspepsia and irritable bowel syndrome.²

Aims:

We investigated the frequency of objective evidence for GERD in patients whose dysphagia cannot be explained by all prior studies including HRM. Additionally, we propose that GERD, by inducing esophageal hypersensitivity, could explain this sensation of dysphagia.

Methods:

A retrospective chart review of high resolution manometry studies, performed for various indications, from 2012-2016 in patients referred to a University Motility Center was conducted. The standard technique described for HRM was utilized and a total of 16 wet swallows were employed. Those patients referred for the specific assessment of dysphagia were categorized according to underlying manometric etiologies for dysphagia as recognized in the current as well as the previous Chicago Classifications which overlapped our study years of 2012-16.^3,4 In patients with no recognized motility disorder on the HRM study, we identified two additional groups: 1) entirely normal manometric findings and 2) minor, non-specific motility findings. We defined the entity of a minor, nonspecific motility abnormalities as having one or more of the following: 1) a decreased resting lower esophageal sphincter (LES) pressure (< 10 mm Hg); low amplitude contractions defined as < 30 mm Hg in less than 30% of the contractions induced by 16 wet swallows at the level of 3 and 7 cm above the LES; a small percentage loss of peristalsis, < 50% of the sequences following wet swallows, where <30% non- peristalsis is regarded as normal.^5-7 Clinical chart reviews were conducted only in patients with dysphagia who had normal or minor non- specific HRM findings. The aim of the chart review was to identify all the diagnostic testing performed for both confirmatory evidence of GERD as well as excluding other causes of dysphagia. We reviewed EGD reports for evidence of esophagitis as per the Los Angeles classification, and/or Barrett’s esophagus and to identify other etiologies such as strictures, masses, rings and hiatal hernias.⁸ We also examined endoscopic esophageal biopsy reports to identify GERD related changes (basal cell hyperplasia, elongation of connective tissue papillae, infiltration by neutrophils and eosinophils) in patients with an endoscopically normal esophagus as well as to identify other etiologies such as eosinophilic esophagitis.⁹ Barium swallow reports were reviewed to identify mechanical obstruction (including strictures or rings), gastroesophageal reflux and hiatal hernia. BRAVO and 24-hour pH impedance tests were also evaluated where applicable.

Results:

319 patients were referred for HRM testing for all indications from 2012-2016. There were 167 (52.4%) patients that met the criteria of dysphagia. These 167 patients had the following manometric entities based on the definitions of the Chicago classifications (Figure 1): achalasia 18 (11%); high amplitude peristaltic contractions with distal contractile integral (DCI) >5000 but <8000 (nutcracker esophagus) 11 (7%); extremely elevated amplitude but peristaltic contractions with DCI > 8000 (Jackhammer esophagus) 4 (2%); scleroderma 6 (4%); diffuse esophageal spasm in 2 (1%); elevated integrated relaxation pressure in 11 (7%); presbyesophagus 6 (4%); and hypertensive LES pressure (> 40 mm Hg) 5 (3%). In addition, 80 (48 %) were judged as having an entirely normal manometry while there was a subgroup of 24 (14%) with non-specific minor motility abnormalities (the criteria for which we have previously defined) (Figure 1). Of those 104 (62%) patients who had either normal or minor non-specific HRM findings, the age range was 15-86 years and 71 (68%) were female. 90% were being managed by a proton pump inhibitor (PPI) for symptomatic GERD at the time of evaluation of dysphagia. Of those 104 patients, 78 had medical chart records available to review results of the diagnostic testing. Based on those studies, Schatzki rings (2 patients) and eosinophilic esophagitis (3 patients) were identified as causes of dysphagia. Fifty-three (73%) of the remaining 73 patients had objective evidence of GERD based on one or more of the following test results: EGD, esophageal biopsy, pH with impedance, BRAVO pH study and barium swallow (Table 1). EGD confirmed esophagitis in 15 patients (LA classification) as well as 4 with Barrett’s epithelial changes confirmed by biopsies. Esophageal biopsies in the patients with normal endoscopic findings were consistent with GERD in 25 patients. Six patients had acid reflux based on 24-hour pH impedance data and one had predominant non-acid reflux. One patient had a positive 48-hour BRAVO study. Barium swallow showed evidences of GE reflux in four patients. Hiatal hernias were observed in one or more of those studies in 16 (30%) patients. While 73% of the patients had confirmatory objective evidence of GERD, 20 (27%) of 73 patients whose charts were available for review had no objective evidence of GERD but 95% were receiving ongoing PPI therapy for symptoms. In this subset of negative GERD findings, the diagnostic testing was suboptimal in that in the setting of a negative EGD other tests were not routinely pursued for the evaluation of GERD.

Discussions:

Based on HRM classifications, there are well identified manometric disorders that can explain dysphagia. However, 104 (62%) of the patients referred for HRM to evaluate dysphagia at our motility center had a normal or minor nonspecific esophageal motility findings. These findings alone would not explain dysphagia without there being other underlying esophageal pathology. Indeed, 73% of our patients with normal or minor nonspecific findings whose medical records were accessible for review had objective evidence of GERD. Therefore, in the setting of either normal or nonspecific HRM findings the presence of GERD could provide evidence for underlying pathology and a possible explanation for their dysphagia.

One of the limitations of our data is that 27% of the patients with normal or non-specific motility findings did not have medical records available for review. This is because they were referred by gastroenterologists in private practice in our city and our access to their medical records was limited. Another limitation of our study is that in the 28% of patients whose medical records were available for review had no objective evidence of GERD and we observed that if their EGD was normal then pH studies and endoscopic esophageal biopsies were usually not pursued. Hence GERD could still have been present. In fact, they were being managed by PPI for symptoms consistent with GERD.

Our findings of esophageal pathology in the form of GERD poses the question of whether GERD related visceral hypersensitivity of esophagus could be an explanation for the sensation of dysphagia. Visceral hypersensitivity is present in other organs and is proposed to be mediated by peripheral, central and psychosocial factors.¹⁰ The sensation of stimuli chemical, mechanical, thermal etc – in contact with the esophageal mucosa is transmitted to the central nervous system (CNS) via either spinal nerves or vagal nerves (Figure 2).¹⁰ This sensation is thought to be physiologically important to help sense the passage of food or foreign material through the esophagus during swallowing.¹¹ In a hypersensitive esophagus, there is a heightened perception of stimuli, discomfort or pain and this could generate a visceral sensation interpreted by the patient as the symptom of dysphagia.¹²

In reflux esophagitis (RE), there is a break in the esophageal mucosa and noxious stimuli can penetrate and activate nociceptive receptors in deep layers of the mucosa resulting in signals, which then are transmitted to the CNS.¹³ Patients with nonerosive reflux disease (NERD) can have heartburn even though damage to the esophageal mucosa is not observed. Here, microscopic changes based on dilation of the intracellular space have been reported.¹⁴ Based on intra-esophageal acid infusion tests, pain response to acid reflux in patients with NERD has been shown to be stronger than in patients with erosive GERD.^15,16 Miwa and et al. suggested that patients with NERD can have increased mucosal permeability that could permit penetration of the mucosa by noxious stimuli such as gastric acid, bile acids, or pepsin.¹⁵ A symptom of heartburn is not specific to acid reflux into the esophagus and has been reported as a symptom response to mechanical stimuli including esophageal dilation and longitudinal contraction of esophageal smooth muscle.^17,18 It is conceivable that dysphagia could be perceived as an uncomfortable sensation accompanying swallowing, when there is esophageal mucosa sensitized by chronic GE reflux, in the absence of mechanical obstruction or a motility disorder. Patients with depression, anxiety, somatization disorders, and fibromyalgia tend to have a higher prevalence of esophageal hypersensitivity and this aspect could also be a contributing factor in sensing the symptom of dysphagia.¹⁹ Hypersensitive esophagus has also been investigated by a balloon distension method. Here, a small balloon is distended in the esophagus to assess which volume induces the first perception of symptoms and the degree of discomfort experienced.¹⁹ The implication from the balloon test results are that touching, stretching, or perturbing the esophagus induces a sensation e.g. heartburn, chest pain and non-specific discomfort. In the setting of eating where food is stretching the esophageal lumen, the resulting sensation could be interpreted as dysphagia by the patient. This balloon testing was not performed in our patients due to the retrospective nature of the study. However, 90% of patients with unexplained dysphagia were being treated with a PPI for symptomatic GERD at the time of evaluation of dysphagia and 73% patients with available medical records had objective evidence of GERD. In addition, 71% of our patients were females similar to the female dominance in such entities as irritable bowel syndrome and non-ulcer dyspepsia where visceral hypersensitivity is thought to be important in the mediation of the symptoms.

CONCLUSION

In conclusion, in patients with unexplained dysphagia when HRM is normal or only minor non-specific findings are present then evidence for concomitant GERD should be sought. We hypothesize that GERD could induce a hypersensitive state in the esophageal mucosa. This leads to a heightened awareness of esophageal movement and touching during swallowing, which is interpreted by the patient as the symptom of “trouble swallowing” or dysphagia. Our observations should be confirmed in more studies in this specific patient setting of unexplained dysphagia and accompanying GERD where testing for assessing visceral hypersensitivity of the esophagus as well as treatment trials to address this entity are included.