Page 42 – Practical Gastro

Allyce Caines,Ghassan Allo,Yousuf Siddiqui

Left-sided portal hypertension (LSPH), also known as splenoportal hypertension, is a rare but life-threatening cause of upper gastrointestinal bleeding. LSPH often occurs in non-cirrhotic patients as a consequence of splenic vein obstruction. We present a case of isolated gastric varices due to mass effect on the splenic vein and likely tumor thrombus due to metastatic ovarian cancer.

INTRODUCTION

Portal hypertension refers to increased pressures in the hepatic portal system. This in turn leads to complications such as variceal hemorrhage from gastric or esophageal varices, ascites and hepatic encephalopathy. Upper gastrointestinal bleeding secondary to portal hypertension in the form of variceal hemorrhage is a recognized lifethreatening cause of gastrointestinal bleeding. In patients with gastrointestinal bleeding due to portal hypertension, bleeding from gastric varices is the cause in 5%-10% of patients.1 Increased resistance to portal flow due to a stiff, cirrhotic liver is often the cause of portal hypertension. However, portal hypertension can also be caused by isolated obstruction of the splenic vein, which is often referred to left sided portal hypertension (LSPH). LSPH accounts for less than 5% of all patient with portal hypertension1. Most of the reported cases of splenic vein obstruction have been the result of malignancy involving the spleen. Pancreatic disorders, including pancreatic carcinoma, acute and chronic pancreatitis, cysts, and pseudocysts which may block the splenic vein via thrombus formation or mass effect, are the most common causes of LSPH. These patients often have no known prior liver disease and have no evidence of cirrhosis on presentation. Bleeding can be catastrophic due to high portal pressures. In these cases, it is important to consider causes of left sided portal hypertension and the available treatment options.

Case Report

A 59 year-old female with a past medical history of metastatic ovarian cancer and obstructive uropathy, secondary to extrinsic compression, presented to her primary gynecologic oncologist with complaints of fatigue, lightheadedness and melena for one week. On laboratory evaluation, she was found to have a hemoglobin of 5.7 g/dL prompting emergency evaluation. Four years prior she was diagnosed with stage IIIC serous carcinoma of the ovary, at which time she underwent total abdominal hysterectomy, omentectomy, pelvic lymphadenectomy, tumor debulking and subtotal colectomy with diverting ileostomy followed by chemotherapy. She remained disease free for approximately nine months when imaging showed disease recurrence. She developed significant disease progression involving the splenic hilum, retroperitoneal lymph nodes and pelvis in addition to bilateral hydronephrosis. On presentation to the emergency department she was hemodynamically stable with unremarkable physical exam. An episode of hematemesis consisting of 500cc of bright red blood occurred in the emergency department with repeat hemoglobin of 4.5 g/dL. Endoscopy revealed type 1 isolated gastric varices (IGV1). She received a total of 6 units of packed red blood cells. The patient was then transferred for consideration of balloon retrograde transvenous obliteration (BRTO). Repeat endoscopy confirmed the findings of type 1 isolated gastric varices with red wale signs (Figure 2). BRTO, splenectomy, gastric vessel ligation and cyanoacrylate injection were discussed as potential therapeutic options. The patient had no further episodes of bleeding and her hemoglobin remained stable. Magnetic resonance imaging (MRI) revealed a hypovascular mass in the splenic hilum with minimal central enhancement concerning for metastatic disease. Areas of hypovascular nodularity around the lesion extending into part of the splenic vein at the hilum and branches were suggestive of tumor thrombus. Liver lesions concerning for metastatic disease were also present. On MRI the hepatic vein, celiac artery, hepatic artery, portal vein and superior mesenteric vein were patent. The splenic artery appeared tortuous and the splenic vein was engorged. The patient was not a candidate for BRTO due to the lack of portosystemic collaterals. She underwent splenic artery embolization to decrease inflow to the spleen and splenectomy the following day. Pathology revealed a 4.4 x 3.7 x 3.1 cm ill-defined mass located within the splenic hilum (Figure 1A), which consisted of poorly differentiated adenocarcinoma (Figure 1B1C). Immunohistochemically, the adenocarcinoma was positive for cytokeratin AE1/AE3, CK7, PAX-8 and estrogen receptor (Figure 1D). The adenocarcinoma was negative for CK20. The morphology and immunohistochemistry were consistent with metastatic adenocarcinoma of müllerian origin, from the patient’s known ovarian adenocarcinoma.

Discussion

LSPH, also known as splenoportal or sinistral hypertension is a rare, but life-threatening cause of upper gastrointestinal bleeding.2 LSPH often occurs in non-cirrhotic patients as a consequence of splenic vein obstruction. Pancreatic disorders, including pancreatic carcinoma, acute and chronic pancreatitis, cysts, and pseudocysts which may block the splenic vein via thrombus formation or mass effect, are the most common causes of LSPH.3 To our knowledge there is only one other case of LSPH with bleeding gastric varices secondary to metastatic ovarian cancer published by Wallace et al in 2004.4 In our case, mass effect on the splenic vein as well as likely tumor thrombus caused splenic venous outflow obstruction. Obstruction of the splenic vein results in venous hypertension in collateral pathways that carry splenic arterial blood via the short gastric, coronary, and gastroepiploic veins to the superior mesenteric and portal veins. In the gastric wall veins of the fundus, blood flow and pressure increase, and submucosal structures consequently dilate, producing gastric varices.4,3 Risk factors for gastric variceal hemorrhage include the size of fundal varices (as there is a linear relationship between size of varices and risk of variceal hemorrhage), endoscopic presence of variceal red spots, and Child-Pugh class in patients with cirrhosis.5 Gastric varices are less frequent than esophageal varices and are present in 5%33% of patients with portal hypertension. The reported incidence of bleeding from gastric varices is approximately 25% in two years, with a higher bleeding incidence for fundal varices.6 Compared to esophageal varices, gastric varices are larger, more extensive, and lie deeper in the submucosa. As a result, standard endoscopic treatments for esophageal varices, including band ligation and sclerotherapy are largely ineffective for gastric varices.7 Management of gastric varices is dependent on the etiology, presence of collaterals and the available treatment modalities. LSPH, for example, has distinct therapeutic management options that are not appropriate for the management of generalized portal hypertension. Currently the gold standard for treatment of fundal (IGV1) varices as a result of splenic vein thrombosis is splenectomy. Surgical removal of the spleen decreases venous outflow through collateral circulations and decompresses IGV to prevent future bleeding.8 Additional therapies have been used to control gastric variceal bleeding and prevent re-bleeding from occurring. These include band ligation and endoscopic sclerotherapy (frequently by cyanoacrylate glue injection). The American Association for the Study of Liver Diseases (AASLD) Society guidelines recommend endoscopic variceal sclerotherapy in patients who bleed from gastric fundal varices otherwise when available, endoscopic variceal ligation is an option. AASLD also recommends that transjugular intrahepatic portosystemic shunt (TIPS) should be considered in patients in whom hemorrhage from fundal varices cannot be controlled or in whom bleeding recurs despite combined pharmacological and endoscopic therapy.5 Left-sided portal hypertension should be considered in the presence of gastrointestinal bleeding with normal liver function and unexplained splenomegaly.1 Isolated gastric varices type 1 should immediately raise the clinician’s suspicion for splenic vein obstruction. Although a rare cause, in patients with prior malignancy or without evidence of pancreatic pathology, malignancy should remain on the differential as a cause of splenic vein obstruction.

INTRODUCTION: DISPATCHES FROM THE GUILD CONFERENCE

Dispatches from the GUILD Conference 2020

Uma Mahadevan

Welcome to the Fourth annual Dispatches from GUILD series! The Gastrointestinal Updates-Inflammatory Bowel DiseaseLiver Disease (GUILD) Conference is an annual CME conference held in Maui, Hawaii every February (GUILD 2020: February 16-19). This meeting offers a cutting edge update in gastroenterology by world class speakers in a setting conducive to learning and interaction with peers. Our topics this year include 2 days of IBD updates, a day of hepatology and a day of obesity related topics. GUILD also recognizes the role played by nurse practitioners and physician assistants in the care of IBD patients and introduced an IBD boot camp in 2019. Scholarships are awarded to 10 NP/PA’s and 10 Gastroenterology fellows to attend the meeting and receive daily mentoring and networking.
To share our learning with the gastroenterology community at large, we are happy to continue our series beginning with the following article, “Prevention in Inflammatory Bowel Disease: An Updated Review”. We look forward to providing informative and educational articles covering IBD, Hepatology and special topics in GI in Practical Gastroenterology over the following months

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #27

Prevention in Inflammatory Bowel Disease: An Updated Review

Millie D. Long

Patients with inflammatory bowel disease (IBD) are subject to complications from the disease itself and also from the immunosuppressive therapies used for treatment. To optimize the care of patients with IBD, providers need to consider primary, secondary and tertiary prevention. Primary prevention is employed to prevent a disease or complication from developing, such as immunizations. Secondary prevention detects a disease early to prevent disability, such as through screening programs. Tertiary prevention employs measures to reduce the impact of long-term disease and disability. This review highlights methods of prevention that can be utilized in patients with IBD via partnership between the primary care and gastroenterology provider.

INTRODUCTION

Inflammatory bowel disease (IBD), including both Crohn’s disease (CD) and ulcerative colitis (UC), causes inflammation and ulceration in the gastrointestinal tract. This inflammation results in considerable morbidity for patients, including symptoms such as diarrhea, abdominal pain, rectal bleeding, and weight loss. The prevalence of IBD is increasing in the United States (US) and worldwide. It is estimated that 2.2 million Americans will be living with IBD by 2025.^1,2 With this growing population, there is an increasing need for effective and safe therapies for management of inflammation. Currently, there are a large number of classes of agents available for treatment of IBD, with varying relationships between safety and efficacy. Immunosuppressive agents used in the treatment of IBD include corticosteroids, biologic agents [anti-tumor necrosis factor alpha (anti-TNF), antiintegrin therapies, anti IL-12/23 inhibitors, janus kinase (JAK) inhibitors, and immunomodulators such as thiopurines or methotrexate]. As we target goals of mucosal healing in our IBD population using immunosuppressive agents, we must also use a patient-centered approach to prevent downstream complications, either of IBD itself, or of the therapies used for treatment of IBD. To do so, a partnership must exist between gastroenterology and primary care providers to target primary, secondary and tertiary prevention for our patients. This article will discuss current guidelines and recommendations for prevention specific to patients with IBD

Primary Prevention

Primary prevention is defined as prevention of disease development. Examples of primary preventive efforts include immunizations against infectious diseases or educational interventions on regular exercise. Primary preventive efforts can occur at an individual level or at a population level. One example of a population level primary preventive effort is fluoridation of the water supply to prevent dental caries. As compared to the agematched general population, patients with IBD are at increased risk for vaccine-preventable illnesses, such as influenza,⁵ pneumococcal pneumonia,⁶ and shingles.⁷ Inactivated vaccines are safe to administer in patients with IBD, regardless of immunosuppression status. Therefore, adherence to vaccination guidelines of inactivated vaccines can reduce these infectious complications. Annual influenza vaccination is indicated in all patients with IBD, pneumococcal vaccination series is indicated in all immunosuppressed patients with IBD and herpes zoster vaccination is indicated in all patients with IBD ≥ 50 years of age. Due to increased risk of shingles in younger IBD populations,⁷ consideration can be given for earlier vaccination while on certain high risk therapies. In particular, tofacitinib is associated with an increased risk of shingles, particularly at higher doses.⁸ However, more data are needed on safety, efficacy and durability in younger populations prior to a definitive recommendation. The human papillomavirus (HPV) vaccine has been shown to protect against specific serotypes of HPV linked to cervical dysplasia and genital warts. This vaccine has been studied specifically in IBD populations. The HPV vaccine has demonstrated both efficacy and safety.⁹ Another method of primary prevention in IBD patients is sunscreen use to prevent skin cancer. Patients with IBD have increased risks of both non-melanoma (NMSC) and melanoma skin cancer.^{10, 11} Evidence has demonstrated that thiopurines specifically increase the risk of NMSC and that the mechanism of action is associated with photosensitivity to ultraviolet-A light.¹² Therefore, this is a potentially preventable complication of therapy through broad-spectrum sunscreen use. Finally, weight bearing exercise and calcium/ vitamin D supplementation, when appropriate, can prevent downstream osteoporotic fracture in these patients who may require recurrent courses of corticosteroids during their lifetimes with IBD. Table 1 shows a summary of primary preventive measures recommended in IBD patients.

Secondary Prevention

Secondary prevention is defined as detecting a disease early to prevent disability; such as through screening programs. Therefore, there are a number of important opportunities for secondary prevention in IBD patients. For example, patients with IBD are known to have an increased risk of melanoma, regardless of immunosuppressive therapy. Individuals on anti tumor necrosis factor alpha (anti-TNF) agents have nearly a two-fold further increased risk of developing melanoma.10 Therefore, a dermatology skin screening program is recommended in all patients with IBD.3 Prior studies have suggested an increased risk of abnormal Pap smear and/or cervical dysplasia in patients with IBD on immunosuppression.13 Therefore, annual cervical cancer screening is recommended in patients with IBD on immunosuppression.3 Patients with IBD who have longstanding colonic inflammation (> 10 years of duration) have an increased risk of developing colorectal dysplasia and cancer. Therefore, patients with longstanding colonic inflammation should undergo routine colonoscopy starting at 8-10 years of colonic disease duration, with subsequent colonoscopy intervals based on the results (often every 1-3 years). From a bone health perspective, all individuals (regardless of gender) with ≥ 3 months duration of corticosteroid use are at risk for osteopenia or osteoporosis. Therefore, screening with DEXA scan for these individuals and in women age ≥ 65 years is recommended. Subsequent DEXA screening can be determined based on the initial results. Finally, depression and anxiety are common in IBD patients.14 Earlier recognition and treatment of depression and anxiety can improve quality of life in patients with IBD. Screening for depression and anxiety is recommended in all patients with IBD.3 Table 2 describes currently recommended secondary preventive efforts in IBD patients.

Tertiary Prevention

Tertiary prevention refers to utilization of measures to reduce the impact of long-term disease and disability. In CD, ongoing inflammation can lead to development of strictures, which may cause obstruction and require bowel resection surgery. Additionally, inflammation can progress to fistulizing disease, including abnormal connections between the bowel and other organs. These fistulas can result in abscesses and other complications ultimately often requiring surgery. In UC, ongoing inflammation can increase the risk of colon cancer and dysplasia. Additionally, disease can extend from only left-sided involvement to pan-colonic involvement over time. Therefore, by intervening early and treating inflammation, with a goal of mucosal healing, we can potentially prevent these morbid and potentially life-threatening, complications of IBD. The paradigm in IBD management has shifted to one of a “treat to target” approach¹⁵. After initiation of medical therapy for the treatment of IBD, guidelines recommend subsequent reassessment to ensure that both symptoms and mucosal inflammation are improved.^16,17 This dual method of reassessment is important, as symptoms do not always correlate with ongoing inflammation. This standard of reassessing a current therapy is also important in post-operative CD, where early evaluation with colonoscopy in the first 6-12 months after a resection, with alteration of medical therapies based on this, has been shown to improve long-term endoscopic outcomes.¹⁸ Therefore, by optimizing therapies to improve mucosal healing, we may be able to impact the long-term disability associated with irreversible bowel damage in IBD.

CONCLUSION

Management of patients with IBD can be difficult. IBD itself can be associated with a number of complications for patients, including ongoing chronic bowel symptoms and structural bowel damage, as well as extra-intestinal manifestations of IBD. These extra-intestinal manifestations
can include significant joint symptoms, skin manifestations, anemia, and kidney stones. While there are a number of effective therapeutic agents for the treatment of IBD and these extraintestinal complications, many of these therapies are themselves immunosuppressive. Therefore, the drugs themselves can result in therapy-related complications. These may include infectious, malignant, or idiopathic complications. As the patient may present to the primary care provider or the gastroenterologist for evaluation of symptoms or complications, it becomes very important for the entire care team to collaborate on diagnostic and management plans for individual patients with IBD. Importantly, prior studies have demonstrated that primary care physicians may not be comfortable addressing preventive care in IBD patients on immunosuppression.³ However, the gastroenterologist may assume that all preventive activities are occurring in primary care. The gastroenterologist may also not be comfortable addressing all of an IBD patient’s preventive health needs. In fact, many patients with IBD consider their gastroenterologist to be their primary care provider. Therefore, a collaboration between primary care and gastroenterology is needed to ensure appropriate adherence to preventive health recommendations in patients with IBD. Each IBD patient should have regular evaluation with both a primary care and gastroenterology provider. Through this partnership, an individualized plan for preventive medicine can be developed for each patient with IBD. This proactive approach of addressing primary, secondary and tertiary prevention in IBD patients can ultimately help to reduce infectious, malignant and long-term disease-related complications. There is an old African proverb stating, “It takes a village to raise a child.” This reflects the emphasis that African cultures place on family and community. In fact, this community of support is also needed for each patient with IBD. By sharing the burden of the complete care of the IBD patient, a care team can deliver evidencebased, patient-centered care. Figure 1 shows the integral components of a care team for a patient with IBD. Through collaboration, a care plan can be implemented for each IBD patient addressing his or her individual needs and goals. By focusing on implementing the three forms of prevention: primary, secondary, and tertiary, we can improve the lives of our patients with IBD.

THE MICROBIOME AND DISEASE, SERIES #8

The Relationship Between Parkinson’s Disease and the Microbiome

Skylar Steinberg,

Sabine Hazan,

Jordan Daniels

Parkinson’s Disease (PD) is a central nervous system movement disorder characterized by the formation of spherical protein deposits in the brain (Lewy bodies) and the development of spindle-like Lewy neurites in the body of the affected neuron. These start in the medulla oblongata and spread in a predictable pattern, resulting in a gradual drop in dopamine levels which causes tremors, rigidity and a progressive loss in mobility and body functions. In the later stages of the disease, behavioral and cognitive issues become prevalent.¹

It has been known that in addition to prominent tremors and motor symptoms associated with Parkinson’s disease, up to 75% of patients display gastrointestinal abnormalities as well.² These symptoms often precede the appearance of motor symptoms by many years, prompting speculation on the role of gut bacteria and the disease. While there are treatments for PD, no cure exists. Recent research examining the gut microbiota and its possible connection to PD offer potential new approaches to treatment. While this research is still in the early stages, it offers a glimmer of hope to Parkinson’s patients.

A study by Sampson et al. investigated the alterations of bacteria in the gut, dysbiosis, and motor deficits in Parkinson’s disease in mice. The team conducted three experiments to test this relationship, assessing bacterial microbiome and motor function in mice and how different microbiota affect symptoms. They first showed that gnotobiotic mice (mice lacking their natural gut microbiome) accumulated less alpha-synuclein in their brains, the primary protein component of Lewy bodies, and as such moved more freely. This provided a model for how the environment and gut flora may play a role in PD development as well as other neurodegenerative disorders. In the second experiment, Sampson’s team examined whether imbalances in short-chain fatty acids (SCFAs) created in gut could be associated with activated immune responses in the brain. They discovered that germ-free mice treated with microbially produced SCFAs had higher levels of neuroinflammation, which is linked to the malfunction of neurons through the activation of microglia. The third experiment treated mice with fecal transplants using donor stool from human patients with and without Parkinson’s disease. Mice that received stool from patients with Parkinson’s developed deficits in motor function.³ Future study by this team will focus on identification of specific organisms in the gut associated with the motor deficits. This could lead to alteration of the microbiome as a treatment for Parkinson’s disease.

However, researchers in Finland have discovered decreased abundance of the Prevotellaceae family of bacteria in the gut microbiome of patients with PD compared to healthy controls. Prevotellaceae is normal in the human gut in varying amounts, however it was discovered that the mean abundance of Prevotellaceae in the feces of PD patients was reduced by 77.6% compared to healthy individuals.⁴ Although PD patients display less Prevotellaceae, some controls had low levels as well, indicating that this cannot be the sole explanation of PD. This demonstration of how bacterial populations may influence disease has important implications for future research.

Another study by Tetz et al. demonstrated a significant correlation of gut bacteria with Parkinson’s disease. The human GI tract is home to bacteria, archaea, fungi, and viruses, including bacteriophages, the last of which are a type of virus that infects, replicates within, and destroys bacteria. This study showed that drug-naïve patients with PD had a 10-fold decrease in Lactococcus species (lactic acid bacteria) compared with healthy controls. It was noted that an increase in lytic bacteriophages was accompanied by a decrease of Lactococcus bacteria, indicating that a depletion of Lactococcus in patients with PD could be caused by lytic phages.⁴ A fourth way that gut bacteria could be implicated in Parkinson’s disease is via the enteric nervous system (ENS). A study by Liu et al. demonstrated that a truncal vagotomy, in which the trunk of the vagus nerve is removed where it enters the stomach from the esophagus, was related to a reduced risk for PD.⁵ Therefore, changes gut microbiota composition could cause alterations in the intestinal barrier function and permeability implicating both the immune system and the ENS, resulting in the development of PD symptoms. A study by Hill-Burns et al. sought to find microbial causes of Parkinson’s disease, partly by interrogating 39 potential confounders.⁶ Of these 39, the test results of eight indicated potential involvement. Once these confounders were taken into consideration, the microbiome sequencing of 197 patients with Parkinson’s disease and 130 controls were compared using three metrics. The team discovered several dysbiotic features of the PD microbiome, including elevated levels of Akkermansia, Lactobacillus, and Bifidobacterium and reduced levels of Lachnospiraceae. This study represents the largest to date of the microbiome in Parkinson’s patients.

It is important to recognize the pivotal impact of microbiome research, since it shows that pathology in the gut can impact neurological diseases. Microbiome research and its relationship with Parkinson’s disease is only in its infancy. Further research will hopefully identify new bacterial markers that contribute to the development of PD and guide new treatments. Although PD is likely a multicausal disease and the microbiome is not fully responsible, it is impossible to ignore the impact the gut microbiome could have on our future knowledge around Parkinson’s Disease.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #195

Mobility and Motility: Constipation Impairs Enteral Feeding in Disabled and Immobile Patients

Stephen M. Borowitz

At least a third of children and adults with neurodevelopmental disabilities with or without limited mobility are significantly undernourished. The incidence and severity of malnutrition increases with the duration and severity of disability. Nutritional support in children and adults with a variety of neurodevelopmental disabilities can result in weight gain, increased muscle mass, improved peripheral circulation, better wound healing, fewer and less severe decubitus ulcers, less irritability and spasticity, and fewer hospitalizations, all of which result in an improved sense of well-being and an improved quality of life. Chronic constipation is a commonly unrecognized contributor to feeding intolerance among children and adults with neurodevelopmental disabilities and/or limited mobility. This article will provide the clinician with tools to recognize and treat what can be a very debilitating condition.

W.R. is a 24-year-old young man who was born extremely prematurely and as a result, has a number of chronic complications including quadriparetic spastic cerebral palsy, cortical blindness, profound global developmental delay with intellectual disability, a chronic seizure disorder, chronic respiratory difficulties that are likely the result of subclinical aspiration, and chronic feeding difficulties for which he had a gastrostomy placed during infancy. He also has a long history of chronic constipation. He has been hospitalized on at least three occasions this past year with acute respiratory illnesses that appear to be related to aspiration events and there are concerns that he is more prone to aspiration because of chronic, inadequately treated constipation. On examination he has the stigmata of severe quadriparetic cerebral palsy and appears quite malnourished with minimal subcutaneous tissue and muscle mass. His height is 152 cm and his weight is 45.8 kg (BMI = 14.49 kg/M2), which is well below the first percentile. It is certainly not surprising W.R. suffers from chronic constipation given his profound spastic cerebral palsy, chronic under nutrition, and lack of mobility. Nearly all children and adults with this constellation of symptoms will have difficulties with constipation. The constipation in this setting is multifactorial, in part due to a lack of mobility, and possibly due to the chronic ingestion of a liquid diet lacking fiber (although data on use of fiber is inconclusive). Spasticity may be a major contributor as well. When patients with spasticity strain to defecate, they often paradoxically contract their pelvic floor and external sphincter making the defecation process inefficient and ineffective. In addition to this, when these patients are ill or in pain, their spasticity often worsens making defecation even less efficient and effective. Nearly all patients like this require some sort of chronic laxative regimen. Laxatives and stool softeners alone are often insufficient to produce regular bowel movements in this population. Clinicians may need to resort to regular use of stimulant suppositories or even large volume enemas to produce regular bowel movements. In some patients with these problems, cecostomy placement to administer antegrade enemas daily can result in a major improvement in their quality of life. It is also quite possible and in fact quite probable that W.R.’s difficulties with constipation are contributing to his recurrent pulmonary difficulties. Chronic constipation can slow gastric emptying and exacerbate or even precipitate the symptoms of GE reflux. As such, in many effected individuals, regulation of their bowel habit improves their tolerance of tube feedings with less bloating, gagging, retching, vomiting and/or signs/ symptoms of GE reflux.

INTRODUCTION

Studies suggest at least 1/3 of children and adults with neurodevelopmental disabilities with or without limited mobility are significantly undernourished, and not surprisingly, the incidence and severity of malnutrition increases with the duration and severity of disability. Historically, this state of malnutrition was considered to be part of the diseases they are suffering from, however a number of studies have demonstrated that nutritional support in children and adults with a variety of neurodevelopmental disabilities can result in weight gain, increased muscle mass, improved peripheral circulation, better wound healing, fewer and less severe decubitus ulcers, less irritability and spasticity, and fewer hospitalizations, all of which are associated with an improved sense of well-being and an improved quality of life.¹ As many as 90% of children and adults with significant disabilities experience gastrointestinal difficulties including, but not limited to, dysphagia, aspiration during swallowing, gastroesophageal reflux, poor gastric emptying, and chronic constipation, any or all of which may interfere with the ability to ingest adequate nutrition2 (Table 1). As oral or enteral intake diminishes and nutritional status deteriorates, gastrointestinal symptoms may worsen, further compromising the patient’s ability to ingest adequate calories resulting in a vicious and self-perpetuating downward spiral. Studies have demonstrated that malnutrition in and of itself can produce feeding intolerance. Nutritional restitution can improve gastric motility and lessen the severity of gastroesophageal reflux,^3,4 in addition to improving gastric compliance and lessening early satiety.⁵ In some cases, the feeding intolerance associated with worsening malnutrition is a result of superior mesenteric artery syndrome in which the third portion of the duodenum is compressed due to narrowing between the superior mesenteric artery and the abdominal aorta⁶ (see Figure 1). In many cases, in undernourished or malnourished individuals, nutritional restoration can improve feeding tolerance. Nutritional repletion, either via a jejunal tube or parenterally, is the treatment of choice for superior mesenteric artery syndrome.

Constipation

Another less commonly recognized contributor to feeding intolerance among children and adults with neurodevelopmental disabilities and/ or limited mobility is chronic constipation. As many as two-thirds of children and adults with disabilities and/or limited mobility suffer from chronic constipation. The severity of constipation in this population is often underestimated and its significance on their quality of life is frequently unrecognized or discounted by health care professionals (Table 2). Abdominal cramping, bloating, and perianal pain due to fissures and/or perineal skin breakdown can be quite debilitating. Moreover, chronic constipation increases the risk of recurrent urinary infections, worsens vesicoureteral reflux, and diminishes enteral feeding tolerance by delaying gastric emptying and producing early satiety.⁹ Numerous studies have demonstrated that otherwise healthy children and adults with chronic constipation have delayed gastric emptying that improves with effective management of the constipation.¹⁰ In healthy adults, voluntary suppression of defecation significantly slows gastric emptying,¹¹ and moreover, intermittent painless rectal distension significantly slows gastric emptying and small bowel motility.¹² The mechanism of the effects of rectal distension on gastric emptying is unclear but likely reflects a combination of both humoral and neural effects.^10,12 Chronic constipation can cause chronic or recurrent vomiting and exacerbate or even precipitate the symptoms of gastroesophageal reflux and once the constipation is adequately treated, the vomiting and symptoms of reflux may abate.

Many factors contribute to the high prevalence of chronic constipation in children and adults with neurodevelopmental disabilities and/or limited mobility. While it is commonly assumed that inadequate intake of dietary fiber and a lack of sufficient fluid intake are major contributors, there is remarkably little evidence this is the case.¹⁴ In contrast, there is good evidence that undernutrition slows colonic motility¹⁴ and that diminished physical mobility slows gastrointestinal motility, and as a result, constipation and fecal impaction are common complications of prolonged immobility.¹⁵ Spasticity and/or dystonia are often significant contributors to chronic constipation as spasticity and dystonia can disrupt normal defecation dynamics. In healthy individuals, rectal distension triggers the recto-inhibitory reflex and cues the individual to the urge to defecate after which he or she increases intra-abdominal pressure by taking a breath, closing their glottis, pushing downward with the diaphragm and tensing the lower abdominal muscles while simultaneously relaxing the muscles of the pelvic floor and the external anal sphincter. Individuals with spasticity or dystonia will often paradoxically contract the pelvic floor muscles and external sphincter while they are straining making the process of defecation extremely inefficient, ineffective, and more painful. Appropriate positioning during defecation may help mitigate these involuntary and counter-productive behaviors. If possible, have the person sit on the toilet. If there is a tendency for their buttocks to slip through the toilet seat, use a seat insert so they do not need to work to suspend themselves above the toilet bowl. While they are sitting, their knees should be flexed and at or above the level of their hips and their feet should be flat on the floor. Often it is necessary to place a step stool beneath their feet so they can achieve the appropriate posture. If the person is unable to sit on the toilet to defecate, have them lie left side down (e.g., the position we usually recommend when administering enemas), knees flexed at or above the level of the hips, and put something immobile beneath their feet to push against like the footboard of the bed.

Assessment of Constipation

Given how often children and adults with neurodevelopmental disabilities and/or limited mobility suffer from constipation, early identification and aggressive management of constipation is warranted. When eliciting a history, it is important not only to ask about the frequency of bowel movements, but whether there is any bleeding with the passage of bowel movements and also about the size, caliber and consistency of the bowel movements (Table 3). If the bowel movements are long and slender “snakes”, or if they pass small bowel movements throughout the day, this suggests the patient is experiencing anismus (failing to relax the pelvic floor muscles and external sphincter during attempted defecation) and is not completely relaxing his or her pelvic floor and external sphincter while straining and thus their defecation process is relatively inefficient/ ineffective.¹⁶ In most cases, anismus is the result of the patient experiencing perianal pain with defecation, however, as mentioned above, patients with spasticity or dystonia frequently paradoxically contract their pelvic floor and external sphincter while straining. Often the best way to determine if the patient is experiencing anismus is to ask about their posture while they are trying to defecate. If their buttocks are clenched and/or their legs are stiff and/or trembling, it is quite likely they are not relaxing their pelvic floor and external sphincter while straining. During the physical exam, it is important to try and determine if there is a fecal impaction. In some patients it is relatively easy to feel a large mass of stool in the descending and/or sigmoid colon. A digital rectal exam may prove useful not only to determine if there is a large amount of firm stool in the rectum, but also to evaluate perianal sensation, anal tone, and the presence of anal fissures or hemorrhoids. If the diagnosis of constipation is unclear based on the history and physical examination, an abdominal radiograph or transabdominal ultrasonography may be helpful in assessing the amount of stool in the colon.¹⁷ Even with a careful history and exam and abdominal imaging, it can be difficult at times to determine if a child or adult with developmental disabilities and/or limited mobility is truly suffering from constipation, and if that is the case, it is reasonable to treat them empirically.

Treatment of Constipation

Once the diagnosis of chronic constipation has been established, aggressive treatment should commence. Initial therapy should be aimed at eliminating a fecal impaction, as there is evidence that treatment outcomes of chronic constipation are better if patents undergo some form of disimpaction procedure before they commence daily laxative therapy.^18,19 High doses of polyethylene glycol given over several days appear to be as effective as a series of enemas in eliminating impactions.¹⁹ The usual regimen for oral/enteral disimpaction is 1 g/kg of polyethylene glycol mixed in 8–12 ounces of fluid given three or four times daily for two or three days until the patient develops watery diarrhea. After disimpaction, some form of bowel regimen should be prescribed to prevent recurrence of the constipation and to produce soft bowel movements ideally every day or every other day.¹⁷ It is probably more important that the patient does not have to strain, and most importantly does not experience pain with defecation, than it is how often the patient is passing bowel movements. While additional fiber and additional fluid are often prescribed, these are rarely sufficient to assure children and adults with neurodevelopmental disabilities and/or limited mobility are regularly passing soft bowel movements without difficulty or pain, and may worsen gas, bloating and abdominal cramping, and further increase the colonic stool burden. Hence, some form of laxative regimen is almost always required.¹⁷ The most commonly prescribed laxatives are polyethylene glycol 3350, magnesium hydroxide, and lactulose, all of which are osmotic stool softeners. While there are no large comparative studies, most of the available evidence and experience suggest that provided they are given in sufficient doses, these agents are all equally effective; hence, the choice of the agent should be based on patient or family preference, cost, ease of administration, and potential side effects. The most common side effect of all of these agents is diarrhea, however lactulose often produces flatulence, distension and bloating. At higher doses magnesium can produce nausea and there are reports of hypermagnesemia when magnesium containing laxatives are given in very high doses and/or if the patient suffers from renal insufficiency.²⁰ While docusate sodium is often prescribed, what little evidence there is suggests that in the doses typically prescribed, this agent is not a very effective stool softener.²¹ Given that many (if not most), children and adults with neurodevelopmental disabilities and/ or limited mobility who suffer from chronic constipation have disordered intestinal motility,^1,2,17 treatment with osmotic stool softeners is often not sufficient to produce regular soft bowel movements without simultaneously causing fecal leakage or seepage. In this group of patients, the use of a stimulant laxative alone or in combination with osmotic stool softeners can be very effective. The most commonly prescribed stimulant laxatives are sennosides or bisacodyl (See Table 4 for different laxative preparations). Regardless of the laxative regimen that is prescribed, it is important to explain to the patient/ family that these agents will almost certainly need to be used chronically, and it is also very important to reassure them that there is no evidence that the chronic use of any of these agents results in dependency or increases the risk of colon cancer .²² In cases that don’t respond adequately to oral laxative therapy, some patients/families opt for regular use of suppositories or saline enemas. Another option is a Malone antegrade continence enema (MACE) procedure or a percutaneous cecostomy (Figure 2). With both of these procedures, there is a surgically constructed conduit from the skin into the proximal colon that allows the administration of antegrade colonic irrigations/enemas.17,23 With either a MACE procedure or percutaneous cecostomy, flushes of between 500 and 1000mL of water containing 17g or polyethylene glycol or 5 ml of glycerin soap are typically administered once or twice daily. For some patients, these procedures can substantially improve their quality of life.^24,25 See Table 4 for treatment options for severe constipation in those with disabilities.

CONCLUSION

A large number of children and adults with neurodevelopmental disabilities, with or without limited mobility, are undernourished and suffer from chronic gastrointestinal difficulties including feeding intolerance and chronic constipation. While it is not always recognized, chronic constipation can clearly worsen feeding intolerance in this group of individuals. Not only will this worsen their nutritional status, but it may worsen their gastrointestinal symptoms, further compromising their ability to ingest adequate calories and producing a vicious downward spiral. Given how often children and adults with neurodevelopmental disabilities and/or limited mobility suffer from constipation and the potential impact of the constipation on their quality of life, as well as the potential for impairing their ability to tolerate enteral feedings, early identification and aggressive management of constipation is not only appropriate, but the right thing to do.

FRONTIERS IN ENDOSCOPY, SERIES #59

Solid Pseudopapillary Tumors of the Pancreas: A Rare but Important Clinical Entity

Douglas G. Adler,

Malan Shiralkar

A 45-year-old man presented with 3 months of progressive left upper quadrant abdominal pain and a sensation of abdominal fullness. Complete blood count and comprehensive metabolic blood panel were normal. A CT scan showed a large solid pancreatic mass in the tail of the pancreas. Endoscopic ultrasound (EUS) was performed at 7.5MHz with Doppler. EUS revealed a hypoechoic, heterogeneous, 7×6 cm solid mass lesion in the pancreatic tail with scattered hyperechogenic foci consistent with some peripheral calcifications. (Figure 1). EUS guided core biopsy was performed with a 22 gauge needle. The pathology report revealed loosely clustered to discohesive monomorphic cells with eccentric nuclei and fine chromatin. There were hyalinized stromal fragments lined by monomorphic, bland-appearing, polygonal cells that appeared to be falling off the underlying stromal core. Immunohistochemical stains were used to aid in the evaluation of the pathology specimen. The cells of interest (associated with the hyalinized stromal core) are positive for B-catenin (nuclear), showed patchy positive staining for CD56. Tissue samples were mostly negative for Cam 5.2 and synaptophysin. The histology and immunohistochemistry together were supportive of a diagnosis of a solid pseudopapillary tumor (SPT). (Figures 2-5) The patient was referred to surgery and underwent a distal pancreatectomy and splenectomy. This confirmed the diagnosis of SPT. All resected lymph nodes were free of disease. He has done well thereafter.

Incidence and Demographics

SPT of the pancreas is a rare tumor that was first described by Virginia Frantz in 1959.¹ SPT has previously been called many other names including solid and papillary epithelial neoplasm, papillary cystic neoplasm, solid and cystic papillary epithelial neoplasm, solid and cystic acinar cell tumor, low grade papillary neoplasm, Hamoudi tumor, and Frantz tumor.² In 2010, the World Health Organization designated the name of this tumor as solid pseudopapillary tumor.² SPT is a rare neoplasm, accounting for 1-2% of all exocrine pancreatic neoplasms and 0.17-2.7% of nonneuroendocrine tumors of the pancreas.^3,4,5 Since 2000, there has been a seven fold increase in SPT, which has largely been attributed to more frequent and improved imaging tests as well as increased clinical awareness of this entity.³ SPT has a marked female predominance, affecting females around ten times more often than males.^3,4,5,6 More than ninety percent of reported cases of SPT affect females in their second decade with a mean age of diagnosis around 22.5 years.⁵ Men are generally found to be diagnosed at a later age than women.¹⁴ The tumor has been found to have a higher prevalence in Asian and Black populations.

Symptoms

SPTs are often asymptomatic and are often incidentally noted.^4,5 In patients who are symptomatic, the most common symptom is abdominal pain or mass with a reported incidence of 63% of symptomatic cases.⁵ Other less common symptoms include nausea, vomiting, fever, weight loss, jaundice, and early satiety. Acute abdomen can occur in the setting of tumor rupture.⁷ SPTs are not typically associated with exocrine or endocrine pancreatic insufficiency.3

Tumor Characteristics

SPTs can occur in any part of the pancreas; however, the most common site of the tumor in adults is the pancreatic tail, followed by the pancreatic head, then the body.^3,5 SPTs are often large in size with a mean size of 7.5cm at time of diagnosis.⁵ There is significant variability in appearance of the tumor due to varying degrees of cystic degeneration within the tumor. There are often solid, cystic, and pseudopapillary components within the tumor.5 Smaller tumors tend to be more solid but less well circumscribed while larger tumors tend to have more cystic degeneration, hemorrhage, and necrosis with a pseudocapsule and variegated cut surface.⁵ Cyst formation tends to be more centrally located while solid components are usually found on the periphery.³ SPTs appear well circumscribed, but do not have a fibrous capsule and microscopically neoplastic cells infiltrate surrounding pancreatic parenchyma entrapping acinar cells and islets.8 Primary SPT can occur outside of the pancreas when there is presence of ectopic pancreatic tissue, but is extremely rare.³ The most common sites that this occurs include the ovary, mesocolon, and omentum.

Imaging

On both CT imaging and MR imaging, SPTs appear to be well circumscribed, encapsulated, and heterogeneous with hemorrhagic and cystic degeneration. MR imaging is more sensitive than CT imaging in evaluating intratumoral hemorrhage, cystic degeneration, and presence of capsule.¹⁴ Transabdominal ultrasound imaging often shows a heterogeneous solid and cystic mass with occasional calcifications.⁹ Findings of pancreatic duct dilation and vessel invasion are suggestive of more aggressive tumor.¹²Other than surgery, the best diagnostic and imaging test is endoscopic ultrasound (EUS) with fine needle aspiration (FNA) or fine needle biopsy (FNB). On EUS examination, the mass will appear as a wellcircumscribed, hypoechogenic, heterogeneous tumor with solid and cystic components with calcifications.¹⁰ EUS has a reported sensitivity of 91-95% and specificity of 92-95% in the diagnosis of SPT3,11 Given concern for seeding of tumor cells to the peritoneum with laparoscopic biopsy, it is not recommended or routinely performed.

Pathology

On cytological examination, cells are typically bland, uniform, round to oval with eccentrically located nuclei, moderate cytoplasm, and finely dispersed chromatin.^8,12 Metachromatic hyaline globules can be found in the cytoplasm.⁸ Clear myxoid material surrounds papillae.¹³ Large, cytoplasmic vacuoles can be helpful in differentiating SPTs from other pancreatic tumors.¹² Clusters of foamy macrophages, multinucleated giant cells, cholesterol, and necrotic debris are occasionally seen. Histologically, the classic finding of a SPT is presence of pseudopapillary areas with fibrovascular stalks or rosette-like structures secondary to poor cohesion of the malignant cells. Immunohistochemically, most SPTs demonstrate intense nuclear localization of B-catenin and loss of membrane expression of E-cadherin with disruption of the activated Wnt pathway.8 SPTs are typically positive for vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and neuron specific enolase. SPTs are typically negative for chromogranin A, epithelial membrane antigen, and cytokeratin.⁷ The presence of the CTNNB1 molecular marker in conjunction with the lack of KRAS, GNAS, RNF43 and LOH on chromosome 18 is helpful in making the diagnosis of SPT.⁷ Histiogenesis and the cell of origin of SPT have yet to be definitively identified. Given the female predominance of SPTs and the increased estrogen receptors associated with SPT, a proposed theory is that female sex hormones may play a role in tumorigenesis.³ In vitro studies have shown an increased proliferation of SPTs with estrogen.

Differential Diagnosis

The differential diagnosis of SPT is broad due to its variable appearance. The differential includes pancreatic neuroendocrine neoplasms, acinar cell cancer, mucinous or serous cystic neoplasms, and lymphoma. Pancreatic neuroendocrine neoplasms can often have similar histologic features as a SPT. The presence of pseudopapillae, hyaline globules, foamy histiocytes, and grooving of the nucleus are more consistent with the diagnosis of SPT. Alternatively, the appearance of speckled chromatin would favor a neuroendocrine tumor.¹² Acinar cell carcinoma of the pancreas can be differentiated from SPTs by the presence of irregular nuclei with maintained cytoplasmic polarity and clusters of cohesive clusters of cells with acinar formation.¹² SPT can be sometimes confused with serous cystadenoma on cross sectional imaging; however, serous cystadenomas are typically well circumscribed nodules with cystic spaces lined by cuboidal cells with clear, glycogen containing cytoplasm.¹² EUS is often helpful in distinguishing SPT from serous cystadenoma, either by visualization alone or with the addition of FNA or FNB. Additionally, serous cystadenomas sometimes contain a central scar with a radiating pattern.

Prognosis

SPTs typically carry a good prognosis as they have low malignant potential. There is a low likelihood of metastases and vascular invasion. Only 10-15% of patients will develop metastases.¹⁵ The most common site of metastasis is the liver.⁵ Peritoneal metastases are less frequently seen and are thought to be a result of trauma or rupture of tumor.⁵ Lymph node metastases occur infrequently with less than 10 reported cases.⁵ There are even few reports of pulmonary metastases.11 Rarely does tumor locally invade into the vasculature, stomach, duodenum, or spleen.⁵ The overall prognosis of SPT even in the presence of metastases is excellent. The reported five-year survival rate is greater than 95% and is highest in patients with SPT limited to the pancreas.⁵ The reported mortality from this tumor is reported as less than 2%.¹⁵ Male patients and elderly patients tend to have a worse prognosis.^3,4 Compared to female patients, males have a twofold higher incidence of metastases and a threefold higher incidence of death.

Treatment

Surgical resection of the tumor, with as much sparing of normal pancreatic tissue, is the treatment of choice for SPTs and is often curative.¹⁷ The type of surgery is dictated by the location and size of the tumor. Tumor invasion to the portal vein or superior mesenteric artery is not considered a contraindication for surgical resection, but may limit complete resection.14 Surgical procedures utilized include pancreatoduodenenectomy, distal pancreatectomy, middle pancreatectomy, duodenum-preserving pancreatic head resection, spleen preserving distal pancreatectomy and local resection.³ More invasive surgical techniques include synchronous portal-superior mesenteric vein or adjacent organ resection if there is evidence of local invasion.³ Due to increased risk of dissemination, higher recurrence rate, and development of pancreatic fistula, tumor enucleation is not recommended.³

Unfortunately, SPT can be unresectable if there is evidence of large vessel invasion. In patients with unresectable tumors due to size or location, neoadjuvant chemotherapy and radiation has been utilized to decrease the size to create conditions favorable for potential resection.³ Long-term survival is thought to be improved after resection of metastatic SPT. In patients with liver metastases, synchronous or metasynchronous surgical resection can be performed.³ Recent studies have shown that a one centimeter margin in hepatic metastasis resection is considered curative. In patients with diffuse hepatic metastases, which are not amenable to resection, liver transplantation (both orthotopic liver transplant and living donor transplant) has been performed in the past, as removal of liver metastases in addition to removal of primary SPT can potentially be curative.¹⁸ Diffuse growth pattern, extensive necrosis, high mitotic rate, and sarcomatoid areas within tumor have been associated with more aggressive tumor behavior.¹⁹ Patients with lymph node metastases, tumors larger than 8cm, cellular atypia, capsule invasion, lymphovascular invasion, perineural invasion, and peripancreatic fat tissue invasion were found to have worse outcomes following surgery.²⁰ The reported incidence of tumor recurrence is around 1.9-6%.

The role of chemotherapy and radiation is unclear at this time. Described chemotherapy regimens have included 5-fluorouracil, doxorubicin, and streptozocin or interferon, cisplatin, and topotecan or gemcitabine-based chemotherapy. Long term follow up is suggested following surgical resection. Given the rarity of this tumor, there does not currently exist guidelines or a current consensus regarding the interval, length, or modality of follow up. Due to the low rate of recurrence of this tumor, no risk factors have been associated with recurrence. A proposed further therapy for SPT includes selective estrogen receptor modulators as in vitro studies have shown the influence of estrogen on tumor proliferation.

CONCLUSION

SPTs are rare pancreatic tumors but are increasingly being identified due to more frequent and better cross sectional abdominal imaging. They typically occur predominantly in a younger female population. Our patient was notable for his age and male sex. SPTs are usually asymptomatic and incidentally noted on imaging, but commonly associated symptoms include abdominal discomfort as experienced by our patient. Luckily, SPTs typically carry a good prognosis as they have low malignant potential with low likelihood of metastases to liver, peritoneum, lungs, and rarely lymph nodes. The reported five-year survival rate of SPT is greater than 95%. Treatment of SPTs includes surgical resection of the mass with as much preservation of the pancreas as possible and in some cases, neoadjuvant chemotherapy may be indicated.

FROM THE LITERATURE

Surgical vs. Endoscopic Resection of Large, Nonmalignant Colorectal Polyps

To determine nationally representative estimates and to identify predictors of in-hospital mortality and morbidity after surgery for nonmalignant colorectal polyps, data was analyzed from a national inpatient sample for 2005 to 2014. All discharges for adult patients undergoing surgery for nonmalignant colorectal polyps were identified. Rates of in-hospital mortality and postoperative wounds, infections, urinary, pulmonary, gastrointestinal or cardiovascular adverse effects were calculated. Multivariable logistic regression using survey-weighted data was used to identify variables associated with postoperative mortality and morbidity. An estimated 262,843 surgeries for nonmalignant colorectal polyps were analyzed. In-hospital mortality was 0.8% and morbidity was 25.3%. Postoperative mortality was associated with open surgical technique (vs. laparoscopic), older age, black race, Medicaid use and burden of comorbidities. Female sex and private insurance were associated with lower risk. Patients developing a postoperative adverse event had a 106% increase in mean hospital length of stay and 91% increase in mean hospitalization cost. It was concluded that surgery for nonmalignant colorectal polyps is associated with almost 1% mortality and common morbidity. Risk vs. benefit discussion for clinicians and patients was indicated, and although confounding by patient selection, cannot be excluded, the risk associated with surgery support consideration of endoscopic resection as a potentially less invasive therapeutic option.

FROM THE PEDIATRIC LITERATURE

Probiotics and Functional Abdominal Pain in Children

Prior research has suggested that specific single nucleotide polymorphisms associated with allergies may carry a risk for functional gastrointestinal disorders (FGIDs). Cow’s milk allergy (CMA) is common in children, and treatment often consists of using hydrolyzed casein formula to reduce inflammation. Probiotics also can be used to treat CMA as the disorder is associated with intestinal dysbiosis. Thus, the authors proposed that use of hydrolyzed casein formula with supplementation with Lactobacillus rhamnosus GG (LGG) in children may reduce the risk of FGIDs in children by affecting both intestinal inflammation and dysbiosis. This study was prospective, non-randomized, and open and included children 4 to 6 years of age with a history of CMA in the past. CMA was defined strictly as occurring when a patient had a reaction using a double-blind, placebo-controlled, food challenge. If a patient was diagnosed with CMA, then they were treated with one standard hydrolyzed formula (Nutramigen, Mead John Nutrition) or the same standard hydrolyzed formula with the addition of Lactobacillus rhamnosus GG (Nutramigen LGG, Mead Johnson Nutrition). Multiple patient conditions were excluded from the study, including patients with other food allergies, other allergic conditions, and patients treated with other prior prebiotics or probiotics. The patients with CMA were compared to sex and age-matched controls. Clinical data was obtained on all enrolled study patients with CMA (including sociodemographic factors, family history of allergic disease, exposures, etc.). Patients then underwent Rome III diagnostic criteria using the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGS) based on Rome III Criteria (QPGS-RIII) to document presence of FGIDs later in life.

The study compared 110 patients with CMA given hydrolyzed formula, 110 patients with CMA given hydrolyzed formula with LGG, and 110 control patients. Baseline demographic data were similar between all groups except that age of immune tolerance to cow’s milk protein was significantly older in patients who had received hydrolyzed formula compared to patients who had received hydrolyzed formula with LGG. An analysis of the presence of FGIDs in the 3 study groups demonstrated an incidence rate of 0.21 (95% CI, 0.12 to 0.29) in the control group, 0.40 (95% CI, 0.31-0.50) in the group who had received hydrolyzed formula, and 0.16 (95% CI, 0.090.23) in the group who had received hydrolyzed formula with LGG. This analysis demonstrated that children who had received hydrolyzed formula with LGG had significantly less risk of developing a FGID long-term compared to children who had received hydrolyzed formula alone (P < 0.001). This significance did not change when corrected for age of CMA diagnosis, breastfeeding and weaning duration, or having a first degree relative with a history of an FGID. This study suggests that children with a prior history of CMA may have an increased risk of developing FGIDs later in life, and probiotics (specifically LGG in this study) may have a protective effect. However, the intestinal microbiome is complex as is determining all causes of FGIDs (including issues involved with visceral hypersensitivity and stress potentially aggravating FGIDs). Thus, although this study is an important step in evaluating potential risk factors for developing FGIDs in children, much more work is needed in identifying specific stool microbiome genetic signatures in children with a history of CMA and subsequent FGIDs as well as identifying specific biomarkers which could prevent FGIDs long term.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #109

Observations on the Neglect of Anal Skin Tags as an Early Marker of Crohn’s Disease in Children

Guillaume Stoffels

Background and Aims Anorectal skin tags (ASTs) are a common, asymptomatic, early manifestation of Crohn’s disease (CD). Usually CD has its onset in childhood (age 18 or younger). This paper aims to identify patients with Crohn’s disease and ASTs, to determine the age of onset of CD, and then estimate the years that ASTs had been present before establishing the diagnosis of CD. Methods From our database of over 3000 patients with inflammatory bowel disease, we identified 263 Crohn’s disease patients with obvious ASTs at first visit for CD, and 57 (21.6%) of these were in patients diagnosed with CD at age 18 or younger. Results In this group of 57 children, the median age at diagnosis of CD was 14 and the median number of years from the first awareness of ASTs was 6. Conclusions The high incidence of ASTs should encourage pediatricians, internists, family physicians and gastroenterologists to spread the buttocks and search for ASTs in children presenting with diarrhea, rectal bleeding, abdominal pain or growth failure. Accordingly, the diagnosis CD might be made so much earlier and effective medical therapy be initiated sooner.

INTRODUCTION

Relatively little attention has been paid to the anal skin tags (ASTs) of Crohn’s disease (CD).1,2 Since ASTs are painless and often overlooked in favor of the more ominous perirectal manifestations such as abscesses and fistulae which require more immediate attention,3,4 their recognition has become progressively more meaningful as an early indicator of CD.5 Examples of ASTs are shown in Figure 1. In the course of management of inflammatory bowel disease (IBD) over the past 50 years, it has been the policy of the section of gastroenterology at Lenox Hill Hospital to search for ASTs at the time of the initial physical examination in patients with known or consideration of the diagnosis of CD. At the time of colonoscopy it has been the routine to spread the buttocks and take a picture of the ASTs if present. In our database of more than 3,000 IBD patients at Lenox Hill Hospital, we have recognized that ASTs are usually present in CD patients at the first visit, regardless of age, and are most commonly recognized during childhood or teenage years. We have gathered information on the history of ASTs, particularly their contribution to the earlier diagnosis of CD with the goal of preventing destruction of tissue and the need for surgery.

OBJECTIVE

To determine the duration of anal skin tags prior to the diagnosis of Crohn’s disease in children (age 18 or younger).

Population

We identified 263 (15.3%) of patients with ASTs at the time of the first consultation out of 1683 with Crohn’s disease.

Results

In 57 of the 263 patients (21.6%) the CD was diagnosed at age 18 or younger (Table 1). The ASTs were identified after excluding them from other anal or perirectal abnormalities including hemorrhoids. Statistical analyses were performed using R version 3.3. (R Foundation for Statistical Computing, Vienna, Austria). The age range at the time of the first visit with ASTs of the CD patients to the IBD service at Lenox Hill Hospital was 3-52 years with a median of 20 and the earlier age range at diagnosis of Crohn’s disease was 1-18 years with a median of age 14 (Tables 1 & 2). In Figure 2 are histograms showing the distributions of both. In all 57 patients, the parent or the patient consistently claimed that the ASTs were already present at the earlier time of diagnosis. The number of years elapsed between Crohn’s disease diagnosis and the time of consultation with ASTs ranged from 0 and 36 years with a median duration of 6 years

DISCUSSION

The characteristic features of ASTs have been reported earlier.1-4 Those studies showed that the ASTs were present more frequently when the colon alone was involved with CD (47%) than ileitis (37%) or ileocolitis (16%). The recognition of ASTs has served to herald the earlier diagnosis of CD in young patients with diarrhea, abdominal pain, and/or growth retardation. The larger ASTs have been called elephant ears; they are usually painless2 except when associated with healed anal fissures or ulcers. Most ASTs are identified coincident with other signs or symptoms of CD. Nevertheless, the ASTs may precede the intestinal symptoms by months or even years5-9 and are independent of other perirectal or perianal manifestations. Since ASTs are rarely symptomatic, they have mostly been ignored in favor of treating other symptoms of CD including more incapacitating abscesses and fistulas. Historically, physicians and surgeons have been cautioned to avoid surgical intervention of the ASTs for fear of failure of healing, incontinence or provoking underlying CD activity. Accordingly, excision and biopsy are infrequently done. Nevertheless, in one study skin tags were purposely excised and the pathology revealed granulomas in 9/26, and when granulomas were present they were more plentiful in the ASTs than in rectal biopsies.10 Granulomas were seen in all sections of the AST tissue in 7/9 patients. Table 2 shows that the median time between CD diagnosis and first gastroenterological consultation was 6 years. Since the ASTs were present at first visit and more likely present at the time of earlier CD diagnosis, the median time interval was 6 years. Other observations from the current study include perirectal manifestations of Crohn’s disease including abscesses, fistulae and strictures to be present along with the ASTs in 33/57 patients, and 41/57 had already had bowel resections at the time of the consultation. The issue about avoiding biopsy of ASTs as to avoid a flare of the CD is not well documented. A review of 135 patients (11 studies) which combine ASTs with hemorrhoids revealed a complication rate of 17% manifested by sepsis, fecal incontinence, anal ulceration or stenosis, but this study did not focus on the ASTs.11 Perirectal lesions may precede the onset of intestinal symptoms in 9.3% by 2 weeks – 12 years.12 In one study with a prevalence of ASTs in 25/37 (68%) new skin tags rarely appeared later following those found initially.13 A study from South Korea calls attention to the high incidence of ASTs in the Pediatric CD population.14 In 1932 when Crohn, Ginzberg and Oppenheimer described Regional Ileitis there was no mention of any peri-rectal disease which is understandable since the focus then was on the sickest patients who presented with surgical emergencies, resections and the resulting pathology;15 subsequently, however, it became evident that ano-rectal lesions are common and may precede the intestinal symptoms. Yet after 85 years later, most reports on Crohn’s disease anorectal manifestations emphasize the abscesses and fistulas; only studies which focus specifically on the anal skin tags serve to describe them in detail.

CONCLUSION

New efforts to target the preclinical phase of Crohn’s disease16 with a more determined search for an early marker of disease are warranted. The presence of ASTs, particularly in children with symptoms of abdominal pain, diarrhea or retarded growth should lead to earlier diagnosis, treatment and prevention of late complications which result in surgery and then recurrent disease. Earliest investigation after discovery of ASTs would certainly accelerate this effort.

References

1. Bonheur JL, Braunstein J, Korelitz BI, Panagopoulos G. Anal Skin Tags in Inflammatory Bowel Disease: New Observations and a Clinical Review. Inflamm Bowel Dis 2008: 14:1236-1239

2. Korelitz BI. Anal Skin Tags: An Overlooked Indicator of Crohn’s Disease. J Clin Gastro 2010; 44:151-2

3. Aronoff JS, Korelitz BI, Sohn N, Ky A, Rajapakse R, Weinstein MA, Cohen FS. Anorectal Crohn’s disease. Bio Drugs 2000; 13: 95-105

4. AGA Technical Review on Perianal Crohn’s disease. Gastroenterology 2003;125:1580-1530

5. Ashton JJ, Harden A, Beattie RM. Pediatric Inflammatory Bowel Disease: Improving Early Diagnosis. Arch Dis Child. 2018;103:307- 308

6. Gray BK, Lockart-Mummery HE, Morson BL. Crohn’s disease of the Anal Region. Gut 1965; 6:515-524

7. Baker WN, Milton-Thompson GJ. The Anal Lesion as the Sole Presenting symptom of Intestinal Crohn’s disease. Gut 1971; 12:865

8. Fielding JF. Perianal lesions in Crohn’s disease. J R Coll Surg Edinb 1972; 17:32-37

9. Buchmann P, Keighley MR, Allan RN, Thompson H, AlexanderWilliams J. Natural History of Perianal Crohn’s disease. Am J Surg 1980; 140:642-644

10. Taylor, B, Williams GT, Hughes LE, Rhodes J. The Histology of Anal Skin Tags in Crohn’s disease: An Aid to Confirmation of the diagnosis. Int J Colorectal Dis 1989; 4: 197-199

11. Cracco N, Zinicola R. Is Haemorrhoidectomy in Inflammatory Bowel Disease Harmful? An Old Dogma Reexamined. Colorectal Disease 2014; 16:516-519

12. Homan WP, Tang C, Thorbjarnarson B. Anal Lesions Complicating Crohn’s disease. Archives of Surgery 1976; 11: 1333-1335

13. Buchmann P, Allan RN, Keighley MRB, Alexander-Williams J. Natural History of Perianal Crohn’s disease. Gut 1979; 20:440-441

14. Lee YA, Chun P, Hwang EH, Mun SW, Lee YJ, Park JH. Clinical Features and Extraintestinal Manifestations of Crohn’s disease in Children. Pediatric Gastroenterol Hepatol Nutr 2016; 19: 236-242

15. Crohn BB, Ginzburg L, Oppenheimer GD. Regional Ileitis: A Pathologic and clinical Entity. JAMA 1932; 99: 1323-1329

16. Peyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, D’Haens G, Dotan I, Dubinsky M, Feagan B, Fiorino G, Gearry R, Krishnareddy S, Lakatos PL, Loftus EV Jr, Marteau P, Munkholm P, Murdoch TB, Ordás I, Panaccione R, Riddell RH, Ruel J, Rubin DT, Samaan M, Siegel CA, Silverberg MS, Stoker J, Schreiber S, Travis S, Van Assche G, Danese S, Panes J, Bouguen G, O’Donnell S, Pariente B, Winer S, Hanauer S, Colombel JF. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE). Am J Gastroenterol 2015; 11:1324-1338

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #194

Treatment of Iron Deficiency in Gastroenterology: A New Paradigm

Michael Auerbach,

Brian W Behm,

Abhinav Sankineni

Iron deficiency is the most common micronutrient deficiency in the world and complicates a host of gastrointestinal maladies associated with blood loss. Oral iron, the frontline standard, is often poorly tolerated and ineffective. Oral iron may also cause injury to gastrointestinal epithelium and has been shown to negatively impact the gut microbiome. Newer formulations of intravenous iron have been to shown to be effective with a similar safely profile to placebo. These formulations contain complex carbohydrates that bind elemental iron more tightly, allowing a complete replacement dose to be administered in a single office visit of 15-60 minutes. Total dose infusion of intravenous iron improves convenience for both physician and patient and decreases the overall cost of care. There is now ample evidence to move intravenous iron to the frontline in all gastrointestinal disorders in which oral iron is ineffective, and should be the preferred route of administration when oral iron intolerance occurs.

INTRODUCTION

Iron deficiency is recognized as the most common micronutrient deficiency, estimated to affect more than 35% of the world’s population.1 Cells with the greatest ability to absorb iron are found in the distal duodenum and proximal jejunum. Patients with GI disease or surgical resections affecting these areas are at high risk for iron deficiency. Bleeding is a common manifestation of many GI disorders, and subsequently iron deficiency, with or without anemia, is a frequent comorbidity.

Iron Absorption

Iron, in the presence of gastric acid, is conjugated to vitamin C, amino acids, and sugars, which protect it from the alkaline secretions of the pancreas, which are necessary for normal digestion. Absent that event, the iron is converted to ferric hydroxide (rust), which is unabsorbable from the GI tract. Dietary iron is best taken on an empty stomach, which allows the gastric acid to promote binding, and is then absorbed in the duodenum and proximal jejunum. Iron homoeostasis is regulated by the protein hepcidin, which has a crucial role in iron availability to tissues by blocking both absorption at the level of the intestinal epithelium and iron release from circulating macrophages. This regulation is mediated by hepcidin’s ability to irreversibly inactivate ferroportin-1 (FPN1), the only known iron export protein in humans.² The inactivation of ferroportin by hepcidin results in decreased absorption and subsequent failure of the intracellular iron to be loaded on to transferrin for subsequent erythropoiesis. Circulating macrophages, a reservoir for iron, are similarly expressed with ferroportin with similar loss of the function of iron export in the presence of hepcidin. Subsequently, high expression of hepcidin (due to inflammation and other co-morbid conditions, oral iron supplementation, iron sufficiency) decreases plasma iron concentrations; low expression (due to iron deficiency, hemochromatosis) increases plasma iron concentrations.

Disease States Altering Iron Absorption

A number of frequently occurring GI disorders may impair iron absorption (Table 1). Helicobacter pylori may cause iron malabsorption by causing atrophic gastritis, resulting in reduced soluble iron for absorption from acid insufficiency.3 Long term use of high dose proton pump inhibitors (PPIs) and autoimmune atrophic gastritis may also contribute to iron deficiency through a similar mechanism.4,5 After roux en y gastric bypass, the blind loop (consisting of distal stomach, duodenum and proximal jejunum) is bypassed. As a result, oral iron is not available for absorption, precipitating iron deficiency in the majority of patients despite oral supplementation.6 Patients with gastric bypass may also have diet alterations as well as a reduction in gastric acid, both of which contribute to iron deficiency.7,8 Celiac disease can cause duodenal inflammation resulting in iron malabsorption and resulting deficiency.9 Iron deficiency with inflammatory bowel disease (IBD), in addition to bleeding, is exacerbated by inflammation in the small bowel with malabsorption and the chronic inflammatory state associated with the disease.10,11 Early on, dietary iron may provide enough iron to maintain normal hemoglobin concentrations as iron stores are depleted. As a result, iron deficiency is often present without anemia, but may result in symptoms of fatigue, decreased exercise tolerance, pagophagia (ice craving), or other forms of pica, and restless leg syndrome.

ORAL IRON SUPPLEMENTATION

It was in 1681 when Sydenham first used iron filings in cold wine to treat the symptoms of the ‘green sickness’,12 later termed chlorosis by Pierre Blaud. It was not long thereafter that oral iron was used to treat patients with wounds during the American Civil war. Today, iron deficiency is the most common micronutrient deficiency on the planet, and oral iron remains frontline therapy for most conditions. The advantages of oral iron are that it is readily available, inexpensive, convenient, and noninvasive. Unfortunately, significant GI side effects frequently occur, which often leads to poor adherence. A recent meta-analysis of prospective studies comparing oral ferrous sulfate to placebo and parenteral iron found more than 70% of patients reported significant GI toxicity with oral iron, including nausea, abdominal pain, diarrhea, and constipation.14

While several oral iron preparations have been marketed with claims of superiority in either tolerability or efficacy, none have been shown in prospective studies to be superior to ferrous sulfate15,16 (Table 2). Oral formulations with slow release of iron and those with enteric coating may result in better GI tolerance, but are released beyond the duodenum and proximal jejunum (primary site for iron absorption). This results in a lack of adequate GI absorption, and thus these formulations should not be prescribed due to their lack of clinical efficacy.15 Studies have shown that oral dosing of iron upregulates hepcidin levels, leading to impairment of intestinal iron absorption.17 Absorption of oral iron tablets decreases when taken daily or twice daily, compared to alternate day therapy,18 thus alternate day dosing of oral iron may be a preferable dosing regimen.

Inflammatory Bowel Disease

Although oral iron is commonly prescribed to treat iron deficiency in patients with IBD, several studies have shown it is not appropriate in the setting of active disease. Oral iron has been shown to exacerbate intestinal inflammation of IBD independent of anemia,19 and cause luminal changes in microbiota and bacterial metabolism, which may negatively alter the microbiome.20,21 Studies have also found response to oral iron therapy depends on levels of C-reactive protein (CRP), with high CRP levels correlating with weaker hemoglobin response.22 Thus, iron should only be given orally to IBD patients with inactive disease, mild anemia, and good tolerance of oral iron; in patients with active IBD oral iron should be avoided. One new oral iron formulation, ferric maltol, has been studied in patients with inactive IBD and was found to be more effective at correcting anemia compared to placebo and did not appear to exacerbate IBD activity.23 This formulation was recently approved by the FDA and appears to be a promising option for this population.

Other GI Disease States

Tolerance of oral iron in other GI diseases is also problematic. In patients with upper GI tract disorders such as erosive esophagitis and peptic ulcer disease, oral iron may exacerbate luminal symptoms leading to patient nonadherence.

Patients with GI motility disorders and small intestinal bacterial overgrowth have symptoms of bloating, abdominal discomfort and altered bowel habits.24 As a result, this population also does not tolerate oral iron well. Finally, strong evidence supports avoidance of oral iron after gastric bypass and with ongoing active blood loss.1

INTRAVENOUS IRON

In the past, many clinicians were taught that intravenous iron was dangerous; much of this misperception stems from the early use of colloidal ferric hydroxide and high molecular weight iron dextran, both of which were associated with toxicity and neither of which are available today.26 In 1954, a solution of iron dextran was introduced by Baird and Padmore for the treatment of iron deficiency by the intramuscular route.27 This painful method of administration, which was neither safer, nor more efficacious than the IV route, gained little enthusiasm among clinicians. In the next two decades it became clear that the administration of parenteral iron by the IV route was better tolerated, easier to administer, and most importantly, more safe.28-30 Nonetheless, IV iron remained a relatively minor product, used in situations where there was an urgent need for iron replacement could not be tolerated. Today there is a much greater appreciation of the role of IV iron across a large number of diagnoses associated with iron deficiency. Currently there are five IV iron formulations available in the U.S. (Table 3). Two of these, iron sucrose (Venofer®) and ferric gluconate (Ferrlecit®), have increased labile free iron after an injection which limits the amount that can be infused during a single session.31 These formulations are reasonable options for hemodialysis patients in whom frequent visits are necessary, but as they require multiple visits to an infusion center, they are not as convenient as other formulations that may be given as a single or total dose infusion. The oldest of the formulations able to be administered as a total dose infusion (TDI) is low molecular weight iron dextran (INFeD®). The method of administration approved by the FDA is 100mg per infusion; however, a TDI of one gram over one hour has been shown to be superior to this regimen.32 In one study, 1288 infusions of iron dextran were administered to 888 patients, with hemoglobin and hematopoietic response (> 2 grams) achieved in 90% of patients with no serious adverse events observed. Compared to the FDA approved method of administration, TDI is less expensive, decreases the chances for minor infusion reactions (observed with all of the formulations), and extravasation risk, and finally, is more convenient for patients and practitioners.33 The second of the formulations approved as a TDI is ferumoxytol (Feraheme®). Ferumoxytol is approved for a 510 mg infusion in 15 minutes. However, equal safety and efficacy of a single 1020mg infusion in 15-30 minutes has been demonstrated.32 Some insurance plans pay for this method of administration, but others do not, which limits the routine administration of the higher dose. Ferumoxytol has been shown to be effective and safe across a broad spectrum of diagnoses. Ferumoxytol has been compared to iron sucrose34 and ferric carboxymaltose35 and has been shown to be equally safe and effective. Ferumoxytol is also paramagnetic and has been used as an offlabel MRI contrast agent. If an MRI is planned, the radiologist should be notified of the use of ferumoxytol and gadolinium avoided. The third formulation approved as a TDI in the United States is ferric carboxymaltose (FCM; Injectafer®). The FDA approved method of administration is 750 mg given over 15 minutes, but studies in Europe have reported the safety and effectiveness of 1000 mg administered over 15 minutes.36 In the United States the only vial size available is 750mg, requiring two visits to administer this dose. While it is possible that 1500mg may offer an advantage, in comparison to ferumoxytol, 1500mg of FCM (two vials) was compared to 1020mg of ferumoxytol (two vials) and at five weeks the differences in hemoglobin response were not clinically significant.35 FCM has been shown to be safe and effective in IBD and has been shown to prevent recurrence of anemia, even in patients with active disease.37 FCM has also been compared to oral iron in IBD and shown to be more effective, significantly better tolerated with less toxicity.38 Of note, FCM has been associated with hypophosphatemia in more and oral iron than 50% of patients to whom it is administered,39 and cases of symptomatic hypophosphatemia have been reported with this agent.40,41 Serum phosphate should be monitored during and after treatment with FCM, and this formulation should be avoided in patients with documented hypophosphatemia (or are at risk for, or actively refeeding). The fourth formulation that may be administered as a TDI is iron isomaltoside (Monofer®), currently available only in Europe. As with other formulations, isomaltoside has been shown to be safe and effective across a similar population with iron deficiency.42,43 Isomaltoside has also been shown to have a very low incidence of hypophosphatemia.

SAFETY OF INTRAVENOUS IRON

While intravenous iron has been shown to be quite safe, there remains a risk of minor infusion reactions due to labile free iron, which occur in 1-3% of administrations. In a recent meta-analysis, the results of more than 10,000 patients who were treated with intravenous iron were reported.44 Compared to oral iron, placebo, and even intramuscular iron (which should never be given), while minor infusion reactions were observed with IV iron, there was no increase in serious adverse events compared to any comparator including placebo. A marked reduction in GI toxicity was reported with IV iron compared to oral iron. Minor infusion reactions typically are self- limited and consist of pressure in the chest or back, or flushing in the face. Notably there is no tachypnea, tachycardia, hypotension, wheezing, stridor or periorbital edema, and the risk of anaphylaxis is very rare. Inappropriate intervention with antihistamines or vasopressors, which are known to cause hypotension, tachycardia, diaphoresis, and somnolence, may convert minor infusion reactions to more serious adverse events. Premedication with antihistamines should be discouraged, although premedication with steroids may decrease the likelihood of minor infusion reactions in those with significant allergic diatheses or prior history of reaction (125mg of methylprednisolone and 50mg of ranitidine or famotidine in patients with more than one drug allergy or asthma or prior minor infusion reaction).

CONCLUSION

Iron deficiency is of global consequence, and patients with gastrointestinal disease are at a heightened risk due to alterations in absorption and increased blood loss. Based on the preponderance of published evidence, the use of oral iron should be discouraged in patients with IBD. In patients who have undergone bariatric surgery or other surgical resection that bypasses the duodenum, oral iron is poorly absorbed and largely ineffective hence, it should also be avoided. For those with GI tract angiodysplasia, oral iron typically cannot keep up with blood loss and IV iron is preferred over oral formulations. Whereas there may be a benefit with oral iron supplementation in other diseases of the GI tract, GI intolerance is common and IV iron typically simplifies care. It is reasonable to recommend oral iron for those patients with inactive disease and good tolerance of oral iron. Until prospective data are available comparing daily or alternate day dosing, we feel that alternate day dosing of oral iron is advisable. If oral iron intolerance or ineffectiveness is observed, switching to the IV route is prudent. Clinicians should familiarize themselves with the available options for iron repletion in GI disease. Based on current evidence, IV iron administration should be moved forward in the treatment paradigm of iron deficiency anemia

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