Page 42 – Practical Gastro

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

February 2020 • Volume XLIV, Issue 2

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

February 2020 • Volume XLIV, Issue 2

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

References

1. Bailey R, West K, Black R. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015; 66:22-33.

2. Camaschella C. New insights into iron deficiency and iron deficiency anemia. Blood Reviews. 2017;31:225-233.

3. Franceschi F, Tortora A, Gasbarrini G, et al. Helicobacter pylori and extragastric diseases. Helicobacter. 2014;19 Suppl 1:52-58.

4. Kulnigg-Dabsch S, Resch M, Oberhuber G, et al. Iron deficiency workup reveals high incidence of autoimmune gastritis with parietal cell antibody as reliable screening test. Seminars in Hematology. 2018;55:256-261.

5. Tran-Duy A, Connell NJ, Vannmolkot FH, et al. Use of proton pump inhibitors and risk of iron deficiency: a populationbased case-control study. J Intern Med. 2019;285(2):205-214.

6. Gesquiere I, Lananoo M, Augustijns P, et al. Iron deficiency after Roux-en-Y gastric bypass: insufficient iron absorption from oral iron supplements. Obesity Surgery. 2014;24:56-61.

7. Behrns K, Smith C, Sarr M. Prospective evaluation of gastric acid secretion and cobalamin absorption following gastric bypass for clinically severe obesity. Dig Dis Sci. 1994;39:315-320.

8. Love A, Billett H. Obesity bariatric surgery, and iron deficiency: true, true, true and related. Am J Hematol. 2009;83:403-409.

9. Rubio-Tapia A, Hill I, Kelly C, et al. American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656-76.

10. Munoz M, Gomez-Ramirez S, Garcia-Erce J. Intravenous iron in inflammatory bowel disease. World J Gastroenterol. 2009;15:4666-4674.

11. Ganz T. Anemia of Inflammation. N Engl J Med. 2019;381:1148-57.

12. Stockman R. The treatment of chlorosis with iron and some other drugs. Br Med J. 1893;1:881-885.

13. Blaud P. Sur les maladies chloropiques et sur un mode de traitement specifique dons ces affecions. Rev Med Fr Etrang. 1832;45:357-367.

14. Tolkien Z, Stecher l, Mander AP, et al. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One 2015;10:e0117383.

15. Auerbach M, Adamson J. How we diagnose and treat iron deficiency anemia. Am J Hematol. 2016;91:31-38.

16. Barraclough KA, Brown F, Hawley CM, et al. A randomized controlled trial of oral heme iron polypeptide versus oral iron supplementation for the treatment of anaemia in peritoneal dialysis patients: Hematocrit Trial. Nephrol Dial Transplant. 2012;27:4146-4153.

17. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absoprtion from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981-1989.

18. Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days as a single morning doses versus twice-daily split dosing in iron depleted women: two openlabel, randomized controlled trials. Lancet Haematology. 2017;4e524-e533.

19. Gasche C, Lomer MC, Cavill I, et al. Iron anaemia, and inflammatory bowel diseases. Gut. 2004;53:1190-1197.

20. Lee T, Clavel T, Smirnov K, et al. Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD. Gut. 2016;66:863- 871.

21. Yilmaz B, Li H. Gut Microbiota and Iron: The Crucial Actors in Health and Disease. Pharmaceuticals (Basel). 2018 Oct 5;11(4) pii: E98.

22. Iqbal T, Stein J, Sharma N, et al. Clinical significance of C-reactive protein levels in predicting responsiveness to iron therapy in patients with inflammatory bowel disease and iron deficiency anemia. Dig Dis Sci. 2015;60(5):1375-81.

23. Gasche C, Ahmad T, Tulassay Z, et al. Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: Results from a phase-3 clinical trial program. Inflamm Bowel Dis. 2015;21:579-588.

24. Wang K, Bertrand R, Senadheera S, et al. Motility changes induced by intraluminal FeSO4 in guinea pig jejunum. Neurogastroenterol motil. 2014;26:385-396.

25. Auerbach M, Deloughery T. Single dose intravenous iron for iron deficiency: a new paradigm. In Hematology 2016. American Society of Hematology Education Program Book. 2016;57-66.

26. Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Heme. 2008;83:580-588.

27. Baird I, Padmore D. Intra-muscular iron therapy in iron deficiency anaemia. Lancet. 1954;2:942.

28. Marchasin S, Wallerstein R. The treatment of iron-deficiency anemia with intravenous iron dextran. Blood. 1964;23:354- 358.

29. Kanakaraddi VP, Hoskatti CG, Nadig VS, et al. Comparative therapeutic study of T.D.I. and I.M. injections of iron dextran in anemia. J Assoc Physicians India. 1973;21:849-853.

30. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731.

31. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kid Dis. 2001;38:988-991.

32. Auerbach M, Strauss W, Auerack S et al. Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J Hematol. 2013 Nov;88(11):944-7.

33. Auerbach M, Macdougall I. The available intravenous iron formulations: History, efficacy, and toxicology. Hemodial Int. 2017 Jun;21 Suppl 1:S83-S92.

34. Macdougall IC, Strauss WE, McLaughlin J. A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD. Clin J Am Soc Nephrol. 2004;9:705-712.

35. Adkinson NF, Strauss WE, Macdougall IC, et al. Comparative safety of intravenous ferumoxytol vs ferric carboxymaltose in iron deficiency anemia: a randomized trial. Am J Hematol. 2018;93:683-690.

36. Geisser P, Rumyantsev V. Pharmacodynamics and safety of ferric carboxymaltose: a multiple-dose study in patients with iron-deficiency anaemia secondary to a gastrointestinal disorder. Arzneimittelforschung. 2010;60:373-85.

37. Evstatiev R, Alexeeva O, Bokemeyer B, et al. Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Clin Gastroenterol and Hepatol. 2013;11:269-277.

38. Vavricka S, Schoepfer A, Safroneeva E, et al. A shift from oral to intravenous iron supplementation therapy is observed over time in a large swiss cohort of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;69:840-846.

39. Wolf M, Chertow GM, Macdougall IC, et al. Randomized trial of intravenous iron induced hypophosphatemia. J Clin Invest Insight. 2018;3(23).

40. Anand G, Schmid C. Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep. 2017 Mar 13;2017.

41. Bartko J, Roschger P, Zandieh S, et al. Hypophosphatemia, severe bone pain, gait disturbance, and fatigue fractures after iron substitution in inflammatory bowel disease: a case report. J Bone Miner Res. 2018;33(3):534–539.

42. Reinisch W, Staun M, Tandon RK, et al. A randomized, open-label, non-inferiority study of intravenous iron iron isomaltoside 1000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). Am J Gastroenterol. 2013;108:1877-1888.

43. Derman R, Roman E, Smith-Nguyen GN, et al. Iron isomaltoside is superior to iron sucrose in increasing hemoglobin in gynecological patients with iron deficiency anemia. Am J Hematol. 2018;03:E148-E150.

44. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90:12-23.

FRONTIERS IN ENDOSCOPY, SERIES #58

Advanced Imaging in Hereditary Colon Cancer Syndromes

Lindsey Bierle,

Priyanka KanthLindsey

Colorectal cancer is the third most commonly diagnosed cancer in the United States and the second most common cause of death from cancer in men and women. Around 6% of all colon cancer arises from hereditary causes. These conditions have an increased risk for development of colorectal cancer and guidelines exist for earlier and more frequent screening and surveillance colonoscopies. Many hereditary conditions present with moderate to heavy colon polyposis. Patients with Lynch syndrome (LS) and serrated polyposis syndrome (SPS), however, may have fewer, sessile polyps and advanced colonoscopy imaging may be of value in these syndromes. There is debate regarding the ideal advanced imaging technique to supplant with colonoscopy in detecting lesions that otherwise could be missed in these patient populations. This review summarizes the current literature available in advanced imaging techniques including the role of narrow band imaging and chromoendoscopy in LS and SPS.

INTRODUCTION

Colorectal cancer is the third most commonly diagnosed cancer as well as the second leading cause of cancer deaths in both men and women in the United States.1 Hereditary etiologies of colorectal cancer comprise upwards of 5-6% of all colorectal cancers diagnosed. These commonly include hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Syndrome (LS), familial adenomatous polyposis syndrome (FAP), and serrated polyposis syndrome (SPS), among others. Due to the high risk for development of colon cancer, guidelines exist for earlier screening and frequent surveillance colonoscopy in these high-risk populations.2 What is less clear, however, is the optimal advanced imaging technique to be utilized or supplemented along with conventional colonoscopy to detect lesions amongst patients with known hereditary gastrointestinal disorders. Advanced imaging may have a useful role in LS and SPS as they do not clinically present with heavy colon polyp burden as noted in typical polyposis conditions like FAP or hamartomatous polyposis syndromes. Patients with lynch and serrated polyposis syndromes may also present with sessile, flat polyps with indistinct margins which are hard to detect and can be potentially missed on traditional colonoscopy.3,4 (Figure 1) In 2014, the European Society of Gastrointestinal Endoscopy (ESGE) published recommendations regarding the use of advanced imaging in both average risk and high-risk populations, including hereditary polyposis syndromes such as LS and SPS.5 In the United States, however, there are currently no guidelines available outlining the use of advanced imaging for surveillance in hereditary polyposis syndromes. The goal of this review is to summarize the available literature in advanced imaging of hereditary gastrointestinal syndromes with special focus on Lynch Syndrome (LS) and Serrated Polyposis Syndrome (SPS).

Endoscopic Imaging

The standard of care for routine colon cancer screening has been through the use of traditional white light colonoscopy, however the main drawback to this procedure lies in its potential for missing polyps, otherwise known as the miss rate.6 Recent advancements have been made in endoscopic imaging in order to better detect polyps and decrease overall miss rates. Highdefinition white light (HDWL) endoscopy involves the use of a high definition monitor to enhance the resolution of images in order to increase the visibility of potential polyps.7 Since the advent of HDWL, additional imaging modalities have been invented and tested against standard white light colonoscopy (SWLC). In 2011, Gross et al. conducted a randomized controlled trial evaluating SWLC versus image enhanced colonoscopy8 . Results from this study demonstrated that use of an image enhanced method for screening led to decreased polyp misses as compared to conventional colonoscopy.8 A limitation of this study is the elucidation of which enhanced imaging modality, such as narrow band imaging, chromoendoscopy, or confocal microscopy would be the superior imaging technique of choice.

Narrow Band Imaging

Narrow band imaging (NBI) is an endoscopic technique which involves light manipulation to enhance visualization of the overall colonic structure. The principle behind NBI lies in its ability to utilize blue and green wavelengths to be absorbed by vessels in the colon while simultaneously being reflected by the mucosa; red wavelengths are canceled out altogether. In this way, the colon’s architecture is maximally highlighted, providing stark contrast of the overall colonic vasculature for the endoscopist to better detect suspicious lesions.9 The advantage of this particular type of imaging is in its ability to illuminate the superficial vasculature of the colon, with the potential to differentiate pre-malignant versus malignant lesions at time of actual endoscopic visualization prior to any histopathological manipulation and analysis9 . Leung and researchers conducted a randomized controlled trial in 2014 comparing NBI to traditional white light endoscopy in terms of adenoma detection rates.10 In this study, the newer NBI equipment—toted to provide double the brightness as the original scope—was utilized and 360 patients were randomized to the NBI or white light endoscopy arm as part of the research design. Their findings revealed NBI to have better adenoma detection rates, however no significant differences were attributed to adenoma miss rates between NBI and conventional colonoscopy.10 In the spring of 2019, a meta-analysis reviewing eleven randomized controlled trials was conducted comparing white light endoscopy to NBI with regards to adenoma detection rate (ADR) on routine colonoscopy.11 This review found NBI to have improved ADR, especially with adequate bowel preparation. While this meta-analysis points to the potential role advanced imaging like NBI may have in the near future as an additional endoscopic tool for routine colon screening, it did not take into account hereditary gastrointestinal syndromes as a separate entity from the general population.

Chromoendoscopy

Chromoendoscopy involves the application of various dyes to the colonic mucosa in real time in order to better visualize lesions that may be missed on routine white light colonoscopy.12 The utility of these pigments is in their ability to enhance the subtle contours of the colon, thereby improving the endoscopist’s likelihood of detecting polyps that may otherwise go unnoticed until they are more advanced in appearance.13 There are several types of pigmented dyes available for use in chromoendoscopy, with indigo carmine or methylene blue being the most commonly used when evaluating for colorectal lesions.5 The blue pigment is able to collect within the mucosal folds and provide a stark contrast to the normal pink mucosa of the colon wall itself. The dyes utilized in surveillance chromoendoscopy are self-limiting as opposed to the permanent dyes employed for tattooing locations of the colon for surgical evaluation at a later date. Chromoendoscopy has been studied against conventional white light colonoscopy as a screening technique for colorectal cancer in average risk populations. Kahi and colleagues conducted a study comparing chromoendoscopy to traditional white light endoscopy in 660 average risk patients presenting for routing colorectal cancer screening.14 The results from this randomized study showed that chromoendoscopy did increase the overall adenoma detection rate, including flat and small adenomas, however the results were similar for advanced neoplasm detection in both the chromoendoscopy and white light colonoscopy groups. Authors concluded that the study could not advocate the use of chromoendoscopy in screening for the average risk population14. Though not currently recommended for the average risk population, chromoendoscopy has been largely studied in inflammatory bowel disease (IBD) as a potential primary surveillance modality given the higher risk for colorectal cancer development in this patient population.15 In a 2007 study involving 161 patients with ulcerative colitis, Kiesslich et al. revealed that the number of neoplastic lesions identified via chromoendoscopy was higher by 4.75-fold than the amount exposed by traditional colonoscopy alone, demonstrating chromoendoscopy’s strength as an advanced imaging technique in IBD.16 Marion and researchers conducted a prospective trial in 2008 which included 115 patients with IBD, 79 with ulcerative colitis, and 23 with Crohn’s disease, and they concluded that biopsies utilizing chromoendoscopy yielded superior results as compared to traditional biopsy methods.15 There is a wealth of literature available demonstrating chromoendoscopy’s benefit as an adjunct imaging modality in the IBD population for surveillance; less research has been done, however, as to its role in alternative high-risk populations, such as the hereditary gastrointestinal syndromes discussed in this review.

Virtual Chromoendoscopy (ISCAN)

While dye chromoendoscopy is more often employed as an advanced imaging modality, the virtual technique is an alternative method of chromoendoscopy that does not involve the utilized to identify difficult to detect colonic lesions, however it utilizes light augmentation in real time whereas other virtual chromoendoscopy techniques modify images utilizing advancements in computer software imaging to detect subtle colonic lesions.17 More research and technological advancements need to be undertaken for virtual chromoendoscopy to be used as an advanced imaging option. We discuss the utility of this technique in high risk populations.

Confocal Laser Microendoscopy

Confocal laser microendoscopy utilizes laser technology to obtain high resolution imaging of the gastrointestinal mucosa.19 The laser light is directed towards the tissue in question, and the light reflected back onto the lens is refocused through a pinhole which allows for enhanced magnification of the tissue layer itself. This concept of light being directed towards the tissue surface via the laser with subsequent reflection back into the same plane through the pinhole lends the confocal portion of the technique’s name.20 In this way, confocal microendoscopy can be utilized in conjunction with traditional white light endoscopy to enhance features of the colonic wall to better detect subtle changes in the mucosa.19 Given its relatively new status in the advanced imaging world, confocal laser microendoscopy has not been widely studied in high risk populations such as hereditary gastrointestinal syndromes. This fact limits its use as an advanced endoscopic imaging tool currently. Additionally, the novelty of this modality restricts its utility given costs accrued with it as compared to alternative imaging modalities more readily accessible. In the end, further research should be completed to evaluate confocal laser microendoscopy’s potential role as an imaging tool in high risk populations including those discussed in this review.

HEREDITARY GASTROINTESTINAL SYNDROMES

Lynch Syndrome

Lynch Syndrome (LS), an autosomal dominant disorder due to DNA mismatch repair dysfunction, is the most common cause of an underlying hereditary etiology for colorectal cancer.22 In normal DNA synthesis, routine errors can occur during DNA replication. These errors are accounted for via mismatch repair (MMR) genes, which serve to identify and remove any abnormalities encountered in the newly synthesized DNA strand. In LS, there is a mutation in one of the vital MMR genes, which allows for unchecked DNA strands to be replicated despite possible errors within the strand. These errors lend themselves to increased risk of cancer development.23 LS comprises roughly 3-5% of all colon cancers, and individuals with this disorder have an overall 50 to 80% increased risk of developing colon cancer as compared to the average population. Overall prevalence of LS is estimated 1 in 440.24 Current surveillance guidelines for LS include screening colonoscopy beginning at 20 to 25-years old with follow-up every 1 to 2 years thereafter. Biopsies obtained during colonoscopic surveillance can be further studied with genetic testing for microsatellite instability and immunohistochemical staining for additional analysis.

Serrated Polyposis Syndrome

Formerly called hyperplastic polyposis syndrome, serrated polyposis syndrome (SPS) is an underdiagnosed disorder in which patients are at increased risk of developing colonic neoplasia.4 The lifetime risk of colon cancer ranges from 16- 42%.22 Due to the rarity of the disease, the overall prevalence is difficult to ascertain. In 2017, a prospective multi-center cross-sectional study analyzed the prevalence of SPS in four European countries.26 Those results revealed SPS prevalence of 0-0.5% at first screening colonoscopy, increasing to 0.4-0.8% prevalence on subsequent endoscopic evaluations.26 The prevalence of SPS in the fecal occult blood test-based Spanish screening cohort was noted to be 1 in 127 subjects and in the Netherlands colonoscopy cohort to be 1 in 238 subjects, suggesting SPS likely is a more prevalent condition than previously thought.26 SPS is diagnosed clinically with one or more of the following criteria set forth by the World Health Organization (WHO): at least five serrated polyps located proximal to the sigmoid colon (of which at least two are ten millimeters or more in size); more than twenty serrated polyps located throughout the colon; and/or any serrated polyps found proximal to the sigmoid colon in a patient with a known first degree relative with SPS.27 In contrast to Lynch Syndrome and Familial Adenomatous Polyposis Syndrome, SPS is not diagnosed through genetic testing, and further research is needed to understand the underlying genetic etiology of SPS.

ADVANCED IMAGING IN LYNCH SYNDROME

Lynch syndrome patients require frequent colonoscopy to surveil for polyps and colorectal cancer.25 However, less is known and controversy exists regarding use of advanced imaging in the detection of adenomas in patients with LS. A systematic review by van de Wetering et al. suggested that chromoendoscopy in LS did not add significant benefit to detection rate in the highrisk LS population as compared to conventional white light endoscopy alone.28 This 2018 review28 echoed Haanstra and colleague’s 2013 review29 of advanced imaging in LS patients. At that time though, only six studies had been published outlining advanced imaging in LS surveillance, none of which demonstrated superiority to white light colonoscopy.29 Chromoendoscopy, narrowband imaging, and autofluorescence endoscopy were the advanced techniques under scrutiny back then, and of these it was determined that chromoendoscopy could be the emerging leader in the field of advanced imaging.29 The limiting factor for those in favor of advanced imaging, though, was the paucity of studies available utilizing advanced imaging in LS patients to determine their efficacy as a surveillance modality compared to conventional white light endoscopy.29 Despite some of the literature suggesting advanced imaging may not have a role in LS surveillance, other studies pointed towards its utility. Stoffel and colleagues conducted a small study in 2008 in which 54 patients with LS received routine colonoscopic surveillance.3 Roughly half of these individuals underwent conventional colonoscopy alone, whilst the other half went on to receive an additional chromoendoscopic exam.3 Those who received chromoendoscopy had more polyps detected, though the findings were not statistically significant3 . Stoffel’s study highlighted the importance of the role chromoendoscopy could play in high-risk populations such as LS and the need for larger study populations to further investigate the role of advanced imaging in these patients.3 Additional studies since then have demonstrated the potential for advanced imaging as primary surveillance modalities in patients with LS. Several years after Stoffel’s initial study, a larger study completed by Rahmi et al revealed that chromoendoscopy in conjunction with colonoscopy improved adenoma detection rates in LS patients as compared to conventional colonoscopy alone.30 Similarly, Lecomte and researchers conducted a prospective study following 36 patients with LS comparing standard endoscopy to chromoendoscopy; their findings demonstrated improved adenoma detection rates with chromoendoscopy as compared to regular colonoscopy.31 While much of the current literature juxtaposes conventional colonoscopy with chromoendoscopy, other advanced imaging techniques have been investigated recently as possible alternatives to white light endoscopy. In 2017, Bisschops and researchers illuminated virtual chromoendoscopy’s role as a potential surveillance agent in patients with LS with their randomized controlled crossover trial.32 This prospective trial with 61 subjects showed that those who received virtual chromoendoscopic surveillance in addition to white light endoscopy had higher adenoma detection rates as compared to those who received surveillance with white light endoscopy alone.32 East and colleagues followed 62 patients with family histories significant for LS and found that narrow band imaging improved adenoma detection rates, especially those of flat morphology, as compared to conventional white light colonoscopy alone.33 Research completed by Huneburg et al. revealed improved adenoma detection rates with chromoendoscopy use as compared to traditional white light endoscopy as well as narrow band imaging.34 These studies suggest that chromoendoscopy may be at the forefront of advanced modalities available for surveillance imaging when compared to narrow band imaging, however more studies need to be commenced in the future for further clarity as to the advanced imaging test of choice. Figures 2, 3, and 4 show endoscopy images of an 8 mm polyp using HDWL, NBI, and chromoendoscopy in a 69-year old patient with Lynch syndrome. Figure 5 shows a sessile polyp highlighted by using chromoendoscopy in a patient with LS.

ADVANCED IMAGING IN SERRATED POLYPOSIS SYNDROME

Serrated polyposis syndrome, one of the uncommon hereditary gastrointestinal disorders, conveys a higher risk for colorectal cancer development than the average risk individual. Earlier screening is recommended in SPS patients, however there is debate in the current literature regarding surveillance frequency and even less is known about the role advanced imaging plays in this highrisk population.35 In 2015, Hazelwinkel et al. examined the use of narrow band imaging (NBI) in patients with known serrated polyposis syndrome as compared to high resolution white light endoscopy (HR-WLE) in terms of polyp miss rate.36 In this multicenter randomized crossover study with a sample size of 52 patients, an initial surveillance colonoscopy was completed to detect polyps; during the subsequent encounter, the same endoscopist then utilized either HR-WLE or NBI to further detect any potential missed polyps. Hazelwinkel and colleagues ultimately did not find a significant difference in polyp miss rates when comparing the two imaging techniques, however this study was largely limited by the small sample size and use of the same endoscopist for all second pass colonoscopies.36 Hazelwinkel’s results conflict with Boparai and researchers’ 2011 randomized crossover study comparing high resolution endoscopy (HRE) to NBI polyp miss rates in patients with known SPS.37 In this single center study comprised of just 22 patients, Boparai et al revealed that the polyp miss rate was significantly reduced when utilizing the advanced technique of NBI in addition to conventional colonoscopy as compared to HRE.37 Their study demonstrates that not only could advanced imaging play a role in SPS polyp detection, but also NBI could be one of the future favorites in the advanced imaging world for SPS. Of note, Boparai’s study found that flat polyp morphology was independently associated with a higher polyp miss rate.37 As a result of their research, Boparai and colleagues recommend incorporating NBI or chromoendoscopy into routine polyp surveillance in patients with SPS.37 Similar to Hazelwinkel’s study design,36 Boparai’s study was limited by small sample size and further studies should be conducted to ensure reproducibility of their initial results.

In 2018, a group of Spanish researchers conducted a multicenter, randomized control trial comparing the efficacy of HD-WLE colonoscopy exams to panchromoendoscopy with indigo carmine dye for polyp detection.38 Panchromoendoscopy, a type of chromoendoscopy, involves the application of dye throughout the entirety of the colon for maximal contour enhancement. Eighty-six patients with SPS from seven centers in Spain were randomized to undergo either tandem HDWLE or panchromoendoscopy; results revealed significantly increased polyp detection rates in those who received panchromoendoscopy as compared to HD-WLE alone. Researchers also noted that panchromoendoscopy yielded a higher rate of serrated lesion identification proximal to the sigmoid colon, though there was no significant difference between the two imaging techniques when detecting lesions larger than ten millimeters. As a result of this study, researchers recommended the use of panchromoendoscopy in surveillance for patients with SPS, along with the suggestion that further studies be completed to evaluate the overall long-term efficacy of this imaging method as a surveillance technique in SPS patients.38 Figure 6 and 7 shows serrated polyps using NBI and Figure 8 shows a serrated polyp highlighted using chromoendoscopy in patients with serrated polyposis syndrome.

While the ESGE recommends the use of high definition endoscopy or virtual narrow band imaging chromoendoscopy as advanced imaging techniques in SPS,5 no guidelines have been put forth in the United States currently. NBI and chromoendoscopy may be top contenders for the advanced imaging test of choice according to the current literature,5,37,38 however the scarcity of studies available to review point to the need for larger prospective trials looking at these advanced techniques and their associated long-term outcomes in order to determine the best imaging modality to be utilized in SPS.

SUMMARY

Patients with hereditary gastrointestinal syndromes such as lynch syndrome and serrated polyposis syndrome are at an intrinsically higher risk of colon cancer development requiring early scrutinized surveillance at more frequent intervals than the average risk population. This review offers a comprehensive analysis of the available literature surrounding current colonoscopy surveillance techniques utilized in LS and SPS, including the introduction of advanced imaging as a possible surveillance modality in these syndromes. Currently, the ESGE recommends NBI or virtual chromoendoscopy advanced imaging modalities for both LS and SPS,5 however to date there are no formal recommendations or guidelines published in the United States. Thus, more research should be devoted to advanced imaging techniques including chromoendoscopy, narrow-band imaging, and virtual chromoendoscopy to better elucidate their role as surveillance tools in these high-risk populations.

References

1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet 2014; 383(9927): 1490-1502.

2. Burt RW, DiSario JA, Cannon-Albright L. Genetics of colon cancer: impact of inheritance on colon cancer risk. Annu Rev Med 1995; 76:275-83.

3. Stoffel EM, Turgeon DK, Stockwell DH et al. Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res (Phila) 2008; 1:470-5.

4. Edelstein DL, Axilbund JE, Hylind LM, et al. Serrated polyposis: rapid and relentless development of colorectal neoplasia. Gut 2013; 62: 404.

5. Kaminski MF, Hassan C, Bisschops R, et al. Advanced imaging for detection and differentiation of colorectal neoplasia: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2014; 46: 435-49.

6. van Rijn JC, Reitsma JB, Stoker J, et al. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006; 101(2): 343-50.

7. Buchner AM, Shahid MW, Heckman MG, et al. High-definition colonoscopy detects colorectal polyps at a higher rate than standard white-light colonoscopy. Clin Gastroenterol Hepatol 2010; 8: 364- 370.

8. Gross SA, Buchner AM, Crook JE, et al. A comparison of high definition-image enhanced colonoscopy and standard white-light colonoscopy for colorectal polyp detection. Endoscopy 2011; 43(12):1045-51.

9. Boeriu A, Boeriu C, Drasovean S, et al. Narrow-band imaging with magnifying endoscopy for the evaluation of gastrointestinal lesions. World J Gastrointest Endosc 2015; 7(2): 110-120.

10. Leung WK, Lo OS, Liu KS, et al. Detection of colorectal adenoma by narrow band imaging (HQ190) vs. high-definition white light colonoscopy: a randomized controlled trial. Am J Gastroenterol 2014; 109(6): 855-63.

11. Atkinson NSS, Ket S, Bassett P, et al. Narrow-band imaging for detection of neoplasia at colonoscopy: a meta-analysis of data from individual patients in randomized controlled trials. Gastroenterology 2019; doi.org/10.1053/j.gastro2019.04.014.

12. Buchner A. Chromoendoscopy for detection of proximal serrated lesions in routine screening colonoscopy. The Lancet 2019; 30079-2.

13. Kiesslich R, von Bergh M, Hahn M, et al. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy 2001; 33: 1001.

14. Kahi CJ, Anderson JC, Waxman I, Kessler WR, Imperiale TF, Li X, Rex DK. High-definition chromocolonoscopy vs. high-definition white light colonoscopy for average-risk colorectal cancer screening. Am J Gastroenterol 2010; 105(6): 1301-7.

15. Marion JF, Waye JD, Present DH, et al. Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. Am J Gastroenterol 2008; 103:2342-9.

16. Kiesslich R, Goetz M, Lammersdorf K, et al. Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology. 2007; 132: 874-82.

17. Milosavljevic T, Popovic D, Zec S, Krstic M, Mijac D. Accuracy and pitfalls in the assessment of early gastrointestinal lesions. Digestive Diseases 2019; 37: 5.

18. G Royero H. Virtual chromoendoscopy with I-Scan and its application for detection and characterization of colon polyps. Revista Colombiana de Gastroenterologia 2017; 32: 1.

19. Wang TD. Confocal microscopy from the bench to the bedside. Gastrointest Endosc 2005; 62: 696-7.

20. Polglase AL, McLaren WJ, Skinner SA, et al. A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower- GI tract. Gastrointest Endosc 2005; 62: 686-95.

FROM THE LITERATURE

Risk for Hepatocellular Carcinoma with Cirrhosis After HCV Eradication

To analyze changes in HCC annual incidence over time, following HCV eradication, dynamic markers of HCC Risk were identified. A total of 48,135 patients who initiated HCV antiviral treatment from 2000 through 2015 and achieved an SVR in the Veterans Health Administration and 29,033 were treated with direct-acting antiviral agents (DAA), with 19,102 treated with Interferon-based regimens. Patients were followed after treatment until 2/14/2019 (average 5.4 years), during which 1509 incident HCCs were identified.

Among patients with cirrhosis before treatment with DAAs (9784), those with pre-SVR FIB4 scores greater than 3.25 had a higher annual incidence of HCC (3.66 %/year), than those with FIB scores less than 3.25 (adjusted hazard ratio 2.14). In DAA-treated patients with cirrhosis and FIB scores greater than 3.25, annual HCC risk decreased from 3.8% per year in the first year after SVR to 2.4% per year by the 4th year. In Interferon-treated patients with FIB-4 scores greater than 3.25, annual HCC risk remained above 2% per year, even 10 years after SVR. A decrease in FIB scores from greater than 3.25 to less than 3.25 post SVR was associated with approximately 50% lower risk of HCC, but the absolute annual risk remained above 2% per year. Patients without cirrhosis before treatment (N = 38,351), had a low risk of HCC, except for those with pre-SVR FIB scores greater than 3.25 and post SVR FIB scores greater than 3.25. Risk remained high for many years after SVR.

It was concluded that patients with cirrhosis before an SVR to treatment for HCV infection continue to have high risk for HCC (greater than 2% per year) for many years, even if their FIB-4 score decreases, and surveillance should continue. Patients without cirrhosis, but with FIB scores greater than 3.25 have a high enough risk to merit HCC surveillance, especially if the FIB-4 remains greater than 3.25 post SVR.

MEDICAL BULLETIN BOARD

GI OnDemand: Gastroenterology’s Virtual Care and Support Platform

December 2019 • Volume XLIII, Issue 12

Telehealth Features Enable Reimbursement for Video Visits; Full-Ecosystem Support Provides Patients with Easy and Convenient Way to Manage Chronic Digestive Health Conditions

San Antonio, TX – Gastro Girl, Inc. in partnership with the American College of Gastroenterology announces a joint venture to bring GI OnDEMAND to market as gastroenterology’s virtual care and support platform. GI OnDEMAND features telehealth capabilities that enable providers to get reimbursed for out-of-office patient support and provide patients with an easy and convenient way to manage their chronic digestive health conditions through virtual office visits with their gastroenterologists and other members of their care team, such as registered dietitians and psychologists who have specific GI expertise. Patients also have access to trusted health information and an online support community.

“In partnership with Gastro Girl, ACG is excited to bring GI OnDEMAND to our members and the millions of patients they collectively serve,” said ACG President Sunanda V. Kane, MD, MSPH, FACG. “This bold initiative is aligned with the College’s mission to advance gastroenterology and improve patient care. We are confident that our members, who like most healthcare providers are navigating an ever-changing and challenging healthcare environment, will find GI OnDEMAND a catalyst to delivering next-generation patient care while expanding their opportunities for reimbursement.”

GI OnDEMAND is created to integrate with a provider’s patient workflow with easy scheduling and documentation of virtual patient appointments. Similar to in-office visits, providers can submit for reimbursement for the telehealth patient care services they provide, according to Jordan J. Karlitz, MD, FACG, Chief Medical Officer and Director of Clinical Operations, Gastro Girl. “When one considers that GIs may provide multiple hours of patient care services per week in between in -erson office visits, frequently by telephone or email, GI OnDemand is a game-changer. It can enhance continuity of care, provide HIPAA-compliant provider-patient communication and can allow reimbursement for out of office encounters.”

“Addressing a critical gap that exists for patients who are living with chronic GI health conditions, GI OnDEMAND provides full-ecosystem support between office visits to improve the collaborative partnership between patients and their digestive health caregivers and help patients better adhere to their treatment plans,” said Gastro Girl Founder, Jacqueline Gaulin. “Gastro Girl’s partnering with ACG, an organization with a unique focus on clinical gastroenterology and the needs of practicing GI clinicians and their patients, means that GI OnDemand has the clinical backbone and essential features to support the professional needs of GI practices in providing high quality care and patient support via telehealth.”

About GI OnDEMAND GI OnDEMAND is a joint venture between the American College of Gastroenterology (ACG) and Gastro Girl, Inc. As gastroenterology’s virtual care and support platform, GI OnDEMAND is offered as an ACG member benefit and features telehealth capabilities that enable providers to get reimbursed for out-of-office patient support and provide patients with an easy and convenient way to manage their chronic digestive health conditions through virtual office visits; access to trusted health information and an online support community. GI OnDEMAND features a comprehensive HIPAAcompliant telehealth suite that includes secure video, end-to-end practice management tools like scheduling, document sharing, EHR integration, billing, and other capabilities and workflow solutions designed for next-generation patient engagement.