Nutrition Issues In Gastroenterology, Series #152

Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery

June 2016 • Volume XL, Issue 6
Kelly O’Donnell

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Hypoglycemia after Roux-en-Y gastric bypass (RGBP) is a rare, yet challenging condition. The optimal treatment of these patients has not been well studied and the underlying etiology requires further research. The goal of this paper is to provide a practical approach to the evaluation and management of the patient who presents with hypoglycemia after RGBP.

Hypoglycemia after Roux-en-Y gastric bypass is a rare, yet challenging condition. Patients typically present with post-prandial hypoglycemia 1-5 years after their surgery, often after weight stabilization. Most concerning are the subset of patients who present with symptoms of neuroglycopenia. Hypoglycemia in these patients is felt to be due to an altered GLP-1 response in the post-prandial period. Treatment options include dietary interventions such as limitation of carbohydrate intake, pharmacotherapy aimed at reducing post-prandial glucose excursion and in more recalcitrant cases, surgical reversion of the bypass. However, the optimal treatment of these patients has not been well studied and the underlying etiology requires further research.

Jennifer L. Kirby, MD-PhD1 Kelly O’Donnell, MS, RD, CNSC2 1Division of Endocrinology and Metabolism, Department of Medicine, 2Surgery Nutrition Support, University of Virginia Health System, Charlottesville, VA

REPRESENTATIVE CASE

A 42 year old female presents with one year of flushing, shaking and diaphoresis. These episodes have been increasing in frequency, occur approximately 1.5-2 hours after meals and improve with food. She has a history of obesity and underwent Roux- en-Y gastric bypass (RGBP) five years earlier. Twenty months after her surgery, she had lost 120 pounds and her weight stabilized. Self-monitoring with capillary blood glucose now reveals values measuring<60 mg/ dL, with the lowest measuring 33 mg/dL, all associated with symptoms. Symptoms resolve with carbohydrate intake. Her episodes have continued to increase in frequency and of late, include a syncopal episode.

INTRODUCTION

Hyperinsulinemic hypoglycemia after RGBP was first described in 2005 by two independent groups.1,2 In the 10 years since, numerous articles have been written about this entity and although much has been learned, our understanding of the etiology and optimum treatment has not been fully elucidated. Initial reports suggested a role for increased b-cell mass or nesidioblastosis.1,3 However, these findings were not universally supported.4 Subsequent studies have shown that in RGBP patients, the rapid passage of nutrients directly into the intestine results in a rapid rise of serum glucose with higher peak values and lower nadirs compared to controls.5 Additionally, RGBP patients have increased post-meal insulin and GLP- 1 responses. Studies involving patients with hypoglycemia suggest that this response is exaggerated and provide evidence for a prominent role of GLP-1.6 Some authors have proposed that hyperinsulinemic hypoglycemia after RGBP is due to dumping syndrome, which occurs due to rapid passage of nutrients from the stomach remnant into the proximal small intestine.7 Regardless of mechanism, a small subset of these patients develop severe neuroglycopenic symptoms (see Table 1) that can result in seizure, syncope and trauma such as a motor vehicle collision.2,3 Often these patients are refractory to conservative therapies with dietary changes and pharmacotherapy. Many have undergone more invasive therapies, such as gastrostomy tube placement, partial/ full pancreatectomy or reversal of the bypass. The goal of this paper is to provide a practical approach to the evaluation and management of the patient who presents with hypoglycemia after RGBP.

DIAGNOSIS

Most patients with hyperinsulinemic hypoglycemia after RGBP present within 1-5 years after surgery, but it has been observed in patients within months post- operatively and as long as 20+ years later. The typical patient develops hypoglycemia 1-3 hours after ingestion of a carbohydrate-containing meal and hypoglycemia is absent in the fasting state. Per Endocrine Society guidelines,8 evaluation should proceed only after Whipple’s triad has been satisfied (development of symptoms typical of hypoglycemia, low serum glucose at the time of symptoms and relief of symptoms with the administration of glucose).

The symptoms of hypoglycemia can be divided into autonomic and neuroglycopenic symptoms (see Table 1). A detailed history of the symptoms of hypoglycemia should be obtained to identify patients who have neuroglycopenic symptoms as these are the most concerning given the potential risk for harm. A reasonable approach to establish the diagnosis of hyperinsulinemic hypoglycemia would be to obtain serum glucose, insulin, and C-peptide levels in addition to a sulfonylurea screen at the time of hypoglycemia. The utility of other studies in the assessment of the patient with post-RGBP hypoglycemia is not clear. Oral glucose tolerance tests are not recommended to diagnose hypoglycemia in any setting.8 Mixed meal testing has been used in research studies, but not all patients with a history of hypoglycemia after RGBP will develop hypoglycemia in this setting.6,9-11 More recently, continuous glucose monitoring (CGM) has shown promise not only for diagnosis, but also for monitoring response to treatment. Notably, results should be viewed with caution as the accuracy of CGM in the hypoglycemic range is poor.12,13 The clinical history, time course with regard to onset after surgery, and symptoms should steer the clinician towards a diagnosis of post-gastric bypass hypoglycemia. It is unclear what role more detailed studies, such as 72- hour fast, radiologic imaging or selective arterial calcium stimulation play in evaluation. However, atypical symptoms in these patients (such as fasting or overnight hypoglycemia) should be fully explained with a thorough evaluation.8 Rarely, hypoglycemia after RGBP has been due to insulinoma.1 See Table 2 for suggested guidelines for the initial evaluation.

INTERVENTION
Dietary Modification

Dietary intervention is recommended as the first treatment option for patients diagnosed with hypoglycemia after RGBP. Several different strategies have been published, but all target reducing carbohydrate intake to avoid an insulin surge (summarized in Table 3). Kellogg et al.5 treated 12 patients with symptoms suggestive of hyperinsulinemic hypoglycemia with a high carbohydrate (79%) meal on day 1 of the study followed by a low (2%) carbohydrate meal on day 2. The meals contained the same amount of calories. After the high carbohydrate meal, serum insulin levels peaked at 30- 90 minutes, while the mean glucose nadir (44 mg/dL) occurred at 90-120 minutes. After the low carbohydrate meal, there was only a modest rise in plasma insulin with very little change in glucose levels. After one month of a low carbohydrate diet, 25% of patients reported complete resolution of symptoms while another 25% had improvement in major symptoms, 33% had improvement in minor symptoms and 17% experienced no improvement at all. Botros et al.14 found that when patients with hyperinsulinemic hypoglycemia consumed a meal containing 30 grams of carbohydrate, none of them experienced hypoglycemia. Based on these results, the authors suggested consuming three meals per day containing 30 grams carbohydrate plus three snacks per day, each containing 15-30 grams carbohydrate while avoiding simple sugars. Because this study occurred in a supervised clinical setting, results and compliance may be altered in real world practice. Also, only 30-gram carbohydrate meals were tested and it may be possible that some patients can tolerate a more liberal carbohydrate allowance. Five of six gastric bypass patients had improvement in symptoms of hyperinsulinemic hypoglycemia with diet modification consisting of three small meals plus 2-3 small snacks with 60 grams of protein daily.16 High carbohydrate, high fat foods were eliminated as well as sugar-containing fluids.

Pharmacotherapy

When dietary modification fails, pharmacotherapy is often employed for treatment. Several agents including acarbose, calcium-channel blockers, diazoxide, octreotide and GLP-1 receptor agonists have been effective in case reports and case series either alone or in combination (see Table 3). To date, these medications have not been rigorously studied for treatment of hyperinsulinemic hypoglycemia after RGBP and are not FDA-approved for this reason. However, patients may clearly benefit from a trial of therapy, particularly when having severe and debilitating symptoms associated with neuroglycopenia. A reasonable approach would be to try each agent and assess effectiveness, leaving in place those agents that prove beneficial and discontinuing those with either intolerable side effects or lack of efficacy. Combinations of agents that target different mechanisms have also shown benefit (e.g., acarbose with calcium-channel blocker).19

Partial or Full Pancreatectomy

Initial reports of nesidioblastosis as a cause of hyperinsulinemic hypoglycemia after RGBP led to many patients being treated with partial or full pancreatectomy. Recently, pancreatectomy has fallen out of favor, likely due to studies providing an alternative mechanism to nesidioblastosis as the underlying cause as well as the significant associated morbidity. A recent review of the literature noted that 34 out of 51 patients (67%) had resolution of symptoms after pancreatic resection.27 However, follow-up in these studies was short; longer-term follow-up has shown that some patients have a return of symptoms farther out from surgery.28 In addition, the risk of developing diabetes and pancreatic exocrine dysfunction increased with more aggressive resection.29

Gastrostomy Tube Placement

In 2010, McLaughlin et al. incidentally noted improvement in neuroglycopenic hypoglycemic symptoms after placement of a gastrostomy tube (G tube) into the remnant stomach of a patient with a small bowel obstruction.7 To formally assess the reason for the improvement, the patient was readmitted to the hospital and given a can of liquid formula by mouth followed by overnight fasting and administration of the same liquid formula through the G tube. Feeding by mouth versus G tube caused symptomatic hypoglycemia at 90-120 minutes (60 mg/dL vs 80 mg/dL) and insulin concentrations that were eight times higher, respectively. The authors concluded that the results were inconsistent with b-cell hyperplasia or increased b-cell activity as a cause of the hypoglycemia. Rather, hyperinsulinemia was a result of nutrients delivered through the bypassed GI tract, but not through the remnant stomach, perhaps due to altered incretin responses. In another study, a G tube was placed in the gastric remnant of 5 patients who were refractory to medical and diet management of their hyperinsulinemic hypoglycemia.15 The patients received 3 bolus feedings per day of a standard formula providing a total of 450 calories and experienced no symptoms of hypoglycemia. All 5 patients had remission of hypoglycemia after placement of the G tube. However, successful resolution of hypoglycemia with G tube placement is not universal.17

Gastric Bypass Reversal

Several groups have now shown successful remission of hypoglycemia with reversal of gastric bypass with or without modified sleeve gastrectomy. In the review by Mala, 13 out of 17 patients (76%) had resolution of symptoms and weight regain was a common outcome.27 In patients with reversal without modified sleeve gastrectomy, weight regain can be an issue.

TREATMENT APPROACH

When approaching a patient with symptoms suggestive of hypoglycemia after gastric bypass, it is important to document evidence of Whipple’s triad. In particular, the provider should assess for symptoms of neuroglycopenia, which place the patient at risk for severe adverse events, such as seizure and death. In patients with documented hypoglycemia, it is reasonable to obtain serum glucose, insulin, and c-peptide levels with a sulfonylurea screen. Provocative testing, such as a mixed meal tolerance test, can be used as a method to confirm the diagnosis. In cases where the history is inconsistent with typical hyperinsulinemic hypoglycemia after RGBP (e.g., fasting or overnight hypoglycemia), further diagnostic testing and imaging are warranted as indicated.8

Initial therapy should be directed at dietary modification to reduce the content of total carbohydrate in the patient’s diet, ideally targeting for 4-6 small meals per day containing 30 grams or less per meal. Elimination of simple sugars is critical. A journal that includes dietary information, blood glucose values and symptoms can be helpful to elucidate particular triggers to guide dietary interventions. If dietary changes are unsuccessful at reducing/eliminating hypoglycemic episodes, pharmacologic agents (listed in Table 4) can be used either alone or in combination. Given that there are no trials comparing these medications, a trial of each agent to assess for benefit may be attempted prior to proceeding with more invasive therapies. Certainly cost and tolerability will play a role in the ability of patients to try these agents. Although it is unclear what utility continuous glucose monitoring (CGM) has in the diagnosis of hyperinsulinemic hypoglycemia, CGM can be useful for patients who have neuroglycopenic symptoms for monitoring to prevent severe episodes and to assess responses to therapy. Again, cost may be a barrier as this is not a traditional use for CGM and may not be covered by many insurance plans.

Surgical procedures such as placement of a gastrostomy tube into the gastric remnant and reversal of the gastric bypass with or without gastrectomy should be used only if more conservative therapies have been tried and failed. In addition, involvement of providers with experience treating these patients should be sought, including dietitians, endocrinologists and bariatric surgeons.

CONCLUSION

Hyperinsulinemic hypoglycemia after gastric bypass, particularly with neuroglycopenia, is a rare and difficult entity to treat. Although our understanding of the pathophysiology underlying this entity has advanced in the 10 years since it was initially described, there are no evidenced-based guidelines for the diagnosis and treatment at this time. Further research regarding the underlying mechanism driving hyperinsulinemia in these patients is needed and will hopefully provide better therapeutic options. Early identification of patients with neuroglycopenia is warranted. These patients may benefit from systematic intervention from dietary changes on up to surgical revision of the bypass in some.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #17

Intestinal Angioedema An Often Misdiagnosed Entity

May 2016 • Volume XL, Issue 5
Obiajulu Kanu,Marco Bustamante-Bernal,Marynna Popp,Richard W. McCallum

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In this article, we aim to heighten the awareness of intestinal angioedema among gastroenterologists as well as help differentiate it from other more common similar gastrointestinal conditions. We review the pertinent literature and provide guidelines which could assist in the timely diagnosis and treatment of this condition.

Most clinicians are familiar with angioedema involving the face and the upper respiratory airways. Bradykinin mediated angioedema may sometimes present with gastrointestinal symptoms alone. Such uncommon presentations are easily misdiagnosed, bearing serious consequences for the patient and the hospital system through unnecessary extensive workups. We include a typical example of the situation where a 60 year old woman presented multiple times to the hospital with gastrointestinal (GI) symptoms due to ACE inhibitor associated angioedema superimposed on hereditary angioedema. Her unusual presentation was initially treated symptomatically and this led to a late diagnosis and intervention consequently prolonging her hospital stay. In addition, we review the pertinent literature and provide guidelines for gastroenterologists encountering this challenging entity which could assist in the timely diagnosis and treatment of this condition.

Obiajulu Kanu, MD1 Marco Bustamante- Bernal, MD1 Marynna Popp, MD1 Richard W. McCallum, MD2 1Department of Internal Medicine, 2Division of Gastroenterology, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

CASE REPORT

A60 year old Hispanic female presented with generalized crampy abdominal pain of 24 hours duration. Pain was acute in onset and associated with nausea, nonbilious emesis, and several bouts of watery, nonbloody diarrhea. She denied fever, chills, dysuria or sick contacts. Medical history was significant for multiple admissions in the past for similar episodes as well as hypertension, diabetes mellitus type 2, chronic deep venous thrombosis and dyslipidemia. Family history is positive for hereditary angioedema in four family members. Social history was negative for alcohol, tobacco or illicit drug use and she had no known allergies. Home medications included warfarin, metformin, Lisinopril, Lantus, and simvastatin.

On physical examination, she was lethargic. Vital signs were BP 68/39mmHg; heart rate 130beats/min; Respiratory rate 16/min; temperature 36.4 o C; Mean arterial pressure 49mmHg. Oxygen saturation was 93% at room air. Other pertinent findings included dry skin and mucous membranes, generalized abdominal tenderness with voluntary guarding but without rebound tenderness. Bowel sounds were hyperactive. Rectal examination was unremarkable and a stool guaiac done was negative.

Laboratory investigations showed: increased White Blood Cell (WBC) count of 15060/mcl and bands of 7%; potassium 3.1mEq/l; chloride 107mEq/l; bicarbonate 17mEq/l with an anion gap of 17; lactate 7.5mEq/l; BUN 17mg/dl and creatinine 1.4mg/dl; plasma glucose 256mg/dl. Her hemoglobin of 15.4 and hematocrit of 46.6 was explained by her severe dehydration and hemoconcentration which also explained the low potassium and borderline changes in renal function.

CT scan of the abdomen and pelvis without contrast showed a small amount of ascites with a ventral wall hernia containing small bowel without any evidence of obstruction or strangulation. The wall of the bowel could not be commented on as contrast was not used due to concerns about the renal function.

Resuscitative management was instituted upon presentation including central line placement, several boluses of intravenous normal saline and norepinephrine drip to address her severe hypotensive state. While being managed as a case of recurrent gastroenteritis, she underwent an extensive work up including antibodies for celiac disease, clostridium difficile stool studies, adrenal insufficiency, and hyperthyroidism which all came out negative. Eventually, C1 inhibitor, functional level was done which showed a low level. This new finding together with her strong family history of angioedema and her recurrent episodes while on Lisinopril led to the diagnosis of ACE inhibitor associated angioedema superimposed on hereditary angioedema.

The patient was properly educated about her condition, including medications to avoid. Her symptoms resolved after four days of symptomatic therapy for nausea, vomiting, abdominal pain and dehydration and she was discharged home in stable condition after her Lisinopril was permanently discontinued and a safer antihypertensive agent of a different class prescribed.

INTRODUCTION

There are two main categories of angioedema: the mast-cell mediated and the bradykinin mediated angioedema.1 Bradykinin mediated angioedema, unlike the mast-cell mediated angioedema is usually without symptoms of pruritus and urticaria and includes 3 major categories. The hereditary form is known as hereditary angioedema (HAE) which is an autosomal dominant condition typically presenting as recurrent attacks of angioedema with a variable age of onset.2,3 Another category is termed acquired C1 inhibitor (C1 INH) deficiency which is a rare syndrome of recurrent episodes of angioedema, without urticaria and is associated with B cell lymphoproliferative disorders in some patients.4 A third presentation is the drug induced angioedema of which the most commonly recognized medication has been Angiotensin Converting Enzyme inhibitor (ACEi). Angioedema has also been reported as a rare event with Angiotensin Receptor Blockers (ARBs), fibrinolytic agents, estrogens, antihypertensive drugs other than ACE inhibitors, psychotropic drugs and nonsteroidal anti-inflammatory drugs.5 Angioedema from ACEi accounts for approximately 30% of all cases of angioedema; however, only 0.1% to 0.5% of patients taking ACEi develop angioedema.6,7 Considering that 35 to 40 million patients are treated worldwide with ACE inhibitors, this drug class could theoretically account for several hundred deaths per year from laryngeal oedema.5 However, ACEi induced angioedema of the gastrointestinal tract is very rare and its incidence is not well described.7-9

C1 esterase inhibitor is a serine protease inhibitor that works directly on complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE and acquired C1 inhibitor (see Figure 1). Hereditary angioedema (HAE) involves quantitative deficiency (type 1) or qualitative dysfunction (type 2) of C1 esterase inhibitor protein (HAE). A third type of familial angioedema is characterized by normal C1INH levels and is called HAE with normal C1INH. The drug-induced angioedema (mostly ACE inhibitors) is as a result of enhanced activity of bradykinin, a potent vasodilating peptide due to inhibition of ACE, an enzyme responsible for its breakdown (see Figure 1 below). Pharmacological inhibition of ACE leads to increased plasma levels of bradykinin and high levels have been demonstrated in plasma during an acute episode of angioedema.10,11 Notably, although degradation of bradykinin is blocked in all patients treated with ACE inhibitors, angioedema only occurs in a small percentage of such patients. Therefore it is likely that factors, other than impaired bradykinin degradation, are involved in the development of angioedema.5 In our patient, the background biochemical profile for HAE could be considered as a predisposing factor when an ACE inhibitor is introduced.

Classically, bradykinin mediated angioedema is located in the pharynx, extremities, or face. However, the bowel wall may be involved concomitantly in up to 75% of cases.12 Rarely, as we present in this case, angioedema of the bowel mucosa may be the only site of angioedema.13,14 The initial clinical presentation in patients with isolated gastrointestinal involvement may include colicky abdominal pain accompanied by nausea and vomiting that may easily be mistaken for other etiologies.13 About a day into an acute attack, the patient may experience watery diarrhea secondary to extravasation of fluid into the intraluminal space.13

Discussion

Abdominal pain is one of the most common conditions in clinical practice and yet a challenging complaint to accurately diagnose due to the vast number of possible etiologies.15 Intestinal angioedema is an uncommon but well described cause of abdominal pain and diarrhea easily misdiagnosed, leading to unnecessary surgical procedures and the possibility of a mortality rate.1 In a series of 235 patients with HAE up to a third of these patients had undergone exploratory laparotomies, appendectomies, or both, during their abdominal attacks.16

Considering the infrequent occurrence of intestinal angioedema, a high index of suspicion with a detailed history and physical examination are paramount for a diagnosis to be made. A detailed history should include the following: appropriate characterization of the attack; history of previous attacks; age at first attack; intervals between attacks; presence or absence of inciting factors or medications; complete medication history; presence or absence of respiratory system involvement, and whether there is a family history of similar attacks.17 Physical examination is most relevant during an acute attack and it will include a proper examination of the skin as well as the face and eyelids and upper airways, the commonly involved areas. For episodes with acute abdominal involvement, the abdominal examination findings are very nonspecific. Palpation of the abdomen may reveal diffuse abdominal tenderness with or without rebound.17 Usually there is no distension to suggest an obstructive picture. Bowel sounds may be hypoactive or hyperactive and the patient may have signs of dehydration from diarrhea depending on the presentation.

Radiologic tests may help confirm a diagnosis of intestinal angioedema. In severe cases, plain abdominal radiographs may show dilated loops of bowel along with “thumbprinting,” which describes an area of mucosal edema (see Figure 2).1 Ultrasonography often reveals mucosal thickening and free peritoneal fluid in dependent areas of the abdomen.18

There may also be a detectable compressible but edematous bowel wall with increased intraluminal fluid and decreased motility.19 The most sensitive diagnostic imaging study is a contrast-enhanced CT scan of the abdomen. CT is more useful for identifying milder degrees of intestinal edema, dilated loops of small or large bowel, and ascites than ultrasound and plain radiographs.20 CT findings typically include massive edema of the small bowel or colon, prominent mesenteric vessels, thickened omentum, moderate ascites, and a normal appearance of the pericolic fat. Normal appearance of pericolic fat is useful for ruling out inflammatory changes seen in other diseases, such as appendicitis or diverticulitis.21,22 If imaging is delayed until after recovery, then radiologic imaging may only show normal results.1 As in the patient described, subtle or mild intestinal edema of any cause may be overlooked by interpreting radiologists even in symptomatic patients.17

Worsening abdominal pain severity after an earlier negative CT scan should not necessarily preclude consideration of intestinal angioedema diagnosis or a repeat imaging study.17 Sometimes these CT findings involving the bowel lead to a Gastroenterology consultation and if colonoscopy is performed, massive edema of the the bowel wall can be documented (Figure 3).

Laboratory tests are necessary to confirm a diagnosis of angioedema.1 However there may be no need to do a further laboratory test in a patient with drug (ACE inhibitor) induced angioedema whose diagnosis can easily be made from history and confirmed with radiologic studies. If HAE is suspected, 4 laboratory tests should be obtained: C1 INH level, C1 INH activity, serum C4 level, and serum C1q, which is a byproduct of C1 INH degradation.15,23,24 Low C4 is always present in HAE. In addition to low C4, a low C1 INH level and activity along with a normal C1q level is consistent with type I HAE. A normal C1 INH level with low functional activity and a normal C1q are consistent with type II HAE.1

Management

Acute management will involve airway protection, hemodynamic stability and symptomatic therapy (antinausea and pain medications) depending on presentation and initial assessment. There are currently three FDA-approved intravenous pharmacologic agents available in the United States for the targeted acute treatment of HAE: plasma-derived C1 INH replacement protein (C1 INHRP), icatibant, and ecallantide (see Figure 4 below).17 Plasma-derived C1 INHRP obtained from pooled human plasma is the best studied first- line therapy for an acute HAE attack and it acts by repleting plasma C1 INH to exert inhibitory effects on the angioedema-causing pathways.25,26 Icatibant, marketed as Firazyr, is a synthetic B2 receptor antagonist that blocks the effects of bradykinin during an acute angioedema attack by competitively binding to B2 receptors resulting in resolution of swelling and pain. Note that bradykinin, generated during HAE attacks, interacts with bradykinin-1 and B2 receptors to cause angioedema.25,27 Ecallantide is a novel plasma kallikrein inhibitor (thereby blocking the production of bradykinin) approved in the United States in Decemeber 2009 for the treatment of acute attacks of HAE. Data from 2 randomized double-blind, placebo-controlled phase 3 trials of ecallantide in 143 patients with HAE to examine the speed of efficacy of ecallantide vs placebo showed that its beneficial effect was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks.28 Most patients given any of the first line therapies take 15 minutes to 2 hours before experiencing onset of relief, and major swelling may take up to 24 hours to completely resolve after drug therapy. A second line agent Fresh frozen plasma may be used when the first line agents are not available or have not shown efficacy.

Following acute management, adequate patient education as well as prophylactic therapy is usually given as patients are prone to having recurrence of attacks. Prophylaxis may be administered short term in anticipation of a procedure or period of stress, or long term for the reduction of attack rates.29 Two agents are currently FDA approved for both long term and short term prophylaxis in the United States: oral attenuated androgens (mainly, danazol) and Cinryze, a nanofiltered C1 INH concentrate.30 Antifibrinolytics (eg, tranexamic acid) currently being used in Europe is not recommended in the United States due to concerns about its prothrombotic side effects. In addition to prophylactic therapy referral to an allergist and/or a geneticist and permanent discontinuation of unsafe medications may be indicated.

Clinical Pearls for Gastroenterologists

Recurrent admissions for presentations of abdominal pain with no unifying diagnosis being made but sometimes accompanied by surgical intervention should prompt consideration of the diagnosis of intestinal angioedema. Even without involvement of any other part of the body like the eyes or the upper airways, this should not be ruled out when there is a high index of suspicion based on the history, physical exam or radiological findings.

Intestinal angioedema can be well managed if diagnosed early. Due to the debilitating nature of this condition, and the risk of complications from misdiagnosis (such as surgery) there is need for a high index of suspicion among clinicians. Clinicians should be cognizant of medications that can induce this condition particularly ACEi in order to immediately discontinue its use. The treatment guideline we have provided will also facilitate management decisions.

This case report and literature review serve to heighten the awareness of intestinal angioedema among gastroenterologists as well as help differentiate the condition from other more common gastrointestinal conditions. Intestinal angioedema should feature in the differential diagnosis when CT and other imaging modalities or colonoscopy identify bowel wall edema.

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A Case Report

A Case Report Of Spontaneous Pneumoperitoneum Related to Scleroderma without Evidence of Pneumatosis Cystoides Intestinalis

May 2016 • Volume XL, Issue 5
Ross Heil,Jason Schairer,Brad Warren

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We report a case of a 72-year-old male with a history of scleroderma who presented to the emergency room with an asymptomatic pneumoperitonum after undergoing a CT thorax for evaluation of intersitial lung disease. Abdominal imaging was performed with oral contrast and did not reveal extravasation of the contrast into the peritoneum suggesting there was no perforated viscus. The patient was managed conservatively with serial abdominal exams, bowel rest, empiric antibiotics, supplemental oxygen, and total parenteral nutrition. The patient was subsequently diagnosed with a spontaneous pneumoperitoneum related to scleroderma without evidence of pneumatosis cystoides intestinalis. Over a course of 3 months the pneumoperitoneum resolved and the patient remained well.

Ross Heil, D.O., Providence Hospital and Medical Center Jason Schairer, M.D., Henry Ford Health System Brad Warren D.O. Providence Hospital and Medical Center

INTRODUCTION

In 1915, Hugo Popper first described the technique of utilizing radiographic methods to detect pneumoperitoneum.2 Radiological techniques that are available for the diagnosis include ultrasound, plain X-ray and computed tomography (CT). Pneumoperitoneum appears as a radiolucency below the diaphragms on chest radiography or in a superiorly dependent location on an abdominal radiograph. Miller and Nelson described a process that can detect as little as one cubic centimeter of gas in the abdominal cavity.8 This includes placing the patient in the left lateral decubitus position for 10 to 20 minutes then exposing a left lateral decubitus film. The patient is then moved into an erect position where an anteroposterior chest film is taken as well as an erect abdominal film. The patient is next tilted to a horizontal position where a supine abdominal film is taken.8 If there is concern that the pneumoperitoneum is from an area above the diaphragm then abdominal x-rays should demonstrate air in the paraspinal area of the retroperitoneum.10 Computed tomography is more sensitive for detecting intraperitoneal air than upright chest radiographs.6 Visceral perforation may not always be detected by contrast examination with computed tomography.10 The causes of most pneumoperitoneum have been linked to intra-abdominal disease. Approximately 90% of the cases of pneumoperitoneum are due to visceral perforation, usually associated with a gastric or duodenal ulcer.2 Pneumoperitoneum due to perforation is a surgical emergency. Generally these patients will present with fever, leukocytosis and peritoneal signs. There are, however, cases of an occult leakage due to visceral perforation where the patient may only demonstrate mild abdominal pain without fever, leukocytosis, or peritoneal signs. These occult leakages may be due to sigmoid diverticulitis, fecal impaction, or peptic ulcer perforations.2 It has been noted that patients with peptic ulcer perforations may present less symptomatic than other sites of perforation or even asymptomatic with subsequent healing without intervention.2

The remaining 10% of cases of pneumoperitoneum not associated with visceral perforation fall into the classification of spontaneous pneumoperitoneum.2 The term spontaneous pneumoperitoneum has been used synonymously with aseptic spontaneous, idiopathic, spontaneous asymptomatic and nonsurgical pneumoperitoneum.2 Causes of spontaneous pneumoperitoneum can be divided into abdominal, thoracic, gynecologic, pseudopneumoperitoneum, miscellaneous and idiopathic etiologies.6

Abdominal causes of spontaneous pneumoperitoneum are the most common.8 The etiologies include abdominal surgery, peritoneal dialysis, and most endoscopic gastrointestinal procedures.6 By far the most common abdominal cause is due to open abdominal surgery. It generally resolves within 2 days in two thirds of the cases and within 5 days in 97% cases when followed by abdominal radiographs.6 If followed by CT, which is more sensitive, intraperitoneal air at 3 days will be detected in 85% of the cases and 50% of cases at day six.6 Older, leaner adults more commonly retain a greater volume of free air over a longer period of time.8

Pneumatosis cystoides intestinalis, also known as cystic lymphomatosis or enteromesenteric emphysema, is the most common abdominal cause of nonsurgical pneumoperitoneum.6 It was first described in 1730 by DuVernoi during a cadaver dissection.10 The development of pneumatosis cystoides intestinalis has been associated with idiopathic development, scleroderma, bone marrow transplant, AIDS, diverticular disease, small bowel resection, intestinal pseudo obstruction, dermatomyositis, nontropical sprue, jejunal-ileal bypass, gastric outlet obstruction, sclerotherapy, and heart transplantation.6 It is characterized by intramural gas filled cysts in any portion of the gastrointestinal tract; however, it is most commonly found in the terminal ileum.6 Even though the small bowel is the most common site for these cysts, they can be found anywhere in the gastrointestinal tract including the stomach (gastric pneumatosis cystoides) and the colon (pneumatosis coli).8 It is the rupture of these cysts that lead to pneumoperitoneum.7 The cysts are constantly filling, rupturing, sealing, and then filling again providing a constant spontaneous pneumoperitoneum. This condition generally resolves spontaneously, but has been known to reoccur. There have been five possible explanations for the development of these cysts. The first two theories suggest that an increase in acidic byproducts result in increased levels of lactic acid leading to a decrease in carbon dioxide and oxygen resorption leading to the cyst formation.8 The mechanical theory states that gas is forced into the bowel by obstructions, anastomotic sites, the pulmonary system, trauma, mucosal breaks, increased pressure, or increased peristalsis. The bacterial theory suggests that bacteria gain entrance to the bowel wall and produce the cysts.10 The last theory is mentioned due to historical interest, which is a neoplastic theory described by Bangs.8

Outside of the abdomen, other locations that may cause pneumoperitoneum include thoracic, gynecolic, and other locations. Thoracic causes include mechanical ventilation, cardiopulmonary resuscitation, and pneumothorax. Thoracic causes are the second most common cause of spontaneous pneumoperitoneum and barotraumas represents the most frequent of the intrathoracic causes.8 Gynecologic etiologies are rare compared to the other locations. These generally occur due to air traveling through the genital tract into the peritoneum via the uterus and fallopian tubes.10 Examples include vaginal insufflation by orogenital sex, vaginal douching, postpartum knee-chest exercises, use of bulb aspiration in pelvic exam, tubal insufflation in hysterosalpingogram, pelvic inflammatory disease, and coitus.10 In the differential of pneumoperitoneum is pseudopneumoperitoneum. This was first described in the 1930s and represents a simulated appearance of free intraperitoneal air.6 This is frequently due to adventitial air shadows, over distension of hollow viscera, the basal lung appearing to lie in the diaphragm, gas trapped in wounds, basal pulmonary atelectasis resembling subphrenic air, subdiaphragmatic extraperitoneal fat, and positioning of colonic hepatic flexure between the right lobe of the liver and diaphragm, also known as Chilaiditi sign.6 Failure of the air to shift during different positioning or to localize to the most superior aspect of the radiographic imaging should lead to the suspicion of pseudopneumoperitoneum.6 Other causes of pneumoperitoneum include scleroderma without pneumatosis cystoides intestinalis, idiopathic, cocaine use, diving and decompression, and dental extraction.

There are many reports of pneumoperitoneum in patients who have mild abdominal pain but no leukocytosis, fever, or peritoneal signs that were treated successfully with conservative management.2 When spontaneous pneumoperitoneum is suspected, emergency surgery is not required. A difficult situation arises when the physical examination is unreliable such as in an unresponsive patient on a ventilator or a patient with a depressed immune system causing a delay in the signs and symptoms of peritonitis. In these cases, a diagnostic peritoneal lavage may aid in the decision where to perform surgery or to treat conservatively.8 Methylene blue may be instilled via a nasogastric tube to help increase the accuracy of detecting an upper gastrointestinal perforation.8 If the lavage is negative and the patient is unremarkable, then continued observation is warranted. Also aiding in the decision for surgery would be to instill water-soluble contrast through a nasogastric tube with a subsequent abdominal film.8

CASE REPORT

Here we report a 72 year-old white male who was having thoracic CT surveillance without contrast for evaluation of interstitial lung disease due to his history of scleroderma. Thoracic CT incidentally revealed free air in his abdomen and he was subsequently instructed to seek further evaluation in the emergency department. The patient’s past medical history included rheumatoid arthritis, scleroderma and a previous gastrointestinal bleed with an unclear etiology five years prior to admission. The patient did not have any surgeries or procedures in the last six months.

Upon admission to the emergency department, his blood pressure was 153/76 mm Hg, heart rate 78 bpm, temperature 97.7 oF and an oxygen saturation of 99% on room air. The patient’s physical exam was benign. The initial complete blood count (CBC) and complete metabolic panel (CMP) were within normal limits. While in emergency department, the patient had a chest X-ray demonstrating free air within the abdomen. A CT of the abdomen without contrast confirmed a pneumoperitoneum (Figure 1). The patient was evaluated by both gastroenterology and surgery. Conservative measures of bowel rest along with serial abdominal and x-ray examinations were undertaken which remained stable throughout the admission. Abdominal imaging did not show evidence of pneumatosis cystoides intestinalis. An upper gastrointestinal series was completed and did not demonstrate extravasation of contrast, shown in Figure 2. The patient’s diet was advanced over six ,days; he tolerated this well and was discharged.

Approximately six weeks later, the patient had a follow up abdominal CT with oral contrast. It demonstrated a mild increase in the pneumoperitoneum along with right pleural calcification, which was noted on a previous thoracic CT. He was again instructed to return to the emergency department. Upon arrival to the emergency department his physical exam, vital signs, CBC and CMP were all normal. The patient remained asymptomatic. Another upper gastrointestinal series was done, again demonstrating no obvious extravasation of contrast. He was treated with bowel rest, supplemental oxygen and placed on total parenteral nutrition for several weeks. Cefazolin and metronidazole were started as empiric treatment for a bacterial source of the gas and antibiotics were continued for one week. An abdominal x-ray one week later demonstrated a resolving pneumoperitoneum. A follow up abdominal CT scan two months after being discharged from his second hospital admission demonstrated no free air in the abdomen.

DISCUSSION

Pneumoperitoneum generally occurs in the presence of a visceral perforation with peritoneal signs; however, in some cases where the patient is asymptomatic, the physician should consider causes of spontaneous pneumoperitoneum. In the case above, we reported a spontaneous pneumoperitoneum thought to be due to scleroderma without relation to pneumatosis cystoides intestinalis. After a thorough search of the medical literature only five published case reports are available for review, making this an extremely rare entity.

Once our patient was in the emergency department, a CT of the abdomen was completed which did not demonstrate any evidence of pneumatosis cystoides intestinalis. When attempting to identify pneumatosis intestinalis with computed tomography, it is best to view the bowel wall in the lung window for evidence of air within the gut wall.3 However, there was always a chance that the pneumatosis cystoides intestinalis was below the resolution of the computed tomography in our patient, although this is unlikely.7 It is also possible that there was a microperforation in the stomach that had subsequently healed. As noted above, patients can be minimally symptomatic, if not asymptomatic, with a microperforation of the stomach. It is interesting to note that the patient had a gastrointestinal bleed in the preceding five years with an unclear etiology. The patient had a colonoscopy in the past, but was never evaluated with an esophagogastroduodenoscopy, leaving room for gastric pathology. The patient did have two upper gastrointestinal series and a CT with oral contrast that did not demonstrate extravasation of contrast. However, that does not rule out a perforation but does make it less likely. Since our patient had a history of scleroderma and demonstrated no obvious source of visceral perforation, was asymptomatic and radiographic imagining did not show evidence of pneumatosis cystoides intestinalis, this led us to believe that the pneumoperitoneum was related to scleroderma.

As stated by Rowe et al., determining which patient with a pneumoperitoneum needs to undergo exploratory laparotomy versus those that can be managed conservatively can be challenging. However, Rowe et al. suggests that the laparotomy rate can be decreased to near zero if a thorough history and physical examination is performed and does not suggest perforation. Since our patient was stable a conservative approach was taken with antibiotics, increased fractional inspired oxygen content to 27% and total parenteral nutrition and he responded well. In the other five known cases, one case report performed a laparotomy, another case report performed a peritoneal lavage, and in the remaining case reports, conservative treatment without invasive intervention was the preferred approach. The conservative approach, rather than an unnecessary exploratory laparotomy, saved our patient significant morbidity and he responded well.

Our patient’s pneumoperitoneum resolved in three months. The other cases reported resolution ranging from six months to two years. This is in drastic contrast to those patients who undergo abdominal surgery or have endoscopic procedures, which generally have resolution of the pneumoperitoneum in five days in approximately 97% of cases followed by abdominal radiographs.

In patients with scleroderma associated with spontaneous pneumoperitoneum without evidence of pneumatosis cystoides intestinalis, the pathophysiology of the pneumoperitoneum is still unclear. It could be that pneumatosis cystoides intestinalis in many of these cases are at an undetectable level from radiographic imaging and could be causing a pneumoperitoneum. The cysts have been postulated to form in scleroderma due to gut hypomotility with subsequent bacterial overgrowth. It was for that reason that empiric antibiotics were used in the conservative approach in our patient to reduced bacterial overgrowth and possible cyst formation. It has also been postulated that there are recurrent microperforations in colonic diverticula causing a pneumoperitoneum in scleroderma without evidence to pneumatosis cystoides intestinalis.7 The microperforations may arise due to intestinal ischemia due to the vasculitic nature of scleroderm.9 It may also be related to the atrophy of the muscularis propria and collagen tissue replacing it, which occurs throughout the gastrointestinal tract in patients with systemic sclerosis.4

CONCLUSION

Spontaneous pneumoperitoneum associated with scleroderma without evidence of pneumatosis intestinalis cystoides is an extremely rare presentation. Surgical intervention is not generally needed unless the history and physical suggests perforation. Patents can be treated conservatively with bowel rest and total parenteral nutrition. Patients should also be educated about the prolonged time of resolution of the pneumoperitoneum as well as the likelihood of the recurrence.

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Colorectal Cancer: Real Progress In Diagnosis And Treatment, Series #3

Update in Genetics of Colorectal Cancer: A Practical Guide to Testing

May 2016 • Volume XL, Issue 5
Swati G. Patel,Dennis J. Ahnen

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The genetic understanding of colorectal cancer (CRC) continues to evolve rapidly. It is becoming increasingly clear that the cancer spectrum of many of the hereditary cancer syndromes is much broader than originally thought. The observed overlap in phenotype, along with the rapidly decreasing costs of next-generation gene sequencing, has led to increasing use of cancer gene panels for diagnosis of the hereditary cancer syndromes. In this review, the clinical features and approach to management of the hereditary CRC syndromes is described along with an approach to selection of families that should be referred for genetic counseling and possible genetic testing.

The genetic understanding of colorectal cancer (CRC) continues to evolve rapidly. Currently, up to 10% of all CRCs are thought to be due to one of over 10 different hereditary syndromes. The colorectal cancer syndromes have been traditionally classified as polyposis and non-polyposis syndromes and the polyposis syndromes have been further separated histologically into adenomatous, hamartomatous and serrated polyposis syndromes. The genetic basis for most of these syndromes is well defined and clinical classifications are being supplemented and increasingly supplanted by genetic classification of the syndromes. Traditionally, genetic testing was performed for syndrome-specific genes in families that met the accepted clinical criteria for a known syndrome but, as more genetic testing is done, it is becoming increasingly clear that the cancer spectrum of many of the hereditary cancer syndromes is much broader than originally thought and that there is substantial overlap in their phenotypes. The observed overlap in phenotype, along with the rapidly decreasing costs of next-generation gene sequencing, has led to increasing use of cancer gene panels for diagnosis of the hereditary cancer syndromes. In this review, the clinical features and approach to management of the hereditary CRC syndromes is described along with an approach to selection of families that should be referred for genetic counseling and possible genetic testing.

Swati G. Patel1,2 Dennis J. Ahnen1,3 1University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Gastroenterology & Hepatology, Aurora, CO 2Veterans Affairs Hospital, Denver, CO 3Gastroenterology of the Rockies, Boulder, CO

INTRODUCTION

Up to 30% of all colorectal cancers (CRCs) have some familial component and about 5% of all CRC are thought to be due to known hereditary syndromes.1,2 Genetic identification of hereditary syndromes allows comprehensive prevention and management strategies tailored for specific mutation carriers and their family members. This review will focus on the approach to recognition of hereditary syndromes with emphasis on identification of patients/ families that should be referred for genetic counseling and possible testing. Genomic analysis of CRCs and individualized treatment base on CRC genetics will be covered in other chapters of this issue.

IDENTIFICATION OF HEREDITARY CRC SYNDROMES
CLASSIFICATION OF SYNDROMES

Hereditary CRC syndromes have been traditionally divided into polyposis or non-polyposis syndromes (Table 1). The main non-polyposis syndromes are Lynch Syndrome (LS) and Familial Colorectal Cancer Type X and the polyposis syndromes have been clinically subdivided by polyp histology (adenomatous, hamartomatous or serrated) although the syndromes are now largely defined by their genetic basis. With the increasing use of genetic testing, it is clear that there is a substantial overlap in the phenotypic expression of the hereditary CRC syndromes. Care of patients with hereditary CRC syndromes and their families is complex and is best coordinated by providers with special expertise in genetics and hereditary cancer syndromes. Primary care providers and general gastroenterologists are critical for initial recognition of these syndromes.

Lynch Syndrome (LS)

LS, previously referred to as hereditary non-polyposis CRC (HNPCC), is the most common hereditary cause of CRC, accounting for 2-5% of all CRC cases and an estimated prevalence of one in 370 in the US.3 It is an autosomal dominant syndrome caused by a germline mutation in one of the mismatch repair (MMR) genes (MLH1, MSh3, MSH6 and PMS2) or deletions in the EPCAM gene which causes hypermethylation and subsequent silencing of the MSh3 gene. Somatic events lead to inactivation of the remaining wild-type allele, resulting in genomic instability due to an inability to correct single-base mismatches or insertion-deletion loops that occur commonly during normal DNA replication. This genomic instability is the basis of the increased colorectal, endometrial, ovarian and other cancer risks in LS (Table 1).

Cancer Risk in LS

CRC and endometrial cancer are the most common cancers in LS (30-60% lifetime risk),4 but LS mutation carriers also have an increased risk of other cancers, including ovarian, gastric, small bowel, ureter/renal pelvis and sebaceous skin cancers, among others (Table 1). Cancer risks in LS are dependent on the genotype with MSH6 and PMS2 generally having lower cancer risks than the other genotypes. Table 1 summarizes LS cancer risks by genotype.

Genetics of LS

MLH1 and MSh3 account for about 80% of LS cases but MLH6 and PMS2 families are likely underrepresented in high-risk registries due to their attenuated phenotype.5 Germline deletions of EPCAM cause the clinical picture of LS with MSh3 deficient, microsatellite unstable tumors but without detectable MSh3 mutation.6 These deletions involved the 3′ end of EPCAM leading to transcriptional read-through into, and subsequent epigenetic silencing of the neighboring MSh3 gene by promoter hypermethylation. CRC risk in EPCAM deletion carriers is similar to those with an MSh3 mutation7 but endometrial cancer risk is lower (Table 1).

Diagnosis

It has been estimated that only 1-2% of the 830,000 LS mutation carriers in the US are aware of their diagnosis.3 This is likely due to a combination of sub-optimal knowledge of multi-generation family history, under- recognition of those who have a family history that place them at risk for LS and poor clinical screening criteria for the detection of Lynch. The approaches to diagnosis of LS are discussed below.

Family History Criteria

The Amsterdam criteria for LS (Table 2) were developed before genetic testing was available; they are highly specific but have a low (≈ 50%) sensitivity and positive predictive value for LS.8 The US Multi-Society Task Force (US-MSTF) recently recommended the use of a three question screening tool (Figure 1)9 to identify families who should be referred for additional family history assessment or genetic evaluation. When studied in a direct referral endoscopy center, this tool had a higher sensitivity for detecting high-risk CRC families (77%), and it identified 95% of patients in a validation cohort of Lynch mutation carriers.10 Individuals who answer yes to any of the three questions should be evaluated with a more detailed family history and/or referred to a genetics clinic.11,12

Quantitative predictive models have also been developed to help identify potential LS patients. Three of these are accessible on the online; MMRPredict (http:// hnpccpredict.hgu.mrc.ac.uk/); PREMM (http://premm. dfci.harvard.edu) and MMRPro (http://66.118.159.147/ HRAExpressEntry/(S(o04sbxj2urqwqghk21sv0o4e))/ default.aspx). MMRPredict is designed to predict risk of gene mutation only in CRC-affected patients, whereas PREMM 1,2,613 and MMRPro predict risk in unaffected individuals as well. These models depend on collection of an accurate multi-generation family history. They performed similarly in predicting MMR mutation and all are superior to Amsterdam and Bethesda criteria.12 Individuals estimated by these models to have ≥5% risk of LS should be referred for genetic counseling/testing.

Tumor Testing for LS

The Bethesda criteria (Table 3) were developed to identify individuals with CRC who should have their cancers tested for evidence of MMR deficiency (loss of MMR protein expression or microsatellite instability [MSI] by polymerase chain reaction [PCR]). Individuals with MMR deficient CRCs should have further evaluation for LS. The Bethesda criteria are about 80% sensitive and specific for LS.8 Essentially all LS-associated CRCs are MMR deficient but about 15% of sporadic CRCs are also MMR deficient due to hypermethyltion and transcriptional silencing of MLH1. If IHC shows loss of MLH1, testing for BRAF mutation or MLH-1 promotor hypermethylation can separate the sporadic MSI CRCs that arise through the CIMP/ Serrated pathway from those that should be referred for genetic counseling/testing for LS.

Universal MSI or IHC Testing

Universal testing of all CRCs for evidence of MMR deficiency has been recommended as a means to increase the detection rate of patients with LS;14-16 it has higher sensitivity (100% vs 86%) for LS than the Bethesda criteria with similar specificity (96% vs 98%),17 and modeling studies suggest that universal testing can identify LS at an acceptable cost.18

Management
Screening & Surveillance

Retrospective data strongly supports colonoscopic screening in LS. Jarvinen et al.19 demonstrated that LS patients who had regular screening had a markedly decreased incidence and mortality from CRC. Multiple professional societies9,15,16 support initiating colonoscopic screening between the age of 20 and 25 and screening every 1-2 years. Screening recommendations for extra-colonic malignancies are based largely on expert consensus20-22 and are summarized in Table 1.

Chemoprevention

A controlled trial of aspirin (600 mg/day) in 861 Lynch mutation carriers23 showed no benefit at the end of 24 months of treatment, but after 56 months of follow up, there was a lower CRC incidence (OR 0.56, 95% CI 0.32-0.99, p=0.05) in the aspirin-treated group. Aspirin chemoprevention is a reasonable option in LS mutation carriers, especially if they have an elevated cardiovascular risk and a low risk of bleeding complications. The optimal dose is not established; a dose-finding trial is currently under way.

Surgical Management

Although a total or subtotal colectomy is generally recommended in LS mutation carriers who require colonic resection, there is little controlled data comparing surgical approaches. Retrospective analyses24 have reported lower rates of metachronous CRCs after total or subtotal colectomy (0-6%) than after a segmental colectomy (22-26%).

Familial Colorectal Cancer Type X (FCCTX)

Families that meet Amsterdam I criteria but with microsatellite stable CRCs are classified as having FCCTX. No genetic basis has yet been found for these families. FCCTX families have an increased risk of CRC but not of endometrial or other Lynch-associated cancers.25 Regular colonoscopic screening is recommended for members of FCCTX families (Table 1).

FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

FAP is a rare syndrome that accounts for less than 1% of all CRC cases with an estimated prevalence of 1/10,000 to 1/30,000.26-28 FAP is an autosomal dominant syndrome due to a germline mutation in the adenomatous polyposis coli (APC) gene. The classic phenotype of FAP is characterized by hundreds to thousands of colonic adenomas beginning in adolescence. Untreated, there is a near 100% lifetime risk of CRC (average age 39 years). Attenuated FAP (AFAP) is a less severe phenotype characterized by fewer adenomatous polyps (10-100), a later age of onset of adenomas and CRCs and a lower lifetime risk of developing CRC (70%).29

Extracolonic Features

A variety of extra-colonic lesions occur in FAP (Table 1) including increased risks of duodenal, thyroid and other cancers. Although desmoid lesions are histologically benign, they are common (≈ 10%) in FAP and they carry a great deal of morbidity and even mortality due to local compression. Nieuwenhuis et al.30 found previous abdominal surgery, APC mutations 3′ of codon 1444 and a family history of desmoids were independent predictors of desmoids. Several benign tumors such as fundic gland polyps, osteomas, fibromas, epidermoid cysts among others are also common in FAP (Table 1).31

Genetics

FAP and AFAP are autosomal dominant conditions that arise from germline mutations of the Adenomatous Polyposis Coli (APC) gene located on chromosome 5q21-q22. More than 1000 different APC mutations have been identified in FAP and most cause a truncated gene product.32 There are substantial genotype/phenotypic correlations with the extra-intestinal manifestations, severity of polyposis and survival in FAP.33,34

Management
Screening & Surveillance

Recommendations are to start annual flexible sigmoidoscopy or colonoscopy screening around age 10-12 for classical or severe FAP and annual colonoscopic screening starting around age 20-25 in AFAP.15,16,35 Surveillance for gastroduodenal adenomas and thyroid cancer is summarized in Table 1.

Surgical Management

Appropriately timed colectomy remains the basis of effective management of CRC risk in profuse FAP. AFAP can sometimes be managed, at least temporarily, with careful endoscopic surveillance and polypectomy. Management of duodenal lesions in FAP is individualized. Most practitioners perform surveillance and remove adenomatous lesions endoscopically, reserving surgery for large and/or histologically advanced lesions or cancer.36

Chemoprevention

Although chemoprevention is not a substitute for properly timed colectomy, numerous studies have shown that sulindac induces a marked reduction in polyp count and single studies of the selective COX- 2 inhibitors celecoxib and rofecoxib showed similar, albeit less dramatic, results37 and aspirin appears to have little effect.38 These drugs are not FDA approved in FAP but sulindac is sometimes used as an adjunct to surgical therapy.

MUTYH ASSOCIATED POLYPOSIS (MAP)

The MUTYH gene is a part of the base-excision repair pathway involved in the repair of oxidative DNA damage. Bi-allelic mutations in MUTYH cause an autosomal recessive colonic polyposis syndrome (MUTYH-Associated Polyposis or MAP) with a clinical picture similar to AFAP. Although MAP is classified as an adenomatous polyposis syndrome, serrated polyps are common.39 It is becoming clear that the clinical spectrum of MUTYH germline mutations is broad and can even include younger-onset CRC without polyposis.40

CRC and Other Cancer Risk

Bi-allelic MUTYH mutation carriers have over a 10 fold increased CRC risk.41,42 Patients with MutYH- related CRCs tend to be younger and more likely to have adenomatous polyps and synchronous CRCs than those with sporadic CRC and the cancers are more often right sided and may have an improved survival.43 Mono-allelic carriers of MUTYH mutations appear to have a marginally increased CRC risk; OR 1.16, 95% CI 1.00-1.30.42 Duodenal adenomas are common MAP and they can progress to cancer. Risks of ovarian, bladder and skin cancer are also increased (Table 1).44

Management of MAP

The screening/surveillance and surgical management of MAP is similar to attenuated FAP and highly dependent on polyp burden (Table 1).

POLYMERASE PROOFREADING- ASSOCIATED POLYPOSIS (PPAP)

Recently, germ-line mutations in the proofreading polymerases POLD1 and POLE have been shown to cause an adenomatous polyposis syndrome and early onset CRC in a few families.45 The magnitude and spectrum of cancer risks in this syndrome are not yet known and screening guidelines have not been established but colonoscopy screening starting in young adulthood seems reasonable (Table 1).

HEREDITARY MIXED POLYPOSIS SYNDROME (HMPS)

Germline mutations in GREM1 cause an autosomal dominant polyposis syndrome characterized by the development of a variety of polyps, including adenomas, hyperplastic or serrated polyps, as well as juvenile polyps and polyps with mixed pathology CRC.46 The cancer risks, and screening recommendations in this group are uncertain but colonoscopy screening in young adulthood seems reasonable.

Peutz-Jeghers Sydrome (PJS)

PJS is an autosomal dominant syndrome that can arise from germline mutations in the serine threonine kinase gene (STK11). It is clinically characterized by classic muco-cutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia or fingers in addition to a histologically distinct type of hamartoma (PJ polyp) of the small and large bowel. The clinical criteria for PJS include any of the following:

  • 2 or more histologically confirmed PJ polyps
  • Any PJ polyps in an individual who also has characteristic mucocutaneous pigmentation
  • Any PJ polyps or characteristic mucocutaneous pigmentation in an individual with a family history of PJS

Cancer/Intussusception Risks

Patients with PJS have a very high cumulative risk of any cancer (up to 85%) and of CRC (>50%).47,48 Hamartomas are thought to serve as precursors to CRC as focal dysplasia and invasive cancer has been seen within hamartomas.49 There is also an exceptionally high rate (10%-50%) of extra-colonic cancers in PJS (Table 1) including gastric, small bowel, pancreatic, breast, ovarian, lung, cervical and uterine/testicular cancer.50 Small bowel hamartomas lead to a high rate of intussusception (up to 65%) that can start in childhood.

Screening & Management

The main management goals in PJS include prevention of polyp-related complications that often necessitate surgery (bowel obstruction from intussusception, bleeding) and prevention/early detection of cancer. Screening guidelines (Table 1) vary,50,51,52 but include upper and lower endoscopic screening and imaging of the small bowel with removal of all polyps >1-1.5 cm in size when possible. In women, screening for breast, uterine and ovarian cancer is recommended starting around age 25; in men annual testicular exam starting around age 10 is generally recommended (Table 1). Some guidelines recommend annual chest radiographs. Discussion of risk reduction surgery (mastectomy, hysterectomy, oophorectomy) is appropriate for women.

JUVENILE POLYPOSIS SYNDROME (JPS)

JPS is characterized by the occurrence of juvenile polyps throughout the intestinal tract (although most typically in the colorectum) and carries an increased risk of CRC. The World Health Organization (WHO) diagnostic criteria for JPS require one of the following:

  • >5 juvenile polyps (JPs) in the colon or rectum,
  • Multiple JPs in the upper gastrointestinal tract or
  • Any JP(s) in a patient with a family history of JPS

Genetics

JPS is an autosomal dominant syndrome although de novo mutations are common (≈ 25%). About 60% of patients with JPS have germline mutations in one of two genes in the transforming growth factor-beta (TGF- beta) signaling pathway (SMAD4, BMPR1A). SMAD4 mutation has also been associated with hereditary hemorrhagic telangiectasia (HHT).

Management
Screening

Patients with known or suspected JPS should undergo annual physical examination and evaluation for anemia and regular upper endoscopy, small bowel imaging and colonoscopy starting in adolescence or at the time of first symptoms (Table 1) with endoscopic removal of polyps when possible.

Surgery

Surgery is generally considered in JPS when the polyps cannot be managed endoscopically, for severe gastrointestinal bleeding, in polyps exhibiting dysplasia or in patients with a strong family history of CRC. The decision between subtotal versus total proctocolectomy is typically made on the basis of the rectal polyp burden. Post-operative endoscopic surveillance is required given the high recurrence rate of polyps in remaining rectal and ileal tissue.

PTEN HAMARTOMATOUS TUMOR SYNDROME (PHTS)

Cowden syndrome (CS) and Bannayan-Riley- Ruvalcaba syndrome (BRRS) can both be caused by a germline mutation of the phosphatase and tensin homolog (PTEN) gene and thus are both included in the PHTS. PHTS is autosomal dominant with relatively high penetrance (estimated 80%). The PTEN tumor suppressor gene is location on 10q23.3 and encodes a dual-specificity phosphatase that can de-phosphorylate protein and phospholipid substrates.

PHTS is characterized by hamartomatous lesions in multiple organs with a high frequency mucocutaneous lesion including trichilemmomas, acral keratoses, facial papules/oral papillomas, and esophageal glycogenic acanthosis. Although classified as a hamartomatous polyposis syndrome, adenomas, hyperplastic polyps, ganglioneuromas and inflammatory polyps also occur commonly in PHTS.

Cancer Risks in PHTS

PHTS is associated with a marked increased risk of many cancers including breast, colorectal, endometrial, renal, thyroid (Table 1).53,54

Diagnosis

A clinical diagnosis of CS is entertained when individuals meet criteria established by the International Cowden Consortium.55 Major and minor clinical criteria and a scoring system have been proposed to help identify such patients (Table 4).55

Management
Screening & Surveillance

Screening recommendations, based on expert opinion, include general physical examination, careful breast, endometrial and colorectal cancer screening starting in young adulthood (Table 1).53 Discussion regarding prophylactic mastectomy and hysterectomy is recommended on a case by case basis.

SERRATED POLYPOSIS SYNDROME (SPS)

SPS (previously called Hyperplastic Polyposis Syndrome) is likely familial but its genetic basis has not yet been defined. SPS is characterized by the presence of multiple serrated polyps of the colon.56 The clinical criteria for SPS57 include any of the following: – 5 or more serrated polyps proximal to the sigmoid colon with at least two being greater than 1cm – 20 or more cumulative serrated polyps of any size distributed throughout the colon – 1 or more proximal serrated polyps in an individual with a first degree relative with SPS

Cancer Risk

The CRC incidence in SPS is based on limited data with estimates varying from around 40% to 70%.58,59 Extra-colonic cancer risks do not appear to be increased in SPS.

Genetics

The genetic basis of SPS has not yet been established but there does appear to be about a 5-fold increased risk of CRC in first degree relatives of patients with SPS.56

Screening & Surveillance

Serial colonoscopy with polypectomy is recommended until all polyps ≥ 5 mm are removed, then colonoscopy every 1 to 3 years depending on polyp burden. Chromoendoscopy may improve polyp detection in SPS. If polyp burden cannot be managed endoscopically or if high-grade dysplasia is detected, patients should be referred for colectomy.

GENERAL APPROACH TO GENETIC COUNSELING AND TESTING IN CRC
INITIAL CLINICAL EVALUATION

Clinical evaluation for a potential hereditary CRC syndrome begins much in the same way as any other clinical encounter: with a careful history and physical examination. Primary care providers and general gastroenterologists play an integral role in initial risk assessment to determine which patients would benefit from referral to a genetics specialist.

History

Early-onset cancer is a hallmark of the hereditary cancer syndromes. Evaluation of persistent symptoms such as rectal bleeding is important even in young individuals and will occasionally identify a patient with a young- onset cancer due to a hereditary syndrome.

The most critical part of the history in evaluation for a hereditary syndrome is a thorough family history. It is important to obtain at least a cancer family history starting with the proband (the patient being evaluated) and extending to all first, second and selected third degree relatives. For each family member, it is important to document the age of diagnosis of all cancers and colonic polyps with number and histology if possible. It can also be helpful to document any benign conditions known to be associated with hereditary syndromes (such as osteomas, desmoid tumors, epidermoid cysts, etc).

Despite its critical importance in the evaluation of hereditary cancer syndromes, an accurate family cancer history is not obtained and/or used to assess risk and direct CRC screening.60-62 In theory, the electronic health record (EHR) systems should facilitate the collection and use of family history data. Although essentially all EHRs have a family history section the information collected varies, it may not be regularly updated and most EHRs have not yet incorporated family history data into clinical decision-making or provided screening alerts based on family history.62

Physical Examination

There are occasional instances when hallmark physical examination findings can suggest hereditary risk. Extra- colonic features of FAP that can be found on physical examination include the presence of jaw osteomas, epidermoid cysts or supernumery teeth. Presence of desmoid tumors (intra-abdominal or abdominal wall) can present as a mass. Though detailed opthomologic examinations may not be performed routinely, presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE) raises the suspicion of FAP. Thyroid pathology (nodules, hyperplasia) is found in approximately 36% of all FAP patients.63 Sebaceous adenomas or adenocarcinomas may be cutaneous signs of LS. If these features are detected on physical examination, it is important to take a detailed family history and consider referral for genetic evaluation.

When to Refer to a Genetic Specialist

It is becoming increasingly complex to determine when a patient is at risk for a specific hereditary cancer syndrome because of the increased number of hereditary CRC syndromes (Table 1) and the broadening and overlapping phenotypes of the syndromes.64-67 Thus, in addition to specific clinical findings for each syndrome detailed above, general guidelines can be utilized by primary care or screening endoscopy physicians (Table 5) to prompt a referral to a genetics expert. If a patient meets any of these criteria, it is very reasonable to refer to a genetics specialist who can expand and verify the cancer family history and then determine the best approach to genetic counseling and testing, if appropriate. Use of a simple screening questionnaire (Figure 1) can help identify these families.

Role of Genetic Counseling

Genetic counseling is critical to informed decision making about genetic testing. Pre-test genetic counseling involves: (1) collection (and often times verification by obtaining medical records) of a thorough multi-generation family history, (2) a risk-assessment to determine whether the family history is suggestive of a hereditary condition, (3) selection of what genetic test(s) to offer, (4) selecting which family member is most appropriate to test, (5) review of the suspected syndrome(s) and inheritance patterns, (6) accuracy and potential ambiguity of genetic tests, (7) possibility of genetic discrimination in life/long term care insurance, confidentiality, economic considerations (8) alternatives to genetic testing, (9) plans for how results will be interpreted and disclosed.64,65

Traditionally, determining which genetic testing to perform was based on the observed inheritance pattern, clinical presentation (polyposis vs non-polyposis) and histology (adenoma vs serrated vs hamartomas). Emerging data on new syndromes and the overlapping phenotype of the known syndromes highlights the risk of missing genetic diagnoses with a single-syndrome evaluation approach: this and the low cost of next- generation gene sequencing has driven the use of cancer gene panels when the clinical diagnosis is in doubt. Panel testing offers the advantages of increased diagnostic yield, decreased cost and decreased anxiety/testing fatigue with sequential testing but insurance coverage of panel testing is highly variable. If a panel testing is recommended, pre-test counseling should include the possiblity of unexpected findings (a pathogenic mutation in the gene that wasn’t considered on the basis of the family history), the potential for finding mutations in low penetrant genes that define a genetic risk but don’t change screening recommendations or finding variants of uncertain significance (VUS). VUS are defined as an alteration in the normal sequence of a gene whose association with disease risk is unknown. VUS rates with multi-gene panel testing are typically in the 10 to 30% range.66-68

Post-test counseling includes estimates of risk and screening recommendations based on the genetic results. Screening recommendations for specific syndromes can be provided (Table 1), the meaning of an unexpected result and the relevance of any VUS can be discussed. If no mutation is found, however, it does not mean that the patient and their family are not at increased cancer risk and screening recommendations should be based on their family history.

CONCLUSION

The clinical spectrum of the hereditary colorectal cancer syndromes is broad. In this review, we attempted to describe the major clinical features, to provide estimates of the cancer risks and summarize the range of screening recommendations for the major hereditary CRC syndromes. The goal of this effort is to provide primary care providers and general gastroenterologists with a guide to the identification of patients who should be referred to a genetics service for further evaluation, genetic counseling and possible genetic testing.

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Colorectal Cancer: Real Progress In Diagnosis And Treatment, Series #2

Colorectal Cancer Precision Medicine

May 2016 • Volume XL, Issue 5
William P.D. Hendricks,Daniel L. Edelstein

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Clinicians have long endeavored to tailor treatment to individual patients. Today, a new wealth of clinically correlated genomic research is uncovering diagnostic and prognostic genetic markers in addition to driving development of new treatments capable of exploiting tumor-specific vulnerabilities. Clinical cancer management is thereby becoming increasingly precise. Colorectal cancer (CRC) patients have particularly benefited from this paradigm. Genetic tests are now available as standard of care for prognosis and prediction of treatment response while emerging technologies and new targeted treatments hold out hope for significant improvements in patient outcomes. Clinicians can now employ several patient- specific tests such as RAS, BRAF, and microsatellite instability testing to assess risk, enhance prognosis, and predict response to therapy. Meanwhile, new technological paradigms such as the liquid biopsy hold out promise for enabling more precise non-invasive, real-time analysis of patient tumor burden. Here, we review CRC’s genetic basis, discuss diagnostic markers relevant to hereditary versus sporadic disease, summarize the recent data on CRC biomarkers, and point to new developments in CRC precision medicine.

William P.D. Hendricks, Ph.D.1 Daniel L. Edelstein, M.S.2 1Assistant Professor, Integrated Cancer Genomics Division, The Translational Genomics Research Institute (TGen), Phoenix, AZ 2Clinical Research Associate, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD

INTRODUCTION

Colorectal cancer (CRC) is a major worldwide public health problem with approximately 1.3 million new cases diagnosed per year.1 It is the second leading cause of cancer mortality in the United States where 1.2 million people are estimated to be affected with the disease.2 Disease stage at the time of diagnosis is the most significant prognostic factor3, but in spite of global screening efforts, 50% of patients will nonetheless either present with or later develop metastases.2,4 In patients with metastatic disease, selection of the most effective treatment strategy remains challenging. The management of patients with metastatic colorectal cancer (mCRC) has advanced significantly over the past decade with the pairing of advanced molecular diagnostic tools to targeted therapies. For example, therapies targeting the epidermal growth factor receptor (EGFR) have transformed mCRC treatment in many cases from non-specific cytotoxic regimens to precise and highly personalized treatments which target the unique genetic underpinnings of an individual patient’s tumor.

Although the management of CRC has improved significantly over the past decade, with five-year survival for patients with localized CRC now at 90%, this number drops to a dismal 10% in patients with metastases at diagnosis. As discussed elsewhere in this issue, advances in screening have largely been responsible for recent progress in reducing CRC mortality. Similarly, the wide availability of risk assessment tools such as genetic testing for hereditary CRC syndromes has increased the detection of familial CRC, thus allowing for early interventions and frequent surveillance to manage CRC risk. Screening has the potential to further dramatically reduce CRC mortality by facilitating detection of tumors at a curable stage. Yet, even with public education campaigns and the introduction of highly sensitive stool-DNA based diagnostics, adherence to screening guidelines is problematic. Regrettably nearly 50% of those at highest risk for developing CRC (individuals over the age of 50) are not screened and most patients are only diagnosed when symptoms present at advanced stage when the tumor is most difficult to treat.5 This situation highlights the need for ongoing innovations not only in CRC treatment, but also in non-invasive screening for early detection.

A Molecular Understanding of Colorectal Cancer

Cancer is fundamentally a genetic disease that arises as a consequence of the accumulation of mutations in genes that regulate cell growth and death. Progress in cancer medicine now depends on identification of these causative mutations alongside determination of their relationship to clinical phenotypes and development of drugs that are selectively toxic in defined mutational contexts. Explosive growth in the understanding of cancer’s genetic basis over the past decade enabled by high-throughput genome sequencing technology has revealed that most cancers are far more complicated than anticipated. A great diversity of mutations exists both within specific tumor types as well as within individual patient tumors themselves.

CRC has long been one of the best understood cancers according to its genetic progression. It was additionally one of the first cancers to undergo comprehensive genomic analysis as early as 2006.6 The CRC mutational landscape has since been exhaustively studied. Understanding of this landscape has radically transformed CRC classification, fueling treatment individualization that ultimately holds out the best hope for improvements in patient survival when screening and prevention fail. This approach is not new to CRC. Clinicians have historically relied on histopathology reports of tumor features and staging according to the TNM (Tumor, Node, Metastasis) system to inform design of treatment regimens. However, the current depth of this individualization is driven by genomic knowledge and advanced diagnostics, both of which enable tumor characterization according to genetic features that may differ dramatically even within similar histological subtypes The initiation and development of malignant CRC results from the stepwise accumulation of genetic events that transform normal epithelial tissue first into a benign polyp and then eventually into an invasive colorectal tumor.7 This multistep process typically proceeds over decades as mutations accumulate, deactivating critical tumor suppressor genes that keep cell growth in check and activating tumor promoter oncogenes that drive growth and invasion into normal tissue, and spread to distant sites. In this traditional model, key events include inactivation of the tumor suppressor genes APC, TP53 and/or PTEN, by which a loss of function transforms normal colonic mucosa into an adenoma. Further downstream, the activation of oncogenes such as KRAS, NRAS, BRAF and/or PIK3CA stimulates aberrant growth of the adenoma that, when coupled with genetic deletions of chromosome 18q, facilitates the final transition from adenoma to carcinoma.7,8

Comprehensive genomic sequencing of large cohorts of CRC tumors has now confirmed CRC is a heterogeneous genetic disease with substantial differences in tumors even of the same subtype.9-11 Mutations in tumor suppressor genes and oncogenes as outlined above (in addition to other mutations) are found at variable frequencies in CRC tumors as are other types of molecular alteration such as methylation and gene expression. In the research setting, many such alterations are being assessed for their impact on tumor biology, potential correlations with clinical phenotypes, and their druggability. While many such novel findings are also currently under evaluation in clinical trials, a key set of foundational molecular markers have already been successfully translated to a CRC classification system to improve prognostic determinations and guide the administration of targeted therapy in routine clinical practice. This article will provide a review of those molecular markers in routine use for treating advanced disease with a look to the future implementation of advanced diagnostic technologies for managing the complex dynamics of tumor evolution in real-time.

Hereditary and Sporadic Disease

The majority of CRC cases are due to sporadic genetic alterations that occur in somatic cells. However, up to 15-20% of all CRC cases have a hereditary component. In CRC, inherited or somatic mutations occur within the colonic epithelium to direct the transformation of a benign polyp into an invasive colorectal tumor. Two of the most common hereditary colorectal cancer syndromes, Familial adenomatous polyposis (FAP) and Lynch Syndrome (LS) have significantly different clinical phenotypes yet increase the lifetime risk of CRC to 80% in HNPCC12 and 100% in FAP. Both syndromes are inherited in an autosomal dominant manner associated with specific germline mutations that significantly increase the risk of colorectal polyp and CRC development early in life. LS is typically caused by mutations in one of the mismatch repair (MMR) genes (MLH1, MLH3, MSh3, MSH3, MSH6 or PMS2) and FAP results from a mutation in APC. These alterations are detectable with widely available germline genetic testing, results of which are evaluated in consultation with a physician and genetic counselor who consider an individual’s family history and clinical symptoms. Germline genetic testing represents the first major advance in individualizing the management of CRC through the use of genomic information and is described in detail elsewhere in this series.

The individualized management of patients with sporadic CRC is achieved with the use of tumor-specific prognostic and predictive biomarkers. The distinction between prognostic and predictive markers is important. Prognostic markers provide an indication of the likely progression of disease whereas predictive markers predict response to treatment. An individual biomarker may have both prognostic and predictive clinical value. Such biomarkers are traditionally detected by the analysis of tumor tissue. However, recent advances in molecular diagnostics have led to wide clinical availability of blood-based and other minimally invasive methods of biomarker evaluation.13 Although this technology is just now emerging for clinical use, blood-based diagnostics may soon simplify the process of detecting the presence of a tumor, monitoring response to therapy, and detecting recurrences, enabling new possibilities for monitoring disease status and modulating therapy in synchrony with ever-changing tumor dynamics.13

CRC Biomarkers

In clinical practice, advanced colorectal tumors are treated according to their molecular classification. The extensive and growing list of mutations and mutational profiles associated with specific colorectal tumor types, their clinical course, and their response to therapy has produced three predictive standard of care tests that are recommended by the NCCN Clinical Practice Guidelines in Oncology for Colon Cancer for use in clinical practice: RAS mutation analysis, BRAF mutation analysis, and Microsatellite Instability (MSI) or MMR testing.14 These tests will be discussed in terms of their clinical context, their biology, and the evidence for their recommended use (Table 1).

RAS Testing and Anti-EGFR Therapy

The rat sarcoma virus (RAS) gene signaling pathway plays an important role in the pathophysiology of CRC, with RAS mutations occurring in approximately 55% of mCRC patients. RAS comprises a family of genes including KRAS, NRAS and HRAS, which, under normal biological conditions mediate extracellular signaling from the epidermal growth factor receptor (EGFR) to deliver intracellular growth signals to the nucleus. In a tumor cell, the constitutive activation of RAS via mutations at specific hotspots such as one occurring in the gene’s second exon (exon 2 RAS mutations) disrupts this normal signaling pathway to drive aberrant growth and metastases. Numerous Phase II and III randomized controlled trials have demonstrated the benefit of anti-EGFR monoclonal antibodies such as cetuximab and panitumumab as single agents or in combination with other chemotherapeutic regimens in mCRC patients.15-19 However, in patients whose tumors harbor KRAS mutations, these drugs have been shown to be ineffective.1-5 The selection of patients lacking KRAS exon 2 mutations (i.e. KRAS exon 2 wild-type patients) was shown to increase response rates to anti-EGFR therapy by as much 60%.20,21 This finding reinforces the approach of incorporating highly specific molecular diagnostics into routine clinical practice.

With KRAS exon 2 mutation analysis widely incorporated into clinical practice for predicting lack of response to anti-EGFR therapy, it became clear that not all KRAS exon 2 wild-type patients responded to treatment. Further refinement in biomarker testing was pursued to improve patient outcomes and avoid unnecessary treatment-related side-effects and costs. Preclinical evidence showed that additional KRAS hotspot mutations such as those occurring in KRAS exons 3 and 4 and in the alternative RAS gene, NRAS, were similarly oncogenic to KRAS exon 2 mutations and conferred resistance to EGFR antibodies.22,23 Thus, a series of retrospective evaluations were performed on tumor specimens selected from clinical studies which had initially demonstrated the predictive value of KRAS exon 2 for response to anti-EGFR therapy. KRAS exon 2 wild-type tumors were evaluated for other RAS mutations and correlated to response to anti-EGFR therapy from numerous clinical trials including PRIME, OPUS, CRYSTAL, CALGB/SWOG-80405, FIRE-3, COIN, PEAK, PICCOLO, 20050181 and 20020408. In aggregate, data from all studies showed that a more comprehensive analysis of RAS mutations, so-called “expanded RAS” including KRAS and NRAS codons 12 and 13 (exon 2), 59 and 61 (exon 3), and 117 and 146 (exon 4), can identify an additional 11% of patients for which anti-EGFR therapy is contraindicated.24

RAS genotyping of primary or metastatic tumors is strongly recommended in patients with mCRC and should be administered as a standard of care test since there is minimal rationale for patients with mutated RAS to endure the toxicity and expense of treatment with anti-EGFR therapy. Figure 1. illustrates the shift in our understanding of RAS. Incorporation of expanded RAS testing into routine practice is expected to increase the proportion of patients ineligible for anti-EGFR therapy from approximately 40% to 55%.24 Current clinical practice guidelines, including the 2016 NCCN CRC guidelines and the American Society of Clinical Oncology (ASCO), now recommend expanded RAS analysis be performed to more precisely identify patients for anti-EGFR therapy.14,25 If RAS is wild type, BRAF testing should be considered as discussed below.

BRAF

BRAF is an oncogene mutated in 5-10% of CRCs. It lies downstream of RAS in the same growth pathway that is activated upstream by EGFR signaling. BRAF codon 600 mutations are early events in CRC tumorigenesis and are typically mutually exclusive with RAS mutations. Currently BRAF is considered a prognostic marker. Patients with BRAF V600E mutations have shorter progression-free survival (PFS) and overall survival (OS), by approximately 15 months, as compared to wild-type patients26. BRAF also has diagnostic value in evaluating Lynch Syndrome because BRAF mutations have been shown not to occur in LS tumors.27 Therefore in the clinical workup of a CRC tumor, the detection of a BRAF mutation alongside microsatellite instability informs the clinician against the diagnosis of LS.28 The workflow for diagnosing hereditary colorectal cancer is discussed elsewhere in this series.

As a predictive marker for anti-EGFR therapy, studies of patients with BRAF mutations have shown mixed results largely due to the small numbers of patients evaluated. Early studies pointed to a predictive role for BRAF mutation status in relation to first-line anti-EGFR therapy. However, recent data from CRYSTAL and OPUS clinical trials demonstrates lack of a relationship between BRAF and cetuximab in the first-line setting29,30 In a retrospective analysis of 370 patients treated with anti-EGFR therapy, BRAF mutations were observed in 6.5% of patients with a treatment response of 8.3%, significantly less than in patients with wild-type BRAF.31 While these results appear to substantiate the value of BRAF as a predictive marker for anti-EGFR therapy, the patient population was small and further clinical studies are required. The strong prognostic value of BRAF as a marker of rapid progression and inferior survival presents a chief challenge in validating the predictive effect of BRAF for anti-EGFR therapy. Any benefit from anti-EGFR seems minimal for patients with BRAF mutations as studies have consistently shown that the addition of anti-EGFR therapy to chemotherapy in first- and subsequent-line treatment does not increase OS or PFS.32

While the predictive value of BRAF for anti- EGFR therapy remains controversial, the clinical utility of BRAF inhibitors in combination with anti- EGFR therapy is currently being explored in clinical trials with promising preliminary results. Hoping to replicate the exceptional efficacy of BRAF inhibitors in BRAF-mutant melanoma, early clinical trials of single- agent BRAF inhibitors in mCRC were disappointing. However, the administration of BRAF inhibitors in combination with anti-EGFR therapy in patients with BRAF mutant mCRC has shown responses in 35% of patients in one study33 and 13% of patients in another.34 These promising results for patients with otherwise dismal responses has led to the launch of a Phase II study of irinotecan and cetuximab +/- vemurafenib in patients with BRAF-mutant mCRC.33 Current clinical practice guidelines recommend BRAF testing for its prognostic value, although it may very well have predictive value in identifying patients for clinical trials evaluating dual BRAF/EGFR inhibition.

Microsatellite Instability

Microsatellite instability (MSI) is a colorectal cancer phenotype and form of genetic instability caused by inactivating alterations in genes of the DNA mismatch repair (MMR) system. The MMR system normally functions to recognize and repair nucleotides mismatched by DNA polymerase. A defective MMR system leads to stretches of repetitive DNA sequences (microsatellites) and instability (MSI). All patients with hereditary Lynch Syndrome and approximately 15% of sporadic CRC patients exhibit MSI and a defective MMR system. In LS the loss of mismatch-repair function is due to an inherited germline mutation in one of the MMR genes (MLH1, MSh3, MSH6 or PMS2). In sporadic CRC, MSI appears to be due to epigenetic modification of the MLH1 gene,35 MSI tumors present with distinct clinical and histologic features including the tendency to occur predominantly in the proximal colon, poor differentiation, lymphocytic infiltration and a signet-ring mucinous histology.35 In both sporadic and familial tumors, the loss of MMR function is readily assessed by either molecular MSI testing with PCR or immunohistochemical analysis (IHC). Molecular MSI analysis is performed by comparing a panel of five microsatellite markers from both tumor and normal tissue. The size of the microsatellite fragments are evaluated and assigned a level of stability according to criteria established by the National Cancer Institute (NCI). Samples with instability in two or more markers, or<30% of the markers, are defined as MSI-H (high- frequency MSI). Samples with one unstable marker are designated MSI-L (low-frequency MSI) and samples with no instability in any of the markers are microsatellite stable (MSS). IHC analysis can also be used to determine MMR function by confirming the presence or absence of each of the four MMR gene protein products from a tumor tissue sample. Molecular MSI testing is currently considered the gold standard, though IHC offers good sensitivity and specificity.37 Both tests should be performed in a CLIA certified lab experienced with these methods.

MSI-H status has traditionally been used as a positive predictor to select patients for germline genetic testing for LS, however it has also recently been shown to correlate with patient survival and serve as a positive prognostic marker in sporadic CRC. Multiple studies have shown that patients with MSI-H tumors had better prognosis than those with MSS tumors.38 MSI-H was shown to be an independent prognostic marker associated with tumors that were less prone to lymph node involvement and metastases, indicating a favorable outcome compared to tumors with MSS. Determination of MSI status is useful for stage II CRC patients, for whom the benefit of adjuvant therapy is often unclear, given their low risk of recurrence. Overall, MSI-H status has shown excellent clinical utility in identifying stage II patients with good prognosis who are unlikely to derive benefit from 5-fluorouracil adjuvant chemotherapy.39,40

MSI status is now additionally guiding new developments in immunotherapy. Immune therapies which are able to activate the patient’s own immune system against their tumor (e.g. “checkpoint blockade” with the anti-CTLA4 antibody ipilimumab or the anti-PD1 antibody nivolumab) have begun to show extraordinary activity in some cancers such as melanoma and lung cancer.41,42 Significant correlations between high mutational burden and response rate to checkpoint inhibitors have been shown in lung cancer and melanoma.43 Similarly, the overall better prognosis for MSI-H patients has been partially attributed to its correlation with increased tumor T-cell infiltration. This effect is thought to be driven by the increased mutational burden characteristic of tumors with defective MMR.44 Somatic mutations in coding regions by definition create protein sequences that are foreign to the host and are immunogenic (or, immunologically speaking are “non-self” or neoantigens). They have the potential to be processed by intracellular antigen presentation machinery and presented to the immune system thereby triggering an immune response.45 Indeed, studies have shown that somatic mutation burden in tumors with MMR defects (1,782 mutations per tumor) is significantly higher than that in MMR-intact tumors (73 mutations per tumor).46 Clinical trials are now testing these agents in MSI-H patients. A Phase II study of the anti-PD-1 antibody pembrolizumab in MMR-deficient versus MMR-intact patients with progressive disease found significantly better outcomes for MMR-deficient (immune-related overall response rate of 40%, PFS 78%) versus MMR-intact (immune-related overall response rate of 0%, PFS 11%) with data on PFS and OS still being collected for MMR-deficient patients. As in lung and melanoma studies, high mutational burden was correlated with response. Additional Phase II trials such as KEYNOTE-164 (pembrolizumab) and Checkmate 142; NCT02060188 (nivolumab) are also testing this approach in MMR-deficient CRC. Thus, molecular MSI analysis should now be used to identify candidates for checkpoint inhibitor treatment.

Advanced Molecular Diagnostics and Targed Therapy

New technologies are now shaping the next generation of tests that will improve clinical management of CRC patients. One such technological paradigm is the liquid biopsy, which exploits the fact that as tumor cells die, they release mutant gene fragments into circulation. The basis for this approach derives from the unique observation that patients with cancer have markedly higher concentrations of cell-free DNA (cfDNA) than healthy individuals.47 As an alternative and complement to tumor tissue genotyping, analysis of tumor DNA derived from plasma of patients with mCRC has been shown to provide a rapid genotype result which accurately reflects the mutation status of tumor tissue.48,49 Current evidence has shown that tumor cfDNA is more readily detected in the blood of patients with more invasive rather than earlier tumors, making it an excellent tumor marker in patients with metastatic disease.48,50 This liquid biopsy approach to genotyping of a patient’s systemic tumor burden can enable a real-time assessment of tumor evolution and response to therapy in contrast to reliance on single site tissue biopsies acquired at diagnosis.

Molecular heterogeneity may pose a diagnostic challenge for managing mCRC patients eligible for surgical resection. For example, patients whose primary tumors revealed RAS mutations may have metastases without RAS mutations, and vice-versa.

A unique feature of blood-based tumor genotyping is its ability to evaluate the extent of an individual patient’s systemic tumor burden (e.g. identifying any mutant RAS even in the absence of such mutation in the primary tumor) thus eliminating tumor biopsy issues related to tissue molecular heterogeneity.48,49,51-56 In the case of anti-EGFR therapy, blood-based RAS mutation testing is particularly useful for systemic assessment of tumor heterogeneity where RAS testing of a single tumor sample may not accurately reflect the RAS mutational status of the patient’s overall disease burden.13 Moreover, comprehensive assessment of RAS status by testing multiple tissue samples is neither practical nor feasible. Heterogeneity within individual tumors or tumor samples may also be substantial. Some reports have demonstrated that testing of DNA from a single colorectal tumor tissue block will wrongly assign KRAS wild-type status in 8-11.6% of patients.57-59 Studies evaluating intertumor heterogeneity between primary tumors and metastases in the same patient have shown that the mutational discordance can be found in 3.6-32.4% of cases.60-66 Both inter- and intratumor heterogeneity are inherent features of metastatic disease67-69 and though outcome studies are just now being performed, preliminary results of select patients support the utility of a liquid biopsy to overcome sampling bias associated with single tumor site specific sampling.70

In spite of the significant therapeutic advances made by targeting EGFR pathways, any clinical benefit is often short-lived due to the inevitable emergence of drug resistance. In RAS wild-type mCRC patients receiving anti-EGFR therapy, the detection of RAS mutations has been associated with disease progression.51,52,54 In fact, using a liquid biopsy approach, independent research has demonstrated that RAS-mutant tumor DNA is detectable in plasma several months in advance of radiological progression,49,51 a key insight that may lead to a refinement in the timing of subsequent treatments. As blood-based approaches allow for longitudinal monitoring of rising or falling levels of genetic mutations linked to resistance or susceptibility to targeted therapies, new clinical decision points will be illuminated.

Meanwhile, new innovative clinical trials aimed at assessing the efficacy of matching targeted therapeutics to genomically defined tumors are ongoing. These include the NCI-Molecular Analysis for Therapy Choice (MATCH) program (which focuses on multiple tumor types including CRC71), the CRC-specific FOCUS 4,72(p4) and SPECTA studies.73 Overall, the pairing of advanced diagnostics with new molecularly targeted therapeutics will ultimately deliver the promise of highly precise treatment individualization, leading to the improved management of and significantly better outcomes for mCRC patients.

Additional Prognostic and Predictive Individualized Tests

There are several additional marketed tests based on genetic and molecular profiling that are intended to provide prognostic or predictive information for the individualization of CRC management, but whose utility in the clinic is still controversial. Such tests include Theraguide 5-FU, Oncotype Dx, ColoPrint, and circulating tumor cell (CTC) analysis. Theraguide 5-FU, recently discontinued by Myriad Laboratories, but still available from other reference laboratories, categorizes risk of 5-FU toxicity into “high,” “moderate,” “low,” or “indeterminate” based on detection of variations in two genes involved in fluoropyrimidine metabolism. The test is indicated for patients experiencing severe toxicity after receiving 5-FU in order to adjust dosage or choose an alternative regimen. Overall, the use of Theraguide 5-FU is controversial as there are no data from prospective randomized trials to demonstrate its impact on improving toxicity without compromising efficacy, thus the test has not yet been widely adopted in the clinic. Though not intended for use in mCRC, Oncotype Dx and ColoPrint are prognostic tests that use gene expression profiling for stage II CRC. These tests evaluate expression of specific gene collections in CRCs that can be correlated to tumor behavior to evaluate risk of recurrence and possibly select low-risk patients who can be spared chemotherapy. Although an Oncotype Dx gene expression profile has been accepted by ASCO and the NCCN as standard of care in breast cancer for the prediction of recurrence in specific contexts, neither of these tests has experienced widespread clinical adoption for CRC since their absolute prognostic and predictive value is still unclear. Both require further validation in prospective trials. Finally, CTC analysis identifies and quantifies CRC cells in the plasma through the identification of tumor specific cell surface markers. Though the US Food and Drug Administration has approved certain methods for identifying CTCs, current guidelines do not recommend using CTCs to assess prognosis or to guide therapy selection due to their low sensitivity and specificity as well as a lack of clinical data. Ongoing evaluations may yet confirm some of these tests for standard of care.

CONCLUSION

An individualized approach to managing colorectal cancer is gradually becoming an integral component of care. This approach will eventually result in more effective treatment with fewer side effects and will promote a more active role for patients in making decisions related to their health care. Future research promises to improve our understanding of the differences between those patients whose cancers respond favorably to certain therapeutics and those that do not. Just as pathology has been used to determine the stage of a colorectal cancer and subsequent prognosis for patients, molecular tools will be increasingly utilized to provide highly specific information to accurately diagnose and treat colorectal cancer. The advent of individualized medicine, while relatively new to CRC medicine, presents patients and physicians with a complex set of tools that when properly utilized, can lead to better treatment outcomes for those with cancer and provide important information for managing and largely eliminating the risk of cancer in hereditary conditions.

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Inflammatory Bowel Disease: A Practical Approach, Series #99

Infliximab in the Home – Does it Affect the Health-Related Quality of Life of Pediatric Patients with Inflammatory Bowel Disease?

May 2016 • Volume XL, Issue 5
Elaine Barfield,Aliza Solomon,Robbyn Sockolow

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Inflammatory bowel disease is characterized by an unpredictable course of relapsing and remitting symptoms often treated with infliximab. Historically infliximab was administered in the hospital setting or infusion centers. However, recently some providers have prescribed infliximab via home infusions. The goal of this study was to compare health-related quality of life in pediatric patients receiving infliximab in the home compared to those receiving infliximab in our hospital infusion center.

Elaine Barfield, MD Aliza Solomon, DO Robbyn Sockolow, MD Division of Pediatric Gastroenterology and Nutrition, Weill Cornell Medical College, New York, NY

Source of support: National Center for Advancing Translational Science of the National Institute of Health under award number UL1TR000457. Objectives

Inflammatory bowel disease is characterized by an unpredictable course of relapsing and remitting symptoms often treated with infliximab. Historically infliximab was administered in the hospital setting or infusion centers. However, recently some providers have prescribed infliximab via home infusions. The goal of this study was to compare health-related quality of life in pediatric patients receiving infliximab in the home compared to those receiving infliximab in our hospital infusion center. Methods

Inclusion criteria included English-speaking patients ages 9-17 years with a confirmed diagnosis of inflammatory bowel disease who were adherent with infliximab infusions. At subsequent visits, subjects (home infusions) and controls (hospital infusions) completed the IMPACT III, a self-administered health-related quality of life questionnaire. Results

38 patients (18 subjects, 20 controls) were included. Of the participants, 43 had Crohn’s, 3 had ulcerative colitis and 2 had indeterminate colitis. The mean age at diagnosis was 11.5 years. Across the 6 domains assessed by the IMPACT III, there were no significant differences in health-related quality of life between subjects and controls. Conclusions

While home infusions allow patients to receive therapy in comfortable settings at convenient times, location of infusions did not affect health-related quality of life scores. Despite this, home infusions are a convenient alternative to hospital-based infusions that should be considered in the patient requiring long-term therapy with infliximab. Measuring health-related quality of life in pediatric patients with inflammatory bowel disease may allow clinicians to identify additional needs and provide supplementary resources to improve their overall well-being. INTRODUCTION

Inflammatory bowel disease (IBD) is a constellation of chronic, inflammatory diseases of the gastrointestinal (GI) tract that is characterized for many individuals by an unpredictable course of relapsing and remitting symptoms.1 Given that IBD in children is commonly more aggressive than in adults, pediatric patients often require therapy with biologics such as infliximab. Infliximab is a chimeric mouse/human IgG1 monoclonal antibody that binds selectively and with great affinity to cell-bound and circulating tumor necrosis factor- alpha (TNF-alpha) which thereby acts to reduce the inflammatory effects of TNF-alpha in patients with IBD.2

Historically, infliximab has been administered in hospital or clinic-based infusion centers. Pressure to reduce length of inpatient stay and to provide cost- conscious care in the 1980s prompted the development of alternative sites for the administration of various types of infusion therapy. Among these alternatives were companies providing home infusion services for therapies with the administration of total parenteral nutrition (TPN), antibiotics and anti-neoplastic agents.3 According to the National Home Infusion Association, over 80,000 patients receive home infusions each year for various indications. It is currently estimated that the alternate-site infusion therapy sector represents approximately $9 – 11 billion dollars a year in U.S. health care expenditures with infusions serviced by over 1,500 infusion pharmacies.4 Despite the convenience and other potential benefits of home infusions, many providers are unwilling to consider this option for fear of safety or compliance issues.

Demand for home administration of other therapies such as biologics has increased over time.3 Home infusions have allowed patients and families to avoid frequent visits to hospital or clinic-based infusion centers. Buisson et al. found that 137 adult IBD patients receiving infliximab spent a median of 6.5 hours outside their home for each infusion including transportation to and from the hospital and time for medication administration.

A large number of patients with IBD in our practice receive infliximab infusions through our home infusion program which was established several years ago. Little has been published on home infusions in the treatment IBD in the pediatric population. In 2004 Condino et al. conducted a retrospective chart review of 10 patients who received home infusions over the course of two years.5 A total of 59 home infusions were administered with a dosing range of 7.5 to 10mg/kg/ dose. The calculated average savings per patient by having the infusion in the home was $1335 per vial (100mg) of infliximab and school absenteeism was decreased. Their conclusion was that home infusions are safe, cost-effective and preferred by patients and families. Limitations of this study included the small sample size and lack of a control group with whom to compare various factors including drug cost, safety, patient satisfaction and school absenteeism.5

Quality of life is a term that describes an overall sense of well-being. Health-related quality of life (HRQOL) is a subset of quality of life that has evolved since the 1980s and has gained acceptance as a measureable outcome.6 It is defined as one’s subjective perception of the effect of a chronic disease on his or her physical, psychological and social well-being.7 It is also defined as a measurement of the impact of a chronic disease by incorporating not only physical well-being but also the mental state, amount of social support, effect of treatment and presence of complications.8 HRQOL therefore provides a more global assessment of health and can be used to determine additional patient needs and support.8

The present study compared the experiences between patients receiving infusions at home versus those receiving therapy in our hospital infusion center. The primary objective was to evaluate the HRQOL between the groups. Materials and Methods

This study was approved by the Weill Cornell Medical College Institutional Review Board. With regard to ethical considerations, we ensured the quality and integrity of our research by obtaining informed consent and assent, respecting the confidentiality of our subjects and ensuring subjects participated voluntarily.

The IMPACT is a self-administered, disease- specific HRQOL questionnaire designed specifically for children and adolescents with IBD.8 The original IMPACT was developed in 1999 by Griffiths et al. and the IMPACT III was adapted from the IMPACT II in 2002. The original language for the questionnaire was English however it has now become available in several other languages after going through a process of linguistic validation. The questionnaire is a valid and reliable reflection of HRQOL in children with IBD ages 9-17 years and is designed for a recall period of 2 weeks. The questions cover six domains including bowel symptoms, systemic symptoms, emotional functioning, social functioning, body image and treatment/interventions. The questionnaire is comprised of 35 questions with five Likert style responses per question each of which are assigned a score from 1 to 5. The responses from all 35 questions are summed to generate a total score with higher scores correlating with better quality of life. Individual domain scores can also be determined by summing the responses for questions based on their assigned domains.

We obtained written permission to use the IMPACT III questionnaire from the original authors. At a subsequent office visit, the IMPACT III questionnaire was completed by subjects and controls after obtaining consent and assent to participate. Inclusion criteria for the study included English-speaking patients between the ages of 9 and 17 years with a confirmed diagnosis of IBD who were receiving infusions of infliximab either at home (subject group) or in our hospital infusion center (control group). Patients also had to have demonstrated adherence with infusions and parents and patients had to provide consent and assent, respectively, to participate. All patients were receiving maintenance infliximab; none were in the induction phase. Exclusion criteria included patients with IBD outside of the desired age range or patients with poor adherence with infusions. Patients with ostomies or other significant concomitant illnesses were also excluded as the validity for the IMPACT-III has not yet been established in these populations. Ethical Considerations

The study involved minimal risk to the participants. Subjects and controls were enrolled only after understanding the nature of the study (which involved completing a questionnaire), and only after providing informed consent/assent to participate. Statistics

Study data were collected and managed using the REDCap (Research Electronic Data Capture) electronic data capture tool hosted at Weill Cornell Medical College.9 REDCap is a secure, web-based application designed to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for importing data from external sources. REDCap is supported by the Clinical and Translational Science Center Grant UL1 TR000457. SAS 9.3 (SAS Institute, Inc, Cary, NC) was used for statistical analysis.

Due the non-normal distribution of quality of life scores on the IMPACT III questionnaire, a non- parametric test – the Wilcoxon Rank Sum test – was used to assess the differences between subject and control groups. A two-sided alpha level of 0.05 was used as a cut-off to declare statistical significance. The criterion for statistical significance was defined as a P value of<0.05. Results

Review of the electronic medical record revealed 41 patients who met criteria for the study. Three were eliminated due to either patient or parent preference. Of the 38 patients enrolled, 33 had CD, 3 had UC and 2 had indeterminate colitis. The mean age at diagnosis was 11.5 years (range, 9 to 17 years). There were 18 subjects and 20 controls. Baseline characteristics of study participants are summarized in Table 1.

All 38 patients completed the IMPACT III self- administered questionnaire. The highest possible score for the 35 questions was 175 as each question had a maximum score of 5 points. The median total score for the subject group was 145.5 (minimum 84, maximum 164) versus 151.5 (minimum 103, maximum 167) for the control group (p=0.49). The p values were not significant for subject versus control group median values among the six individual domains suggesting that there was no significant difference in the HRQOL among domains between the groups (Table 2).

DISCUSSION

At the time this was written, we were treating 38 patients with home infusions and 37 patients with hospital-based infusions (with 5 hospital-based patients planning to switch to home infusions per family preference). We utilize several home health care companies that provide the nursing care, supplies and medications necessary for home infusions. “Home” infusions may take place at home, work, camp, or in the university setting (either dorm or campus health clinic) for our college aged patients. Our protocols for home and hospital administration of infliximab are identical in terms of Infliximab in the Home

The routine blood work drawn prior to infusions, the rate of the infusions and the use of diphenhydramine as a pre-medication to decrease the likelihood of infusion- related reactions. Nurses are present for the duration of home infusions and therapies for resuscitation or anaphylaxis including intravenous fluids and intramuscular epinephrine are readily available as is the case in the hospital infusion center.

Our results showed no significant difference in HRQOL between patients receiving infliximab infusions at home versus in the hospital infusion center. Initially this was surprising as patients and families often relay how appreciative they are to receive infusions in the home. Home infusions enable them to avoid missing school, remain in their extracurricular activities, and reduce travel time to the infusion center. Many patients also relay that receiving infusions in the comfort of their homes reduces patient anxiety of coming to the hospital and being around other patients who may be ill. Parental missed days of work may also be avoided as the scheduled home infusions often occur in the evenings or during weekends. Our results however suggest that despite these factors related to the convenience and comfort of having infusions in the home environment, patients’ perceptions of their overall functionality across the six domains do not differ from those of patients who receive hospital infusions. In other words, providing flexibility and an element of convenience with regard to location of infusions did not impact HRQOL in our patients. One reason for this could be that the location of infusions does not mitigate the burden of disease or eradicate the unpredictable and isolating nature of IBD which is likely present among both groups regardless of infusion location. Younger patients may not appreciate the benefits of avoiding school and work absences and avoiding the inconvenience of traveling to the hospital and exposure to other sick individuals that they avoid by having infusions in the home.

The ability to measure HRQOL broadens the traditional markers of health status in IBD and allows the clinician to appreciate how patients function on a day to day basis and to understand how they cope with having a chronic disease.10 Many measures of HRQOL exist mainly in the form of relatively short questionnaires and when possible, self-report is preferred over parent-proxy report.7 Increased disease activity has been shown to correlate with poor HRQOL, poor functioning across psychosocial and physical health domains, and the use of less adaptive coping strategies.7 The Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI) are used to track disease activity over time by incorporating symptoms, physical exam findings and laboratory values into an overall score; however, while measuring functionality and activity, these indices do not specifically address quality of life or emotional well-being. A disease activity index score correlating to remission is less meaningful if a patient is suffering from poor HRQOL as manifested through subclinical depression or poor functionality across various life domains. Given this, measuring HRQOL allows the clinician to delve deeper beyond disease activity indices and laboratory values in order to hone in on patients’ emotional well-being.6 Without screening for HRQOL clinicians may overlook a subgroup of patients with subtle needs and may miss critical opportunities to offer resources or referrals for additional psychological, educational or social services.1

There are important limitations to consider for this study which may affect the validity or generalizability of the findings. The first limitation is the small sample size. One factor that contributed to this was the exclusion of patients outside the age range of 9-17. Elimination of patients based on age was done because the IMPACT III is valid only for the specific age range of 9-17 years. In the future another measure of HRQOL such as the IBD Questionnaire (IBDQ), a valid and reliable self- administered tool to assess health-related quality of life in the older population, could be employed so that the older patients could be included.11 Additionally, subjects and controls were asked to complete the IMPACT III only once during the study. Although the IMPACT III has been shown to be a valid and reliable self-assessment tool, there was likely an element of recall bias given that patients were asked to recall their symptoms and subjective feelings over the prior 2 week period. It would be more valuable to implement the IMPACT III at more frequent time intervals to see whether HRQOL changes over time and is correlated with disease remission or flares.

Ryan et al. examined the clinical utility of youth and parent proxy-reported HRQOL screening in pediatric patients with IBD. They found that HRQOL was correlated with health care utilization such that over one year, lower HRQOL at baseline was associated with more IBD-related admissions, psychology clinic visits, emergency department visits, referrals for pain management, and telephone encounters to the clinician.1 These trends are consistent with findings in the adult chronic illness literature.1 While poor HRQOL is associated with increased use of health care resources, improvement of patients’ functional and health status has been shown to reduce health care costs over time.1 If assessing HRQOL with a relatively short, self- administered questionnaire at the time of routine visits can identify patients who are prone to utilize more healthcare services, this would be a valuable tool for clinicians to use to regularly monitor such patients so that they can intervene and potentially provide preventative services in a timely manner.

In summary, while home infusions allow patients to receive therapy in comfortable settings at convenient times, location of infusions did not affect HRQOL scores. Despite this, home infusions are a convenient alternative to hospital-based infusions that should be considered as an option in the patient requiring long-term therapy with infliximab. Additionally, incorporating measures of HRQOL into clinical visits for patients with IBD may allow clinicians to identify additional needs and provide supplementary resources and support to improve the functional and health status of these patients. Acknowledgements

The authors thank Dr. Zhengming Chen from the Weill Cornell Medical College Clinical and Translational Science Center (CTSC) for his statistical analysis and contribution and Dr. Stanley Cohen for his guidance. Research reported in this publication was supported by the National Center for Advancing Translational Science of the National Institute of Health under award number UL1TR000457.

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A Case Report

Infliximab-Induced Interstitial Pneumonitis in a Pediatric Patient with Ulcerative Colitis

April 2016 • Volume XL, Issue 4
Tanaz Farzan Danialifar,Hillel Naon,Shengmei Zhou

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Interstitial pneumonitis secondary to infliximab therapy has been described in adults with inflammatory bowel disease or rheumatologic disease. In this article we describe the first reported case of a pediatric patient developing interstitial pneumonitis secondary to infliximab therapy and highlight the presence of human anti-chimeric antibodies (HACA).

Tanaz Farzan Danialifar, MD and Hillel Naon, MD, Division of Gastroenteroogy, Hepatology and Nutrition, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California; Shengmei Zhou, MD, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California

CASE PRESENTATION

A 12-year-old Hispanic female was diagnosed with severe pancolitis secondary to ulcerative colitis (UC). She received an initial induction dose of infliximab 5mg/kg with minimal clinical response and received an increased dose of infliximab 10mg/kg after 4 days. Prior to initiation of infliximab she had a normal chest radiograph and negative QuantiFERON®-TB Gold. Two days after the second dose of infliximab she continued to have minimal clinical response and methylprednisolone 20 mg intravenously twice daily was commenced. Within 5 days she had significant clinical response and was transitioned to oral prednisone 20 mg twice daily. She received subsequent 10mg/kg infliximab doses at weeks 6, 10, 14, and 22 (delay was secondary to missed infusion appointment). Prednisone taper was initiated at week 6 and completed by week 14. The patient remained in clinical remission.

Three weeks following the last dose of infliximab the patient began to develop shortness of breath with exertion and infliximab dose was withheld while further evaluation was initiated. Due to progressive symptoms of dyspnea at rest and hypoxia (oxygen saturation of 87% at room air), she was hospitalized six weeks following final dose of infliximab. She had no fever or cough and her UC was in clinical remission with pediatric ulcerative colitis activity index (PUCAI) score 0. Physical examination was notable for tachypnea with inability to speak in complete sentences, nasal flaring, and decreased aeration at lung bases bilaterally. Oxygen saturations normalized with 0.5-2 liters per minute oxygen by nasal cannula.

She was started on azithromycin and ceftriaxone for empiric treatment of pneumonia. Chest radiograph demonstrated severe diffuse interstitial disease bilaterally with patchy opacities at bilateral lung bases. Computed tomography (CT) of the chest (Figure 1) demonstrated patchy opacities, interstitial disease and minor early honeycombing peripherally with minimal bronchiectasis that were interpreted as nonspecific findings that could represent vasculitis, connective tissue disease, inflammatory or infectious process.

Pulmonary function testing (PFT) was consistent with restrictive lung disease with decreased vital capacity. Infectious causes were extensively ruled-out by laboratory assessment and bronchoalveolar lavage. Rheumatologic evaluation was notable for positive ANA and double stranded-DNA. She did not meet clinical criteria for diagnosis of systemic lupus erythematosus. Human anti-chimeric antibody (HACA) level assessed six weeks following last dose of infliximab was positive at 15.1 U/mL with undetectable serum infliximab level. Lung wedge biopsy of right lower and middle lobe demonstrated a diffuse inflammatory process within the interstitium composed of predominantly lymphocytes admixed with plasma cells, plasmacytoid cells and histiocytes (Figure 2A and B). The airspaces appeared largely consolidated by increased collection of foamy macrophages (Figure 2C). There was septal and pleural fibrosis (Figure 2D). Special stains for yeast, fungus, bacteria and acid-fast organisms were negative. The final diagnosis was interstitial pneumonitis with extensive accumulation of foamy alveolar macrophages.

She was treated with solumedrol 1 gram daily for three days with improvement of her respiratory symptoms including reduced oxygen requirement, improvement in appearance of chest radiograph and significant improvement in PFTs. The family refused any further immunosuppression. At time of last follow-up eight months following hospitalization, the patient was asymptomatic, off oxygen and PFTs had normalized. She had normal chest radiograph. She has maintained clinical remission with mesalamine.

CONCLUSION

This is the first reported case of interstitial pneumonitis secondary to infliximab therapy in a pediatric patient and the first report to demonstrate presence of HACA.

Methotrexate toxicity has been implicated in the development of interstitial pneumonitis in rheumatoid arthritis patients receiving anti-TNFa therapies.1,2 More recently there have been case reports of interstitial lung disease developing in patients with Crohn’s disease, UC and rheumatoid arthritis, and psoriatic arthritis on exclusive anti-TNF therapy.3-5 In all of these patients the diagnosis was made based on clinical and histopathological findings in the setting of a temporal relationship between anti-TNF administration and development of symptoms. Presence of HACA was not reported in any of these cases. While up to 40% of patients with UC may develop extraintestinal manifestation, pulmonary involvement is rare and there are only case reports of interstitial pneumonitis attributed to UC alone.6,7

Our patient’s UC was in clinical remission and she was on infliximab monotherapy when she developed interstitial lung disease. Furthermore, the presence of HACA makes infliximab the likely cause of pneumonitis. This may represent a type of infliximab hypersensitivity and is supported by the complete resolution of pulmonary symptoms with short steroid course and discontinuation of infliximab.

Infliximab hypersensitivity reactions have been described in up to 38% of pediatric patients.8 Both immediate and delayed hypersensitivity reactions to infliximab have been described and are associated with prolonged dosing interval and presence of HACA.

This case highlights a potential serious side effect of infliximab therapy in pediatric patients with inflammatory bowel disease and the need to consider concomitant immunosuppressive or immunomodulator therapy in patients at risk of developing HACA.

A Case Report

Not All Gastric Ulcers are Peptic Ulcer Disease: Unusual Case of Gastric Metastases

April 2016 • Volume XL, Issue 4
Abdul Haseeb,Erinn Downs-Kelly,Kathryn Peterson,Iliana Doycheva

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Metastases to the stomach from non-gastric neoplasms have been identified in 2 to 5% of patients at autopsy. We present a rare case of gastric metastases from dedifferentiated chondrosarcoma. No particular characteristic appearance on endoscopy defines metastatic disease, making histology compulsory for accurate diagnosis and appropriate management. Although rare, gastric metastases should always be considered in patients with a known history of malignancy.

Abdul Haseeb, MD1 Erinn Downs-Kelly, DO2 Kathryn Peterson1 MD, Iliana Doycheva, MD3 1Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, University of Utah School of Medicine, Salt lake City, UT 2Department of Pathology, University of Utah School of Medicine, Salt lake City, UT

INTRODUCTION

The stomach is a rare site for metastases of common malignancies.1 However, an increasing number of reported metastatic lesions in the stomach have been noted due to improved tools for diagnosis and treatment of cancer patients. The most frequently reported primary sites of tumor metastasizing to the stomach are melanoma, lung and breast (especially those with a lobular phenotype).1 Herein we report a case of gastric metastases from a dedifferentiated chondrosarcoma in a gentleman who presented with melena and worsening anemia. This unusual clinical scenario underscores the importance of obtaining a pertinent clinical history and endoscopic biopsies to diagnose gastric metastases.

CASE PRESENTATION

The patient is a 68-year-old male with a past medical history of type 2 diabetes mellitus, hypertension, hyperlipidemia and prostate cancer status post prostatectomy. A rapidly growing and painful right thigh mass brought him to clinical attention in November 2011. The mass was finally diagnosed as a dedifferentiated chondrosarcoma. The patient underwent a radical resection of the 5.7 cm right distal femoral mass in December 2011; he was staged at that time as pT1 pN0 with negative margins. A metastatic work-up prior to resection was negative. Histologically, the resected tumor was composed of an admixture of conventional low-grade chondrosarcoma with areas of dedifferentiation (Figure 1). Nearly two years later, the patient developed metastatic disease to the lung, bone and paraspinal muscles. In July 2013 he was initiated on pazopanib, a tyrosine kinase inhibitor that carried the potential side effects of mucosal surface ulceration and slowed healing of intestinal ulcerations.2 Six months later, the patient presented to the emergency department with new onset melena, fatigue and shortness of breath. His laboratory findings were significant for hemoglobin of 7.7 mg/dl from a prior normal value three months earlier. The patient had no history of nonsteroidal anti-inflammatory drug (NSAID) use, reflux disease or peptic ulcer disease. Esophagogastroduodenoscopy (EGD) revealed seven large, non-bleeding, cratered ulcers with heaped edges in the body of the stomach (Figure 2). Biopsy of these ulcers demonstrated an atypical spindle cell proliferation (Figure 3). Based on the histomorphology alone, the differential diagnosis would include a gastrointestinal stromal tumor, smooth muscle neoplasm and schwannoma or reactive granulation tissue. Given the patient’ s history, the chondrosarcoma resection material was reviewed and compared to the gastric spindle cell proliferation and a diagnosis of metastatic dedifferentiated chondrosarcoma was rendered. Restaging scans showed progressive bone disease and the patient chose to be transferred to palliative care.

DISCUSSION

Dedifferentiated chondrosarcoma is a rare and highly aggressive variant, histologically typified by areas of low-grade chondrosarcoma with abrupt transitions to areas of high-grade non-cartilaginous sarcoma. The prognosis is poor with overall five year survival rates ranging from 7% to 24%.3-6 Like most sarcomas, the lung is the most common site for metastases. Metastatic lesions to the stomach have been rarely described.7

Metastases to the gastrointestinal tract are more commonly seen in the upper tract that in the lower.8 Metastases to the stomach from non-gastric neoplasms have been identified in 2 to 5% of patients at autopsy based on different studies.9,10 The common presentations of gastric metastases include anemia, bleeding, dyspepsia, or epigastric pain.1 Gastric involvement may be characterized as single or multiple lesions, with single lesions being more common.1,7,10 Solitary lesions are mainly located in the upper or middle one-third of the stomach and have a predilection to involve the greater curvature. Different endoscopic patterns include nodules, bulls-eye, extrinsic mass lesions, polypoid tumor or volcano-like lesions.1,8 No particular characteristic appearance defines metastatic disease, making histology compulsory for diagnosis. For the pathologist, knowledge of the clinical history is key and may allow for a diagnosis to be rendered on routinely stained slides with comparison to the primary, avoiding a costly immunohistochemical work up. In this particular case, given the paucity of immunohistochemical stains that could confirm the diagnosis, correlation with previous histology along with clinical and endoscopic findings were essential in arriving at the diagnosis.

CONCLUSION

Although rare, gastric metastases should always be considered in patients with a known history of malignancy. Endoscopic evaluation along with biopsies of suspicious lesions, help us differentiate metastases from other etiologies including infection or chemotherapy related mucosal lesions.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #16

Hypermobility Syndrome and Gastric Emptying Disorders

April 2016 • Volume XL, Issue 4
Richard W. McCallum,Gehan Botrus,Omar Baker,Erica Borrego

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Joint hyper mobility syndrome (JHS) is a common hereditary non inflammatory connective tissue disorder associated with a variation of clinical presentations. While JHS has been primarily a rheumatological disorder, recent research and literature suggest that there is a strong correlation between JHS and Gastrointestinal disorders. The purpose of this review article is to evaluate the existing research and literature regarding the associations between JHS and gastroparesis and to raise awareness of JHS as the reason behind chronic unexplained symptoms suggesting a gastric motility disorder as well as present the current standard tests used to identify suspected JHS cases.

Joint hypermobility syndrome (JHS) is a common hereditary non inflammatory connective tissue disorder associated with a variety of clinical presentations, including hypermobile joints that may be unilateral or bilateral, hyper extensible skin, easy bruising, frequent dislocations, poor wound healing, and abnormal scar formation. JHS continues to be misdiagnosed due to the wide range of symptoms and lack of specific testing for the various forms of the hereditary connective tissue disorder. While JHS has been primarily a rheumatological disorder, recent research and literature suggest that there is a strong correlation between JHS and Gastrointestinal disorders. The purpose of this review article is to evaluate the existing research and literature regarding the associations between JHS and gastroparesis. Our goal is to raise awareness of JHS as the reason behind chronic unexplained symptoms suggesting a gastric motility disorder as well as present the current standard tests used to identify suspected JHS cases.

Richard W. McCallum MD, FACP, FRACP, FACG, AGAF Professor and Founding Chair, Department of Medicine, Director, Center for Neurogastroenterology/ GI Motility. Gehan Botrus, MD, PhD, PGY-1 Resident Physician, Internal Medicine. Omar Baker, MS-3 Medical Student. Erica Borrego MS-3 Medical Student. Paul Foster Medical School El Paso, TX

INTRODUCTION

Surprisingly, hypermobility syndrome has been present throughout history dating as far back as 1250 B.C. Researchers explored the possibility of hypermobility syndrome portrayed in artifacts from Mesoamerica from 1250 B.C. to 900 B.C. The artifact is of a Tlatilco sculptural vessel in which an individual is portrayed lying ventrally with his feet positioned flat on his head.1 (Figure 1) From 1250 B.C. to 900 A.D. hypermobility has been identified at numerous historical relics of the Ta”no civilization in the Greater Antilles at the Caribbean region, western and central Mexico, Guatemala, Cuba, Peru and Mayan cultures.1 These artifacts depict distorted human images thought to represent either individuals who were well-trained or had the pathology of hyperextensibilty of joints.1

In a review of literature to include rheumatology in art, researchers found paintings dating back to 1638 that portrayed individuals with possible manifestations of hypermobile joints to include scoliosis, hyperlordosis, flat feet, hyperextended fingers, and Trendelenburg sign depicting a weakened hip joint.2 The painting referenced here (Figure 2) is “The Three Graces” by Peter Paul Rubens in which the painting is thought to be of his second wife and her sisters (Figure 2). In the painting, all three women portray symptoms of hypermobility, which would support the theory that the painting in fact portrays benign familial hypermobility syndrome, which is thought to have a strong genetic component.2,3,4

The first written description of hypermobility dates back to Hippocrates’ writings in “Airs, Waters and Places” in 400 BC in which he described the Nomands and Scythians having lax joints and scars in which he thought was due to attempts to scar and stiffen the joints by cauterization.5,6 The first comprehensive case report of hypermobility syndrome was described in 1892 by Dr. Tschernogobow at Moscow Venereology & Dermatology Society in which he described a 17 year old boy with hyperelasticity of the skin, hypermobility and laxity of joints.5 Edvard Lauritz Ehlers presented a case of a patient who had lax joints, hyperextensible skin and tendency of bruising with a history of delayed walking at the Dermatological Society of Denmark in 1899 combined with Henri-Alexandre Danlos’ report of a patient with vascular and inflammatory symptoms. This would come to be known as Ehlers-Danlos Syndrome as suggested by Frederick Parkes-Weber in 1936.5 In 1986 at a conference in Berlin, the foundation for diagnostic criteria for heritable connective tissue disorders (HCTDs) was developed.7

Types of Hypermobility Disorders

Joint hypermobility disorders are associated with three recognized inheritable disorders of connective tissue. There are three principle disorders that must be considered when a patient shows signs and symptoms of hypermobility to include 1) Marfan syndrome (MFS), 2) Ehlers-Danlos syndrome (EDS) and 3) Benign joint hypermobility syndrome (BJHS). These primary disorders can have overlapping symptomatology, but there appears to be distinct features that set them apart including molecular biology and genetic abnormalities.4

JHS is considered by many experts in rheumatology to be indistinguishable from the most common variant of EDS, EDS hypermobility type EDS-HM. Joint hypermobility may be assessed using the Beighton score, which is a measure of generalized joint laxity or by using a validated 5 point screening questionnaire8,9 (Table 1. and Figure 3.), that highlight the questions to ask and physical exam findings in patients with the suspected diagnosis of hypermobility syndrome.

Prevalence of Hypermobility Syndrome

The prevalence of hypermobility syndrome varies depending on age, gender, and ethnicities.11 The highest prevalence of hypermobility syndrome appears to be in children, women, and individuals of Asian, African, and Caucasian in descending order.12 The estimated prevalence of diffuse hypermobility has been estimated to be between 10% to 35%.13 Women have a higher incidence of hypermobility than men.12 Prevalence of hypermobility syndrome is increased in the following clinical conditions:

  • 64.8% in patients with fibromyalgia14
  • 65.6% of children with arthralgia15
  • 13.2% of patients screened in rheumatology clinics.16

According to Tinkle, recognition of joint hypermobility syndrome in the United States may be lower than other areas due to lack of training in recognition and management of the syndrome.17

Gastrointestinal Manifestations and JHS

Joint hypermobility syndrome is associated with a complex array of both physical findings as well as a manifestation of symptoms that may influence patient well-being. Although heretofore they were not being considered nor appreciated; one study found that among patients referred to a GI clinic by their primary care provider as many as 33% of patients had undiagnosed JHS18 which is considerably higher than the general population whose prevalence of JHS is thought to be 19.5% overall 11.

A case-control study conducted by Fikree and colleagues found that out of the 336 patients with functional gastrointestinal disorders (FGID), 39.0% were also diagnosed with JHS. FGID reported in this analysis included epigastric pain syndrome, postprandial distress syndrome, functional dyspepsia, functional vomiting, chronic idiopathic nausea, and unspecified belching. The most notable association with JHS in this study was post prandial distress syndrome where 51.0% of FGID participants were diagnosed with JHD19. Another study conducted by Fikree evaluated 180 patients with JHS in which 41.4% reported postprandial fullness whereas only 27.1% of the non-JHS group presented with postprandial fullness with a calculated odds ratio of 1.74 (CI: 1.2-2.6, p=0.006)18

The Mayo clinic analysis of Ehlers-Danlos syndrome (EDS) related GI symptoms conducted by Nelson et al. found that 5.8% of all EDS patients suffer from increased postprandial fullness with a prevalence of 7.0% in Ehlers-Danlos syndrome- hypermobility type (EDS-HM) and classic EDS subtypes.20 The difference in prevalence of nausea between EDS subtypes yielded no significant results.

Our purpose of this review article is to shine the light on JHS as one of the differential diagnosis in gastric motility disorders and related symptoms.

What is the Explanation for Impaired Gastric Emptying in JHS?

Postural orthostatic tachycardia syndrome (POTS) is an aggregate of symptoms caused by dysfunctional autonomic control mechanisms and is seen in many instances both in association with and outside of the setting of JHS. The diagnosis of POTS is made by an increase in heart rate of greater than 30 beats per minute within ten minutes of standing (or a head-up tilt) in the absence of hypertension with a resulting heart rate above 120 beats per minute.21 The clinical picture includes manifestations such as palpitations (92%), lightheadedness upon standing (87%), headaches (87%) and fatigue (90%).22 POTS may occur as an autoimmune phenomenon in conjunction with multiple autoimmune manifestations such as multiple sclerosis, Sjogren’s syndrome, systemic lupus erythematosus and raynaud’s phenomenon.23 According to Benarroch POTS is also commonly found to be associated with insomnia and fibromyalgia.21

The relationship between POTS and EDS-HM was exemplified by an analysis of 35 patients conducted by De Wandele et al. They found that Quantitative Sudomotor Axon Reflex Testing (QSART) (an assessment of peripheral sympathetic nerve function) illustrated lower provoked sweat volumes at all sites and only 35% of the study population elicited a normal response.24 Another study conducted by Zarate et al., found that six out of the 21 patients with BJHS demonstrated symptomatic evidence of autonomic dysfunction suggesting a higher prevalence of POTS in patients with co-existent JHS and FGID.25

A large cohort study of 163 patients with POTS was evaluated and 55 (34%) were found to have a normal gastric emptying time, 30 (18%) had a delayed or slowed gastric emptying time, and 78 (48%) were found to have rapid gastric emptying.26 This analysis by Loavenbruck illustrated that, while POTS is associated with delayed gastric emptying, the association with rapid gastric emptying is much greater.26 However, whether delayed or accelerated it is clear that aberrations from normal emptying physiology are associated with POTS as 66% of the study population had abnormal gastric emptying times. The study also revealed the Tilt-test to induce elevations in heart rate more frequently in patients with delayed gastric emptying. Delayed gastric emptying was associated with moderate to severe adrenergic dysfunction (p=0.02) as well as a greater increase in heart rate with deep breathing when compared to patients that fell within the normal gastric emptying time range (p=0.02).26 The participants reported GI complaints that included nausea (21% of the study population), vomiting (10%), constipation (19%), and dyspepsia (18%). The only symptom found to be associated with a specific gastric emptying anomaly was vomiting. Another study conducted by Park et al. aimed at assessing the gastric emptying patterns in individuals with Postural Orthostatic Tachycardia Syndrome. 36 % of patients with POTS in this cohort had delayed (9 %) or rapid (27 %) gastric emptying.27 In summary, two- thirds of patients with POTS and GI symptoms had abnormal gastric emptying. Rapid gastric emptying was the most frequently observed abnormality.26,27

Gastroparesis may also occur in patients with joint hypermobility syndrome outside of the setting of postural orthostatic tachycardia syndrome. An interesting study published by Mayo clinic showed that abnormal gastric emptying was observed in 22.3% of EDS patients (17/76), 11.8% delayed and 10.5% accelerated20. Another study by Zarate and his colleagues had shown delayed gastric emptying in patients with EDS.25 Several mechanisms have been proposed to explain the etiology of abnormal gastric emptying and related symptoms in this patient population. A valuable consideration in the pathogenesis of dysmotility is the composition of the extracellular matrix in which the other components of the gut wall are embedded. The composition of the gut wall contributes directly to the mechanical properties of the gut wall including extensibility.25 Alterations from physiologic norms in that regard are likely present with greater prevalence in patients with joint hypermobility syndrome leading to the association with gastroparesis. Zarate et al. further explains that changes in the degree of the stretch capacity of the gut wall influence the functional capacity of mechano-receptors altering the receptive signals that facilitate gastric emptying.25

From review of the literatures, it seems that rapid gastric emptying is more common than delayed emptying in the settings of POTS with JHS. However in the case of JHS without POTS gastroparesis or rapid emptying seems to occur in approximately equal proportions. These findings need to be confirmed and further evaluated in a larger cohort of patients with JHS.

CONCLUSION

JHS is considered a common disorder associated with multiple signs and symptoms included but not limited to hypermobility of joints, skin hyper extensibility, easy bruising, and many others. For years JHS was considered mainly a joint disorder with less focus on other systemic manifestation such as GI. Studies have confirmed the association between JHS and gastric abnormalities, also concluding that abnormal gastric emptying can be associated with or without accompanying POTS. GI practitioners should consider JHS as one of the differential diagnoses for idiopathic gastroparesis or nausea and vomiting of unknown etiology. In patients presenting with GI signs and symptoms, JHS can be recognized if practitioners are familiar with its manifestations. Gastroenterologists should definitely incorporate into their office exam a new repertoire focusing on hand and joint flexibility; particularly patients’ ability to place the palms flat on the ground without knee bending, hyperextensin of elbows and or knees beyond 90 degree. Hypermobility joint syndrome has definitely arrived as a new under- recognized condition which contributes to the spectrum of idiopathic gastric motility disorders.

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Nutrition Issues In Gastroenterology, Series #151

Enhanced Recovery After Surgery: If You Are Not Implementing it, Why Not?

April 2016 • Volume XL, Issue 4
Aditya J. Nanavati,Subramaniam Prabhakar

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The basic premise of Enhanced Recovery After Surgery (ERAS) is that the impact of surgery on the metabolic and endocrine response is reduced leading to earlier recovery. Implementation leads to reduced length of hospital stay and earlier return to productivity. It has also been shown to actually reduce complications without a rise in re-admissions. Beginning with colorectal surgery, the scope of ERAS has gradually been expanded to other surgical sub-specialties. Implementation at an institutional level needs the constitution of a multi-disciplinary team with representatives from all specialties involved in patient care. Nutrition plays a central role in ERAS, with almost all interventions related to it either directly or indirectly.

Multimodal interventions, under the umbrella of a single program applied to the care of the surgical patient in the peri-operative period, have come to be known as Enhanced Recovery After Surgery (ERAS). The basic premise is that the impact of surgery on the metabolic and endocrine response is reduced leading to earlier recovery. Implementation leads to reduced length of hospital stay and earlier return to productivity. It has also been shown to actually reduce complications without a rise in re-admissions. Beginning with colorectal surgery, the scope of ERAS has gradually been expanded to other surgical sub-specialties. With focused research in the area, both contraindications and limitations seem to be diminishing. Implementation at an institutional level needs the constitution of a multi-disciplinary team with representatives from all specialties involved in patient care. Nutrition plays a central role in ERAS, with almost all interventions related to it either directly or indirectly.

Aditya J. Nanavati1 Subramaniam Prabhakar2 1Surgical Registrar, Department of Surgery, Sir JJ Group of Hospitals, Mumbai, India 2Professor, Department of Surgery, Lokmanya Tilak Municipal Medical College, Mumbai, India

INTRODUCTION
What is Enhanced Recovery After Surgery (ERAS)?

Surgical intervention leads to an endocrine and metabolic stress reaction, which slows down recovery.1 Effectively modulating these responses to attenuate the impact of surgery may help promote an early recovery and has been associated with reduced2::

  • length of stay
  • complication rates
  • use of analgesia
  • costs for patients
  • increased patient comfort and satisfaction

A single program incorporating multimodal interventions in the peri-operative period to expedite recovery has come to be known as Enhanced Recovery after Surgery (ERAS), or Fast-track surgery (FTS). The interventions included in ERAS are shown in (but are not limited to) Table 1.The program was initially developed and promulgated for use in colorectal surgery.3,4 However, recently it has been effectively expanded to various surgical sub-specialties.5,6

How Does it Work?

The basic principle behind ERAS is successfully delivering surgical care with minimum deviation from normal physiology/functioning. It may be better understood by plotting the physiologic or functional state versus time in the peri-operative period (Figure 1(a). When undergoing surgery, the fall from normal physiologic state actually exceeds a level caused by illness alone. This is due to the endocrine and metabolic impact of the surgical stress.7 This is followed by a slow recovery back to a pre-existing level of functioning. When ERAS is implemented a graph is likely to show an earlier recovery (Figure 1 (b). Three distinct phases shown in the graph are pre-, intra-, and post-operative phases. In the pre-operative phase, the upswing in the graph is a reflection of the attempt to optimize the patient. This has also been called ‘prehabilitation’. In the intra-operative phase surgical and anesthetic maneuvers are used to minimize the downswing i.e. the surgical stress response. The small vertical arrow demonstrates a reduced impact observed as a smaller fall in functional status. The post-operative rehabilitation seeks to hasten recovery demonstrated by shortening of the recovery to pre-existing functioning (long horizontal arrow). It may be ideal to rehabilitate the patient to a level as close to optimum as possible (dotted line). A sample institutional protocol and how it differs from conventional care is shown in Table 2.

Why Implement ERAS?

ERAS programs, when implemented successfully, have been associated with a 35-40% reduction in length of hospital stay.8 This benefit has been observed without a concurrent rise in complications or re-admissions. Some studies have noted a fall in surgical (anastomotic leaks, etc.), as well as non-surgical complications (nosocomial infections, etc.) in the post-operative period.9 ERAS has also been associated with an earlier return to work and productivity.10 Compared to conventional care, ERAS is associated with better quality of life outcomes.8,11 Institutes benefit from ERAS as implementation of a structured peri-operative program streamlines patient care. Written protocols are available to staff members minimizing errors in care delivery. Early discharge means patient turnover times are reduced and institutes may be able to serve more patients within the available infrastructure. Another favorable impact of ERAS has

been cost-control. Studies from both developed, as well as developing countries, have noted a 28-32% fall in healthcare costs incurred.12,13

When Should ERAS be Used?
Are There any Limitations?

ERAS has traditionally been used in elective colorectal surgery. Programs tailored to upper gastrointestinal, hepatobiliary and pancreatic surgeries have been described in recent years.14,15 Scope of ERAS has been expanded to other surgical sub-specialties like cardiovascular, orthopaedic and gynecologic surgery.5,6,16 The patient populations in early studies have belonged to the young and middle-aged populations with a few, or no, co-morbidities. There had been some controversy regarding safety and applicability of ERAS in the elderly, but recent evidence suggests that they can achieve success on the program also.17 Patients needing complex abdominal or pelvic surgery have also been observed to benefit from the program in spite of initial fears of failure. Success with multicavity surgeries like Ivor-Lewis esophagectomy in the elderly on the other hand has been limited.18 While the horizons of ERAS expand gradually, the limitations and contraindications for it seem to diminish. Tailored programs to various sub-specialties as well as individual surgical procedures help overcome most limitations. However, an important issue is that of compliance. Even in large multi-centric trials, adherence of approximately 65% has been observed.19 It has been widely acknowledged that full compliance may be difficult to achieve.20

How is it Implemented?

Implementing ERAS at an institutional level requires the formation of a multi-disciplinary team. According to this author, the core team should consist of a representative from each the following branches: surgical, anesthesia, and nursing. Other important members include nutritionists, physicians (belonging to various specialties), physical & occupational therapists and social workers. Membership may be extended to any other staff from specialties/branches who are involved with patient care. This team is given the responsibility of reviewing available literature and formulating the ERAS program to be implemented at their institute. This assumes that the components of the program will be tailored to match locally available expertise and facilities. Each member is expected to communicate the role of his/her specialty in the program. Understanding where the needs of two or more specialties may converge is imperative for the smooth delivery of peri-operative care. Once formulated, written protocols must be made available to all those involved. An important component of implementation is receiving feedback, provisions for which should be provided for within the program.

Feedback is taken in the form of ease of delivering care and problems encountered by each worker within their specialty in carrying out work designated under ERAS programs. Feedback from individual staff members must be made available to the multidisciplinary team at subsequent team meetings. Along with regular audits, feedback provides a sound basis for process improvement to advocate and implement changes to the program. Apart from these internal quality check mechanisms, an external review or audit may be asked for if needed. Once changes are made the entire cycle must be re-initiated.

Nutrition in ERAS

Almost all the interventions in ERAS are either directly or indirectly related to the nutrition of the patient. In the pre-operative period the patient’s nutritional status should be evaluated. Ensuring a good nutritional status is crucial to the success of the program.21 Consultation and evaluation by a nutritionist is preferable and should be followed by advice to meet objective dietary goals to achieve designated end-points (like optimum body weight, etc.). ERAS protocols do not recommend specific tools for nutrition screening or assessment. However, a nutritional assessment might include:

  • Insufficient oral intake
  • Percent unintentional loss of usual body weight over time
  • Low BMI

In the immediate pre-operative period under ERAS it is advised to keep starvation time to a minimum. A 2-hour fast for liquids and a 6-hour fast for solids are considered safe and adequate.22 Along with minimal starvation an oral carbohydrate drink 2 hours before surgery is administered (See Table 3 for available options). Oral carbohydrate loading is known to attenuate insulin resistance, minimize protein and muscle loss, and improve patient comfort.7,23 There is a possibility that scheduling cases in the morning may interfere with the ability to adequately maintain this interval. This must be accounted and planned for in advance. This author prefers to advise patients to consume what they normally would for dinner and administers 100g of an oral carbohydrate drink (complex carbohydrate maltodextrin based formula with water) early in the morning up to 2 hours before surgery; however, even 50gm has been shown to be adequate.24 As an added safety measure, the author’s institution prefers to use a prokinetic agent early in the pre-operative period. The safety and efficacy of avoiding mechanical bowel preparation has been adequately demonstrated with only some controversy remaining around its use in rectal surgery;25 there are surgeons who may still suggest its use in cases of low anterior resections.

Although operative interventions are not directly related to nutrition, it is important to note that any untoward incident in the operating room can impact the nutrition of the patient and, by extension, his/her hospital stay. Principles of minimal tissue handling, selective use of drains and catheters are crucial to be able to promote ambulation, as well as to initiating oral/ enteral nutrition early in the post-operative period and epidural catheter insertion for analgesia in the post- operative period. This has been shown to reduce the incidence of ileus, improve post-operative insulin resistance, improve quality of life scores, facilitate earlier discharge and reduce overall morbidity and mortality after surgery.26-28 Intra-operative goal-directed fluid therapy29 and minimizing use of opioids/ using opioid antagonists like alvimopam contribute to the early return of bowel function in the post-operative period.30

In the post-operative period nutritional management is carried out in the form of early oral (see Table 4 for one institution’s diet progression post-op) or enteral nutrition (EEN). Within ERAS programs EEN is facilitated by prophylaxis against post-operative nausea and vomiting, epidural analgesia, minimizing use of nasogastric tubes (Salem sump type decompression tubes) and other drains, catheters and tubes. Oral or Enteral nutrition can be started as early as 6-8 hours after surgery.31 Even though early post-operative feeding is recommended the evidence base for these recommendations is weak at best32 and there have been varying opinions regarding to the best time to initiate oral feeding. In the experience of this author, an overwhelming majority of the surgeons are more comfortable starting oral feeds on the morning after the surgery. Oral feeding is usually started with liquids. Once tolerated transition to regular diet is immediate while some may prefer to advise eating ad libitum (Food items allowed/excluded in a typical transition diet and a sample menu is shown in Table 5 and Table 6 respectively). Early oral or enteral nutrition has been demonstrated to be safe, promotes sense of well-being, preserves post-operative nutritional profile, reduces incidence of ileus and does not lead to an increase in anastomotic dehiscence.31,33

CONCLUSION

Developments in ERAS have highlighted the importance of peri-operative care. The ability to achieve a reduced hospital stay, patient satisfaction, and reduced rate of complications without an increase in re-admissions has demonstrated how powerful a tool ERAS can be. ERAS has resulted in a significantly increased understanding of peri-operative physiology and how to modulate it to improve outcomes. This has led to the belief among some that the role peri-operative care plays may be so crucial that it warrants recognition as a separate sub-specialty since it does not exclusively fall into the domain of any of the existing specialties.34 Until ERAS becomes a routine reality, it may be in the best interest of all those involved in the peri-operative care of the surgical patient to be familiar with ERAS and its principles.

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